Prodrugs in interleukin regulation.

Abstract

The following formula: TIFF2022541772000071.tif121153 The present invention discloses prodrugs of the compound of formula (I), which are useful for modulating IL-12, IL-23 and / or IFNα by inhibiting signal transduction pathways through Tyk-2.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Application No. 62 / 874,531, filed June 16, 2019, which is hereby incorporated by reference in its entirety.

[0002] FIELD OF THEINVENTION The present invention relates to compounds useful as prodrugs in modulating IL-12, IL-23 and / or IFNα by causing signaling inhibition acting on Tyk-2. Provided herein are prodrugs of amide-substituted heterocyclic compounds, compositions comprising said compounds and methods of their use. The present invention further relates to pharmaceutical compositions comprising at least one compound of the present invention useful for treating conditions associated with the modulation of IL-12, IL-23 and / or IFNα in a mammal. [Background technology]

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

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

[0005] In human disease, high expression of p40 and p19 has been observed in psoriatic lesions, and Th17 cells have been 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);Tzartos, JS et al., "Interleukin-17 production in central nervous system infiltrating T cells and glial cells is associated with active disease in multiple sclerosis", Am. J. Pathol., 172:146-155 (2008)). The mRNA levels of p19, p40 and p35 in patients with active SLE were also shown to be significantly higher compared to those in patients with inactive SLE (Huang, X. et al., "Dysregulated expression of interleukin-23 and interleukin-12 subunits in systemic lupus erythematosus patients", Mod. Rheumatol., 17:220-223(2007)), and T cells from lupus patients have a predominant Th1 phenotype (Tucci, M. et al., "Overexpression of interleukin-12 and T helper 1 predominance in lupus nephritis", Clin. Exp. Immunol., 154:247-254(2008)).

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

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

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

[0009] In patients with systemic lupus erythematosus (SLE), a potentially fatal autoimmune disease, elevated serum levels of interferon (IFN) alpha (type I interferon) or elevated expression of type I IFN-regulated genes (the so-called IFN alpha signature) in peripheral blood mononuclear cells and affected organs have been demonstrated in the majority of patients (Bennett, L. et al, "Interferon and granulopoiesis signatures in systemic lupus erythematosus blood", J. Exp. Med., 197:711-723(2003);Peterson, KS et al., "Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli", J. Clin. Invest., 113:1722-1733(2004)), and several studies have demonstrated that serum IFNα levels correlate with both disease activity and severity (Bengtsson, AA et al., "Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies", Lupus, 9:664-671 (2000)). A direct role for IFNα in the pathophysiology of lupus is demonstrated by the observation that a lupus-like syndrome can be induced by administration of IFNα to patients suffering from malignant or viral diseases.Furthermore, deletion of IFNAR in lupus-prone mice strongly suppresses autoimmunity, disease severity and mortality (Santiago-Raber, ML et al., "Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice", J. Exp. Med., 197:777-788 (2003)), and genome-wide association studies have identified loci that are associated with lupus and 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, JK et al., "A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE", Eur. J. Hum. Genet., 19:479-484 (2011)).In addition to lupus, there is evidence that aberrant activation of type I interferon-mediated pathways is important in the pathophysiology of other autoimmune diseases such as Sjogren's syndrome and scleroderma (Baeve, U. et al., "Activation of the type I interferon system in primary Sjoegren's syndrome: a possible etiopathogenic mechanism", Arthritis Rheum, 52:1185-1195 (2005); Kim, D. et al., "Induction of interferon-alpha by scleroderma sera containing autoantibodies to topoisomerase I: association of higher interferon-alpha activity with lung fibrosis", Arthritis Rheum., 58:2163-2173 (2008)). Thus, agents that inhibit the action of type I interferon responses are expected to have therapeutic value in human autoimmune diseases.

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

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

[0012] Given the conditions that may benefit from treatment involving cytokine and / or interferon modulation, novel compounds capable of modulating cytokines and / or interferons, such as IL-12, IL-23 and / or IFNα, and methods of using these compounds, may provide substantial therapeutic benefit to a wide range of patients in need of such treatment.

[0013] U.S. Patent No. 9,663,467 discloses compounds useful for treating diseases and conditions associated with the regulation of IL-12, IL-23 and / or IFNα (e.g., autoimmune and inflammatory diseases), which is assigned to the present applicant and is incorporated herein by reference in its entirety.

[0014] The following compounds are disclosed therein: [ka] exhibits activity against said target.

[0015] U.S. Patent No. 9,505,748 also discloses compounds useful for treating diseases and conditions associated with the regulation of IL-12, IL-23 and / or IFNα (e.g., autoimmune and inflammatory diseases), which is assigned to the present applicant and is incorporated herein by reference in its entirety. The following compounds are disclosed therein: [ka] exhibits activity against said target.

[0016] As can be appreciated, there is a need to improve the delivery of such compounds to patients.

[0017] Applicants have discovered prodrugs of compounds (I) and (II) that are useful for the administration of compounds (I) and (II), respectively. The prodrugs exhibit greater solubility at physiologically relevant pH values ​​than compounds (I) and (II), surprisingly allowing the administration of compounds (I) and (II) in a wider range of dosages and / or in a wider range of pharmaceutical dosage forms. These prodrug compounds exhibit pharmaceutical utility with desirable stability, bioavailability, therapeutic index and toxicity values ​​critical to their efficacy.

[0018] SUMMARY OF THEINVENTION The present invention relates to prodrugs of compounds (I) and (II) that are useful as modulators of IL-12, IL-23 and / or IFNα by inhibiting signaling through Tyk2.

[0019] The present invention also provides processes and intermediates for making the compounds of the present invention.

[0020] The present invention also provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and at least one compound of the present invention.

[0021] The present invention provides methods for modulating IL-12, IL-23 and / or IFNα by inhibiting signaling through Tyk-2, comprising administering to a host in need of said treatment a therapeutically effective amount of at least one compound of the present invention.

[0022] The present invention provides methods for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases, comprising administering to a host in need of said treatment a therapeutically effective amount of at least one compound of the present invention.

[0023] A preferred embodiment is a method for treating inflammatory and autoimmune diseases or disorders. For purposes of this invention, inflammatory and autoimmune diseases or disorders include any disease that has an inflammatory or autoimmune component.

[0024] Another preferred embodiment is a method for treating metabolic diseases, including type II diabetes and atherosclerosis.

[0025] The invention also provides the use of a compound of the invention in the manufacture of a medicament for treating cancer.

[0026] The present invention provides a compound of the invention for use in therapy.

[0027] These and other features of the invention will now be described in a broader form in accordance with the disclosure.

[0028] The present invention will now be described with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0029] [Figure 1] Figure 1 shows the PK of the prodrugs of Compound I. Rats were dosed PO at the following doses with the following symbols: (◇) -5mpk, (□) -25mpk, and (△) -150mpk. The maximum blood circulating prodrug observed was <0.05% of the parent drug (150mpk dose). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] DETAILED DESCRIPTION OF EMBODIMENTS OF THE PRESENTINVENTION In a first aspect of the invention, there are provided prodrugs of compounds (I) and (II) as shown below: [ka] and [ka] .

[0031] In a second aspect of the invention, the following compounds of the invention are provided: [ka] [ka] [ka] or a salt thereof.

[0032] In a third aspect of the invention, there is provided a prodrug of compound (I), as shown below: [ka] [ka] or a salt thereof.

[0033] In a fourth aspect of the present invention, there is provided a prodrug of compound (II), as shown below: [ka] or a salt thereof.

[0034] In another aspect, there is provided a compound selected from the examples exemplified within the scope of the first aspect, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0035] In another aspect, there is provided a compound selected from any subset list of compounds within the scope of any of the above aspects.

[0036] In another embodiment, there is provided a pharmaceutical composition comprising one or more compounds of formula I and a pharma- ceutically acceptable carrier or diluent.

[0037] The present invention also relates to a pharmaceutical composition useful for treating diseases associated with the regulation of IL-12, IL-23 and / or IFNα by acting on Tyk-2 to inhibit signal transduction, comprising a compound of formula I or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable carrier or diluent.

[0038] The present invention further relates to a method for treating diseases associated with the regulation of IL-12, IL-23 and / or IFNα, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

[0039] The present invention also provides processes and intermediates for making the compounds of the present invention.

[0040] The present invention provides methods for the treatment of proliferative, metabolic, allergic, autoimmune and inflammatory diseases (or the use of compounds of the invention in the manufacture of a medicament for treating such diseases), comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the invention.

[0041] The present invention provides a method for treating an inflammatory or autoimmune disease (or the use of a compound of the invention in the manufacture of a medicament for treating such a disease), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

[0042] The invention provides a method for treating a disease (or the use of a compound of the invention in the manufacture of a medicament for treating such a disease) comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I, the disease being rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, inflammatory bowel disease, psoriasis, Crohn's disease, psoriatic arthritis, Sjogren's syndrome, systemic scleroderma, ulcerative colitis, Graves' disease, discoid lupus erythematosus, adult-onset Still's disease, systemic juvenile idiopathic arthritis, gout, gouty arthritis, type I diabetes, insulin-dependent idiopathic arthritis, and the like. These include: diabetes mellitus, sepsis, septic shock, bacterial dysentery, pancreatitis (acute or chronic), glomerulonephritis, autoimmune gastritis, diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, pancreatitis (acute or chronic), ankylosing spondylitis, pemphigus vulgaris, Goodpasture's disease, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, pemphigus complex, Kawasaki disease, chronic inflammatory demyelinating polyneuropathy (CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barré syndrome, autoimmune pneumonia, autoimmune thyroiditis, autoimmune inflammatory eye disease, and chronic demyelinating polyneuropathy.

[0043] The present invention provides a method for treating an inflammatory or autoimmune disease (or the use of a compound of the invention in the manufacture of a medicament for treating such a disease), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I, wherein the disease is selected from systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, Crohn's disease, ulcerative colitis, type I diabetes, psoriasis, rheumatoid arthritis, systemic juvenile idiopathic arthritis, ankylosing spondylitis and multiple sclerosis.

[0044] The present invention provides a method for treating rheumatoid arthritis (or the use of a compound of the invention for the manufacture of a medicament for the treatment of rheumatoid arthritis), which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

[0045] The invention further provides a method for treating a condition (or the use of a compound of the invention in the manufacture of a medicament for treating such a condition) comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I, the condition including acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, solid tumors, ocular and neonatal hemangiomas, B-cell lymphoma, systemic lupus erythematosus (SLE), lymphomas of the arthritis, and the like. Selected from uterine arthritis, psoriatic arthritis, polyangiitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type I diabetes mellitus, membranous nephropathy, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm agglutinin disease, Evans syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), sarcoidosis, Sjogren's syndrome, peripheral neuropathy, pemphigus vulgaris and asthma.

[0046] The invention also provides a method for treating IL-12, IL-23 and / or IFNα mediated diseases (or the use of a compound of the invention in the manufacture of a medicament for treating these diseases), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

[0047] The invention also provides a method of treating an IL-12, IL-23 and / or IFNα mediated disease (or the use of a compound of the invention in the manufacture of a medicament for treating such a disease), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I, wherein the IL-12, IL-23 and / or IFNα mediated disease is a disease modulated by IL-12, IL-23 and / or IFNα.

[0048] The invention also provides a method of treating a disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I in combination with another therapeutic agent.

[0049] The present invention also provides a compound of the invention for use in therapy.

[0050] In another embodiment, the compound of formula I is selected from an exemplified compound, a combination of exemplified compounds, or another embodiment herein.

[0051] In another embodiment, IC 50 <1000 nM.

[0052] The present invention may be embodied in other specific forms without departing from its spirit or essential attributes. The present invention includes all combinations of the preferred aspects and / or embodiments of the present invention described herein. It is understood that any and all embodiments of the present invention may be combined with any other embodiment or embodiments to describe additional, more preferred embodiments. It is also to be understood that each individual element of a preferred embodiment is its own independent preferred embodiment. Furthermore, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe additional embodiments. Detailed Description of the Invention

[0053] Below are definitions of terms used in the specification and the appended claims. Unless otherwise specified, the definition first given for a group or term in this specification applies to that group or term individually or as part of another group throughout the specification and claims.

[0054] The compounds of the present invention may have one or more asymmetric centers. Unless otherwise specified, all chiral forms (enantiomers and diastereomers) and racemates of the compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like may also exist in the compounds, and all such stable isomers are contemplated in the present invention. Cis- and trans-geometric isomers of the compounds of the present invention are described and may be isolated as mixtures of isomers or resolved isomers. The compounds of the present invention may be isolated in optically active or racemic forms. Methods for preparing optically active forms, such as by resolution of racemic forms or synthesis from optically active starting materials, are well known in the art. All chiral forms (enantiomers and diastereomers), racemates, and all geometric isomers of a structure are intended, unless a specific stereochemistry or isomer is specifically indicated.

[0055] In any component or formula for a compound, any variable group (e.g., R 3 When any radical R 2 occurs more than one time, its definition is independent of its definition at every other occurrence. Thus, for example, R 2 3 When indicated to be substituted with, the group may optionally be substituted with up to two R 3 may be substituted with R 3 are R 3 Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0056] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, such substituent may be bonded to any atom on that ring. When such a substituent is described without indicating through which atom it is bonded to the remainder of the compound of the described formula, such substituent may be bonded through any atom within such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0057] When nitrogen atoms (e.g., amines) are present on the compounds of the invention, they can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and / or hydrogen peroxide) to give other compounds of the invention. Thus, all shown and claimed nitrogen atoms are considered to include both the shown nitrogen and its N-oxide (N→O) derivative.

[0058] In accordance with convention used in the art, to represent the bond that is the site of attachment of a group or substituent to a core or backbone structure, [ka] is used in the structural formulas herein.

[0059] A dash "-" that is not between two letters or symbols is used to indicate the point of attachment of a substituent, for example, -CONH2 is attached through a carbon atom.

[0060] The compounds of formula I may exist in free form (without ionization) or may form salts that are within the scope of the present invention. Unless otherwise specified, a description of the compounds of the present invention is understood to include a description of the free form and its salts. The term "salt" refers to acid salts and / or base salts formed with inorganic and / or organic acids and bases. In addition, for example, when a compound of formula I contains both a basic group, such as an amine, a pyridine ring, or an imidazole ring, and an acidic group, such as a carboxylic acid, the term "salt" may also include zwitterions (internal salts). Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts, in which the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts are considered to be within the scope of the present invention, for example, as they may be useful in isolation or purification steps that may be used during preparation. Salts of compounds of formula I may be formed, for example, by reacting a compound of formula I with an amount, e.g., an equivalent, of an acid or base in a solvent or aqueous solvent in which the salt precipitates, followed by lyophilization.

[0061] Examples of acid addition salts include acetates (e.g., formed with acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, and the like. salts such as phosphate, 2-hydroxyethanesulfonate, lactate, maleate (formed with maleic acid), methanesulfonate (formed with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (such as formed with sulfuric acid), sulfonate (such as those described herein), tartrate, thiocyanate, toluenesulfonate such as tosylate, undecanoate, and the like.

[0062] Examples of base salts include alkali metal salts such as ammonium, sodium, lithium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc and aluminum salts; salts with organic bases (e.g., organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or similar amines that are pharma- ceutically acceptable, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl bromide and phenethyl bromide), etc. Preferred salts include monohydrochlorides, hydrogen sulfates, methanesulfonates, phosphates, or nitrates.

[0063] The phrase "pharmacologically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0064] As used herein, "pharmaceutical acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by making its acid or base salt. Examples of pharmaceutical acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines, and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound, formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids; as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like.

[0065] The pharma- ceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic groups by conventional chemical methods.In general, such salts can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of an appropriate base or acid in water, an organic solvent, or a mixture of the two; non-aqueous solvents such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred.A list 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.

[0066] All stereoisomers of the compounds of the present invention are included either in mixtures or in pure or substantially pure form. Stereoisomers include compounds that are optical isomers due to one or more chiral atoms and compounds that are optical isomers due to restricted rotation about one or more bonds (atropisomers). The definition of the compounds of the present invention includes all possible stereoisomers and their mixtures. The definition particularly includes racemates and isolated optical isomers with the specified activity. Racemates can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

[0067] The present invention is intended to include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. Common examples, without limitation, areotopes of hydrogen, including deuterium and tritium. Isotopes of carbon, including 13 C and 14 C. Isotopically labeled compounds of the invention can generally be prepared by methods analogous to those described herein, using conventional techniques known to those of skill in the art, or substituting the appropriate isotopically labeled reagent for the unlabeled reagent used otherwise.

[0068] The compounds of formula I and their salts may exist in their tautomeric forms, in which hydrogen atoms are transferred to other parts of the molecule, resulting in rearrangement of the chemical bonds between the atoms of the molecule. It should be understood that all tautomeric forms are included within the present invention, insofar as they may exist. Furthermore, the compounds of the present invention may have trans and cis isomers.

[0069] It should further be understood that solvates (eg, hydrates) of the compounds of formula I are also within the scope of the present invention. Methods of solvation are generally known in the art.

[0070] (usefulness) The compounds of the invention modulate IL-23 stimulated and IFNα stimulated cellular functions (e.g., gene transcription). Another type of cellular function that may be modulated by the compounds of the invention includes, but is not limited to, IL-12 stimulated responses.

[0071] Thus, the compounds of formula I, by acting on Tyk2 to mediate signal transduction, have utility in modulating IL-23 or IFNα function, and in particular in treating conditions associated with the selective inhibition of IL-23, IL-12 and / or IFNα function, including IL-23, IL-12 or IFNα associated diseases in which pathophysiological mechanisms are mediated by these cytokines.

[0072] As used herein, the term "treating" or "treatment" encompasses the treatment of a disease condition in a mammal, particularly a human, and includes (a) preventing or delaying the onset of a disease condition in a mammal, particularly where said mammal is predisposed to a disease condition but has not yet been diagnosed with the disease condition, (b) inhibiting a disease condition, i.e., halting the progression of a disease condition, and / or (c) completely or partially reducing a symptom or disease condition, and / or alleviating, ameliorating, reducing or curing a disease or disorder, and / or its symptoms.

[0073] In view of their activity as regulators of cellular responses stimulated by IL-23, IL-12 and IFNα, the compounds of formula I are useful for treating IL-23, IL-12 or IFNα associated diseases, including, but not limited to, inflammatory diseases such as Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease, respectively; autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, psoriasis; CAPS, TRAPS, FMF, adult-onset Still's disease, systemic juvenile idiopathic arthritis, gout, gouty arthritis, and the like. autoinflammatory diseases including arthritis; metabolic diseases including type II diabetes, atherosclerosis, myocardial infarction; destructive bone disorders such as bone resorption disorders, osteoarthritis, osteoporosis, multiple myeloma-related bone disorder; proliferative disorders such as acute myeloid leukemia, chronic myeloid leukemia; angiogenic disorders including solid tumors, ocular neovascularization and neonatal 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 trauma; neoplastic and viral diseases such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma, HIV infection, CMV retinitis, AIDS.

[0074] More specifically, specific conditions or diseases that may be treated using the compounds of the present invention include, but are not limited to, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active pulmonary disease, chronic ... Hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta-cell diseases; diseases characterized by extensive infiltration of neutrophils; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic inflammatory lung diseases, silicosis, pulmonary sarcoidosis, bone resorption diseases, allogeneic transplantation. Graft rejection, fever and myalgia due to infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, fever, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative diseases caused by trauma; angiogenic disorders including solid tumors, ocular neovascularization and neonatal hemangiomas; acute hepatitis infection (type A) Hepatitis, including hepatitis B and C), HIV infection, CMV retinitis, AIDS, ARC or viral diseases including malignant tumors and herpes; stroke, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia [hypoxia], vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase synthase-2 and pemphigus vulgaris. Preferred methods of treatment are those in which the condition is selected from Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris.Another preferred method of treatment is one in which the condition is selected from ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury resulting from stroke, and cardiac ischemia-reperfusion injury resulting from myocardial infarction. Another preferred method of treatment is one in which the condition is multiple myeloma.

[0075] As used herein, the terms "IL-23-, IL-12- and / or IFNα-associated condition" or "IL-23-, IL-12- and / or IFNα-associated disease or disorder" are intended to encompass all of the conditions identified above, as detailed above, as well as any other condition affected by IL-23, IL-12 and / or IFNα.

[0076] Accordingly, the present invention also provides methods for treating such conditions, comprising administering to a subject in need of treatment a therapeutically effective amount of at least one compound of formula I, or a salt thereof. "Therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit the function of IL-23, IL-12 or IFNα and / or treat the disease.

[0077] Methods of treating IL-23, IL-12 or IFNα associated conditions may include administering the compounds of formula I, alone or in combination with each other and / or in combination with other appropriate therapeutic agents useful for treating such conditions. Thus, a "therapeutically effective amount" is also intended to include an amount of a combination of the claimed compounds that is effective to inhibit the function of IL-23, IL-12 or IFNα and / or treat a disease associated with IL-23, IL-12 or IFNα.

[0078] Examples of such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokine suppressing anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide and other immunosuppressants; nuclear transport inhibitors such as deoxyspergualin (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antivirals such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®); antimalarials such as hydroxychloroquine; cytotoxic agents such as azathioprine and cyclophosphamide; tenidap, anti-TNF antibodies or soluble TNF receptors, and TNF-α inhibitors such as rapamycin (sirolimus or RAPAMUNE®) or its derivatives.

[0079] The other therapeutic agents described above, when used in combination with the compounds of the invention, may be used, for example, in amounts set forth in the US Pharmacopoeia (PDR) or in amounts determined by one of skill in the art. In the methods of the invention, such additional therapeutic agent(s) may be administered prior to, simultaneously with, or after administration of the compounds of the invention. The invention also provides pharmaceutical compositions capable of treating IL-23, IL-12 or IFNα-associated conditions, including IL-23, IL-12 or IFNα-mediated diseases as described above, by inhibiting Tyk2-mediated signaling.

[0080] The compositions of the invention may contain other therapeutic agents, as described above, and may be formulated, for example, according to techniques such as those well known in the art of pharmaceutical formulation, using conventional solid or liquid vehicles or diluents, and pharmaceutical additives (e.g., excipients, binders, preservatives, stabilizers, flavorings, and the like) of a type appropriate to the desired method of administration.

[0081] Therefore, the present invention includes compositions comprising one or more compounds of formula I and further a pharma- ceutically acceptable carrier.

[0082] "Pharmaceutically acceptable carrier" refers to a vehicle generally accepted in the art for delivering biologically active agents to animals, particularly mammals. Pharmaceutically acceptable carriers are formulated according to many factors well within the purview of one of ordinary skill in the art, including, but not limited to, the type and nature of the active agent being formulated; the subject to whom the composition containing the agent is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can contain many different ingredients and additives in addition to the active agent, and such additional ingredients may be included in the formulation for a variety of reasons well known to those skilled in the art, such as, for example, stabilization of the active agent, binders, and the like. Descriptions of suitable pharmacopoeia acceptable carriers and the factors involved in their selection are found in a variety of readily available sources, such as, for example, Remington's Pharmaceutical Sciences, 17th Edition (1985), the entire contents of which are incorporated herein by reference.

[0083] The compound of formula I may be administered by any method suitable for the condition to be treated, and the method may vary depending on the need for site-specific treatment or the amount of drug to be delivered. Although alternative methods of administration are contemplated, topical administration is generally preferred for skin-related diseases, and systemic treatment is preferred for cancerous or precancerous conditions. For example, the compound may be delivered orally, such as in the form of liquid preparations including tablets, capsules, granules, powders, or syrups; topically, such as in the form of solutions, suspensions, gels, or ointments; sublingually; buccal; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as aqueous or non-aqueous solutions or suspensions for sterile injection); nasally, such as by inhalation spray; topically, such as in the form of creams or ointments; rectally, such as in the form of suppositories; or liposomally. The compound may be administered in a unit dosage form containing a non-toxic pharma- ceutically acceptable vehicle or diluent. The compound may be administered in a form suitable for immediate or sustained release. Immediate or sustained release may be achieved by the use of suitable pharmaceutical compositions or, particularly for sustained release, by the use of devices such as subcutaneous implants or osmotic pumps.

[0084] Examples of compositions for topical administration include topical carriers such as PLASTIBASE® (mineral oil gelled with polyethylene).

[0085] Examples of compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for bulking, alginic acid or sodium alginate as a suspending agent, methylcellulose as a thickening agent, and sweeteners or flavorings, such as those known in the art; and immediate release tablets that may contain, for example, microcrystalline cellulose, dibasic calcium phosphate, starch, magnesium stearate and / or lactose, and / or other excipients, binders, fillers, disintegrants, diluents and lubricants, such as those known in the art.The compounds of the present invention may be orally delivered by sublingual and / or buccal administration, for example, using moistened tablets, compressed tablets or freeze-dried tablets.Examples of compositions may contain fast-dissolving diluents, such as mannitol, lactose, sucrose and / or cyclodextrin. Also included in such formulations may be high molecular weight excipients such as cellulose (AVICEL®) or polyethylene glycol (PEG); excipients to aid in mucoadhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and / or maleic anhydride copolymers (e.g., GANTREZ®); and agents to control release such as polyacrylic acid copolymers (e.g., CARBOPOL 934®). Lubricants, glidants, flavors, colorants, and stabilizers may also be added for ease of manufacture and use.

[0086] Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to enhance absorption and / or bioavailability, and / or other solubilizing or dispersing agents as known in the art.

[0087] Examples of compositions for parenteral administration include injectable solutions or suspensions which may contain a suitable non-toxic parenterally acceptable diluent or solvent, such as, for example, mannitol, 1,3-butanediol, water, isotonic sodium chloride solution, Ringer's solution, or other suitable dispersing or wetting agents and suspending agents, including synthetic mono- or diglycerides, and fatty acids, such as oleic acid.

[0088] Examples of compositions for rectal administration include suppositories which may contain suitable non-irritating excipients such as cocoa butter, synthetic glyceride esters, or polyethylene glycols which are solid at ordinary temperatures but liquefy and / or melt in the rectal cavity to release the drug.

[0089] Therapeutically effective amounts of the compounds of the present invention may be determined by one of skill in the art, and typical dosages for mammals include about 0.05-1000 mg / kg; 1-1000 mg / kg; 1-50 mg / kg; 5-250 mg / kg; 250-1000 mg / kg body weight of active compound per day, which may be administered in the form of a single dose or individual divided doses, such as 1-4 times per day. It will be understood that for any particular subject, the specific dose level and frequency of administration may vary and will depend on a variety of factors, including the activity of the particular compound used, the metabolic stability and duration of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the method and frequency of administration, excretion rate, drug combination, and the severity of the particular pathology. 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, the term "patient", as used herein, is intended to include all subjects, most preferably mammalian species, that are susceptible to modulation of functions mediated by IL-23, IL-12 and / or IFNα.

[0090] (Manufacturing method) The compounds of the present invention may be synthesized by many methods available to those skilled in the art of organic chemistry. General synthetic schemes for preparing the compounds of the present invention are described below. These schemes are illustrative and do not limit the techniques that a person skilled in the art may use to prepare the compounds disclosed herein. Different methods for preparing the compounds of the present invention will be apparent to those skilled in the art. Furthermore, various steps in the synthesis may be performed in a different order to yield the desired compound or compounds. Examples of compounds of the present invention prepared by the methods described in the general schemes are described in the preparation methods and examples provided below. EXAMPLES

[0091] The preparation of compounds of formula I, and intermediates used in the preparation of compounds of formula I, can be prepared using procedures set forth in the following examples and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these examples, are not intended to be limiting, but rather to demonstrate how compounds of formula I can be prepared. If the starting materials and reagents used in these examples are not prepared by the procedures described herein, they are generally either commercially available, reported in the chemical literature, or may be prepared by using procedures described in the chemical literature.

[0092] In the described examples, the phrase "dried and concentrated" generally refers to drying a solution in an organic solvent with either sodium sulfate or magnesium sulfate, followed by filtration and removal of the solvent from the filtrate (generally under reduced pressure and at a temperature appropriate to the stability of the material being prepared). Column chromatography was performed using an Isco medium pressure chromatography apparatus (Teledyne Corporation) and prepacked silica gel cartridges, eluted with the given solvent or solvent mixtures. Chemical names were determined using ChemDraw Ultra, version 9.0.5 (CambridgeSoft). The following abbreviations may be used: [Table 1] TIFF0007618642000013.tif123155

[0093] The analytical purity of the compounds was determined using the following method: Analytical HPLC Method A: SUNFIRE C18 [150x4.6 mm] column; 0.05% trifluoroacetic acid / water (pH 2.5) as buffer; Mobile phase A = buffer:MeCN [95:5]; Mobile phase B: MeCN:buffer [95:5]; 10% B to 100% B; 23 min; flow rate: 1.0 mL / min); Analytical HPLC Method B: XBridge phenyl C18 [150x4.6 mm] column; 0.05% trifluoroacetic acid / water (pH 2.5) as buffer; Mobile phase A = buffer:MeCN [95:5]; Mobile phase B: MeCN:buffer [95:5]; 10% B to 100% B; 23 min; flow rate: 1.0 mL / min); Analytical LCMS Method C: BEH C18 [2.1x50 mm, 1.7 μm particles] column; 0.05% trifluoroacetic acid as buffer; Mobile phase A = water; Mobile phase B: MeCN; 2% B to 98% B (0-1 min); 98% B (1 min-1.5 min); 98% to 2% B (1.5 min-1.6 min); Gradient time (total) = 1.6 min; Analysis time = 2.2 min; Flow rate: 0.8 mL / min; Detector: UV at 254 nM and MS (ESI+)

[0094] Example 1 [ka] [ka] Step 1: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-methylnicotinamide (11 g, 25.9 mmol) and potassium carbonate (10.72 g, 78 mmol) were added to a flask (500 mL) containing acetonitrile (commercial grade anhydrous) (260 mL). The slurry was stirred at room temperature for 30 minutes, after which sodium iodide (11.63 g, 78 mmol) and di-tert-butyl(chloromethyl)phosphate (27.3 wt% / MeCN, density=0.824 g / mL, 89 mL,78 mmol) were added. The vessel was fitted with a water-cooled condenser and heated at 50° C. for 18 hours. The reaction solution was cooled to room temperature and filtered through Celite, eluting with DCM:MeOH (1:1) (~800 mL). The filtrate was concentrated and used in the next step. Bisalkylation (major): LC retention time 0.92 [C]; MS (E+) m / z: 870.7 (MH + ). Monoalkylated (positional isomer unknown). LC retention time 0.82[C]; MS(E+) m / z: 648.5(MH + ).

[0095] Step 2: The crude product from step 1 was dissolved in acetic acid (28.8 mL) and water (14 mL); the solution was initially homogeneous but became a slurry as product formed. After complete conversion to the desired material, water (~200 mL) was added. The slurry was sonicated and then stirred at room temperature. The vessel was briefly cooled in a freezer until the solution was below room temperature, at which point the precipitate was collected by filtration and washed with water (15 mL). The filter cake was air-dried and washed with diethyl ether (1 L). The solid was collected and sonicated in DCM (20 mL) before being filtered to collect the resulting solid (4.6 g). LC retention time 0.59 [C]. MS(E+) m / z: 536.1 (MH + ).

[0096] Step 3: The free acid (6.75 g, ∼90% pure by HPLC) was suspended in MeCN (25 mL) and DDI water (90 mL). To this solution was added 1M NaOH (aq., 27.7 mL, 27.7 mmol) over 1 min. The viscous brown suspension became a milky white suspension. After stirring for 5 min, the solution was filtered through two medium glass frits to give a slightly hazy yellow solution. Water (200 mL) was added to give a nearly homogeneous solution. Acetone was added to the solution until the total volume was ∼3 L, at which point seed crystals were added and fine white crystals immediately formed, the amount of which rapidly increased. After 15 min, a fine suspension-like solution formed. After an additional 30 min, additional acetone was added (total volume = 4 L) and the suspension was stored at 8 °C overnight. The solids were collected by filtration and rinsed with acetone. The solid was collected, triturated in ~200 mL of acetone, and sonicated. The product was collected by filtration and dried under vacuum (<0.1 torr) overnight to give small yellow crystals (72% yield, 8.12 mmol) (4.75 g). 1313C NMR (126 MHz, DEUTERIUM OXIDE) δ 182.7, 167.6, 161.7, 156.4, 153.4, 150.4, 140.5, 133.5, 126.3, 125.8, 125.3, 120.8, 109.3, 99.4, 74.4, 74.4, 61.2, 39.6, 17.2, 7.7. 1 1H NMR (500 MHz, DEUTERIUM OXIDE) δ 8.43 (s, 1H), 7.58 (dd, J = 1.22, 7.78 Hz, 1H), 7.43 (dd, J = 1.22, 7.93 Hz, 1H), 7.25 (t, J = 7.93 Hz, 1H), 6.95 (s, 1H), 5.60 (d, J = 9.16 Hz, 2H), 4.38 (s, 3H), 3.56 (s, 3H), 1.60 - 1.72 (m, 1H), 0.66 - 0.81 (m, 4H) LC retention time 0.59 [C]. MS (E+) m / z: 536.1 (MH + ).

[0097] Example 2

Chemistry

[0098] Step 1 To a suspension of 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (0.5 g, 1.175 mmol) in DMF (9.04 mL) was added cesium carbonate (11.49 g, 35.3 mmol) in a single lot and the resulting mixture was stirred at room temperature for 30 minutes. Di-tert-butyl(chloromethyl)phosphate (1.288 mL, 5.88 mmol) was then added to the reaction and the reaction mixture was stirred at room temperature for 15 hours. After 15 hours, the reaction was incomplete so additional di-tert-butyl(chloromethyl)phosphate (1.288 mL, 5.88 mmol) was added and the reaction was continued for an additional 24 hours. Water was added to the reaction mixture and the product was extracted with ethyl acetate (x2), the organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was collected and used in the next step. LC retention time = 0.77 [C]. MS (E+) m / z: 648.5 (MH + ).

[0099] Process 2 The crude mixture from step 1 was dissolved in acetone (4 mL) and water (4 mL) and the solution was heated to 50° C. until the reaction was complete (1 h). The reaction solution was concentrated under reduced pressure using a room temperature heating bath and rotary evaporator. The crude product was diluted with water (total volume=60 mL) and then washed with DCM (~500 mL x2). The aqueous layer was loaded onto a reversed phase (gold) isco 50 g cartridge and purified using a water (DDI, no buffer) / MeCN (no buffer) gradient (0-40% MeCN:H2O). 1H NMR(400MHz, DMSO-d6) δ 11.74(s, 1H), 9.38(br. s., 1H), 8.58(s, 1H), 8.21(s, 1H), 7.83(d, J=7.9 Hz, 1H), 7.56(d, J=6.7 Hz, 1H), 7.36(t, J=7.9 Hz, 1H), 5.91(d, J=11.7 Hz, 2H), 3.95(s, 3H), 3.76(s, 3H), 2.32(d, J=1.8 Hz, 1H), 1.06 - 0.76(m, 4H). LC retention time 0.54 [C]. MS(E+) m / z: 536.4(MH + The structure was determined in part as in Example 1 and also from the low molecular weight crystal structure of the decomposition product obtained after prolonged exposure to sodium hydroxide: Di-tert-butyl(chloromethyl)phosphate [ka] A solution of potassium di-tert-butylphosphate (8.5 g, 34.2 mmol), sodium bicarbonate (11.50 g, 137 mmol) and tetrabutylammonium hydrogen sulfate (1.162 g, 3.42 mmol) in DCM (104 mL) and water (124 mL) was prepared and stirred at 0° C. for 15 minutes. To this was added chloromethylsulfochloridate (6.93 mL, 68.5 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (100 ml) and washed with water (4x200 mL) followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo without heating (keep temperature below 25° C.) to give a colorless liquid. 1 H NMR(500MHz, chloroform-d) δ 5.58(d, J=14.8 Hz, 2H), 1.46(d, J=0.8 Hz, 18H)

[0100] Example 3 [ka] Process 1 (E)-6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-methyl-1-((methylthio)methyl)-1,6-dihydropyridine-3-carboxamide [ka] To a solution of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-methylnicotinamide (0.500 g, 1.184 mmol) in DMF (10 mL) was added potassium carbonate (0.981 g, 7.10 mmol). The mixture was stirred at RT for 30 min, then chloromethyl methylsulfide (0.977 mL,11.84 mmol) and sodium iodide (0.887 g, 5.92 mmol) were added. The mixture was stirred at 50° C. for 16 h under nitrogen. The reaction mixture was diluted with water and extracted with ethyl acetate (3x50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by RP-HPLC (preparative column: kinetex C18 (150x21.2 mm; 5 micron), mobile phase A: 10 mM ammonium acetate (pH 4.5), mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 20, 30 / 100) to give the title compound (0.230 g, 0.477 mmol, 40.3% yield) as a pale yellow solid. 1 H NMR(400 MHz, DMSO-d6) δ 0.64 - 0.76(m, 4 H), 1.45 - 1.56(m, 1 H), 2.26(s, 3 H), 2.82(d, J =4.02 Hz, 3 H), 3.74(s, 3 H), 4.46(s, 3 LC-MS(ES): m / z =483.2 [M+H] +

[0101] Process 2 (E)-1-(chloromethyl)-6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-methyl-1,6-dihydropyridine-3-carboxamide [ka] To a solution of (E)-6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-methyl-1-((methylthio)methyl)-1,6-dihydropyridine-3-carboxamide (0.100 g, 0.207 mmol) in dichloromethane (2.5 mL) was added sulfuryl chloride (0.084 mL, 1.036 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes and concentrated in vacuo at 30° C. to give the title compound (0.110 g, 0.198 mmol, 95% yield) as an off-white solid. The crude product was used as is. LC-MS (ES): m / z =471.2 [M+H] +

[0102] Process 3 (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-(methylcarbamoyl)pyridin-1(2H)-yl)methyl 3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoate [ka] To a solution of (E)-1-(chloromethyl)-6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-methyl-1,6-dihydropyridine-3-carboxamide (0.110 g, 0.234 mmol) and DIPEA (0.245 mL, 1.402 mmol) in tetrahydrofuran (2 mL) was added 3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoic acid (0.169 g, 0.350 mmol) at 0° C. The mixture was stirred at RT for 3 h and then concentrated in vacuo at 30° C. to give the crude product as a brown gum. RP-HPLC purification (preparative column: X-bridge phenyl (250x19 mm; 5 micron), mobile phase A: 10 mM ammonium acetate / water (at pH 4.5), mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 30, 15 / 80) afforded the title compound (0.115 g, 0.119 mmol, 50.8% yield) as an off-white solid. 1 H NMR(300 MHz, DMSO-d6) δ 0.55 - 0.69(m, 4 H), 1.49(s, 7 H), 2.01 - 2.08(s, 3 H), 2.39(s, 3 H), 2.77(d, J =4.15 Hz, 3 H), 2.91(s, 2 H), 3.72(s, 3 H), 4.46(s, 3 H), 5.11(d, J =8.31 ​​Hz, 4 H), 5.88(br. s, 2 H), 6.64(s, 1 H), 6.88(s, 1 H), 7.23 - 7.40(m, 10 H), 7.51 - 7.60(m, 1 H), 7.66(br. s, 1 LC-MS(ES):m / z =917.4 [M+H] +

[0103] Process 4 (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-(methylcarbamoyl)pyridin-1(2H)-yl)methyl 3-(2,4-dimethyl-6-(phosphonooxy)phenyl)-3-methylbutanoate [ka] To a solution of (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-(methylcarbamoyl)pyridin-1(2H)-yl)methyl 3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoate (0.090 g, 0.098 mmol) in 1,2-dichloroethane (4 mL) was added TFA (0.756 mL, 9.82 mmol) and anisole (0.536 mL, 4.91 mmol) at 0° C. After stirring at 50° C. for 1 h, the solvent was removed in vacuo to give the crude product. After RP HPLC purification (preparative column: Sunfire C18 (150x19 mm; 5 micron), mobile phase A: 10 mM ammonium acetate / water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 10, 25 / 100), the title compound (0.015 g, 0.020 mmol, 20.52% yield) was obtained as an off-white solid. 1H NMR(400 MHz, DMSO-d6) δ 0.73 - 0.97(m, 4 H), 1.31 - 1.67(m, 6 H), 1.83 - 1.95(m, 3 H), 2.09 - 2.29(m, 4 H), 2.73 - 3.00(m, 3 H), 3.09 - 3.21(m, 2 H), 3.72 - 3.83(m, 3 H), 4.35 - 4.54(m, 3 H), 5.79 - 5.96(m, 2 H), 6.17 - 6.27(m, 1 H), 6.97 - 7.06(m, 1 H), 7.43 - 7.52(m, 2H), 7.59 - 7.70(m, 1 H), 7.81 - 7.92(m, 1 H), 8.71 - 8.79(m, 1 H). LC-MS(ES):m / z =737.2 [M+H] + ;HPLC RT and Purity: 6.410 min and 98.91% (Method A) & 7.749 min and 98.89% (Method B).

[0104] Example 4 [ka] Process 1 (E)-6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)-1-((methylthio)methyl)-1,6-dihydropyridine-3-carboxamide [ka] To a mixture of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (0.500 g, 1.175 mmol) and potassium carbonate (0.975 g, 7.05 mmol) in DMF (10 mL) was added chloromethyl methylsulfide (0.970 mL,11.75 mmol) and sodium iodide (0.881 g, 5.88 mmol). After stirring at 50° C. under nitrogen for 16 hours, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by RP-HPLC (preparative column: Sunfire C18 (150x4.6mm; 5 micron), mobile phase A: 10 mM ammonium acetate, mobile phase B: acetonitrile, flow rate: 1.0 mL / minute, gradient: 0 / 10, 20 / 100) to give the title compound (0.210 g, 0.424 mmol, 36.1% yield) as a pale yellow solid. 1 H NMR(300 MHz, DMSO-d6) δ 0.58 - 0.79(m, 4 H), 1.52 - 1.58(m, 1 H), 2.07(s, 3 H), 3.74(s, 3 H), 4.46(s, 3 H), 5.21(s, 2 H), 7.35(t, J =7.80 Hz, 1H), 7.60(br. S, 1H), 7.66(d, J =7.93 Hz, 1 H), 7.90 - 8.04(br. S, 1 H), 8.49(s, 1 H), 8.56 - 8.65(br. S, 1 H), 10.71(br. S, 1H);LC-MS(ES):m / z =486.2 [M+H] +

[0105] Process 2 (E)-1-(chloromethyl)-6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)-1,6-dihydropyridine-3-carboxamide [ka] To a solution of (E)-6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-methyl-1-((methylthio)methyl)-1,6-dihydropyridine-3-carboxamide (0.100 g, 0.206 mmol) in dichloromethane (2.5 mL) was added sulfuryl dichloride (0.083 mL, 1.030 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes. The reaction mixture was concentrated in vacuo at 30° C. to give the title compound (0.112 g, 0.199 mmol, 96% yield) as an off-white solid. The crude product was used directly in the next step. LC-MS (ES): m / z =474.2 [M+H] +

[0106] Process 3 (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-1(2H)-yl)methyl 3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoate [ka] To a solution of (E)-1-(chloromethyl)-6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-methyl-1,6-dihydropyridine-3-carboxamide (0.112 g, 0.199 mmol) and DIPEA (0.208 mL, 1.191 mmol) in tetrahydrofuran (2 mL) was added 3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoic acid (0.144 g, 0.298 mmol) at 0° C. After stirring at room temperature for 3 hours, the reaction mixture was concentrated in vacuo at 30° C. The residue was purified by RP-HPLC (preparative column: kinetex C18 (150x4.6 mm; 5 micron), mobile phase A: 10 mM ammonium acetate, mobile phase B: acetonitrile, flow rate: 1.0 mL / min, gradient: 0 / 30, 20 / 100, 25 / 100, 28 / 30, 33 / 30) to give the title compound (0.060 g, 0.063 mmol, 31.5% yield) as an off-white solid. 1 H NMR(300 MHz, DMSO-d6) δ 0.55 - 0.69(m, 4 H), 1.49(s, 7 H), 2.05(s, 3 H), 2.39(s, 3 H), 2.91(s, 2 H), 3.73(s, 3 H), 4.46(s, 3 H), 5.09(s, 2 H), 5.12(s, 2 H), 5.89(br. S, 2 H), 6.64(s, 1 H), 6.87(s, 1 H), 7.23 - 7.41(m, 10 H), 7.57(d, J =6.00 Hz, 1H), 7.68(d, J =7.20 Hz, 1H), 7.91(br. S, 1H), 8.30(s, 1 H), 8.50(br. S, 1 H), 10.79(br. S, 1 H);LC-MS(ES):m / z =920.4 [M+H] +

[0107] Process 4 (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-1(2H)-yl)methyl 3-(2,4-dimethyl-6-(phosphonooxy)phenyl)-3-methylbutanoate [ka] To a solution of (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-1(2H)-yl)methyl 3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoate (0.045 g, 0.049 mmol) in 1,2-dichloroethane (2 mL) was added TFA (0.377 mL, 4.89 mmol) and anisole (0.267 mL, 2.446 mmol) at 0° C. The mixture was stirred at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a crude product. RP-HPLC purification (preparative column: Sunfire C18 (150x19 mm; 5 micron), mobile phase A: 0.1% HCOOH / water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 30, 10 / 45) afforded the title compound (0.014 g, 0.018 mmol, 37.5% yield) as an off-white solid. 1H NMR(400 MHz, DMSO-d6) δ 0.79 - 0.88(m, 4 H), 1.50(s, 6 H), 1.95(s, 3 H), 2.12(br. S, 1 H), 2.32(s, 3 H), 3.16(br. S, 2 H), 3.78(s, 3 H), 4.48(s, 3 H), 5.90(s, 2 H), 6.30(s, 1 H), 7.05(s, 1 H), 7.48(d, J =8.03 Hz, 2 H), 7.66(d, J =8.03 Hz, 1 H), 7.86(d, J =6.53 Hz, 1 H), 8.80(s, 1 H), 10.10(br. S, 1 H), 11.67(br. S, 1 H);LC-MS(ES):m / z =740.4 [M+H] + ;HPLC RT and Purity: 6.386 min and 97.03% (Method A) & 7.746 min and 97.45% (Method B).

[0108] Example 5 [ka] Process 1 Methyl 4-((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate [ka] To a solution of methyl 4-hydroxy-3-methoxybenzoate (3.000 g, 16.47 mmol) in dichloromethane (30 mL) was added dibenzyl-N,N-diisopropylphosphoramidite (8.30 mL, 24.70 mmol) followed by 1H-tetrazole (73.0 mL, 24.70 mmol) (0.45 M in acetonitrile) and the mixture was stirred at room temperature for 8 h. The reaction was cooled at 0° C. H2O2 (5.05 mL, 165 mmol) was added. After stirring at room temperature for 2 h, the reaction mixture was concentrated to remove acetonitrile and the remaining aqueous layer was diluted with water and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by ISCO [silica gel 60-120 mesh, column size 80 g, ethyl acetate / hexane as eluent]. The product was eluted with 30% ethyl acetate / hexane to give the title compound (8.200 g, 15.94 mmol, 97% yield) as a colorless oil. 1 H NMR(400 MHz, CDCl3) δ 3.84(s, 3H), 3.91(s, 3H), 5.16(s, 2H), 5.18(s, 2H), 7.25(d, J =8.00 Hz, 1H), 7.31-7.37(m, 10H), 7.57(d, J =9.20 Hz, 2H).;LC-MS(ES):m / z =443.2 [M+H] +

[0109] Process 2 4-((Bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoic acid [ka] To a solution of methyl 4-((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate (3.000 g, 5.83 mmol) in tetrahydrofuran (30 mL) and water (30 mL) was added LiOH (0.279 g, 11.66 mmol) at 0° C. After stirring at 0° C. for 1 h, the mixture was extracted with ethyl acetate (2x100 mL). The aqueous layer was acidified with 1.5 N HCl solution (pH~1) and extracted with ethyl acetate (3x100 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (1.700 g, 1.746 mmol, 29.9% yield) as a colorless gum. The crude product was used as is. 1 H NMR(400 MHz, DMSO-d6) δ 3.80(s, 3H), 5.17(s, 2H), 5.20(s, 2H), 6.85(dd, J =2.40, 6.40 Hz, 1H), 7.40-7.52(m, 10H), 7.53(dd, J =2.00, 8.40 Hz, 1H), 7.59(s, 1H), 12.60(br. s, 1H). LC-MS(ES):m / z =429.0 [M+H] +

[0110] Process 3 (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-1(2H)-yl)methyl 4-((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate [ka] To a solution of (E)-1-(chloromethyl)-6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)-1,6-dihydropyridine-3-carboxamide (0.100 g, 0.211 mmol) and DIPEA (0.221 mL, 1.266 mmol) in tetrahydrofuran (5 mL) at 0° C. was added 4-((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoic acid (0.205 g, 0.211 mmol). The mixture was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo at 30° C. to give the crude product as a brown gum. RP-HPLC purification (preparative column: Sunfire C18 (150x19 mm; 5 micron), mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 10, 10 / 45) afforded the title compound (0.040 g, 0.026 mmol, 12.26% yield) as an off-white solid. LC-MS (ES): m / z =866.2 [M+H] +

[0111] Process 4 (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-1(2H)-yl)methyl 3-methoxy-4-(phosphonooxy)benzoate [ka] To a solution of (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-1(2H)-yl)methyl 4-((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate (0.070 g, 0.081 mmol) in 1,2-dichloroethane (2 mL) was added TFA (0.623 mL, 8.08 mmol) followed by anisole (0.442 mL, 4.04 mmol) at 0° C. The mixture was stirred at 50° C. for 2 hours and then concentrated under reduced pressure to give the crude product as a brown gum. RP-HPLC purification (preparative column: Sunfire C18 (150x19 mm; 5 micron), mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 10, 10 / 35) afforded the title compound (0.026 g, 0.038 mmol, 46.4% yield) as an off-white solid. 1 H NMR(400 MHz, DMSO-d6) δ 0.66 - 0.81(m, 4 H), 1.71(br. s, 1 H), 3.74(s, 3 H), 3.81(s, 3 H), 4.46(s, 3 H), 6.27(br. s, 2 H), 7.38(t, J =7.60 Hz, 1H), 7.48 - 7.56(m, 3 H), 7.61 - 7.68(m, 1 H), 7.71 - 7.86(m, 2 H), 8.74 - 8.93(m, 2 H), 11.01 - 11.03(m, 1 H);LC-MS(ES):m / z =686.2 [M+H] + HPLC RT and Purity: 10.082 min and 99.31% (Method A) & 11.877 min and 98.83% (Method B).

[0112] Example 6 [ka] (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-1(2H)-yl)methyl 1-hydroxycyclopropane-1-carboxylate [ka] To a solution of (E)-1-(chloromethyl)-6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)-1,6-dihydropyridine-3-carboxamide (0.025 g, 0.032 mmol) and DIPEA (0.033 mL, 0.190 mmol) in tetrahydrofuran (2 mL) was added 1-hydroxycyclopropanecarboxylic acid (3.88 mg, 0.038 mmol) at 0° C. After stirring at room temperature for 3 hours, the reaction mixture was concentrated in vacuo at 30° C. to give the crude product. RP-HPLC purification (preparative column: Sunfire (150x4.6mm; 5 micron), mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, flow rate: 1.0 mL / min, gradient: 0 / 10, 20 / 100) afforded the title compound (0.011 g, 0.019 mmol, 59.9% yield) as an off-white solid. 1 H NMR(400 MHz, DMSO-d6) δ 0.86 - 0.94(m, 4 H), 1.04 - 1.09(m, 2 H), 1.19 - 1.24(m, 2 H), 2.07(m, 1 H), 3.74(s, 3 H), 4.46(s, 3 H), 6.19(br. s, 2 H), 6.42(br. s, 1 H), 7.41 - 7.50(m, 1 H), 7.64(s, 1 H), 7.90(br. s, 1 H), 9.01(br. s, 1 H), 9.09(br. s, 1 H), 10.94(br. s, 1 H), 11.51(br. s, 1 H);LC-MS(ES):m / z =540.2 [M+H] +;HPLC RT and Purity: 10.047 min and 93.15% (Method A) & 12.826 min and 91.08% (Method B).

[0113] Example 7 [ka] ((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4-yl)(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)methyl(2-(2-methoxyethoxy)ethyl)hydrogenphosphate [ka] To a solution of ((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4-yl)(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)methyl dihydrogen phosphate (30 mg, 0.056 mmol, 1 equiv.) in DMF (0.5 mL) was added 2-(2-methoxyethoxy)ethanol (8.08 mg, 0.067 mmol, 1.200 equiv.) and EDC (10.74 mg, 0.056 mmol). The mixture was stirred at RT for 16 h. The crude product was purified using RP HPLC (Preparative column: Sunfire C18 (19x250 mm; 5 micron), Mobile phase A: 10 mM ammonium acetate / water, Mobile phase B: acetonitrile, Flow rate: 18 mL / min, Gradient: 0 / 20, 10 / 35). The fractions were concentrated under high vacuum at 30°C. The residue was dissolved in a mixture of acetonitrile and water. The resulting solution was frozen and lyophilized for 12 hours to give the title compound (15.6 mg, 0.024 mmol, 43.4% yield) as a yellow solid. 1H NMR(400 MHz, D2O) δ 8.43(s, 1 H), 7.83(br. s, 1 H), 7.68(d, J =8.03 Hz, 1 H), 7.49(dd, J =8.03, 1.51 Hz, 1 H), 7.34(t, J =7.78 Hz, 1 H), 6.03(d, J =12.05 Hz, 2 H), 3.92 - 3.98(m, 5 H), 3.55 - 3.63(m, 7H), 3.48 - 3.52(m, 2 H), 3.29(s, 3 H), 1.91(br.s, 1 H), 0.98 - 1.02(m, 4H).LC-MS(ES):m / z =638.2 [M+H] + HPLC RT and Purity: 5.74 min and 99.51% (Method A) & 5.90 min and 99.44% (Method B).

[0114] Example 8 [ka] (E)-((((6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-3-((methyl-d3)carbamoyl)pyridazin-1(6H)-yl)methoxy)(hydroxy)phosphoryl)oxy)methyl pivalate [ka] To a solution of (E)-(6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-3-((methyl-d3)carbamoyl)pyridazin-1(6H)-yl)methyl dihydrogen phosphate (60 mg, 0.112 mmol, 3 equiv.) in DMF (1 mL) was added DIPEA (0.059 mL, 0.336 mmol) and methyl iodide pivalate (81 mg, 0.336 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was directly purified using RP HPLC (Preparative column: Kinetex (21.2x150 mm; 5 micron), Mobile phase A: 0.1% formic acid, Mobile phase B: acetonitrile, Flow rate: 20 mL / min.). The fractions were concentrated under high vacuum at 30° C. The residue was dissolved in a mixture of acetonitrile and water, frozen, and lyophilized for 12 h to give the title compound (9.42 mg, 0.014 mmol, 12.37% yield) as a yellow solid. 1 H NMR(400 MHz, D2O) δ 8.38(s, 1 H), 7.77(s, 1 H), 7.70(d, J =7.72 Hz, 1 H), 7.45(dd, J =7.97, 1.51 Hz, 1 H), 7.33 - 7.38(m, 1 H), 6.05(d, J =13.11 Hz, 2 H), 5.41(d, J =13.55 Hz, 2 H), 3.97(s, 3H), 3.51(s, 3H), 1.82(bs, 1 H), 1.07(s, 9 H), 0.93 - 1.01(m, 4 H). LC-MS(ES): m / z =650.2 [M+H] + HPLC RT and Purity: 7.045 min and 95.58% (Method A) & 6.85 min and 95.71% (Method B).

[0115] Example 9 [ka] Process 1 4,6-Dichloro-N-(methyl-d3)-N-((methylthio)methyl)nicotinamide [ka] To a stirred solution of 4,6-dichloro-N-(methyl-d3)nicotinamide (450 mg, 2.163 mmol) in anhydrous DMF (10 mL) at 0° C. was added NaH (112 mg, 2.81 mmol). The mixture was stirred for 1 h. Chloromethyl methylsulfide (230 mg, 2.379 mmol) was added and the reaction mixture was allowed to come to room temperature and stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2x50 mL). The organic layer was washed with H2O (1x10 mL) and saturated NaCl (1x10 mL), dried over anhydrous Na2SO4, filtered and concentrated under high vacuum. The crude product was purified using CombiFlash (40 g silica gel column; petroleum ether:ethyl acetate as eluent). The desired product was eluted using 15% ethyl acetate / petroleum ether. The desired fraction was evaporated under reduced pressure to give the title compound (350 mg, 1.109 mmol, 46.2% yield) as a brown oil. 1 H NMR(300 MHz, DMSO-d6) δ 2.17(s, 3H), 4.37(s, 1H), 4.68(br. s 1H), 7.96(d, J =10.80 Hz, 1H), 8.48(d, J =6.90 Hz, 1H). LC-MS(ES):m / z =268.0 [M+H] +

[0116] Process 2 6-Chloro-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)-N-((methylthio)methyl)nicotinamide [ka] To a stirred solution of 2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)aniline (260 mg, 1.267 mmol) and 4,6-dichloro-N-(methyl-d3)-N-((methylthio)methyl)nicotinamide (340 mg, 1.267 mmol) in anhydrous THF (10 mL) was added 1M LiHMDS / THF (3.17 mL, 3.17 mmol) dropwise at room temperature. After stirring for 1 h, the reaction mixture was cooled to 0° C., quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (2x50 mL). The organic layer was washed with HO (1x30 mL) and saturated NaCl solution (1x30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (550 mg, 1.032 mmol, 81% yield) as a brown semi-solid. LC-MS (ES): m / z = 437.2 [M+H] +

[0117] Process 3 6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)-N-((methylthio)methyl)nicotinamide [ka] A stirred suspension of 6-chloro-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)-N-((methylthio)methyl)nicotinamide (550 mg, 1.259 mmol), cyclopropanecarboxamide (118 mg, 1.385 mmol), Cs2CO3 (1230 mg, 3.78 mmol), Xantphos (146 mg, 0.252 mmol) and Pd2(dba)3 (115 mg, 0.126 mmol) in anhydrous dioxane (10 mL) was purged with nitrogen gas and then sealed in a sealed tube. The mixture was stirred at 110 °C overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (25 mL). The black suspension was filtered through a bed of Celite and the bed was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to give the crude product as a black semi-solid. The residue was purified using CombiFlash (40 g silica gel column; MeOH:chloroform as eluent). The desired product was eluted using 4% MEOH / chloroform. The desired fractions were evaporated under reduced pressure to give the title compound (500 mg, 0.875 mmol, 69.5% yield) as a yellow solid. 1 H NMR(400 MHz, DMSO-d6) δ 0.63 - 0.77(m, 4 H), 1.97 - 1.99(m, 1 H), 2.07(br. s, 3 H), 3.70(s, 3 H), 4.45(s, 3 H), 4.67(s, 2 H), 7.32(t, J =7.78 Hz, 1 H), 7.60 - 7.63(m, 2 H), 8.00(s, 1H), 8.16(s, 1 H), 8.48 - 8.51(m, 1 H), 10.76(s, 1 H);LC-MS(ES):m / z =486.2 [M+H] +

[0118] Process 4 (6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)nicotinamide)methyl dihydrogen phosphate [ka] To a stirred solution of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)-N-((methylthio)methyl)nicotinamide (100 mg, 0.206 mmol) in anhydrous THF (5 mL) was added powdered molecular sieves (15 mg) and NIS (93 mg, 0.412 mmol). The reaction mixture was stirred at room temperature for 5 min and phosphoric acid (605 mg, 6.18 mmol) was added in one portion. The reaction mixture was stirred for 5 min and cooled to 0 °C. MeOH (1 mL) was added followed by addition of Na2CO3 solution to adjust the pH to about 8. The reaction mixture was filtered through a bed of Celite and the bed was washed with THF (20 mL). The filtrate was concentrated under high vacuum at 30 °C to give the crude product as a semi-solid. The crude compound was purified by reversed-phase prep-HPLC (preparative column: INERTSIL ODS (250x19 mm; 3.5 micron), mobile phase A: water, mobile phase B: acetonitrile, flow rate: 17 mL / min, gradient: 0 / 0, 12 / 20). The fractions containing the desired product were concentrated under high vacuum at 30°C. The residue was dissolved in a mixture of acetonitrile and water, and the solution was lyophilized for 24 hours to give the title compound (40 mg, 0.068 mmol, 33.1% yield) as an off-white solid. 1 H NMR(400 MHz, D2O) δ 0.89 - 0.98(m, 4 H), 1.83(m, 1 H), 3.63 - 3.67(m, 3 H), 4.45 - 4.49(m, 3H), 5.04 - 5.13(m, 2 H), 7.36 - 7.46(m, 1 H), 7.54 - 7.63(m, 2 H), 7.71 - 7.81(m, 1 H), 8.24 - 8.31(m, 1 H). LC-MS(ES):m / z =536.2 [M+H] +;HPLC RT and Purity: 5.918 min and 99.73% (Method A) & 5.748 min and 99.68% (Method B).

[0119] Example 10 [ka] Process 1 (2-(methylamino)pyridin-3-yl)methyl-N-(tert-butoxycarbonyl)-N-methylglycinate [ka] To a stirred solution of (2-(methylamino)pyridin-3-yl)methanol (100 mg, 0.724 mmol) in anhydrous DCM (2 mL) was added 2-((tert-butoxycarbonyl)(methyl)amino)acetic acid (137 mg, 0.724 mmol), EDC (180 mg, 0.941 mmol), and finally DMAP (88 mg, 0.724 mmol). After stirring at room temperature for 16 h, the reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with H2O and saturated NaCl, dried over anhydrous Na2SO4, filtered, and concentrated under high vacuum. The residue was purified using CombiFlash (12 g silica gel column; 40% ethyl acetate / petroleum ether) to give the title compound (210 mg, 0.563 mmol, 78% yield) as a brown semi-solid. 1 H NMR(400 MHz, DMSO-d6) δ 1.16 - 1.40(m, 9 H), 2.82 - 2.87(m, 6 H), 4.00(m, 2 H), 4.99(d, J =14.56 Hz, 2 H), 6.18(br. s, 1 H), 6.51(dd, LC-MS(ES):m / z =310.2 [M+H] +

[0120] Process 2 (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl N-(tert-butoxycarbonyl)-N-methylglycinate [ka] To a stirred solution of (2-(methylamino)pyridin-3-yl)methyl 2-((tert-butoxycarbonyl)(methyl)amino)acetate (220 mg, 0.711 mmol) in anhydrous DCM (3 mL) at 0° C. was added DIPEA (0.621 mL, 3.56 mmol) followed by dropwise addition of chloromethyl chloroformate (275 mg, 2.133 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was cooled to 0° C., treated with saturated sodium bicarbonate solution and extracted with DCM. The organic layer was washed with H2O and saturated NaCl, dried over anhydrous Na2SO4, filtered and concentrated under high vacuum. The residue was purified using CombiFlash (12 g silica gel column; 30% ethyl acetate / petroleum ether) to give the title compound (200 mg, 0.428 mmol, 60.2% yield) as a yellow semi-solid. LC-MS (ES): m / z =402.2 [M+H] +

[0121] Process 3 (E)-(2-((((2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-(methylcarbamoyl)pyridin-1(2H)-yl)methoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl methyl glycinate trifluoroacetate [ka] To a stirred solution of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-methylnicotinamide (150 mg, 0.355 mmol) in anhydrous acetonitrile (2.5 mL) was added K2CO3 (147 mg, 1.065 mmol), (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-((tert-butoxycarbonyl)(methyl)amino)acetate (428 mg, 1.065 mmol), followed by sodium iodide (186 mg, 1.243 mmol). The reaction mixture was heated to 80° C. and stirred under nitrogen for 30 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with H2O and saturated NaCl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound as a mixture of mono- and di-alkylated products as a brown semi-solid. To this crude mixture (400 mg, 0.170 mmol) in anhydrous DCM (5 mL) was added 4M HCl / dioxane (5 mL, 20.00 mmol) at 0°C. After stirring for 15 minutes, the reaction mixture was concentrated to dryness. The crude compound was purified by reversed-phase prep-HPLC (preparative column: Symmetry C8 (300x19 mm; 7 micron), mobile phase A: 0.1% TFA / water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 10, 5 / 20). The fractions were concentrated under high vacuum at 30°C. The residue was dissolved in a mixture of acetonitrile and water, and the solution was lyophilized to afford the title compound (20 mg, 0.024 mmol, 13.94% yield) as an off-white solid. 1H NMR(400 MHz, MeOH-d4) δ 0.95 - 1.02(m, 4 H) 1.92 - 2.02(m, 1 H) 2.77(s, 3 H) 2.99(s, 3 H) 3.37 - 3.45(m, 3 H) 3.84(s, 3 H) 4.04 - 4.11(m, 2 H) 4.49(s, 3 H) 5.14 - 5.34(m, 2 H) 6.09 - 6.38(m, 2 H) 7.42 - 7.56(m, 2 H) 7.65 - 7.80(m, 2 H) 7.99 - 8.09(m, 2 H) 8.45 - 8.57(m, 1H) 8.70 - 8.94(m, 1 H). LC-MS(ES):m / z =688.2 [M+H] + ;HPLC RT and Purity: 8.827 min and 99.49% (Method A) & 11.610 min and 95.18% (Method B).

[0122] Example 11 [ka] Process 1 Methyl 4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoate [ka] To a stirred solution of methyl 4-(hydroxymethyl)benzoate (2 g, 12.04 mmol) and tetrazole (27.3 g, 24.07 mmol) in acetonitrile was added dibenzyldiisopropylphosphoramidite (4.16 g, 12.04 mmol) at room temperature. After stirring for 16 h, the reaction mixture was cooled to 0 °C and diluted with H2O. 2(To the resulting mixture was added dropwise (2.108 mL, 24.07 mmol). After stirring at 0° C. for 20 min, the mixture was quenched with saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with H2O and saturated NaCl. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified using CombiFlash (40 g silica gel column; 25% ethyl acetate / petroleum ether as eluent). The desired fractions were evaporated under reduced pressure to give the title compound (3.0 g, 5.63 mmol, 46.8% yield) as a brown semi-solid. 1 H NMR(300 MHz, CDCl3) δ 3.92(s, 3H), 4.99 - 5.08(m, 6H), 7.29 - 7.38(m, 10H), 7.42(dd, J =5.70, 7.50 Hz, 2H), 7.45 - 8.05(m, 2H).

[0123] Process 2 4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoic acid [ka] To a stirred solution of methyl 4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoate (1 g, 2.345 mmol) in THF (10 mL) at 0 °C was added a solution of LiOH (0.112 g, 4.69 mmol) in water (10 mL) dropwise. The reaction mixture was allowed to warm to RT and stirred for 16 h. The mixture was cooled to 0 °C, treated with 1.5 N HCl solution (20 mL), and extracted with EtOAc. The organic layer was washed with H2O and saturated NaCl, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (600 mg, 0.757 mmol, 32.3% yield) as a brown solid. The crude product was used as is. 1H NMR(400 MHz, MeOH-d4) δ 8.02(d, J =8.00 Hz, 2H), 7.48(d, J =8.0 Hz, 2H), 7.42 - 7.32(m, 10H), 5.10 - 5.04(m, 4H), 4.70(s, 2H).

[0124] Process 3 (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-(methylcarbamoyl)pyridin-1(2H)-yl)methyl 4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoate [ka] To a stirred solution of (E)-1-(chloromethyl)-6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-methyl-1,6-dihydropyridine-3-carboxamide (50 mg, 0.106 mmol) in anhydrous THF (2.5 mL) at 0° C. was added DIPEA (0.037 mL, 0.212 mmol) followed by 4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoic acid (43.8 mg, 0.106 mmol). The reaction mixture was stirred at 0° C. for 2 hours. The mixture was then diluted with water (5 mL) and extracted with ethyl acetate (2x25 mL). The organic layer was washed with HO (1x10 mL) and saturated NaCl (1x10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under high vacuum. The crude compound was purified by reverse-phase prep-HPLC (preparative column: SUNFIRE C18 (150x19 mm; 5 micron), mobile phase A: 10 mM ammonium acetate / water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 30, 10 / 70). The preparative fractions containing the desired product were concentrated under high vacuum at 30°C. The residue was dissolved in a mixture of acetonitrile and water and lyophilized for 24 hours to give the title compound (20 mg, 0.023 mmol, 21.80% yield) as an off-white solid. 1 H NMR(400 MHz, MeOH-d4) δ 0.69 - 714(m, 2 H), 0.91 - 093(m, 2 H), 1.61 - 1.7(m, 1 H), 2.94(s, 3 H), 3.82(s, 3 H), 4.45(s, 3 H), 5.02(s, 2 H), 5.05(s, 2 H), 5.07(s, 2 H), 6.32(s, 2 H), 7.31 - 7.40(m, 11 H), 7.40(d, J =9.04 Hz, 3 H), 7.70(d, J =7.53 Hz, 1 H), 7.79(s, 2 H), 7.99(d, J =8.03 Hz, 2 H), 8.52(s, 1 H);LC-MS(ES):m / z =847.2 [M+H] +

[0125] Process 4 (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-(methylcarbamoyl)pyridin-1(2H)-yl)methyl 4-((phosphonooxy)methyl)benzoate [ka] To a stirred solution of (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-(methylcarbamoyl)pyridin-1(2H)-yl)methyl 4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoate (20 mg, 0.024 mmol) in anhydrous DCE (0.7 mL) was added anisole (2.58 μL, 0.024 mmol) followed by TFA (1.820 μL, 0.024 mmol). The reaction mixture was heated to 50° C. and stirred for 16 h. The mixture was concentrated to dryness under high vacuum. The crude compound was purified by reversed-phase prep-HPLC (preparative column: Xbridge phenyl (250x19 mm; 5 micron), mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 20, 6 / 30). The fractions containing the desired product were concentrated under high vacuum at 30°C. The residue was dissolved in a mixture of acetonitrile and water and lyophilized for 24 hours to give the title compound (10 mg, 0.015 mmol, 62.2% yield) as an off-white solid. 1H NMR(400 MHz, DMSO-d6) δ 0.55 - 0.74(m, 4 H), 1.45 - 1.51 m, 1 H), 2.82(d, J =4.52 Hz, 3 H), 3.75(br. s, 3 H), 4.46(s, 3 H), 4.96(d, J =7.53 Hz, 2 H), 6.26(br. s, 2 H), 7.37(br. s, 1 H), 7.54(d, J =8.53 Hz, 2 H), 7.64(br. s, 1 H), 7.70(br. s, 1 H), 7.92(br. s, 1 H), 7.97(d, J =8.03 Hz, 2 H), 8.65(s, 1 H), 8.73(br. s, 1 H), 10.77(br. s, 1 H);LC-MS(ES):m / z =667.2 [M+H] + ;HPLC RT and Purity: 4.675 min and 98.23% (Method A) & 6.088 min and 98.58% (Method B).

[0126] Example 12 [ka]

[0127] Process 1 3-((Bis(benzyloxy)phosphoryl)oxy)-4-methoxybenzoic acid [ka] To a stirred solution of 3-hydroxy-4-methoxybenzoic acid (300 mg, 1.784 mmol) in anhydrous acetonitrile (10 mL) at 0°C was added 1H-tetrazole (91 mg, 2.68 mmol) followed by dibenzyldiisopropylphosphoramidite (678 mg, 1.963 mmol) dropwise. After addition, the reaction mixture was allowed to come to room temperature and stirred for 16 hours. The mixture was cooled to 0°C and H2O2 (0.312 mL, 3.57 mmol) was added dropwise. After stirring for 20 minutes, the reaction mixture was extracted with ethyl acetate (2x25 mL). The organic layer was washed with H2O (1x10 mL) and saturated NaCl (1x10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude compound was purified by reversed-phase prep-HPLC (preparative column: SUNFIRE C18 (150x19 mm; 5 micron), mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 10, 10 / 55). The fractions containing the desired product were concentrated under high vacuum at 30° C. to give the title compound (350 mg, 0.809 mmol, 45.3% yield) as a pale yellow oil. 1 H NMR(300 MHz, DMSO-d6) δ 3.85(s, 3 H), 5.16(s, 2 H), 5.19(s, 2 H), 7.22(d, J =8.31 ​​Hz, 1 H), 7.75 - 7.77(m, 10 H), 7.80(d, J =8.69 Hz, 2 H), 12.88(br. s, 1 H);LC-MS(ES):m / z =429.0 [M+H] +

[0128] Process 2 (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-(methylcarbamoyl)pyridin-1(2H)-yl)methyl 3-((bis(benzyloxy)phosphoryl)oxy)-4-methoxybenzoate [ka] To a stirred solution of (E)-1-(chloromethyl)-6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-methyl-1,6-dihydropyridine-3-carboxamide (30 mg, 0.064 mmol) in anhydrous THF (2.5 mL) at 0° C. was added DIPEA (0.1 mL, 0.573 mmol) followed by 3-((bis(benzyloxy)phosphoryl)oxy)-4-methoxybenzoic acid (30.0 mg, 0.070 mmol). The reaction mixture was stirred at 0° C. for 2 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2x25 mL). The organic layer was washed with HO (1x10 mL) and saturated NaCl (1x10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (80 mg, 0.046 mmol, 72.8% yield) as a brown semi-solid. The crude product was used directly in the next step. LC-MS (ES): m / z = 863.5 [M+H] +

[0129] Process 3 (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-(methylcarbamoyl)pyridin-1(2H)-yl)methyl 4-methoxy-3-(phosphonooxy)benzoate [ka] To a stirred solution of (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-(methylcarbamoyl)pyridin-1(2H)-yl)methyl 3-((bis(benzyloxy)phosphoryl)oxy)-4-methoxybenzoate (80 mg, 0.046 mmol) in anhydrous DCE (2.5 mL) was added anisole (0.1 mL, 0.915 mmol) followed by TFA (0.2 mL, 2.60 mmol) at room temperature. The reaction mixture was heated to 50° C. and stirred for 16 h. The reaction mixture was concentrated to dryness under high vacuum. The crude compound was purified by reversed-phase prep-HPLC (preparative column: Kinetex C18 (150x19 mm; 5 micron), mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 10, 10 / 35). The fractions containing the desired product were concentrated under high vacuum at 30°C. The residue was dissolved in a solvent mixture of acetonitrile and water, and the solution was lyophilized for 24 hours to give the title compound (10 mg, 0.014 mmol, 31.0% yield) as an off-white solid. 1 H NMR(400 MHz, DMSO-d6) δ 0.80 - 0.82(m, 4 H), 1.99 - 2.00(m, 1 H), 2.83(d, J =4.52 Hz, 3 H), 3.75(s, 3 H), 3.86(s, 3 H), 4.46(s, 3 H), 6.38(br. s, 2 H), 7.03-7.45(m, 4 H), 7.66-7.73(m, 2 H), 7.84(br. s, 1 H), 8.03(s., 1 H), 9.03 - 9.24(m, 1 H), 11.35(br. s, 1 H);LC-MS(ES):m / z =683.2 [M+H] + ;HPLC RT and Purity: 10.551 min and 98.75% (Method A) & 12.137 min and 98.30% (Method B).

[0130] Example 13 [ka] Process 1 (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-1(2H)-yl)methyl 4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoate [ka] To a stirred solution of (E)-1-(chloromethyl)-6-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)-1,6-dihydropyridine-3-carboxamide (80 mg, 0.169 mmol) in anhydrous THF (2.5 mL) at 0° C. was added DIPEA (0.059 mL, 0.338 mmol) followed by 4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoic acid (104 mg, 0.253 mmol). The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2x25 mL). The organic layer was washed with H2O (1x10 mL) and saturated NaCl (1x10 mL), dried over anhydrous Na2SO4, filtered and concentrated under high vacuum. The crude compound was purified by reversed-phase prep-HPLC (preparative column: X-bridge phenyl (250x19 mm; 5 micron), mobile phase A: 10 mM ammonium acetate / water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 30, 10 / 67). The fractions containing the desired product were concentrated under high vacuum at 30°C. The residue was dissolved in a mixture of acetonitrile and water, and the solution was lyophilized for 24 hours to give the title compound (30 mg, 0.034 mmol, 20.08% yield) as an off-white solid. LC-MS (ES): m / z =850.4 [M+H] + .

[0131] Process 2 (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-1(2H)-yl)methyl 4-((phosphonooxy)methyl)benzoate [ka] To a stirred solution of (E)-(2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-1(2H)-yl)methyl 4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoate (30 mg, 0.035 mmol) in anhydrous DCE (2.5 mL) was added anisole (0.1 mL, 0.915 mmol) followed by TFA (0.2 mL, 2.60 mmol) at room temperature. The reaction mixture was heated to 50° C. and stirred for 16 h. The reaction mixture was concentrated to dryness under high vacuum. The crude compound was purified by reverse phase prep-HPLC using formic acid as a buffer. The fractions containing the desired product were concentrated under high vacuum at 30° C. The residue was dissolved in a mixture of acetonitrile and water and the solution was lyophilized for 24 h to give the title compound (10 mg, 0.015 mmol, 41.5% yield) as an off-white solid. 1H NMR(400 MHz, DMSO-d6) δ 0.62 - 0.82(m, 4 H), 1.65 - 1.75(m, 1 H), 3.75(s, 3 H), 4.46(s, 3 H), 4.98(d, J =7.53 Hz, 2 H), 6.33(br. s, 2 H), 7.28(s, 1 H), 7.41(d, J =8.03 Hz, 1 H), 7.55(d, J =8.03 Hz, 2 H), 7.77(br. s, 2 H), 7.99(d, J =8.03 Hz, 2 H), 8.85(br. s, 2 H), 11.05(br.s, 1H);LC-MS(ES):m / z =670.2 [M+H] + ;HPLC RT and Purity: 11.080 min and 98.35% (Method A) & 11.919 min and 98.66% (Method B).

[0132] Example 14 [Table 2]

[0133] As shown in Table 1 above, the compound of Example 1 was administered PO to rats to determine whether the prodrug was present in the blood circulation after administration. The results showed that there was no exposure to the prodrug at therapeutic doses (5 and 25 mpk). It was also shown that at the 150 mpk dose, less than 0.05% of the prodrug was observed. This demonstrated that the prodrug was converted to the parent drug in vivo.

Claims

1. The following formula: 【Chemistry 1】 【Chemistry 2】 【Chemistry 3】 or a salt thereof.

2. The compound of the following formula: 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 2. The compound according to claim 1, wherein

3. The compound of the following formula: 【Chemistry 7】 【Chemistry 8】 2. The compound according to claim 1, wherein:

4. A compound of the following formula: 【Chemistry 9】 【Chemistry 10】 4. The compound according to claim 3, wherein

5. The compound of the following formula: 【Chemistry 11】 2. The compound according to claim 1, wherein:

6. A compound of the following formula: 【Chemistry 12】 6. The compound according to claim 5, wherein

7. The compound of the following formula: 【Chemistry 13】 2. The compound according to claim 1, wherein:

8. The compound of the formula: 【Chemistry 14】 8. The compound according to claim 7, wherein

9. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 8 and a pharma- ceutically acceptable carrier or diluent.

10. 10. The pharmaceutical composition according to claim 9 for treating a disease, wherein the disease is an inflammatory disease or an autoimmune disease.

11. 11. The pharmaceutical composition of claim 10, wherein the inflammatory or autoimmune disease is multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, Sjogren's syndrome or scleroderma.

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