PYRIDINSULFONE ALKYLAMIDE-SUBSTITUTED HETEROARYL COMPOUNDS

Abstract

A pharmaceutical composition comprising them and their use in the treatment of autoimmune inflammatory diseases.

Description

26737 PYRIDINESULFONE ALKYLAMIDE SUBSTITUTED HETEROARYL COMPOUNDS CROSS REFERENCE TO RELATED REQUESTS The present application claims the benefit of US Provisional Application No. 62 / 589165, filed on November 21, 2017, the disclosure of which is incorporated herein by reference in its entirety. FIELD OF INVENTION The present invention relates to compounds useful for the modulation of IL12, IL-23 and / or IFNa that act on Tyk-2 to generate inhibition of signal transduction. Provided herein are amide-substituted heterocyclic compounds, compositions comprising these compounds, and methods of use. The invention also relates to pharmaceutical compositions containing at least one compound according to the invention that is useful for the treatment of conditions related to the modulation of IL-12, IL-23 and / or IFNa in a mammal. BACKGROUND OF THE INVENTION The heterodimeric cytokines interleukin (IL)-12 and IL-23, which share a common p40 unit, are produced by activated antigen-presenting cells and are essential for the differentiation and proliferation of Th1 and Th17 lymphocytes, two lineages of T lymphocytes. effectors that have key functions in autoimmunity. IL-23 is composed of a p40 subunit along with a single p19 subunit. IL-23, which acts through a heterodimeric receptor composed of IL-23R and IL-12RP1, is essential for the survival and expansion of Th17 lymphocytes that produce proinflammatory cytokines, such as IL-17A, IL-17F, IL-6 and TNF -α (McGeachy, M.J. et al., The link between IL-23 and Th17 cell-mediated immune pathologies, Semin. Immunol., 19:372-376 (2007)). These cytokines are instrumental in mediating the pathobiology of several autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and lupus. IL-12, in addition to the p40 subunit it shares with IL-23, contains a p35 subunit and acts through a heterodimeric receptor composed of IL-12Rp1 and IL-12Rβ2. IL-12 is essential for the development of Th1 lymphocytes and the secretion of IFNy, a cytokine that plays a fundamental role in immunity by stimulating MHC expression, the class exchange of B lymphocytes to IgG subclasses and the macrophage activation (Gracie, J.A. et al., Interleukin-12 induces interferongamma-dependent switching of IgG alloantibody subclass, Eur. J. Immunol., 26:1217 IF-2019-16830169-APN-ANP#INPI Page 1 of 134 1221 (1996); Schroder, K. et al., Interferon-gamma: an overview of signals, mechanisms and functions, J. Leukoc. Biol., 75(2):163-189 (2004)). The importance of p40-containing cytokines in autoimmunity is demonstrated by the discovery that mice deficient in p40, p19, or IL23R are protected from disease in models of 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); al., Interleukin-23 drives innate and T cell-mediated intestinal inflammation, J. Exp. Med., 203:2473-2483 (2006); cytokine for autoimmune inflammation of the brain, Nature, 421:744-748 (2003); Murphy, C.A. 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)). In human diseases, high expression of p40 and p19 was measured in psoriatic lesions, and Th17 lymphocytes were identified in active lesions in the brain of 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); 17 production in central nervous system infiltrating T cells and glial cells is associated with active disease in multiple sclerosis, Am. J. Pathol., 172:146-155 (2008)). The mRNA levels of p19, p40 and p35 in patients with active SLE were also shown to be significantly higher than in those patients with inactive SLE (Huang, X. et al., Dysregulated expression of interleukin-23 and interleukin-12 subunits in systemic lupus erythematosus patients, Mod. Rheumatol., 17:220-223 (2007)), and T lymphocytes from patients with lupus 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)). Furthermore, genome-wide association studies have identified several loci associated with chronic inflammatory and autoimmune diseases that encode factors that function in the IL-23 and IL-12 pathways. These genes include IL23A, IL12A, IL12B, IL12RB1, IL12RB2, IL23R, JAK2, TYK2, STAT3 and STAT4 (Lees, C.W. et al., New IBD genetics: common pathways with other diseases, Gut, 60:17391753 (2011) Tao , J.H. et al., Meta-analysis of TYK2 gene polymorphisms association IF-2019-16830169-APN-ANP#INPI Page 2 of 134 with susceptibility to autoimmune and inflammatory diseases, Mol. Biol. Rep., 38:46634672 (2011); Cho, J.H. et al., Recent insights into the genetics of inflammatory bowel disease, Gastroenterology, 140:1704-1712 (2011). In fact, anti-p40 treatment, which inhibits both IL-12 and IL-23 as well as IL-23-specific anti-p19 treatments, has been shown to be effective in treating autoimmunity in diseases including psoriasis, Crohn's disease and psoriatic arthritis (Leonardi, C.L. et al., PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12 / 23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebocontrolled trial (PHOENIX 1), Lancet, 371:1665-1674 (2008); Sandborn, W.J. et al., Ustekinumab Crohn's Disease Study Group A randomized trial of Ustekinumab, a human interleukin-12 / 23 antibody. , in patients with moderate-to-severe Crohn's disease, Gastroenterology, 135:1130-1141 (2008); blind, placebo-controlled, crossover trial, Lancet, 373:633-640 (2009)). Therefore, agents that inhibit the action of IL-12 and IL-23 are expected to have therapeutic benefits in human autoimmune disorders. The type I interferon (IFN) group, which includes the members of IFNa and also IFNp, IFNe, IFNk and IΡΝω, acts through a heterodimeric IFNa / β receptor (IFNAR). Type I IFNs have multiple effects on the innate and adaptive immune systems, including activation of cellular and humoral immune responses, as well as enhancement of the expression and release of autoantigens (Hall, J.C. et al., Type I interferons : crucial participants in disease amplification in autoimmunity, Nat. Rev. Rheumatol., 6:40-49 (2010)). In patients with systemic lupus erythematosus (SLE), a life-threatening autoimmune disease, increased serum levels of interferon (IFN)a (a type I interferon) or increased gene expression have been demonstrated in the majority of patients. regulated by type I IFN (a so-called characteristic IFNa) in peripheral blood mononuclear cells and in affected organs (Bennett, L. et al., Interferon and granulopoiesis signatures in systemic lupus erythematosus blood, J. Exp. Med., 197:711 -723 (2003); Peterson, K.S. et al., Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli, J. Clin Invest., 113:1722-1733 (2004) Several studies showed that serum levels of IFNa correlate with the activity and severity of the disease (Bengtsson, A.A. et al., Activation of IF-2019-16830169-APN-ANP#INPI Page 3 of 134 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 IFNa in the pathobiology of lupus is evidenced by the observation that administration of IFNa to patients with cancer or viral diseases can induce a lupus-like syndrome. Furthermore, deletion of IFNAR in lupus-prone mice provides high protection against autoimmunity, disease severity and mortality (Santiago-Raber, M.L. et al., Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice, J. Exp. Med., 197:777-788 (2003)), and genome-wide association studies have identified lupus-associated loci that encode factors that function in the type I interferon pathway, including IRF5, IKBKE, TYK2, and STAT4 (Deng, Y. et al., Genetic susceptibility to systemic lupus erythematosus in the genomic era, Nat. Rev. Rheumatol., 6:683-692 (2010); Sandling, J.K. et al. , A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE, Eur. J. Hum., 19:479-484 (2011). In addition to lupus, there is evidence that abnormal activation of type I interferon-mediated pathways is important in the pathobiology of other autoimmune diseases, such as Sjógren's syndrome and scleroderma (Báve, U. et al., Activation of the type I interferon system in primary Sjogren's syndrome: a possible etiopathogenic mechanism, Arthritis Rheum., 52:11851195 (2005); Kim, D. et al., Induction of interferon-alpha by scleroderma sera containing autoantibodies to topoisomerase I: association of higher interferon-alpha activity with lung fibrosis, Arthritis Rheum., 58:2163-2173 (2008)). Therefore, agents that inhibit the action of type I interferon responses are expected to have therapeutic benefits in human autoimmune disorders. Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases, and has been shown to be essential for the regulation of the signal transduction cascade downstream of IL receptors. -12, IL-23 and type I interferons in both mice (Ishizaki, M. et al., “Involvement of Tyrosine Kinase-2 in Both the IL-12 / Th1 and IL-23fTh17 Axes In Vivo” J. Immunol., 187:181-189 (2011); , 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 IF-2019-16830169-APN-ANP#INPI Page 4 of 134 generates the dimerization of STAT proteins and the transcription of STAT-dependent proinflammatory genes. Tyk2-deficient mice are resistant to experimental models of colitis, psoriasis, and multiple sclerosis, demonstrating the importance of Tyk2-mediated signaling in autoimmune and related disorders (Ishizaki, M. et al., “Involvement of Tyrosine Kinase-2 in Both the IL12 / 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)). In humans, individuals expressing an inactive variant of Tyk2 are protected against 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 showed that other Tyk2 variants 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 Loti, Am. J. Hum. Genet., 90:636-647 (2012); across the tyrosine kinase gene, TYK2 in UK SLE families, Rheumatology (Oxford), 46:927-930 (2007); ., 44:1336-1340 (2012)). In view of the diseases that may benefit from treatment that includes the modulation of cytokines and / or interferons, new compounds capable of modulating cytokines and / or interferons, such as IL-12, IL-23 and / or IFNa , and methods of using these compounds can provide considerable therapeutic benefits to a wide variety of patients in need. SUMMARY OF THE INVENTION The invention relates to compounds of Formula I, infra, which are useful as modulators of IL-12, IL-23 and / or IFNa by inhibiting Tyk2-mediated signal transduction. The present invention also provides processes and intermediates for obtaining the compounds of the present invention. IF-2019-16830169-APN-ANP#INPI Page 5 of 134 The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention. The present invention also provides a method for the modulation of IL-12, IL-23 and / or IFNa by inhibiting Tyk-2-mediated signal transduction, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention. The present invention also provides a method for the treatment of proliferative, metabolic, allergic, autoimmune and inflammatory diseases, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention. A preferred embodiment is a method for the treatment of inflammatory and autoimmune diseases or illnesses. For the purposes of the present invention, an inflammatory and autoimmune disease or disorder includes any disease that has an inflammatory or autoimmune component. An alternative preferred embodiment is a method for the treatment of metabolic diseases, including type 2 diabetes and atherosclerosis. The present invention also provides the use of the compounds of the present invention to manufacture a medicament for the treatment of cancer. The present invention also provides the compounds of the present invention for use in treatment. These and other features of the invention will be explained in more detail throughout the disclosure. DETAILED DESCRIPTION OF THE WAYS OF EMBODIMENT OF THE INVENTION In a first aspect of the present invention, there is provided a compound of Formula (I) Yo Rsen where And it is N OR CR6; IF-2019-16830169-APN-ANP#INPI Page 6 of 134 R1is H, CD3o C,_3alkyl; R2es -C(O)R2a; o Cy.6alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2aor a 5-14 membered heterocycle containing 1-4 heteroatoms selected from N, O and S, each group substituted with 0- 4 R2a; R2a, in each case, is independently hydrogen, OH, halo, OCF3, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O) ORb, -(CH2)rOC(O)Rb, CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, -NRbC(O ) NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)PRC, C,.6 alkyl substituted with 0-3 Ra, 0,.6 haloalkyl, C2.6alkenyl substituted with 0-3 Ra, -(CH2)r-substituted 3-14 membered carbocycle with 0-1 Rao a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-2 Ra; X is absent, it is O NH; R4 and R5 are independently hydrogen, C,.4 alkyl substituted with 0-1 Rf, (CH2)r.phenyl substituted with 0-3 Rdo a -(CH2)-heterocycle of 5-7 members containing 1-4 heteroatoms selected from N , O and S(O)P; R6 is hydrogen, halo, C1.4 alkyl, C1.4 alkyoxy, C1.4 haloalkyl, C1.4 haloalkoxy, C3.6 cycloalkyl, CN, NO2u OH; R11, in each case, is independently hydrogen, C,.4 alkyl substituted with 0-3 Rf, CF3, C3.10cycloalkyl substituted with 0-1 Rf, (CH2)r-phenyl substituted with 0-3 Rdo -(CH2) 5-7 membered r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rd; Ray Ra1, in each case, are independently hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, - (CH2)rC(O)ORb, -(CH2)rOC(O)Rb, -(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC ( O)ORC, -NRbC(O)NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, C,.6 0-3 substituted alkyl Rf, C,.6 haloalkyl, C2.6alkenyl substituted with 0-3 Ra, C2.6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-heterocycle 5-7 members containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rf; Rbes hydrogen, C,.6 alkyl substituted with 0-3 Rd, C,.6 haloalkyl, C3.6 IF-2019-16830169-APN-ANP#INPI Page 7 of 134 0-2 Rdo-substituted cycloalkyl -(CH2)r-5-7-membered heterocycle containing 1-4 heteroatoms selected from N, O and 0-3 Rf-substituted S(O)P, or (CH2 )r-phenyl substituted with 0-3 Rd; Rces Oi-e alkyl substituted with 0-3 Rf, (CH2)r-C3.6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf; You release independently, in each case, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)Rc, -NReRe, -NReC(O)ORc, alkyl or (CH2 )r-phenyl substituted with 0-3 Rf; Reis independently, in each case, hydrogen, Ci.6alkyl, C3.6cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf¡ Rfes independently, in each case, hydrogen, halo, CN, NH2, OH, C3.3cycloalkyl, CF3, O(Cr6alkyl) or a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N , O and S(O)P; p is 0, 1 or 2; r is 0, 1, 2, 3 or 4, or a stereoisomer or a pharmaceutically acceptable salt thereof. In a second aspect of the invention, a compound of Formula II is provided Yo R5 II where R1es H, CD3o Cvs alkyl; R2es -C(O)R2a; o Cy.6alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2aor a 5-14 membered heterocycle containing 1-4 heteroatoms selected from N, O and S, each group substituted with 0- 4 R2a! R2a, in each case, is independently hydrogen, OH, halo, OCF3, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O) ORb, -(CH2)rOC(O)Rb, CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, -NRbC(O ) NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)PRC, Page 8 of 134 haloalkyl, C2.6alkenyl substituted with 0-3 Ra, a 3-14 membered -(CH2)r-carbocycle substituted with 0-1 Rao a 5-7 membered -(CH2)r-heterocycle containing 1 -4 heteroatoms selected from N, O and S(O)Psubstituted with 0-2 Ra; X is absent, it is O or NH; R4 and R5 are independently hydrogen, alkyl substituted with 0-1 Rf, (CH2)r.phenyl substituted with 0-3 Rdo a -(CH2)-heterocycle of 5-7 members containing 1-4 heteroatoms selected from N, O and S (O)P; R6 is hydrogen, halo, C1.4 alkyl, C1.4 alkyoxy, C1.4 haloalkyl, C1.4 haloalkoxy, C3.6 cycloalkyl, CN, NO2u OH; R11, in each case, is independently hydrogen, C1.4 alkyl substituted with 0-3 Rf, CF3, C3.10 cycloalkyl substituted with 0-1 Rf, (CH2)r-phenyl substituted with 0-3 Rdo -(CH2) 5-7 membered r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rd; Ray Ra1, in each case, are independently hydrogen, F, Cl, Br, OCF3, CF3, CHF2i CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -( CH2)rC(O)ORb, -(CH2)rOC(O)Rb, -(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC( O)ORC, -NRbC(O)NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, CV6 alkyl substituted with 0-3 Rf, Cve haloalkyl , C2.6alkenyl substituted with 0-3 Ra, C2.6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rf; Rbes hydrogen, Ci.6 alkyl substituted with 0-3 Rd, CV6 haloalkyl, C3.6cycloalkyl substituted with 0-2 Rdo -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O and S(O)P substituted with 0-3 Rf, or (CH2)r-phenyl substituted with 0-3 Rd; Rces Ci-6 alkyl substituted with 0-3 Rf, (CH2)r-C3.6cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf; You release independently, in each case, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)Rc, -NReRe, -NReC(O)ORc, CV6alkyl or (CH2 )r-phenyl substituted with 0-3 Rf; R· is independently, in each Page 9 of 134 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf; Rfes independently, in each case, hydrogen, halo, CN, NH2, OH, C3.6cycloalkyl, CF3, 0(0^6 alkyl) or a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and S(0)p; p is 0, 1 or 2; res O, 1,2, 3 or 4, or a pharmaceutically acceptable stereoisomer or salt thereof. In a third aspect of the invention, a compound of Formula III is provided III where R1is H, CD3o CV3alkyl; R2es -C(O)R2a; o Cy.6alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2aor a 5-14 membered heterocycle containing 1-4 heteroatoms selected from N, O and S, each group substituted with 0- 4 R2a; R2a, in each case, is independently hydrogen, OH, halo, OCF3, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O) ORb, -(CH2)rOC(O)Rb, CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, -NRbC(O ) NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)PRC, C^e alkyl substituted with 0-3 Ra, haloalkyl, C2.6alkenyl substituted with 0-3 Ra, -(CH2 3-14 membered r-carbocycle substituted with 0-1 Rao a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-2 Ra ; R3es X is absent, it is O or NH! R4 and R5 are independently hydrogen, C-m alkyl substituted with 0-1 Rf, and KIÉ-2019-16830169-APN-ANP#INPI Page 10 of 134 (CH2)r.phenyl substituted with 0-3 Rdo a 5-7 membered -(CH2)-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)P; R6 is hydrogen, halo, C1.4 alkyl, C1.4 alkyoxy, C1.4 haloalkyl, C1.4 haloalkoxy, C3.6 cycloalkyl, CN, NO2u OH; R11, in each case, is independently hydrogen, C1.4 alkyl substituted with 0-3 Rf, CF3, C3.10 cycloalkyl substituted with 0-1 Rf, (CH2)r-phenyl substituted with 0-3 Rdo -(CH2) 5-7 membered r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rd; Ray Ra1, in each case, are independently hydrogen, F, Cl, Br, OCF3, CF3, CHF2i CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -( CH2)rC(O)ORb, -(CH2)rOC(O)Rb, -(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC( O)ORC, -NRbC(O)NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, Ον6 alkyl substituted with 0-3 Rf, Ci- e haloalkyl, C2.6alkenyl substituted with 0-3 Ra, C2.6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle contains 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rf; Rbes hydrogen, C1.6 alkyl substituted with 0-3 Rd, C1.6 haloalkyl, C3.6 cycloalkyl substituted with 0-2 Rdo -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N , O and S(O)P substituted with 0-3 Rf, or (CH2)r-phenyl substituted with 0-3 Rd; Rces Ci-6 alkyl substituted with 0-3 Rf, (CH2)r-C3.6cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf; Rades independently, in each case, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)Rc, -NReRe, -NReC(O)ORc, C,.ealkyl or (CH2)r-phenyl substituted with 0-3 Rf; Reis independently, in each case, hydrogen, C1.6 alkyl, C3.6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf; Rfes independently, in each case, hydrogen, halo, CN, NH2, OH, C3.6 cycloalkyl, CF3, O(Ci-6alkyl) or a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)P; p is 0, 1 or 2; r is 0, 1.2, 3 or 4, or a stereoisomer or a pharmaceutically acceptable salt thereof. IF-2019-16830169-APN-ANP#INPI Page 11 of 134 In a fourth aspect of the invention, a compound according to the first and second aspects of Formula II is provided. where R1 is H, CD3o 0^3 alkyl; R2es -C(O)R2a; o Cy.6alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2aor a 5-14 membered heterocycle containing 1-4 heteroatoms selected from N, O and S, each group substituted with 0- 4 R2a; R2a, in each case, is independently hydrogen, OH, halo, OCF3, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O) ORb, -(CH2)rOC(O)Rb, CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, -NRbC(O ) NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)PRC, Cve alkyl substituted with 0-3 Ra, Cm haloalkyl, C2.6 alkenyl substituted with 0-3 Ra, -(CH2 3-14 membered r-carbocycle substituted with 0-1 Rao a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-2 R , Xes O; R4 and R5 are independently hydrogen, Cm alkyl substituted with 0-1 Rf, (CH2)r-phenyl substituted with 0-3 Rdo a -(CH2)-heterocycle of 5-7 members containing 1-4 heteroatoms selected from N, O and S(O)P; R6is hydrogen, halo, Cm alkyl, Cm alkyoxy, Cm haloalkyl, Cm haloalkoxy, C3-6 cycloalkyl, CN, NO2u OH; R11, in each case, is independently hydrogen, Cm alkyl substituted with 0-3 Rf, CF3, C3-io cycloalkyl substituted with 0-1 Rf, (CH2)r-phenyl substituted with 0-3 Rdo -(CH2)r- 5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rd; Ray Ra1, in each case, are independentsnwi^l^PO^^P^-^I^ÍN?^^' Page 12 of 134 CF3, CHF2, CN, N02, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O)ORb, -(CH2)rOC(O)Rb, -(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC( O)ORC, -NRbC(O)NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, 0-3 Rf substituted alkyl, Ci.6haloalkyl, 0-3 Ra substituted C2.6alkenyl, 0-substituted C2.6 alkynyl -3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 RF; Rbes hydrogen, C^e alkyl substituted with 0-3 Rd, Ove haloalkyl, C3.3cycloalkyl substituted with 0-2 Rdo -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O and S(O)P substituted with 0-3 Rf, or (CH2)r-phenyl substituted with 0-3 Rd; Rces C1.6 alkyl substituted with 0-3 Rf, (CH2)r-C3.6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf; You release independently, in each case, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)Rc, -NReRe, -NReC(O)ORc, alkyl or (CH2 )r-phenyl substituted with 0-3 Rf; Reis independently, in each case, hydrogen, Ci.6alkyl, C3.6cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf; Rfes independently, in each case, hydrogen, halo, CN, NH2, OH, C3.6 cycloalkyl, CF3, O(Cr6alkyl) or a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)P; p is 0, 1 or 2; r is 0, 1.2, 3 or 4, or a stereoisomer or a pharmaceutically acceptable salt thereof. In a fifth aspect of the invention, a compound of FormulaXR3 is provided Or H.N. where R1is H, CD3o C^ alkyl; R2es -C(O)R2a; o Cve alkyl, -(CH2)r-substituted 3-14 membered carbocycle IF-2019-16830169-APN-ANP#INPI Page 13 of 134 with 0-1 R2ao a 5-14 membered heterocycle containing 1-4 heteroatoms selected from N, O and S, each group substituted with 0-4 R2a¡ R2a, in each case, is independently hydrogen, OH, halo, OCF3, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O) ORb, -(CH2)rOC(O)Rb, CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, -NRbC(O ) NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)PRC, CV6 alkyl substituted with 0-3 Ra, haloalkyl, C2.e alkenyl substituted with 0-3 Ra, -(CH2) 3-14 membered r-carbocycle substituted with 0-1 Rao a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-2 Ra; R6 is hydrogen, halo, C-m alkyl, C1.4 alkyoxy, C1.4 haloalkyl, C1.4 haloalkoxy, C3.6 cycloalkyl, CN, NO2u OH; R11, in each case, is independently hydrogen, C1.4 alkyl substituted with 0-3 Rf, CF3, C3.io cycloalkyl substituted with 0-1 Rf, (CH2)r-phenyl substituted with 0-3 Rdo -(CH2) 5-7 membered r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rd; Ray Ra1, in each case, are independently hydrogen, F, Cl, Br, OCF3, CF3, CHF2i CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -( CH2)rC(O)ORb, -(CH2)rOC(O)Rb, -(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC( O)ORC, -NRbC(O)NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, C^e alkyl substituted with 0-3 Rf, Ci.6 haloalkyl, C2.6 alkenyl substituted with 0-3 Ra, C2.6alkymlo substituted with 0-3 Ra, -(CH2)r-carbocycle of 3-14 members or -(CH2)r-heterocycle of 5-7 members containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rf; Rbes hydrogen, C^e alkyl substituted with 0-3 Rd, C^ haloalkyl, C3.6 cycloalkyl substituted with 0-2 Rdo -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O and S(O)P substituted with 0-3 R, or (CH2)r-phenyl substituted with 0-3 Rd; Rces Ci-6 alkyl substituted with 0-3 Rf, (CH2)r-C3.6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf; You generate independently, in each case, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO? -ORe-(CH2)rC(O)Rc, -NReRe, -NReC(O)ORc, Cve alkyl or (CH2)r-substituted phenyl inu2, ,vIF-2019-16830169-APN-ANP#INPI Page 14 of 134 with 0-3 Rf; Reis independently, in each case, hydrogen, C1.6 alkyl, C3.6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf; Rfes independently, in each case, hydrogen, halo, CN, NH2, OH, C3.6 cycloalkyl, CF3, 0(0Ί-6alkyl) or a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)P; p is 0, 1 or 2; res 0, 1, 2, 3 or 4, or a stereoisomer or a pharmaceutically acceptable salt thereof. In a sixth aspect of the invention, a compound of the FormulaXR3 Or H.N. where R1 is H, CD3o C1.3alkyl; R2es -C(O)R2a; o Cve alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2aor a 5-14 membered heterocycle containing 1-4 heteroatoms selected from N, O and S, each group substituted with 0-4 R2a; R2a, in each case, is independently hydrogen, OH, halo, OCF3, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O) ORb, -(CH2)rOC(O)Rb, CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, -NRbC(O ) NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)PRC, 0.6 alkyl substituted with 0-3 Ra, Ove haloalkyl, C2.6alkenyl substituted with 0-3 Ra, - 0-1 substituted 3-14 membered (CH2)r-carbocycle Rao a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and 0-substituted S(O)P 2 Ra; R3es R6 is hydrogen, halo, C1.3 alkyl, C,.3alkyoxy or C3.6 cycloalkyl; IF-2019-16830169-APN-ANP#INPI Page 15 of 134 R11, in each case, is independently hydrogen, C1.4 alkyl substituted with 0-3 Rf, CF3, C3.10 cycloalkyl substituted with 0-1 Rf, (CH2)r-phenyl substituted with 0-3 Rdo -(CH2) 5-7 membered r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rd; Ray Ra1, in each case, are independently hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2i -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -( CH2)rC(O)ORb, -(CH2)rOC(O)Rb, -(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC( O)ORC, -NRbC(O)NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, alkyl substituted with 0-3 Rf, Ci.6haloalkyl , C2.6alkenyl substituted with 0-3 Ra, C2.6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle containing 1 -4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rf; Rbes hydrogen, C-|.6 substituted alkyl with 0-3 Rd, Ci-e haloalkyl, C3.6 substituted cycloalkyl with 0-2 Rdo -(CH2)r-5-7 membered heterocycle containing 1-4 selected heteroatoms of N, O and S(O)P substituted with 0-3 Rf, or (CH2)r-phenyl substituted with 0-3 Rd; Rces Cve alkyl substituted with 0-3 Rf, (CH2)r-C3.6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf; Rdes independently, in each case, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)Rc, -NReRe, -NReC(O)ORc, C^e alkyl or (CH2)r-phenyl substituted with 0-3 Rf; Reis independently, in each case, hydrogen, C1.6 alkyl, C3.6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf; Rfes independently, in each case, hydrogen, halo, CN, NH2, OH, C3.6cycloalkyl, CF3, 0(^-6 alkyl) or a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)P; p is 0, 1 or 2; r is 0, 1, 2, 3 or 4, or a stereoisomer or a pharmaceutically acceptable salt thereof. In a seventh aspect of the invention, there is provided a compound of the Formula IF-2019-16830169-APN-ANP#INPI Page 16 of 134 ,R3 Or H.N. where R1 is H, CD3o C-j-3 alkyl; R2es -C(O)R2a; R2a, in each case, is independently hydrogen, OH, halo, OCF3, C1.6 alkyl substituted with 0-2 Ra, C-|.6 haloalkyl, Ον6alkoxy substituted with 0-2 Ra, C2-6 alkenyl substituted with 0- 2 Rao C3.6cycloalkyl substituted with 0-2 Ra; R6 is hydrogen, halo, C3.3alkyl, C3.3alkyoxy or C3.3cycloalkyl; R11, in each case, is independently hydrogen, Ci.4 alkyl substituted with 0-3 Rf, CF3, C3.-io cycloalkyl substituted with 0-1 Rf, (CH2)r-phenyl substituted with 0-3 Rdo -(CH2 )r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rd; Ray Ra1, in each case, are independently hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO,, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O)ORb, -(CH2)rOC(O)Rb, -(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2) rNRbC( O)ORC, -NRbC(O)NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, Ci.6 0-3 substituted alkyl Rf, C^e haloalkyl, C2.6alkenyl substituted with 0-3 Ra, C2.6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-membered heterocycle -7 members containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rf; Rbes hydrogen, C-|.6 alkyl substituted with 0-3 Rd, C^ haloalkyl, C3.6cycloalkyl substituted with 0-2 Rdo -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N , O and S(O)Psubstituted with 0-3 R, or (CH2)r-phenyl substituted with 0-3 Rd; Rces Cve alkyl substituted with 0-3 Rf, (CH2)r-C3.6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf; You release independently, in each case, hydrogen, F, Cl, Br, OCF3, CF3, CN, IF-2019-16830169-APN-ANP#INPI Page 17 of 134 SICKLE, -0Re, -(CH2)rC(O)Rc, -NReRe, -NReC(O)ORc, CV6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf¡ Reis independently, in each case, hydrogen, C^e alkyl, C3.6cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf; Rfes independently, in each case, hydrogen, halo, CN, NH2, OH, C3.6cycloalkyl, CF3, O(Cr6alkyl) or a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N , O and S(O)P; p is 0, 1 or 2; r is 0, 1, 2, 3 or 4, or a stereoisomer or a pharmaceutically acceptable salt thereof. In an eighth aspect of the invention, a compound of the Formula R3O is provided HN,R2 N H where R1is H, CD3o C^ alkyl; R2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, triazole, isoxazole, isothiazole or quinoline, each group substituted with 0-4 R2a; R2a, in each case, is independently hydrogen, OH, halo, OCF3, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O) ORb, -(CH2)rOC(O)Rb, CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, -NRbC(O ) NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)PRC, CV6 alkyl substituted with 0-3 Ra, C^ haloalkyl, C2.6alkenyl substituted with 0-3 Ra, -(CH2 3-14 membered r-carbocycle substituted with 0-1 Rao a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-2 Ra ; R3es R6 is hydrogen, halo, C^s alkyl, C^salkyoxy or C3.6cycloalkyl; IF-2019-16830169-APN-ANP#INPI Page 18 of 134 R11, in each case, is independently hydrogen, Cv4 alkyl substituted with 0-3 Rf, CF3, C3.10 cycloalkyl substituted with 0-1 Rf, (CH2)r-phenyl substituted with 0-3 Rdo -(CH2)r- 5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rd; Ray Ra1, in each case, are independently hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, - (CH2)rC(O)ORb, -(CH2)rOC(O)Rb, -(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC ( O)ORC, -NRbC(O)NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, alkyl substituted with 0-3 Rf, CV6haloalkyl, C2.6alkenyl substituted with 0-3 Ra, C2.6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle containing 1- 4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rf; Rbes hydrogen, 0-3 Rd substituted alkyl, Ci.6haloalkyl, 0-2 Rdo-substituted C3.6cycloalkyl -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O and S( O)P substituted with 0-3 Rf, or (CH2)r-phenyl substituted with 0-3 Rd; Rces 0^6 alkyl substituted with 0-3 Rf, (CH2)r-C3.6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf; Rdes independently, in each case, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)Rc, -NReRe, -NReC(O)ORc, C^ alkyl or (CH2)r-phenyl substituted with 0-3 Rf; Reis independently, in each case, hydrogen, C-|.6alkyl, C3.6cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf; Rfes independently, in each case, hydrogen, halo, CN, NH2, OH, C3.6 cycloalkyl, CF3, 0(Cr6alkyl) or a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)P¡ p is 0, 1 or 2; r is 0, 1.2, 3 or 4, or a stereoisomer or a pharmaceutically acceptable salt thereof. In a ninth aspect of the invention, a compound of Formula III is provided IF-2019-16830169-APN-ANP#INPI Page 19 of 134 ill R1 is H, CD3o Ct-3 alkyl; R2es -C(O)R2a; o Cy.6alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2aor a 5-14 membered heterocycle containing 1-4 heteroatoms selected from N, O and S, each group substituted with 0- 4 R2a; R2a, in each case, is independently hydrogen, OH, halo, OCF3, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O) ORb, -(CH2)rOC(O)Rb, CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, -NRbC(O)NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)PRC, Cm alkyl substituted with 0-3 Ra, Ci-6haloalkyl, C2.6alkenyl substituted with 0-3 Ra , 3-14 membered -(CH2)r-carbocycle substituted with 0-1 Rao a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-2 Ra; X is O; R4 and R5 are independently hydrogen, Cm alkyl substituted with 0-1 Rf, (CH2)r.phenyl substituted with 0-3 Rdo a -(CH2)-heterocycle of 5-7 members containing 1-4 heteroatoms selected from N, O and S(O)P; R6is hydrogen, halo, Ci.4alkyl, Cm haloalkyl, -OCm haloalkyl, OCm alkyl, CN, NO2u OH; R11, in each case, is independently hydrogen, Cm alkyl substituted with 0-3 Rf, CF3, C3.io cycloalkyl substituted with 0-1 Rf, (CH2)r-phenyl substituted with 0-3 Rdo -(CH2)r- 5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rd; Ray Ra1, in each case, are independently hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, - (CH2)rC(O)ORb, -(CH2)rOC(O)Rb, -(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC (IF-2019-16830169-APN-ANP#INPI Page 20 of 134 O)ORC, -NRbC(O)NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, 0,.6alkyl substituted with 0-3 Rf, haloalkyl, C2.6alkenyl substituted with 0-3 Ra, C2.6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-containing 5-7 membered heterocycle 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rf; Rbes hydrogen, C1.6 alkyl substituted with 0-3 Rd, Cj.6 haloalkyl, C3.6 cycloalkyl substituted with 0-2 Rdo -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N , O and S(O)P substituted with 0-3 Rf, or (CH2)r-phenyl substituted with 0-3 Rd; Rces Cve alkyl substituted with 0-3 Rf, (CH2)r-C3-6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf; Rades independently, in each case, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)Rc, -NReRe, -NReC(O)ORc, Ον6alkyl or (CH2 )r-phenyl substituted with 0-3 Rf; Reis independently, in each case, hydrogen, C-i-e alkyl, C3.6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf; Rfes independently, in each case, hydrogen, halo, CN, NH2, OH, C3.6 cycloalkyl, CF3, O(Ci-6alkyl) or a 5-7 membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and S(O)P; p is 0, 1 or 2; res 0, 1,2, 3 or 4, or a stereoisomer or a pharmaceutically acceptable salt thereof. In a tenth aspect of the invention, there is provided a compound of the Formula R3 Or H.N. where R1 is H, CD3o C1-3 alkyl; R2es -C(O)R2a; o -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2ao a 5-14 membered heterocycle containing 1-4 heteroatoms selected from N, IF-2019-16830169-APN-ANP#INPI Page 21 of 134 O and S replaced with 0-4 R2a; R2a, in each case, is independently hydrogen, OH, halo, OCF3, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -(CH2)rC(O) ORb, -(CH2)rOC(O)Rb, CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC(O)ORc, -NRbC(O)NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)PRC, Cv6alkyl substituted with 0-3 Ra, Cve haloalkyl, C2.6alkenyl substituted with 0-3 Ra, - 0-1-substituted 3-14-membered (CH2)r-carbocycle Rao a 5-7-membered -(CH2)r-heterocycle containing 1-4 heteroatoms selected from N, O and 0-substituted S(O)P 2 Ra; X is O; R6 is hydrogen, halo, CV3alkyl, Ci.3alkyoxy¡ or C3.6cycloalkyl; R11, in each case, is independently hydrogen, alkyl substituted with 0-3 Rf, CF3, C3.10cycloalkyl substituted with 0-1 Rf, (CH2)r-phenyl substituted with 0-3 Rdo -(CH2)r-heterocycle of 5-7 members containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rd; Ray Ra1, in each case, are independently hydrogen, F, Cl, Br, OCF3, CF3, CHF2i CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(O)Rb, -( CH2)rC(O)ORb, -(CH2)rOC(O)Rb, -(CH2)rNR11R11, -(CH2)rC(O)NR11R11, -(CH2)rNRbC(O)Rc, -(CH2)rNRbC( O)ORC, -NRbC(O)NR11R11, -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, Ci.e alkyl substituted with 0-3 Rf, C^ haloalkyl, C2.6alkenyl substituted with 0-3 Ra, C2.6 alkynyl substituted with 0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O and S(O)Psubstituted with 0-3 Rf; Rbes hydrogen, Ci.6 alkyl substituted with 0-3 Rd, Ci.6 haloalkyl, C3.6cycloalkyl substituted with 0-2 Rdo -(CH2)r-5-7 membered heterocycle containing 1-4 heteroatoms selected from N, O and S(O)P substituted with 0-3 R, or (CH2)r-phenyl substituted with 0-3 Rd; Rces Ci-6 alkyl substituted with 0-3 Rf, (CH2)r-C3.6 cycloalkyl substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rf; In each case, it is independently hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)Rc, -NReRe, -NReC(O)ORc, Cve alkyl or (CH2 )r-phenyl substituted with 0-3 Rf; IF-2019-16830169-APN-ANP#INPI Page 22 of 134 Re, in each case, is independently selected from hydrogen, Cm alkyl, C3.6cycloalkyl and (CH2)r-phenyl substituted with 0-3 Rf; Rfin independently, in each case, is hydrogen, halo, CN, NH2, OH, C3.6 cycloalkyl, CF3, O(Cr6 alkyl) or a 5-7 membered -(CH2)r-heterocycle containing 1-4 selected heteroatoms of N, O and S(O)P; p is 0, 1 or 2; r is 0, 1.2, 3 or 4, or a stereoisomer or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a compound selected from the examples within the scope of the first aspect, or a pharmaceutically acceptable salt or stereoisomer thereof. In another aspect, a compound selected from any list of subsets of compounds within the scope of any of the above aspects is provided. In another aspect, a compound (IUPAC naming convention) selected from 6-cyclopropanamido-4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methylpyridazin3-carboxamide; 6-[(5-fluoropyridin-2-yl)amino]-4-[(3-methanesulfonylpyridin-2-yl)amino]-N(2H3)methylpyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-6-[(6-methoxypyridazin-3-yl)amino]-N(2H3)methylpyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-[(1-methyl-1H-pyrazol-3yl)amino]pyridazine-3-carboxamide; 6-[(6-cyclopropyl-2-methylpyrimidin-4-yl)amino]-4-[(3-methanesulfonylpyridin-2yl)amino]-N-(2H3)methylpyridazine-3-carboxamide; 6-{[5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino}-4-[(3-methanesulfonylpyridin-2yl)amino]-N-(2H3)methylpyridazine-3-carboxamide; 6-[(6-cyclopropylpyrimidin-4-yl)amino]-4-[(3-methanesulfonylpyridin-2-yl)amino]-N(2H3)methylpyridazine-3-carboxamide; 6-[(6-cyclopropylpyridazin-3-yl)amino]-4-[(3-methanesulfonylpyridin-2-yl)amino]-N(2H3)methylpyridazine-3-carboxamide; 6-1(1 5-dimethyl-1H-pyrazol-3-yl)amino]-4-[(3-methanesulfonylpyridin-2-yl)amino]-N’ IF-2019-16830169-APN-ANP#INPI Page 23 of 134 (2H3)methylpyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-{[5-(trifluoromethyl)pyridin-2yl]amino}pyridine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-{[6-(trifluoromethyl)pyridazin-3yl]amino}pyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-6-[(2-methoxypinmidin-4-yl)amino]-N(2H3)methylpyridazine-3-carboxamide; 6-{[5-fluoro-4-(2-hydroxypropan-2-yl)pyridin-2-yl]amino}-4-[(3-methanesulfonylpyridin2-yl)amino]-N-(2H3)methylpyridazin-3- carboxamide; 6-{[5-(2-aminopropan-2-yl)pyridin-2-yl]amino}-4-[(3-methanesulfonylpyridin-2yl)amino]-N-(2H3)methylpyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-{[1-(2,2,2-trifluoroethyl)-1Hpyrazol-3-yl]amino}pyridazin-3- carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-6-{[6-(2H3)methoxypyridazin-3-yl]amino}-N(2H3)methylpyridazine-3-carboxamide; 6-[(5-cyanopyridin-2-yl)amino]-4-[(3-methanesulfonylpyridin-2-yl)amino]-N(2H3)methylpyridine-3-carboxamide; methyl N-{2-[6-({5-[(3-methanesulfonylpyridin-2-yl)amino]-6[(2H3)methylcarbamoyl]pyridazin-3-yl}amino)pyridin-3-yl]propan-2 -il}carbamate; 6-{[5-(1-cyanocyclopropyl)pyridin-2-yl]amino}-4-[(3-methanesulfonylpyridin-2-yl)amino]N-(2H3)methylpyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-{[5-(morpholin-4-yl)pyridin-2yl]amino}pyridazine-3-carboxamide; 6-[(5-cyclopropylpyrazin-2-yl)amino]-4-[(3-methanesulfonylpyridin-2-yl)amino]-N(2H3)methylpyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-[(6-methylpyridazin-3yl)amino]pyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-{[5-(trifluoromethyl)pyridin-2yl]amino}pyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-[(5-methylpyrazin-2yl)amino]pyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-6-{[4-(methoxymethyl)pyridin-2-yl]amino}-N(2H3)methylpyridazine-3-carboxamide; 6-[(2,6-dimethylpyrimidin-4-yl)amino]-4-[(3-methanesulfonylpyridin-2-yl)amino]-N(2H3)methylpyridazine-3-carboxamide; if-2019-16830169-APN-ANP#INPI Page 24 of 134 6-{[6-(2,6-difluorophenyl)pyridazin-3-yl]amino}-4-[(3-methanesulfonylpyridin-2-yl)amino]N-(2H3)methylpyridazine-3-carboxamide; 6-cyclopropanamido-4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methylpyridine-3carboxamide; 6-[(1S,2R)-2-fluorocyclopropanamido]-4-[(3-methanesulfonylpyridin-2-yl)amino]-N(2H3)methylpyridazine-3-carboxamide; 6-[(1S,2S)-2-fluorocyclopropanamido]-4-[(3-methanesulfonylpyridin-2-yl)amino]-N(2H3)methylpyridazine-3-carboxamide; 4-[(3-methanesulfonylpindin-2-yl)amino]-N-(2H3)methyl-6-[(1R,2R)-2methylcyclopropanamido]pyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-{spiro[2.2]pentan-1amidoJpyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-[(1R,2R)-2methylcyclopropanamido]pyridazine-3-carboxamide; 6-[(6-cyclopropylpyrimidin-4-yl)amino]-4-[(3-methanesulfonylpyridin-2-yl)amino]-N(2H3)methylpyridine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-[(2-methyl-2H-1,2,3-triazol-4yl)amino]pyridazine-3-carboxamide; 6-[(6-cyclopropyl-2-methylpyrimidin-4-yl)amino]-4-[(3-methanesulfonylpyridin-2yl)amino]-N-(2H3)methylpyridine-3-carboxamide; 6-{[5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino}-4-[(3-methanesulfonyl-6-methylpyridin-2yl)amino]-N-(2H3)methylpyridazin-3- carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-{[5-(trifluoromethoxy)pyridin2-yl]amino)pyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-[(1S)-spiro[2.2]pentan-1amido]pyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-[(1R)-spiro[2.2]pentan-1amido]pyridazine-3-carboxamide; 6-{[4-chloro-5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino}-4-[(3-methanesulfonyl-6methylpyridin-2-yl)amino]-N-(2H3) methylpyridazine-3-carboxamide; 6-cyclopropanamido-4-[(3-methanesulfonyl-6-methylpyridin-2-yl)amino]-N(2H3)methylpyridine-3-carboxamide; 6-{[4-chloro-5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino}-4-[(3-methanesulfonyl-6methoxypyridin-2-yl)amino]-N-(2H3) methylpyridazine-3-carboxamide; 6-[(2-cyclopropyl-6-methylpyrimidin-4-yl)amino]^ Page 25 of 134 yl)amino]-N-(2H3)methylpyridazine-3-carboxamide: 6-{[6-fluoro-5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino}-4-[(3-methanesulfonylpyridin2-yl)amino]-N-(2H3)methylpyridazin-3- carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-6-{[5-(methoxymethyl)pyridin-2-yl]amino}-N(2H3)methylpyridazine-3-carboxamide: 4-[(3-methanesulfonylpyridin-2-yl)amino]-6-({5-[(2H3)methoxymethyl]pyridin-2-yl}amino)N-(2H3)methylpyridazine-3-carboxamide; 6-{[6-(difluoromethoxy)pyridazin-3-yl]amino}-4-[(3-methanesulfonylpyridin-2-yl)amino]N-(2H3)methylpyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-{[6-(propan-2-yl)pyridazin-3yl]amino}pyridazine-3-carboxamide; 6-[(6-tert-butylpyridazin-3-yl)amino]-4-[(3-methanesulfonylpyridin-2-yl)amino]-N(2H3)methylpyridazin-3-carboxamide; 6-{[6-(difluoromethyl)pyridazin-3-yl]amino}-4-[(3-methanesulfonylpyridin-2-yl)amino]-N(2H3)methylpyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-[(1S,2S)-2methylcyclopropanamido]pyridazine-3-carboxamide; either 6-cyclopropanamido-4-[(3-methanesulfonyl-6-methylpyridin-2-yl)amino]-N(2H3)methylpyridazine-3-carboxamide; or a pharmaceutically acceptable stereoisomer or salt thereof. In another aspect, a compound (IUPAC naming convention) selected from 6-cyclopropanamido-4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methylpyridazine3-carboxamide; 6-[(6-cyclopropyl-2-methylpyrimidin-4-yl)amino]-4-[(3-methanesulfonylpyridin-2¡l)amino]-N-(2H3)methylpyridazín-3-carboxamide; 6-[(6-cyclopropylpyrimidin-4-yl)amino]-4-[(3-methanesulfonylpyridin-2-yl)amino]-N(2H3)methylpyridazine-3-carboxamide; 6-[(6-cyclopropylpyridazin-3-yl)amino]-4-[(3-methanesulfonylpyridin-2-yl)amino]-N(2H3)methylpyridazine-3-carboxamide; 6-cyclopropanamido-4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methylpyridine-3carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-[(1R,2R)-2methylcyclopropanamido]pyridazine-3-carboxamide, 1F.2019-16830169-ΑΡΝ-ΑΝΡ#ΓΝΡΙ Page 26 of 134 4-[(3-methanesulfonylpyridin-2-yl)annino]-N-(2H3)methyl-6-{spiro[2.2]pentan-1amido}pyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-[(1S,2S)-2methylcyclopropanamido]pyridazine-3-carboxamide; 6-cyclopropanamido-4-[(3-methanesulfonyl-6-methylp1ridin-2-yl)amino]-N(2H3)methylpyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-{[5-(trifluoromethoxy)pyridin-2yl]amino}pyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-[(1S)-spiro[2.2]pentan-1amido]pyridazine-3-carboxamide; 4-[(3-methanesulfonylpyridin-2-yl)amino]-N-(2H3)methyl-6-[(1R)-spiro[2.2]pentan-1amido]pyridazine-3-carboxamide; either 6-{[4-chloro-5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino}-4-[(3-methanesulfonyl-6methylpyridin-2-yl)amino]-N-(2H3) methylpyridazine-3-carboxamide or a pharmaceutically acceptable stereoisomer or salt thereof. In another embodiment, a pharmaceutical composition is provided comprising one or more compounds of Formula I, and a pharmaceutically acceptable carrier or diluent. The present invention also relates to pharmaceutical compositions useful for the treatment of diseases associated with the modulation of IL-12, IL-23 and / or IFNa, which act on Tyk-2 to generate inhibition of signal transduction, which comprise compounds of Formula I, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or diluents. The invention also relates to methods for the treatment of diseases associated with the modulation of IL-12, IL-23 and / or IFNa, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to the invention. Formula I. The present invention also provides processes and intermediates for obtaining the compounds of the present invention. The present invention also provides a method for the treatment of proliferative, metabolic, allergic, autoimmune and inflammatory diseases (or the use of the compounds of the present invention for the manufacture of an IF-2019-16830169-APN-ANP#INPI Page 27 of 134 medication for the treatment of these diseases), which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention. The present invention also provides a method for the treatment of an inflammatory or autoimmune disease (or the use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases), comprising administering to a patient who needs that treatment a therapeutically effective amount of a compound of Formula I. The present invention also provides a method for the treatment of a disease (or the use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases), which comprises administering to a patient in need of such treatment a quantity therapeutically effective of a compound of Formula I, wherein the disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, inflammatory bowel disease, psoriasis, Crohn's disease, psoriatic arthritis, Sjógren's syndrome , systemic scleroderma, ulcerative colitis, Graves' disease, discoid lupus erythematosus, adult Still's disease, systemic-onset juvenile idiopathic arthritis, gout, gouty arthritis, type 1 diabetes, insulin-dependent diabetes mellitus, sepsis, septic shock, Shigellosis, pancreatitis ( acute or chronic), glomerulonephritis, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, pancreatitis (acute or chronic), ankylosing spondylitis, pemphigus vulgaris, vasculitis, pemphigus, Kawasaki disease, demyelinating polyneuropathy chronic inflammatory disease (CIPD), dermatomyositis, polymyositis, uveitis, Guillain-Barré syndrome, autoimmune pulmonary inflammation, autoimmune thyroiditis, autoimmune inflammatory eye disease and chronic demyelinating polyneuropathy. The present invention also provides a method for the treatment of an inflammatory or autoimmune disease (or the use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases), comprising administering to a patient who needs that treatment a therapeutically effective amount of a compound of Formula I, wherein the disease is selected from systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, Crohn's disease, ulcerative colitis, type 1 diabetes, psoriasis, rheumatoid arthritis, arthritis juvenile idiopathic systemic onset, spondylitis IF-2019-16830169-APN-ANP#INPI Page 28 of 134 ankylosing and multiple sclerosis. The present invention also provides a method for the treatment of rheumatoid arthritis (or the use of the compounds of the present invention for the manufacture of a medicament for the treatment of rheumatoid arthritis), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula I. Furthermore, the present invention also provides a method for the treatment of a condition (or the use of the compounds of the present invention for the manufacture of a medicament for the treatment of these conditions) 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 acute myeloid leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi sarcoma, multiple myeloma, solid tumors, ocular neovasculization and infantile hemangiomas, B cell lymphoma, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, multiple vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type 1 diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, hot and cold agglutinin disease, Evans syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), sarcoidosis, Sjógren's syndrome, peripheral neuropathies, pemphigus vulgaris and asthma. The present invention also provides a method for the treatment of a disease mediated by IL-12, IL-23 and / or IFNa (or the use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases). , -which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula I. The present invention also provides a method for the treatment of a disease mediated by IL-12, IL-23 and / or IFNa (or the use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases). , which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula I, wherein the disease mediated by IL-12, IL-23 and / or IFNa is a disease modulated by IL-12, IL -23 and / or IFNa. The present invention also provides a method for treating diseases, comprising administering to a patient in need of that treatment IF-2019-16830169-APN-ANP#INPI Page 29 of 134 a therapeutically effective amount of a compound of Formula I in combination with other therapeutic agents. The present invention also provides the compounds of the present invention for use in treatment. In another embodiment, the compounds of Formula I are selected from the exemplified compounds or from combinations of the exemplified compounds or from other embodiments herein. In another embodiment, compounds are provided that have an IC50 <1000 nM in at least one of the assays described below. The present invention can be carried out in other specific ways without departing from the spirit or its essential attributes. The present invention encompasses all combinations of the preferred aspects and / or embodiments of the invention set forth herein. It should be noted that all embodiments of the present invention can be taken together with any other embodiment, in order to describe additional more preferred embodiments. Furthermore, it should be noted that each individual element of the preferred embodiments is its own independent preferred embodiment. Likewise, any element of one embodiment is intended to be combined with any other element of any of the embodiments to describe a further embodiment. DETAILED DESCRIPTION OF THE INVENTION Definitions of the terms used herein and in the appended claims are set forth below. The initial definition provided for a group or term herein applies to that group or term throughout the specification and claims, individually or as part of another group, unless otherwise indicated. Compounds of the present invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of the compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C=N double bonds and the like may also be present in the compounds, and all such stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms. The present compounds can be isolated in forms IF-2019-16830169-APN-ANP#INPI Page 30 of 134 optically active or racemic. In the state of the art, it is known how to prepare optically active forms, for example, by resolving racemic forms or by synthesizing optically active starting materials. All chiral (enantiomeric and diastereomeric) and racemic forms, as well as all geometric isomeric forms of a structure, are anticipated unless the stereochemical or isomeric form is specifically indicated. When any variable (for example, R3) occurs more than once in any constituent or formula of a compound, its definition, in each case, is independent of its definition in each of the other cases. So, for example, if a group is shown to be replaced with 0-2 R3, then that group can optionally be replaced with up to three R3 groups, and R3, in each case, is selected independently of the definition of R3. Furthermore, combinations of substituents and / or variables are only permitted if the combinations produce stable compounds. When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then that substituent can bond to any atom in the ring. When a substituent is listed without indicating the atom through which the substituent is attached to the rest of the compound of a given formula, that substituent can be attached through any atom in that substituent. Combinations of substituents and / or variables are only allowed if the combinations produce stable compounds. When nitrogen atoms (e.g., amines) exist in compounds of the present invention, these can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and / or hydrogen peroxides) to obtain other nitrogen compounds. the present invention. Therefore, all indicated and claimed nitrogen atoms are considered to include the indicated nitrogen and its N-oxide derivative (N->0). In accordance with a convention used in the state of the art, it is used in structural formulas herein to represent the bond that is the point of attachment of the moiety or substituent to the core or main structure. A hyphen that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is linked through the carbon atom. The expression optionally substituted, referring to a particular portion IF-2019-16830169-APN-ANP#INPI Page 31 of 134 of the compound of Formula I (for example, an optionally substituted heteroaryl group), refers to a moiety having 0, 1.2 or more substituents. For example, optionally substituted alkyl encompasses both alkyl and substituted alkyl as defined below. Those of mid-level skill will understand, with respect to any group containing one or more substituents, that these groups are not intended to introduce any substitution or substitution patterns that are spherically impractical, not viable from the point of view of synthesis and / or or intrinsically unstable. As used herein, the term at least one chemical entity is interchangeable with the term a compound. As used herein, the terms alkyl or alkylene include straight-chain or branched aliphatic saturated hydrocarbon groups having the specified number of carbon atoms. For example, C1.C10 alkyl (or alkylene) is intended to include Ci, C2, C3, C4, C5, C3, C7, C3, Cg and Cw alkyl groups. Additionally, for example, “C-i-Ce alkyl” indicates that the alkyl has 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted, such that one or more of their hydrogens are replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl ( for example, n-pentyl, isopentyl, neopentyl) and the like. The terms alkenyl or alkenylene include hydrocarbon chains of linear or branched configuration that have one or more carbon-carbon double bonds that can occur at any stable point in the chain. For example, C2-6 alkenyl (or alkenylene) includes C2, C3, C4, C5, and C6alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl , 2-methyl-2-propenyl, 4-methyl-3-pentenyl and the like. Alkynyl or alkynylene include hydrocarbon chains of linear or branched configuration that have one or more carbon-carbon triple bonds that can occur at any stable point in the chain. For example, C2.6alkynyl (or alkynylene) includes C2, C3, C4, C5 and C3alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. Persons in the mid-level trade will understand that when the designation C02 is used herein, it refers to the —c-o— group. When the term alkyl is used together>tO2(Q®nifPÍJPlen Page 32 of 134 arylalkyl, this combination defines, with greater specificity, at least one of the substituents that the substituted alkyl will contain. For example, arylalkyl refers to a substituted alkyl group, as defined above, wherein at least one of the substituents is an aryl, such as benzyl. Thus, the term aryl(Co-4)alkyl includes a substituted lower alkyl having at least one aryl substituent and also includes an aryl attached directly to another group, i.e., aryl(Co)alkyl. The term heteroarylalkyl refers to a substituted alkyl group, as defined above, wherein at least one of the substituents is a heteroaryl. When referring to an alkenyl, alkynyl, alkylene, alkenylene or substituted alkynylene group, these groups are substituted with one to three substituents, as defined above for the substituted alkyl group. The term alkoxy refers to an oxygen atom substituted with alkyl or substituted alkyl, as defined herein. For example, the term alkoxy includes the group -O-Cvealkyl, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2 -hexoxy, 3hexoxy, 3-methylpentoxy and the like. Lower alkoxy refers to alkoxy groups having one to four carbons. It should be noted that selections for all groups, including, for example, alkoxy, thioalkyl, and aminoalkyl, will be performed by a mid-level trade person to obtain stable compounds. The term “substituted,” as used herein, means that one or more hydrogens on the designated atom or group are replaced by a selection of the indicated group, provided that the normal valence of the designated atom is not exceeded. When a substituent is oxo or keto (i.e. =0), 2 hydrogens are replaced on the atom. Keto substituents are not present on the aromatic moieties. Unless otherwise specified, substituents are indicated in the nuclear structure. For example, it should be noted that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the nuclear structure is the alkyl moiety. Ring double bonds, as used herein, are double bonds that form between two adjacent ring atoms (e.g., C=C, C=N, or N=N). Combinations of substituents and / or variables are allowed only if the combinations result in stable compounds or useful synthetic intermediates. A stable compound or a stable structure refers to a compound that is potent enough to survive isolation in a reaction mixture IF-2019-16830169-APN-ANP#INPI Page 33 of 134 in useful degree of purity, and subsequent formulation into an effective therapeutic agent. It is preferred that the compounds cited herein do not contain an N-halo, S(O)2H or S(O)H group. The term cycloalkyl refers to cyclized alkyl groups, including monocyclic, bicyclic or polycyclic ring systems. C3.7 cycloalkyl includes C3, C4, C5, C6, and C7cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and the like. As used herein, carbocycle or carbocyclic residue means any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic ring, or any 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring. members; and any of them can be saturated, partially unsaturated, unsaturated or aromatic. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [ 4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Unless otherwise specified, preferred carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl. When the term carbocycle is used, it includes aryl. A bridged ring occurs when one or more carbon atoms bond to two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It should be noted that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, the substituents listed for the ring may also be present on the bridge. The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl groups, each of which can be substituted. Accordingly, in compounds of Formula I, the term cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclooctyl, etc., as well as the following ring systems: \------ , IF-2019-16830169-APN-ANP#INPI 34 Page 34 of 134 and the like, which can be optionally substituted on any of the available ring atoms. Preferred cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl and '. The terms halo or halogen refer to chlorine, bromine, fluoro and iodine. The term haloalkyl means a substituted group having one or more halo substituents. For example, haloalkyl includes mono-, bi- and trifluoromethyl. The term haloalkoxy means an alkoxy group having one or more halo substituents. For example, haloalkoxy includes OCF3. Therefore, examples of ring groups include: (fluorenyl) and the like, which can be optionally substituted on any of the available carbon or nitrogen atoms. The terms heterocycle, heterocycloalkyl, heterocycle, heterocyclic or heterocyclyl may be used interchangeably and refer to substituted and unsubstituted 3- to 7-membered monocyclic groups, 7- to 11-membered bicyclic groups, and 10- to 15-membered tricyclic groups. where at least one of the rings has at least one heteroatom (O, S or N), and the ring containing the heteroatom preferably has 1, 2 or 3 heteroatoms selected from O, S and N. Each ring of the group containing a heteroatom can or Page 35 of 134 sulfur and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. The fused rings that complete the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or fully unsaturated. The heterocycle group can be attached to any available nitrogen or carbon atom. As used herein, the terms heterocycle, heterocycloalkyl, heterocycle, heterocyclic and heterocyclyl include heteroaryl groups, as defined below. In addition to the heteroaryl groups described below, exemplary monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2- oxopyrrolodinyl, 2oxoazepinyl, azepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl and the like. Exemplary bicyclic heterocycle groups include quinuclidinyl. Other additional monocyclic heterocyclyl groups include R Ω O The term heteroaryl refers to 5- or 6-membered monocyclic or 9- or 10-membered bicyclic groups, substituted and unsubstituted aromatics, and 11- to 14-membered tricyclic groups having at least one heteroatom (O, S, or N) in al minus one of the rings; the heteroatom-containing ring preferably has 1, 2 or 3 heteroatoms selected from O, S and N. Each ring of the heteroaryl group containing a heteroatom may contain one or two oxygen or sulfur atoms and / or 1 to 4 atoms of nitrogen, as long as the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The fused rings that complete the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. Heteroaryl groups that are bicyclic or tricyclic must include at least one fully aromatic ring, but the other fused rings may be aromatic. Page 36 of 134 can bond to any available nitrogen or carbon atom of any ring. When valency permits, if that other ring is cycloalkyl or heterocycle, it is also optionally replaced with =0 (oxo). Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like. Exemplary heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl and Similar. Exemplary tricyclic heteroaryl groups include carbazolyl, bencidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like. In compounds of Formula I, preferred heteroaryl groups include: , and the like, which can be optionally substituted on any of the available carbon or nitrogen atoms. Unless otherwise indicated, when referring to an aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocycle (e.g., pyrrolidinyl, piperidinyl, and morpholinyl), or heteroaryl (e.g., tetrazolyl, imidazolyl , pyrazolyl, triazolyl, thiazolyl and furyl) specifically, the reference is intended to include rings having 0 to 3, preferably, 0 to 2 substituents selected from those listed above for the aryl, cycloalkyl, heterocycle and / or heteroaryl groups, as appropriate. The term carbocyclyl or carbocyclic refers to a saturated or unsaturated monocyclic or bicyclic ring in which all atoms of all rings are carbon. Therefore, the term includes cycloalkyl and aryl rings. Monocyclic carbocycles have 3 to 6 ring atoms, enifem^l^^^íW-^I^PlLos37 Page 37 of 134 Bicyclic carbocycles have 7 to 12 ring atoms, for example, arranged as a bicycle system [4,5], [5,5], [5,6] or [6,6], or 9 or 10 ring atoms arranged as a [5,6] or [6,6] bicycle system. Examples of monocyclic and bicyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1- enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl and naphthyl. The carbocyclic ring may be substituted, in which case the substituents are selected from those indicated above for the cycloalkyl and aryl groups. The term “heteroatoms” includes oxygen, sulfur and nitrogen. When the term unsaturated is used herein to refer to a ring or a group, the ring or group may be completely or partially unsaturated. Throughout the specification, the person of mid-level craft can choose groups and substituents thereof to obtain stable moieties and compounds, and useful compounds such as pharmaceutically acceptable compounds and / or intermediate compounds useful to obtain compounds. acceptable from a pharmaceutical point of view. The compounds of Formula I may exist in free form (without ionization) or may form salts which are also within the scope of the present invention. Unless otherwise indicated, reference to a compound of the invention is intended to include reference to the free form and salts thereof. The term salts indicates acidic and / or basic salts formed with organic and / or inorganic acids and bases. Additionally, the term salts may include zwitterions (internal salts), for example, when a compound of Formula I contains a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. . Preferred are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts such as, for example, acceptable amine and metal salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may also be useful, for example, in isolation or purification steps that may be used during preparation and are therefore contemplated within the scope of the invention. Salts of the compounds of Formula I can be formed, for example, by the reaction of a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium, such as one in which the salt precipitates or in an aqueous medium, and subsequent freeze-drying. Exemplary acid addition salts include acetates (such as those set forth IF-2019-16830169-APN-ANP#INPI Page 38 of 134 form with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanpropionates, digluconates, dodecylsulfates, ethanesulfonates , fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), iodhydrates, 2hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid ), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as mentioned herein), tartrates, thiocyanates, toluenesulfonates, such as tosylates, undecanoates and the like. Examples of basic salts include ammonium salts, alkali metal salts, such as sodium, lithium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts; barium, zinc and aluminum salts; salts with organic bases (for example, organic amines), such as trialkylamines, such as triethylamine, procaine, dibenzylamine, N-benzyl-p-phenethylamine, 1-ephenamine, N,N'dibenzylethylene diamine, dehydroabiethylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or amines and similar pharmaceutically acceptable salts with amino acids, such as arginine, Usine and the like. Basic nitrogen-containing groups can be quaternized with agents, such as lower alkyl halides (for example, methyl, ethyl, propyl, butyl chlorides, bromides and iodides), dialkyl sulfates (for example, dimethyl, diethyl, dibutyl and diamyl), long chain halides (for example, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (for example, benzyl and phenethyl bromides) and others. Preferred salts include monohydrochloride, hydrogen sulfate, methanesulfonate, phosphate or nitrate salts. The term "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings. and animals without causing excessive toxicity, irritation, allergic reaction or other problems or complications proportional to a reasonable risk / benefit ratio. As used herein, the term acceptable salts from the point of view of IF-2019-16830169-APN-ANP#INPI Page 39 of 134 pharmaceutical view refers to derivatives of the described compounds where the parent compound is modified by the preparation of acidic or basic salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, organic or mineral acid salts of basic groups, such as amines; and alkali or organic salts of acidic groups, such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, of non-toxic organic or inorganic acids. For example, conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids; and prepared salts of organic acids, such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic acids. , fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isotonic and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, salts can be prepared by reacting the basic or free acid forms of these compounds with a stoichiometric amount of the appropriate base or acid in water, in an organic solvent, or in a mixture of the two; In general, non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is incorporated herein by reference. All stereoisomers of the compounds of the present invention are contemplated, whether mixed or in pure or substantially pure form. Stereoisomers may include compounds that are optical isomers by possession of one or more chiral atoms, as well as compounds that are optical isomers by limited rotation around one or more bonds (atropisomers). The definition of the compounds according to the invention includes all possible stereoisomers and their mixtures. In particular, it includes racemic forms and isolated optical isomers having specified activity. Racemic forms can be resolved by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by IF-2019-16830169-APN-ANP#INPI Page 40 of 134 chiral column chromatography. Individual optical isomers can be obtained from racemates by conventional methods, such as salt formation with an optically active acid followed by crystallization. The present invention is intended to include all isotopes of atoms that occur in these compounds. Isotopes include atoms that have the same atomic number, but different mass numbers. To provide general examples and without limitation, isotopes of hydrogen include deuterium and tritium. Carbon bases include 13C and 14C. Generally, isotopically labeled compounds of the invention can be prepared by conventional techniques known to those of ordinary skill in the art or by processes analogous to those described herein, using a suitable isotopically labeled reagent in instead of an unlabeled reagent. Prodrugs and solvates of the inventive compounds are also contemplated. The term prodrug indicates a compound that, after administration to a subject, undergoes a chemical conversion by metabolic or chemical processes to obtain a compound of Formula I and / or a salt and / or a solvate thereof. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound of Formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxy group can form physiologically hydrolyzable esters that function as prodrugs that are hydrolyzed in the body to obtain the compounds of Formula I themselves. Preferably, such prodrugs are administered orally, since hydrolysis occurs in many cases mainly under the influence of digestive enzymes. Parenteral administration can be used when the ester per se is active, or in cases where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of the compounds of Formula I include alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, Ci_6alkanoyloxy-Ci-6 alkyl, for example, acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl, Ci-6 alkoxycarbonyloxy-Ci-6 alkyl, for example, methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4yl)-methyl and other known physiologically hydrolyzable esters used, for example, in the field technician of penicillin and cephalosporin. Such esters can be prepared by conventional techniques known in the art. Various forms of prodrugs are known in the state of the art. For examples of such prodrug derivatives, see. IF-2019-16830169-APN-ANP#INPI Page 41 of 134 a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985) and Widder, K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press (1985); b) Bundgaard, H., chapter 5, “Design and Application of Drugs”, Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and Development, pp. 113-191, Harwood Academic Publishers (1991); and c) Bundgaard, H., Adv. Drug Discov. Rev., 8:1-38 (1992), each of which is incorporated herein by reference. Compounds of Formula I and their salts can exist in tautomeric form, where hydrogen atoms are rearranged to other parts of the molecules, and the chemical bonds between the atoms of the molecules are rearranged accordingly. It should be noted that all tautomeric forms, if they exist, are included in the invention. Furthermore, the inventive compounds may have trans and cis isomers. Furthermore, it should be noted that the solvates (e.g., hydrates) of the compounds of Formula I are also within the scope of the present invention. In general, solvation methods are known in the state of the art. UTILITY The compounds of the invention modulate cellular functions stimulated by IL-23 and by IFNα, including gene transcription. Other types of cellular functions that can be modulated by the compounds of the present invention include, among others, responses stimulated by IL-12. Accordingly, the compounds of Formula I are useful for the treatment of conditions associated with the modulation of the function of IL-23 or IFNa, in particular, the selective inhibition of the function of IL-23, IL-12 and / or IFNa that act on Tyk2 to mediate signal transduction. These conditions include diseases associated with IL-23, IL-12 or IFNa, where the pathogenic mechanisms are mediated by these cytokines. As used herein, the terms treat or treatment encompass the treatment of a disease in a mammal, in particular, a human, and include: (a) preventing or delaying the onset of the disease in a mammal, in particular, when this mammal has a predisposition to the disease, but has not yet been diagnosed; (b) inhibit the disease, that is, stop its development; and / or (c) achieve total or partial reduction of symptoms or disease, and / or alleviate, IF-2019-16830169-APN-ANP#INPI Page 42 of 134 improve, reduce or cure the disease or disorder and / or its symptoms. In view of their activity as modulators of cellular responses stimulated by IL-23-, IL-12 and IFNa, the compounds of Formula I are useful for the treatment of diseases associated with IL-23, IL-12 and IFNa including , among others, inflammatory diseases, such as 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, lupus nephritis, discoid lupus erythematosus, psoriasis; autoinflammatory diseases, including CAPS, TRAPS, FMF, adult Still's disease, systemic-onset juvenile idiopathic arthritis, gout, gouty arthritis; metabolic diseases, including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders, such as bone resorption disease, osteoarthritis, osteoporosis, multiple myeloma-related bone disorder; proliferative disorders, such as acute myelogenous leukemia, chronic myelogenous leukemia; angiogenic disorders, such as angiogenic disorders including solid tumors, ocular neovasculization and infantile hemangiomas; infectious diseases, such as sepsis, septic shock and Shigellosis; neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injuries, oncological diseases and viral diseases, such as metastatic melanoma, Kaposi sarcoma, multiple myeloma and HIV infection, and CMV retinitis and AIDS, respectively. More particularly, specific conditions or diseases that can be treated with the compounds of the 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 reaction, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, arthritis rubella, acute synovitis, pancreatic □ lymphocyte disease; diseases characterized by infiltration IF-2019-16830169-APN-ANP#INPI Page 43 of 134 massive neutrophils; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic inflammatory lung disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejection, fever and myalgia due to infections, cachexia secondary to infections, keloid formation, formation of tissue scars, ulcerative colitis, heartburn, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock and Shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative disease caused by traumatic injuries; angiogenic disorders including solid tumors, ocular neovascularization, and infantile hemangiomas; viral diseases, including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy and herpes; stroke, myocardial ischemia, ischemia in stroke and heart attacks, organ hypoxia, vascular hyperplasia, cardiac and renal revascularization injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, prostaglandin-associated conditions endoperoxidase synthase 2 and pemphigus vulgaris. Preferred treatment methods are those where the condition is selected from Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris. Alternatively, preferred treatment methods are those in which the condition is selected from ischemia-revascularization injury, which includes cerebral ischemia-revascularization injury arising from stroke, and cardiac ischemia-revascularization injury arising from myocardial infarction. Another preferred treatment method is one where the condition is multiple myeloma. When the terms IL-23, IL-12 and / or IFNa associated condition or IL-23, IL-12 and / or IFNa associated disease or disorder are used herein, each is intended to encompass all of the conditions previously identified as if they recur in their entirety, as well as any other condition that is affected by IL-23, IL-12 and / or IFNa. The present invention provides methods for the treatment of these 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. Therapeutically effective amount includes an amount of a compound of the present invention that is effective when administered alone or in combination for IF-2019-16830169-APN-ANP#INPI Page 44 of 134 inhibit the function of IL-23, IL-12 and / or IFNa and / or to treat diseases. Methods for the treatment of conditions associated with IL-23-, IL-12- and / or IFNa may comprise administering the compounds of Formula I alone or in combination with each other and / or other suitable therapeutic agents useful for the treatment of those conditions. . Accordingly, therapeutically effective amount also includes an amount of the combination of the claimed compounds, which is effective to inhibit the function of IL-23, IL-12 and / or IFNa and / or to treat diseases associated with IL-23, IL -12 or IFNa. Examples of these 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 deoxyspergualine (DSG); non-spheroid 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®); antimalarial agents, such as hydroxychloroquine; cytotoxic drugs, such as azatypine and cyclophosphamide; TNF-O inhibitors, such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or RAPAMUNE®) or derivatives thereof. The above other therapeutic agents, when used in combination with the compounds of the present invention, may be employed, for example, in the amounts indicated in the Physicians Desk Reference (PDR) manual or as determined by a person of the mid-level job. In the methods of the present invention, other therapeutic agents may be administered before, during or after administration of the inventive compounds. The present invention also provides pharmaceutical compositions capable of treating conditions associated with IL-23, IL-12 or IFNa by inhibiting Tyk2-mediated signal transduction, including diseases mediated by IL23, IL-12 and / or IFNa, such as were described above. The compositions of the invention may contain other therapeutic agents, as described above, and may be formulated, for example, by the use of conventional solid or liquid carriers or diluents, as well as pharmaceutical additives of a type suitable for the desired mode of administration. (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) in accordance with the techniques known in the field of formulation IF-2019-16830169-APN-ANP#INPI Page 45 of 134 pharmaceutical. Accordingly, the present invention also includes compositions comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier. A “pharmaceutically acceptable carrier” refers to generally accepted means in the state of the art for delivering biologically active agents to animals, in particular, mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors that are within the reach of mid-level practitioners. These 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 administered; the intended route of administration of the composition; and therapeutic indications. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers may include several different ingredients and additives, in addition to the active agent; These additional ingredients are included in the formulation for various reasons, for example, stabilization of the active agent, binders, etc., known to those in the mid-level trade. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in various readily accessible sources, such as Remington's Pharmaceutical Sciences, 17th edition (1985), which is incorporated herein by reference. In its whole. The compounds of Formula I may be administered by any means suitable for the condition being treated, which may depend on the site-specific treatment need or the amount of drug to be administered. In general, although other modes of administration are contemplated, topical administration is preferred for skin diseases and systematic treatment for cancerous or precancerous conditions. For example, the compounds may be administered in oral form, for example, in the form of tablets, capsules, granules, powders or liquid formulations, including syrups; topically, for example, in the form of solutions, suspensions, gels or ointments; sublingually; in oral form; parenterally, for example, by subcutaneous, intravenous, intramuscular or intrasternal infusion or injection techniques (for example, as sterile injectable aqueous or non-aqueous solutions or suspensions) nasally, for example, by inhalation spray; in IF-2019-16830169-APN-ANP#INPI Page 46 of 134 topically, for example, in the form of a cream or ointment; rectally, for example, in the form of suppositories; or in liposomal form. Dosage unit formulations containing non-toxic, pharmaceutically acceptable carriers or diluents may be administered. The compounds may be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved with suitable pharmaceutical compositions or, in particular, in the case of extended release, with devices, such as subcutaneous implants or osmotic pumps. Exemplary compositions for topical administration include a topical carrier, such as PLASTIBASE® (polyethylene gelled mineral oil). Exemplary compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for bulk generation, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents, such as which are known in the state of the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, expanders, disintegrants, diluents and lubricants, such as those known in the state of the art. The inventive compounds may also be administered orally by sublingual and / or buccal administration, for example, with molded tablets, tablets or lyophilized. Exemplary compositions may include fast dissolving diluents, such as mannitol, lactose, sucrose and / or cyclodextrins. These formulations may also include high molecular weight excipients, such as celluloses (AVICEL®) or polyethylene glycols (PEG); a mucosal adhesion auxiliary excipient, such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC) and / or maleic anhydride copolymer (e.g., GANTREZ®); and release control agents, such as polyacrylic copolymer (e.g., CARBOPOL 934®). Lubricating, slipping, flavoring, coloring and stabilizing agents can also be added to facilitate its manufacture and use. Exemplary compositions for administration by inhalation or nasal spray include solutions that may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to improve absorption and / or bioavailability, and / or other solubilizing or dispersing agents, such as those known in the state of the art. IF-2019-16830169-APN-ANP#INPI Page 47 of 134 Exemplary compositions for parenteral administration include injectable solutions or suspensions that may contain, for example, suitable non-toxic diluents or solvents acceptable for parenteral administration, such as mannitol, 1,3-butanediol, water, Ringer's solution, a solution isotonic sodium chloride or other suitable dispersing, wetting or suspending agents, including synthetic monoglycerides and diglycerides, and fatty acids, including oleic acid. Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at room temperature, but which liquefy and / or dissolve. into the rectal cavity to release the drug. The therapeutically effective amount of a compound of the present invention can be determined by a person of average skill in the art and includes example dose amounts for a mammal of about 0.05 to 1000 mg / kg; 1-1000 mg / kg; 1-50 mg / kg; 5-250 mg / kg; 250-1000 mg / kg body weight of the active compound per day, which can be administered as a single dose or in the form of individual divided doses, such as 1 to 4 times per day. It will be understood that the specific dose level and dosing frequency for any particular subject may vary and will depend on various factors, including the activity of the specific compound employed, the metabolic stability and duration of action of that compound, the species , age, body weight, general health, sex and diet of the subject, mode and time of administration, rate of excretion, drug combination and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses and the like. Therefore, when the term “patient” is used herein, it includes all subjects, most preferably mammalian species, affected by modulation of functions mediated by IL-23, IL-12 and / or IFNa. PREPARATION METHODS The compounds of the present invention can be synthesized by various methods available to those skilled in organic chemistry. General synthetic schemes for preparing compounds of the present invention are described below. These diagrams are illustrative and are not intended to limit the IF-2019-16830169-APN-ANP#INPI Page 48 of 134 possible techniques that the mid-level skilled person can use to prepare the compounds described herein. The different methods for preparing the compounds of the present invention will be apparent to those in the mid-level trade. Furthermore, the various steps of the syntheses can be carried out in an alternating sequence to obtain the desired compound(s). Examples of the compounds of the present invention prepared with the methods described in the general schemes are provided in the preparations and examples section below. EXAMPLES The preparation of the compounds of Formula (I), and the intermediates used for the preparation of the compounds of Formula (I), can be carried out using the procedures shown in the following Examples and related procedures. The methods and conditions used in these examples, and the compounds themselves prepared in these examples, are not limiting, but are intended to demonstrate how the compounds of Formula (I) can be prepared. The starting materials and reagents used in these examples, when not prepared by a procedure described herein, are generally commercially available or reported in the chemical literature, or can be prepared using the procedures described herein. chemical literature. In the Examples provided, the phrase dried and concentrated generally refers to the drying of a solution in an organic solvent, either sodium sulfate or magnesium sulfate, and subsequent filtration and removal of the solvent from the filtrate ( in general, at reduced pressure and at a temperature suitable for the stability of the material being prepared). Column chromatography was performed with prepackaged silica gel cartridges using an Isco medium pressure chromatography apparatus (Teledyne Corporation), which was eluted with the indicated solvent or solvent mixture. Chemical names were determined using CHEMDRAW Ultra, version 9.0.5 (CambridgeSoft). The following abbreviations were used: Abbreviations: Abbreviation Meaning Ac Acetyl ________________________________________________—--- ACN Acetonitrile AcOH acetic acid ____— anhyd. Anhydrous ac. Aqueous Bn Benzyl___________________________________________—------ Bu Butyl __________________________————------------- Boc Ter-butoxycarbonyl _______IF-2019-16830169-ΑΡΝ-ΑΝΡΰΤΝΡΤ---- Page 49 of 134 Abbreviation Meaning ____. BOP Benzotriazole-1-¡loxytris-(dimethylamino)-phosphonium hexafluorophosphate CV Column volumes DCE Dichloroethane _______________ DCM Dichloromethane DIPEA Diisopropylethylamine DMF Dimethylformamide DMSO Dimethylsulfoxide EtOAc Ethyl acetate Ethyl Etyl___________________________________________________________________________________ EtOH Ethanol HoH2 Hydrogen h Hours HATU Hexafluor ophosphate of O-(7-azabenzotriazol-1-yl)-N, N, Ν', N'- tetramethyluronium hex Hexane i Iso IPA Isopropyl alcohol ISCO Automated chromatography HOAc Acetic acid HCI Hydrochloric acid HPLC High pressure liquid chromatography__ LC liquids ______— LIHMDS Lithium bis(trimethylsilyl)amide M Molar mM Millimolar Me Methyl _____ MeOH Methanol __________________________________________________ MHz Megahertz min Minute(s) M+1 (M+H)+ MS Mass spectrometry η or N Normal __— nm Nanometer_________________________________________________ nM Nanomolar NMP N-methylpyrrolidine ___ Pd / C Palladium on carbon PdCI2(dppf)2 _[Vrbs(diphenylphosphino)ferrocene]dichloropalladium(ll) _________________ Pd2dba3 Tris(dibenzylideneacetone)dipalladium (0) Ph Phenyl PPh3 Triphenylphosphine Pr Propyl PSI Pounds per square inch rb Round rt Ambient temperature ______ Rt. Retention time sat. Saturated SFC Supercritical Fluid Chromatography TEA Triethylamine TFA Trifluoroacetic Acid THF ' Tetrahydrofuran_________________IF-2019-16830169-APN-ANP#INPI____ Page 50 of 134 Preparations The preparations indicated below are for the synthesis of reagents that were not obtained from commercial sources and were used for the preparation of compounds of Formula I of the invention. All chiral compounds in the tables and schemes are racemic unless otherwise indicated. Reverse-phase preparative high-performance liquid chromatography (HPLC) was carried out with Shimadzu 8A liquid chromatographs using YMC S5 ODS columns (20 x 100, 20 x 250, or 30 x 250 millimeters (“mm”)). Gradient elution was performed with methanol (“MeOH”) / water mixtures in the presence of 0.1% trifluoroacetic acid (“TFA”). Analytical HPLC method used in characterization of examples Analytical HPLC was performed on Shimadzu LC10AS liquid chromatographs using the following methods: Method A (used in all cases unless otherwise noted): Linear gradient from 0 to 100% solvent B over 4 minutes (“min”), with 1 minute (“min”) holding at 100% B. Ultraviolet (“UV”) viewing at 220 nanometers (“nm”) Column: YMC S5 ODS Ballistic 4.6 x 50 mm Flow rate: 4 milliliters (ml) / min Solvent A: 0.2% phosphoric acid, 90% water, 10% methanol Solvent B: 0.2% phosphoric acid, 90% methanol, 10% water Method B: Column: PHENOMENEX® Luna C18(2), 4.6 x 50 mm x 5 pm Mobile phase: (A) 10:90 methanol:water; (B) 90:10 methanokawater Shock absorber: 0.1% TFA Gradient range: 0-100%B Gradient time: 4 min Flow rate: 4ml / min Analysis time: 5 min Detection: Detector 1: UV at 220 nm Detector 2: MS(ESI+) Detector 3: ELSD: Method C: IF-2019-16830169-APN-ANP#INPI Page 51 of 134 Column: Waters SunFire C18, 4.6 x 50 mm x 5 pm Mobile phase: (A) 10:90 methanokawater; (B) 90:10 methanokawater Shock absorber: 0.1% TFA Gradient range: 0-100%B Gradient time: 4 min Flow rate: 4ml / min Analysis time: 5 min Detection: Detector 1: UV at 220 nm Detector 2: MS(ESI+) Detector 3: ELSD: Method D: Column: Acquity BEH C18, 2.1 x 50 mm, 1.7 pm Mobile phase: (A) water; (B) acetonitrile Buffer: 0.05% TFA. Gradient range: 2-98% B (1 min); 98% B (0.5 min); 98-2% B (0.6 min) Running time: 1.7 min Flow rate: 0.8ml / min Analysis time: 1.7 min Detection: Detector 1: UV at 254 nm Detector 2: MS(ESI+) Method E: Column: Waters XBridge C18, 2.1 x 50 mm x 1.7 pm Mobile phase: (A) 5:95 acetonitrile:water (B) 95:5 methanokawater Shock absorber: 0.1% TFA Gradient: 0-100% B Gradient time: 3 min Running time: 3.75 min Flow rate: 1ml / min Analysis time: 3.75 min Detection: Detector 1: UV at 254 nm Detector 2: MS(ESI+) IF-2019-16830169-APN-ANP#INPI Page 52 of 134 Intermediary 1 ch3cn Stage 1 OOO 1. pph3, diethyl ether O 2. acetic acid aq. I μ® I — ·;© Stage 2 N POCI3 Stage 3 LiOH THF Stage 4 THF Stage 5 methylamine 1-propanphosphonic anhydride, TEA DMF Stage 6 Stage 1 Dimethyl 3-oxopentanedioate (3.77 g, 21.65 mmol) was dissolved in acetonitrile (70 ml), and triethylamine (3.02 ml, 21.65 mmol) was added. After cooling to 0 °C, 4-acetamidobenzenesulfonyl azide (5.2 g, 21.65 mmol) was added slowly to the reaction in portions over ∼5 min. After the addition was almost complete, a heavy yellow precipitate formed. The mixture was stirred at room temperature for ~1h and then filtered to remove the precipitated solid. The filter cake was rinsed moderately with additional ACN until the yellow color was completely washed from the solid to obtain a white solid and a cloudy yellow filtrate. The filtrate containing the product was concentrated in vacuo to obtain a yellow solid, which was suspended in a 1:1 mixture of hexanes / Et2O (~ 150 ml), and the suspension was filtered again. The solid was rinsed moderately with 1:1 hexanes / additional Et2O, and the resulting cloudy yellow filtrate was concentrated to obtain 4.59 g of a yellow oil containing a small amount of solid as the crude product mixture containing dimethyl 2- diazo-3-oxopentanedioate. This material was used directly in the next stage. IF-2019-16830169-APN-ANP#INPI Page 53 of 134 Stage 2 To a mixture of the crude product dimethyl 2-diazo-3-oxopentanedioate (20.92 g, 104 mmol) in diethyl ether (250 mL) at room temperature, Ph3P (27.3 g, 104 mmol) was added, and the resulting mixture It was stirred at room temperature for 1 day. The heterogeneous reaction mixture was concentrated to remove ether, and the resulting solids were taken up into AcOH (240 ml) and water (24 ml), and refluxed for 4 h. The reaction was cooled and concentrated in vacuo to obtain a pale yellow semisolid that was coevaporated with 2 portions of toluene (2 x 50 ml) to remove residual AcOH. The resulting solids were then suspended in 75 ml of saturated aqueous sodium carbonate and 75 ml of water, and the mixture was extracted with DCM (4 x 200 ml) to remove impurities. The aqueous layers were filtered to obtain a clear yellow solution which was cooled in an ice bath and carefully made acidic by dropwise addition of 6N aqueous HCl. Once the desired pH (~1-2) was reached, a heavy cream-colored precipitate formed. The mixture was stirred at 0 °C for ~5 min, then the solid was collected by vacuum filtration and rinsed moderately with ice water. The solid was partially air dried in the funnel, then the still wet solid was transferred into a round flask (rb) and dried under vacuum over the weekend to obtain methyl 4,6dihydroxypyridazine-3-carboxylate (11.76 g , 69.1 mmol, 66.5% yield). Stage 3 A suspension of methyl 4,6-dihydroxypyridazin-3-carboxylate (11.7 g, 68.8 mmol) in POCl3 (110 ml, 1180 mmol) was heated to reflux for 3 h, during which time , the mixture became an almost homogeneous dark brown solution. The reaction mixture was cooled to room temperature, allowed to stand overnight, and concentrated in vacuo. The resulting dark brown residue was dissolved in DCM (~300 ml) and slowly poured into ~500 ml of crushed ice while shaking the flask. After the addition was complete, 200 mL water was slowly added until the mixture became stirrable, and the mixture was stirred while warming to room temperature for ~3 h. The resulting phases were separated, and the aqueous portion was extracted with additional DCM (3 x 100 ml). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to obtain a white solid as the pure product, methyl 4,6dichloropyridazine-3-carboxylate (9.16 g, 44.2 mmol, 64.3% yield). The material was used as is without further purification. MS (M+1) m / z: 206.9 (MH+). LC retention time 0.80 min [A]. IF-2019-16830169-APN-ANP#INPI Page 54 of 134 Stage 4 To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (5.5 g, 26.6 mmol) in THF (60 mL), at 0 °C, was added 1 M lithium hydroxide solution (39.9 e, 39.9 mmol) with stirring. The resulting mixture was stirred continuously at 0 °C for 40 min. The THF was removed, and the aqueous layer was acidified with 1.5 N HCl to obtain a white solid. The mixture was filtered, and the solid filter cake was washed with water and dried under vacuum overnight to obtain 4,6-dichloropyridazine-3-carboxylic acid (5 g, 25.9 mmol, 98% yield). MS (M+1) m / z: 193 (MH+). LC retention time 0.19 min [D], Stage 5 To a solution in THF (20 ml) of 4,6-dichloropyridazine-3-carboxylic acid (0.734 g, 3.80 mmol) and 3-(methylthio)pyridin-2-amine (0.68 g, 4.85 mmol), LIHMDS (9.51 ml, 9.51 mmol) was added slowly at 0 °C. The reaction was stirred at 0 °C for 15 min and then warmed to room temperature for 2 h. The reaction was quenched with water (~5 ml) and acidified with HCl (1 N, 15 ml). The resulting precipitate was filtered, washed with water and dried under vacuum overnight to obtain, as an orange solid, 6-chloro-4-((3-(methylthio)pyridin-2-yl)amino)pyridazin-3 acid. -carboxylic acid (0.712 g, 2.40 mmol, 63.1% yield). MS (M+1) m / z\ 297.0 (MH+). LC retention time 0.86 min [A]. 1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 9.15 (s, 1H), 8.34 (dd, J=4.9, 1.7 Hz, 1H), 7 .95 (dd, J=7.7, 1.7 Hz, 1H), 7.18 (dd, J=7.7, 4.8 Hz, 1H), 2.53 (s, 3H). Stage 6 1-Propanphosphonic anhydride (0.409 mL, 0.700 mmol) was added to a DMF solution (1.9 mL) of 6-chloro-4-((3-(methylthio)pyridin-2-yl)amino)pyridazine-3carboxylic acid. (0.1385 g, 0.467 mmol) and TEA (0.130 mL, 0.933 mmol) at room temperature. After 2 min, a suspension was formed. The reaction was stirred at room temperature for 1 hour before the addition of methylamine (0.439 g, 4.67 mmol). The reaction was stirred for 2 hours at room temperature, diluted with water, and the suspension was filtered and washed with water. The solid was dried under vacuum overnight to obtain the product 6-chloro-N-methyl-4-((3-(methylthio)pyridin-2yl)amino)pyridazine-3-carboxamide (0.112 g, 0.362 mmol, 78% performance, Intermediate 1). MS (M+1) m / z: 311.1 (MH+). LC retention time 0.92 min [E], NMR (400 MHz, DMSO-d6) δ 12.35 - 12.30 (m, 1H), 9.49 (br d, J=4.4 Hz, 1H), 9.14 (s, 1H), 8 .30 (dd, J=4.8, 1.4 Hz, 1H), 7.93 - 7.87 (m, 1H), 7.16 (dd, J=7.7, 4.9 Hz, 1H ), IF-2019-16830169-APN-ANP#INPI Page 55 of 134 2.88 (d, J=4.9 Hz, 3H), 2.55 (s, 3H). PPh3diethyl ether acetic acid, water Stage 1 Intermediary 2 LiOH THF, MeOH, Water Stage 2 et N-Et, cd3nh2.hci, dipea POCI3 Stage 3 Lee THF Stage 4 Stage 1 Diethyl 2-diazo-3-oxopentanedioate (180 g, 789 mmol) was dissolved in diethyl ether (1800 ml), triphenylphosphine (207 g, 789 mmol) was added, and stirring continued overnight. The diethyl ether was removed under reduced pressure, and the thick orange mass was dissolved in acetic acid (180 ml) and water (1800 ml). The clear solution was heated to 110 °C which was held for 3 h. The starting material was consumed. The acetic acid was removed under reduced pressure. The obtained thick mass was kept for one day in a cold room at about 0 °C during crystallization. DCM was added, and the suspension was stirred and filtered. The filter cake was washed with DCM and collected as the desired product, ethyl 4,6-dihydroxypyridazine-3-carboxylate (80 g, 434 mmol, 55.1% performance). MS (M+1) m / z: 185.1 (MH+). LC retention time 0.51 min [A]. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.45 - 6.22 (m, 1H), 4.65 - 4.40 (m, 2H), 1.60 -1.40 (m, 3H). Stage 2 In a 5000 ml round flask, ethyl 4,6-dihydroxypyridazine-3 carboxylate (200 g, 1086 mmol) was dissolved in THF (2000 ml), methanol (1000 ml), and water (800 ml). LiOH (137 g, 3258 mmol) was added slowly at room temperature and stirred at room temperature for 3-4 h. The starting material was removed. The solvent was removed at 50 °C under reduced pressure to obtain a yellow solid. The solid was acidified reuru d ou k, d picov h IF-2019-16830169-APN-ANP#INPI Page 56 of 134 with aqueous HCl solution (400 ml) (1:1 ratio) at 0 °C and stirred at room temperature for 30-40 minutes. The solid was filtered and washed with water. It was then dried under vacuum for 1–2 h. This solid was absorbed into 300 ml of methanol:DCM (2:8) and stirred at room temperature for 20-25 minutes. The mixture was filtered, and the solid was washed with methanol and dried under vacuum for 1 h. The desired product was obtained as a yellow solid, 4,6-dihydroxypyridazine-3-carboxylic acid (153 g, 951 mmol, 88% yield). MS (M+1) m / z: 156.9 (MH+). LC retention time 0.31 min [A].1H NMR (400 MHz, deuterium oxide) δ 6.00 - 5.34 (m, 1H), 4.75 (s, 7H) Step 3 A suspension of 4,6-dihydroxypyridazine-3-carboxylic acid, HCl (15 g, 78 mmol) and Ν,Ν-diethylaniline (12.39 ml, 78 mmol) in POCl3 (200 ml) was stirred at 110° C in a drying tube for 1 h. The reaction was complete after 1 h. POCI3 was removed in vacuo and coevaporated 3x with DCE. The crude intermediate, acid chloride, was dissolved in 200 ml of THF. D3-methylamine, HCl salt (2.75 g, 38.9 mmol) was added as a solid. The reaction was cooled to 0 °C. 2x DIPEA (13.61 mL, 78 mmol) was added. The ice bath was removed, and the reaction was stirred at room temperature. After 45 min, the reaction was complete. The THF was removed in vacuo. The crude product was suspended in DCM, then evaporated in Celite. This solid material was eluted with 0-100% EtOAc in hexanes through a 330 g silica gel column. The reaction afforded 4,6-dichloro-N-[D3]-methylpyridazine-3-carboxamide (6.1 g, 29.2 mmol, 74.9% yield). MS (M+1) m / z: 209.1 (MH+) · LC retention time 0.64 min [B]. 13C NMR (101 MHz, chloroform-d) δ 161.7, 158.43 - 156.22 (m, 1C), 149.8, 139.8, 130.7, 26.5 Stage 4 To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide and 3(methylthio)pyridin-2-amine (0.205 g, 1.464 mmol) in THF (10 mL) at room temperature, bis(trimethylsilyl) was added. lithium amide in THF (3.59 ml, 3.59 mmol) for 5 min. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 ml). The mixture was adjusted with 11 N HC solution to pH 9-10, and further diluted with water (80 ml). The precipitated product, 6-chloro-Ntrideuteromethyl-4-((3-(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (0.297 g, 0.950 mmol, 66.2% yield, Intermediate 2), was collected as a pale solid by suction filtration and dried at 50 °C under vacuum. IF-2019-16830169-APN-ANP#INPI Page 57 of 134 MS (M+1) m / z: 313.1 (MH+). LC retention time 0.90 min [A], Intermediary 3 Stage 1 To a white heterogeneous solution of 4,6-dichloronicotinic acid (24.00 g, 125 mmol) in dichloromethane (250 ml) in nitrogen at 0 °C, N,N-dimethylformamide (1 ml, 12.91 mmol). Oxalyl dichloride (14 ml, 162 mmol) was then added for 12 min. After 15 min, the ice-water bath was removed, and the reaction was stirred to room temperature. After 1 h, N,N-dimethylformamide (1 ml, 12.91 mmol) was added to the still homogeneous white solution. After a total of 2.5 h, the reaction showed >95% conversion to the desired product. After a further 30 min, the reaction was concentrated in vacuo. DCM (100 ml) was added, and the solution was concentrated in vacuo. Another portion of DCM (100 ml) was added, and the solution was concentrated in vacuo to obtain the crude product that was used in the next step. The sample was inactivated with ethanol. The detected mass is o Cle,oA¿1 MS (M+1) m / z: 220.08 (MH+). LC retention time 0.95 min [B], Stage 2 To a solution of 4,6-dichloronicotinoyl chloride (26.3 g, 125 mmol) and methand3-amine, HCl salt (11.46 g, 163 mmol) in DCM (250 ml) in nitrogen at 0 °C, DIPEA (65.5 ml, 375 mmol) was added with a syringe. After 20 min, the ice-water bath was removed, and the reaction was stirred to room temperature. The reaction was stirred overnight and completed. The reaction mixture was washed with 0.5 N aqueous HCl (50 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 150 ml). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The reaction mixture containing the product was purified with silica gel chromatography (1.5 kg Gold silica column) which was eluted with hexane and ethyl acetate. The product was collected at 60% ethyl acetate. 22.83 g of a slightly yellow solid were obtained, which was crushed with EtOAc (40 ml) and ςρ pniuaoó with EtOAc (20 ml) to obtain 4,6-diclpro-N-(methyl-d3)nicotinamide (21 .93 rinsed with my, Tf-20 19-16830169-APN-ANP#INPI Page 58 of 134 g, 105 mmol, 84% yield) as a white solid. MS (M+1) m / z\ 208.1 (MH+). LC retention time 0.58 min [Bj. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.71 - 8.63 (m, 1H), 7.47 - 7.40 (m, 1H), 6.35 -6.08 (m, 1H). Example 1 Na2WO4.2H2O 30% h2o2 Acetic Acid Stage 2 Stage 1 A solution of Intermediate 2 (0.1028 g, 0.329 mmol, 6-chloro-Ntrideuteromethyl-4-((3-(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide), 5-fluoropyridin2-amine ( 0.0845 g, 0.754 mmol), N-methyl2-pyrrolidinone (1 ml) was microwaved at 150 °C for 1 h. The entire reaction mixture was diluted in ethyl acetate (10 mL) and filtered through Celite. The filtrate was concentrated in vacuo. DMSO (1 ml) and water (20 ml), and then saturated NaHCO3, were added to the residue. The precipitate was collected, filtered and washed with water to obtain the crude product as an orange solid. The crude product was purified by flash chromatography using a 4 g ISCO column that was eluted with 05% MeOH / DCM (4 cv, 0%; 40 cv, 0-5%). Appropriate fractions (2-3% elution) were collected and concentrated in vacuo to obtain the product, 6-((5fluoropyridin-2-yl)amino)-N-(methyl-d3)-4-((3-( methylthio)pyridin-2-yl)amino)pyridazine-3carboxamide, (0.035 g, 0.078 mmol, 23.85% yield) as a light yellow solid. MS (M+1) m / z: 389.2 (MH+). LC retention time 0.94 min [BJ. Stage 2 To a homogeneous yellow solution of the reagent, 6-((5-fluoropyridin-2-¡l)amino)N-(methyl-d3)-4-((3-(methylthio)pyridin-2-yl)amino)pyridazin- 3-carboxamide (0.035 g, 0.090 IF-2019-1683 0169-APN-ANP#INPI Page 59 of 134 mmol), in acetic acid (0.3 ml), sodium tungstate dihydrate (0.0311 g, 0.094 mmol) was added to obtain a suspension. 30% hydrogen peroxide (0.2 ml, 1.958 mmol) was added, resulting in homogeneity. After 1.5 h, water (2 ml) was added to the reaction, which was extracted with ethyl acetate (3 x 15 ml). The organic layers were combined and washed with saturated aqueous sodium bisulfite (5 mL) and water (5 mL) successively, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was diluted with DMSO (0.5 ml) and MeOH (1.5 ml) and subjected to autopreparative HPLC. Appropriate fractions were collected; NaHCO3 (solid) was added, and the fractions were concentrated in vacuo and not to dryness. The reaction mixture was extracted with DCM (3x), the organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo to obtain the product, 6-((5-fluoropyridin-2-yl)amino)- N-(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2yl)amino)pyridazine-3-carboxamide (0.00435 g, 10.35 pmol, 11.48% yield). MS (M+1) m / z: 421.1 (MH+). LC retention time 0.61 min [B],1H NMR (400 MHz, DMSO-d6) δ 12.26 - 11.92 (m, 1H), 10.54 - 10.32 (m, 1H), 9.67 9.32 (m, 1H), 9.26 - 9.05 (m, 1H), 8.87 - 8.58 (m, 1H), 8.42 - 8.19 (m, 2H) , 7.88 - 7.64 (m, 2H), 7.47-7.15 (m, 1H). Or HN^N Yo R5 The following examples were prepared in a similar manner to the preparation of Example 1. Table 1 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 2 H 432.47 433.2 0.61 [B] 3 H 416.47 IF-2019-4 417.2 6830169 -A 0.59 [B] PN-ANP / / INPI-—। Page 60 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 4 xz^ ---n 420.44 421.1 0.60 [B] 5 F ?snaJ H 420.44 421 .2 0.66 [B] 6 , 64 [A] 9 0 407.46 408.1 0.73 [A] 10 H 416.47 417.2 0.60 [B] 12 / n-n ΓΝ H 430.46 431.1 0.68 [A] 13 OH H 460.53 461.3 0.58 [B] 14 z—Z o z=A zx 443.5 444.1 0.60 [A] IF-2019-16830169-APN-ANP#INPI Page 61 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 15 2 y 2= / 2X 443.5 444.1 0.59 [A] 16 U. zx 'Άΐ 420.44 421.0 0.64 [A] 17 / N-\ H 419.48 420.2 0.60 [B] 18 zx 433.46 434.1 0.61 [A] 19 xz V=z z / / Tl - π τι 471.43 472.1 0.72 [A] 20 A zx 455.46 456.0 0.66 [A] 21 N^N ft / / H 433.46 434.1 0.58 [B] 22 N < / 0HH 478.52 479.1 0.66 [A] 23 A'A H 365.43 366.2 1.3 [QC-ACNAA-XB] 24 N^i^NH2 H 459.54 460.2 1 [QC-ACNTFA-XB] IF-2019-16830169-APN-ANP#INPI Page 62 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 25 I 0 A aJi h H 501.58 502.1 1.3 [QC-ACNAA-XB] 26 F r'V H 473.45 474.0 0.65 [A] 27 IZ^ V=z o / -2 °-A “Π n 471.43 472.1 0.78 [B] 28 eo Q 0-0 zx 436.48 437.0 0.57 [A] 29 / Cl N < z U- UX \ / \ / ​​° \ / “ z= / zx 528.53 528.8 0.69 [A] 32 H 653.16 653.1 1.9 [QC-ACNAA-XB] 33 H 467, 52 468.2 1.4 [QC-ACNAA-XB] IF-2019-16830169-APN-ANP#INPI Page 63 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 34 N^N H I 446.5 446.9 0.58 [A] 35 N^N H 458.52 458.9 0, 58 [A] 36 OH ς II J / H 490.55 490.9 0.60 [A] 37 z Q ZI 443.5 444.0 0.65 [A] 38 I „!< _N. H 446.5 446.9 0.54 [A] 39 < JL H 431.49 431.9 0.63 [A] 40 Ϊ N^N ?ΝΛΑ H 443.5 444.0 0.56 [A] 41 OMe N^N ?baa Η V 487.55 488 1.1 [QC-ACNTFA-XB] 42 N'^AyA^o^ H 447.49 447.9 0.58 [A] 43 O S^V / Η V 411.43 411.9 0.67 [A] IF-2019-16830169-APN-ANP#INPI Page 64 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 44 u. ^Zl 411.43 412.0 0.63 [A] 45 O Η V F 429.42 430.0 0.70 [A] 46 O !iV 407.46 408.08 0.69 [A] 47 °=< ZI 419.47 420.0 0.71 [A] 48 o Η V 407.46 408.08 0.69 [A] 49 O ib Η V 407.46 408.08 0.69 [A] 50 . ΐ J H 541.52 541.8 0.65 [A] 51 IZ^ hk z 406.44 406.8 0.61 [A] 52 H 567.56 567.7 0.74 [A] 53 % iz h z 406 .44 406.8 0.58 [A] 56 IZ^ h 1 432.48 433.3 0.68 [B] 57 n^n -- x·^-7 H 434.49 434.8 0.64 [ TO] Page 65 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 58 N'<> H 406.44 406.8 0.67 [A] 59 Η V 467.52 468.2 0 .75 [B] 60 ZI 441.48 441.8 0.64 [A] 61 zx 457.53 457.8 0.58 [A] 62 N-Sx H 422.5 422.8 0.60 [A] 63 P o zx %> 489.53 489.9 0.58 [A] 64 „hL .0. / k N' γ H 477.51 478.2 0.59 [A] 65 / O ΓνΤΊ^ΝΗ! H 516.6 516.9 0.8 [QC-ACNTFA-XB] 66 0 h 455.51 456.2 0.78 [A] 67 \ / 0 N<=Y^0^VNH2 H 517.58 518, 3 0.8 [QC-ACNTFA-XB] IF-2019-16830169-APN-ANP#INPI Page 66 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 68 Η V 437.53 438.08 0.91 [A] Example 69 1. Xantphos, CsCO3iPd2dba3Dioxane 2.Na2WO4.2H2O,H2O2,Na2S2O3 Acetic acid________ Stage 1 Stage 1 A mixture of 6-chloro-N-(methyl-d3)-4-((3-(methylthio)pyridin-2-yl)amino)pyridazine-3carboxamide (20 mg, 0.064 mmol, Intermediate 2), N-(( 6-aminopyridin-3yl)methyl)acetamide (15.84 mg, 0.096 mmol), Pd2(dba)3 (5.86 mg, 6.39 pmol), Xantphos (7.40 mg, 0.013 mmol) and Cs2CO3 (41.7 mg, 0.128 mmol) in dioxane (1.0 ml) was purged with nitrogen for 5 min. The reaction was placed in a preheated heating block at 130 °C for 2 h to obtain the sulfide intermediate (M+H=442). The solvent was concentrated, and the material was redissolved in AcOH (2 ml). Sodium tungstate dihydrate (6.33 mg, 0.019 mmol) and hydrogen peroxide (98 μΙ, 3.20 mmol) were added to the solution, and the mixture was stirred at room temperature for 1 h. Sodium thiosulfate (505 mg, 3.20 mmol) was added, and the reaction mixture was stirred for 10 min. The solvent was removed to obtain 6-((5-(acetamidomethyl)pyridin-2j|)amino)-N-(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2-yl)amino)pyridazin- 3-carboxamide (3 mg, 5.7 pmol, 8.92% yield, 90% purity). MS (M+1) m / z: 421.1 (MH+) LC retention time 0.61 min [B],1H NMR (500 MHz, DMSO-d6) δ 12.14 - 12.02 (m , 1H), 10.36 - 10.25 (m, 1H), 9.57 9.43 (m, 1H), 9.18 - 9.05 (m, 1H), 8.69 - 8.59 ( m, 1H), 8.40 - 8.33 (m, 1H), 8.32 - 8.25 IF-2019-16830169-APN-ANP#INPI Page 67 of 134 (m, 1H), 8.22 - 8.14 (m, 1H), 7.67 - 7.59 (m, 2H), 7.38 - 7.28 (m, 1H), 4 .21 (br s, 3H), 3.41 - 3.33 (m, 2H), 1.89 - 1.83 (m, 3H). The following examples were prepared in a similar manner to the preparation of the product of Example 69. Table 2 Example No. NR2R5 MW m / z [M+Hf Rt (min) [Method] 70 _ zz 501.58 502.3 0.9 [QC-ACNTFA-XB] 71 r~° H 376.46 377.2 0.8 [QC-ACNTFA-XB] 72 II H γν x γ Η / \ 501.62 502.3 1.1 [QC-ACN-AAXB] 73 ΙΖ^1 Ζ- 487.6 487.9 1.4 [QC-ACN -AAXB] 74 0 Η 517.58 518.2 1 [QC-ACNTFA-XB] 75 ν / 0 Η 529.59 530.37 0.98 [QC-ACNTFA-XB] IF-2019-16830169-APN-ANP#INPI Page 68 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 76 / 0 N'XfXX, jJ O ΓΝ H 527.62 528.2 1.3 [QC-ACN-AAXB] 77 OH H 490.55 491 1.3 [QC-ACN-AAXB] 78 O i N N < h H______________________ 545.63 546.1 1.5 [QC-ACNTFA-XB] 79 O ,,Χ-ο-χ H 531 .61 532 1.5 [QC-ACN-AAXB] 80 N < JL^n H 433.46 434.1 1.3 [QC-ACN-AAXB] 81 xz^ Q 487.55 488.17 1.12 [ QC-ACNTFA-XB] 82 nX H 416.47 417.3 1.5 [QC-ACN-AAXB] 83 / 0. / N X H 447.49 448.2 1.1 [QC-ACN-AAXB] 85 xz Vz (\ z A / / 417.46 418.2 0.8 [QC-ACNTFA-XB] IF-2019-16830169-APN-ANP#INPI Page 69 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 86 •Z Ί Z= / ZI 421.43 422.3 0.9 [QC-ACNTFA-XB] 87 u. or. zx 438.43 439 1.4 [QC-ACN-AAXB] 88 / N'N < AACF· H 473.45 474.2 1.5 [QC-ACN-AAXB] 89 N / 5A^N\í;; :^'CI 5£νΛ·^ Η 529.97 530 1.4 [QC-ACN-AAXB] 90 % χζ ο 437.88 438 1.3 [QC-ACN-AAXB] 91 / ^ / CF3 Η 470, 45 471.18 1.73 [QC-ACN-AAXB] 92 co Γ / \\ U. / / V. ο—ν y ^ζχ 563.53 563.9 1.6 [QC-ACNTFA-XB] 93 ? Λ*Ν Η 417.46 417.9 1 [QC-ACNTFA-XB] 94 / Cl N Ά<ί>Ν ΓΝ H 555.53 556.2 95 n LL. O z z= / zx 471.43 472.2 1.6 [QC-ACN-AAXB] IF-2019-16830169-APN-ANP#INPI Page 70 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 96 N^i H 446.5 447.1 1.1 [QC-ACNTFA-XB] 97 ^ZI 501.54 502 .2 0.8 [QC-ACNTFA-XB] 98 -R ZI 431.49 432.1 0.7 [QC-ACNTFA-XB] 99 xz fx z \ 1 471.55 472.1 1.6 [QC- ACN-AAXB] 100 r^° N H 515.61 516.1 1.5 [QC-ACN-AAXB] 101 á zx 461.52 462.2 1.2 [QC-ACN-AAXB] 102 ?snaR H 478, 55 479.2 1.8 [QC-ACN-AAXB] 103 r^° Y inaJ ' H 501.58 502 1.4 [QC-ACN-AAXB] 104 ,N. X) <f H 515.51 ------- IE 516.1 -2019 16830169-A 1.5 [QC-ACN-AAXB] LPN-ANP#INPI— Page 71 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 105 iz^1 o a-o i--------------------- -------------------------------------------------- -------------------------------------------------- -------------------------------------------------- -------------------------------------------------- -------------------------------------------------- -------------------------- 515.61 516.2 1.1 [QC-ACNTFA-XB] 106 sSnAA H 479.53 480, 3 1.6 [QC-ACN-AAXB] 107 0 J H 558.63 559 1.5 [QC-ACN-AAXB] 108 0 H 395.45 396.2 1.3 [QC-ACN-AAXB] 109 cf3 H 546.54 547.2 1.7 [QC-ACNTFA-XB] 110 N Ύ jSnAJ H 488.54 489.2 1.2 [QC-ACN-AAXB] 111 OX ZT 479.53 479.9 1.4 [ QC-ACNTFA-XB] 112 0 H 383.4 384.1 1 [QC-ACN-AAXB] IF-2019-16830169-APN-ANP#INPI Page 72 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 113 cf3 H 470.45 471.1 1.7 [QC-ACN-AAXB] 114 H 479.53 480.2 1 .7 [QC-ACN-AAXB] 115 < JÍ^N H 479.53 480.1 1.6 [QC-ACN-AAXB] 116 N^N Η 459.54 459.9 1.5 [QC-ACN-AAXB ] 117 IZ Z / ) A / / 478.55 479 1.5 [QC-ACNTFA-XB] 118 O H 411.45 412.13 1.07 [QC-ACN-AAXB] 119 0 H 409.48 410.2 1.5 [QC-ACN-AAXB] 120 0 I H 407.46 408.2 1.3 [QC-ACN-AAXB] 121 0 Η H 396.44 397.2 0.8 [QC-ACNTFA-XB] 122 0 I ______________Η H__________ 424.49 425.1 1.4 [QC-ACN-AAXB] IF-2019-16830169-APN-ANP#INPI Page 73 of 134 Example No. NR2R5 MW m / z [M+Hf Rt (min) [Method] 123 0 H 449.5 449.9 1 [QC-ACNTFA-XB] 124 0 H 449.5 450 1.1 [QC- ACNTFA-XB] 125 0 h Vk F 425.45 426.1 1.19 [QC-ACN-AAXB] 126 0 425.45 426.1 1.31 [QC-ACN-AAXB] 127 cf3 vA <¿N^ N H 471.43 472.1 1.4 [QC-ACNTFA-XB] 128 H 447.53 448.1 1.7 [QC-ACN-AAXB] 129 0 I H 409.48 410.2 1.3 [QC- ACNTFA-XB] 130 N^N H 445.52 446.3 1.4 [QC-ACN-AAXB] 131 0 fiV 395.45 396.1 1.2 [QC-ACN-AAXB] 132 o H 397.42 398 1.2 [QC-ACNTFA-XB] 133 u O H 473.52 474 1.5 [QC-ACNTFA-XB] IF-2019-16830169-APN-ANP#INPI Page 74 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 134 xz^ >° _ 1--------------------- -------------------------------------------------- -------------------------------------------------- -------------------------------------------------- -------- 411.45 412.2 1.2 [QC-ACNTFA-XB]___ 135 0 H 370.42 371.2 1.1 [QC-ACNTFA-XB] 136 0 H 411.45 412.3 1.4 [QC-ACNTFA-XB] 137 0 H 383.44 384.2 1 [QC-ACNTFA-XB] 138 cf3 N^'N 5Sn^ H 471.43 472.3 1.4 [QC -ACN-AAXB] 139 0 1 H 423.51 424.2 1.4 [QC-ACNTFA-XB] 140 n UO / o 0 zx 486.44 487.3 1.68 [QC-ACN-AAXB] 141 N / W ÍnAzN H 442.47 443.2 1 [QC-ACNTFA-XB] 142 O II .XT H 478.48 479.1 1.1 [QC-ACN-AAXB] 143 / N-N _ 0 OH Π 449.46 450.1 0.9 [QC-ACN-AAXB] 144 IF-2019-16830169-APN-ANP#INPI Page 75 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 145 o Η V 421.49 421.9 1.4 [QC-ACN-AAXB] 147 ZZ^ z — A—\ O ) ' z / 523.02 523.4 1.7 [QC-ACN-AAXB] 148 ) 2 504.58 505.4 1.3 [QC-ACN-AAXB] 151 F OH H 478.52 479.1 1 [QC-ACNTFA-XB] 152 H 442.51 442.9 1.6 [QC- ACN-AAXB] 153 O Η V 421.49 422.1 1.4 [QC-ACN-AAXB] 154 H 446.5 447.1 1.2 [QC-ACN-AAXB] 155 / CD3 H 449.52 450 .2 1.2 [QC-ACN-AAXB] 156 Ή H 449.52 450.2 1.4 [QC-ACN-AAXB] IF-2019-16830169-APN-ANP#INPI Page 76 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 157 z—¿ zx 474.55 475.3 1.1 [QC-ACNTFA-XB] 158 IZ^ o o 476.53 477.2 1.04 [QC-ACNTFA-XB] Example 159 , Xantphos, CsCO3iPd2dba3 Dioxane Stage 2 Stage 1 Lithium bis(trimethylsilyl)amide (0.581 ml, 0.581 mmol, 1 M in THF) was quickly added to a solution of 3-(methylsulfonyl)pyridin-2-amine (0.05 g, 0.290 mmol) and 4,6dichloro-. N-trideuteromethylpyridazine-3-carboxamide (0.073 g, 0.348 mmol) in THF (5 ml) at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for thirty minutes. The reaction mixture was quenched with 1N HCl and MeOH, and concentrated in vacuo. The product was subjected to silica gel chromatography using ISCO and eluted with 010% MeOH / DCM. The fractions containing the product were combined and concentrated in vacuo to obtain 6-chloro-N-(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2yl)amino)pyridazine-3-carboxamide (40 mg , 0.116 mmol, 40% yield). MS (M+1) m / z: 345.08 (MH+) · LC retention time 0.71 min [A]. Stage 2 A stirred mixture of 6-chloro-N-trideuteromethyl-4-((3-(methylsulfoníl)pyridín-2yl)amino)pyridazín-3-carboxamide (0.025 g, 0.073 Page 77 of 134 (6.79 mg, 0.080 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.664 mg, 0.725 pmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.420 mg, 0.725 pmol ) and cesium carbonate (0.071 g, 0.218 mmol) in 1,4-dioxane (2 mL) was heated in a sealed container at 130 °C for one hour. The reaction mixture was diluted with ethyl acetate (5 mL), filtered, and the filtrate was concentrated. The residue was dissolved in 1 ml of DMF and purified with preparative HPLC. The desired fractions were collected and concentrated to obtain 6-(cyclopropanecarboxamido)-N-trideuteromethyl-4-((3-(methylsulfonyl)pyridin-2yl)amino)pyridazine-3-carboxamide (4 mg, 10.17 pmol, 10 .4% performance). MS (M+1) m / z\ 394.08 (MH+)· LC retention time 0.64 min [A],1H NMR (500 MHz, DMSO-d6) δ 9.61 - 9.36 (m , 1H), 9.31 - 9.08 (m, 1H), 8.80 - 8.53 (m, 1H), 8.37 - 8.07 (m, 1H), 7.52 - 7.20 (m, 1H), 2.19 - 2.04 (m, 1H), 0.94 - 0.73 (m, 4H). The following examples were prepared in a similar manner to the product of Example 159: Table 3 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 160 Q ^zz 402.5 403.1 0.56 [A] 161 1Z o 439.9 440.1 0.64 [TO] Example 163 IF-2019-16830169-APN-ANP#INPI Page 78 of 134 , Xantphos, CsCO3iPd2dba3 Dioxane, N-Methyl-2-pyrrolidinone Stage 1 Stage 1 A mixture of 6-chloro-N-trideuteromethyl-4-((3-(methylthio)pyridin-2yl)amino)pyridazine-3-carboxamide (100 mg, 0.320 mmol, Intermediate 2), acetamide (41.5 mg, 0.703 mmol), tris(dibenzyl acetone)dipalladium(0) (43.9 mg, 0.048 mmol), in 1,4 dioxane (6 ml) was heated under microwave conditions at 150 °C for 1 h. The mixture was diluted with ethyl acetate (8 mL) and filtered through Celite. The filtrate was concentrated in vacuo. DMSO (5 ml) was added to the residue, then water (55 ml) and saturated NaHCO3 solution (3 ml). The insoluble material was collected by filtration, and further purified by ISCO (24 g silica gel, solid loading, 0-5% MeOH / dichloromethane) to obtain the desired product, 6-acetamido-Ntrideuteromethyl-4-(( 3-(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (21 mg, 0.063 mmol, 19.58% yield) as a white solid. MS (M+1) m / z: 336.1 (MH+). LC retention time 0.67 min [B]. Stage 2 To a solution of 6-acetamido-N-trideuteromethyl-4-((3-(methylthio)pyridin-2yl)amino)pyridazín-3-carboxamide (21 mg, 0.063 mmol) in acetic acid (1.5 ml) , sodium tungstate dihydrate (21.69 mg, 0.066 mmol) was added, and then 30% hydrogen peroxide (0.192 ml, 1.878 mmol). The solution was stirred at room temperature overnight. The sulfide starting material was consumed, but sulfoxide was the predominant product. Sodium tungstate dihydrate (21.69 mg, 0.066 mmol) and 30% hydrogen peroxide (0.192 ml, 1.878 mmol) were added. The mixture was heated at 50 °C for 1 h. The product was overoxidized to produce N-oxide. The mixture was diluted with water (15 ml), basified with solid Na2CO3 and extracted with DCM (3 x 30 IF-2019-16830169-APN-ANP#INPI Page 79 of 134 mi). The combined extraction was dried over anhydrous Na2SO4. The product, 2((6-acetamido-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-3-(methylsulfonyl)pyridine 1-oxide (12 mg, 0.031 mmol, 50.0% yield), was isolated as a white solid by preparative HPLC. MS (M+1) m / z: 384.08 (MH+). LC retention time 0.59 min [A], Stage 3 To a solution of 2-((6-acetamido-3(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-3-(methylsulfonyl)pyridine 1-oxide (12 mg, 0.031 mmol) in THF (3 ml) and ethanol (1 ml), 10% Pd / C (24.98 mg, 0.023 mmol) was added, followed by cyclohexene (0.101 ml, 1.002 mmol). The mixture was heated at 80 °C in a closed vial for 16 h. The solid phase was removed by filtration. The filtrate was concentrated in vacuo, and the residue was subjected to ISCO (12 g silica gel, solid loading, 0-5% MeOH / dichloromethane) to obtain the desired product, 6-acetamido-Ntrideuteromethyl-4-(( 3-(methylsulfoníl)pyridin-2-íl)amino)pyridazine-3-carboxamide (2.7 mg, 7.13 pmol, 22.78% yield), as a white solid. MS (M+1) m / z: 368.08 (MH+). LC retention time 0.57 min [A],1H NMR (400 MHz, DMSO-d6) δ 12.15 - 12.06 (m, 1H), 11.19 - 11.02 (m, 1H), 9.59 9.44 (m, 1H), 9.26 - 9.12 (m, 1H), 8.66 - 8.56 (m, 1H), 8.34 - 8.23 ​​(m, 1H) , 7.38 - 7.26 (m, 1H), 3.39 - 3.35 (s, 3H), 2.19 - 2.15 (s, 3H). OxX / ° H.N. either D3C.3N h The following examples were prepared Example 163: x2 N Yo R® in a similar way to the product of Table 4 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 164 O Λ H 407.46 408.08 0.72 [A] IF-2019-16830169-APN-ANP#INPI Page 80 of 134 Na2WO4.2H2O 30% H2O2 Acetic acid Stage 2 Stage 1 A mixture of 6-chloro-N-trideuteromethyl-4-((3-(methylthio)pyridin-2yl)amino)pyridazine-3-carboxamide (100 mg, 0.320 mmol, Intermediate 2), 1-methyl-1Hpyrazole- 3-amine (68.3 mg, 0.703 mmol) and 4-methylbenzenesulfonic acid monohydrate (91 mg, 0.480 mmol) in THF (7 ml) were heated in a closed vial at 100 °C for 36 h. The mixture was concentrated in vacuo until dry. The residue was diluted with DMSO (1.2 ml) and MeOH (4.8 ml), divided into 3 portions and purified by preparative HPLC. The desired fractions were combined, concentrated in vacuo, basified with 1.5 N K2HPO4a pH 10 solution and extracted with DCM (3 x 35 ml). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain the desired product, N-trideuteromethyl-6-((1-methyl1 H-pyrazol-3-yl)amino)-4-((3 -(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (49 mg, 0.131 mmol, 41.0% yield), as a white solid. Stage 2 To a solution of N-thdeuteromethyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-4-((3(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (49 mg, 0.131 mmol) in acetic acid (3 ml) at room temperature, sodium tungstate dihydrate (54.1 m or 164 mmol) was added in one portion, and then 30% hydrogen peroxide (0.227 ml, mg , u, ioh iiniu; p » IF-2019-16830169-APN-ANP#INPI Page 81 of 134 3.94 mmol). The solution was stirred at room temperature for 1 h. The mixture was diluted with water (25 ml), basified with solid Na2COs, and extracted with DCM (3 x 45 ml). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in DMSO (1 ml) and MeOH (3 ml), which was divided into two portions, and purified by preparative HPLC. The desired fractions were combined, concentrated in vacuo, basified to pH 10-11 with 1 N K2HPO4 solution, and extracted with DCM (3 x 40 ml). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain the desired product, N-trideuteromethyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-4-(( 3(methylsulfonyl)pyridin-2-yl)amino)pyridazine-3-carboxamide (28 mg, 0.068 mmol, 52.1% yield), as a white solid. MS (M+1) m / z: 406.1 (MH+). LC retention time 0.56 min [A]. The following examples were prepared in a similar manner to the product of the Example 166: Table 5 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 167 ^^z^N \ / z \ ZI 431.49 432.08 0.62 [A] F 168 zx 405, 47 406.08 0.69 [A] Example169if.2019-16830169-APN-ANP#INPI Page 82 of 134 NaBH3CN, TEA, Na2WO4.2H2O, H2O2Na2S2O3 Acetic acid Stage 2 Stage 1 A mixture of 6-chloro-N-(methyl-d3)-4-((3-(methylthio)pyridin-2-yl)amino)pyridazine-3carboxamide (50 mg, 0.160 mmol, Intermediate 2), 5-(2 -aminopropan-2-yl)pyridin-2amine (31.4 mg, 0.208 mmol), , 0.240 mmol) in dioxane (1.5 ml) was purged with nitrogen for 2 min, then stirred at 130 °C for 3 h. After cooling, the solid was collected by filtration and used in its current state in the next reaction. MS (M+1) m / z: 428.35 (MH+). LC retention time 0.90 min [A]. Stage 2 6-((5-(2-aminopropan-2-yl)pyridin-2-yl)amino)-N-(methyl-d3)-4-((3-(methylthio)pyridin2-¡l)amino)pyridazin -3-carboxamide (13 mg, 0.030 mmol) was mixed with 1 ml of DCM, propan-2-one (1.766 mg, 0.030 mmol) was added, and then sodium cyanoborohydride (3.82 mg, 0.061 mmol) was added. mmol) and TEA (8.48 pl, 0.061 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (20 ml), washed with saturated NaHCO3 (10 ml) and brine (10 ml), dried and concentrated in vacuo. The resulting residue was mixed with AcOH (1 ml), sodium tungstate dihydrate (3.01 mg, 9.12 pmol) and then hydrogen peroxide (0.155 ml, 1.520 mmol). The mixture was stirred at room temperature for 1 h. Sodium thiosulfate (961 mg, 1,520 mmol) was added to the mixture and then stirred for 10 min. The mixture was filtered and purified with preparative HPLC to obtain the desired product, 6-((5-(2-(isopropylamino)propan2-yl)pyridin-2-yl)amino)-N-(methyl-d3)-4 -((3-(methylsulfonyl)pyridin-2-yl)amino)pyridazine-3carboxamide (3.8 mg, 7.5 pmol, 24.66% yield). MS (M+1) m / z: 502 (MH+). LC retention time 1.3 min [QC-ACN-AA-XB],1H NMR (500 MHz, DMSO-d6) δ 9.59 - 9.44 (m, Page 83 of 134 (m, 1H), 8.40 - 8.33 (m, 1H), 8.31 - 8.24 (m, 1H), 7.92 - 7.84 (m, 1H), 7 .65 - 7.56 (m, 1H), 7.37 - 7.29 (m, 1H), 1.48 -1.33 (m, 6H), 0.93 - 0.76 (m, 6H) . The following example was prepared similarly to the product of Example 169: Table 6 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 170 \ zx z— ^zz 515.60 516.4 0.84 [C] Example 171 H H Stage 1 Stage 1 A heterogeneous solution of 6-((5-(2-hydroxypropan-2-yl)pyridin-2-íl)amino)-N(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2 -yl)amino)pyridazine-3-carboxamide (0.0627 g, 0.136 mmol, Example 13) and DMAP (0.0183 g, 0.150 mmol) in 0.054 M acetic anhydride / THF (6.30 ml, 0.340 mmol) in a sealed vial was heated to 80 °C. The reaction was stirred for 2 days. The reaction was cooled to room temperature. Acetic anhydride (0.020 ml, 0.212 mmol, 1.56 eq.) was added, and heating continued. The reaction was stirred for another day, and the starting material was consumed. The reaction was cooled to room temperature, and DMAP and EtOH were added. Heating continued for another day, and the reaction was cooled to room temperature. The reaction was diluted with EtOAc (50 mL) and washed with water (20 mL). The organic layer was washed with brine, s^^e^Na^SO^.^^ΡθΙΝ?!®9084 Page 84 of 134 silica gel (~0.4 g) to the filtrate and concentrated in vacuo. The crude product was purified by flash chromatography using a 24 g ISCO column that was eluted with 05% MeOH / ethyl acetate. Appropriate fractions were collected and concentrated in vacuo to obtain a residue containing the desired product. This residue was triturated with MeOH and dried overnight under vacuum to obtain 2-(6-((6((methyl-d3)carbamoyl)-5-((3-(methylsulfonyl)pyridin-2-yl)amino) pyridazin-3-yl)amino)pyridin-3yl)propan-2-yl acetate (0.01025 g, 0.019 mmol, 14.23% yield) with a white solid. MS (M+1) m / z: 503.2 (MH+). LC retention time 0.67 min [B],1H NMR (400 MHz, DMSO-d6) δ 12.18 - 12.04 (m, 1H), 10.40 - 10.29 (m, 1H), 9.58 9.45 (m, 1H), 9.23 - 9.08 (m, 1H), 8.75 - 8.64 (m, 1H), 8.38 - 8.19 (m, 2H) , 7.79 - 7.71 (m, 1H), 7.70 - 7.62 (m, 1H), 7.38 - 7.30 (m, 1H), 3.42 - 3.35 (m, 3H), 2.07 - 1.95 (m, 3H), 1.82- 1.65 (m, 6H). Example 172 Na2WO4.2H2O, 30% H2O2 Acetic Acid Stage 2 Stage 1 To a suspension of 6-((5-formylpyridin-2-yl)amino)-N-(methyl-d3)-4-((3(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (130 mg, 0.326 mmol) in DCM (11 ml) at room temperature, (diethylamino)sulfur trifluoride (DAST) (0.28 ml, 2.119 mmol) was added dropwise. The mixture was heated at 45 °C for 16 h. After cooling to room temperature, the reaction was carefully quenched with water (20 ml). The resulting mixture was basified with solid Na2CO3 until pH 9-10 and extracted with DCM (3 x 40 ml). The combined extracts were dried over anhydrous Na2SO4. The desired product, 6-((5-(difluoromethyl)pyridin-2-yl)amino)-N-(methyl-d3)-4-((3(methylthio)pyridin-2-yl)amino) pyridazine-3-carboxamide (47 mg, 0.112 mmol, 34.3% yield), was isolated as a white solid by ISCO (40 g silica gel, solid loading, 0-5% methanol / dichloromethane). IF-2019-16830169-APN-ANP#INPI Page 85 of 134 MS (M+1) m / z: 421.08 (MH+). LC retention time 0.74 min [B], Stage 2 To a solution of 6-((5-(difluoromethyl)pyridin-2-yl)amino)-N-(methyl-d3)-4-((3(methylthio)pyridin-2-yl)amino)pyridazin-3- carboxamide (47 mg, 0.112 mmol) in acetic acid (4 ml) at room temperature, sodium tungstate dihydrate (46.1 mg, 0.140 mmol) was added in one portion, and then 30% hydrogen peroxide (0.343 ml, 3.35 mmol). The solution was stirred at room temperature for 1 h. The mixture was diluted with water (30 ml), basified with solid Na2CO3 and extracted with DCM (3 x 45 ml). The combined extracts were dried over anhydrous Na2SO4. The desired product, 6((5-(difluoromethyl)pyridin-2-yl)amino)-N-(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2yl)amino)pyridazine-3-carboxamide ( 20 mg, 0.044 mmol, 39.1% yield), was isolated as a white solid by ISCO (24 g silica gel, solid loading, 0-5% MeOH / DCM). MS (M+1) m / z: 453.08 (MH+). LC retention time 0.63 min [A],1H NMR (400 MHz, DMSO-d6) δ 12.19 - 12.09 (m, 1H), 10.72 - 10.61 (m, 1H), 9.66 9.54 (m, 1H), 9.26 - 9.16 (m, 1H), 8.79 - 8.64 (m, 1H), 8.56 - 8.45 (m, 1H) , 8.35 - 8.24 (m, 1H), 8.01 - 7.89 (m, 1H), 7.85 - 7.73 (m, 1H), 7.40 - 7.29 (m, 1H), 7.25 - 6.81 (m, 1H), 3.34-3.30 (m, 3H). Example 173 N ll Η2ΝΛ^Ν> Xantphos, CsCO3iPd2dba3 Oxone o, ,o Dioxane Stage 1 Stage 1 A mixture of 6-chloro-N-(methyl-d3)-4-((3-(methylthio)pyridin-2-yl)amino)pyridazine-3carboxamide (30 mg, 0.096 mmol, Intermediate 2), 6-methylpyrazin- 2-amine (31.4 mg, 0.288 mmol), Dioxane (1.5 ml) was purged with nitrogen for 2 min, then stirred at 130 °C for 3 h. The mixture was mixed with MeOH / DCM (1:1.5 ml), filtered, and the filtrate was concentrated, and the residue was used in the next step. The previous residue was mixed with MeOH (1 ml), acetone (1 ml) and water (0.5 ml). Oxone (177 mg, 0.288 mmol) was added, and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to dryness, then dissolved in DMSO and purified with preparative HPLC. The Page 86 of 134 methylpyrazin-2-yl)amino)-4-((3-(methylsulfonyl)pyridin-2-yl)amino)pyridazin-3-carboxamide (3.4 mg, 7.74 pmol, 8% yield ). MS (M+1) m / z: 418.1 (MH+). LC retention time 0.95 min [QC-ACN-TFA-XB].1H NMR (500 MHz, DMSO-d6) δ 12.27 - 12.00 (m, 1H), 10.74 - 10.47 (m, 1H), 9.68 9.55 (m, 1H), 9.27 - 9.10 (m, 1H), 8.77 - 8.61 (m, 2H), 8.38 - 8, 21 (m, 1H), 8.13 - 8.00 (m, 1H), 7.42 - 7.31 (m, 1H), 3.37 (s, 3H), 2.47 - 2.41 ( m, 3H). Example 174 OMe Stage 1 DCM Stage 3 Acetic acid Stage 4 Na2WO4.2H2O, 30% H2O2 Stage 1 6-Chloro-N-(methyl-d3)-4-((3-(methylthio)pyridin-2-yl)amino)pyridazine-3carboxamide (0.5304 g, 1.696 mmol, Intermediate 2) and ( 2,4-dimethoxyphenyl)methanamine (2.1068 g, 12.60 mmol) at 145 °C. Vapors appeared at 88 °C. After 1.5 h, EtOAc (150 mL) and 1 M aqueous K2HPO4 (40 mL) were added. After layer separation, the organic layer was washed with 1 M aqueous K2HPO4 (40 mL) and brine (40 mL) successively, dried over Na2SO4, and filtered. Silica gel was added to the filtrate and concentrated in vacuo. The crude product was purified by flash chromatography using a 120 g ISCO column that was eluted with 0-5% MeOH / DCM (0%, cv2; 0-5%, cv12). The appropriate fractions (1.6-2.2%) were collected and concentrated in vacuo to obtain 6-((2,4-dimethoxybenzyl)amino)-N-(methyl-d3)-4-((3 (methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (0.7215 g, 1.627 mmol, 96% IF-2019-16830169-APN-ANP#INPI Page 87 of 134 performance) as a yellow solid. MS (M+1) m / z: 444.2 (MH+). LC retention time 0.79 min [A], Stage 2 To a homogeneous yellow solution of 6-((2,4-dimethoxybenzyl)amino)-N-(methyld3)-4-((3-(methylthio)pyridin-2-yl)amino)pyridazin-3- carboxamide (0.7215 g, 1.627 mmol) in dichloromethane (20 mL) at 0 °C in nitrogen, trifluoroacetic acid (20 mL, 260 mmol) was added dropwise. After 10 min, the ice-water bath was removed, and the reaction was stirred at room temperature overnight. The mixture was concentrated in vacuo and diluted with DCM (100 ml) and 1.5 M aqueous K2HPO4 (25 ml). After layer separation, the aqueous layer was extracted with DCM (4 x 100 ml). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo (0.68 g). THF was added, and the heterogeneous solution was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a 120 g ISCO column that was eluted with 0-75% MeOH / CH2CI2. The appropriate fractions were collected and concentrated in vacuo to obtain 6amino-N-(methyl-d3)-4-((3-(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (0.2534 g, 0.864 mmol, 53.1% yield) as a yellow solid. MS (M+1) m / z. 294.0 (MH+). LC retention time 0.60 min [A]. Stage 3 To a heterogeneous solution of 6-amino-N-(methyl-d3)-4-((3-(methylthio)pyridín-2¡l)amino)pyridazine-3-carboxamide (0.042 g , 0.143 mmol) in dichloromethane (2.0 ml), pyridine (0.05 ml, 0.618 mmol) was added. A solution of 2,2-dichlorocyclopropanecarbonyl chloride in DCM (0.17 M, 1.0 ml, 0.17 mmol) was then added, which produced homogeneity. After 1 h of the reaction, 2,2-dichlorocyclopropanecarbonyl chloride in DCM (0.17 M, 1.0 ml, 0.17 mmol) was added. Stirring continued for several hours, and then additional 2,2-dichlorocyclopropancarbonyl chloride in DCM (0.17 M, 1.0 ml, 0.17 mmol) was added, and stirring continued overnight. Additional 2,2-dichlorocyclopropanecarbonyl chloride / in DCM (0.47 M, 0.61 ml, 0.29 mmol) was added and after conversion, it was determined to be ~50%. Heating the reaction vessel to 50 °C did not result in additional conversion. The reaction was cooled to room temperature, diluted with DCM (40 ml) and washed with water (5 ml). The organic layer was further washed with water (5 mL) and brine (5 mL) successively, dried over Na2SO4, and filtered. Silica gel was added to the filtrate and concentrated in vacuo. The crude product was purified by flash chromatography using a 12 g ISCO column eluted with 0-10% IF-2019-16830169-APN-ANP#INPI Page 88 of 134 MeOH / CH2CI2. Appropriate fractions were collected and concentrated in vacuo to obtain the desired impure product (∼50% purity, 52.8 mg), used as-is in the subsequent reaction. Stage 4 To a homogeneous yellow solution of 6-(2,2-dichlorocyclopropan-1carboxamido)-N-(methyl-d3)-4-((3-(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (0 .0528 g, 0.123 mmol) in acetic acid (1.5 ml), sodium tungstate dihydrate (0.0561 g, 0.170 mmol) was added, and then 30% hydrogen peroxide (0.4 ml, 3.92 mmol). After 1.5 h, water (25 ml) was added, and the reaction was immersed in an ice-water bath. Na2CO3 (solid) was added until the pH was basic using iridescent paper. This was extracted with DCM (4 x 50 mi). The organic layers were combined and then washed with 1 N aqueous HCl (30 mL), saturated aqueous NaHCO3 (30 mL), and brine (30 mL) successively, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography using a 12 g ISCO column eluted with 0-5% MeOH / DCM (0%, cv2; 0-10%, cv20). The appropriate fractions were collected, concentrated in vacuo and dried in a desiccating oven at 50 °C to obtain 6-(2,2-dichlorocyclopropan-1carboxamido)-N-(methyl-d3)-4-((3-( methylsulfoníl)pyridín-2-yl)amino)pyridazine-3carboxamide (0.00691 g, 0.015 mmol, 12.2% yield). MS (M+1) m / z: 462.1 (MH+) · LC retention time 0.79 min [BJ. 1H NMR (400 MHz, DMSO-d6) δ 12.24 - 12.08 (m, 1H), 11.91 - 11.77 (m, 1H), 9.59 9.46 (m, 1H), 9 .35 - 9.20 (m, 1H), 8.75 - 8.52 (m, 1H), 8.37 - 8.19 (m, 1H), 7.40 - 7.26 (m, 1H) , 3.39 - 3.34 (m, 3H), 3.22 - 3.13 (m, 1H), 2.16 -1.99 (m, 2H). Examples 175 and 176 IF-2019-16830169-APN-ANP#INPI Page 89 of 134 TFA DCM Stage 2 Pyridine, BOP, DIPEA Na2WO4.2H2O, 30% H2O2 Acetic acid Stage 4 DMF Stage 3 Stages 1 and 2 Follow the procedures shown above to prepare the Example 174. Stage 3 A mixture of 6-amino-N-(methyl-d3)-4-((3-(methylthio)pyridin-2-yl)amino)pyridazine3-carboxamide (97 mg, 0.331 mmol), (±)-trans- 2-(trifluoromethyl)cyclopropane-1carboxylic acid (76 mg, 0.496 mmol), BOP (205 mg, 0.463 mmol) and N,N-düsopropylethylamine (0.202 ml, 1.157 mmol) in DMF (2 ml) were heated to 60 °C for 2 hours The desired product was detected, but most of the starting material remained. The mixture was continued to heat at 60 °C overnight but no change was observed. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water (3x15 ml) and brine (15 ml), and dried over anhydrous MgSO4. The product, (±)-N-(methyl-d3)-4-((3(methylthio)pyridin-2-yl)amino)-6-((1R,2R)-2-(trifluoromethyl)cyclopropan-1carboxamido) pyridazine-3-carboxamide (23.6 mg, 0.055 mmol, 16.62% yield), was isolated as a beige solid. MS (M+1) m / z: 430.2 (MH+). LC retention time 0.90 min [A], The starting material, 6-amino-N-(methyl-d3)-4-((3-(methylthio)pyridin-2¡l)amino)pyridazin-3 -carboxamide (60 mg, 0.205 mmol, 61.9% yield), was partially recovered as a beige solid. Stage 4 To a solution of (±)-N-(methyl-d3)-4-((3-(riiptgtj^pi^g^fey)AWPÍTfr^iHF?R)· Page 90 of 134 2-(trifluoromethyl)cyclopropan-1-carboxamido)pyridazine-3-carboxamide (23.6 mg, 0.055 mmol) in acetic acid (4 mL) at room temperature, sodium tungstate dihydrate (22.66 mg, 0.069 mmol) was added ) in one portion, and then 30% hydrogen peroxide (0.168 ml, 1.649 mmol) was added dropwise. The solution was stirred at room temperature for 1 h. The mixture was diluted with water (20 ml), basified with solid Na2CO3 and extracted with DCM (4 x 30 ml). The combined extract was dried over anhydrous Na2SO4. The title compound, N-(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2-yl)amino)-6((1 R,2R)-2-(trifluoromethyl)cyclopropan-1-carboxamido )pyridazine-3-carboxamide (10 mg, 0.022 mmol, 39.4% yield), was isolated as a white solid by ISCO (24 g silica gel, solid loading, 0-5% MeOH / dichloromethane). MS (M+1) m / z: 462.1 (MH+) · LC retention time 0.79 min [A]. A racemate sample (10 mg) obtained as mentioned above was subjected to chiral separation to obtain N-(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2yl)amino)-6-(( 1S,2S)-2-(trifluoromethyl)cyclopropan-1-carboxamido)pyridazine-3carboxamide (4.52 mg, 9.31 pmol, 86% yield),1H NMR (400 MHz, DMSOd6) δ 12.19 - 12 .09 (m, 1H), 11.73 - 11.63 (m, 1H), 9.53 - 9.47 (m, 1H), 9.32 - 9.20 (m, 1H), 8.65 - 8.54 (m, 1H), 8.38 - 8.24 (m, 1H), 7.41 - 7.29 (m, 1H), 3.38 - 3.35 (m, 3H), 2 .71 - 2.61 (m, 1H), 2.41 - 2.28 (m, 1H), 1.41 - 1.30 (m, 2H), and N-(methyl-d3)-4-( (3(methylsulfonyl)pyridin-2-l)amino)-6-((1R,2R)-2-(trifluoromethyl)cyclopropan-1carboxamido)pyridazine-3-carboxamide (4.36 mg, 8, 98 pmol, 83 % yield) as white solids, 1H NMR (400 MHz, DMSO-de) δ 12.20 - 12.08 (m, 1H), 11.73 11.58 (m, 1H), 9, 57 - 9.44 (m, 1H), 9.33-9.18 (m, 1H), 8.69 - 8.50 (m, 1H), 8.37 - 8.21 (m, 1H), 7.41 - 7.25 (m, 1H), 3.40 - 3.34 (m, 3H), 2.72 - 2.62 (m, 1H), 2.42 - 2.30 (m, 1H) ), 1.40- 1.29 (m, 2H). The absolute stereochemistry of the two enantiomers was randomly assigned. Example 177 IF-2019-16830169-APN-ANP#INPI Page 91 of 134 , Xantphos, CsCO3iPd2dba3 Dioxane, N-Methyl-2-pyrrolidinone Stage 1 Na2WO4.2H2O, 30% H2O2 Acetic acid Stage 2 Na2WO4.2H2O, 30% H2O2 Acetic acid Stage 3 Stage 1 A mixture of 6-chloro-N-trideuteromethyl-4-((3-(methylthio)pyridin-2yl)amino)pyridazín-3-carboxamide (150 mg, 0.480 mmol) , 3,3difluorocyclobutanecarboxamide (87 mg, 0.647 mmol), tris(dibenzylideneacetone) dipalladium(O) (65.9 mg, 0.072 mmol), Xantphos (41.6 mg, 0.072 mmol), and cesium carbonate (281 mg, 0.863 mmol ) in 1,4-dioxane (10 ml) was microwaved at 145 °C for 1 h. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered through Celite. The filtrate was further diluted with ethyl acetate (20 mL) and filtered through Celite. The filtrate was concentrated in vacuo until dry. Water (50 ml) was added to the residue, and then saturated NaHCO3 solution (5 ml). The insoluble material was collected by suction filtration and further purified by ISCO (40 g silica gel, solid loading, 0-4% MeOH / DCM) to obtain the desired product, 6-(3,3-difluorocyclobutane- 1-carboxamido)-N-(methyl-d3)-4((3-(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (57 mg, 0.139 mmol, 28.9% yield), as a solid beige. MS (M+1) m / z: 412.2 (MH+) LC retention time 0.89 min [A], Stage 2 To a suspension of 6-(3,3-difluorocyclobutane-1-carboxamido)-N-(methyl-d3)-4((3-(methylthio)pyridin-2-yl)amino)pyridazin-3- carboxamide (57 mg, 0.139 mmol) in acetic acid (20 ml) at room temperature, sodium tungstate dihydrate (57.1 mg, 0.173 mmol) was added in one portion, and then 30% hydrogen peroxide (0.425 ml, 4.16 mmol). The solution was stirred at room temperature for 1 h. The starting material was completely converted to sulfoxide, but not the desired sulfone. Additional sodium tungstate dihydrate (57.1 mg, 0.173 mmol) and 30% hydrogen peroxide (0.213 ml, 2.08 mmol) were added. The heterogeneous mixture was stirred at IF-2019-16830169-APN-ANP#INPI Page 92 of 134 room temperature for one more hour. The mixture was diluted with water (40 ml), basified with solid Na2CO3 and extracted with DCM (4 x 50 ml). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product, 6-(3,3-difluorocyclobutan-1-carboxamido)-N-(methyl-d3)-4-((3(methylsulfinyl)pyridin-2-yl)amino)pyridazine-3-carboxamide (15 mg, 0.035 mmol, 25.3% yield), was isolated as a white solid by ISCO (24 g silica gel, solid loading, 0-5% MeOH / DCM). MS (M+1) m / z: 428.2 (MH+) LC retention time 0.7 min [A], Stage 3 To a suspension of 6-(3,3-difluorocyclobutan-1-carboxamido)-N-(methyl-d3)-4((3-(methylsulfinyl)pyridin-2-yl)amino)pyridazine-3-carboxamide (15 mg , 0.035 mmol) in acetic acid (3 ml) at room temperature, sodium tungstate dihydrate (14.47 mg, 0.044 mmol) was added in one portion, and then 30% hydrogen peroxide (0.108 ml, 1.053 mmol). The solution was stirred at room temperature for 1.5 h. The mixture was diluted with water (20 ml), basified with solid Na2CO3 and extracted with DCM (3 x 40 ml). The combined extract was dried over anhydrous Na2SO4 and concentrated in vacuo to dryness. The residue was dissolved in DMSO (1.2 ml) and purified by preparative HPLC. The desired product was obtained, 6-(3,3-difluorocyclobutane-1carboxamido)-N-(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2-yl)amino)pyridazine-3carboxamide. (5.8 mg, 0.013 mmol, 36.2% yield). MS (M+1) m / z: 444.0 (MH+). LC retention time 1.39 min [QC-ACN-TFA-XB], Example 178 THF Stage 1 Xantphos, CsCO3 Pd2dba3Dioxane 2. Na2WO4.2H2O, H2O2, Na2S2O3Acetic Acid Step 2 Stage 1 IF-2019-16830169-APN-ANP#INPI Page 93 of 134 To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide (114 mg, 0.544 mmol) and 6-fluoro-3-(methylthio)pyridin-2-amine (86 mg, 0.544 mmol) in THF (5 ml) at room temperature, lithium bis(trimethylsilyl)amide in THF (1.359 ml, 1.359 mmol) was added over 5 min. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 ml), the mixture was adjusted with 1 N HCl solution to pH 9-10, and further diluted with water (10 ml). The precipitated product, 6-chloro-4-((6-fluoro-3-(methylthio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3carboxamide (145 mg, 0.438 mmol, 81% yield), was collected as a pale solid by suction filtration and dried under vacuum. MS (M+1) m / z: 331.25 (MH+). LC retention time 1.19 min [C]. 1H NMR (400 MHz, DMSO-d6) δ 12.65 - 12.53 (m, 1H), 9.62 - 9.42 (m, 1H), 9.04 - 8.85 (m, 1H), 8.22 - 8.06 (m, 1H), 7.00 - 6.83 (m, 1H). Stage 2 A mixture of 6-chloro-4-((6-fluoro-3-(methylthio)pyridin-2-yl)amino)-N-(methyld3)pyridazine-3-carboxamide (30 mg, 0.091 mmol), 2.6 -dimethylpyrimidin-4-amine (16.75 mg, 0.136 mmol), , 0.181 mmol) in dioxane (1.5 ml) was purged with nitrogen for 2 min, then stirred at 130 °C for 3 h. The mixture was mixed with MeOH / DCM (1:1.5 ml), filtered, and the filtrate was concentrated. The resulting residue was used in the next step. The residue was mixed with AcOH (1 ml), and sodium tungstate dihydrate (8.97 mg, 0.027 mmol) was added. Hydrogen peroxide (278 pl, 2.72 mmol) was added, and the mixture was stirred at room temperature for 1 h. To this mixture was added sodium thiosulfate (430 mg, 2.72 mmol), and the reaction was stirred for 10 min. The mixture was filtered and purified with preparative HPLC to obtain the product, 6-((2,6dimethylpyrimidin-4-yl)amino)-4-((6-fluoro-3-(methylsulfonyl)pyridin-2-yl)amino )-N-(methyld3)pyridazine-3-carboxamide (6.8 mg, 0.014 mmol, 15.85% yield). MS (M+1) m / z: 449.9 (MH+). LC retention time 1.11 min [QC-ACN-TFA-XB],1H NMR (500 MHz, DMSO-d6) δ 10.83 - 10.68 (m, 1H), 9.48 - 9.34 (m, 1H), 9.32 - 9.15 (m, 1H), 8.52 - 8.35 (m, 1H), 7.42 - 7.24 (m, 1H), 7.02 (br s, 1H), 3.39 (br s, 3H), 2.57 2.53 (m, 6H). IF-2019-16830169-APN-ANP#INPI Page 94 of 134 The following examples were prepared in a similar manner to the product of Example 178: Table 7 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 179 0 H 399.41 399.9 1.26 [QC-ACNTFA-XB] 180 O 411.42 412.2 1 .16 [QC-ACNTFA-XB] 181 N H 451.45 452.0 1.24 [QC-ACN-AAXB] 182 ¿ λ—u. •z. A z=Z zx 533.5 533.9 1.62 [QC-ACN-AAXB] Example 183 IF-2019-16830169-APN-ANP#INPI Page 95 of 134 Stage 1 Xantphos, CsCO3>Pd2dba3Dioxane 2. Na2WO4.2H2O, H2O2iNa2S2O3iAcetic Acid Step 2 Stage 1 To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide (144 mg, 0.687 mmol) and 6-methyl-3-(methylthio)pyridin-2-amine (106 mg, 0.687 mmol) in THF (5 ml) at room temperature, lithium bis(trimethylsilyl)amide in THF (1.718 ml, 1.718 mmol) was added over 5 min. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 ml), the mixture was adjusted with 1 N HCl solution to pH 9-10, and further diluted with water (10 ml). The precipitating product, 6-chloro-N-(methyl-d3)-4-((6-methyl-3-(methylthio)pyridin-2-yl)amino)pyridazine-3carboxamide (160 mg, 0.490 mmol, 71.2 % yield), was collected as a pale solid by suction filtration and dried under vacuum. MS (M+1) m / z: 327.3 (MH+). LC retention time 1.27 min [C]. 1H NMR (400 MHz, DMSO-d6) δ 12.41 -12.25 (m, 1H), 9.49 - 9.36 (m, 1H), 9.29 - 9.14 (m, 1H), 7.91 - 7.77 (m, 1H), 7.10 - 6.96 (m, 1H), 2.49 - 2.48 (m, 6H) Stage 2 A mixture of 6-chloro-N-(methyl-d3)-4-((6-methyl-3-(methylthio)pyridin-2yl)amino)pyridazine-3-carboxamide (30 mg, 0.092 mmol), 6-methoxypyridazine -3-amine (17.23 mg, 0.138 mmol), mmol) in dioxane (1.5 ml) was purged with nitrogen for 2 min, then stirred at 130 °C for 3 h. The mixture was mixed with MeOH / DCM (1:1.5 ml), filtered, and the filtrate was concentrated, and the residue was used in the next step. The resulting residue was mixed with AcOH (1 ml) and sodium tungstate dihydrate (9.08 mg, 0.028 mmol). Hydrogen peroxide (281 pl, 2.75 mmol) was added, and the mixture was stirred at room temperature for 1 h. To this mixture was added sodium thiosulfate (435 mg, 2.75 mmol), and the mixture was stirred for 10 min. IF-2019-16830169-APN-ANP#INPI Page 96 of 134 The mixture was filtered and purified with preparative HPLC to obtain the product, 6-((6methoxypyridazin-3-yl)amino)-N-(methyl-d3)-4-((6-methyl-3-(methylsulfonyl)pyridin -2¡l)amino)pyridazine-3-carboxamide (4.2 mg, 9.10 pmol, 9.92% yield). MS (M+1) m / z: 447.8 (MH+). LC retention time 1.01 min [QC-ACN-TFA-XB]. d3cx The following examples were prepared in a similar manner to the product of the Example 183: Table 8 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 184 ,N Y) N F H 529.54 530.3 1.41 [QC-ACNTFA-XB] 185 N^N H 445.5 446.1 0.89 [QC-ACNTFA-XB] 186 0 H 395.45 396.3 1.24 [QC-ACN-AAXB] 187 0 Η V 407.46 408.1 1.35 [QC-ACN- AAXB] 188 YV H 474.55 475.2 1.20 [QC-ACN-AAXB] 189 °—C / ^° '—2 ^2=^ ^zi 544.0 ---------IE . 544.3 2019 16830169 A 1.40 [QC-ACN-AAXB] ΡΝ-ΑΝΡ#ΙΝΡΊ— Page 97 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 190 «o O ¿ / ° '—z h zz 577.55 578.3 1.57 [QC-ACN-AAXB] 191 0 Η H 410.46 411.1 1.30 [QC-ACN-AAXB] 192 zz^ O 501.58 502.2 1.23 [QC-ACNTFA-XB] 193 0 Η H 438.52 440.5 1 .48 [QC-ACN-AAXB] 194 H 509.0 509.3 1.49 [QC-ACN-AAXB] 195 n N Ν' H 456.5 457.1 1.26 [QC-ACN-AAXB] 196 ιλΑ < 0 ΓΝ H 515.56 516.4 1.09 [QC-ACN-AAXB] 197 Η V 456.53 458.5 1.62 [QC-ACN-AAXB] 198 0 Η V 435.51 436.2 1.63 [QC-ACN-AAXB] Example 199 IF-2019-16830169-APN-ANP#INPI Page 98 of 134 CL THF Stage 1 Xantphos, CsCO3iPd2dba3Dioxane 2. Na2WO4.2H2O, H2O2, Na2S2O3Acetic Acid Stage 2 Stage 1 To a solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (491 mg, 2,350 mmol) and 6-methoxy¡-3-(methylthio)pyridine-2-amine (400 mg, 2 .35 mmol) in THF (5 ml) at room temperature, lithium bis(trimethylsilyl)amide in THF (5.87 ml, 5.87 mmol) was added over 5 min. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with 1 N HCl (1.5 ml), and water (20 ml) was added. The mixture was extracted with DCM (3 x 20 ml), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to obtain the product 6-chloro-4-((6-methoxy¡-3(methylthio)pyridin-2 -yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (600 mg, 1.75 mmol, 74.5% yield). The material was used in the next stage in the state in which it was found. MS (M+1) m / z: 343.3 (MH+). LC retention time 1.19 min [C]. Stage 2 A mixture of 6-chloro-4-((6-methoxy-3-(methylthio)pyridin-2-yl)amino)-N-(methyld3)pyridazine-3-carboxamide (35 mg, 0.102 mmol), propionamide (11 .19 mg, 0.153 mmol), .7 ml) was purged with nitrogen for 2 min, then stirred at 130 °C for 3 h. The mixture was mixed with MeOH / DCM (1:1.5 ml), filtered, and the filtrate was concentrated, and the residue was used in the next step. The residue was mixed with AcOH (1 ml), and sodium tungstate dihydrate (10.10 mg, 0.031 mmol) was added. Hydrogen peroxide (313 pl, 3.06 mmol) was added, and the mixture was stirred at room temperature for 1 h. Sodium thiosulfate (484 mg, 3.06 mmol) was added to the mixture and stirred for 10 min. The mixture was filtered and purified by preparative HPLC to obtain 4-((6-methoxy-3-(methylsulfonyl)pyridin-2-yl)amino)-N-(methyl-d3)-6propionamidopyridazine-3-carboxamide (13, 0 mg, Ο,Οδ-ΙΙΤΜΡ^ΙΟίδΟ-^Ρ^ΑβίΙϊΐΜϊΦΦ^0)· 99 Page 99 of 134 MS (M+1) m / z: 412.4 (M+H+). LC retention time 1.26 min [QC-ACN-TFA-XB].1H NMR (500 MHz, DMSO-d6) δ 12.13 - 11.98 (m, 1H), 11.23 - 11.02 (m, 1H), 9.44 9.29 (m, 1H), 9.24 - 9.12 (m, 1H), 8.19 - 8.07 (m, 1H), 6.79 - 6, 57 (m, 1H), 4.03 - 3.90 (m, 3H), 3.48 - 3.39 (m, 3H), 2.49 - 2.44 (q, 2H), 1.08 ( s, 3H). The following examples were prepared in a similar manner to the product of Example 199: Table 9 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 200 O Η V 423.5 424.4 1.4 [QC-ACN-AAXB] 201 ÍnXX H 490.6 491, 4 1.3 [QC-ACN-AAXB] 202 ZZ o Y— O \ z 525 525.1 1.6 [QC-ACN-AAXB] 203 sY'Y H 517.6 518.2 1.3 [QC- ACN-AAXB] 204 zz 435.5 436 1.3 [QC-ACN-AAXB] 205 N Ν' H 472.5 473.1 1.4 [QC-ACN-AAXB] IF-2019-16830169-APN-ANP#INPI 100 Page 100 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 206 & LL. o / o ^Z=^ ZI 516.5 517.4 1.9 [QC-ACN-AAXB] Example 207 Stage 1 To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide (209 mg, 0.999 mmol) and 6-cyclopropyl-3-(methylthio)pyridin-2-amine (180 mg, 0.999 mmol) in THF (10 ml) at room temperature, lithium bis(trimethylsilyl)amide in THF (2.496 ml, 2.496 mmol) was added over 5 min. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 ml), and the mixture was adjusted with 1 N HCl solution to pH 9-10, and further diluted with water (10 ml). The precipitated product was collected by suction filtration and dried under vacuum to obtain 6-chloro-4-((6-cyclopropyl-3-(methylthio)pyridin-2-yl)amino)-N-(methyld3)pyridazin-3 -carboxamide (260 mg, 0.737 mmol, 73.8% yield) as a pale solid. MS (M+1) m / z: 353.4 (MH+) LC retention time 1.40 min [Cj.1H NMR (499 MHz, DMSO-d6) δ 12.35 - 12.22 (m, 1H), 9.44 - 9.31 (m, 1H), 9.16 - 9.00 (m, 1H), 7.90 - 7.73 (m, 1H), 7.17 - 6.98 ( m, 1H), 2.47 - 2.44 (m, 3H), 2.21 - 2.11 (m, 1H), 1.09 - 1.03 (m, 2H), 1.00 - 0, 94 (m, 2H). Stage 2 A mixture of 6-chloro-4-((6-cyclopropyl-3-(methylthio)pyridin-2-yl)amino)-N-(methyld3)pyridazine-3-carboxamide (100 mg, 0.283 mmol), 2-( 6-amino-4-chloropyridin-3yl)propan-2-ol (63.5 mg, 0.340 mmol), Xantphos (24.60 mg, 0.043 mmol), Pd2(dba)3IF-2019-16830169-APN-ANP# INPI 101 Page 101 of 134 (19.46 mg, 0.021 mmol) and Cs2CO3 (185 mg, 0.567 mmol) in dioxane (0.7 mL) were purged with nitrogen for 2 min, then stirred at 130 °C for 3 h. The resulting mixture was mixed with MeOH / DCM (1:1.5 ml), filtered, and the filtrate was concentrated, and the residue was used in the next step. The resulting residue was mixed with AcOH (1 ml), sodium tungstate dihydrate (28.0 mg, 0.085 mmol) and hydrogen peroxide (289 μΙ, 2.83 mmol). After 1 h at room temperature, sodium thiosulfate (672 mg, 4.25 mmol) was added, and the mixture was stirred for 10 min. The mixture was filtered and purified by preparative HPLC to obtain the product, 4-((6-cyclopropyl-3(methylsulfonyl)pyridin-2-yl)amino)-6-((4-(2-hydroxypropan-2-yl )phenyl)amino)-N-(methyld3)pyridazine-3-carboxamide (8.3 mg, 0.015 mmol, 5.42% yield). MS (M+1) m / z: 535.4 (M+H+). LC retention time 1.65 min [QC-ACN-AA-XB], The following example was prepared similarly to the product of Example 207: Table 10 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 208 H 500.59 501.5 1.39 [QC-ACN-AAXB] Example 209 IF-2019-16830169-APN-ANP#INPI 102 Page 102 of 134 Pd2dba3 1,1'-bis(dicyclohexylphosphino)ferrocene K3PO4 Na2WO4.2H2O, 30% H2O2 Acetic Acid Stage 2 Dioxane Stage 1 209 Stage 1 A suspension of tris(dibenzylideneacetone)dipalladium(0) (7.40 mg, 8.09 pmol), 1,T-bis(dicyclohexylphosphino)ferrocene (9.36 mg, 0.016 mmol ), 6-chloro-N-methyl-4-((3(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (0.1002 g, 0.323 mmol), 6methoxypyridazin-3-amine (0.081 g, 0.647 mmol) and tribasic potassium phosphate (0.404 ml, 0.809 mmol) in 1,4-dioxane (2.5 ml) in a 1 dram vial was vacuum / N2 cycled three times. The reaction mixture was heated at 80 °C for 3 hours, then diluted with water and filtered. The solid was washed with water and dried under vacuum overnight to obtain 6-((6-methoxypyridazin-3-yl)amino)-N-methyl-4-((3-(methylthio)pyridin-2¡l) Crude amino)pyridazine-3-carboxamide (0.119 g, 0.299 mmol, 92% yield). 14 mg of the crude oil was purified with preparative HPLC to obtain a pure product, 6-((6-methoxypyridazin-3-yl)amino)-N-methyl-4-((3-(methylthio)pyridin-2-yl)amino )pyridazine-3carboxamide (8.5 mg, 0.021 mmol, 6.40% yield). MS (M+1) m / z: 399.3 (MH+). LC retention time 1.487 min [QC-ACN-AA-XB], 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.37 (s, 1H), 9.30 ( s, 1H), 9.20 (br d, J=4.6 Hz, 1H), 8.21 (d, J=3.7 Hz, 1H), 8.02 (d, J=9.5 Hz , 1H), 7.83 (d, J=6.7 Hz, 1H), 7.23 (d, J=9.5 Hz, 1H), 7.09 (dd, J=7.6, 4, 9 Hz, 1H), 3.99 (s, 3H), 2.86 (d, J=4.6 Hz, 3H), 2.53 (s, 3H). Stage 2 To a solution of 6-((6-methoxypyridazin-3-yl)amino)-N-methyl-4-((3(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (0.1 g, 0.251 mmol) in acetic acid (15 ml) at room temperature, sodium tungstate dihydrate (0.159 g, 0.482 mmol) was added in one portion, and then 30% hydrogen peroxide (0.769 ml, 7.53 mmol). The solution was stirred at room temperature for 1 hour. The reaction is IF-2019-16830169-APN-ANP#INPI 103 Page 103 of 134 added 0.8 ml of 30% H2O2, which was stirred at room temperature for 6 hours. The reaction mixture was diluted with ice water and basified with Na2CO3 powder. The aqueous layer was extracted three times with DCM, and the combined organic layers were dried (Na2SO4), filtered and concentrated. The resulting solid was dissolved in 14 ml of AcOH, and then sodium tungstate dihydrate (0.124g) and 0.8 ml of 30% hydrogen peroxide were added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was purified by preparative HPLC to obtain the product 6-((6-methoxypyridazin-3-¡l)amino)-N-methyl-4((3-(methylsulfonyl)pyridin-2-yl)amino)pyridazin -3-carboxamide (8.6 mg, 0.020 mmol, 7.96% performance). 1H NMR (500 MHz, DMSO-d6) δ 12.09 - 11.97 (m, 1H), 9.24 - 9.16 (m, 1H), 9.13 - 9.02 (m, 1H), 8.65 - 8.53 (m, 1H), 8.34 - 8.23 ​​(m, 1H), 7.94 (s, 1H), 7.31 (br s, 1H), 7.27 7, 17 (m, 1H), 4.05 - 3.92 (m, 3H), 3.41 - 3.30 (m, 3H), 2.89 - 2.81 (m, 3H). This reaction also produced the secondary product 6-((6-methoxypyridazín-3yl)amino)-N-methyl-4-((3-(methylsulfinyl)pyridin-2-yl)amino)pyridazine-3-carboxamide (6 .6 mg, 0.016 mmol, 6.35% yield). MS (M+1) m / z: 415.2 (MH+). LC retention time 0.89 min [QC-ACN-TFA-XB], Example 210 Na2WO4.2H2O, 30% H2O2 Acetic Acid Stage 2 Stage 1 A suspension of tosic acid (0.091 g, 0.479 mmol), 6-chloro-N-methyl-4-((3(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (0.099 g, 0.320 mmol) and 1-methyl-1Hpyrazole-3-amine (0.184 g, 1.895 mmol) in THF (2 ml) was heated at 100 °C for 8 hours. The reaction was diluted with ethyl acetate, and washed with 1N NaOH and water. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated to obtain the crude product N-methyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-4- ((3IF-2019-16830169-APN-ANP#INPI 104 Page 104 of 134 (methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (0.1268 g, 0.342 mmol, 107% yield). A portion (23 mg) of the crude product was purified by preparative HPLC to obtain N-methyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-4-((3(methylthio)pyridin-2 -yl)amino)pyridazine-3-carboxamide (12.4 mg, 0.031 mmol, 9.85% yield). MS (M+1) m / z: 371.2 (MH+) LC retention time 1.377 min [QC-ACN-AA-XB],1H NMR (500 MHz, DMSO-d6) δ 12.05 - 11 .86 (m, 1H), 9.89 - 9.72 (m, 1H), 9.21 - 9.00 (m, 2H), 8.32 - 8.12 (m, 1H), 7.93 - 7.69 (m, 1H), 7.63 - 7.47 (m, 1H), 7.17 - 6.97 (m, 1H), 6.33 - 6.17 (m, 1H), 3 .82 - 3.75 (m, 3H), 2.89 - 2.79 (m, 3H). Stage 2 To a solution of N-methyl-6-((1-methyl-1H-pyrazol-3-¡l)amino)-4-((3(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide ( 0.1158 g, 0.313 mmol) in acetic acid (15 ml) at room temperature, sodium tungstate dihydrate (0.129 g, 0.391 mmol) was added in one portion, and then 30% hydrogen peroxide (0.958 ml, 9, 38 mmol). The solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with ice water and basified with Na2CO3 powder. The aqueous layer was extracted three times with DCM. The organic layer was washed with sodium thiosulfate (5%), dried (Na2SO4), filtered and concentrated. The crude residue was purified by preparative HPLC to obtain N-methyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-4((3-(methylsulfonyl)pyridin-2-yl)amino)pyridazin -3-carboxamide (56 mg, 0.138 mmol, 44.1% yield). MS (M+1) m / z: 402.9 (MH+) · LC retention time 0.817 min [QC-ACN-TFA-XB]. 1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 9.94 (s, 1H), 9.12 (brd, J=4.6 Hz, 1H), 9.06 (s , 1H), 8.65 (dd, J=4.8, 1.8 Hz, 1H), 8.28 (dd, J=7.8, 1.8 Hz, 1H), 7.59 (d, J=2.2 Hz, 1H), 7.30 (dd, J=7.8, 4.8 Hz, 1H), 6.28 (d, J=2.1 Hz, 1H), 3.79 ( s, 3H), 3.38 (s, 3H), 2.85 (d, J=4.8 Hz, 3H). Example 211 IF-2019-16830169-APN-ANP#INPI 105 Page 105 of 134 χ^,ΝΗζ .HCI 1-Propanphosphonic anhydride, TEA 1,T-bis(dicyclohexylphosphino)ferrocene K3PO4 Dioxane Stage 2 Na2WO4.2H2O, 30% H2O2 Acetic Acid Stage 3 Stage 1 1-Propanphosphonic anhydride (0.698 mL, 1.196 mmol) was added to a DMF solution (2.5 mL) of 6-chloro-4-((3-(methylthio)pyridin-2-yl)amino)pyridazine-3carboxylic acid. (0.2365 g, 0.797 mmol) and TEA (0.222 ml, 1.594 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour before adding ethanamine hydrochloride (0.3383 g, 4.15 mmol) and TEA (0.2 ml). The reaction was stirred for 16 hours at room temperature, diluted with water, and the suspension was filtered and washed with water. The solid was dried under vacuum overnight. The crude product was purified with silica gel flash chromatography (ISCO, 12 g column) and eluted with 0 to 50% ethyl acetate in hexane to obtain the desired product 6-chloroN-ethyl-4-((3 -(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (102 mg, 0.315 mmol, 39.6% yield). MS (M+1) m / z: 324.0 (MH+). LC retention time 0.97 min [A],1H NMR (400 MHz, CHLOROFORM-d) δ 12.59 - 12.44 (m, 1H), 9.33 - 9.27 (m, 1H), 8.57 - 8.51 (m, 1H), 8.45 - 8.31 (m, 2H), 7.39 - 7.31 (m, 1H), 3.67 - 3.49 (m, 2H) ), 3.06 2.79 (m, 3H), 1.39- 1.27 (m, 3H). Stage 2 A suspension of tris(dibenzyl¡denacetone)d¡palladium(0) (2.262 mg, 2.471 pmol), 1,1'-bis(dicyclohexylphosphino)ferrocene (2.86 mg, 4.94 pmol), 6-chloro -N-ethyl-4-((3(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamideIF(20q^68^16§,^_mmol^p2-(6106 Page 106 of 134 aminopyridin-3-yl)propan-2-ol (0.0182 g, 0.120 mmol) and potassium phosphate, tribasic (0.124 ml, 0.247 mmol) in 1,4-dioxane (0.5 ml) in A 1 dram vial was subjected to a vacuum / N2 cycle three times. The reaction mixture was heated at 80 °C for 3 hours. The reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. The crude product, N-ethyl-6-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-4-((3(methylthio)pyridin-2-yl)amino) was obtained. pyridazine-3-carboxamide (41.3 mg, 0.094 mmol, 95% yield). The raw product was used as it was in the next step. MS (M-1) m / z: 438.4 (MH+). LC retention time 0.89 min [E], Stage 3 To a solution of N-ethyl-6-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-4-((3(methylthio)pyridin-2-yl)amino) pyridazine-3-carboxamide (0.0412 g, 0.094 mmol) in acetic acid (3 mL) at room temperature, sodium tungstate dihydrate (0.039 g, 0.117 mmol) was added in one portion, and then 30% hydrogen peroxide (0.287 mi, 2.81 mmol). The solution was stirred at room temperature for 1 hour. 0.3 ml of 30% H2O2 was added and the reaction was stirred for an additional 1 hour. This was repeated three more times. The reaction mixture was diluted with ice water and basified with Na2CO3 powder. The aqueous layer was extracted three times with DCM. The DCM layer was washed with sodium thiosulfate (5%) once, dried (Na2SO4), filtered, and concentrated. The crude oil was purified with preparative HPLC to obtain the desired product, N-ethyl-6-((5(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-4-((3-(methylsulfonyl)pyridin -2-yl)amino)pyridazine-3carboxamide (12.3 mg, 0.026 mmol, 27.8% yield). MS (M+1) m / z: 472.1 (MH+). LC retention time 1.299 min [QC-ACN-AA-XB],1H NMR (500 MHz, DMSO-d6) δ 12.16 - 11.97 (m, 1H), 10.33 - 10.17 (m , 1H), 9.53 9.37 (m, 1H), 9.30 - 9.08 (m, 1H), 8.72 - 8.60 (m, 1H), 8.43 - 8.33 ( m, 1H), 8.32 - 8.22 (m, 1H), 7.85 - 7.75 (m, 1H), 7.70 - 7.60 (m, 1H), 7.37 - 7, 29 (m, 1H), 2.56 - 2.54 (m, 5H), 1.51 -1.43 (m, 6H), 1.21 -1.13 (m, 3H). R5 The following example was prepared as Ifiij¿|^_^^^t^^[1’ 107 Page 107 of 134 Table 11 Pd2dba31,T-bis(dlcyclohexylphosphino)ferrocene K3PO4 Dioxane Stage 2 Na2WO4.2H2O, 30% H2O2 Acetic Acid Stage 3 Stage 1 1-Propanphosphonic anhydride (0.416 mL, 0.712 mmol) was added to a DMF solution (2 mL) of 6-chloro-4-((3-(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxylic acid. (0.1408 g, 0.475 mmol) and TEA (0.132 ml, 0.949 mmol) at room temperature. The reaction was diluted with diethyl ether and filtered. The solid was collected as a brown rubbery solid. The remainder of the material (filtrate) was combined, concentrated, and treated with NH4OH overnight. The brown rubbery solid was suspended in 1 ml of DMSO, and NH4OH (2 ml) was added. The suspension was shaken vigorously. After 1 hour, the mixture showed complete conversion to the primary amide. All of the above were combined, diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. The crude product, 6-chloro-4-((3-(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (97.4 IF-2019-16830169-APN-ANP#INPI 108 Page 108 of 134 mg, 0.329 mmol, 69.4% yield), was used as it was in the next step. MS (M+1) m / z: 296.1 (MH+) · LC retention time 0.86 min [E]. Stage 2 A suspension of tris(dibenzylidenacetone)d¡palladium(0) (7.54 mg, 8.23 ​​pmol), 1,T-bis(dicyclohexylphosphino)ferrocene (9.53 mg, 0.016 mmol ), 6-chloro-4-((3(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (0.0974 g, 0.329 mmol), 6methoxypyridazin-3-amine (0.082 g, 0.659 mmol) and Potassium phosphate, tribasic (0.412 ml, 0.823 mmol) in 1,4-dioxane (2.5 ml) in a 1 dram vial was vacuum / N2 cycled three times. The reaction mixture was heated at 80 °C for 3 hours. During heating, the reaction mixture became a clear solution. The reaction mixture was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated to obtain a crude product. MS (M+1) m / z: 385.2 (MH+) · LC retention time 0.76 min [EX. 1H NMR (400 MHz, CHLOROFORM-d) δ 12.09 (s, 1H), 9.15 (s, 1H), 8.33 (d, J=9.5 Hz, 1H), 8.30 (dd , J=4.9, 1.7 Hz, 1H), 8.09 (br d, J=2.9 Hz, 1H), 7.90 (s, 1H), 7.78 (dd, J=7 .6, 1.7 Hz, 1H), 7.06 (d, J=9.4 Hz, 1H), 6.98 (dd, J=7.6, 4.9 Hz, 1H), 5.55 (br d, J=3.2 Hz, 1H), 4.13 (s, 3H), 2.52 (s, 3H). Stage 3 To a solution of 6-((6-methoxypyridazin-3-yl)amino)-4-((3-(methylthio)pyridin-2yl)amino)pyridazin-3-carboxamide (0.0329 g, 0.086 mmol) in acid acetic acid (3 ml) at room temperature, sodium tungstate dihydrate (0.035 g, 0.107 mmol) was added in one portion, and then 30% hydrogen peroxide (0.262 ml, 2.57 mmol). The solution was stirred at room temperature for 20 min, and a suspension was observed. The reaction was stirred at room temperature for 3 hours. The reaction was diluted with water (50 ml) and basified with Na2CO3 powder. The aqueous layer was extracted with DCM three times. The DCM layer was combined, dried (Na2SO4), filtered and concentrated to obtain the crude product. The crude product was purified with preparative HPLC to obtain the desired product, 6-((6-methoxypyridazin-3-yl)amino)-4-((3(methylsulfonyl)pyridin-2-yl)amino)pyridazin-3 -carboxamide (2.6 mg, 6.24 pmol, 7.30% yield). MS (M+1) m / z: 417.3 (MH+) · LC retention time 0.907 min [QC-ACN-TFA-XB].1H NMR (500 MHz, DMSO-d6) δ 12.23 - 12 .14 ​​(m, 1H), 10.54 - 10.39 (m, 1H), 9.33 9 17 (m 1H), 8.65 - 8.61 (m, 1H), 8.59 - 8, 53 (m, 1H), 8.31 - 8.26 (m, 1H), 8.07 - 8.01 IF-2019-16830169-APN-ANP#INPI 109 Page 109 of 134 (m, 1H), 7.88 - 7.83 (m, 1H), 7.37 - 7.31 (m, 1H), 7.27 - 7.23 (m, 1H), 4 .02 - 3.95 (m, 3H). R5 The following example was prepared similarly to the product of Example 213: Table 12 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 214 I z ^ZI 388.4 389.2 0.766 [QC-ACNTFA-XB] Example 215 THF Stage 1 , Xantphos, CsCO3jPd2dba3ri21^ ΠΙ Dioxane, N-Methyl-2-pyrrolidinone Stage 2 Na2WO4.2H2O 50% H2O2 Acetic Acid Stage 3 Stage 1 To a solution of 4,6-dichloro-N-(methyl-d3)nicotinamide (30 mg, 0.144 mmol) and 3-(methylthio)pyridín-2-amine (22.24 mg, 0.159 mmol) )2(eri)-ir(HF0l(^^il)NaAmí^Mtura 110 Page 110 of 134 ambient, lithium bis(trimethylsilyl)amide in THF (0.360 ml, 0.360 mmol) was added for 5 min. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with 1 N HCl (1.5 ml), and water (20 ml) was added. The mixture was extracted with DCM (3 x 20 ml) which was combined, dried (Na2SO4) and concentrated in vacuo, and used as is in the next step. MS (M+1) m / z: 312.2 (MH+). LC retention time 1.06 min [C]. Stage 2 A solution of 6-chloro-N-(methyl-d3)-4-((3-(methylthio)pyridin-2yl)amino)nicotinamide (0.13 g, 0.412 mmol), 5-fluoropyrid ¡n-2-amine (0.104 g, 0.928 mmol), N-methyl2-pyrrolidinone (2.00 ml) was microwaved in a sealed vial up to 150 °C for 1 h. Once the reaction was complete, the reaction mixture was diluted with ethyl acetate (10 mL) and filtered through Celite. The filtrate was concentrated in vacuo. DMSO (3 mL) and water (45 mL), and then saturated NaHCO3 (4 mL), were added to the residue. The precipitate was collected, filtered and washed with water to obtain the crude product as an orange solid. The crude product (readily soluble in THF) was purified by flash chromatography using a 40 g ISCO column (solid loading) that was eluted with 0-10% MeOH / DCM (0%, 1 cv; 0-5%, 20 cv; 5-10%, 8 cv). Appropriate fractions (5.07.5% elution) were collected and concentrated in vacuo to obtain 6-((5fluoropyridin-2-yl)amino)-N-(methyl-d3)-4-((3-( methylthio)pyridin-2-yl)amino)nicotinamide (0.0367 g, 0.095 mmol, 22.97% yield) as a light yellow solid. MS (M+1) m / z: 388.1 (MH+) · LC retention time 0.70 min [F]. Stage 3 A 6-((5-fluoropyridin-2-yl)amino)-N-(methyl-d3)-4-((3-(methylthio)pyridin-2¡l)amino)nicotinamide (0.0367 g, 0.095 mmol), acetic acid (3 ml) was added to obtain a heterogeneous solution. The solution was heated slightly and became homogeneous. After cooling to room temperature, sodium tungstate dihydrate (0.0411 g, 0.125 mmol) was added, followed by 50% hydrogen peroxide (0.2 ml, 3.47 mmol). Within 1 min, the solution became heterogeneous. After 0.5 h, the starting material was consumed. The reaction mixture was stirred for an additional 1 h to achieve complete oxidation. Water (25 ml) was added to the reaction, and then sodium carbonate until the pH was shown to be basic by iridescent paper. The mixture was extracted with DCM (4 x 50 ml). The organic layers were combined, dried over Na2SO4, and filtered. Silica gel was added to the filtrate and concentrated in vacuo. IF-2019-16830169-APN-ANP#INPI 111 Page 111 of 134 Crude product was purified by flash chromatography (solid loading) using a 24 g ISCO column that was eluted with 0-5% MeOH / DCM (0%, 1 cv; 0-5%, 15 cv; 5 %, 5 hp). Suitable fractions (4.5-5.0%) were collected and concentrated in vacuo to obtain the desired product. MeOH was added, and the ground material was washed with MeOH and dried in a desiccator oven at 55 °C to obtain 6-((5-fluoropyridin-2-yl)amino)-N-(methyl-d3)-4- ((3-(methylsulfonyl)pyridin-2¡l)amino)nicotinamide (0.012 g, 0.029 mmol, 30.3% yield). MS (M+1) m / z: 420.1 (MH+) · LC retention time 0.59 min [B]. 1H NMR (400 MHz, DMSO-d6) δ 11.56 - 11.47 (m, 1H), 10.02 - 9.85 (m, 1H), 8.89 8.78 (m, 1H), 8 .70 - 8.59 (m, 1H), 8.57 - 8.50 (m, 2H), 8.26 - 8.20 (m, 2H), 7.83 - 7.74 (m, 1H) , 7.71 - 7.58 (m, 1H), 7.28 - 7.20 (m, 1H), 3.39 - 3.34 (m, 3H). The following examples were prepared in a similar manner to the product of the Example 215 Table 13 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 216 Q 401.45 402.1 0.56 [B] 217 / XCI H 435.90 436.0 0.62 [ A] 218 H 433.47 434.1 0.62 [A] 219 ^.CF3 H 469.46 470.2 0.67 [F] IF-2019-16830169-APN-ANP#INPI 112 Page 112 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method]___ 220 iz^ o z 426.47 427.0 0.59 [B] 221 H 426.47 427.0 0.65 [F] 222 z M ^ZI 442.51 443.0 0.63 [A] 223 N CF3 ,XI ΓΝ H 470.44 471.2 1.47 [QC-ACNAA-XB] 224 IZ^ z / / * \ 402.44 403.1 0.86 [QC-ACNAA-XB] 225 IZ^ Q “Π GJ 470.44 471.2 0.65 [B] 226 IZ^ - 430.46 431.1 0.68 [ A] 227 z— / o z= / zx 458.55 459.0 0.64 [A] 228 I N^N Η V 482.57 482.8 0.64 [A] 229 iz^ Y=z 4 / ) 2 —z 456.5 457.08 0.59 [A] 230 Ν|-γ H 440.5 440.8 0.61 [A] IF-2019-16830169-APN-ANP#INPI 113 Page 113 of 134 Stage 2 and 3 Stage 1 Follow the procedure of preparation 3, Example 1, Step 1. Stage 2 A mixture of 6-chloro-N-(methyl-d3)-4-((3-(methylthio)pyridín-2¡l)amino)nicotinamide (25 mg, 0.080 mmol), 5-phenylpyridín -2-amine (17.74 mg, 0.104 mmol), Pd2(dba)3(7.34 mg, 8.02 pmol), Xantphos (9.28 mg, 0.016 mmol), Cs2CO3(34.0 mg, 0.104 mmol) in dioxane (1.0 ml) was purged with nitrogen for 5 min, and the reaction was placed in a heating block preheated to 130 °C for 2 h to obtain N-(methyl-d3)-4-(( 3-(methylthio)pyridin-2-yl)amino)-6-((5-phenylpyridin-2yl)amino)nicotinamide (M+H=446). The solution was diluted with AcOH (2 ml) and passed through a filter. Sodium tungstate dihydrate (7.93 mg, 0.024 mmol), 30% hydrogen peroxide (164 pl, 1.604 mmol) was added to the solution and stirred at room temperature for 1 h. Sodium thiosulfate (254 mg,HIF-2019-16830169-APN-ANP#INPI) was added to the mixture 114 Page 114 of 134 1.604 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 10 min. The solid was filtered, and the solvent was removed in vacuo to obtain the desired impure product. The reaction mixture was diluted with DMSO, filtered and purified with preparative HPLC to obtain N-(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2-yl)amino)-6-((5phenylpyridin -2-yl)amino)nicotinamide (3.5 mg, 7.33 pmol, 9.14% yield). MS (M+1) m / z: 478.2 (MH+). LC retention time 1.72 min [QC-ACN-AA-XB],1H NMR (500 MHz, DMSO-d6) δ 10.09 - 9.93 (m, 1H), 9.04 - 8.92 (m, 1H), 8.73 - 8.63 (m, 1H), 8.61 - 8.50 (m, 3H), 8.28 - 8.18 (m, 1H), 8.07 - 7 .96 (m, 1H), 7.85 - 7.73 (m, 1H), 7.73 - 7.65 (m, 2H), 7.53 - 7.43 (m, 2H), 7.41 - 7.32 (m, 1H), 7.29 - 7.18 (m, 1H). The following examples were prepared in a similar manner to the product of the Example 234: Table 14 Example No. NR2R5 R3 MW m / z [M+H]+ Rt (min) [Method] 235 O H H 380.4 381 1 [QC-ACNAA-XB] 236 IZ r H 392.5 393.1 1.5 [QC-ACNAA-XB] 237 0 H H 382.4 382.7 0.7 [QC-ACNTFA-XB] 238 H H 477.6 477.9 1.7 [QC-ACNAA-XB] 239 O H 406.5 407 .1 1.2 [QC-ACNAA-XB] IF-2019-16830169-APN-ANP#INPI 115 Page 115 of 134 Example No. NR2R5 R3 MW m / z [M+Hf Rt (min) [Method] 240 «o U. O O ^2==^ ^ZI H 485.5 486.1 1.2 [QC-ACNTFA-XB ] 241 O H X 394.5 395 1.2 [QC-ACNAA-XB] 242 O Vx? X 406.5 407.1 1.2 [QC-ACNAA-XB] 243 or QC-ACNAA-XB] Example 245 Na2WO4.2H2O AcOH / H2O2Stage 2 TFA Stage 3 pmb-nh2 / kf DMSO Stage 1 Dioxane Xantphos / Pd2dba3 / Cs2CO3 Stage 4 Stage 1 4-Methoxybenzylamine (4.95 ml, 37.9 mmol), 6-chloro-N-(methyl-d3)4-((3-(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide were combined (2.370 g, 7.58 mmol) and potassium fluoride (1.321 g, 22.74 mmol) in DMSO (20 ml) and heated to 120 °C for 6 hours. The reaction was then cooled to room temperature, diluted with EtOAc and washed with basic aqueous buffer (K3PO41.5 M), water, saturated aqueous ammonium chloride and brine. The aqueous layer was re-extracted once with EtOAc, and the organic layers were combined. The organic layer was subsequently dried over sodium sulfate, filtered and concentrated. The product 6-((4methoxybenzyl)amino- / V-(methyl-d3)-4-((3-(methylthio)pyridin-2-yl)amino)pyridazine-3carboxamide was purified by automated flash chromatography which was eluted with methanol. in DCM from 0 to 10% (2.78 g, 89% of theFeMlfhybrit^.l^S^(M+AHf^Jl4l14.3 116). Page 116 of 134 (MH+)· LC retention time 0.75 min [D].1H NMR (400 MHz, CHLOROFORM-d) δ 12.11 - 12.04 (m, 1H), 8.44 - 8 .40 (m, 1H), 8.28 - 8.22 (m, 1H), 8.19 - 8.12 (m, 1H), 7.73 - 7.66 (m, 1H), 7.39 - 7.33 (m, 2H), 6.95 - 6.86 (m, 3H), 5.31 - 5.25 (m, 1H), 4.62 4.57 (m, 2H), 3, 82 (s, 3H), 2.53 - 2.48 (m, 3H). Stage 2 Sodium tungstate dihydrate (0.831 g, 2.52 mmol) was added to a suspension in AcOH (20 mL) of hydrogen peroxide (30% solution in water, 5.14 mL, 50.4 mmol) and 6-( (4-methoxybenzyl)amino)-N-(methyl-d3)-4-((3-(methylthio)pyridin-2yl)amino)pyridazine-3-carboxamide (1.041 g, 2.52 mmol) at room temperature. After stirring at room temperature for 1 hour, the reaction was diluted with water, basified with Na2CO3 powder, and extracted three times with ethyl acetate. The ethyl acetate layer was combined, washed twice with 1.5 M K2HPO4 solution and once with Na2S2O3 (5% solution). The organic layer was dried (Na2SO4), filtered and concentrated. The product 6-((4-methoxybenzyl)amino-A / -(methyl-d3)-4-((3(methylsulfonyl)pyridin-2-yl)amino)pyridazine-3-carboxamide was purified by automated flash chromatography that was eluted with methanol in 0 to 10% DCM (0.66 g, 59%) MS (M+1) m / z: 446.1 (MH+)· LC retention time 0.66 min [D], Stage 3 A mixture of TFA (4 ml, 51.9 mmol), 6-((4-methoxybenzyl)amino)-N-(methyl-d3)4-((3-(methylsulfonyl)pyridin-2-yl)amino )pyridazine-3-carboxamide (0.4881 g, 1.096 mmol) was heated at 60 °C for 2 hours. The solvent was removed in vacuo. Ethyl acetate was added to the crude oil, and the organic layer was washed with 1.5 M K2HPO4 and water. The ethyl acetate layer was dried (Na2SO4) and filtered. The filter cake was washed with DCM to minimize product loss. The solvent was removed in vacuo, and the product was purified by automated chromatography that was eluted with 0 to 100% ethyl acetate in hexane, kept at 100%, and then changed to 0 to 10% methanol in DCM to obtain the product 6-amino- / V-(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2yl)amino)pyridazine-3-carboxamide as a light yellow solid. (0.14 g, 40% yield). MS (M+1) m / z: 326.3 (MH+). LC retention time 0.50 min [D],1H NMR (400 MHz, CHLOROFORM-d) δ 12.74 -12.63 (m, 1H), 8.73 - 8.65 (m, 1H), 8.64 8.58 (m, 1H), 8.45 - 8.37 (m, 1H), 7.89 - 7.78 (m, 1H), 3.37 - 3.28 (m, 3H) . Stage 4 The mixture of 3-(tert-butyl)-6-chlorophyridazine (10.49 mg, 0.061 mmol), Pd2(dba)3 (1.407 mg, 1.537 pmol), 6-amino- / V-(methyl-d3 )-4-((3-(methylsulfonyl)pyridin-2yl)amino)pyridazine-3-carboxamide (10 mg, 0.031 mmol), Xantphos (1.778 mg, 3.07 IF-2019-16830169-APN-ANP#INPI 117 Page 117 of 134 pmol) and cesium carbonate (10.01 mg, 0.031 mmol) in dioxane (0.3 ml) were degassed by a vacuum / N2 filling cycle three times and then heated at 110 °C for 16 hours . The reaction was diluted with methanol, filtered and purified by preparative reverse phase HPLC to obtain the product 6-((6-(tert-butyl)pyridazínyl-3yl)amino)-A / -(methyl-d3) -4-((3-(methylsulfonyl)pyridin-2-yl)amino)pyridazine-3-carboxamide (3.8 mg, 26% yield). MS (M+1) m / z: 460.3 (MH+). LC retention time 1.17 min [E],1H NMR (500 MHz, DMSO-d6) δ 12.03 (s, 1H), 10.43 (br s, 1H), 9.22 (s, 1H) ), 9.04 (br s, 1H), 8.61 (br d, J=4.5 Hz, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.05 (d , J=9.3 Hz, 1H), 7.74 (d, J=9.3 Hz, 1H), 7.34 (dd, J=7.7, 4.8 Hz, 1H), 1.38 (s, 9H) (3H was buried beneath the DMSO peak). Example 246 6-((6-(difluoromethoxy)pyridazin-3-yl)amino)-N-(methyl-d3)-4-((3-(methylsulfonyl)pyridin2-yl)amino)pyridazine-3-carboxamide The preparation of Example 245 was continued using 3-chloro-6-(difluoromethox¡)pyridazine as the starting material to obtain the title compound (4.5 mg, 36% yield). MS (M+1) m / z: 470.0 (MH+). LC retention time 1.21 min [E], Example 247 6-((6-isopropylpyridazin-3-yl)amino)-N-(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2yl)amino)pyridazine-3-carboxamide The preparation of Example 245 was continued using 3-chloro-6-isopropylpyridazine as the starting material to obtain the title compound (16.7 mg, 54% yield). MS (M+1) m / z: 446.3 (MH+) LC retention time 1.05 min [E], Example 248 6-((6-(difluoromethyl)pyridazin-3-yl)amino)-N-(methyl-d3)-4-((3-(methylsulfonyl)pyridan-2yl)amino)pyridazin -3-carboxamide IF-2019-16830169-APN-ANP#INPI 118 Page 118 of 134 DIBAL-H (5.89 ml, 5.89 mmol) was added to a THF solution (29.5 ml) of methyl 6-chloropyridazine-3-carboxylate (0.5083 g, 2.95 mmol) at 0°. c. The reaction was stirred at 0 °C for 30 min. The reaction was quenched at 0 °C by adding water (5 ml) and HCl1 N (5.89 ml). The reaction mixture was warmed to room temperature, and NaHCO3 (saturated aqueous solution) was added. The crude product was extracted three times with DCM. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude product was purified by automated flash chromatography with 0 to 80% ethyl acetate in hexane to obtain the title product (0.22 g, 52%). HPLC retention time: 0.82 min [BJ.1H NMR (400 MHz, CHLOROFORM-d) δ 10.34 (s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7 .77 - 7.71 (m, 1H). Step 2: 3-chloro-6-(difluoromethyl)pyridazine F DAST (0.147 mL, 1.115 mmol) was added to a DCM solution (5 mL) of 6chloropyridazin-3-carbaldehyde (0.106 g, 0.744 mmol) at 0 °C. The reaction was stirred for 16 hours while warming to room temperature. The reaction was cooled back to 0 °C and quenched with water. The reaction was diluted with DCM and washed with NaHCO3 (saturated aqueous solution). The DCM layer was separated, dried (Na2SO4), filtered and concentrated to obtain the crude product, which was used as is (0.12 g, 36%). MS (M+1) m / z: 165.1 (MH ). LC retention time 0.62 min [D],1H NMR (400 MHz, CHLOROFORM-d) δ 7.87 - 7.79 (m, 1H), 7.77 - 7.68 (m, 1H), 7.10 - 6.78 (t, J=54.34Hz, 1H).19F NMR (376 MHz, CHLOROFORM-d) δ -114.89 (s, 2F). Stage 3 The preparation of Example 245 was continued using 3-chloro-(6-difluoromethyl) IF-2019-16830169-APN-ANP#INPI 119 Page 119 of 134 pyridazine as the starting material to obtain the title compound 6-((6(difluoromethyl)pyridazin-3-yl)amino)-N-(methyl-d3)-4-((3-(methylsulfonyl) pyridin-2yl)amino)pyridazine-3-carboxamide (5.7 mg, 12% yield). MS (M+1) m / z: 454.2 (MH+). LC retention time 0.66 min [D],1H NMR (400 MHz, CHLOROFORMOd) δ 12.50 (s, 1H), 9.24 (s, 1H), 8.62 (dd, J=4, 8, 1.8 Hz, 1H), 8.51 (d, J=9.3 Hz, 1H), 8.38 (dd, J=7.8, 1.9 Hz, 2H), 8.24 ( br s, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.21 (dd, J=7.8, 4.8 Hz, 1H),6.88 (t, J= 56.0 Hz, 1H), 3.33 (s, 3H);19F NMR (376 MHz, CHLOROFORMOd) δ-113.93 (s, 2F). Example 249 6-((5-(1,3-dioxolan-2-yl)pyridin-2-yl)amino)-N-(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2yl)amino)pyridazin -3-carboxamide Stage 1: 2-chloro-5-(1,3-dioxolan-2-¡l)pyridine The mixture of p-toluenesulfonic acid monohydrate (0.0766 g, 0.403 mmol), ethane-1,2-diol (0.2445 g, 3.94 mmol) and 6-chloronicotinaldehyde (0.3174 g, 2.242 mmol) in toluene (3 ml) was heated to 120 °C for 2 hours. The reaction was diluted with ethyl acetate and washed with 1N NaOH and then water. The ethyl acetate layer was separated, dried (Na2SO4) and filtered. The product was purified by automated flash chromatography eluted with 0 to 30% ethyl acetate in hexane (0.26 g, 62%). MS (M+1) m / z: 185.9 (MH+)· LC retention time 0.70 min [D].1H NMR (400 MHz, CHLOROFORM-d) δ 8.50 (d, 7=2 .3 Hz, 1H), 7.77 (dd, J=8.2, 2.4 Hz, 1H), 7.37 (d, J=8.3Hz, 1H), 5.86 (s, 1H) , 4.15-4.06 (m, 4H). Stage 2 The preparation of Example 245 was continued using 2-chloro-5-(1,3-dioxolan-2-yl)pyridine as the starting material to obtain the title compound 6-((5-(1,3dioxolan-2- il)pyridin-2-yl)amino)-N-(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2yl)amino)pyridazine-3-carboxamide (4.7 mg, 31% yield) . MS (M+1) m / z: 475.2 (MH+). LC retention time 1.15 min [E]. IF-2019-16830169-APN-ANP#INPI 120 Page 120 of 134 Example 250 Ν-(ιηβίίΙ-ά3)-6-((5-(2-ηιβίίΙ-1,3-άίοχοΐ3η-2-ίΙ)ρίΐΊάΙη-2-ΙΙ)3ΠΉηο)-4-((3(methylsulfonyl)pyridin-2- yl)amino)pyridazine-3-carboxamide Η Step 1: 2-chloro-5-(2-methyl-1,3-dioxolan-2-yl)pyridine The preparation of Example 249 Step 1 was continued using 1-(6-chloropyridin-3yl)ethan-1-one as the starting material to obtain the title product 2-chloro-5-(2methyl-1,3-dioxolan- 2-yl)pyridine (0.125 g, 45%). MS (M+1) m / z: 200.0 (MH ). LC retention time 0.79 min [D],1H NMR (400 MHz, CHLOROFORM-d) δ 8.53 - 8.50 (m, 1H), 7.75 (dd, J=8.2, 2 .5 Hz, 1H), 7.31 (dd, J=8.2, 0.7 Hz, 1H), 4.10 - 4.07 (m, 2H), 3.80-3.78 (m, 2H), 1.66 (s, 3H). Stage 2 The preparation of Example 245 was continued using 2-chloro-5-(2-methyl-1,3dioxolan-2-yl)-pyridine as the starting material to obtain the title compound N(methyl-d3)-6 -((5-(2-methyl-1,3-dioxolan-2-yl)pyridin-2-yl)amino)-4-((3-(methylsulfonyl)pyridin-2¡l)amino)pyridazin-3- carboxamide (4.4 mg, 27% yield). MS (M+1) m / z: 489.2 (MH+). LC retention time 1.29 min [E].1H NMR (500 MHz, DMSO-d6) δ 12.10 - 12.01 (m, 1H), 10.39 - 10.27 (m, 1H), 9.52 - 9.44 (m, 1H), 9.16 - 9.07 (m, 1H), 8.72 8.62 (m, 1H), 8.36 - 8.23 ​​(m, 2H) , 7.77 - 7.71 (m, 1H), 7.70 - 7.63 (m, 1H), 7.37 - 7.28 (m, 1H), 4.03 - 3.96 (m, 2H), 3.80 - 3.72 (m, 1H), 3.64 - 3.54 (m, 2H), 1.65 - 1.56 (m, 3H) (3H buried below DMSO peak ). Example 251 N-(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2-yl)amino)-6-(pyridazin-3ylamino)pyridazine-3-carboxamide IF-2019-16830169-APN-ANP#INPI 121 Page 121 of 134 Step 1: N-(methyl-d3)-4-((3-(methylthio)pyridin-2-yl)amino)-6-(pyridazin-3-ylamino)pyridazine-3 carboxamide The mixture of 1,1'-bis(dicyclohexylphosphino)ferrocene (6.27 mg, 10.84 pmol), Pd2(dba)3(4.14 mg, 4.52 pmol), 6-chloro-N-(methyl -d3)-4-((3-(methylthio)pyridin-2yl)amino)pyridazine-3-carboxamide (56.5 mg, 0.181 mmol), pyridazine-3-amine (25.8 mg, 0.271 mmol) and tribasic potassium phosphate (2 M in water, 0.226 ml, 0.452 mmol) in dioxane (2 ml) was degassed by using a vacuum / N2 filling cycle three times and then heated to 110 °C for 1.5 hours. The reaction was diluted with ethyl acetate and washed three times with water. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. Flash chromatography eluted with 0 to 10% methanol in DCM produced the desired product. (39.3 mg, 59% yield). MS (M+1) m / z: 372.1 (MH+). LC retention time 0.69 min [D], Stage 2 Sodium tungstate dihydrate (0.035 g, 0.106 mmol) was added to a suspension of hydrogen peroxide (30% solution in water, 0.325 ml, 3.18 mmol) and N-(methyld3)-4-((3-( methylthio)pyridin-2-yl)amino)-6-(pyridazin-3-ylamino)pyridazine-3-carboxamide (0.0394 g, 0.106 mmol) in AcOH (1 mL) at room temperature. After stirring at room temperature for 6 hours, the reaction was diluted with water, basified with Na2CO3 powder, and extracted three times with DCM. The DCM layer was combined, washed with Na2S2O3 (5% solution), dried (Na2SO4), filtered and concentrated. The crude oil was purified by preparative reverse-phase HPLC to obtain the title compound (11 mg, 24% yield). MS (M+1) m / z: 404.2 (MH+) LC retention time 0.80 min [D],1H NMR (500 MHz, DMSO-d6) δ 12.02 (s, 1H), 10.55 - 10.44 (m, 1H), 9.31 (s, 1H), 9.01 (br s, 1H), 8.84 (d, J=4.2 Hz, 1H), 8, 62 (br d, J=4.6 Hz, 1H), 8.29 (d, J=6.6 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H), 7.62 (dd, J=9.0, 4.6 Hz, 1H), 7.33 (dd, J=7.7, 4.8 Hz, 1H)(3H buried below peak dfrQM§Q>)83OI69- APN-ANP#INPI 122 Page 122 of 134 Chiral Amide Synthesis of Intermediates 4 and 5: (S)-spiro[2.2]pentan-1-carboxamide and (R)-spiro[2.2]pentan-1-carboxamide d) Intermediary 4 Intermediary 5 Stage 4 SyR to). Di-tert-butyl (E)-diazen-1,2-dicarboxylate / PPh3 / THF; b) Separation of chiral SFC c). LIOH / THF / H2O / MeOH; d). Oxalyl chloride (overnight); NH3 / MeOH Stage 1: Naphthalen-2-ylmethyl spiro[2.2]pentan-1-carboxylate Di-tert-butyl (E)-diazen-1,2-dicarboxylate (0.407 g, 1.766 mmol) was added to a THF solution (5 ml) of spiro[2.2]pentan-1-carboxylic acid (0.1650 g , 1.472 mmol, Chembridge-BB), naphthalen-2-ylmethanol (0.279 g, 1.766 mmol) and triphenylphosphine (0.463 g, 1.766 mmol) at 0 °C. After the addition was complete, the reaction was warmed to room temperature and stirred for 14 hours. The reaction was diluted with DCM, and silica gel was added. The volatile organic solvents were evaporated in vacuo, and the resulting silica gel was loaded into a precolumn. The product was purified by automated flash chromatography eluted with 0 to 5% ethyl acetate in hexane (274 mg, 74% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 7.90 - 7.83 (m, 4H), 7.55 - 7.46 (m, 3H), 5.37 - 5.24 (m, 2H), 2.12 - 2.05 (m, 1H), 1.61 -1 .58 (m, 1H), 1.46 - 1.39 (m, 1H), 1.06 - 0.96 (m, 2H), 0.95 - 0.90 (m, 2H). HPLC retention time (Method A): Ír = 3.69 min. Stage 2 (pk1) and (pk2) IF-2019-16830169-APN-ANP#INPI 123 Page 123 of 134 Naphthalen-2-ylmethyl (5)-spiro[2.2]pentan-l-carboxylate Naphthalen-2-ylmethyl (7?)-spiro[2.2]pentan-l-carboxylate / ,.. (pk2) (pkl) ’ 0.403 g of the compound from Step 1 was separated by chiral SFC described above. The two isolated isomers were named “pk1” and “pk2” in the elution. 0.1917 g of the title compound pk1 (47% yield) and 0.1728 g of the title compound pk2 (43% yield) were obtained. Stereochemical assignment based on comparison with literature values ​​of the corresponding carboxylic acid (see below). Naphthalen-2-ylmethyl (S)-spiro[2.2]pentan-1-carboxylate, pk1:1H NMR (400 MHz, CHLOROFORM-d) δ 7.90 - 7.82 (m, 4H), 7.55 - 7 .46 (m, 3H), 5.31 (q, J=12.5 Hz, 2H), 2.07 (dd, J=7.5, 4.2 Hz, 1H), 1.59 (t, J=4.0 Hz, 1H), 1.43 (dd, J=7.6, 3.8 Hz, 1H), 1.07 0.88 (m, 4H). SFC retention time: Ír = 2.21 min. Optical rotation (OR): 72.90 (20°C). Naphthalen-2-ylmethyl (R)-spiro[2.2]pentan-1-carboxylate, pk2:1H NMR (400 MHz, CHLOROFORM-d) δ 7.89 - 7.83 (m, 4H), 7.54 - 7 .46 (m, 3H), 5.31 (q, J=12.4 Hz, 2H), 2.07 (dd, J=7.5, 4.2 Hz, 1H), 1.58 (t, J=4.0 Hz, 1H), 1.43 (dd, J=7.6, 3.8 Hz, 1H), 1.07 0.87 (m, 4H),SFC retention time: Ir = 3.17 min, OR: -76.09 (20°C). Stage 3S: (S)-spiro[2.2]pentan-1-carboxylic acid or A A A mixture of lithium hydroxide (0.066 g, 2.78 mmol) and naphthalen-2-ylmethyl (S)spiro[2.2]pentan-1-carboxylate (0.1751 g, 0.694 mmol) in THF (2 ml), water (0.5 ml) and MeOH (0.5 ml) was stirred at room temperature for 16 hours. The volatile organics were removed in vacuo, and water was added to the residue. The aqueous solution was washed four times with DCM (discarded), and then acidified with 1 N HCl (3.5 ml). The crude product was extracted from the aqueous layer three times with DCM. The combined DCM layers were dried (Na2SO4), filtered and concentrated to obtain the IF-2019-16830169-APN-ANP#INPI 124 Page 124 of 134 Desired title compound (62.7 mg, 81% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 1.99 (dd, J=7.5, 4.2 Hz, 1H) , 1.58 (t, J=4.0 Hz, 1H), 1.48 (dd, J=7.6, 3.8 Hz, 1H), 1.05-0.91 (m, 4H). OR: 188.25 (20°C). Stage 3R: (R)-spiro[2.2]pentan-1-carboxylic acid or The title product was prepared in the same manner as Step 3S of pk2 to obtain the title compound (R)-spiro[2.2]pentan-1-carboxylic acid. (60.0 mg, 83% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 1.99 (dd, J-7.6, 4.1 Hz, 1H), 1.58 (t, J =4.0 Hz, 1H), 1.47 (dd, J=7.6, 3.8 Hz, 1H), 1.04 - 0.90 (m, 4H).OR: -187.72 (20 °C). Literature OR [a]D25= -113.3° to -172.7° depending on optical purity (K. B. Wiberg, C. Osterle, J. Org. Chem, 64, 7763-7767 (1999). 4S stage: (S)-spiro[2.2]pentan-1-carboxamide Oxalyl chloride (0.054 mL, 0.612 mmol) was added to a DCM solution (3 mL) of (S)-spiro[2.2]pentan-1-carboxylic acid (0.0572 g, 0.510 mmol) at room temperature. The reaction was stirred for 16 hours, then the volatile organics were removed in vacuo. DCM (1.5 ml) was added to the crude acid chloride, and then ammonia solution (7 M in MeOH, 2.5 ml, 17.50 mmol) was added to the intermediate at 0 °C. The reaction was stirred overnight while warming to room temperature. The solvent was removed in vacuo to obtain a tan solid as the title compound (39.8 mg, 70% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 5.51 - 5.16 (m , 2H), 1.91 -1.84 (m, 1H), 1.50 -1.44 (m, 1H), 1.43 -1.38 (m, 1H), 0.96 (s, 4H) ). Step 4R: (R)-spiro[2.2]pentan-1-carboxamide or The title product was prepared in the same manner as Step 4S of (R)-spiro[2.2]pentan-1-carboxylic acid as starting material to obtain the title compound (53 5 mg 98% yield).1H NMR2(400l (MHnoGUPROftQBWPtd) δ 125 Page 125 of 134 5.51 - 5.22 (m, 2H), 1.91 - 1.85 (m, 1H), 1.48 - 1.43 (m, 1H), 1.43 - 1.37 (m, 1H) ), 0.96 (s, 4H). General scheme for Examples 252 and 253: a.) Pd2(dba)3 / Xantphos / Cs2CO3 / Dioxane; b). Sodium tungstate dihydrate / H202 / AcOH Example 252 Stage 1 A mixture of cesium carbonate (149 mg, 0.457 mmol), )-4-((3(methylthio)pyridin-2-yl)amino)pyridazine-3-carboxamide (65 mg, 0.208 mmol) and (R)spiro[2.2]pentan-1-carboxamide (50.8 mg, 0.457 mmol) in dioxane (3 ml) was degassed by a vacuum / N2 fill cycle three times. The reaction was heated at 110 °C for 16 hours. The reaction was diluted with water and DCM. The DCM layer was separated and washed two more times with water, and then dried (Na2SO4), filtered and concentrated. Purification by automated flash chromatography, eluted with 0 to 10% methanol in DCM, afforded the title compound (R)-N-(methyld3)-4-((3-(methylthio)pyridin-2-yl) amino)-6-(spiro[2.2]pentan-1-carboxamido)pyridazine-3carboxamide (54 mg, 67% yield).1H NMR (400 MHz, CHLOROFORM-d) δ 12.15 (brs, 1H), 9 .88 (s, 1H), 8.68 (brs, 1H), 8.36 (brd, J=3.5 Hz, 1H), 8.25 (brs, 1H), 7.72 (br d, J =7.4 Hz, 1H), 6.97 (br dd, J=7.0, 5.1 Hz, 1 H),2.51 (s, 3H), 2.21 - 2.09 (m, 1H), 1.58 -1.10 (m, 6H), 1.08 - 0.93 (m, 5H). LCMS (ESI) m / e 388.1 [(M+H)+, calculated for C^H^DsNeC^S!, 388.1]; LC / MS retention time (method D): Ir = 0.80 min. IF-2019-16830169-APN-ANP#INPI 126 Page 126 of 134 Stage 2 To a suspension of hydrogen peroxide (30% solution in water, 0.258 ml, 2.52 mmol) and (R)-N-(methyl-d3)-4-((3-(methylthio)pyridin-2-yl )amino)-6-(spiro[2.2]pentan1-carboxamido)pyridazine-3-carboxamide (0.0489 g, 0.126 mmol) in AcOH (1 ml), sodium tungstate dihydrate (0.042 g, 0.126 mmol) was added ) at room temperature. After stirring at room temperature for 1 hour, the reaction was diluted with water, basified with Na2CO8 powder, and extracted three times with DCM. The DCM layers were combined, washed with Na2S20s (5% solution), dried (Na2SO4), filtered, and concentrated. The crude product was purified by preparative reverse phase HPLC to obtain the title compound (R)-N-(methyl-d3)-4-((3(methylsulfonyl)pyridin-2-yl)amino)-6-(spiro [2.2]pentan-1-carboxamido)pyridazine-3carboxamide (16.2 mg, 31%) as a colorless solid.1H NMR (500 MHz, DMSO-d6) δ 12.07 (s, 1H), 11.22 ( s, 1H), 9.49 (s, 1H), 9.16 (s, 1H), 8.63 (dd, J=4.6, 1.5 Hz, 1H), 8.29 (dd, J =7.8, 1.4 Hz, 1H), 7.34 (dd, J=7.8, 4.7 Hz, 1H),2.48 - 2.43 (m, 1H), 1.46 1 .41 (m, 1H), 1.42 - 1.36 (m, 1H), 0.95 - 0.82 (m, 3H), 0.80 - 0.73 (m, 1H). (3H methylsulfone was buried below the DMSO peak). LCMS (ESI) m / e 420.0 [(M+H), calculated for C18H18D3N6O4S, 420.1]; LC / MS retention time (method E): tR= 1.38 min; OR: -205.39 (20°C). Example 253 Stage 1 After the preparation of Example 252 (Step 1) by using (S)spiro[2 2]pentan-1-carboxamide, the title compound (S)-N-(methyl-d3)-4IF-2019 was obtained -16830169-APN-ANP#INPI 127 Page 127 of 134 ((3-(methylthio)pyridin-2-yl)amino)-6-(spiro[2.2]pentan-1-carboxamido)pyridazine-3carboxamide (55 mg, 72% yield). LCMS (ESI) m / e 388.1 [(M+H)+, calculated for Ci8H18D3N6O2Si, 388.1]; LC / MS retention time (method D): tR= 0.80 min. After the preparation of Example 252, the title compound (S)-N-(methyl-d3)-4-((3-(methylsulfonyl)pyridin-2-yl)amino)-6-(spiro[2.2) was obtained ]pentan-1carboxamido)pyridazine-3-carboxamide (13.3 mg, 23% yield) as a colorless solid.1H NMR (500 MHz, DMSO-d6) δ 12.02 (s, 1H), 11.07 ( s, 1H), 9.53 (s, 1H), 9.09 7 (s, 1H), 8.67 - 8.55 (m, 1H), 8.36 - 8.23 ​​(m, 1H), 7.40 - 7.25 (m, 1H), 2.47 - 2.43 (m, 1H), 1.50 - 1.42 (m, 1H), 1.40 - 1.34 (m, 1H) ), 1.00 - 0.83 (m, 3H), 0.83 - 0.73 (m, 1H). (3H methylsulfone was buried below the DMSO peak). LCMS (ESI) m / e 420.1 [(M+H)+, calculated for C18H18D3N6O4S, 420.1]; LC / MS retention time (method E): tR= 1.39 min. OR: 160.12 (20°C). O II X J O HN^IU 'X... N N I R5 The following examples were prepared in a similar manner to the product of Example 177, Step 2. Table 15 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 254 nXn xa H 415.49 ------IF- 416 2019 16830169 A ΊΝ-ΑΝΡ#ΙΝΡΙ-- 128 Page 128 of 134 Example No. NR2R5 MW m / z [M+H]+ Rt (min) [Method] 255 N S^N Aa H 417.47 417.9 1.87 Method A (254 nm) 256 NN H 389.46 390 .2 1.84 Method A (254 nm) BIOLOGICAL TESTS The following assay is used to show activity for the compounds of the invention. IFNα-induced STAT phosphorylation in human blood After a one-hour incubation with the compound, human blood (extracted with EDTA or ACD-A as anticoagulant) was stimulated with 1000 U / ml of recombinant human IFNa A / D (R&D Systems 11200-2) for 15 min. Stimulation was stopped by the addition of Fix / Lyse buffer (BD 558049). Cells were stained with an anti-CD3 FITC antibody (BD 555916), washed, and permeabilized on ice using Perm III buffer (BD 558050). Cells were then stained with an antibody against pSTAT5 (pY694) Alexa-Fluor 647 (BD 612599) for 30 min before analysis on FACS Canto II. The amount of pSTAT5 expression was quantified by the median fluorescence intensity after regulating the CD3-expressing population. Inhibition data of IFNa-induced STAT phosphorylation in human blood Example No. Phosph. of Stat induced by IFNa (IC50, μΜ) 1 0.012 2 0.026 4 0.032 5 0.013 7 0.042 8 0.049 9 0.077 10 0.021 12 0.038 13 0.002 14 0.011 15 0.013 16 34 17 ΙΗ32©18-16830169-ΑΡ> -ANP#INPI 129 Page 129 of 134 Example No. Phosph. of Stat induced by IFNa (IC50, pM) _____ 19 0.044 20 0.047 21 0.037 22 0.031 23 2.14 24 0.009 25 0.015 26 0.049 27 0.088 28 0.028 29 0.092 30 31 0.031 32 0.036 33 0.018 34 0.115 35 0.090 36 0.022 37 0.026 38 0.018 39 0.015 40 0.018 41 0.024 42 0.015 43 0.026 44 0.014 45 0.034 46 0.053 47 0.048 48 0.040 49 0.058 50 0.03 51 0.029 52 0.092 53 0.132 56 0.018 57 0.059 58 0.024 59 0.219 61 0.018 62 1.682 63 0.013 64 0.079 65 0.193 66 1.237 67 3.581 68 1.345 69 0.012 IF-2019-16830169-APN 130 -ANP#INPI Page 130 of 134 Example No. Phosph. of Stat induced by IFNa (IC50, μΜ) 70 1.096 71 0.032 72 0.023 73 0.076 74 0.004 75 0.018 76 0.02 77 0.398 78 0.04 79 0.024 80 0.057 81 0.003 8 2 0.037 83 0.076 84 0.042 85 0.011 86 0.04 87 0.417 88 0.047 89 0.032 90 0.013 91 0.043 92 0.013 93 0.028 94 0.162 95 0.133 96 0.004 97 0.013 98 0.049 99 0.044 100 .015 101 0.095 102 0.138 103 0.016 104 0.046 105 0.009 106 0.124 107 0.013 108 0.167 110 0.02 111 0.248 112 0.142 113 0.088 115 0.190 116 0.782 117 0.334 118 0.131 119 0.073 IF-2019-16830169-APN-ANP#INPI 131 Page 131 of 134 Example No. Phosph. of Stat induced by IFNa (IC50, μΜ) 120 0.062 121 0.039 122 0.156 123 0.183 124 0.037 125 0.272 126 0.343 127 0.302 128 0.061 129 0.08 130 0 131 0.434 132 0.209 133 1.569 134 0.296 135 0.227 136 0.349 137 0.141 138 0.447 139 0.893 140 0.034 145 0.255 147 0.231 148 0.408 149 0.141 151 0.002 152 0.04 153 0.36 154 0.006 155 0.007 156 0.007 157 0.021 158 0.01 159 0.012 160 0.011 161 0.047 163 0.095 164 0.088 165 0.023 166 0.04 167 0.06 168 0.016 169 0.008 170 0.011 171 0.009 172 0.018 173 0.017 174 1.808 IF-2019-16830169-APN-ANP#INPI 132 Page 132 of 134 Example No. Phosph. of Stat induced by IFNa (ICso. μΜ) 175 0.278 176 0.132 177 0.648 178 0.474 179 1.062 180 0.073 181 0.55 182 2.227 183 0.105 184 0.263 185 186 0.132 187 0.032 188 0.006 189 0.106 190 0.061 191 0.066 192 0.013 193 0.165 194 0.035 195 0.211 196 0.012 197 0.058 198 0.262 199 1.034 200 0.198 201 0.024 202 0.05 203 0.046 204 0.579 207 0.229 0.067 209 0.056 211 0.09 212 1.082 213 0.114 214 0.046 215 0.021 216 0.028 217 0.052 218 0.034 219 0.024 220 0.015 221 0.013 222 0.059 223 0.094 224 0.044 225 0.164 -ANP#INPI 133 Page 133 of 134 Example No. Phosph. of Stat Induced by IFNa | (ICso, μΜ) 226 0.217 227 0.009 228 0.181 229 0.047 230 0.022 231 0.36 232 0.131 233 0.061 234 0.636 235 0.144 236 0.013 237 .082 238 2.454 239 0.288 240 0.115 241 0.203 242 0.05 243 0.832 244 0.42 245 0.01 246 0.034 247 0.006 251 0.007 252 0.053 253 0.047 254 0.186 255 0.466 256 _____________0.744_____________ IF-2019-16830169-APN-ANP#INPI 134 Page 134 of 134 Argentine Republic - National Executive Branch 2019 - Year of Export Additional Signature Sheet Graphic report Number: IF-2019-16830169-APN-ANP#INPI CITY OF BUENOS AIRES Wednesday, March 20, 2019 Reference: 20180103395 The document was imported by the GEDO system with a total of 134 page / s. Digitally signed by GESTION DOCUMENTAL ELECTRONICA - GDE DN: cn=ELECTRONIC DOCUMENT MANAGEMENT - GDE, c=AR, o=GOVERNMENT SECRETARY OF MODERNIZATION, ou=ADMINISTRATIVE MODERNIZATION SECRETARY, serialNumber=CUIT 30715117564 Date: 2019.03.20 09:56:42 -03'00' Eduardo Ricardo Arias Commissar National Patent Administration National Institute of Industrial Property Digitally signed by GESTION DOCUMENTAL ELECTRONICA GDE DN: cn=GEST10N ELECTRONIC DOCUMENTARY - GDE, c=AR, o=GOVERNMENT SECRETARY OF MODERNIZATION, ou=ADMINISTRATIVE MODERNIZATION SECRETARY, serialNumber=CUIT 30715117564 Date: 2019.03.20 09:56:43 -03'00'

Claims

1. A compound characterized in that it has the formula: (FORMULA) or a pharmaceutically acceptable formulation thereof. Three claims follow.