Substituted Heterocyclic Compounds

Abstract

Formula I: TIFF2024518554000226.tif65138 [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 / 318,149, filed March 9, 2022, the disclosures of which are incorporated herein by reference in their entireties.

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

[0003] Interleukin (IL)-12 and IL-23, heterodimeric cytokines that share a common p40 subunit, are produced upon activation of antigen-presenting cells and are crucial for the differentiation and proliferation of Th1 and Th17 cells, two effector T cell lineages that play key roles in autoimmunity. IL-23 is composed of a p40 subunit together with a unique p19 subunit. IL-23 acts through a heterodimeric receptor composed of IL-23R and IL-12Rβ1 and is essential for the survival and proliferation of Th17 cells, which produce inflammatory cytokines such as IL-17A, IL-17F, IL-6, and TNF-α (McGeachy, MJ, et al., "The link between IL-23 and Th17 cell-mediated immune pathologies," Semin. Immunol., 19:372-376 (2007)). These cytokines are crucial in mediating the pathology of many autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and lupus. IL-12 contains a p35 subunit in addition to the p40 subunit shared with IL-23, and acts through a heterodimeric receptor consisting of IL-12Rβ1 and IL-12Rβ2. IL-12 is essential for developing Th1 cells and secreting IFNγ, a cytokine that plays a key role in immune function by stimulating MHC expression, class switching of B cells to IgG subclasses, and activation of macrophages (Gracie, JA et al., "Interleukin-12 induces interferon-gamma-dependent switching of IgG alloantibody subclass," Eur. J. Immunol., 26:1217-1221(1996); Schroder, K. et al., "Interferon-gamma: an overview of signals, mechanisms and functions," J. Leukoc. Biol., 75(2):163-189(2004)).

[0004] The importance of p40-containing cytokines in autoimmunity is demonstrated by the finding that mice lacking either p40, p19 or IL-23R are protected from disease in experimental multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus and psoriasis, among others (Kyttaris, V. C. et al., "Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL / 6-lpr / lpr mice", J. Immunol., 184:4605-4609 (2010); Hong, K. et al., "IL-12, independently of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis like skin disorder", J. Immunol., 162:7480-7491 (1999); Hue, S. et al., "Interleukin-23 drives innate and T cell-mediated intestinal "Inflammation", J. Exp. Med., 203:2473-2483(2006);Cua, DJ et al., "Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain", Nature, 421:744-748(2003);Murphy, CA et al., "Divergent pro- and anti-inflammatory roles for IL-23 and IL-12 in "Joint autoimmune inflammation", J. Exp. Med., 198:1951-1957 (2003)).

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

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

[0007] Indeed, anti-p40 therapy, which blocks both IL-12 and IL-23, as well as IL-23-specific anti-p19 therapy, have been shown to be effective in treating autoimmune diseases including psoriasis, Crohn's disease, and psoriatic arthritis (Leonardi, CL et al., "PHOENIX1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12 / 23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX1)", Lancet, 371:1665-1674 (2008); Sandborn, WJ et al., "Ustekinumab Crohn's Disease Sudy Group. A randomized trial of Ustekinumab, human interleukin-12 / 23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease", Gastroenterology, 135:1130-1141(2008); Gottlieb, A. et al., "Ustekinumab, a human interleukin 12 / 23 monoclonal antibody, for psoriatic arthritis: randomized, double-blind, placebo-controlled, crossover trial," Lancet, 373:633-640(2009)). Thus, agents that inhibit the action of IL-12 and IL-23 may be considered therapeutic in human autoimmune disorders.

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

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

[0010] Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and has been shown to be important in regulating signaling cascades downstream of the receptors for IL-12, IL-23, and type I interferon in both mice and humans (in mice, Ishizaki, M. et al., "Involvement of Tyrosine Kinase-2 in Both the IL-12 / Th1 and IL-23 / Th17 Axes In vivo," J. Immunol., 187:181-189(2011); Prchal-Murphy, M. et al., "TYK2 kinase activity is required for functional type I interferon responses in vivo," PLoS One, 7:e39141(2012), and in humans, Minegishi, Y. et al., "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired " immunity " Immunity, 25:745-755 (2006). Tyk2 mediates receptor-induced phosphorylation of members of the STAT family of transcription factors, an essential signal that leads to dimerization of STAT proteins and transcription of STAT-dependent inflammatory genes.Tyk2-deficient mice are resistant to experimental models of colitis, psoriasis, and multiple sclerosis, highlighting the importance of Tyk2-mediated signaling in autoimmune and related disorders (Ishizaki, M. et al., "Involvement of Tyrosine Kinase-2 in Both the IL-12 / Th1 and IL-23 / Th17 Axes In vivo," J. Immunol., 187:181-189(2011); Oyamada, A. et al., "Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis," J. Immunol., 183:7539-7546(2009)).

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

[0012] TYK2 inhibition may also be utilized in both solid tumors and hematological malignancies, both as monotherapy and in combination with existing standards of care, including immunotherapy.

[0013] Ex vivo studies in T-cell acute lymphoblastic leukemia (T-ALL) revealed that Tyk2 is required for T-ALL survival, suggesting that TYK2 inhibitors may be involved in a direct cancer killing mechanism in this indication (Sanda, T. et al., TYK2-STAT1-BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia. Cancer Discov. 3, 564-577(2013)). Multiple TYK2 activating mutations were detected and characterized in T-ALL cell lines. NPM1-TYK2 gene fusions have also been identified in a subgroup of cutaneous T-cell lymphomas (CTCL), revealing TYK2 as an oncogenic driver of transformation (Kuravi, S. et al., Functional characterization of NPM1-TYK2 fusion oncogene. Npj Precis. Oncol. 6, 3(2022)). Loss of TYK2 signaling can reduce this transforming potential.

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

[0015] Therefore, compounds with low efflux ratios in in vitro experiments may potentially have a greater chance of effectively treating some carcinogenic indications.

[0016] In view of conditions that may benefit from treatment involving modulation of cytokines and / or interferons, novel compounds capable of modulating cytokines and / or interferons, such as IL-12, IL-23 and / or IFNα, and methods of using these compounds, may provide substantial therapeutic benefit to a wide variety of patients in need thereof. Summary of the Invention

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

[0018] The present invention also provides methods for modulating IL-12, IL-23 and / or IFNα by inhibiting Tyk2-mediated signaling, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention. The present invention also provides a method of treating a neurodegenerative disease, comprising administering a therapeutically effective amount of at least one compound of the present invention to a host in need of such treatment.

[0019] The present invention also provides a compound of the invention for use in therapy. These and other features of the invention will be described in expanded form as the present disclosure continues. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] In a first embodiment of the present invention, a compound of the formula: [ka] [In formula: X is -N- or -CH-; R 1 HA-C(O)R 1a or a 5-8 membered heterocycle containing 1-2 heteroatoms selected from N, O and S, each heterocycle having 0-2 R 1b is replaced by; R 1a COOC 1-3 Alkyl, or C 3-6 cycloalkyl, the cycloalkyl group having 0 to 2 R1b is replaced by; R 1b is independently, at each occurrence, F or C 1-3 is alkyl; R 2 is OMe or OCHF2; R 3 CD3, C 1-3 Alkyl, C 3-6 cycloalkyl or (CH2)F; and R 4 is hydrogen, halo, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 is cycloalkyl] or a stereoisomer or pharma- ceutically acceptable salt thereof.

[0021] In a second aspect of the present invention, a compound of formula II: [ka] [In formula: R 1 HA-C(O)R 1a or a 5-8 membered heterocycle containing 1-2 heteroatoms selected from N, O and S, each heterocycle having 0-2 R 1b is replaced by; R 1a COOC 1-3 Alkyl, or C 3-6 Cycloalkyl, the cycloalkyl group having 0 to 2 R 1b is replaced by; R 1b is independently, at each occurrence, F or C 1-3 is alkyl; R 2 is OMe or OCHF2; R 3 CD3, C 1-3 Alkyl, C 3-6 cycloalkyl or (CH2)F; and R 4 is hydrogen, halo, C 1-4 Alkyl, C1-4 Alkoxy or C 3-6 is cycloalkyl] or a stereoisomer or pharma- ceutically acceptable salt thereof.

[0022] In a third aspect of the present invention, a compound of formula II: [ka] [In formula: R 1 HA-C(O)R 1a or a 5-8 membered heterocycle containing 1-2 heteroatoms selected from N, O and S, each heterocycle having 0-2 R 1b is replaced by; R 1a COOC 1-3 Alkyl, or C 3-6 cycloalkyl, the cycloalkyl group having 0 to 2 R 1b is replaced by; R 1b is independently, at each occurrence, F or C 1-3 is alkyl; R 4 is hydrogen, F or CH3] or a stereoisomer or pharma- ceutically acceptable salt thereof.

[0023] In a fourth aspect of the present invention, a compound of formula III: [ka] [In formula: R 1 HA-C(O)R 1a or a 5-8 membered heterocycle containing 1-2 heteroatoms selected from N, O and S, each heterocycle having 0-2 R 1b is replaced by; R 1a COOC 1-3 Alkyl, or C 3-6 Cycloalkyl, the cycloalkyl group having 0 to 2 R1b is replaced by; R 1b is independently, at each occurrence, F or C 1-3 is alkyl; R 2 is OMe or OCHF2; R 3 CD3, C 1-3 Alkyl, C 3-6 cycloalkyl or (CH2)F; and R 4 is hydrogen, halo, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 is cycloalkyl] or a stereoisomer or pharma- ceutically acceptable salt thereof.

[0024] In a fifth embodiment of the present invention, a compound of the formula: [ka] [In formula: R 1 HA-C(O)R 1a or a 5-8 membered heterocycle containing 1-2 heteroatoms selected from N, O and S, each heterocycle having 0-2 R 1b is replaced by; R 1a COOC 1-3 Alkyl, or C 3-6 Cycloalkyl, the cycloalkyl group having 0 to 2 R 1b is replaced by; R 1b is independently, at each occurrence, F or C 1-3 is alkyl; R 4 is hydrogen, F or CH3] or a stereoisomer or pharma- ceutically acceptable salt thereof.

[0025] 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.

[0026] In another embodiment, there is provided a compound selected from any subgroup list of compounds within the scope of any of the above embodiments.

[0027] In another aspect, 6-Cyclopropanamido-4-{[3-(2-ethyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-6-[(6-methoxypyridazin-3-yl)amino]-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[5-fluoro-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[2-Methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methyl-6-[(pyridin-2-yl)amino]pyridazine-3-carboxamide; Methyl N-(5-{[2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-6-[( 2 H3) methylcarbamoyl]pyridazin-3-yl)carbamate; 6-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]-4-{[2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[2-Methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methyl-6-[(1R)-spiro[2.2]pentan-1-amido]pyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-5-fluoro-2-methoxyphenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(2-ethyl-2H-1,2,3-triazol-4-yl)-4-fluoro-2-methoxyphenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[4-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-3-methoxypyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({3-[2-(2-fluoroethyl)-2H-1,2,3-triazol-4-yl]-2-methoxyphenyl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({3-[2-(2,2-difluoroethyl)-2H-1,2,3-triazol-4-yl]-2-methoxyphenyl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-5-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-methoxy-5-methylphenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[5-chloro-3-(2-ethyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl]amino}-6-cyclopropanamide-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-4-fluoro-2-methoxyphenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[4-fluoro-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[5-fluoro-2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide;

[0028] 6-Cyclopropanamido-4-{[3-(5-ethyl-2-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[5-ethyl-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[6-fluoro-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; Methyl 3-({6-cyclopropanamido-3-[( 2 H3) methylcarbamoyl]pyridazin-4-yl}amino)-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate; 6-Cyclopropanamide-4-({2-methoxy-3-[2-( 2 H3) Methyl-2H-1,2,3-triazol-4-yl]phenyl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2,5-dimethoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[2-Methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methyl-6-[(1-methyl-1H-pyrazol-3-yl)amino]pyridazine-3-carboxamide; 4-{[2-Methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) Methyl-6-[(1R,2S)-2-methylcyclopropanamido]pyridazine-3-carboxamide; 4-{[2-Methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2H3) Methyl-6-[(1R,2S)-2-methylcyclopropanamido]pyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(2-cyclopropyl-5-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[2-Methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methyl-6-[2-oxo-3-(propan-2-yl)imidazolidin-1-yl]pyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; Ethyl N-(5-{[2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-6-[( 2 H3) methylcarbamoyl]pyridazin-3-yl)carbamate; 6-[(1S,2R)-2-fluorocyclopropanamido]-4-{[2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[2-Methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) Methyl-6-[(1S,2R)-2-methylcyclopropanamido]pyridazine-3-carboxamide; 6-[(1S,2S)-2-fluorocyclopropanamido]-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[4-cyclopropyl-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-(2,2-difluorocyclopropanamido)-4-{[2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide;

[0029] 6-[(azetidine-1-carbonyl)amino]-4-{[2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({2-methoxy-3-[2-(oxetan-3-yl)-2H-1,2,3-triazol-4-yl]phenyl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[3-(2-cyclobutyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl]amino}-6-cyclopropanamide-N-( 2 H3) methylpyridazine-3-carboxamide; 6-(2,2-Dimethylcyclopropanamido)-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-(difluoromethoxy)-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-(2 H3) methylpyridazine-3-carboxamide; 6-[(Dimethylcarbamoyl)amino]-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) Methyl-6-[(1S,2R)-2-methylcyclopropanamido]pyridazine-3-carboxamide; 4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) Methyl-6-[(1R,2R)-2-methylcyclopropanamido]pyridazine-3-carboxamide; 6-(4-fluorobutanamido)-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(difluoromethoxy)-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; {[(6E)-6-(cyclopropanecarbonylimino)-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-3-[( 2 H3) methylcarbamoyl]-1,6-dihydropyridazin-1-yl]methoxy}phosphonic acid; 4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) Methyl-6-[(1S,2S)-2-methylcyclopropanamido]pyridazine-3-carboxamide; 6-[(1R,2R)-2-Ethylcyclopropanamido]-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[4-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-3-methoxypyridin-2-yl]amino}-6-[(1S,2S)-2-fluorocyclopropanamide]-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methyl-6-{[methyl(propan-2-yl)carbamoyl]amino}pyridazine-3-carboxamide; 6-{[ethyl(methyl)carbamoyl]amino}-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[4-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-3-methoxypyridin-2-yl]amino}-6-[(dimethylcarbamoyl)amino]-N-( 2 H3) methylpyridazine-3-carboxamide; Propan-2-yl 3-({6-cyclopropanamide-3-[( 2 H3) methylcarbamoyl]pyridazin-4-yl}amino)-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate; 6-Cyclopropanamido-4-{[2-methoxy-5-(methoxymethyl)-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[6-fluoro-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamide-4-({3-methoxy-4-[2-( 2 H3) Methyl-2H-1,2,3-triazol-4-yl]pyridin-2-yl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide;

[0030] 4-{[3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) Methyl-6-[(1R,2R)-2-methylcyclopropanamido]pyridazine-3-carboxamide; 4-{[3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) Methyl-6-[(1S,2S)-2-methylcyclopropanamido]pyridazine-3-carboxamide; 4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methyl-6-[(pyridin-2-yl)amino]pyridazine-3-carboxamide; 6-[(2,6-dimethylpyrimidin-4-yl)amino]-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-{[5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino}-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methyl-6-{[5-(morpholin-4-yl)pyridin-2-yl]amino}pyridazine-3-carboxamide; 6-{[4-(2-hydroxypropan-2-yl)pyridin-2-yl]amino}-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; and 6-((1S,2S)-2-Fluorocyclopropane-1-carboxamide)-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide Provided is a compound (IUPAC nomenclature rules), or a pharma- ceutically acceptable salt thereof, selected from:

[0031] In another embodiment, pharmaceutical compositions are provided comprising one or more compounds of formula I and a pharma- ceutically acceptable carrier or diluent.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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).

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] In another embodiment, the compound of formula I is selected from an exemplified compound, or a combination of the exemplified compounds, or other embodiments described herein. In another embodiment, the IC 50 <1000 nM.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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).

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] "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.

[0057] 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.

[0058] An exemplary composition for topical administration includes PLASTIBASE® (mineral oil gelled with polyethylene).

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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 those skilled in the art is Greene and Wuts (Protective Groups In Organic Synthesis, Third Edition, Wiley and Sons, 1999).

[0066] 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.

[0067] Figure 1 [ka]

[0068] Scheme 1 shows how intermediate Ia (wherein X is a halogen such as iodide when R is a simple alkyl (methyl, ethyl, etc.)) can be combined with intermediate Ib in the presence of a suitable base, preferably potassium carbonate, in a suitable solvent, preferably DMF, to give intermediates of formula II. When R is cyclopropyl, Ib can be treated with cyclopropylboronic acid in the presence of copper(II) acetate, 2,2'-bipyridine, and sodium carbonate in dichloroethane at elevated temperature. II can then be subjected to monodebromination in the presence of a strong reducing base, particularly isopropylmagnesium bromide in THF solution, in ether at low temperature to give intermediates of formula IIa. II can also be used as is to prepare more highly substituted 1,2,3-triazoles. IIa can be used as is or can be converted to the corresponding boronic acid (IIb) by metal-halogen exchange followed by quenching with a trialkylborate, specifically trimethylborate or triisopropylborate. A preferred base for metal halide exchange may be isopropylmagnesium chloride-lithium chloride complex in THF at low temperature.

[0069] Scheme 1 [ka]

[0070] Scheme 2 shows how one skilled in the art can combine intermediate IIa or IIb with intermediate Ic (where Y is a boronate in the case of reaction with IIa and Y is a halide in the case of reaction with IIb) to obtain intermediates of general formula III. (Intermediates of general formula Ic are commercially available or can be prepared using methods well known to those skilled in the art of organic synthesis.) The transformation can be achieved 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 achieved in a Suzuki-type coupling using PdCl2(dppf)[DCM] as catalyst and aqueous potassium tribasic phosphate as base at elevated temperature in a solvent such as 1,4-dioxane. Similar chemical reactions can be performed with intermediate II to generate fully substituted 1,2,3-triazoles (intermediates of general formula IIa). In these cases, it is necessary to remove the corresponding bromo-triazole and subject it to a palladium-catalyzed addition coupling with an alkyl or alkenyl boronate (followed by an olefin reduction, i.e., catalytic hydrogenation, using methods known in the art).

[0071] Scheme 2 [ka]

[0072] Scheme 3 shows how a person skilled in the art of organic synthesis can couple intermediates of general formula Id (see Moslin et al., J. Med. Chem 2019, 62, 8953-8972 or US Pat. No. 9,505,748) and Ie (see US Pat. No. 10,899,745) with intermediates of general formula III to obtain intermediates of general formula IV or IVa. 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. In the case of IVa, the trideuteromethylamide can be installed in a later step.

[0073] Scheme 3 [ka]

[0074] Scheme 4 shows how one skilled in the art of organic synthesis can couple compound IV to a suitable 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 Ig or an aromatic amine of general formula Ih under transition metal catalyzed conditions. In particular, preferred conditions for this reaction include utilizing a Buchwald-type coupling using Pd2(dba)3 as catalyst, Xantphos as ligand, and Cs2CO3 as base in 1,4-dioxane as solvent at elevated temperature. This catalyst / ligand / base system can be modified in ways known to those skilled in the art. Alternatively, a compound of general formula IV can be treated with a primary amine at elevated temperature in a suitable solvent, in particular 4-methoxybenzylamine, which can give a product that 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 temperature 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.

[0075] Scheme 4 [ka]

[0076] Scheme 5 shows an alternative synthesis of compounds of general formula I (A=nitrogen). Compound Ie can be coupled to compounds of general formula III (A=nitrogen) as described above to give compounds of general formula IVa. These compounds can then be used to prepare compounds of general formula VI by Buchwald-type coupling (as described above) with appropriate primary amides of general formula If. Compounds of general formula VI can be treated with an amide bond coupling reagent system known to those skilled in the art of synthetic organic chemistry, in particular N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and HOBT, in a suitable solvent, in particular NMP / AcCN, at elevated temperature to produce compounds of general formula VII. These compounds can be treated with trideuteromethylamine hydrochloride in a suitable solvent, in particular DMSO, in the presence of a base, in particular diisopropylethylamine, at elevated temperature.

[0077] [ka]

[0078] manufacturing Unless otherwise stated, all commercially available reagents were used without further purification. All reactions involving air- or moisture-sensitive reagents were carried out under an inert atmosphere. Proton and carbon magnetic resonance ( 1 H and 13 C NMR spectra were recorded on either a Bruker Avance 400 or a JEOL Eclipse 500 spectrometer and are reported in ppm relative to the reference solvent for the sample on which they were run. HPLC and LCMS analyses were performed using a Shimadzu LC-10AS liquid chromatograph and SPD UV-vis detector at 220 or 254 nm, and MS detection was performed on a Micromass Platform LC spectrometer. GCMS analyses were performed using an Agilent Technologies GC (7890B)-MS (5977B).

[0079] 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")

[0080] Method B: 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: 0.1% TFA in HO 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")

[0081] 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® BEH C18 1.7 μM Flow rate: 1 milliliter ("mL") / min Solvent A: 0.05% trifluoroacetic acid, 95% water, 5% acetonitrile Solvent B: 0.05% trifluoroacetic acid, 5% water, 95% acetonitrile

[0082] 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

[0083] Method E: Run a linear gradient from 0% to 100% solvent B over 1 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: 1 milliliter ("mL") / min Solvent A: 0.05% trifluoroacetic acid, 95% water, 5% acetonitrile Solvent B: 0.05% trifluoroacetic acid, 5% water, 95% acetonitrile

[0084] Method F: 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 min Subjected to ultraviolet ("UV") visualization at 220 nanometers ("nm") Column: Zorbax XDB C-18 (50x4.6mm) 3.5μm Flow rate: 1.5 milliliters ("mL") per minute Solvent A: 0.1% formic acid, 95% water, 5% acetonitrile Solvent B: Acetonitrile

[0085] Method G: 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 220 nanometers ("nm") Column: Waters Xbridge C18 (2.1mm x 50mm) 1.7μM Flow rate: 1 milliliter ("mL") / min Solvent A: 95% 10 mM ammonium acetate (in water), 5% acetonitrile Solvent B: 5% 10 mM ammonium acetate (in water), 95% acetonitrile

[0086] Method H: Run a linear gradient from 0% to 100% solvent B over 1 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: 1 milliliter ("mL") / min Solvent A: 0.1% trifluoroacetic acid, 95% water, 5% acetonitrile Solvent B: 0.1% trifluoroacetic acid, 5% water, 95% acetonitrile

[0087] 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 BEH C18 1.7μM (2.1x50mm) Flow rate: 1 milliliter ("mL") / min Solvent A: 0.05% trifluoroacetic acid, 95% water, 5% acetonitrile Solvent B: 0.05% trifluoroacetic acid, 5% water, 95% acetonitrile

[0088] Method J: A linear gradient from 20% to 98% solvent B over 1.5 min, held at 98% B for 1.5 min, followed by a 0.1 min gradient to 20% B, held at 20% B for 0.5 min Solvent A: 5 mM ammonium formate pH 3.3:ACN (98:02) Solvent B:ACN:Buffer (98:02) Flow rate: 0.7ml / min Column: Kinetics XB-C18 (75x3.0) mm, 2.6 μm Ultraviolet ("UV") visualization at 220 nanometers ("nm")

[0089] Method K: A linear gradient from 2% to 40% solvent B over 4 min, held at 100% B for 0.6 min, followed by a 0.1 min gradient to 20% B, held at 20% B for 0.3 min Solvent A: 5 mM ammonium formate pH 3.3:ACN (98:02) Solvent B:ACN:Buffer (98:02) Flow rate: 1.0ml / min Column: Kinetics XB-C18 (75x3.0) mm, 2.6 μm Subjected to ultraviolet ("UV") visualization at 220 nanometers ("nm")

[0090] GCMS method 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; air flow: 400 mL / min; H2 flow: 40 mL / min; heating schedule: hold at 120°C for 3 min, then ramp to 300°C at 40°C / min and hold for 2 min; source temperature: 230°C.

[0091] [Table 1] [Table 2]

[0092] Intermediate 1 [ka]

[0093] 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 layers were combined, 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]

[0094] Step 2: To a stirred solution of 3-bromo-2-methoxyaniline (1.80 g, 8.91 mmol) in 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 5 min, then PdCl2(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 (2x50 mL) and brine (2x50 mL). The organic extracts were collected, dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which 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]

[0095] Intermediate 2 [ka]

[0096] Step 1: To a stirred solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (53.8 g, 188 mmol) in HO (150 mL) at 0° C., 2H-1,2,3-triazole (10 g, 145 mmol) was added portionwise. After the addition was complete, the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was filtered, the residue was washed with water and dried under vacuum to give 4,5-dibromo-2H-1,2,3-triazole (26 g, 115 mmol, 79% yield) as a pale yellow solid. GCMS: 226.8 [M], retention time = 3.40

[0097] Step 2: To a solution of triphenylphosphine (1.52 g, 5.78 mmol) in THF (8 mL) was added DIAD (0.95 mL, 4.89 mmol) at -10 °C. After 10 min, 4,5-dibromo-2H-1,2,3-triazole (1 g, 4.45 mmol) was added in portions, followed by 2-fluoroethan-1-ol (0.4 g, 6.23 mmol). The reaction mixture was allowed to reach room temperature and stirred for 2 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with diethyl ether (2x40 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (5% ethyl acetate in petroleum ether) to give 4,5-dibromo-2-(2-fluoroethyl)-2H-1,2,3-triazole (730 mg, 2.69 mmol, 60.6% yield) as a yellow liquid. GCMS=272.9 [M], retention time=3.63.

[0098] Process 3 To a solution of 4,5-dibromo-2-(2-fluoroethyl)-2H-1,2,3-triazole (0.7 g, 2.57 mmol) in THF (10 mL) was added isopropylmagnesium chloride (3.85 mL, 7.70 mmol) dropwise at 0° C. and stirred at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with diethyl ether (2×30 ml). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under low vacuum to give the desired product as a brown liquid, which was used as is without further purification. GCMS: 193.0, retention time=5.84

[0099] Intermediate 3 [ka]

[0100] Process 1 2,2-Difluoroethan-1-ol (2.0 g, 24.38 mmol) was cooled to 0° C. in a sealed test tube and Tf2O (5.77 ml, 34.1 mmol) was added dropwise. The reaction vessel was sealed and heated at 80° C. for 1 h. The reaction mixture was cooled to room temperature and poured into cold 10% NaHCO3 solution (50 mL). The aqueous layer was extracted with diethyl ether (2×50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude 2,2-difluoroethyl trifluoromethanesulfonate (5.1 g, 23.82 mmol, 98% yield) was used directly without further purification. 1 H NMR(CDCl3):6.22-5.92(m,1H), 4.64-4.57(m,2H)

[0101] Process 2 To a stirred solution of 2,2-difluoroethyl trifluoromethanesulfonate (5.0 g, 23.35 mmol) and 4,5-dibromo-2H-1,2,3-triazole (6.36 g, 28.0 mmol) in DMF (20 mL) was added K2CO3 (6.45 g, 46.7 mmol) at 0 °C. The reaction was allowed to reach room temperature and stirred for 16 h. The reaction mixture was quenched with cold water (100 mL) and extracted with DCM (2x100 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified using silica gel column chromatography (10% ethyl acetate in petroleum ether) to give 4,5-dibromo-2-(2,2-difluoroethyl)-2H-1,2,3-triazole (2.3 g, 7.91 mmol, 33.9% yield) as a colorless liquid. 1 H NMR(CDCl3):6.36-6.06(m,1H), 4.78-4.71(m,2H)

[0102] Process 3 To a solution of 4,5-dibromo-2-(2,2-difluoroethyl)-2H-1,2,3-triazole (1.5 g, 5.16 mmol) in THF (20 mL) was added isopropylmagnesium chloride (9 ml, 18.00 mmol, 2 M solution in THF) dropwise at 0° C. The reaction mixture was stirred at this temperature for 1.5 h. The reaction mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with diethyl ether (2×50 mL). The organic extract was dried over anhydrous Na2SO4 and concentrated under low vacuum to give crude 4-bromo-2-(2,2-difluoroethyl)-2H-1,2,3-triazole (1.05 g) as a deep red oil. The crude product was used as is without further purification. GCMS: 210.9, retention time=5.37

[0103] Intermediate 4 [ka]

[0104] Step 1: To a stirred solution of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.31 g, 9.26 mmol) and 4-bromo-2-methyl-2H-1,2,3-triazole (1.50 g, 9.26 mmol) in DME (15 mL) and water (5 mL) was added sodium carbonate (2.45 mg, 23.15 mmol). The reaction mixture was purged with nitrogen for 5 min and Pd(Ph3P)4 (1.07 g, 0.93 mmol) was added under nitrogen. The reaction mixture was stirred at 90° C. for 6 h. The reaction mixture was filtered through a celite pad and washed with methanol (50 mL). The filtrate was then concentrated under reduced pressure. The crude residue was partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was collected, dried over anhydrous Na2SO4 and concentrated. The crude residue was purified by silica gel column chromatography (50% ethyl acetate in petroleum ether) to give the desired 2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (1.70 g, 7.67 mmol, 83% yield) as a brown crystalline solid. MS (M+1) m / z: 205.2 (M+H). + ;LC retention time 1.20[A]

[0105] Step 2: To a solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (see Moslin et al., J. Med. Chem 2019, 62, 8953-8972) (0.35 g, 1.67 mmol) and 2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (0.41 g, 2.01 mmol) in THF (10 mL) at 0° C., LiHMDS (6.70 mL, 6.70 mmol, 1 M solution in THF) was added dropwise and stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc (2×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (40% ethyl acetate in petroleum ether) to give the desired 6-chloro-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (0.37 g, 0.97 mmol, 58.2% yield) as a light brown solid. MS (M+1) m / z: 377.2 (M+H). + ;LC retention time 2.167[A]

[0106] The following intermediates (4a-4e) were prepared in a similar manner to the preparation of intermediate 4. [ka] [Table 3]

[0107] Example 1 [ka]

[0108] To a solution of 6-chloro-4-((2-methoxy-3-(2-ethyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (101 mg, 0.26 mmol) in dioxane (2.5 mL) was added cyclopropanecarboxamide (110 mg, 1.29 mmol) and the reaction mixture was purged under N2 for 5 min. To this solution was added Xantphos (30 mg, 0.052 mmol), Pd2dba3 (24 mg, 0.026 mmol) and cesium carbonate (337 mg, 1.03 mmol) and the mixture was stirred at 130° C. for 45 min. After cooling to room temperature, the reaction mixture was purified using a 12 g ISCO silica gel cartridge eluting with a 0-10% MeOH / DCM gradient. The pure fractions were concentrated to give 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(2-ethyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (79 mg, 66%) as an off-white solid. MS(M+1) m / z: 440.2[M+H] + ;LC retention time 1.53 min [I]; 1 H NMR (400MHz, DMSO-d6) δ 11.33(s,1H), 11.01(s,1H), 9.16(s,1H), 8.14(d,J=7.9Hz,2H), 7.72(dd,J=7.9, 1.5Hz,1H), 7.47(dd,J=8.0, 1.5Hz,1H ), 7.30(t,J=8.0Hz,1H), 4.52(q,J=7.3Hz,2H), 3.66(s,3H), 2.13-2.05(m,1H), 1.52(t,J=7.3Hz,3H), 0.87-0.78(m,4H)

[0109] The following Examples 2-8 were prepared in a manner similar to that of Example 1. [ka] [Table 4] a = dcpf ligand, 100°C, 2 hours, MW; b = purified by silica gel column chromatography

[0110] Intermediate 5 [ka]

[0111] Process 1 To a solution of 1H-1,2,3-triazole (0.52 mL, 9 mmol) in water (5 mL) at 50° C., bromine (0.62 mL, 12 mmol) was added. The reaction mixture was stirred at 50° C. for 90 min, at which time the precipitated product was isolated by filtration. The precipitate was air-dried on the filter. To the filtrate was added additional bromine (0.62 mL, 12 mmol), and the mixture was then stirred at room temperature overnight. The slurry was then filtered, and the solid was combined with the previously obtained precipitate to give 4,5-dibromo-1H-1,2,3-triazole (1.83 g, 87% yield).

[0112] Process 2 (Org. Lett. 2010, 12, 4632-4635) To a cooled (-10°C) solution of 4,5-dibromo-1H-1,2,3-triazole (2.3 g, 10 mmol) in DMF (23 mL) was added potassium carbonate (2.80 g, 20.3 mmol). The reaction mixture was stirred for 15 min, then iodoethane (1.2 mL, 15 mmol) was added dropwise. Stirring was maintained for 30 min, then 10 mL of water was added. The crude product was extracted with EtOAc (2x50 mL), the organic layers were combined and washed with 10% (aqueous) LiCl solution and brine. The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by ISCO automated chromatography eluting with 0-100% EtOAc in hexanes to give 4,5-dibromo-2-ethyl-2H-1,2,3-triazole (1.1 g, 46% yield) as a white solid. The product did not ionize under LCMS conditions. 1H NMR (400 MHz, chlorochrome-d) δ 4.43 (q, J = 7.3 Hz, 2H), 1.60-1.54 (m, 3H)

[0113] Process 3 (Org. Lett. 2010, 12, 4632-4635) To a cooled (-20°C) solution of 4,5-dibromo-2-ethyl-2H-1,2,3-triazole (1.11 g, 4.35 mmol) in THF (6 mL) was slowly added isopropylmagnesium chloride (2M in THF, 6.5 mL, 13 mmol). The reaction was stirred for 30 min with the cooling bath maintained at -20°C. The reaction was quenched through the addition of saturated aqueous ammonium chloride solution. The product was extracted with EtOAc (2x50 mL). The EtOAc layers were combined, washed with brine solution and then dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure to give intermediate 5 (627 mg, 82% yield) as a yellow oil. The product did not ionize under LCMS conditions. 1 H NMR (400 MHz, chlorochrome-d) δ 7.53 (s, 1H), 4.46 (q, J = 7.3 Hz, 2H), 1.56 (t, J = 7.4 Hz, 3H)

[0114] Intermediate 6 [ka]

[0115] A sealed vessel containing 3-bromo-4-fluoro-2-methoxyaniline (1.0 g, 4.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.50 g, 5.91 mmol), PdCl2(dppf)·DCM (0.186 g, 0.227 mmol) and potassium acetate (1.34 g, 13.6 mmol) in dioxane (22 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. The product-containing fractions were combined and concentrated under reduced pressure to give intermediate 6 as a pale yellow solid (244 mg, 20% yield). MS(M+1) m / z:268.3(MH + );LC retention time 1.05 min [C]

[0116] Intermediate 7 [ka]

[0117] A stirred solution of intermediate 5 (241 mg, 1.37 mmol), intermediate 6 (244 mg, 0.91 mmol) and PdCl2(dppf)·DCM (37 mg, 0.046 mmol) in dioxane (4 mL) was degassed by bubbling nitrogen through the mixture for 5 min. An aqueous solution of K3PO4 (2 M, 1.4 mL, 2.8 mmol) was then added and the reaction mixture was heated at 100 °C for 15 min. The reaction was cooled to room temperature and diluted with EtOAc (75 mL). The resulting solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was then purified using automated chromatography (0-100% EtOAc / Hexanes). Pure fractions were collected and concentrated to give intermediate 7 (124 mg, 56% yield) as a colorless oil. MS (M+1) m / z: 237.3 (MH + );LC retention time 1.04 min [C]; 1H NMR (400MHz, chlorochrome-d) δ 7.88(d,J=2.0Hz,1H), 6.85-6.77(m,1H), 6.75-6.67(m,1H), 4.58(q,J=7.3Hz,2H), 3.77(brs,2H), 3.62(s,3H), 1.63(t,J=7.3Hz,3H)

[0118] Intermediate 8 [ka]

[0119] Process 1 A stirred solution of 4,5-dibromo-1H-1,2,3-triazole (3.0 g, 13 mmol), copper(II) acetate (2.88 g, 15.9 mmol), 2,2'-bipyridine (2.48 g, 15.9 mmol) and sodium carbonate (2.80 g, 26.4 mmol) in dichloroethane (40 mL) was degassed by bubbling nitrogen through the reaction mixture for 5 min. To the degassed mixture was added cyclopropylboronic acid (3.41 g, 39.7 mmol). The reaction was heated at 85° C. overnight. The reaction was cooled to room temperature and then partitioned between 200 mL of EtOAc and a 100 mL mixture of saturated (aqueous) ammonium chloride and concentrated ammonium hydroxide (1:1). The layers were separated and the aqueous layer was extracted with 75 mL of EtOAc (2×). The EtOAc layers were combined and then washed with saturated (aqueous) ammonium chloride and with brine. The EtOAc layers were then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using automated chromatography (0-70% EtOAc / Hexanes). Pure fractions were combined and concentrated under reduced pressure to give 4,5-dibromo-2-cyclopropyl-2H-1,2,3-triazole (979 mg, 28% yield). The product did not ionize under LCMS conditions. 1 H NMR (400 MHz, chlorochrome-d) δ 4.03-3.95 (m, 1H), 1.38-1.32 (m, 2H), 1.16-1.09 (m, 2H)

[0120] Process 2 To a cooled (-20°C) solution of 4,5-dibromo-2-cyclopropyl-2H-1,2,3-triazole (0.950 g, 3.56 mmol) in THF (5 mL) was slowly added isopropylmagnesium chloride (2M in THF, 5.3 mL, 10.7 mmol). The reaction was stirred for 30 min with the cooling bath maintained at -20°C. The reaction was quenched through the addition of saturated aqueous ammonium chloride solution. The product was extracted with EtOAc (2x50 mL). The EtOAc layers were combined, washed with brine solution, and then dried over anhydrous sodium sulfate. The drying agent was removed via filtration and the filtrate was concentrated under reduced pressure to give intermediate 8 (605 mg, 81% yield) as a yellow oil. The product did not ionize under LCMS conditions. 1 H NMR (400 MHz, chlorochrome-d) δ 7.51 (s, 1H), 3.99 (tt, J = 7.5, 3.8 Hz, 1H), 1.39-1.32 (m, 2H), 1.15-1.07 (m, 2H)

[0121] Intermediate 9 [ka]

[0122] A stirred solution of intermediate 8 (249 mg, 1.32 mmol), intermediate 3 (220 mg, 0.88 mmol) and PdCl2(dppf)·DCM (36 mg, 0.044 mmol) in dioxane (4 mL) was degassed by bubbling nitrogen through the mixture for 5 min. An aqueous solution of K3PO4 (2 M, 1.3 mL, 2.6 mmol) was then added and the reaction mixture was heated at 80 °C for 30 min. The reaction was cooled to room temperature and diluted with EtOAc (75 mL). The resulting solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was then purified using automated chromatography (0-100% EtOAc / Hexanes). Pure fractions were collected and concentrated to give intermediate 9 (153 mg, 71% yield) as a colorless oil. MS (M+1) m / z: 231.1 (MH + );LC retention time 1.07 min [C]; 1H NMR (400MHz, chlorochrome-d) δ 8.01(s,1H), 7.31-7.27(m,1H), 6.99(t,J=7.9Hz,1H), 6.76(dd,J=7.9, 1.6Hz,1H), 4.05(tt, J=7.5, 3.9Hz,1H), 3.94-3.79(m,2H), 3.73-3.61(m,3H), 1.45-1.39(m,2H), 1.17-1.09(m,2H)

[0123] Intermediate 10 [ka]

[0124] A sealed vessel containing 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), PdCl2(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. The product-containing fractions were combined and concentrated under reduced pressure to give Intermediate 10 as a pale yellow solid (2.55 g, 54% yield). MS(M+1) m / z: 268.3 (MH + );LC retention time 1.50 min [C]

[0125] Intermediate 11 [ka]

[0126] A stirred solution of intermediate 8 (348 mg, 1.85 mmol), intermediate 10 (330 mg, 1.24 mmol) and PdCl2(dppf)·DCM (50.4 mg, 0.062 mmol) in dioxane (6 mL) was degassed by bubbling nitrogen through the mixture for 5 min. An aqueous solution of K3PO4 (2 M, 1.85 mL, 3.7 mmol) was then added and the reaction mixture was heated at 50 °C for 30 min. The reaction was cooled to room temperature and diluted with EtOAc (75 mL). The resulting solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was then purified using automated chromatography (0-100% EtOAc / hexanes). Pure fractions were combined and concentrated under reduced pressure to give intermediate 11 (188 mg, 61% yield) as a colorless oil. MS (M+1) m / z: 249.2 (MH + );LC retention time 1.40 min [C]; 1 H NMR (400 MHz, chlorochrome-d) δ 8.03 (s, 1H), 7.00 (dd, J = 9.6, 3.0 Hz, 1H), 6.46 (dd, J = 9.5, 3.0 Hz, 1H), 4.11-4.04 (m, 1H), 4.04-3.97 (m, 2H), 3.67 (s, 3H), 1.47-1.40 (m, 2H), 1.19-1.12 (m, 2H).

[0127] Intermediate 12 [ka]

[0128] Process 1 2-Bromo-4-methyl-6-nitrophenol (1.00 g, 4.31 mmol) was combined with potassium carbonate (1.19 g, 8.62 mmol) and iodomethane (0.40 mL, 6.5 mmol) in DMF (15 mL) and stirred at room temperature overnight. Ethyl acetate (50 mL) and water (50 mL) were added to the reaction and the two layers were separated. The EtOAc layer was washed with 1N NaOH (aq), 10% LiCl (aq) and brine solution. The EtOAc layer was then dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The crude product was then purified using automated chromatography (0-30% EtOAc / Hexanes) to give 1-bromo-2-methoxy-5-methyl-3-nitrobenzene. The product did not ionize. 1 H NMR (400 MHz, chlorochrome-d) δ 7.61 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 3.98 (s, 3H), 2.37 (s, 3H)

[0129] Process 2 1-Bromo-2-methoxy-5-methyl-3-nitrobenzene (0.979 g, 3.98 mmol) was combined with ammonium chloride (2.13 g, 39.8 mmol) in ethanol (21 mL) and water (3 mL). To this was added zinc (2.60 g, 39.8 mmol) in a dropwise manner over 10 minutes. The resulting heterogeneous mixture was stirred at room temperature overnight. Dichloromethane (200 mL) was added to the reaction, which was then filtered through Celite and the filtrate was collected. The filtrate was washed with water (100 mL) and dried over sodium sulfate. The drying agent was removed via filtration and the crude product was concentrated under reduced pressure. Purification was carried out using automated chromatography (0-50% EtOAc / Hexanes) to give 3-bromo-2-methoxy-5-methylaniline (0.763 g, 89% yield) as a colorless oil. MS(M+1) m / z: 216.1(MH + );LC retention time 0.90 min [E]; 1H NMR (400MHz, DMSO-d) δ 6.64(d,J=8.1Hz,1H), 6.30(dt,J=8.0, 1.1Hz,1H), 4.56(bs,2H), 3.70(s,3H), 3.31(s,3H)

[0130] Process 3 A sealed vessel containing 3-bromo-2-methoxy-5-methylaniline (150 mg, 0.694 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (229 mg, 0.90 mmol), PdCl2(dppf)·DCM (28 mg, 0.035 mmol) and potassium acetate (204 mg, 2.08 mmol) in dioxane (4 mL) was heated to 100 °C. Heating was continued overnight, at which point partial conversion was observed. Additional 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (229 mg, 0.90 mmol), PdCl2(dppf)·DCM (28 mg, 0.035 mmol) and potassium acetate (204 mg, 2.08 mmol) were added and heating was continued for 2 h. The reaction mixture was used directly in the subsequent step. MS(M+1) m / z: 264.1 (MH + );LC retention time 0.82 min [E]

[0131] Process 4 To the reaction mixture from step 3, intermediate 8 (170 mg, 0.904 mmol) was added and the mixture was degassed by bubbling nitrogen through for 5 min. To this, K3PO4 (2M aqueous 1.04 mL, 2.09 mmol) was added quickly. The mixture was heated at 100° C. for 1 h and then cooled to room temperature. The reaction was partitioned between EtOAc (30 mL) and brine solution (20 mL). The EtOAc layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using automated chromatography (0-70% EtOAc / Hexanes). Pure fractions were collected and concentrated to give intermediate 12 (87 mg, 51% yield for two steps) as a yellow oil. MS (M+1) m / z: 245.1 (MH +);LC retention time 0.80 min [E]

[0132] Intermediate 13 [ka]

[0133] To a cooled (10° C.) stirred solution of intermediate 8 (712 mg, 3.79 mmol) in THF (10 mL) was slowly added isopropylmagnesium chloride-lithium chloride complex (1.3 M in THF, 3.5 mL, 4.5 mmol). The reaction was stirred at 10° C. for 2 h and then further cooled to −20° C. To this solution was added trimethyl borate (0. mL, 5.7 mmol). The reaction mixture was stirred at −20° C. for 1 h and then quenched through the addition of 1N (aqueous) HCl. The product was extracted with EtOAc (×2), the organic layers were combined, washed with brine solution, and then dried over anhydrous sodium sulfate. The drying agent was removed via filtration and the filtrate was concentrated under reduced pressure to give a solid intermediate 13 (499 mg, 73% yield). The material used was recovered.

[0134] Intermediate 14 [ka]

[0135] A stirred solution of intermediate 13 (245 mg, 1.60 mmol), 4-bromo-3-methoxypyridin-2-amine (250 mg, 1.23 mmol) and PdCl2(dppf)·DCM (50.3 mg, 0.062 mmol) in dioxane (3 mL) was degassed by bubbling nitrogen through the mixture for 5 min. An aqueous solution of K3PO4 (2 M, 1.85 mL, 3.7 mmol) was then added and the reaction mixture was heated at 100 °C for 45 min. The reaction was cooled to room temperature and diluted with EtOAc (75 mL). The resulting solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was then purified using automated chromatography (0-100% EtOAc / hexanes). Pure fractions were combined and concentrated under reduced pressure to give intermediate 14 (155 mg, 54% yield) as an off-white crystalline solid. MS(M+1) m / z:232.3(MH + );LC retention time 0.83 min [C]; 1 H NMR (400MHz, chlorochrome-d) δ 8.08(s,1H), 7.87(d,J=5.3Hz,1H), 7.19(d,J=5.3Hz,1H), 4.71(brs,2H), 4. 09(dt,J=7.5, 3.7Hz,1H), 3.73(s,3H), 1.49-1.39(m,2H), 1.21-1.12(m,2H)

[0136] Intermediate 15 [ka]

[0137] To a cooled (10° C.) stirred solution of intermediate 5 (244 mg, 1.39 mmol) in THF (3.3 mL) was slowly added isopropylmagnesium chloride-lithium chloride complex (1.3 M in THF, 1.3 mL, 1.7 mmol). The reaction was stirred at 10° C. for 2 h and then further cooled to −20° C. To this solution was added trimethyl borate (0.23 mL, 2.1 mmol). The reaction mixture was stirred at −20° C. for 1 h and then quenched through the addition of 1N (aqueous) HCl. The product was extracted with EtOAc (×2), the organic layers were combined, washed with brine solution, and then dried over anhydrous sodium sulfate. The drying agent was removed via filtration and the filtrate was concentrated under reduced pressure to give a solid intermediate 15 (115 mg, 50% yield). MS (M+1) m / z: 142.3 (MH + );LC retention time 0.37 min [C]; 1 H NMR (400MHz, DMSO-d6) δ 7.92(s,1H), 4.45(q,J=7.3Hz,2H), 1.44(t,J=7.3Hz,3H)

[0138] Intermediate 16 [ka]

[0139] A stirred solution of intermediate 15 (99 mg, 0.23 mmol), 3-bromo-5-chloro-2-methoxyaniline (50 mg, 0.21 mmol) and PdCl2(dppf)·DCM (8.6 mg, 0.010 mmol) in dioxane (1.5 mL) was degassed by bubbling nitrogen through the mixture for 5 min. An aqueous solution of K3PO4 (2 M, 0.32 mL, 0.63 mmol) was then added and the reaction mixture was stirred at room temperature for 90 min, then heated at 50 °C for 30 min, and then stirred at room temperature overnight. The reaction was diluted with EtOAc (75 mL). The resulting solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was then purified using automated chromatography (0-100% EtOAc / hexanes). Pure fractions were combined and concentrated under reduced pressure to give intermediate 16 (23 mg, 43% yield) as a yellow oil. MS(M+1) m / z:253.1(MH + );LC retention time 1.34 min [C]

[0140] Intermediate 17 [ka]

[0141] A stirred solution of intermediate 13 (60.3 mg, 0.394 mmol), 3-bromo-4-fluoro-2-methoxyaniline (62 mg, 0.28 mmol) and PdCl2(dppf)·DCM (11.5 mg, 0.014 mmol) in dioxane (5 mL) was degassed by bubbling nitrogen through the mixture for 5 min. An aqueous solution of K3PO4 (2 M, 0.42 mL, 0.84 mmol) was then added and the reaction mixture was heated at 100 °C for 30 min. The reaction was cooled to room temperature and diluted with EtOAc (75 mL). The resulting solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was then purified using automated chromatography (0-100% EtOAc / hexanes). Pure fractions were combined and concentrated under reduced pressure to give intermediate 17 (35 mg, 50% yield) as a yellow oil. MS(M+1) m / z:249.1(MH+ );LC retention time 1.01 min [C]

[0142] Intermediate 18 [ka]

[0143] Process 1 To a cooled (-10°C) solution of 4,5-dibromo-1H-1,2,3-triazole (2.0 g, 8.8 mmol) in DMF (20 mL) was added potassium carbonate (2.68 g, 19.4 mmol). The reaction mixture was stirred for 15 min, then iodomethane (1.10 mL, 17.6 mmol) was added dropwise. Stirring was maintained overnight, then 10 mL of water was added. The crude product was extracted with EtOAc (2x50 mL), the organic layers were combined and washed with 10% (aqueous) LiCl solution and brine. The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using ISCO automated chromatography eluting with 0-100% EtOAc in hexane to give 4,5-dibromo-2-methyl-2H-1,2,3-triazole (1.33 g, 63% yield) as a white solid. The product did not ionize under LCMS conditions. LC retention time 1.26 min [C]

[0144] Process 2 To a cooled (-20°C) solution of 4,5-dibromo-2-methyl-2H-1,2,3-triazole (1.33 g, 5.52 mmol) in diethyl ether (6 mL) was slowly added isopropylmagnesium chloride (2M in THF, 8.28 mL, 16.6 mmol). The reaction was stirred for 30 min with the cooling bath maintained at -20°C. The reaction was quenched through the addition of saturated aqueous ammonium chloride solution. The product was extracted with EtOAc (2x50 mL). The EtOAc layers were combined, washed with brine solution, and then dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure to give intermediate 18 (31) (627 mg, 82% yield) as a colorless oil. The product did not ionize under LCMS conditions. LC retention time 0.81 min [C]; 1 H NMR (400 MHz, chlorochrome-d) δ 7.54(s,1H), 4.19(s,3H)

[0145] Intermediate 19 [ka]

[0146] To a solution of 4-bromo-2-methyl-2H-1,2,3-triazole (0.896 g, 5.53 mmol) in THF (12 mL) cooled to 10° C. was slowly added isopropylmagnesium chloride-lithium chloride complex (1.3 M in THF, 8.51 mL, 11.06 mmol). The reaction was stirred under cooling for 2 h. It was then cooled to −20° C. Trimethyl borate (1.854 mL, 16.59 mmol) was added and the mixture was stirred for 1 h. At this point, the reaction mixture was quenched with 1N HCl, transferred to a separatory funnel, and extracted with EtOAc (2×). The organics were combined, washed with brine, and then dried over anhydrous sodium sulfate. Filtration and concentration gave (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (533 mg, 3.78 mmol, 68.3% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 8.31(brs,2H), 7.89(s,1H), 4.16(s,3H)

[0147] Intermediate 20 [ka]

[0148] Process 1 A sealed vessel containing 3-bromo-2-methoxy-5-methylaniline (150 mg, 0.694 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (229 mg, 0.90 mmol), PdCl2(dppf)·DCM (28 mg, 0.035 mmol) and potassium acetate (204 mg, 2.08 mmol) in dioxane (4 mL) was heated at 100 °C for 8 h. The reaction mixture was used directly in the subsequent step. MS (M+1) m / z: 264.1 (MH + );LC retention time 0.82 min [E]

[0149] Process 2 To the reaction mixture from step 1, intermediate 18 (146 mg, 0.904 mmol) was added and the mixture was degassed by bubbling nitrogen through for 5 min. To this, K3PO4 (2M aqueous 1.04 mL, 2.09 mmol) was added quickly. The mixture was heated at 100° C. for 1 h and then cooled to room temperature. The reaction was partitioned between EtOAc (30 mL) and brine solution (20 mL). The EtOAc layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using automated chromatography (0-70% EtOAc / Hexanes). Pure fractions were collected and concentrated to give intermediate 20 (120 mg, 79% yield for two steps) as a yellow oil. MS(M+1) m / z: 219.3 (MH + );LC retention time 0.71 min [E]

[0150] Intermediate 21 [ka]

[0151] To a stirred solution of intermediate 18 (100 mg, 0.62 mmol) in dioxane (3 mL) was added intermediate 3 (185 mg, 0.74 mmol) and potassium carbonate (256 mg, 1.85 mmol). The reaction mixture was degassed by bubbling nitrogen through the mixture for 10 min. PdCl2(dppf)·DCM (25 mg, 0.031 mmol) was then added and the mixture was degassed again by bubbling nitrogen through the mixture for 10 min. The reaction was heated to 110 °C in a microwave for 2 h. The reaction was cooled to room temperature, filtered and concentrated. The crude product was then purified using reverse phase chromatography (A: 0.1% formic acid in water; B: 100% acetonitrile) to give intermediate 21 as a brown amorphous solid (70 mg, 55% yield). MS (M+1) m / z: 205.1 (MH + );LC retention time 1.25 min [F]; 1 H NMR (400MHz, DMSO-d) δ 8.02(s,1H), 7.02(dd,J=8.0, 1.6Hz,1H), 6.89(t,J=8.0Hz,1H), 6.70(dd,J=8.0, 1.6Hz,1H), 5.06(brs,2H), 4.19(s,3H), 3.59(s,3H)

[0152] Example 9 [ka]

[0153] Process 1 4,6-Dichloro-N-(methyl-d3)pyridazine-3-carboxamide (73 mg, 0.35 mmol) and intermediate 22 (96 mg, 0.35 mmol) were combined in THF (3 mL) at room temperature. To this was added LiHMDS (1M in THF, 1.2 mL, 1.2 mmol) dropwise over 10 min. The reaction mixture was stirred at room temperature for 30 min and then quenched via addition of 2 mL of saturated aqueous ammonium chloride solution. The reaction mixture was partitioned between EtOAc (30 mL) and saturated aqueous ammonium chloride solution (20 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude brown solid, which was purified using automated chromatography (0-100% EtOAc / Hexanes). Pure fractions were combined to give 6-chloro-4-((3-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-methoxy-5-methylphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (72 mg, 50% yield) as a light yellow solid. MS(M+1) m / z: 417.1 (MH + );LC retention time 1.09 min [E]

[0154] Process 2 A mixture of 6-chloro-4-((3-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-methoxy-5-methylphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (72 mg, 0.17 mmol), cyclopropanecarboxamide (29 mg, 0.34 mmol), tris(dibenzylideneacetone)dipalladium(0)·chloroform adduct (17.8 mg, 0.017 mmol), 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene (Xantphos) (20 mg, 0.035 mmol) and cesium carbonate (225 mg, 0.69 mmol) in dioxane (0.7 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction vessel was then sealed and heated to 130° C. for 45 min. The reaction was cooled to room temperature, diluted with DMF, filtered through a 0.45 micron nylon filter, and then purified using preparative HPLC purification to give 47 (26.7 mg, 33% yield). MS(M+1) m / z: 466.2 (MH + );LC retention time 1.94 min [G]; 1 H NMR (500MHz, DMSO-d6) δ 11.27(s,1H), 10.89(s,1H), 9.11(s,1H), 8.07(d,J=1.4Hz,2H), 7.52(s,1H), 7.27(s,1H), 4.18(dt,J=7.5, 3. 8Hz,1H), 3.59(s,3H), 2.32(s,3H), 2.17-2.00(m,1H), 1.35-1.18(m,2H), 1.18-1.06(m,2H), 0.88-0.73(m,4H)

[0155] The following examples were prepared in a similar manner to the preparation of Example 9, using the intermediates and commercially available reagents indicated, with some minor modifications in solvents, reaction times, etc.

[0156] [ka]

[0157] Table 1 [Table 5] [Table 6] [Table 7] [Table 8]

[0158] Example 19 [ka]

[0159] [ka]

[0160] Step 1: To a solution of 2-bromo-4-fluoro-3-methyl-6-nitrophenol (266 mg, 1.064 mmol) in DMF (4 mL) was added potassium carbonate (441 mg, 3.19 mmol). The mixture was stirred for 15 min, then iodomethane (0.133 mL, 2.128 mmol) was added. The resulting mixture was stirred at room temperature overnight. LCMS showed complete conversion to the product. Cold water (75 mL) was added, the mixture was stirred, then sonicated, after which the solid was collected by filtration. This material was then dissolved in EtOAc (150 mL). The solution was washed with 1x10% LiCl, 1xbrine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was loaded onto a 12 g silica gel column and purified by flash chromatography eluting with 0-50% EtOAc in hexanes. The pure fractions were concentrated to give 3-bromo-1-fluoro-4-methoxy-2-methyl-5-nitrobenzene (231 mg, 0.875 mmol, 82% yield) as a pale yellow solid. MS(M+1) m / z:n / a(M+H) +LC retention time 1.572[C][nitro product does not ionize]

[0161] [ka]

[0162] Step 2: A mixture of 3-bromo-1-fluoro-4-methoxy-2-methyl-5-nitrobenzene (230 mg, 0.871 mmol) and tin(II) chloride dihydrate (786 mg, 3.48 mmol) in ethyl acetate (8.5 mL) was stirred for 1 h. After cooling to room temperature, the reaction was then diluted with ethyl acetate (100 ml). The solution was washed with 3x2.5N NaOH, 1xwater and 1xbrine. Drying over anhydrous sodium sulfate and concentration gave 3-bromo-5-fluoro-2-methoxy-4-methylaniline (136 mg, 0.581 mmol, 66.7% yield) as a light brown oil. MS(M+1) m / z: 235.9(M+H) + ;LC retention time 1.37[C]

[0163] [ka]

[0164] Step 3: A stirred mixture of (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (65.1 mg, 0.513 mmol), 3-bromo-5-fluoro-2-methoxy-4-methylaniline (60 mg, 0.256 mmol) and PdCl2(dppf)-dichloromethane adduct (10.47 mg, 0.013 mmol) in dioxane (3 mL) was degassed by bubbling nitrogen through the mixture for 5 min. 2M K3PO4(aq) (0.385 mL, 0.769 mmol) was added quickly and the reaction mixture was heated at 100° C. for 30 min. The reaction turned dark almost immediately. LC-MS showed the starting material was completely consumed. The reaction mixture was cooled to room temperature and then diluted with EtOAc (75 mL). The solution was then dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography eluting with 0-100% EtOAc to give 5-fluoro-2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (44 mg, 0.186 mmol, 72.7% yield) as a yellow oil. MS (M+1) m / z: 237.2 (M+H). + ;LC retention time 1.08[C]; 1 H NMR (400MHz, chlorochrome-d) δ 7.69(s,1H), 6.52(d,J=10.6Hz,1H), 4.28(s,3H), 3.84(brs,2H), 3.43(s,3H), 2.05(d,J=2.3Hz,3H)

[0165] [ka]

[0166] Step 4: To a solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (38 mg, 0.182 mmol) and 5-fluoro-2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (42.9 mg, 0.182 mmol) in tetrahydrofuran (1.5 mL) was added lithium bis(trimethylsilyl)amide (1M in THF, 0.454 mL, 0.454 mmol) in a dropwise fashion via syringe and the reaction was stirred until done by LCMS (approximately 15 min). Saturated aqueous ammonium chloride solution was added to quench remaining base. The reaction was then partitioned between EtOAc and water. The aqueous layer was extracted 1x with ethyl acetate, then the organic layers were combined and washed with saturated ammonium chloride solution (1x) and with brine (1x). The organic layers were combined and then dried over anhydrous sodium sulfate, filtered and concentrated. The material was used directly in the next step as is: 6-chloro-4-((5-fluoro-2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (56 mg, 0.137 mmol, 75% yield); MS (M+1) m / z: 409.1 (M+H). + ;LC retention time 1.35[C]

[0167] [ka]

[0168] Step 5: A mixture of 6-chloro-4-((5-fluoro-2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (37 mg, 0.091 mmol), Xantphos (10.47 mg, 0.018 mmol), and cyclopropanecarboxamide (38.5 mg, 0.453 mmol) in dioxane (1.5 mL) was degassed by bubbling N2 through it for 5 min. Cs2CO3 (118 mg, 0.362 mmol) and Pd2(dba)3 (8.29 mg, 9.05 μmol) were then added, the vessel was sealed, and the reaction was stirred at 130 °C for 2 h. The reaction was complete by LC-MS and was diluted to 2 mL with DMF and then purified by preparative HPLC to give 6-(cyclopropanecarboxamido)-4-((5-fluoro-2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (17.8 mg, 0.039 mmol, 43.0% yield). MS(M+1) m / z: 458.1(M+H). + ;LC retention time 1.25[C]; 1 H NMR (500MHz, DMSO-d6) δ 11.35(s,1H), 10.97(s,1H), 9.14(s,1H), 8.17(s,1H), 7.91(s,1H), 7.40(d,J=10.7 Hz,1H), 4.25(s,3H), 2.55(s,3H), 2.09(brd,J=1.8Hz,4H), 0.85(brd,J=6.1Hz,4H)

[0169] Example 20 [ka]

[0170] [ka]

[0171] Step 1: A stirred mixture of 4,5-dibromo-2-methyl-2H-1,2,3-triazole (0.273 g, 1.133 mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.268 g, 1.077 mmol) and PdCl2(dppf)-dichloromethane adduct (0.046 g, 0.057 mmol) in dioxane (8 mL) was degassed by bubbling nitrogen through the mixture for 5 min. 2M K3PO4(aq) (1.700 mL, 3.40 mmol) was added quickly and the reaction mixture was heated at 50° C. for 25 min. LC-MS showed that the starting material was completely consumed. The reaction mixture was cooled to room temperature and then diluted with EtOAc (75 mL). The solution was then dried over sodium sulfate, filtered, concentrated, and purified by flash chromatography eluting with 0-100% EtOAc in hexanes to give 3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyaniline (144 mg, 0.509 mmol, 44.9% yield) as a yellow oil. MS (M+1) m / z: 282.8 / 284.8 (M+H). + ;LC retention time 1.05[C]

[0172] [ka]

[0173] Step 2: A mixture of 3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyaniline (144 mg, 0.509 mmol), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine [S-Phos] (22.97 mg, 0.056 mmol), palladium(II) acetate (5.71 mg, 0.025 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (196 mg, 1.272 mmol) in dioxane (3 mL) was purged with nitrogen for 1 min. 2M K3PO4(aq) (1.399 mL, 2.80 mmol) was added and the reaction mixture was heated at 100°C for 1 h. LCMS showed that the SM was consumed. The mixture was concentrated and then purified by flash chromatography on a 24 g silica gel column eluting with 0-50% EtOAc in hexanes to give 2-methoxy-3-(2-methyl-5-vinyl-2H-1,2,3-triazol-4-yl)aniline (111 mg, 0.434 mmol, 85% yield). MS (M+1) m / z: 231.0 (M+H). + ;LC retention time 0.93[C]

[0174] [ka]

[0175] Step 3: 10% Palladium on carbon (5.13 mg, 0.048 mmol) was added to a solution of 2-methoxy-3-(2-methyl-5-vinyl-2H-1,2,3-triazol-4-yl)aniline (111 mg, 0.482 mmol) in ethanol (5 mL). The resulting mixture was degassed by vacuum and then stirred overnight at room temperature under a hydrogen atmosphere. After stirring overnight, the mixture was filtered and the filtrate was concentrated to give 3-(5-ethyl-2-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyaniline (115 mg, 0.446 mmol, 92% yield) as a waxy white solid. 1H NMR (400MHz, chlorochrome-d) δ 7.01-6.94(m,1H), 6.80(dd,J=7.9, 1.6Hz,1H), 6.75(dd,J=7.6, 1.6Hz,1H), 4.20 (s,3H), 3.91(brs,2H), 3.50(s,3H), 2.71(q,J=7.6Hz,2H), 1.21(t,J=7.6Hz,3H)

[0176] [ka]

[0177] Step 4: To a solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (113 mg, 0.542 mmol) and 3-(5-ethyl-2-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyaniline (105 mg, 0.452 mmol) (repurified) in THF (4 mL) was added lithium bis(trimethylsilyl)amide (1M in THF, 1.582 mL, 1.582 mmol) in a dropwise fashion (<5 min) via syringe and the reaction was stirred until complete by LCMS (~15 min). Saturated ammonium chloride (aq) was added to quench remaining base. The reaction was then partitioned between EtOAc and water. The aqueous layer was extracted 1x with ethyl acetate, then the organic layers were combined and washed with saturated ammonium chloride (aq) (1x) and brine (1x). The organic layers were combined, then dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was chromatographed on a 12 g ISCO column eluting with 0-100% EtOAc in hexanes to give 6-chloro-4-((3-(5-ethyl-2-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (122 mg, 0.301 mmol, 66.7% yield) as a pale yellow solid. MS(M+1) m / z: 405.1(M+H) + ;LC retention time 1.43[C]

[0178] [ka]

[0179] Step 5: A mixture of 6-chloro-4-((3-(5-ethyl-2-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40 mg, 0.099 mmol), Xantphos (11.43 mg, 0.020 mmol), and cyclopropanecarboxamide (42.0 mg, 0.494 mmol) in dioxane (1.3 mL) was degassed by bubbling nitrogen through it for 5 min. Cesium carbonate (129 mg, 0.395 mmol) and Pd2(dba)3 (9.05 mg, 9.88 μmol) were then added, the vessel was sealed, and the reaction was stirred at 130° C. for 2 h. The reaction was complete by LC-MS and was diluted to 2 mL with DMF, filtered, and purified by preparative HPLC to give 6-(cyclopropanecarboxamido)-4-((3-(5-ethyl-2-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (17.8 mg, 0.039 mmol, 39.7% yield). MS (M+1) m / z: 454.1 (M+H). + ;LC retention time 1.23[C]; 1 H NMR (500MHz, DMSO-d6) δ 11.31(s,1H), 10.95(s,1H), 9.12(s,1H), 8.13(s,1H), 7.51(d,J=7.6Hz,1H), 7.28(t,J=7.8Hz,1H), 7.20(d,J=7.6H) z,1H), 4.15(s,3H), 3.42(s,3H), 2.60(q,J=7.4Hz,2H), 2.12-2.06(m,1H), 1.12(t,J=7.6Hz,3H), 0.88-0.80(m,4H)

[0180] Example 21 [ka]

[0181] [ka]

[0182] Step 1: A stirred mixture of (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (209 mg, 1.649 mmol), 3-bromo-5-chloro-2-methoxyaniline (300 mg, 1.269 mmol) and PdCl2(dppf)-dichloromethane adduct (51.8 mg, 0.063 mmol) in dioxane (3 mL) was degassed by bubbling nitrogen through the mixture for 5 min. 2M K3PO4(aq) (1.903 mL, 3.81 mmol) was added quickly and the reaction mixture was heated at 50° C. for 30 min. LC-MS showed that the starting material was not completely consumed. The reaction mixture was cooled to room temperature and then diluted with EtOAc (75 mL). The solution was then dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography eluting with 0-100% EtOAc in hexanes to give 5-chloro-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (101 mg, 0.423 mmol, 33.4% yield) as an off-white solid. MS (M+1) m / z: 239.0 (M+H). + ;LC retention time 1.20[C]

[0183] [ka]

[0184] Step 2: A mixture of 5-chloro-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (101 mg, 0.423 mmol), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine [S-Phos] (19.11 mg, 0.047 mmol), palladium(II) acetate (4.75 mg, 0.021 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (163 mg, 1.058 mmol) in dioxane (3 mL) was purged with nitrogen for 1 min. 2M K3PO4(aq) (1.164 mL, 2.327 mmol) was added and the reaction mixture was heated at 100°C overnight. LC-MS showed that the SM was consumed. The reaction mixture was concentrated and purified by flash chromatography eluting with 0-50% EtOAc in hexanes to give 2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)-5-vinylaniline (100 mg, 0.391 mmol, 92% yield). MS (M+1) m / z: 231.0 (M+H). + ;LC retention time 1.04[C]

[0185] [ka]

[0186] Step 3: 10% Pd on carbon (4.62 mg, 0.043 mmol) was added to a solution of 2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)-5-vinylaniline (100 mg, 0.434 mmol) in ethanol (5 ml). The resulting mixture was degassed by vacuum and then stirred overnight at room temperature under a hydrogen atmosphere. LCMS showed complete conversion to product. Filtration and concentration gave 5-ethyl-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (100 mg, 0.387 mmol, 89% yield) as a colorless oil. MS (M+1) m / z: 233.1 (M+H). + ;LC retention time 1.06[C]

[0187] [ka]

[0188] Step 4: To a mixture of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (108 mg, 0.517 mmol) and 5-ethyl-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (100 mg, 0.431 mmol) in THF (4 mL) was added lithium bis(trimethylsilyl)amide, 1M in THF (1.507 mL, 1.507 mmol) in a dropwise fashion (<5 min) via syringe and the reaction was stirred until done by LCMS (~15 min). Saturated ammonium chloride (aq) was added to quench remaining base. The reaction was then partitioned between EtOAc and water. The aqueous layer was extracted 1x with ethyl acetate, then the organic layers were combined and washed with saturated ammonium chloride (aq) (1x) and brine (1x). It was then dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was chromatographed on a 12 g silica gel cartridge eluting with 0-100% EtOAc in hexanes to give 6-chloro-4-((5-ethyl-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (94 mg, 0.232 mmol, 53.9% yield) as a pale yellow solid. MS(M+1) m / z: 405.0(M+H). + ;LC retention time 1.54[C]

[0189] [ka]

[0190] Step 5: A mixture of 6-chloro-4-((5-ethyl-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40 mg, 0.099 mmol), Xantphos (11.43 mg, 0.020 mmol), and cyclopropanecarboxamide (42.0 mg, 0.494 mmol) in dioxane (1.3 mL) was degassed by bubbling nitrogen through it for 5 min. Cesium carbonate (129 mg, 0.395 mmol) and Pd2(dba)3 (9.05 mg, 9.88 μmol) were then added, the vessel was sealed, and the reaction was stirred at 130° C. for 2 h. The reaction was complete by LC-MS and was diluted to 2 mL with DMF, filtered, and purified by preparative HPLC to give 6-(cyclopropanecarboxamido)-4-((5-ethyl-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (9.7 mg, 0.021 mmol, 21.65% yield). MS (M+1) m / z: 454.3 (M+H). + ;LC retention time 1.25[C]; 1 H NMR (500MHz, DMSO-d6) δ 11.30(s,1H), 10.95(s,1H), 9.13(s,1H), 8.19(s,1H), 8.10(s,1H), 7.53(s,1H), 7.33(s,1H), 4.23(s ,3H), 3.62(s,3H), 2.62(q,J=7.6Hz,2H), 2.12-2.05(m,1H), 1.22(t,J=7.6Hz,3H), 0.88-0.77(m,4H)

[0191] Example 22 [ka]

[0192] [ka]

[0193] Step 1: To a solution of 6-bromo-3-fluoro-2-nitrophenol (262 mg, 1.110 mmol) in DMF (3 mL) was added potassium carbonate (460 mg, 3.33 mmol). The mixture was stirred for 15 min, then iodomethane (0.193 mL, 2.20 mmol) was added. The resulting mixture was stirred at room temperature overnight. LCMS showed complete conversion to product. Cold water (75 mL) was added, the mixture was stirred, then sonicated and the solid was collected by filtration. The material was then dissolved in EtOAc (150 mL), transferred to a separatory funnel and washed with 10% LiCl (1x) and brine (1x). Drying over anhydrous sodium sulfate and concentration gave a residue which was purified by flash chromatography on a silica gel column eluting with 0-50% EtOAc in hexanes to give 1-bromo-4-fluoro-2-methoxy-3-nitrobenzene (278 mg, 1.001 mmol, 90% yield) as a yellow oil. MS (M+1) m / z: n / a (M+H). + ;LC retention time 1.54[C]

[0194] [ka]

[0195] Step 2: A mixture of 1-bromo-4-fluoro-2-methoxy-3-nitrobenzene (278 mg, 1.112 mmol) and tin(II) chloride dihydrate (1004 mg, 4.45 mmol) in EtOAc (10 mL) was stirred at reflux for 1 h. The reaction was then diluted with ethyl acetate (100 ml), washed with 2.5 N NaOH (3x50 ml), water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate and concentrated to give 3-bromo-6-fluoro-2-methoxyaniline (149 mg, 0.677 mmol, 60.9% yield) as a maroon oil. MS (M+1) m / z: 219.9 / 221.9 (M+H) + ;LC retention time 1.276[C]

[0196] [ka]

[0197] Step 3: A stirred mixture of (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (59.6 mg, 0.470 mmol), 3-bromo-6-fluoro-2-methoxyaniline (94 mg, 0.427 mmol) and PdCl2(dppf)-dichloromethane adduct (17.44 mg, 0.021 mmol) in dioxane (3 mL) was degassed by bubbling nitrogen through the mixture for 5 min. 2M K3PO4(aq) (0.641 mL, 1.282 mmol) was added quickly and the reaction mixture was heated at 50° C. for 30 min. LC-MS showed that the starting material was completely consumed. The reaction mixture was cooled to room temperature and diluted with EtOAc (75 mL). The solution was then dried over sodium sulfate, filtered, concentrated and purified by flash chromatography on a silica gel column eluting with 0-100% EtOAc in hexanes to give 6-fluoro-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (52 mg, 0.234 mmol, 54.8% yield) as an off-white solid. MS (M+1) m / z: 223.1 (M+H). + ;LC retention time 1.02[C]

[0198] [ka]

[0199] Step 4: To a solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (51.4 mg, 0.246 mmol) and 6-fluoro-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (52 mg, 0.234 mmol) in THF (2 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 0.585 mL, 0.585 mmol) in a dropwise fashion (<5 min) via syringe. The reaction was stirred until complete by LCMS (approximately 15 min). Saturated ammonium chloride (aq) was added to quench remaining base. The reaction was then partitioned between EtOAc and water. The aqueous layer was extracted 1x with ethyl acetate, then the organic layers were combined and washed with saturated ammonium chloride (aq) (1x) and brine (1x). The mixture was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was chromatographed on a silica gel column eluted with 0-100% EtOAc in hexanes to give 6-chloro-4-((6-fluoro-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (67 mg, 0.170 mmol, 72.5% yield) as an off-white solid. MS(M+1) m / z: 395.1(M+H). + ;LC retention time 1.29[C]

[0200] [ka]

[0201] Step 5: A mixture of 6-chloro-4-((6-fluoro-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40 mg, 0.101 mmol), Xantphos (11.72 mg, 0.020 mmol), and cyclopropanecarboxamide (43.1 mg, 0.507 mmol) in dioxane (1.3 mL) was degassed by bubbling nitrogen through it for 5 min. Cesium carbonate (132 mg, 0.405 mmol) and Pd2(dba)3 (9.28 mg, 10.13 μmol) were then added, the vessel was sealed, and the reaction was stirred at 130° C. for 2 h. The reaction was complete by LC-MS and was diluted to 2 mL with DMF, filtered, and purified by preparative HPLC to give 6-(cyclopropanecarboxamido)-4-((6-fluoro-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (6.6 mg, 0.015 mmol, 14.69% yield). MS(M+1) m / z: 444.2(M+H). + ;LC retention time 1.195[C]; 1 H NMR (500MHz, DMSO-d6) δ 11.39-11.25(m,1H), 10.55(s,1H), 9.17(s,1H), 8.07(s,1H), 7.85(dd,J=8.9, 6.4Hz,1H), 7.52(d, J=3.4Hz,1H), 7.30(t,J=9.3Hz,1H), 4.23(s,3H), 3.67(s,3H), 2.11-1.99(m,1H), 0.84-0.71(m,4H)

[0202] Example 23 [ka]

[0203] [ka]

[0204] Step 1: A mixture of 3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyaniline (180 mg, 0.636 mmol), tricyclohexylphosphine (19.61 mg, 0.070 mmol), palladium(II) acetate (7.14 mg, 0.032 mmol) and 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane (253 mg, 1.780 mmol) in toluene (3 mL) was purged with nitrogen for 1 min. 2M K3PO4(aq) (1.748 mL, 3.50 mmol) was added and the reaction mixture was heated at 100° C. overnight. LCMS showed that the SM was consumed. Concentration and purification by flash chromatography on a silica gel column eluting with 0-50% EtOAc in hexanes gave 3-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-2-methoxyaniline (124 mg, 0.511 mmol, 80% yield). MS (M+1) m / z: 219.2 (M+H). + ;LC retention time 0.91[C]; 1 H NMR (400 MHz, chlorochrome-d) δ 6.99 (t, J = 7.4 Hz, 1H), 6.81 (t, J = 9.0 Hz, 2H), 4.31-4.20 (m, 3H), 3.93 (brs, 2H), 3.55-3.49 (m, 3H), 2.32 (s, 3H)

[0205] [ka]

[0206] Step 2: To a solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (130 mg, 0.620 mmol) and 3-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-2-methoxyaniline (123 mg, 0.564 mmol) in THF (3 mL) was added lithium bis(trimethylsilyl)amide (1.578 mL, 1.578 mmol) in a dropwise fashion (<5 min) via syringe and the reaction was stirred until complete by LCMS (~15 min). Saturated ammonium chloride (aq) was added to quench remaining base. The reaction was then partitioned between EtOAc and water. The aqueous layer was extracted 1x with ethyl acetate, then the organic layers were combined and washed with saturated ammonium chloride (aq) (1x) and brine (1x). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was chromatographed on a silica gel column eluting with 0-100% EtOAc in hexanes to give 6-chloro-4-((3-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (109 mg, 0.251 mmol, 44.5% yield) as a pale yellow solid. MS(M+1) m / z: 391.1(M+H). + ;LC retention time 1.24[C]

[0207] [ka]

[0208] Step 3: A mixture of 6-chloro-4-((3-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40 mg, 0.102 mmol), Xantphos (11.84 mg, 0.020 mmol), and cyclopropanecarboxamide (43.5 mg, 0.512 mmol) in dioxane (1.3 mL) was degassed by bubbling nitrogen through it for 5 min. Cesium carbonate (133 mg, 0.409 mmol) and Pd2(dba)3 (9.37 mg, 10.23 μmol) were then added, the vessel was sealed, and the reaction was stirred at 130° C. for 2 h. The reaction was complete by LC-MS and was diluted to 2 mL with DMF, then filtered and purified by preparative HPLC to give 6-(cyclopropane-carboxamido)-4-((3-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (34.9 mg, 0.079 mmol, 78% yield). MS (M+1) m / z: 440.2 (M+H). + ;LC retention time 1.17[C]; 1 H NMR (500MHz, DMSO-d6) δ 11.30(s,1H), 10.94(s,1H), 9.10(s,1H), 8.14(s,1H), 7.51(brd,J=7.3Hz,1H), 7.32-7.25(m,1H), 7 .25-7.19(m,1H), 4.14(s,3H), 3.42(s,3H), 2.23-2.14(m,3H), 2.10-2.02(m,1H), 0.88-0.79(m,4H)

[0209] Example 24 [ka]

[0210] [ka]

[0211] Step 1:

[0212] A stirred mixture of (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (48.1 mg, 0.379 mmol), 3-bromo-2,5-dimethoxyaniline (80 mg, 0.345 mmol) and PdCl2(dppf)-dichloromethane adduct (14.08 mg, 0.017 mmol) in dioxane (2.5 mL) was degassed by bubbling nitrogen through the mixture for 5 min. 2M K3PO4(aq) (0.517 mL, 1.034 mmol) was added quickly and the reaction mixture was heated at 50° C. for 30 min. LC-MS showed that the starting material was completely consumed. The reaction mixture was cooled to room temperature and then diluted with EtOAc (75 mL). The solution was then dried over sodium sulfate, filtered, concentrated and purified by flash chromatography eluting with 0-100% EtOAc in hexanes to give 2,5-dimethoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (63 mg, 0.269 mmol, 78% yield) as an off-white solid. MS(M+1) m / z:235.2(M+H) + ;LC retention time 0.99[C]

[0213] [ka]

[0214] Step 2: To a solution of 2,5-dimethoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (63 mg, 0.269 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (59.0 mg, 0.282 mmol) in THF (1.3 mL) at room temperature was added lithium bis(trimethylsilyl)amide (1 M in THF, 0.807 mL, 0.807 mmol) slowly. After 15 min, LC-MS showed the reaction was complete. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and then extracted 2x with EtOAc. The organic layers were combined, washed with brine (1x), and then dried over anhydrous sodium sulfate. Filtration and concentration gave 6-chloro-4-((2,5-dimethoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (101 mg, 0.223 mmol, 83% yield) as a tan solid. MS (M+1) m / z: 407.2 (M+H). + ;LC retention time 1.296[C]

[0215] [ka]

[0216] Step 3: A mixture of 6-chloro-4-((2,5-dimethoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40 mg, 0.098 mmol), Xantphos (11.38 mg, 0.020 mmol), and cyclopropanecarboxamide (41.8 mg, 0.492 mmol) in dioxane (1.3 mL) was degassed by bubbling nitrogen through it for 5 min. Cesium carbonate (128 mg, 0.393 mmol) and Pd2(dba)3 (9.00 mg, 9.83 μmol) were then added, the vessel was sealed, and the reaction was stirred at 130° C. for 2 h. The reaction was complete by LC-MS and was diluted to 2 mL with DMF, then filtered and purified by preparative HPLC to give 6-(cyclopropane-carboxamido)-4-((2,5-dimethoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (16.1 mg, 0.035 mmol, 35.4% yield). MS (M+1) m / z: 456.2 (M+H). + ;LC retention time 1.13[C]; 1 H NMR (500MHz, DMSO-d6) δ 11.35(s,1H), 11.08(s,1H), 9.15(s,1H), 8.29(s,1H), 8.13(s,1H), 7.18(d,J=2.4Hz,1H), 7. 08(d,J=2.4Hz,1H), 4.24(s,3H), 3.81(s,3H), 3.61(s,3H), 2.16-2.03(m,1H), 0.84(brs,4H)

[0217] Example 25 [ka]

[0218] [ka]

[0219] Step 1: A stirred mixture of (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (182 mg, 1.437 mmol), 3-bromo-2-methoxyaniline (264 mg, 1.307 mmol) and PdCl2(dppf)-dichloromethane adduct (53.4 mg, 0.065 mmol) in dioxane (5 mL) was degassed by bubbling nitrogen through the mixture for 5 min. 2M K3PO4(aq) (1.960 mL, 3.92 mmol) was added quickly and the reaction mixture was heated at 50° C. for 30 min. LC-MS showed that the starting material was completely consumed. The reaction mixture was cooled to room temperature and then diluted with EtOAc (75 mL). The solution was then dried over sodium sulfate, filtered, concentrated and purified by flash chromatography eluting with 0-100% EtOAc in hexanes to give 2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (211 mg, 1.033 mmol, 79% yield) as a colorless oil. MS (M+1) m / z: 205.2 (M+H). + ;LC retention time 0.93[C]

[0220] [ka]

[0221] Step 2: To a solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (238 mg, 1.136 mmol) and 2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (211 mg, 1.033 mmol) in THF (7 mL) was added lithium bis(trimethylsilyl)amide (1M in THF, 2.58 mL, 2.58 mmol) in a dropwise fashion (<5 min) via syringe and the reaction was stirred until complete by LCMS (~15 min). Saturated ammonium chloride (aq) was added to quench remaining base. The reaction was then partitioned between EtOAc and water. The aqueous layer was extracted 1x with ethyl acetate and the organic layers were combined and washed with saturated ammonium chloride (aq) (1x) and brine (1x). Drying over anhydrous sodium sulfate and concentration gave a residue which was chromatographed on a silica gel column eluting with 0-100% EtOAc in hexane to give 6-chloro-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (420 mg, 1.003 mmol, 97% yield) as a pale yellow solid. MS (M+1) m / z: 377.3 (M+H). + ;LC retention time 1.33[C]

[0222] [ka]

[0223] Step 3: A mixture of 6-chloro-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40 mg, 0.106 mmol), Xantphos (12.28 mg, 0.021 mmol), and 1-methyl-1H-pyrazol-3-amine·HCl (35.4 mg, 0.265 mmol) in dioxane (1.3 mL) was degassed by bubbling nitrogen through it for 5 min. Cesium carbonate (138 mg, 0.425 mmol) and Pd2(dba)3 (9.72 mg, 10.62 μmol) were then added, the vessel was sealed, and the reaction mixture was stirred at 130° C. for 6 h. LC-MS showed the reaction was complete. The reaction mixture was diluted to 2 mL with DMF, filtered, and purified by preparative HPLC to give 4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)-6-((1-methyl-1H-pyrazol-3-yl)amino)pyridazine-3-carboxamide (7.7 mg, 0.016 mmol, 14.87% yield). MS(M+1) m / z: 438.2(M+H). + ;LC retention time 1.05[C]; 1 H NMR (500MHz, DMSO-d6) δ 11.04(s,1H), 10.18(brs,1H), 9.06(s,1H), 8.14(s,1H), 7.72(brd,J=7.6Hz,1H), 7.64- 7.54(m,3H), 7.35(t,J=7.8Hz,1H), 6.14(brs,1H), 4.24(s,3H), 3.73(s,3H), 3.69(s,3H)

[0224] Example 26 [ka]

[0225] [ka]

[0226] Step 1: A mixture of 6-chloro-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (420 mg, 1.115 mmol), (4-methoxyphenyl)methanamine (765 mg, 5.57 mmol), and potassium fluoride (194 mg, 3.34 mmol) in NMP (2.5 mL) was stirred at 120° C. for 2 h. The reaction was complete by LC-MS and was diluted to 150 mL with ethyl acetate and washed with water (1×), 10% aqueous LiCl (2×), and brine (1×). After drying over anhydrous sodium sulfate, the organic layer was filtered and concentrated to give a residue that was applied to a 40 g ISCO column and eluted with 0-100% EtOAc in hexanes. The pure fractions were concentrated to give 4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-6-((4-methoxybenzyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (265 mg, 0.555 mmol, 49.8% yield) as an off-white solid. MS (M+1) m / z: 478.4 (M+H). + ;LC retention time 1.10[C]; 1 H NMR (400MHz, chlorochrome-d) δ 10.84-10.67(m,1H), 8.11(s,1H), 8.06(s,1H), 7.72(dd,J=6.7, 2.8Hz,1H), 7.26-7.25(m,1H), 7.25-7.22(m,1H), 7.13-7.06 (m,2H), 6.88(d,J=8.7Hz,2H), 6.09(s,1H), 5.24(brs,1H), 4.43(d,J=5.6Hz,2H), 4.27(s,3H), 3.85-3.81(m,3H), 3.70(s,3H)

[0227] [ka]

[0228] Step 2: A mixture of 4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-6-((4-methoxybenzyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (265 mg, 0.555 mmol) in 1,2-dichloroethane (3 mL) and trifluoroacetic acid (1.5 mL) was warmed to 60° C. and stirred for 120 min. The mixture was concentrated to a solid and coevaporated from dichloroethane (3×). The residue was dissolved in 150 mL of DCM and the solution was transferred to a separatory funnel and washed with 1.5 M potassium phosphate solution (2×) and with brine (1×). Drying over anhydrous sodium sulfate and concentration gave 6-amino-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (169 mg, 0.449 mmol, 81% yield) as a light tan solid which was used without further purification. MS(M+1) m / z: 358.2(M+H). + ;LC retention time 0.92[C]

[0229] [ka]

[0230] Step 3: A solution of 6-amino-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (26 mg, 0.073 mmol), cis-2-methylcyclopropane-carboxylic acid (9.47 mg, 0.095 mmol), and 1-propanephosphonic anhydride (50% solution in DMF, 139 mg, 0.218 mmol) and TEA (0.051 mL, 0.364 mmol) in DMF (1 mL) was stirred at 40° C. overnight, when LC-MS showed the reaction to be complete. The mixture was diluted to 2 mL with DMF, filtered, and purified by preparative HPLC to give 4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)-6-((1R,2S)-2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide (3.5 mg, 7.96 μmol, 10.95% yield). MS(M+1) m / z: 440.2(M+H). + ;LC retention time 1.16[C]; 1 H NMR (500MHz, DMSO-d6) δ 11.20(s,1H), 11.02(s,1H), 9.13(s,1H), 8.17(s,1H), 8.12(s,1H), 7.70(d,J=7.3Hz,1H), 7.49(d,J=7.0Hz,1H), 7.31(t,J=8.1Hz,1H) , 4.24(s,3H), 3.66(s,3H), 2.13-2.06(m,1H), 1.35-1.27(m,1H), 1.07(d,J=6.4Hz,3H), 0.99(td,J=8.0, 3.8Hz,1H), 0.81-0.76(m,1H)

[0231] Example 27 [ka]

[0232] [ka]

[0233] Step 1: A stirred mixture of 4,5-dibromo-2-cyclopropyl-2H-1,2,3-triazole (Intermediate 8, Step 1, 545 mg, 2.043 mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (509 mg, 2.043 mmol) and PdCl2(dppf)-dichloromethane adduct (83 mg, 0.102 mmol) in dioxane (12 mL) was degassed by bubbling nitrogen through the mixture for 5 min. 2M K3PO4(aq) (3.06 mL, 6.13 mmol) was added quickly and the reaction mixture was heated at 100° C. for 120 min. After 2 h, LC-MS showed the starting material was completely consumed. The reaction mixture was cooled to room temperature and then diluted with EtOAc (75 mL). The solution was then dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel chromatography eluting with 0-100% EtOAc in hexanes. Pure fractions were concentrated to give 3-(5-bromo-2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-methoxyaniline as a yellow oil. This material was carried on directly to the next step. MS(M+1) m / z: 309.0 / 311.0(M+H). + ;LC retention time 1.19[C]

[0234] [ka]

[0235] Step 2: A mixture of 3-(5-bromo-2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-methoxyaniline (126 mg, 0.408 mmol), tricyclohexylphosphane (12.57 mg, 0.045 mmol), palladium(II) acetate (4.57 mg, 0.020 mmol) and 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane (162 mg, 1.141 mmol) in toluene (3 mL) was purged with nitrogen for 1 min. 2M K3PO4(aq) (1.121 mL, 2.242 mmol) was added and the reaction mixture was heated at 100° C. for 36 h. The organic layer was concentrated onto Celite and chromatographed on a 12 g ISCO column eluting with 0-50% EtOAc in hexanes. The pure fractions were concentrated to give 3-(2-cyclopropyl-5-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyaniline (51 mg, 0.209 mmol, 51.2% yield, 2 steps). MS (M+1) m / z: 245.2 (M+H). + ;LC retention time 1.01[C]

[0236] [ka]

[0237] Step 3: To a solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (48.0 mg, 0.230 mmol) and 3-(2-cyclopropyl-5-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyaniline (51 mg, 0.209 mmol) in THF (2.3 mL) was added lithium bis(trimethylsilyl)amide (0.626 mL, 0.626 mmol) in a dropwise fashion (<5 min) via syringe and the reaction was stirred until complete by LCMS (~15 min). Saturated ammonium chloride (aq) was added to quench remaining base. The reaction was then partitioned between EtOAc and water. The aqueous layer was extracted 1x with ethyl acetate, then the organic layers were combined and washed with saturated ammonium chloride (aq) (1x) and brine (1x). After drying over anhydrous sodium sulfate and concentration, the residue was chromatographed on a 12 g ISCO column and eluted with 0-100% EtOAc in hexanes. Pure fractions were concentrated to give 6-chloro-4-((3-(2-cyclopropyl-5-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (27 mg, 0.065 mmol, 31.0% yield) as a pale yellow solid. MS (M+1) m / z: 417.1 (M+H). + ;LC retention time 1.510[C]

[0238] [ka]

[0239] Step 4: A mixture of 6-chloro-4-((3-(2-cyclopropyl-5-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (27 mg, 0.065 mmol), Xantphos (7.49 mg, 0.013 mmol), and cyclopropanecarboxamide (27.6 mg, 0.324 mmol) in dioxane (1.3 mL) was degassed by bubbling N2 through it for 5 min. Cesium carbonate (84 mg, 0.259 mmol) and Pd2(dba)3 (5.93 mg, 6.48 μmol) were added, the vessel was sealed, and the reaction was stirred at 130 °C for 2 h. The reaction was complete by LC-MS. The mixture was diluted to 2 mL with DMF, filtered, and purified by preparative HPLC. The pure fractions were concentrated to give 6-(cyclopropanecarboxamido)-4-((3-(2-cyclopropyl-5-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (6.7 mg, 0.014 mmol, 22.22% yield). MS (M+1) m / z: 466.3 (M+H). + ;LC retention time 1.19[C]; 1 H NMR (500MHz, DMSO-d6) δ 11.30(s,1H), 10.93(s,1H), 9.10(s,1H), 8.13(s,1H), 7.51(d,J=7.3Hz,1H), 7.30-7.25(m,1H), 7.23-7.20(m,1H), 4.11 -4.06(m,1H), 3.42(s,3H), 2.19(s,3H), 2.11-2.02(m,1H), 1.23-1.18(m,2H), 1.11-1.05(m,2H), 0.82(brd,J=5.5Hz,4H)

[0240] Example 28 [ka]

[0241] [ka]

[0242] A mixture of 6-chloro-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (44 mg, 0.117 mmol), Xantphos (13.51 mg, 0.023 mmol), and ethyl carbamate (52.0 mg, 0.584 mmol) in dioxane (1.3 mL) was degassed by bubbling nitrogen through it for 5 min. Cesium carbonate (152 mg, 0.467 mmol) and Pd2(dba)3 (10.69 mg, 0.012 mmol) were then added, the vessel was sealed, and the reaction was stirred at 130° C. for 2 h. The reaction was complete by LC-MS. The mixture was diluted to 2 mL with DMF, then filtered and purified by preparative HPLC. The pure fractions were concentrated to give ethyl (5-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)carbamate (9.2 mg, 0.021 mmol, 18.35% yield). MS(M+1) m / z: 430.1(M+H). + ;LC retention time 1.11[C]; 1 H NMR (500MHz, DMSO-d6) δ 10.99(s,1H), 10.72(s,1H), 9.12(s,1H), 8.13(s,1H), 7.87(s,1H), 7.71(d,J=7.9Hz,1H), 7.50(brd,J= 7.3Hz,1H), 7.31(t,J=7.9Hz,1H), 4.24(s,3H), 4.13(q,J=7.2Hz,2H), 3.67(s,3H), 1.22(t,J=7.0Hz,3H)

[0243] Example 29 [ka]

[0244] [ka]

[0245] To a solution of 6-amino-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (20 mg, 0.056 mmol) and 1-propanephosphonic anhydride in 50% DMF (107 mg, 0.168 mmol) in DMF (1 mL) and TEA (0.039 mL, 0.280 mmol) was added (1S,2R)-2-fluorocyclopropane-1-carboxylic acid (11.65 mg, 0.112 mmol) and then stirred at 60° C. for 2 h, at which time LC-MS indicated the reaction was complete. The mixture was diluted to 2 mL with DMF, filtered, and purified by preparative HPLC. Concentration gave 6-((1S,2R)-2-fluorocyclopropane-1-carboxamide)-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (7.7 mg, 0.017 mmol, 29.6% yield). MS (M+1) m / z: 444.2 (M+H). + ;LC retention time 1.22[C]; 1 H NMR (500MHz, DMSO-d6) δ 11.48(brs,1H), 11.01(s,1H), 9.17(s,1H), 8.12(s,1H), 8.09(s,1H), 7.71(d,J=7.3Hz,1H), 7.46(brd,J=7.9Hz,1H), 7.29(t, J=7.9Hz,1H), 5.00-4.80(m,1H), 4.24(s,3H), 3.66(s,3H), 2.68-2.58(m,1H), 1.61-1.48(m,1H), 1.25(dq,J=13.3, 6.4Hz,1H)

[0246] Example 30 [ka]

[0247] [ka]

[0248] To a solution of 6-amino-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (30 mg, 0.084 mmol) and 1-propanephosphonic anhydride in 50% DMF (160 mg, 0.252 mmol) in DMF (1 mL) and TEA (0.059 mL, 0.420 mmol) was added (1S,2R)-2-methylcyclopropane-1-carboxylic acid (21.01 mg, 0.210 mmol), and the resulting mixture was stirred at 50° C. overnight, at which time LC-MS indicated the reaction was complete. It was diluted to 2 mL with DMF, then filtered and purified by preparative HPLC. The pure fractions were concentrated to give 4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)-6-((1S,2R)-2-methylcyclopropane-1-carboxamido)-pyridazine-3-carboxamide (12.8 mg, 0.029 mmol, 34.7% yield). MS(M+1) m / z: 440.4(M+H) + ;LC retention time 1.20[C]; 1 H NMR (500MHz, DMSO-d6) δ 11.21(s,1H), 11.02(s,1H), 9.14(s,1H), 8.17(s,1H), 8.12(s,1H), 7.70(d,J=7.9Hz,1H), 7.49(brd,J=7.3Hz,1H), 7.31(t,J=7.8Hz,1H), 4.24(s,3H), 3.66(s,3H), 2.13-2.06(m,1H), 1.36-1.27(m,1H), 1.07(d,J=6.1Hz,3H), 0.99(td,J=7.8, 3.7Hz,1H), 0.78(brd,J=5.5Hz,1H)

[0249] Example 31 [ka]

[0250] [ka]

[0251] To a solution of 6-amino-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (30 mg, 0.084 mmol) and 1-1-propanephosphonic anhydride in 50% DMF (160 mg, 0.252 mmol) in DMF (1 mL) and TEA (0.059 mL, 0.420 mmol) was added 2,2-difluorocyclopropane-1-carboxylic acid (15.37 mg, 0.126 mmol) and the resulting mixture was stirred at 50° C. for 1 h, at which time LC-MS indicated the reaction was complete. The mixture was diluted to 2 mL with DMF, filtered, and purified by preparative HPLC. The pure fractions were concentrated to give 6-(2,2-difluorocyclopropane-1-carboxamido)-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (10.3 mg, 0.022 mmol, 26.3% yield). MS (M+1) m / z: 462.4 (M+H). + ;LC retention time 1.28[C]; 1 H NMR (500MHz, DMSO-d6) δ 11.53(s,1H), 11.02(s,1H), 9.17(s,1H), 8.12(s,1H), 8.09(s,1H), 7.72(d,J=7.6Hz,1H), 7.48(d, J=7.9Hz,1H), 7.32(t,J=7.9Hz,1H), 4.24(s,3H), 3.66(s,3H), 3.07-2.99(m,1H), 2.07-1.97(m,2H)

[0252] Example 32 [ka]

[0253] [ka]

[0254] Step 1: 3-Amino-5-bromo-4-methoxybenzoate A mixture of methyl 3-bromo-4-methoxy-5-nitrobenzoate (1000 mg, 3.45 mmol) and tin(II) chloride dihydrate (3112 mg, 13.79 mmol) in 35 ml of EtOAc was heated at reflux for 1 h. After cooling to room temperature, the reaction mixture was diluted with 35 ml of EtOAc and transferred to a separatory funnel whereupon it was washed with 2.5 N NaOH (3x50 ml), water (50 ml) and brine (25 ml). After drying over anhydrous sodium sulfate, the organic layer was concentrated to give methyl 3-amino-5-bromo-4-methoxybenzoate (823 mg, 3.16 mmol, 92% yield) as an off-white oil. MS(M+1) m / z: 260.4 / 262.4(M+H) + ;LC retention time 0.96[E]; 1 H NMR (400MHz, DMSO-d6) δ 7.32(d,J=2.0Hz,1H), 7.24(d,J=2.0Hz,1H), 5.58(s,2H), 3.80(s,3H), 3.71(s,3H)

[0255] [ka]

[0256] Step 2: Methyl 3-amino-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate A stirred mixture of (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (73.2 mg, 0.577 mmol), methyl 3-amino-5-bromo-4-methoxybenzoate (100 mg, 0.384 mmol) and PdCl2(dppf)-CH2Cl2-adduct (15.70 mg, 0.019 mmol) in dioxane (2 mL) was degassed by bubbling nitrogen through the mixture for 5 min. 2M K3PO4(aq) (0.577 mL, 1.153 mmol) was added quickly and the reaction mixture was heated at 100° C. for 1 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (30 ml) and brine (20 ml). After drying over anhydrous sodium sulfate solution, the organic layer was concentrated and the residue was chromatographed on a 12 g ISCO silica gel cartridge eluting with a 0-70% EtOAc / hexane gradient. The pure fractions were concentrated to give methyl 3-amino-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate (66 mg, 0.252 mmol, 65.5% yield) as an off-white solid. MS (M+1) m / z: 263.5 (M+H). + ;LC retention time 0.82[E]

[0257] [ka]

[0258] Step 3: Methyl 3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate

[0259] To a solution of methyl 3-amino-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate (66 mg, 0.252 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (52.6 mg, 0.252 mmol) in THF (1.5 mL) at room temperature, LiHMDS (1 M in THF, 0.755 mL, 0.755 mmol) was added dropwise over 10 minutes. The reaction mixture was allowed to stir at room temperature for 30 minutes. After quenching with 2 ml of saturated ammonium chloride solution, the organic liquid was removed. Additional water (approximately 5 ml) was added and the suspension was allowed to stand for 30 minutes. Filtration, rinsing the filter cake with water and ethyl ether, and drying gave methyl 3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate (95 mg, 0.218 mmol, 87% yield) as a tan solid. MS (M+1) m / z: 435.6 (M+H). + ;LC retention time 0.98[E]

[0260] Example 32: A mixture of methyl 3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate (95 mg, 0.218 mmol), cyclopropanecarboxamide (93 mg, 1.092 mmol), Pd2(dba)3·chlorochrome adduct (22.57 mg, 0.022 mmol), Xantphos (25.3 mg, 0.044 mmol) and Cs2CO3 (285 mg, 0.874 mmol) in dioxane (1.5 mL) was degassed by bubbling N2 through the mixture for 5 min. The reaction vessel was sealed and heated at 130 °C for 30 min. The reaction mixture was concentrated to dryness and the residue was suspended in water. The pH was adjusted to about 2 with 1N HCl. The suspension was filtered and washed with water followed by ethyl ether. Upon drying, 101 mg of residue was obtained, of which 20 mg was dissolved in DMSO and purified via preparative LC / MS under the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile:water + ammonium acetate; Mobile phase B: 95:5 acetonitrile:water + ammonium acetate; Gradient: 11% B at 0 min hold, 11-61% B over 20 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was initiated by the MS signal. Fractions containing the desired product were combined and dried via centrifugal evaporation to give methyl 3-((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)-pyridazin-4-yl)amino)-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate (6.2 mg, 28.1% yield). MS(M+1) m / z: 484.1(M+H). + ;LC retention time 1.56[I]; 1H NMR (500MHz, DMSO-d6) δ 11.33(brs,1H), 11.06(brs,1H), 9.15(brs,1H), 8.32(brs,1H), 8.15(s,1H), 8.08(brs,1H), 7.99( brs,1H), 4.25(brs,3H), 3.86(brs,3H), 3.73(brs,3H), 2.06(brd,J=1.2Hz,1H), 0.90-0.71(m,4H)

[0261] Example 33 [ka]

[0262] [ka]

[0263] Step 1: 4-Bromo-2-chloro-3-methyl-6-nitrophenol All operations were performed behind a blast shield: to a solution of 4-bromo-2-chloro-3-methylphenol (500 mg, 2.258 mmol) in acetic acid (7 mL) in an ice bath, nitric acid (70%, 0.216 mL, 3.39 mmol, prepared in ice bath) in AcOH (1.5 mL) was added dropwise over 5 min. After allowing to warm to room temperature, the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between EtOAc (50 mL) and 1.5 M dibasic potassium phosphate solution (50 mL). The basic layer was acidified to pH<1 with 1N HCl and extracted with EtOAc (150 mL). The organic layer was washed with brine (50 mL). The organics were combined, dried over anhydrous magnesium sulfate, and concentrated to give 4-bromo-2-chloro-3-methyl-6-nitrophenol (602 mg, 99% yield) as a yellow solid. 1 H NMR (400 MHz, chlorochrome-d) δ 11.03(s,1H), 8.28(s,1H), 2.62(s,3H)

[0264] [ka]

[0265] Step 2: 1-Bromo-3-chloro-4-methoxy-2-methyl-5-nitrobenzene A mixture of 4-bromo-2-chloro-3-methyl-6-nitrophenol (597 mg, 2.240 mmol), potassium carbonate (1548 mg, 11.20 mmol) and MeI (0.700 mL, 11.20 mmol) in DMF (10 mL) at room temperature was stirred for approximately 60 h. The reaction mixture was partitioned between EtOAc (50 ml) and water (50 ml). The organic layer was washed with 10% LiCl solution (2x50 ml) and brine (50 ml). After drying over anhydrous sodium sulfate, the organic layer was concentrated to give a residue which was chromatographed on a 24 g ISCO silica gel cartridge and eluted with a 0-40% EtOAc / hexane gradient. The pure fractions were concentrated to give 1-bromo-3-chloro-4-methoxy-2-methyl-5-nitrobenzene (510 mg, 81% yield) as a white solid. 1 H NMR (400 MHz, chlorochrome-d) δ 8.00(s,1H), 4.01(s,3H), 2.59(s,3H)

[0266] [ka]

[0267] Step 3: 5-Bromo-3-chloro-2-methoxy-4-methylaniline To a mixture of 1-bromo-3-chloro-4-methoxy-2-methyl-5-nitrobenzene (405 mg, 1.444 mmol) and ammonium chloride (772 mg, 14.44 mmol) in EtOH (10 mL) and water (1.5 mL) at room temperature was added zinc (944 mg, 14.44 mmol) in portions over 10 min. The resulting heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (200 ml) and filtered through Celite. The filtrate was washed with water (100 ml), dried over anhydrous sodium sulfate, and concentrated to give 5-bromo-3-chloro-2-methoxy-4-methylaniline (354 mg, 98% yield) as a yellow oil. 1 H NMR (400 MHz, chlorochrome-d) δ 6.90(s,1H), 3.81(s,5H), 2.39(s,3H)

[0268] [ka]

[0269] Step 4: 3-Chloro-2-methoxy-4-methylaniline To a solution of 5-bromo-3-chloro-2-methoxy-4-methylaniline (283 mg, 1.130 mmol) in THF (10 mL) at -78°C, n-BuLi (2.5 M, 0.994 mL, 2.485 mmol) was added dropwise over 5 min, and the resulting mixture was stirred at -78°C for 15 min. An additional aliquot of n-BuLi (2.5 M, 0.994 mL, 2.485 mmol) was added, and the reaction was allowed to warm slowly to room temperature. The reaction mixture was partitioned between saturated ammonium chloride solution (40 ml) and EtOAc (40 ml). The organic layer was washed with brine (40 ml), dried over anhydrous sodium sulfate, and concentrated to a combined mixture. The residue was chromatographed on a 12 g ISCO silica gel cartridge, eluting with a 0-50% EtOAc / Hexane gradient. The purest fractions were concentrated to give 3-chloro-2-methoxy-4-methylaniline (45 mg, 0.262 mmol, 23.21% yield) as a yellow oil. The material was very impure and was used as is. MS (M+1) m / z: 172.0 (174.0 chlorine pattern) (M+H). + ;LC retention time 0.76[E]

[0270] [ka]

[0271] Step 5: 2-Methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline

[0272] A degassed mixture of 3-chloro-2-methoxy-4-methylaniline (45 mg, 0.262 mmol), (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (66.6 mg, 0.524 mmol), 1,1'-bis(di-t-butylphosphino)ferrocene (12.44 mg, 0.026 mmol) and potassium phosphate tribasic (2M, 0.393 mL, 0.787 mmol) in dioxane (2 mL) was stirred at 100° C. for 90 min. At this point, the reaction mixture was cooled and an additional ½ aliquot of boronic acid, catalyst and base was added and the reaction was degassed and heated at 100° C. for an additional 30 min. After cooling, the reaction mixture was partitioned between EtOAc (30 mL) and brine (30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to a residue which was chromatographed on a 4 g ISCO silica gel cartridge eluting with a 0-100% EtOAc / Hexanes gradient. Pure fractions were concentrated to give 2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (14 mg, 0.064 mmol, 24.46% yield) as a yellow oil (impurity). MS (M+1) m / z: 219.1 (M+H). + ;LC retention time 0.61[E]

[0273] [ka]

[0274] Step 6: 6-chloro-4-((2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide To a solution of 2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (14 mg, 0.064 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (20.11 mg, 0.096 mmol) in THF (0.75 mL) at room temperature was added LiHMDS (1 M in THF, 0.289 mL, 0.289 mmol) dropwise over 10 min. The reaction mixture was allowed to stir at room temperature for 30 min. After quenching with 2 ml of saturated ammonium chloride solution, the reaction mixture was partitioned between EtOAc (30 ml) and saturated ammonium chloride solution (20 ml). The organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated to give a brown solid, which was chromatographed on a 4 g ISCO silica gel cartridge and eluted with a 0-100% EtOAc / hexane gradient. The pure fractions were concentrated to give 6-chloro-4-((2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (20 mg, 0.051 mmol, 80% yield) as a light yellow solid. MS (M+1) m / z: 391.3 (M+H). + ;LC retention time 1.00[E]

[0275] Example 33: 6-(cyclopropanecarboxamido)-4-((2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide A mixture of 6-chloro-4-((2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (20 mg, 0.051 mmol), cyclopropanecarboxamide (8.71 mg, 0.102 mmol), Pd2(dba)3·chlorochrome adduct (5.29 mg, 5.12 μmol), Xantphos (5.92 mg, 10.23 μmol) and Cs2CO3 (66.7 mg, 0.205 mmol) in dioxane (0.5 mL) was degassed by bubbling N2 through the mixture for 5 min. The reaction vessel was sealed and heated at 130 °C for 45 min. The reaction mixture was diluted with DMF. The mixture was filtered through a 0.45 micron nylon filter and the filtrate was purified via preparative LC / MS under the following conditions: Column: Xbridge C18, 200mmx19mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; Gradient: 13% B hold for 0 min, 13-53% B over 20 min, then 100% B hold for 0 min; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was initiated by the MS signal. Fractions containing the desired product were combined and dried via centrifugal evaporation to give 6-(cyclopropanecarboxamido)-4-((2-methoxy-4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (8.4 mg, 37.4%). MS (M+1) m / z: 440.3 (M+H). + ;LC retention time 1.48[I]; 1H NMR (500MHz, DMSO-d6) δ 11.28(s,1H), 10.79(s,1H), 9.09(s,1H), 8.08(s,1H), 7.86(s,1H), 7.39(d,J=8.2Hz,1H), 7.1 6(d,J=8.2Hz,1H), 4.22(s,3H), 3.41(s,3H), 2.19(s,3H), 2.12-2.04(m,1H), 0.87-0.77(m,4H)

[0276] Example 34 [ka]

[0277] [ka]

[0278] Step 1: Isopropyl 3-bromo-4-methoxy-5-nitrobenzoate To a solution of 3-bromo-4-methoxy-5-nitrobenzoic acid (236 mg, 0.855 mmol), 2-propanol (0.198 mL, 2.56 mmol) and triphenylphosphine (336 mg, 1.282 mmol) in THF (5 mL) at 0° C., DIAD (0.249 mL, 1.282 mmol) was added dropwise over 5 min. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and the residue was chromatographed on a 24 g ISCO silica gel cartridge eluting with a 0-40% EtOAc / hexane gradient. Pure fractions were concentrated to give isopropyl 3-bromo-4-methoxy-5-nitrobenzoate (272 mg, 0.855 mmol, 99% yield) as a yellow oil. The product contains some reduced DIAD by NMR. 1 H NMR (400MHz, chlorochrome-d) δ 8.43(d,J=2.1Hz,1H), 8.37(d,J=2.1Hz,1H), 5.25(m,J=10.3, 6.3Hz,1H), 4.06(s,3H), 1.38(d,J=6.2Hz,6H)

[0279] [ka]

[0280] Step 2: Isopropyl 3-amino-5-bromo-4-methoxybenzoate

[0281] A mixture of isopropyl 3-bromo-4-methoxy-5-nitrobenzoate (272 mg, 0.855 mmol) and tin(II) chloride dihydrate (772 mg, 3.42 mmol) in ethyl acetate (10 mL) was refluxed for 90 min. After cooling to room temperature, the reaction mixture was diluted with 25 ml of EtOAc and transferred to a separatory funnel. The organic layer was washed with 2.5 N NaOH (3x30 ml), water (30 ml) and brine (30 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give an oil which was chromatographed on a 12 g ISCO silica gel cartridge eluting with a 0-70% EtOAc / Hex gradient. Pure fractions were concentrated to give isopropyl 3-amino-5-bromo-4-methoxybenzoate as a colorless oil. 1 H NMR (400MHz, chlorochrome-d) δ 7.59(d,J=2.0Hz,1H), 7.35(d,J=2.0Hz,1H), 5.20(dt,J=12.5, 6.2Hz,1H), 4.01(brs,2H), 3.86(s,3H), 1.34(d,J=6.2Hz,6H)

[0282] [ka]

[0283] Step 3: Isopropyl 3-amino-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate A stirred mixture of (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (94 mg, 0.743 mmol), isopropyl 3-amino-5-bromo-4-methoxybenzoate (153 mg, 0.531 mmol), PdCl2(dppf)-CH2Cl2 adduct (21.68 mg, 0.027 mmol) and 2M K3PO4(aq) (0.796 mL, 1.593 mmol) in dioxane (4 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction mixture was heated at 100° C. for 1 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (50 ml) and brine (20 ml). After drying over anhydrous sodium sulfate, the organic layer was concentrated and the residue was chromatographed on a 24 g ISCO silica gel cartridge eluting with a 0-100% EtOAc / hexane gradient. The pure fractions were concentrated to give isopropyl 3-amino-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate (57 mg, 0.196 mmol, 37.0% yield) as a tan solid. MS (M+1) m / z: 291.0 (M+H). + ;LC retention time 0.84[E]

[0284] [ka]

[0285] Step 4: Isopropyl 3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate To a solution of isopropyl 3-amino-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate (57 mg, 0.196 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (65.7 mg, 0.314 mmol) in THF (2 mL) at room temperature, LiHMDS (1 M in THF, 0.785 mL, 0.785 mmol) was added dropwise over 10 min. The reaction mixture was allowed to stir at room temperature for 30 min. After quenching with 2 ml of saturated ammonium chloride solution, the reaction mixture was partitioned between saturated ammonium chloride solution (20 ml) and EtOAc (20 ml). The organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated to give a residue that was chromatographed on a 12 g ISCO silica gel cartridge, eluting with a 0-70% EtOAc / Hex gradient. The pure fractions were concentrated to give isopropyl 3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate (71 mg, 78% yield) as a white solid. MS (M+1) m / z: 463.1 (465.1 chlorine pattern) (M+H). + ;LC retention time 0.97[E]

[0286] Example 34: 3-((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate A mixture of isopropyl 3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate (40 mg, 0.086 mmol), cyclopropane-carboxamide (36.8 mg, 0.432 mmol), Pd2(dba)3·chloroform adduct (8.93 mg, 8.64 μmol), Xantphos (10.00 mg, 0.017 mmol) and Cs2CO3 (113 mg, 0.346 mmol) in dioxane (0.6 mL) was degassed by bubbling N2 through the mixture for 5 min. The reaction vessel was sealed and heated at 130 °C for 30 min. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC. The pure fractions were concentrated to give isopropyl 3-((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(2-methyl-2H-1,2,3-triazol-4-yl)benzoate (17.5 mg; 39.6%). MS(M+1) m / z: 512.2(M+H) + ;LC retention time 1.83[I]; 1 H NMR (500MHz, DMSO-d6) δ 11.36(s,1H), 11.22(s,1H), 9.16(s,1H), 8.27(d,J=2.0Hz,1H), 8.22(s,1H), 8.17(s,1H), 8.03(d,J=2.0Hz,1H) , 5.15(quin,J=6.2Hz,1H), 4.26(s,3H), 3.73(s,3H), 2.15-2.01(m,1H), 1.32(d,J=6.2Hz,6H), 0.89-0.74(m,4H)

[0287] Example 35 [ka]

[0288] [ka]

[0289] Step 1: (3-bromo-4-methoxy-5-nitrophenyl)methanol To a solution of methyl 3-bromo-4-methoxy-5-nitrobenzoate (1000 mg, 3.45 mmol) in dioxane (18 mL) and water (7.5 mL) at room temperature was added sodium borohydride (913 mg, 24.13 mmol) in portions over 10 minutes, and the resulting mixture was allowed to stir at room temperature overnight.

[0290] The reaction mixture was cooled to 0° C. and 1N HCl was added slowly to minimize gas evolution. When gas evolution ceased, the mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue which was chromatographed on a 24 g ISCO silica gel cartridge eluting with a 0-100% EtOAc / hexanes gradient. Pure fractions were concentrated to give (3-bromo-4-methoxy-5-nitrophenyl)methanol (406 mg, 1.549 mmol, 44.9% yield) as a light yellow solid. 1 H NMR (400 MHz, chlorochrome-d) δ 7.83-7.79 (m, 1H), 7.78-7.74 (m, 1H), 4.72 (d, J = 5.8 Hz, 2H), 4.01 (s, 3H), 1.90 (t, J = 5.8 Hz, 1H)

[0291] [ka]

[0292] Step 2: 1-Bromo-2-methoxy-5-(methoxymethyl)-3-nitrobenzene To a solution of (3-bromo-4-methoxy-5-nitrophenyl)methanol (200 mg, 0.763 mmol) in THF at 0° C. was added sodium hydride (60% in mineral oil, 61.0 mg, 1.526 mmol) in portions over 5 min. The reaction turned dark brown. After stirring for 30 min, MeI (0.095 mL, 1.526 mmol) was added and stirring was continued for 90 min while allowing to warm to room temperature. At this point, the reaction was quenched with water and partitioned between water (40 ml) and EtOAc (40 ml). The organic layer was washed with brine (25 ml), dried over anhydrous sodium sulfate, and concentrated to a residue which was chromatographed on a 24 g ISCO silica gel cartridge eluting with a 0-100% EtOAc / Hexane gradient. The pure fractions were concentrated to give 1-bromo-2-methoxy-5-(methoxymethyl)-3-nitrobenzene (83 mg, 39.4% yield) as a colorless oil. 1 H NMR (400 MHz, chlorochrome-d) δ 7.77 (d, J = 2.1 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 4.44 (s, 2H), 4.01 (s, 3H), 3.43 (s, 3H)

[0293] [ka]

[0294] Step 3: 3-Bromo-2-methoxy-5-(methoxymethyl)aniline A mixture of 1-bromo-2-methoxy-5-(methoxymethyl)-3-nitrobenzene (82 mg, 0.297 mmol) and tin(II) chloride dihydrate (268 mg, 1.188 mmol) in ethyl acetate (3 mL) was heated at reflux temperature for 1 h. After cooling to room temperature, the reaction mixture was diluted with 20 ml of EtOAc and transferred to a separatory funnel. The organic layer was washed with 2.5 M NaOH (2x25 ml), water (25 ml) and brine (25 ml). After drying over anhydrous sodium sulfate, the organic layer was concentrated and the residue was chromatographed on a 4 g ISCO silica gel cartridge eluting with a 0-70% EtOAc / hexane gradient. Pure fractions were concentrated to give 3-bromo-2-methoxy-5-(methoxymethyl)aniline (36 mg, 49.3% yield) as a light yellow oil. MS(M+1) m / z: 245.9 / 247.9(M+H) + ;LC retention time 0.83[E]

[0295] [ka]

[0296] Step 4: 2-Methoxy-5-(methoxymethyl)-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline A stirred mixture of (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (36.1 mg, 0.284 mmol), 3-bromo-2-methoxy-5-(methoxymethyl)aniline (35 mg, 0.142 mmol), PdCl2(dppf)-CH2Cl2 adduct (5.81 mg, 7.11 μmol) and 2M K3PO4(aq) (0.213 mL, 0.427 mmol) in dioxane (1 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction mixture was heated at 100° C. for 0.75 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (50 ml) and brine (20 ml). After drying over anhydrous sodium sulfate solution, the organic layer was concentrated and the residue was chromatographed on a 4 g ISCO silica gel cartridge eluting with a 0-100% EtOAc / hexane gradient. The pure fractions were concentrated to give 2-methoxy-5-(methoxymethyl)-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (22 mg, 62.3% yield) as a yellow oil. MS (M+1) m / z: 249.1 (M+H). + ;LC retention time 0.69[E]

[0297] [ka]

[0298] Step 5: 6-chloro-4-((2-methoxy-5-(methoxymethyl)-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide To a solution of 2-methoxy-5-(methoxymethyl)-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (22 mg, 0.089 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (37.0 mg, 0.177 mmol) in THF (1 mL) at room temperature, LiHMDS (1 M in THF, 0.354 mL, 0.354 mmol) was added dropwise over 10 min. The reaction mixture was allowed to stir at room temperature for 30 min. After quenching with 2 ml of saturated ammonium chloride solution, the reaction mixture was partitioned between saturated ammonium chloride solution (20 ml) and EtOAc (20 ml). The organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated to give a residue that was chromatographed on a 4 g ISCO silica gel cartridge, eluting with a 0-100% EtOAc / Hex gradient. The pure fractions were concentrated to give 6-chloro-4-((2-methoxy-5-(methoxymethyl)-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (25 mg, 0.059 mmol, 67.0% yield) as a white solid. MS (M+1) m / z: 421.0 (M+H). + ;LC retention time 0.89[E]

[0299] Example 35: 6-(cyclopropanecarboxamido)-4-((2-methoxy-5-(methoxymethyl)-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide A mixture of 6-chloro-4-((2-methoxy-5-(methoxymethyl)-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (25 mg, 0.059 mmol), cyclopropanecarboxamide (25.3 mg, 0.297 mmol), Pd2(dba)3·chloroform adduct (6.14 mg, 5.94 μmol), Xantphos (6.87 mg, 0.012 mmol) and Cs2CO3 (77 mg, 0.238 mmol) in dioxane (0.5 mL) was degassed by bubbling N2 through the mixture for 5 min. The reaction vessel was sealed and heated at 130 °C for 30 min. The reaction mixture was diluted with DMSO, filtered and purified by preparative HPLC. The product was concentrated to give 6-(cyclopropane-carboxamido)-4-((2-methoxy-5-(methoxymethyl)-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (16.3 mg; 57.7%). MS(M+1) m / z: 470.0(M+H) + ;LC retention time 1.46[I]; 1 H NMR (500MHz, DMSO-d6) δ 11.29(s,1H), 10.95(s,1H), 9.13(s,1H), 8.10(d,J=9.0Hz,2H), 7.67(d,J=1.8Hz,1H), 7.39(d,J=1 .7Hz,1H), 4.42(s,2H), 4.23(s,3H), 3.64(s,3H), 3.30(s,3H), 2.14-2.00(m,1H), 0.87-0.73(m,4H)

[0300] Example 36 [ka]

[0301] [ka]

[0302] Step 1: (See also Intermediate 19) To a solution of 4,5-dibromo-1H-1,2,3-triazole (3.5 g, 15.43 mmol) in DMF (40 mL) at -10°C (in ice-water bath) was added potassium carbonate (4.69 g, 33.9 mmol). After stirring for 15 min, iodomethane (1.929 mL, 30.9 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight at which point it was quenched with 10 mL of water. The mixture was extracted with EtOAc (2x50 ml) and then the organic layers were combined and washed with 10% aqueous LiCl and brine. After drying over anhydrous sodium sulfate, the organic layers were filtered and concentrated to give a residue that was loaded onto a 40 g silica gel column and purified by flash chromatography eluting with 0-100% ethyl acetate in hexanes. Concentration of pure fractions afforded 4,5-dibromo-2-methyl-2H-1,2,3-triazole (2.17 g, 58.4% yield) as a white crystalline solid. LC retention time 1.24 [C] [desired dibromo product does not ionize]

[0303] [ka]

[0304] Step 2: (See also Intermediate 19) To a solution of 4,5-dibromo-2-methyl-2H-1,2,3-triazole (2.55 g, 10.59 mmol) in ether (18 mL) cooled to -20°C was slowly added isopropylmagnesium chloride (2M in THF, 17.47 mL, 34.9 mmol). The reaction was cooled and stirred at -20°C for 30 minutes. The reaction mixture was allowed to warm to 0°C for 2 hours. After quenching with saturated ammonium chloride solution, the mixture was extracted with ether (2x50 ml). The organic layers were combined and washed with brine (1x). After drying over anhydrous sodium sulfate, the organic layer was filtered, concentrated and purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexanes. Pure fractions were concentrated to give 4-bromo-2-methyl-2H-1,2,3-triazole (1.13 g, 65.9% yield) as a yellow oil. MS(M+1) m / z:188.1(M+H) + ;LC retention time 0.87[C]

[0305] [ka]

[0306] Step 3: (See also Intermediate 19) To 4-bromo-2-methyl-2H-1,2,3-triazole (1.59 g, 9.82 mmol) in THF (20 mL) cooled to 10° C. was slowly added isopropylmagnesium chloride-lithium chloride complex (1.3 M in THF, 15.10 mL, 19.63 mmol). The reaction was stirred cold for 2 h and then cooled to −20° C. Trimethyl borate (3.29 mL, 29.4 mmol) was added and the resulting mixture was stirred for 1 h. After quenching with 1N HCl, the mixture was extracted with ethyl acetate (1×). The organic layer was washed with brine (1×), dried over anhydrous sodium sulfate, filtered, and concentrated to give (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (899 mg, 72.2% yield) as a white solid. LC retention time 0.95[C]; 1H NMR (400MHz, DMSO-d6) δ 8.31(brs,2H), 7.89(s,1H), 4.16(s,3H)

[0307] [ka]

[0308] Step 4: A stirred mixture of (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (100 mg, 0.788 mmol), 4-bromo-3-methoxypyridin-2-amine (80 mg, 0.394 mmol) and PdCl2(dppf)-dichloromethane adduct (16.09 mg, 0.020 mmol) in dioxane (2 mL) was degassed by bubbling nitrogen through the mixture for 5 min. 2M K3PO4(aq) (0.591 mL, 1.182 mmol) was added quickly and the reaction mixture was heated at 100° C. for 30 min. The reaction turned dark almost immediately. LC-MS showed the starting material was completely consumed. The reaction mixture was cooled to room temperature and then diluted with EtOAc (75 mL). The solution was then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash chromatography eluting with 0-100% EtOAc in hexanes. Pure fractions were concentrated to give 3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (45 mg, 54.5% yield) as a yellow oil. MS (M+1) m / z: 206.1 (M+H). + ;LC retention time 0.60[C]

[0309] [ka]

[0310] Step 5: To a solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (48.1 mg, 0.230 mmol) and 3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (45 mg, 0.219 mmol) (repurified) in THF (2 mL) was added lithium bis(trimethylsilyl)amide (0.548 mL, 0.548 mmol) in a dropwise fashion (<5 min) via syringe and stirred until the reaction was complete by LCMS. Saturated ammonium chloride (aqueous) was added to quench the remaining base, at which time a solid crashed out of solution. The solid was the desired product. The reaction solution was partitioned between ethyl acetate and water. The aqueous layer was extracted 1x with ethyl acetate, then the organic layers were combined and washed with saturated ammonium chloride (aqueous) (1x) and brine (1x). The organic layers were then dried over anhydrous sodium sulfate, filtered and concentrated. No desired product was found in the residue. The solid that was filtered and dried was the only product. The solid was dried to give 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (37 mg, 44.7% yield) as an off-white solid. MS(M+1) m / z: 378.1(M+H) + ;LC retention time 1.445[C]

[0311] [ka]

[0312] Step 6: A mixture of 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (37 mg, 0.098 mmol), Xantphos (11.33 mg, 0.020 mmol), and cyclopropanecarboxamide (41.7 mg, 0.490 mmol) in dioxane (1.5 mL) was degassed by bubbling nitrogen through it for 5 min. Cesium carbonate (128 mg, 0.392 mmol) and Pd2(dba)3 (8.97 mg, 9.79 μmol) were added, the vessel was sealed, and the reaction was stirred at 130° C. for 2 h. The reaction was complete by LC-MS. The reaction mixture was diluted to 2 mL with DMF, filtered, and purified by preparative HPLC. The pure fractions were concentrated to give 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (11.5 mg, 27.3% yield). MS (M+1) m / z: 427.1 (M+H). + ;LC retention time 1.16[C]; 1 H NMR (500MHz, DMSO-d6) δ 12.41(s,1H), 11.33(s,1H), 9.85(s,1H), 9.24(s,1H), 8.31(s,1H), 8.15(d,J=5.2Hz,1H ), 7.47(d,J=5.5Hz,1H), 4.27(s,3H), 3.82(s,3H), 2.19-2.09(m,1H), 0.97-0.83(m,4H)

[0313] Alternative synthesis of Example 36: 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0314] [ka]

[0315] [ka]

[0316] Step 1: 2-Fluoro-3-methoxypyridin-4-yl)boronic acid: To a solution of 2-fluoro-3-methoxypyridine (0.5 g, 3.93 mmol) in THF at -78°C was added TMEDA (1.25 ml, 8.26 mmol) and n-BuLi (1.88 ml, 4.72 mmol). The mixture was stirred for 2 hours while being warmed from -78°C to -55°C, at which point the reaction mixture was cooled back to -78°C and triisopropylborate (1.370 ml, 5.90 mmol) was added. The mixture was stirred for 2 hours while being warmed from -78°C to -55°C, at which point it was quenched with water (2 ml) and allowed to warm to room temperature. The mixture was concentrated under vacuum and additional water (20 ml) was added. The resulting mixture was washed with ether (20 ml) and the separated aqueous layer was acidified to pH with AcOH. The aqueous layer was extracted with EtOAc (2x20ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give 2-fluoro-3-methoxypyridin-4-yl)boronic acid (650mg; 97% yield). MS (M+1) m / z: 172.1 (M+H). + ;LC retention time 0.66 min [H]; 1 H NMR (400 MHz, chlorochrome-d) δ 7.93 (dd, J = 4.7, 1.7 Hz, 1H), 7.55 (dd, J = 4.7, 1.4 Hz, 1H), 6.25-5.41 (m, 2H), 4.09 (d, J = 3.3 Hz, 3H)

[0317] [ka]

[0318] Step 2: 2-Fluoro-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine: A stirred mixture of 4-bromo-2-methyl-2H-1,2,3-triazole (shown in Intermediate 19 and in the first method) (281 mg, 1.738 mmol), (2-fluoro-3-methoxypyridin-4-yl)boronic acid (270 mg, 1.580 mmol) and PdCl2(dppf)-CH2Cl2 adduct (64.5 mg, 0.079 mmol) in dioxane (6.9 mL) was degassed by bubbling nitrogen through for 5 min. 2M K3PO4(aq) (2.4 mL, 4.74 mmol) was added quickly and the reaction mixture was heated at 80° C. for 1 h. The reaction turned dark almost immediately. The mixture was diluted with EtOAc (20 mL) and filtered through a Celite pad. The filter cake was washed with EtOAc (2x) and the organic layers were combined, washed with brine (20ml), dried over sodium sulfate and concentrated under vacuum to give a residue which was purified on an ISCO column (24g, AcOEt / Hexanes=0-50%, gradient time=15min, flow rate=35ml / min). Pure fractions were concentrated and dried to give 2-fluoro-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine (245mg; 74.5% yield). MS(M+1) m / z: 209.1(M+H) + ;LC retention time 0.81 min [H]; 1 H NMR (400MHz, chlorochrome-d) δ 8.15(s,1H), 7.91(dd,J=5.2, 1.5Hz,1H), 7.75(d,J=5.2Hz,1H), 4.27(s,3H), 4.02(d,J=2.6Hz,3H)

[0319] [ka]

[0320] Step 3: 3-Methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine: A stirred mixture of 2-fluoro-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine (50 mg, 0.240 mmol), O-methylhydroxylamine·HCl (80 mg, 0.961 mmol) in n-BuOH (1044 μl) was stirred at 100 °C under N2 for 4 h. After cooling, the solid MeONH2·HCl was filtered off and washed with EtOAc (2x1 ml). The filtrate and washings were combined and extracted with 1N HCl (2x2 ml), the acidic layer was washed with EtOAc (2x1 ml) and basified with Na2CO3. The resulting mixture was extracted with EtOAc (2x3 ml), the organic layers were combined, washed with brine (2 ml), dried over anhydrous sodium sulfate and concentrated to a residue that was used as is. To a mixture of the residue in ethanol (1.5 ml) and AcOH (0.2 ml) was added zinc (62.8 mg, 0.961 mmol). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete and the mixture was filtered and concentrated in vacuo to give a residue which was dissolved in EtOAc (10 ml) and washed with half-saturated NaHCO3 (10 ml) and brine (5 ml). Drying over anhydrous sodium sulfate and concentration gave 3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (45 mg; 80% yield). MS (M+1) m / z: 206.1 (M+H) + ;LC retention time 0.69 min [H]; 1 H NMR (400MHz, chlorochrome-d) δ 8.09(s,1H), 7.87(d,J=5.3Hz,1H), 7.17(d,J=5.3Hz,1H), 4.74(brs,2H), 4.27(s,3H), 3.73(s,3H)

[0321] [ka]

[0322] Step 4: 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)pyridazine-3-carboxylic acid: To a solution of 3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (7 g, 34.1 mmol) and lithium 4,6-dichloropyridazine-3-carboxylate·H2O (mentioned in patent: US 10,899,745) (12.22 g, 54.6 mmol) in 2-Me-THF (227 ml) (fresh bottle) at room temperature, 1M LiHMDS in THF (153 ml, 153 mmol) was added dropwise over 30 min. The internal temperature rose to 34° C. and the reaction mixture was heated in a 45° C. oil bath for 2 h (internal temperature gradually rose to 43° C.) and then heated with stirring at 50° C. for 30 min. After cooling, the mixture was quenched with water (50 ml) at 10-15° C. and then concentrated under vacuum to remove most of the solvent. 800 ml of water and citric acid (16.38 g, 85 mmol) were added to the residue and the mixture was stirred at 10° C. for 30 min. The resulting suspension was filtered and the filter cake was washed with water (3×), (slowly filtered), air-dried o / n and then dried under vacuum at 50° C. for 6 h to give 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)pyridazine-3-carboxylic acid (10.7 g; 87% yield). MS (M+1) m / z: 362.0 (364.0, chloro pattern) (M+H). + LC retention time 0.89 min [H]

[0323] [ka]

[0324] Step 5: 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)pyridazine-3-carboxylic acid: In a 2000 ml 4-neck flask, 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)pyridazine-3-carboxylic acid (31 g, 86 mmol) and cyclopropanecarboxamide (21.88 g, 257 mmol) were suspended in 2-Me-THF (714 ml). DBU (19.38 ml, 129 mmol) and sodium trifluoroacetate (98%, 17.48 g, 129 mmol) were added and the mixture was purged with N2 for 5 min. (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (2.091 g, 3.77 mmol) and allylpalladium chloride dimer (minimum 98%, 0.627 g, 1.714 mmol) were then added and the reaction mixture was purged with N2 for an additional 5 min and then heated under N2 with mechanical stirring at 80-82 °C (internal temperature) for 18 h. LC-MS showed that the starting material had been consumed. The reaction mixture was cooled to room temperature and a solution of citric acid (52.7 g, 274 mmol) in 300 ml ACN and 600 ml water was added. The mixture was stirred for 1 h and then allowed to stand for 1 h. The suspension was filtered and the filter cake was washed with ACN (2x), water (3x), and ACN (2x). Drying overnight at 45° C. in a vacuum oven gave 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)pyridazine-3-carboxylic acid (31.3 g; 89% yield). MS (M+1) m / z: 411.1 (M+H). + LC retention time 0.76 minutes [H]

[0325] [ka]

[0326] Step 6: N-(6-methoxy-7-(2-methyl-2H-1,2,3-triazol-4-yl)-11-oxo-11H-pyrido[1',2':1,2]pyrimido[5,4-c]pyridazin-3-yl)cyclopropanecarboxamide: A mixture of 1-methylimidazole (1.259 ml, 15.79 mmol) and 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)pyridazine-3-carboxylic acid (10.8 g, 26.3 mmol) in NMP / ACN (202 ml) (146 / 56 ml) was stirred at room temperature for 20 minutes. 1-Hydroxybenzotriazole hydrate (97%, 2.252 g, 13.16 mmol) wetted with no more than 14% by weight water and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (7.06 g, 36.8 mmol) were added and the reaction mixture was heated in an oil bath at 65°C for 1.5 hours (internal temperature briefly rose to 74.5°C and remained above 70°C). The reaction mixture was cooled to room temperature and stirred for 30 minutes, after which point it was cooled in an ice-water bath until the internal temperature was 6°C. After standing for 30 minutes, the suspension was filtered and the filter cake was washed with acetonitrile until no color emerged through the washings. Drying at 45° C. for approximately 60 hours gave N-(6-methoxy-7-(2-methyl-2H-1,2,3-triazol-4-yl)-11-oxo-11H-pyrido[1',2':1,2]pyrimido[5,4-c]pyridazin-3-yl)cyclopropanecarboxamide (8.78 g; 85% yield). MS (M+1) m / z: 393.1 (M+H). + ;LC retention time 0.82 min [H]; 1 H NMR (400MHz, DMSO-d6) δ 11.95(s,1H), 8.75(d,J=7.7Hz,1H), 8.43(s,1H), 8.39(s,1H), 7.60(d,J=7. 7Hz,1H), 4.31(s,3H), 4.14(s,3H), 2.24-2.12(m,1H), 0.94(d,J=6.1Hz,4H)

[0327] [ka]

[0328] Step 7: 6-(cyclopropanecarboxamide)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide:

[0329] A mixture of N-(6-methoxy-7-(2-methyl-2H-1,2,3-triazol-4-yl)-11-oxo-11H-pyrido[1',2':1,2]pyrimido[5,4-c]pyridazin-3-yl)cyclopropanecarboxamide (8.77 g, 22.35 mmol), anhydrous DMSO (160 ml), DIEA (17.57 ml, 101 mmol) and methane-d3-amine·HCl (6.31 g, 89 mmol) was stirred in a pressure vessel at 100 °C (oil bath) for 15 h. After cooling to room temperature, the mixture was filtered twice through glass filter paper and the vessel was washed with DMSO (2x5 ml and 3 ml). The clear filtrate was heated to 60 °C and water was added slowly with stirring. A total of 21 ml of water was added. The mixture was allowed to slowly cool down to room temperature and stirred for 1 h. The resulting suspension was filtered and the filter cake was washed with DMSO (2x6ml) and ACN (3x15ml). After drying, the crude product was mixed with 75ml of anhydrous DMSO and stirred at 95°C under N2 for 1 hour. After cooling to 60°C, 10ml of water was added slowly with stirring. After the water addition, the mixture was stirred, cooled to room temperature, filtered and the solid was washed with DMSO (5ml) and acetonitrile (3x20ml). Drying under vacuum at 45°C for approximately 60 hours gave N-(6-methoxy-7-(2-methyl-2H-1,2,3-triazol-4-yl)-11-oxo-11H-pyrido[1',2':1,2]pyrimido[5,4-c]pyridazin-3-yl)cyclopropanecarboxamide (7.8g; 82%). See other syntheses mentioned above for analytical data.

[0330] Example 37 [ka]

[0331] [ka]

[0332] Step 1:

[0333] A mixture of 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (60 mg, 0.159 mmol), Xantphos (18.38 mg, 0.032 mmol), and tert-butyl carbamate (74.4 mg, 0.635 mmol) in dioxane (1.3 mL) was degassed by bubbling nitrogen through it for 5 min. Cesium carbonate (207 mg, 0.635 mmol) and Pd2(dba)3 (14.54 mg, 0.016 mmol) were then added, the vessel was sealed, and the reaction was stirred at 130° C. for 2 h. The reaction was complete by LC-MS. The reaction mixture was directly purified on a small cartridge and silica gel column eluting with 0-15% MeOH in DCM. Pure fractions were concentrated to give 6-amino-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (23 mg, 0.064 mmol, 40.4% yield). MS (M+1) m / z: 359.1 (M+H). + ;LC retention time 0.99[C]

[0334] [ka]

[0335] Step 2: A solution of (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (8.02 mg, 0.077 mmol) and 1-propanephosphonic anhydride (50% in DMF, 123 mg, 0.193 mmol) in DMF (1 mL) and TEA (0.045 mL, 0.321 mmol) was added to 6-amino-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (23 mg, 0.064 mmol) and the resulting mixture was stirred at 50° C. for 2 h. LC-MS showed the reaction was complete. The mixture was diluted to 2 mL with DMF, filtered, purified by preparative HPLC, and the pure fractions were concentrated to give 6-((1S,2S)-2-fluorocyclopropane-1-carboxamido)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (4.6 mg, 15.47% yield). MS(M+1) m / z: 445.1(M+H). + ;LC retention time 1.078[C]; 1 H NMR (500MHz, DMSO-d6) δ 12.43(s,1H), 11.38(s,1H), 9.86(s,1H), 9.26(s,1H), 8.31(s,1H), 8.18(d,J=5.2Hz,1H), 7.48(d,J=5.5Hz ,1H), 5.11-4.90(m,1H), 4.28(s,3H), 3.82(s,3H), 2.40-2.30(m,1H), 1.81-1.67(m,1H), 1.37-1.16(m,1H)

[0336] Example 38 [ka]

[0337] [ka]

[0338] Step 1: To a solution of 2,2-dimethylcyclopropane-1-carboxylic acid (65 mg, 0.569 mmol) and oxalyl chloride (0.065 mL, 0.740 mmol) in DCM (5 mL) at room temperature was added 3 drops of DMF. Gas evolution was observed. The reaction mixture was stirred at room temperature for 45 min. Volatiles were removed under vacuum. The crude acid chloride was dissolved in DCM (5 mL) and added slowly to a solution of ammonia (0.5 M in dioxane, 7.12 mL, 2.85 mmol) and diisopropylethylamine (0.298 mL, 1.708 mmol). After stirring at room temperature for 1 h, the reaction mixture was concentrated to a solid. Drying overnight afforded impure 2,2-dimethylcyclopropane-1-carboxamide (55 mg, 85% yield) as a white solid. Used directly in the next step.

[0339] [ka]

[0340] Step 2: A mixture of 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (20 mg, 0.053 mmol), 2,2-dimethyl-cyclopropane-1-carboxamide (23.96 mg, 0.212 mmol), Pd2(dba)3 (5.47 mg, 5.29 μmol), Xantphos (6.13 mg, 10.59 μmol) and cesium carbonate (69.0 mg, 0.212 mmol) in dioxane (1.0 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction vessel was sealed and heated at 130° C. for 90 min. The reaction mixture was diluted with DMF, filtered through a 0.45 micron nylon filter, and the filtrate was purified by preparative HPLC. Pure fractions were concentrated to give 6-(2,2-dimethylcyclopropane-1-carboxamido)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (4.2 mg, 17.46% yield). MS(M+1) m / z: 455.3(M+H). + ;LC retention time 1.29[C]; 1 H NMR (500MHz, DMSO-d6) δ 12.38(s,1H), 11.14(s,1H), 9.84(s,1H), 9.22(s,1H), 8.29(s,1H), 8.16(d,J=5.2Hz,1H), 7.47(d,J=5.2Hz,1H), 4.27(s,3H) , 3.87-3.79(m,3H), 2.00(brd,J=6.4Hz,1H), 1.17(brd,J=10.7Hz,6H), 1.07(brt,J=3.8Hz,1H), 0.87(brdd,J=7.5, 3.5Hz,1H)

[0341] Example 39 [ka]

[0342] [ka]

[0343] A mixture of 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (20 mg, 0.053 mmol), 1,1-dimethylurea (23.32 mg, 0.265 mmol), Pd2(dba)3 (5.47 mg, 5.29 μmol), Xantphos (6.13 mg, 10.59 μmol) and cesium carbonate (69.0 mg, 0.212 mmol) in dioxane (1.0 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction vessel was sealed and heated at 130° C. for 90 min. The reaction mixture was diluted with DMF. The mixture was filtered through a 0.45 micron nylon filter and the filtrate was purified by preparative HPLC. Pure fractions were concentrated to give 6-(3,3-dimethylureido)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (4 mg, 16.98% yield). MS(M+1) m / z: 430.2(M+H). + ;LC retention time 1.07[C]; 1 H NMR (500MHz, DMSO-d6) δ 12.34(brs,1H), 9.49(s,1H), 9.14(brs,1H), 8.30(brd,J=0.8Hz,1H), 8.15(brd,J=5. 2Hz,1H), 7.46(brd,J=5.2Hz,1H), 4.27(s,3H), 3.81(s,3H), 3.50(m,1H), 3.00(s,6H)

[0344] Example 40 [ka]

[0345] [ka]

[0346] Step 1: To a solution of (1S,2R)-2-methylcyclopropane-1-carboxylic acid (82 mg, 0.819 mmol) in THF (2 mL) was added first TEA (0.171 mL, 1.229 mmol) and then ethyl chloroformate (0.087 mL, 0.901 mmol). After stirring for 1 h, a white precipitate formed. This precipitate was filtered and then suspended in 5 mL of THF. The suspension was added to ammonia in THF (0.4 M, 10.24 mL, 4.10 mmol) and stirred at 25° C. overnight. The solvent was removed under vacuum to give a white solid that was used as is.

[0347] This method was utilized to prepare the carboxamides used in the preparation of each of the analogs listed below.

[0348] [ka]

[0349] Step 2: A mixture of 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (20 mg, 0.053 mmol), (1S,2R)-2-methylcyclopropane-1-carboxamide (20.99 mg, 0.212 mmol), Pd2(dba)3 (5.47 mg, 5.29 μmol), Xantphos (6.13 mg, 10.59 μmol) and cesium carbonate (69.0 mg, 0.212 mmol) in dioxane (1.0 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction vessel was sealed and heated at 130° C. for 20 min. The reaction mixture was diluted with DMF. The mixture was filtered through a 0.45 micron nylon filter and the filtrate was purified by preparative HPLC. Pure fractions were concentrated to give 4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)-6-((1S,2R)-2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide (3.1 mg, 13.29% yield). MS(M+1) m / z: 441.2(M+H). + ;LC retention time 1.21[C]; 1 H NMR (500MHz, DMSO-d6) δ 12.41(s,1H), 11.22(s,1H), 9.85(s,1H), 9.24(s,1H), 8.31(s,1H), 8.17(brd,J=4.9Hz,1H), 7.48(brd,J=4.9Hz,1H), 4.36-4 .31(m,1H), 4.28(s,3H), 3.82(s,3H), 2.15(brd,J=6.1Hz,1H), 1.39-1.29(m,1H), 1.15(brd,J=5.8Hz,3H), 1.07-0.83(m,1H)

[0350] Example 41 [ka]

[0351] [ka]

[0352] A mixture of 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (20 mg, 0.053 mmol), (1R,2R)-2-methylcyclopropane-1-carboxamide (20.99 mg, 0.212 mmol), Pd2(dba)3 (5.47 mg, 5.29 μmol), Xantphos (6.13 mg, 10.59 μmol) and cesium carbonate (69.0 mg, 0.212 mmol) in dioxane (1.0 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction vessel was sealed and heated at 130° C. for 90 min. The reaction mixture was diluted with DMF. The mixture was filtered through a 0.45 micron nylon filter and the filtrate was purified by preparative HPLC. Pure fractions were concentrated to give 4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)-6-((1R,2R)-2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide (4.6 mg, 18.86% yield). MS(M+1) m / z: 441.2(M+H). + ;LC retention time 1.25[C]; 1 H NMR (500MHz, DMSO-d6) δ 12.35(s,1H), 11.21(s,1H), 9.81(s,1H), 9.19(s,1H), 8.28(s,1H), 8.14(brd,J=5.5Hz,1H), 7.46(brd,J=4.9Hz,1H), 4.25(s,3H) ), 3.84-3.77(m,1H), 3.62-3.54(m,3H), 1.84(brdd,J=8.1, 4.4Hz,1H), 1.40-1.27(m,1H), 1.11(brd,J=5.8Hz,3H), 0.74(brs,1H)

[0353] Example 42 [ka]

[0354] [ka]

[0355] A mixture of 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (50 mg, 0.132 mmol), (1S,2S)-2-methylcyclopropane-1-carboxamide (52.5 mg, 0.529 mmol), Pd2(dba)3 (13.67 mg, 0.013 mmol), Xantphos (15.32 mg, 0.026 mmol) and cesium carbonate (172 mg, 0.529 mmol) in dioxane (1.0 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction vessel was sealed and heated at 130° C. for 30 min. The reaction mixture was diluted with DMSO. The mixture was filtered through a 0.45 micron nylon filter and the filtrate was purified by preparative HPLC. Pure fractions were concentrated to give 4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)-6-((1S,2S)-2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide (6.7 mg, 10.92% yield). MS(M+1) m / z: 441.2(M+H). + ;LC retention time 1.22[C]; 1H NMR (500MHz, DMSO-d6) δ 12.39(s,1H),11.23(s,1H),9.82(s,1H),9.23(s,1H),8.29(s,1H),8.14(d,J=5.3Hz,1H),7.46(d,J=5.3Hz,1H),4.27(s,3H),3 .81(s,3H), 1.88(dt,J=7.9,4.2Hz,1H), 1.37-1.28(m,1H), 1.12(d,J=6.0Hz,3H), 1.10(brs,1H), 0.73(brdd,J=6.1,4.3Hz,1H)

[0356] Example 43

change

[0357]

change

[0358] A mixture of 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (50 mg, 0.132 mmol), (1R,2R)-2-ethylcyclopropane-1-carboxamide (59.9 mg, 0.529 mmol), Pd2(dba)3 (13.67 mg, 0.013 mmol), Xantphos (15.32 mg, 0.026 mmol) and cesium carbonate (172 mg, 0.529 mmol) in dioxane (1.0 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction vessel was sealed and heated at 130° C. for 15 min. The reaction mixture was diluted with DMSO. The mixture was filtered through a 0.45 micron nylon filter and the filtrate was purified by preparative HPLC. Pure fractions were concentrated to give 6-((1R,2R)-2-ethylcyclopropane-1-carboxamido)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (14.2 mg, 0.031 mmol, 23.61% yield). MS(M+1) m / z: 455.3(M+H). + ;LC retention time 1.33[C]; 1 H NMR (500MHz, DMSO-d6) δ 12.40(s,1H), 11.25(s,1H), 9.84(s,1H), 9.24(s,1H), 8.30(s,1H), 8.15(d,J=5.3Hz,1H), 7.47(d,J=5.3Hz,1H), 4.27(s,3H), 3.81( s,3H), 1.93(dt,J=7.8, 3.7Hz,1H), 1.45-1.38(m,1H), 1.33-1.26(m,2H), 1.12-1.05(m,1H), 0.97(t,J=7.1Hz,3H), 0.80-0.73(m,1H)

[0359] Example 44 [ka]

[0360] [ka]

[0361] A mixture of 6-chloro-4-((4-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-3-methoxypyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40 mg, 0.099 mmol), (1S,2S)-2-fluorocyclopropane-1-carboxamide (40.8 mg, 0.396 mmol), Pd2(dba)3 (10.23 mg, 9.90 μmol), Xantphos (11.46 mg, 0.020 mmol) and cesium carbonate (129 mg, 0.396 mmol) in dioxane (1.0 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction vessel was sealed and heated at 130° C. for 20 min. The reaction mixture was diluted with DMSO. The mixture was filtered through a 0.45 micron nylon filter and the filtrate was purified by preparative HPLC. Pure fractions were concentrated to give 4-((4-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-3-methoxypyridin-2-yl)amino)-6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (8.2 mg, 0.016 mmol, 16.01% yield). MS(M+1) m / z: 471.2(M+H). + ;LC retention time 1.31[C]; 1 H NMR (500MHz, DMSO-d6) δ 12.43(s,1H), 11.38(s,1H), 9.87(s,1H), 9.25(s,1H), 8.30(s,1H), 8.17(d,J=5.3Hz,1H), 7.48(d,J=5.3Hz,1H), 5.10-4.89(m,1H), 4.26( dt,J=7.4, 3.7Hz,1H), 3.81(s,3H), 2.39-2.29(m,1H), 1.78-1.67(m,1H), 1.33-1.28(m,2H), 1.27-1.21(m,1H), 1.17(dd,J=7.4, 2.2Hz,2H)

[0362] Example 45 [ka]

[0363] [ka]

[0364] A solution of 4-fluorobutanoic acid (8.88 mg, 0.084 mmol) and 1-propanephosphonic anhydride (50% in DMF, 80 mg, 0.126 mmol) in DMF (0.5 mL) was stirred for 20 min and then added to a mixture of 6-amino-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (15 mg, 0.042 mmol) and DIEA (0.037 mL, 0.209 mmol) in 0.5 mL DMF. The resulting mixture was stirred at 50° C. overnight. The reaction was incomplete. A solution of 10 mg of 4-fluorobutanoic acid and 200 μL of 50% 1-propanephosphonic anhydride in DMF was prepared and stirred for 20 minutes, then added to the reaction solution and stirring was continued at 50° C. for another night. After stirring for two nights, LC-MS showed the reaction was complete. The reaction mixture was diluted to 2 mL with DMF, filtered, and purified by preparative HPLC. Pure fractions were concentrated to give 6-((1S,2S)-2-fluorocyclopropane-1-carboxamido)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (2.9 mg, 6.50 μmol, 15.52% yield). MS(M+1) m / z: 447.2(M+H) + ;LC retention time 1.08[C]; 1H NMR (500MHz, DMSO-d6) δ 12.38(s,1H), 11.04(s,1H), 9.87(s,1H), 9.21(s,1H), 8.29(s,1H), 8.17(d,J=5.2Hz,1H), 7.48(d,J=5.3Hz,1H) , 4.55(t,J=6.1Hz,1H), 4.45(brt,J=5.9Hz,1H), 4.26(s,3H), 3.80(s,3H), 2.66-2.59(m,2H), 2.07-1.93(m,2H)

[0365] Example 46 [ka]

[0366] [ka]

[0367] Step 1: 4-Bromo-6-methyl-2-nitropyridin-3-ol

[0368] Concentrated sulfuric acid (1 mL) was added dropwise to solid 4-bromo-6-methylpyridin-3-ol (0.267 g, 1.420 mmol) in a flask at -10°C [with salt and ice bath]. Fuming nitric acid (0.063 mL, 1.420 mmol) was then added dropwise. The reaction mixture was stirred overnight allowing the reaction to slowly warm to room temperature. The reaction mixture was poured onto about 50 g of ice. After the ice had melted, the mixture was transferred to a separatory funnel and extracted with DCM (3x50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give 4-bromo-6-methyl-2-nitropyridin-3-ol (165 mg, 0.708 mmol, 49.9% yield) as a yellow solid. 1 H NMR (400 MHz, chlorochrome-d) δ 10.63(s,1H), 7.75(s,1H), 2.57(s,3H)

[0369] [ka]

[0370] Step 2: 4-Bromo-3-methoxy-6-methyl-2-nitropyridine A mixture of 4-bromo-6-methyl-2-nitropyridin-3-ol (160 mg, 0.687 mmol), potassium carbonate (474 ​​mg, 3.43 mmol) and MeI (0.215 mL, 3.43 mmol) in DMF was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc (30 ml) and water (30 ml). The organic layer was washed with 10% LiCl (2x30 ml) and brine (30 ml), dried over anhydrous sodium sulfate and concentrated to give 4-bromo-3-methoxy-6-methyl-2-nitropyridine (133 mg, 0.538 mmol, 78% yield) as a brown solid. MS (M+1) m / z: 247.0 (249.0) (M+H) + ;LC retention time 1.02[E]

[0371] [ka]

[0372] Step 3: 4-Bromo-3-methoxy-6-methylpyridin-2-amine To a solution of 4-bromo-3-methoxy-6-methyl-2-nitropyridine (133 mg, 0.538 mmol) in ethanol (0.6 mL), acetic acid (0.3 mL) and water (0.6 mL) stirred at 0° C., iron powder (210 mg, 3.77 mmol) was added and the resulting mixture was allowed to warm to room temperature and stirred for a total of 2 hours. The reaction mixture was filtered through Celite® and the filter cake was rinsed with EtOAc and water. The filtrate was transferred to a separatory funnel and 50 ml of 1.5 M potassium phosphate dibasic was added. After shaking, the layers were separated and the organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated to give 4-bromo-3-methoxy-6-methylpyridin-2-amine (101 mg, 0.465 mmol, 86% yield) as a cream-colored solid. MS(M+1) m / z:217.0(219.0)(M+H) +;LC retention time 0.64[E]

[0373] [ka]

[0374] Step 4: 3-Methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine A stirred mixture of (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (Intermediate 19) (89 mg, 0.698 mmol), 4-bromo-3-methoxy-6-methylpyridin-2-amine (101 mg, 0.465 mmol) and PdCl2(dppf)-CH2Cl2 adduct (19.00 mg, 0.023 mmol) in dioxane (3.5 mL) was degassed by bubbling nitrogen through the mixture for 5 min. 2M K3PO4(aq) (0.698 mL, 1.396 mmol) was added quickly and the reaction mixture was heated at 100° C. for 0.75 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (30 ml) and brine (20 ml). After drying over anhydrous sodium sulfate solution, the organic layer was concentrated and the residue was chromatographed on a 12 g ISCO silica gel cartridge, eluting with a 0-100% EtOAc / Hexanes gradient. Pure fractions were concentrated to give 3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (75 mg, 0.342 mmol, 73.5% yield) as a light yellow solid. MS (M+1) m / z: 220.2 (M+H). + ;LC retention time 0.68[E]

[0375] [ka]

[0376] Step 5: 6-chloro-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide To a solution of 3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (75 mg, 0.342 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (143 mg, 0.684 mmol) in THF (3 mL) at room temperature, KHMDS (1 M in THF, 1.539 mL, 1.539 mmol) was added dropwise over 10 minutes. The reaction mixture was allowed to stir at room temperature for 30 minutes. After quenching with 2 ml of saturated ammonium chloride solution, the organics were evaporated on a rotovap and the residue was diluted with water. Filtration, rinsing the filter cake with ethyl ether and drying gave 6-chloro-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40 mg, 0.102 mmol, 29.8% yield) as a tan solid. MS (M+1) m / z: 392.2 (M+H). + ;LC retention time 1.13[E]

[0377] Example 46: 6-(cyclopropanecarboxamido)-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide A mixture of 6-chloro-4-((2-methoxy-5-(methoxymethyl)-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (25 mg, 0.059 mmol), cyclopropanecarboxamide (25.3 mg, 0.297 mmol), Pd2(dba)3·chlorochrome adduct (6.14 mg, 5.94 μmol), Xantphos (6.87 mg, 0.012 mmol) and Cs2CO3 (77 mg, 0.238 mmol) in dioxane (0.5 mL) was degassed by bubbling N2 through the mixture for 5 min. The reaction vessel was sealed and heated at 130 °C for 30 min. The reaction mixture was diluted with DMSO and filtered. The filtrate was purified via preparative LC / MS under the following conditions: Column: Xbridge C18, 200 mm x 19 mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; Gradient: 15% B hold for 0 min, 15-55% B over 20 min, then 100% B hold for 0 min; Flow rate: 20 mL / min; Column temperature: 25° C. Fraction collection was initiated by the MS signal. Fractions containing the desired product were combined and dried via centrifugal evaporation to give 6-(cyclopropanecarboxamido)-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (18.3 mg; 40.7% yield). MS(M+1) m / z: 441.2(M+H). + ;LC retention time 1.77[G]; 1 H NMR (500MHz, DMSO-d6) δ 12.33(s,1H), 11.31(s,1H), 10.10(s,1H), 9.24(s,1H), 8.29(s,1H), 7.34(s,1H) ), 4.28(s,3H), 3.79(s,3H), 2.53(brs,3H), 2.22-1.96(m,1H), 1.19-0.84(m,4H)

[0378] The following examples were prepared using methods similar to Example 46.

[0379] Example 47 [ka]

[0380] Example 47: 4-((3-Methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)-6-((1R,2R)-2-methylcyclopropane-1-carboxamide)pyridazine-3-carboxamide. MS(M+1) m / z: 455.3(M+H) + ;LC retention time 1.69[I]; 1 H NMR (400MHz, DMSO-d6) δ 12.31(s,1H), 11.21(s,1H), 10.07(s,1H), 9.23(s,1H), 8.27(s,1H), 7.32(s,1H), 4.26(s,3H), 3.77(s,3H), 2. 47(s,3H), 1.90(dt,J=8.0, 4.2Hz,1H), 1.38-1.25(m,1H), 1.19-1.04(m,4H), 0.72(ddd,J=7.8, 6.2, 3.7Hz,1H)

[0381] Example 48 [ka]

[0382] Example 48: 4-((3-Methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)-6-((1S,2S)-2-methylcyclopropane-1-carboxamide)pyridazine-3-carboxamide. MS(M+1) m / z: 455.3(M+H) + ;LC retention time 1.69[I]; 1H NMR (400MHz, DMSO-d6) δ 12.31(s,1H), 11.21(s,1H), 10.07(s,1H), 9.23(s,1H), 8.27(s,1H), 7.32(s,1H), 4.26(s,3H), 3. 77(s,3H), 2.48(s,3H), 1.95-1.86(m,1H), 1.40-1.25(m,1H), 1.18-1.05(m,4H), 0.77-0.68(m,1H)

[0383] Example 49 [ka]

[0384] [ka]

[0385] Step 1: (E)-Di-tert-butyl ((6-((cyclopropanecarbonyl)imino)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-3-((methyl-d3)carbamoyl)pyridazin-1(6H)-yl)methyl)phosphate To a suspension of 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (550 mg, 1.290 mmol) in DMF (7 mL) was added Cs2CO3 (2521 mg, 7.74 mmol) in one portion. After stirring the reaction mixture at room temperature for 20 min, di-tert-butyl(chloromethyl)phosphate (1668 mg, 6.45 mmol) was added and stirring was continued at room temperature for 24 h. The reaction mixture was poured into ice-cold water (100 mL) and extracted with EtOAc (2x100 mL). The organic layers were combined, washed with saturated brine solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was used as a mixture in the next step.

[0386] [ka]

[0387] Step 2: (E)-tert-butyl ((6-((cyclopropanecarbonyl)imino)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-3-((methyl-d3)carbamoyl)pyridazin-1(6H)-yl)methyl) hydrogen phosphate A solution of (E)-di-tert-butyl ((6-((cyclopropanecarbonyl)imino)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-3-((methyl-d3)carbamoyl)pyridazin-1(6H)-yl)methyl)phosphate (2.1 g, 3.24 mmol) in 32 ml of acetone and 8 ml of AcOH was stirred at 30° C. for 16 h and then at 40° C. for 2 h. The reaction mixture was cooled and diluted with ice water (100 ml) to which NaHCO3 was added until the pH was adjusted between 5 and 6. The resulting mixture was transferred to a separatory funnel and extracted with EtOAc (4×80 ml). The organic layers were combined, washed with half-saturated NaCl (100 ml), dried over anhydrous sodium sulfate, and concentrated to give a residue that was purified using an ISCO column (40 g, solid loading, MeOH / DCM=0-10%, gradient time=20 min, flow rate=40 ml / min). Pure fractions were concentrated to give (E)-tert-butyl ((6-((cyclopropanecarbonyl)imino)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-3-((methyl-d3)carbamoyl)pyridazin-1(6H)-yl)methyl)hydrogen phosphate (1.15 g; 50.2% yield over two steps). MS(M+1) m / z: 593.2(M+H) + LC retention time 0.79 min [H]

[0388] [ka]

[0389] Step 3: (E)-(6-((cyclopropanecarbonyl)imino)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-3-((methyl-d3)carbamoyl)pyridazin-1(6H)-yl)methyl dihydrogen phosphate A solution of (E)-tert-butyl ((6-((cyclopropanecarbonyl)imino)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-3-((methyl-d3)carbamoyl)pyridazin-1(6H)-yl)methyl)hydrogen phosphate (0.88 g, 1.485 mmol) in 5.6 ml of AcOH and 5.6 ml of water was stirred at 45° C. for 5 hours. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature, left for 1 hour and filtered. The solid was washed with water (3x) and vacuum filtered to give (E)-(6-((cyclopropanecarbonyl)imino)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-3-((methyl-d3)carbamoyl)pyridazin-1(6H)-yl)methyl dihydrogen phosphate (680 mg; 85% yield). MS(M+1) m / z: 537.1(M+H). + LC retention time 0.71 min [H]

[0390] [ka]

[0391] Example 48: (E)-(6-((cyclopropanecarbonyl)imino)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-3-((methyl-d3)carbamoyl)pyridazin-1(6H)-yl)methyl dihydrogen phosphate disodium salt To a solution of (E)-(6-((cyclopropanecarbonyl)imino)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-3-((methyl-d3)carbamoyl)pyridazin-1(6H)-yl)methyl dihydrogen phosphate (680 mg, 1.268 mmol) in deionized water (7 ml) and acetonitrile (2 ml) was added NaOH (1N, 2535 μl, 2.54 mmol) dropwise with stirring at room temperature. After stirring for 10 min, the clear pale yellow solution was filtered through an Acrodisc (0.45 μm) syringe filter. The resulting solution was lyophilized overnight to give (E)-(6-((cyclopropanecarbonyl)imino)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-3-((methyl-d3)carbamoyl)pyridazin-1(6H)-yl)methyl dihydrogen phosphate disodium salt (735 mg; 100% yield) as a yellow solid. MS(M+1) m / z: 537.1(M+H). + ;LC retention time 0.71 min [H]; 1 H NMR (400MHz, heavy water) δ 9.26(brs,1H), 8.25(s,1H), 8.11(d,J=5.3Hz,1H), 7.41(d,J=5.3Hz,1H), 5.89( d,J=8.3Hz,2H), 4.28(s,3H), 3.77(s,3H), 2.07-1.74(m,1H), 1.16-0.91(m,4H)

[0392] Intermediate-22: [ka]

[0393] Process-1: To a solution of 4,5-dibromo-2H-1,2,3-triazole (0.5 g, 2.204 mmol) in DMF (3 mL) was added K2CO3 (1.217 g, 8.82 mmol) and 3-bromooxetane (0.302 g, 2.204 mmol). The reaction mixture was stirred in a sealed tube at 80 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with EtOAc (2x50 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by flash column chromatography using 0-10% EtOAc in petroleum ether to give the desired 4,5-dibromo-2-(oxetan-3-yl)-2H-1,2,3-triazole (0.40 g, 1.414 mmol, 64.1% yield) as an oil. GCMS-EI[M] m / z: 282.9(M) + ;GC retention time 7.57 minutes

[0394] Process-2: To a solution of 4,5-dibromo-2-(oxetan-3-yl)-2H-1,2,3-triazole (0.35 g, 1.237 mmol) in THF (3 mL) at -78°C, n-BuLi (0.773 mL, 1.237 mmol) was added dropwise and stirring was continued for 1 h. The reaction mixture was allowed to warm to 0°C, quenched with saturated NH4Cl (10 mL) and extracted with diethyl ether (2x50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure at room temperature to give crude 4-bromo-2-(oxetan-3-yl)-2H-1,2,3-triazole (0.235 g, 1.152 mmol, 93% yield), which was used as is without further purification. 1 H-NMR (400MHz, DMSO-d6): δ 7.66(s,1H), 5.80-5.71(m,1H), 5.21-5.01(m,4H)

[0395] The following intermediates (22a-22b) were prepared in a similar manner to the preparation of intermediate 22. [ka]

[0396] [Table 9]

[0397] Intermediate 23 [ka]

[0398] 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 powder (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. The crude residue was diluted with EtOAc (100 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic layers were combined, dried over anhydrous Na2SO4 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 min [Method A]

[0399] 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 KOAc (2.62 g, 26.7 mmol). The reaction was purged with N2 gas for 5 min, then PdCl2(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 celite pad and the filtrate was washed with water (2x50 mL) and brine (2x50 mL). The organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (25% EtOAc 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 min [Method A]

[0400] Step 3: To a stirred solution of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.31 g, 9.26 mmol) and 4-bromo-2-methyl-2H-1,2,3-triazole (1.50 g, 9.26 mmol) in DME (15 mL) and water (5 mL) was added Na2CO3 (2.45 mg, 23.15 mmol). The reaction mixture was purged with N2 for 5 min and Pd(Ph3P)4 (1.07 g, 0.93 mmol) was added under N2. The reaction mixture was stirred at 90 °C for 6 h. The reaction mixture was filtered through a celite pad and washed with methanol (50 mL). The filtrate was then concentrated under reduced pressure. The crude residue was partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was collected, dried over anhydrous Na2SO4 and concentrated. The crude residue was purified by silica gel column chromatography (50% EtOAc in petroleum ether) to give the desired 2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (1.70 g, 7.67 mmol, 83% yield) as a brown crystalline solid. MS (M+1) m / z: 205.2 (M+H). + LC retention time 1.20 min [Method A]

[0401] The following intermediates (23a-23c) were prepared in a similar manner to the preparation of intermediate 23. [ka]

[0402] [Table 10]

[0403] Intermediate-24: [ka]

[0404] Process-1 In a 250 mL three-neck round bottom flask cooled to -10°C, 4-bromopyridin-3-ol (1.70 g, 9.77 mmol) was added. Concentrated sulfuric acid (5 mL) was added dropwise over 10 min at -10°C with slow stirring under N2 atmosphere. The mixture was kept stirring at the same temperature for 10 min to completely dissolve 4-bromopyridin-3-ol and form a clear solution. Nitric acid (fuming nitric acid, 437 μL, 9.77 mmol) was added dropwise over 10 min at -10°C. The resulting mixture was allowed to gradually (in about 1.5 h) attain room temperature and stirred for 10 h. The reaction mixture was carefully poured into crushed ice (about 150 g). After complete quenching, the reaction mixture was extracted with CHCl (3x50 mL). The resulting organic layer was washed with saturated brine solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 4-bromo-2-nitropyridin-3-ol (1.01 g as crude), which was used in the next step without further purification. GCMS (M) m / z: 218.0 [M] + ;GC retention time 7.36 minutes; 1 H-NMR (400MHz, MeOH-d4): δ 8.00(d,J=4.8Hz,1H), 7.94(d,J=4.8Hz,1H)

[0405] Process-2 A 250 mL three-neck round bottom flask equipped with a stir bar was charged with 4-bromo-2-nitropyridin-3-ol (6 g, 27.4 mmol) and DMF (100 mL). The reaction mixture was stirred at room temperature (about 5 min) to form a clear solution. K2CO3 (7.57 g, 54.8 mmol) was added portionwise to the solution and the mixture was stirred at room temperature for 10 min. Methyl iodide (3.43 mL, 54.8 mmol) was added dropwise over 5 min and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (60 mL) and extracted with EtOAc (3x100 mL). The organic layers were combined and washed successively with ice-cold water (2x100 mL) and saturated brine solution (100 mL). The resulting organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. It was purified by silica gel column chromatography using 0-25% EtOAc in petroleum ether to give 4-bromo-3-methoxy-2-nitropyridine (4.61 g, 71% yield) as an off-white solid. MS (M+1) m / z: 234.9 [M+H] + LC retention time 0.66 min [Method B]

[0406] 1 H-NMR (400MHz, DMSO-d6): δ 8.25(d,J=5.2Hz,1H), 8.20(d,J=5.2Hz,1H), 3.97(s,3H)

[0407] Process-3 A 250 mL three-neck round bottom flask equipped with a stir bar was charged with 4-bromo-3-methoxy-2-nitropyridine (4.70 g, 21.5 mmol), AcOH (20 mL), EtOH (20 mL) and water (10 mL). The mixture was stirred at room temperature (for about 5 min) to form a clear solution. The mixture was cooled to 0° C. Iron powder (12.0 g, 151 mmol) was added portionwise over 10 min at 0° C. The mixture was allowed to warm to room temperature and stirred for 4 h. The mixture was filtered through a Celite pad and washed with EtOAc (100 mL). The filtrate was washed successively with saturated aqueous NaHCO3 (100 mL) and saturated brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica column chromatography (230-400 mesh) using 0% to 60% EtOAc in petroleum ether to give 4-bromo-3-methoxypyridin-2-amine (3.5 g, 80% yield) as an off-white solid. MS (M+1) m / z: 205.0 [M+H] + LC retention time 0.66 min [Method B] 1 H-NMR (400MHz, DMSO-d6): δ 7.54(d,J=5.2Hz,1H), 6.72(d,J=5.2Hz,1H), 3.69(s,3H)

[0408] Intermediate-24 [ka]

[0409] Process-1 To a stirred solution of 4-bromo-2-methyl-2H-1,2,3-triazole (5.0 g, 30.9 mmol) in THF (50 mL) was added isopropylmagnesium chloride-lithium chloride complex (3.17 g, 30.9 mmol) slowly at 0° C. The reaction was stirred at this temperature for 2 h and then further cooled to −20° C. To this solution was added trimethyl borate (0.64 mL, 5.7 mmol) slowly. The reaction mixture was stirred at −20° C. for 1 h and then the reaction mixture was acidified to pH approx. 5 with aqueous 1N HCl. The resulting mixture was stirred at 0° C. for 10 min. The reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was collected, the aqueous layer was extracted again with EtOAc (2×100 mL), the organic layers were combined, washed with brine solution (50 mL), and then dried over anhydrous Na2SO4. The organic solvent was removed under reduced pressure to give the crude product. The resulting crude product was washed with 20 mL of n-pentane to give the desired (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (2.6 g, 66.3% yield) as a white solid. MS (M+1) m / z: 128.0 [M+H] + ;LC retention time 0.66 min [Method B]; 1 H-NMR (400MHz, DMSO-d6): δ 8.34 (s, 2H), 7.89 (s, 1H), 4.12 (S, 3H)

[0410] Process-2 A solution of 4-bromo-3-methoxypyridin-2-amine (0.3 g, 1.478 mmol) in 1,4-dioxane (3 mL) and water (0.5 ml) was added with Cs2CO3 (0.963 g, 2.96 mmol), (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (0.281 g, 2.216 mmol), purged with N2 gas for 5 min, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.085 g, 0.074 mmol), and then heated in a sealed tube at 120° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (25 mL), filtered through a pad of celite, and washed with ethyl acetate (25 mL). The filtrate was washed successively with water (25 mL) and saturated brine solution (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography using 0-30% EtOAc in petroleum ether to give the desired product 3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (0.22 g, 72.6% yield) as a yellow solid. MS(M+1) m / z: 206.2[M+1] + LC retention time 0.36 min [Method A]

[0411] Intermediate 25 [ka]

[0412] Process 1 To a stirred solution of 2-fluoro-3-methoxypyridine (5.0 g, 39.3 mmol) and TMEDA (11.87 mL, 79 mmol) in THF (50 mL) was added n-butyllithium (29.5 mL, 47.2 mmol) at -78°C. It was then stirred at the same temperature for 2 h. Triisopropylborate (13.70 mL, 59.0 mmol) was added to the reaction mixture at -78°C and stirred for 2 h. The reaction mixture was quenched with water (20 mL) and then it was extracted with diethyl ether (2x50 mL). The aqueous layer was acidified with AcOH (pH approx. 4) and extracted with ethyl acetate (2x100 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The desired product (2-fluoro-3-methoxypyridin-4-yl)boronic acid (6 g, 33.7 mmol, 86% yield) was obtained as an off-white solid. MS (M+1) m / z: 172.2 [M+1] + LC retention time 0.63 min [Method J]

[0413] Process 2 To a stirred solution of (2-fluoro-3-methoxypyridin-4-yl)boronic acid (0.35 g, 2.048 mmol) and 4-bromo-2-(methyl-d3)-2H-1,2,3-triazole (0.399 g, 2.416 mmol) in 1,4-dioxane:water (8 mL:2 mL) in a 40 mL sealed tube, K3PO4 (1.304 g, 6.14 mmol) and PdCl2(dppf)·[DCM] (0.167 g, 0.205 mmol) were added and the reaction mixture was degassed with N2 for 10 min. The resulting reaction mixture was heated at 110 °C for 4 h, 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) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue was purified by reverse phase column chromatography (C18 column, ammonium formate method) to give 2-fluoro-3-methoxy-4-(2-(methyl-d3)-2H-1,2,3-triazol-4-yl)pyridine (0.25 g, 1.095 mmol, 53.5% yield) as an off-white solid. MS (M+1) m / z: 212.0 [M+1] + LC retention time 1.50 min [Method J]

[0414] Process 3 To 2-fluoro-3-methoxy-4-(2-(methyl-d3)-2H-1,2,3-triazol-4-yl)pyridine (0.2 g, 0.947 mmol) in an 8 mL pressure release vial was added (2,4-dimethoxyphenyl)methanamine (1.583 g, 9.47 mmol). The resulting reaction mixture was heated at 130° C. for 16 h. After 16 h, the reaction mixture was diluted with ethyl acetate (30 mL), washed with water (2×10 mL) followed by brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The resulting crude product was purified by silica gel column chromatography using 30-40% EtOAc in petroleum ether to give N-(2,4-dimethoxybenzyl)-3-methoxy-4-(2-(methyl-d3)-2H-1,2,3-triazol-4-yl)pyridin-2-amine (220 mg, 0.528 mmol, 55.8% yield) as an off-white solid. MS(M+1) m / z: 359.2[M+1] + LC retention time 1.41 min [Method J]

[0415] Process 4 To a stirred solution of N-(2,4-dimethoxybenzyl)-3-methoxy-4-(2-(methyl-d3)-2H-1,2,3-triazol-4-yl)pyridin-2-amine (0.22 g, 0.614 mmol) in 20 mL of DCM was added TFA (0.142 mL, 1.841 mmol) at 0° C. under nitrogen. The resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the solvent was evaporated under reduced pressure and the resulting crude was diluted with DCM (100 mL), washed with NaHCO3 saturated solution (50 mL) followed by brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude. The resulting crude mixture was washed with n-pentane (25 mL) to give 3-methoxy-4-(2-(methyl-d3)-2H-1,2,3-triazol-4-yl)pyridin-2-amine (100 mg, 0.437 mmol, 71.1% yield) as a light brown solid. MS (M+1) m / z: 209.2 [M+1] + LC retention time 1.44 min [Method B]

[0416] Intermediate-26 [ka]

[0417] Process 1 To a stirred solution of 2-bromo-6-nitrophenol (1 g, 4.59 mmol) and KOH (3.86 g, 68.8 mmol) in acetonitrile (15 mL) and water (5 mL) was added diethyl (bromodifluoro-methyl)phosphonate (1.47 g, 5.50 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was collected, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel (230-400 mesh) column chromatography using 25% EtOAc in petroleum ether as eluent to give the desired 1-bromo-2-(difluoromethoxy)-3-nitrobenzene (1.1 g, 3.86 mmol, 84% yield) as a brown solid. MS(M+1) m / z: 269.0[M+1] + LC retention time: 2.58 min [Method A] 1 H NMR (400MHz, DMSO-d6) δ 8.16(dd,J=1.6, 8.0Hz,1H), 8.11(dd,J=1.4, 8.2Hz,1H), 7.55(t,J=8.0Hz,1H), 7.26(t,J=71.6Hz,1H)

[0418] Process 2 To a stirred solution of 1-bromo-2-(difluoromethoxy)-3-nitrobenzene (1.0 g, 3.73 mmol) in methanol (10 mL) and THF (5 mL) was added ammonium chloride (1.397 g, 26.1 mmol) and zinc powder (3.66 g, 56.0 mmol) at ambient temperature. It was then stirred at room temperature for 16 h. The reaction mixture was filtered through a Celite pad and washed with ethyl acetate (100 mL). The filtrate was collected and concentrated under reduced pressure. The crude product was washed with hexane and dried to give 3-bromo-2-(difluoromethoxy)aniline (900 mg, 3.14 mmol, 84% yield) as a brown solid. MS(M+1) m / z: 239.9[M+1] + LC retention time: 2.35 min [Method A]

[0419] Process 3 To a stirred solution of 3-bromo-2-(difluoromethoxy)aniline (0.8 g, 3.36 mmol) in 1,4-dioxane (15 mL) was added bis(pinacolato)diboron (1.71 g, 6.72 mmol) and KOAc (0.82 g, 8.40 mmol) at ambient temperature. The reaction mixture was degassed under N2 for 5 min. PdCl2(dppf)·[DCM] (549 mg, 0.672 mmol) was added to the reaction mixture and degassed for 5 min. The resulting reaction mixture was heated at 100 °C in a sealed tube for 16 h. The reaction mixture was filtered through a celite pad under reduced pressure and washed with ethyl acetate (100 mL). The crude was concentrated under reduced pressure and used as is without further purification. MS(M+1) m / z: 286.2[M+1] + LC retention time: 2.83 min [Method A]

[0420] Process 4 To a stirred solution of 4-bromo-2-methyl-2H-1,2,3-triazole (0.70 g, 4.32 mmol) in DMA (10 mL) and water (1.0 mL) was added Na2CO3 (1.14 g, 10.80 mmol) and 2-(difluoromethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.85 g, 6.48 mmol) at room temperature, which was then degassed under N2 for 10 min. Tetrakis(triphenyl-phosphine)palladium(0) (1.0 g, 0.864 mmol) was added to the reaction mixture and degassed for 5 min. The reaction mixture was stirred at 100° C. for 16 h in a sealed test tube. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (100 mL). The filtrate was collected, washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel (230-400 mesh) column chromatography using 40% EtOAc in petroleum ether to give 2-(difluoromethoxy)-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (400 mg, 1.332 mmol, 30.8% yield) as a light brown solid. MS(M+1) m / z: 241.1[M+1] + LC retention time 1.45 min [Method B]

[0421] Intermediate-27 [ka]

[0422] Process 1 To a stirred solution of 2-amino-4-bromopyridin-3-ol (5 g, 26.5 mmol) in DCM (80 mL) and N,N-dimethylformamide (5 mL) was added triethylamine (22.12 mL, 159 mmol) followed by pivaloyl chloride (6.38 g, 52.9 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was quenched with water, which was then extracted with DCM (2×200 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel (230-400 mesh) column chromatography using 25% EtOAc in petroleum ether to give 4-bromo-2-pivalamidopyridin-3-yl pivalate (2.7 g, 34.0% yield) as an off-white solid. MS(M+1) m / z:357.2[M+1] + LC retention time 2.27 min [Method A]

[0423] Process 2 To a stirred solution of 4-bromo-2-pivalamidopyridin-3-yl pivalate (2.7 g, 7.56 mmol) in acetonitrile (30 mL) and water (6 mL) was added KOH (6.36 g, 113 mmol) followed by diethyl (bromodifluoromethyl)phosphonate (8.07 g, 30.2 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The crude product was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) column chromatography eluting with 35% ethyl acetate in petroleum ether to give N-(4-bromo-3-(difluoromethoxy)pyridin-2-yl)pivalamide (580 mg, 21.37% yield) as an off-white solid. MS(M+1) m / z:323.0;LC retention time: 1.98 minutes [Method A]

[0424] Process 3 To a stirred solution of N-(4-bromo-3-(difluoromethoxy)pyridin-2-yl)pivalamide (640 mg, 1.981 mmol) and (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (302 mg, 2.377 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added K3PO4 (862 mg, 4.95 mmol) at ambient temperature, which was then degassed under N2 for 10 min. PdCl2(dppf)·[DCM] (323 mg, 0.396 mmol) was added to the reaction mixture. The resulting mixture was degassed for another 5 min and then heated at 100 °C in a sealed tube for 16 h. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (100 mL). The filtrate was collected, washed with brine, dried over anhydrous Na2SO4 and concentrated. The concentrated product was purified by silica gel (230-400 mesh) column chromatography using 40% EtOAc in petroleum ether to give N-(3-(difluoromethoxy)-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)pivalamide (450 mg, 65.7% yield) as an off-white solid. MS (M+1) m / z: 326.2; LC retention time 1.71 min [Method A] 1 H NMR (400MHz, DMSO-d6): δ 9.71(s,1H), 8.44(d,J=4.8Hz,1H), 8.21(s,1H), 7.85(d,J=5.2Hz,1H), 6.87(t,J=73.2Hz,1H), 4.28(s,3H), 1.24(s,9H)

[0425] Process 4 A stirred solution of N-(3-(difluoromethoxy)-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)pivalamide (460 mg, 1.414 mmol) in aqueous 2N HCl (8 mL, 16.00 mmol) was heated at 100 for 6 h. The reaction mixture was then concentrated under reduced pressure. The concentrated crude product was neutralized with 10% NaHCO3 solution and extracted with ethyl acetate (2x50 mL). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel (230-400 mesh) column chromatography using 70% EtOAc in petroleum ether to give 3-(difluoromethoxy)-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (260 mg, 69.4% yield) as an off-white solid. MS(M+1) m / z:242.0;LC retention time 0.77 min [Method A]

[0426] Intermediate-28 [ka]

[0427] Process 1 To a stirred solution of 3-chloro-4-iodo-2-methoxyaniline (3 g, 10.58 mmol) in 1,4-dioxane (60 mL), water (10 mL) in a 250 mL sealed test tube, cyclopropylboronic acid (1.091 g, 12.70 mmol) and K3PO4 (2.246 g, 10.58 mmol) were added followed by PdCl2(dppf)[DCM] (8.64 g, 10.58 mmol). The reaction mixture was degassed with N2 for 10 min. The resulting reaction mixture was heated at 100 °C for 3 h. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (100 mL), filtered through a celite pad and washed with ethyl acetate (200 mL). The filtrate was washed with water (200 mL), followed by brine (200 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue was purified by reverse phase column chromatography (C18 column) using 60% acetonitrile in 0.1% aqueous ammonium formate to give 3-chloro-4-cyclopropyl-2-methoxyaniline (400 mg, 1.922 mmol, 18.17% yield) as a brown liquid. MS(M+1) m / z: 198.0[M+H] + LC retention time 2.21 min [Method A]

[0428] Process 2 To a stirred solution of 3-chloro-4-cyclopropyl-2-methoxyaniline (0.2 g, 1.012 mmol) in 1,4-dioxane (15 mL) and water (3 mL) in a 50 mL sealed test tube, (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (0.257 g, 2.024 mmol) and K2CO3 (0.280 g, 2.024 mmol) were added followed by PdCl2(dtbpf) (0.033 g, 0.051 mmol). The reaction mixture was degassed under N2 for 10 min. The resulting reaction mixture was heated at 120 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), filtered through a celite pad and washed with ethyl acetate (100 mL). The filtrate was washed with water (2x100 mL) followed by brine (100 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue obtained was purified by column chromatography on silica gel (230-400 mesh) using 12-20% EtOAc in petroleum ether to give 4-cyclopropyl-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (50 mg, 0.164 mmol, 16.18% yield) as a tan solid. MS(M+1) m / z: 245.1[M+H] + LC retention time 1.43 min [Method B]

[0429] Intermediate 29 [ka]

[0430] Process 1 To a solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (0.35 g, 1.67 mmol) and 2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (0.41 g, 2.01 mmol) in THF (10 mL) at 0° C., LiHMDS (6.70 mL, 6.70 mmol, 1 M solution in THF) was added dropwise and stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (40% EtOAc in petroleum ether) to give the desired 6-chloro-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (0.37 g, 0.97 mmol, 58.2% yield) as a light brown solid. MS (M+1) m / z: 377.2 (M+H). + LC retention time 2.16 min [Method A]

[0431] The following intermediates (29a-29e) were prepared in a similar manner to the preparation of intermediate 29. [ka]

[0432] [Table 11]

[0433] Example 50 [ka]

[0434] To a stirred solution of 6-chloro-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (150 mg, 0.398 mmol) in 1,4-dioxane (10 mL) in a 50 mL sealed test tube, 1-isopropylimidazolidin-2-one (61.2 mg, 0.478 mmol), Cs2CO3 (130 mg, 0.398 mmol) were added. The reaction mixture was then purged with N2 for 10 min, followed by the addition of 1,1-bis(dicyclohexylphosphino)ferrocene (23.01 mg, 0.040 mmol), Pd2(dba)3 (18.23 mg, 0.020 mmol) and the resulting reaction mixture was allowed to stir at 130° C. for 4 h. After completion of the reaction, the reaction mixture was filtered through a celite pad and washed with ethyl acetate (100 mL). 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-(3-isopropyl-2-oxoimidazolidin-1-yl)-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (100 mg, 52.1% yield) as a white solid. MS(M+1) m / z: 469.2[M+H] + , LC retention time 2.194 min [Method A]; 1 H-NMR (400MHz, DMSO-D6):δ 10.93(s,1H), 9.20(s,1H), 8.30(s,1H), 8.14(s,1H), 7.69(dd,J=1.60, 7.80Hz,1H), 7.49(dd,J=1.20, 7.80Hz,1H), 7.30(t,J=7.60Hz,1H), 4.24(s,3H), 4.13-4.02(m,3H), 3.66(s,3H), 3.46(t,J=7.60Hz,2H), 1.12(d,J=6.80Hz,6H)

[0435] The following examples (51-56) were prepared in a manner similar to the preparation of Example 50.

[0436] [ka]

[0437] [Table 12]

[0438] Example 57 [ka]

[0439] To a stirred solution of 6-chloro-4-((3-methoxy-4-(2-(methyl-d3)-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (0.15 g, 0.150 mmol) in 1,4-dioxane (5 mL) in a 20 mL pressure release vial was added cyclopropanecarboxamide (0.013 g, 0.150 mmol) and Pd2(dba)3 (6.85 mg, 7.48 μmol), 1,1'-bis(dicyclohexylphosphino)-ferrocene (4.33 mg, 7.48 μmol), followed by Cs2CO3 (0.098 g, 0.299 mmol). The reaction mixture was degassed with N2 for 5 min. The resulting reaction mixture was heated at 110° C. for 3 h, cooled to room temperature, diluted with ethyl acetate (50 mL), filtered through a pad of celite and washed with ethyl acetate (100 mL). The filtrate was washed with water (2×50 mL) followed by brine (50 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue was purified by reverse phase column (C18) chromatography using 45-50% water in acetonitrile (0.1% ammonium formate) to give 6-(cyclopropane-carboxamido)-4-((3-methoxy-4-(2-(methyl-d3)-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (21 mg, 0.046 mmol, 30.7% yield) as an off-white solid. MS(M+1) m / z: 430.2 [M+H] + , LC retention time 2.18 min [Method A]; 1 H-NMR (400MHz, DMSO-d6):δ 12.43(s,1H), 11.35(s,1H), 9.86(s,1H), 9.27(s,1H), 8.32(s,1H), 8.15(d,J=5.2 0Hz,1H), 7.47(d,J=5.20Hz,1H), 3.82(s,3H), 2.17-2.09(m,1H), 0.90-0.87(m,4H)

[0440] The following examples (58-60) were prepared in a manner similar to the preparation of Example 57.

[0441] [ka]

[0442] [Table 13]

[0443] [Table 14] [Table 15]

[0444] Example 61 [ka]

[0445] [ka]

[0446] A mixture of 6-chloro-4-((4-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-3-methoxypyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (44 mg, 0.109 mmol), 1,1-dimethylurea (38.4 mg, 0.436 mmol), Pd2(dba)3 (11.26 mg, 10.90 μmol), 1,1'-bis(biscyclohexylphosphino)ferrocene (12.61 mg, 0.022 mmol) and cesium carbonate (142 mg, 0.426 mmol) in dioxane (1.0 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction vessel was sealed and heated at 130° C. for 30 min. No reactant was detected by LCMS. Methanesulfonato(2-dicyclohexyl-phosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (X-phos, 4th generation) (12 mg, 0.014 mmol) was added and the reaction mixture was degassed again and then heated at 125°C for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with DMSO. The mixture was filtered through a 0.45 micron nylon filter and the filtrate was purified by preparative HPLC. - The pure fractions were concentrated to give 4-((4-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-3-methoxypyridin-2-yl)amino)-6-(3,3-dimethylureido)-N-(methyl-d3)pyridazine-3-carboxamide (7.7 mg, 14.17% yield). MS (M+1) m / z: 456.0 (M+H) + ;LC retention time 1.40[I]; 1 H NMR (500MHz, DMSO-d6) δ 12.34(s,1H), 9.48(s,1H), 9.46(s,1H), 9.14(s,1H), 8.30(s,1H), 8.14(d,J=5.3Hz,1H), 7.45(d,J=5 .2Hz,1H), 4.25(tt,J=7.5, 3.7Hz,1H), 3.81(s,3H), 3.00(s,6H), 1.33-1.25(m,2H), 1.19-1.11(m,2H)

[0447] Example 62 [ka] 6-(Cyclopropanecarboxamido)-4-((6-fluoro-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0448] 6-Fluoro-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine [ka]

[0449] Synthesis of 6-fluoro-4-iodopyridin-3-ol (Step 1) In a 100 mL round bottom flask, HCl (1.5 M in H2O, 15 mL) was added to a solution of 2-fluoro-4-iodo-5-methoxymethoxy-pyridine (5 g, 17.67 mmol) in THF (40 mL). The mixture was stirred at 60 °C for 3 h. The mixture was cooled to room temperature and its pH was adjusted to 7 by slow addition of saturated aqueous NaHCO3. The mixture was extracted with EtOAc (3 x 100 mL). The organic layers were combined and washed with saturated brine solution. The resulting organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (4.15 g crude) as a yellow solid, which was used in the next reaction without further purification. MS (EI) m / z 240 [M+1] +

[0450] Synthesis of 6-fluoro-4-iodo-2-nitropyridin-3-ol (Step 2) To a stirred solution of 6-fluoro-4-iodopyridin-3-ol (500 mg, 2.09 mmol) in acetonitrile (20 mL) was added nitronium tetrafluoroborate (1.10 g, 8.37 mmol) at 0° C. The reaction mixture was then stirred at room temperature for 16 h. After completion, ice-cold water (50 mL) was added to the reaction and the mixture was extracted with ethyl acetate (300 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (700 mg). GC-MS (EI) m / z 283 [M+]

[0451] 6-Fluoro-4-iodo-3-methoxy-2-nitropyridine (Step 3) To a stirred solution of 6-fluoro-4-iodo-2-nitropyridin-3-ol (2.8 g, 9.86 mmol) in DMF (10 mL) was added K2CO3 (4.09 g, 29.6 mmol) and methyl iodide (1.850 mL, 29.6 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was added to ice-cold water (100 mL) and extracted with EtOAc (2x200 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was subjected to a neutral alumina column and purified using EtOAc in petroleum ether (0-30%) as the mobile phase to give 6-fluoro-4-iodo-3-methoxy-2-nitropyridine (650 mg, 1.963 mmol, 19.91% yield) as a white solid.

[0452] 6-Fluoro-4-iodo-3-methoxypyridin-2-amine (Step 4) To a stirred solution of 6-fluoro-4-iodo-3-methoxy-2-nitropyridine (650 mg, 2.181 mmol) in EtOH (4 mL), AcOH (4 mL) & H2O (2 mL) was added iron powder (853 mg, 15.27 mmol) slowly at 0°C. The reaction was stirred at room temperature for 1 h. After complete disappearance of starting material (monitored by TLC), the reaction mixture was filtered and the filtrate was concentrated to give a sticky crude mass. This sticky mass was dissolved in EtOAc (150 mL) and water (50 mL) and then pH was adjusted to 9 using NaHCO3 solid. The organic layer was separated and washed with brine (40 mL). The resulting organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (550 mg crude), which was used in the next step without further purification. LCMS (EI) m / z=269[M+1]

[0453] 6-Fluoro-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (Step 5) To a solution of 6-fluoro-4-iodo-3-methoxypyridin-2-amine (550 mg, 2.05 mmol), (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (260 mg, 2.05 mmol) (Intermediate 19) in 1,4-dioxane (8 mL) was added PdCl2(dppf)-CH2Cl2-adduct (168 mg, 0.21 mmol), K3PO4 (1.31 g, 6.16 mmol) in a 50 mL sealed test tube. The reaction mixture was degassed under N2 for 5 min. The sealed test tube was capped and the mixture was stirred at 110 °C for 1.5 h. The reaction mixture was filtered through a Celite pad and the Celite pad was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to give the crude product, which was purified by neutral alumina column chromatography (0-50% EtOAc in petroleum ether) to give the desired product 6-fluoro-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (450 mg, 1.855 mmol, 90% yield) as a white solid. LCMS: (EI) m / z=224[M+1]; 1H-NMR (400MHz, DMSO-d6): δ 8.18(s,1H), 6.48(m,3H), 4.23(s,3H), 3.61(s,3H)

[0454] 6-Chloro-4-((6-fluoro-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (Step 6)

[0455] [ka]

[0456] To a stirred solution of 6-fluoro-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (200 mg, 0.90 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (281 mg, 1.34 mmol) in THF (10 mL) in a 50 mL round bottom flask, LiHMDS (600 mg, 3.58 mmol, 1M in THF) was added at 0° C. The reaction mixture was then stirred at room temperature for 4 h. After completion of the reaction, ice-cold water (60 mL) was added and extracted with EtOAc (2×100 mL). The organic layers were combined and washed with brine solution (100 mL). The resulting organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. To remove impurities, the reaction was triturated three times with 50% EtOAc in petroleum ether (60 mL each), petroleum ether (20 mL), and finally Et2O (20 mL) to give 250 mg of a brown solid (72% desired product by LCMS).

[0457] 6-(Cyclopropanecarboxamido)-4-((6-fluoro-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka]

[0458] In a 50 mL sealed test tube containing a solution of 6-chloro-4-((6-fluoro-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (100 mg, 0.253 mmol), cyclopropanecarboxamide (64.55 mg, 0.758 mmol) in 1,4-dioxane (10 mL) and DMA (1 mL), Cs2CO3 (247 mg, 0.758 mmol) and 1,1-bis(dicyclohexylphosphino)ferrocene (29.3 mg, 0.051 mmol) were added in a sealed test tube. The reaction mixture was degassed under N2 for 5 min and Pd2(dba)3 (23.15 mg, 0.025 mmol) was added. The resulting mixture was stirred at 110° C. for 8 h. The reaction mixture was filtered through a Celite pad; the Celite pad was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to give the crude product.

[0459] Product yield: 19% (after RP PREP HPLC purification); LCMS: (EI) m / z=445.2[M+1]; 1 H-NMR (400MHz, DMSO-d6):δ 12.64(s,1H), 11.43(s,1H), 9.68(s,1H), 9.34(s,1H), 8.37(s,1H), 7.0 9(m,1H), 4.29(s,3H), 3.82(s,3H), 2.18-2.08(m,1H), 0.92-0.87(m,4H)

[0460] RP PREP HPLC purification method: Column: Sunfire C18 (19*150mm*5μ) Mobile phase A: 0.1% TFA in water Mobile phase B: ACN LCMS: m / z:[M+1]:445.2, RT:2.421 min Column: Xbridge C18 (50 x 4.6 mm) 5 μm Mobile phase: A: 0.1% TFA in H2 Mobile phase: B: 0.1% TFA in ACN Flow rate: 1.0ml / min Purity: 94.55%.

[0461] HPLC: HPLC method 1: Column: Kinetics Biphenyl (100x4.6) mm, 2.6 μm Mobile phase: A:0.05% TFA:ACN (95:5) in H2O Mobile phase: B:ACN:0.05% TFA in H2O (95:5) Flow rate: 1.0mL / min Purity: 97.76%

[0462] HPLC method 2: Column: Kinetics EVO C18 (100x4.6) mm, 2.6 μm Mobile phase: A: 0.05% TFA in water: ACN Mobile phase: B: 0.05% TFA in ACN: water Flow rate: 1.0mL / min Purity: 97.30%.

[0463] Example 63 [ka]

[0464] To a stirred solution of 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (100 mg, 0.265 mmol) in 1,4-dioxane (15 mL) and DMA (1.5 mL) was added Cs2CO3 (216 mg, 0.662 mmol) at ambient temperature. The reaction mixture was degassed under N2 for 5 min. Pyridin-2-amine (29.9 mg, 0.318 mmol) and Pd2dba3 (36.4 mg, 0.040 mmol) and 1,1'-bis(dicyclohexylphosphino)ferrocene (22.96 mg, 0.040 mmol) were added to the reaction mixture and degassed for 5 min. The resulting reaction mixture was heated under microwave conditions at 110° C. for 2 h. The reaction mixture was filtered through a pad of Celite under reduced pressure and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel (230-400 mesh) column chromatography using 2-3% MeOH in DCM as eluent to give 4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)-6-(pyridin-2-ylamino)pyridazine-3-carboxamide (26.98 mg, 0.061 mmol, 23.17% yield) as an off-white solid. MS(M+1) m / z:436.0[M+H] + LC retention time 1.34 min [Method A] 1 H-NMR (400MHz, DMSO-d6):δ 12.35(s,1H), 10.28(s,1H), 9.79(s,1H), 9.20(s,1H), 8.34(d,J=4.0Hz,1H), 8.31(s,1H), 8.20(d,J=5.2Hz) ,1H), 7.73-7.75(m,1H), 7.65-7.71(m,1H), 7.46-7.47(m,1H), 6.99-6.97(m,1H), 4.28(s,3H), 3.83(s,3H)

[0465] The following example was prepared in a manner similar to the preparation of Example 63.

[0466] [ka]

[0467] [Table 16]

[0468] [Table 17]

[0469] Example 69 [ka]

[0470] Example 69 was prepared in a manner similar to that described for Example 46 from the amide prepared from the appropriate commercially available carboxylic acid in a manner similar to that described for Example 40 to give 6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (12 mg, 18.46% yield). MS(M+1) m / z: 459.3(M+H). + ;LC retention time 1.20[C]; 1 H NMR (400 MHz, DMSO-d6) δ 12.34(s,1H), 11.35(s,1H), 10.10(s,1H), 9.25(s,1H), 8.28(s,1H), 7.34(s,1H), 5.29-4.65(m,1H), 4.27(s,3H), 3.78(s,3H), 2.38-2.28(m,1H), 1.83-1.61(m,1H), 1.34-1.15(m,1H); one methyl peak is obscured under solvent.

[0471] The following table shows additional prodrugs (AIs) that can be prepared to potentially enhance certain properties of Example 36.

[0472] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22]

[0473] Biological assays The following assays are used to demonstrate activity for the compounds of the invention.

[0474] In vivo assay of brain penetrance Pharmacokinetic studies were performed in C57BL6 wild-type mice (n=3 per study) to measure the exposure of the compounds of the present invention to brain and plasma. Compounds were orally administered at 5mL / kg at a final concentration of 10mg / kg in a solution of 5% ethanol; 90% PEG300; 5% TPGS. Mice were sacrificed 1 hour after administration, and plasma and brains were collected and frozen for analysis. Brain tissue was homogenized with blank C57BL6 mouse plasma at 1:1 volume. Compound concentrations in plasma and brain homogenates were measured by LC-MS analysis.

[0475] MOG in multiple sclerosis 1-125 EAE experiments: in vivo and in vitro Female C57BL / 6J mice (Jackson Labs #000664) were approximately 10-11 weeks old at the start of the study. After acclimation for at least 1 week, mice were inoculated with human recombinant myelin oligodendrocyte glycoprotein 1-125 (MOG) in complete Freund's adjuvant. 1-125Disease was induced by subcutaneous (SC) immunization with an emulsion containing 0.1 mL of emulsion per site at two dorsal sites. Pertussis toxin (PTX) was then injected intraperitoneally (approximately 4 and 24 hours after SC injection of the emulsion) such that each injection contained the same dose of PTX. Mice were then monitored for disease progression using standard clinical disease scores and randomly assigned to treatment groups (N=12) approximately 11 days later, with once-daily treatment with vehicle or test compound beginning after disease onset. The treatment period was 21 days, with body weights and clinical disease scores measured daily. Tissue samples were collected at various times after the last dose for pharmacokinetic evaluation of compound plasma and brain levels. In addition, spinal cords were collected at various times after the last dose for evaluation of inflammation and target-related parameters by flow cytometric analysis, Western blotting, and other laboratory techniques. Spinal cords were analyzed ex vivo as follows:

[0476] · JESS Western Blot: Snap frozen tissues were homogenized in RIPA with protease / phosphatase inhibitors and centrifuged to remove debris. Protein concentration was measured using the BCA assay and lysates were normalized to 0.5mg / mL and denatured by mixing with loading buffer. These were then run in JESS for markers of inflammation and pathway activation. Antibodies to pStat1 were used at 1:50 dilution along with control proteins (usually alpha / beta tubulin at 1:1500 dilution).

[0477] FACS analysis: Single cell suspensions were prepared using Miltenyi's ABDK protocol and divided according to the number of panels. FACS panels assessing surface markers and transcription factors utilized standard protocols (eBioscience Protocol B: 1-step protocol: Intracellular (nuclear) proteins) and panels assessing pStat1 or other phosphoproteins also used standard protocols (BioLegend's True-Phos protocol). For cytokine assessment by FACS, cells were cultured in microglia medium + brefherin-A + P / S for 18 hours and then stained using standard protocols for staining (Biolegend CytoFix / Perm or CytoLast).

[0478] Figure 1: Disease scores for Example 36 in the EAE MOG1-125 study [Table 23]

[0479] 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.

[0480] 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.

[0481] 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.

[0482] 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 1.8x10 5 cells / cm 2 At a density of approximately 2.0x10 per well 4 Cells were seeded at 1000 x g / mL. 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 37° C. in a 95% relative humidity and 5% CO2 atmosphere. Cells were assessed for tight junction formation immediately prior to assay (see Quality Control section below).

[0483] 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.

[0484] 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.

[0485] Immediately 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 for 2 hours at 37°C in an atmosphere of 95% relative humidity and 5% CO2. 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 concentrations of the indicated and control compounds.

[0486] 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).

[0487] 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).

[0488] [Table 24] A = 0.2% formic acid in water; B = 0.2% formic acid in acetonitrile

[0489] 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.

[0490] Data analysis The following results: permeability coefficient (Pc [nanometers per second]), efflux ratio, and recovery were reported for the compounds listed;

[0491] The Pc value is calculated using the following formula:

number

[0492] The emission ratio was calculated as follows:

number

[0493] 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

[0494] 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.

[0495] 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.

[0496] 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.

[0497] [Table 25] Values ​​are means ± standard deviation. Pc = Permeability coefficient A → B = from top to bottom B → A = from bottom to top

[0498] Table 2: Potency and permeability data for example compounds in human whole blood assay and CACO2 permeability assay [Table 26] [Table 27]

[0499] Table 3: Percentage of measured concentrations of example compounds in brain and plasma homogenates 1 hour after oral administration of 10 mpk of compound. [Table 28]

[0500] *The example compounds were administered as an IV solution at a dose of 2 mpk. **Example compounds were administered as an IV solution at a dose of 2 mpk and exposure was measured over a 40 minute period. ***Example compounds were administered as nanosuspensions in a vehicle of 0.5% Methocel A4M; 0.1% Tween 80; 99.4% water. ****Example 49 is a prodrug of Example 36; thus, exposure was measured as the observed concentration of Example 36. Dosing was at 5 mpk equivalent of the parent drug, in a solution of vehicle: 0.5% Methocel; 0.1% Tween 80; 99.4% water. ***** Example compounds were administered as an IV solution at a dose of 2 mpk and exposure measured over a 90 minute period.

[0501] Table 4: Comparison of CNS penetration profiles of compounds of Examples 36 and 11 and prior art compounds: [ka]

[0502] [Table 29]

[0503] Surprisingly, it has been found that the 1,2,3-substituted triazole compounds of the present invention have a significantly higher brain to plasma ratio than the structurally similar 1,2,4-substituted triazole compounds, and thus the compounds of the present invention can cross the blood-brain barrier and may be useful in the treatment of certain neurological disorders.

Claims

1. Formula II: 【Chemistry 1】 [In the formula: R １ HA -C(O)R １ａ or a 5-8 membered heterocycle containing 1-2 heteroatoms selected from N, O and S, each heterocycle containing 0-2 R １ｂ is substituted with; R １ａ COOC １－３ Alkyl, or C ３－６ cycloalkyl, the cycloalkyl group being 0 to 2 R １ｂ is substituted with; R １ｂ is independently, at each occurrence, F or C １－３ is alkyl; R ２ is OMe or OCHF ２ and R ３ CD ３ , C １－３ Alkyl, C ３－６ Cycloalkyl or (CH ２ ) F; and R ４ is hydrogen, halo, C １－４ Alkyl, C １－４ Alkoxy or C ３－６ is cycloalkyl. or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

2. structure: 【Chemistry 2】 [In the formula: R １ HA -C(O)R １ａ or a 5-8 membered heterocycle containing 1-2 heteroatoms selected from N, O and S, each heterocycle containing 0-2 R １ｂ is substituted with; R １ａ COOC １－３ Alkyl, or C ３－６ cycloalkyl, the cycloalkyl group being 0 to 2 R １ｂ is substituted with; R １ｂ is independently, at each occurrence, F or C １－３ is alkyl; R ４ is hydrogen, F or CH ３ is] 2. The compound according to claim 1, wherein:

3. structure: 【Chemistry 3】 or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

4. structure: 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

5. structure: 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof.

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

7. A pharmaceutical composition comprising one or more compounds according to claim 2 or stereoisomers thereof, or pharma- ceutically acceptable salts thereof, and a pharma- ceutically acceptable carrier or diluent.

8. A pharmaceutical composition comprising one or more compounds according to claim 3 or stereoisomers thereof, or pharma- ceutically acceptable salts thereof, and a pharma- ceutically acceptable carrier or diluent.

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

10. 10. A pharmaceutical composition comprising one or more compounds according to claim 5 or pharma- ceutically acceptable salts thereof and a pharma- ceutically acceptable carrier or diluent.

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