Prodrugs that modulate interleukins

Abstract

Disclosed are prodrugs of compounds of the formula below. The prodrugs can be used to regulate IL-12, IL-23 and / or IFNa by acting on Tyk-2 to cause signal transduction inhibition. #imgabs0#

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 874,531, filed on July 16, 2019, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention relates to compounds that can be used as prodrugs for regulating IL-12, IL-23 and / or IFNa by acting on Tyk-2 to cause signal transduction inhibition. Provided herein are prodrugs of amide-substituted heterocyclic compounds, compositions comprising such compounds, and methods of use thereof. The present invention further relates to pharmaceutical compositions containing at least one compound according to the present invention, which can be used to treat disorders associated with the regulation of IL-12, IL-23 and / or IFNa in mammals. Background Art

[0004] Heterodimer cytokines interleukin (IL) -12 and IL-23, which share a common p40 subunit, are produced by activated antigen presenting cells and are essential in 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 p40 subunits and unique p19 subunits. IL-23 acts through a heterodimer receptor composed of IL-23R and IL-12Rβ1, and is essential for the survival and expansion of Th17 cells that produce proinflammatory cytokines such as IL-17A, IL-17F, IL-6 and TNF-a (McGeachy, MJ et al., "The link between IL-23and Th17 cell-mediated immune pathologies", Semin.Immunol., 19: 372-376 (2007)). These cytokines are critical in mediating the pathobiology of many autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and lupus. IL-12 contains a p35 subunit in addition to the p40 subunit shared with IL-23 and acts through a heterodimeric receptor composed of IL-12Rβ1 and IL-12Rβ2. IL-12 is essential for the development of Th1 cells and the secretion of IFNγ, a cytokine that plays a decisive role in immunity by stimulating the expression of MHC, switching the class of B cells to the IgG subclass, and activating 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)).

[0005] The importance of p40-containing cytokines in autoimmunity is demonstrated by the following findings: mice lacking p40, p19 or IL-23R are protected from diseases such as 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 skindisorder", 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 criticalcytokine for autoimmune inflammation of the brain", Nature, 421: 744-748 (2003); Murphy, CA et al., "Divergent pro- and anti-inflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation", J. Exp. Med., 198: 1951-1957 (2003)).

[0006] In human disease, high expression of p40 and p19 has been measured 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 23p19 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 active SLE patients were also shown to be significantly higher than those in inactive SLE patients (Huang, X. et al., “Dysregulated expression of interleukin-23 and interleukin-12 subunits in systemic lupus erythematosus patients”, Mod. Rheumatol., 17:220-223 (2007)), and T cells from lupus patients have a dominant Th1 phenotype (Tucci, M. et al., “Overexpression of interleukin-12 and T helper1 predominance in lupus nephritis”, Clin. Exp. Immunol., 154:247-254 (2008)).

[0007] Furthermore, genome-wide association studies have identified a number of loci associated with chronic inflammatory and autoimmune diseases that encode factors that function in the IL-23 and IL-12 pathways. These genes include IL23A, IL12A, IL12B, IL12RB1, IL12RB2, IL23R, JAK2, TYK2, STAT3 and STAT4 (Lees, CW et al., “New IBD genetics: common pathways with other diseases”, Gut, 60: 1739-1753 (2011); Tao, JH et al., “Meta-analysis of TYK2 gene polymorphisms association with susceptibility to autoimmune and inflammatory diseases”, Mol. Biol. Rep., 38: 4663-4672 (2011); Cho, JH et al., “Recent insights into the genetics of inflammatory bowel disease”, Gastroenterology, 140: 1704-1712 (2011)).

[0008] Indeed, anti-p40 therapy (inhibiting both IL-12 and IL-23) and IL-23-specific anti-p19 therapy have been shown to be effective in the treatment of autoimmunity in diseases including 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 Disease 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, it can be expected that agents that inhibit the action of IL-12 and IL-23 will have therapeutic benefits in human autoimmune disorders.

[0009] The I type interferon (IFN) group including IFNa members and IFNP, IFNe, IFNK and IFNω works through heterodimer IFNa / β receptor (IFNAR). I type IFN has multiple effects in the innate immune system and the adaptive immune system, including activating cellular and humoral immune responses and enhancing the expression and release of autoantigens (Hall, JC et al., "Type I interferons: crucial participants in disease amplification in autoimmunity", Nat. Rev. Rheumatol., 6: 40-49 (2010)).

[0010] In patients with systemic lupus erythematosus (SLE), a potentially fatal autoimmune disease, increased serum levels of interferon (IFN) alpha (type I interferon) or increased expression of genes regulated by type I IFN (the so-called IFNα signature) in peripheral blood mononuclear cells and affected organs have been demonstrated in most 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 some studies have shown that serum IFNα levels are associated with disease activity and severity (Bengtsson, AA et al., "Activation of IFNα in peripheral blood mononuclear cells", 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)). of type I interferon system in systemic lupuserythematosus correlates with disease activity but not with antiretroviralantibodies”, Lupus, 9: 664-671 (2000)). The direct role of IFNa in lupus pathobiology is demonstrated by the observation that administration of IFNa to patients with malignant or viral diseases can induce a lupus-like syndrome.In addition, the absence of IFNAR in lupus-prone mice provides a high degree of protection against autoimmunity, disease severity, and lethality (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 lupus-associated loci that encode factors that function in the type I interferon pathway, including IRF5, IKBKE, TYK2, and STAT4 (Deng, Y. et al., "Genetic susceptibility to systemic lupus erythematosus in the genomic era", Nat. Rev. Rheumatol., 6:683-692 (2010); Sandling, 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 abnormal activation of type I interferon-mediated pathways is important in the pathobiology of other autoimmune diseases such as Sjogren's syndrome and scleroderma (. U. et al., “Activation of the type I interferon system in primary 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)). Therefore, agents that inhibit the effects of type I interferon responses can be expected to have therapeutic benefits in human autoimmune diseases.

[0011] Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and has been shown to be activated in mice (Ishizaki, M. et al., “Involvement of Tyrosine Kinase-2in Both the IL-12 / Th1 and IL-23 / Th17 Axes In vivo”, J. Immunol., 187:181-189 (2011); Prachal-Murphy, M. et al., “TYK2 kinase activity is required for functional type I interferon responses in vivo”, PLoS One, 7:e39141 (2012)) and humans (Minegishi, Y. et al., “Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired Tyk2 is an important signaling pathway downstream of the receptors that regulate IL-12, IL-23, and type I interferon in both immunity and pro-inflammatory cytokines. Tyk2 mediates receptor-induced phosphorylation of members of the STAT family of transcription factors, which is an important signal leading to STAT protein dimerization and STAT-dependent pro-inflammatory gene transcription. Tyk2-deficient mice are resistant to experimental models of colitis, psoriasis, and multiple sclerosis, demonstrating the importance of Tyk2-mediated signaling in autoimmunity and related disorders (Ishizaki, M. et al., “Involvement of Tyrosine Kinase-2 in Both the IL-12 / Th1 and IL-23 / Th17 Axes In vivo” J. Immunol., 187: 181-189 (2011); Oyamada, A. et al., “Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis” J. Immunol., 183: 7539-7546 (2009)).

[0012] In humans, individuals expressing an inactive variant of Tyk2 are protected from multiple sclerosis and possibly other autoimmune disorders (Couturier, N. et al., “Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility”, Brain, 134:693-703 (2011)). Genome-wide association studies have shown that other variants of Tyk2 are associated with autoimmune disorders such as Crohn's disease, psoriasis, systemic lupus erythematosus and rheumatoid arthritis, further demonstrating the importance of Tyk2 in autoimmunity (Ellinghaus, D. et al., "Combined Analysis of Genome-wide Association Studies for Crohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci" Am. J. Hum. Genet., 90: 636-647 (2012); Graham, D. et al., "Association of polymorphisms across the tyrosine kinase gene, TYK2 in UK SLE families", Rheumatology (Oxford), 46: 927-930 (2007); Eyre, S. et al., "High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis" arthritis", Nat. Genet., 44: 1336-1340 (2012)).

[0013] In view of the conditions that may benefit from treatment involving cytokine and / or interferon modulation, new compounds capable of modulating cytokines and / or interferons (such as IL-12, IL-23 and / or IFNa) and methods of using these compounds may provide substantial therapeutic benefit to a wide variety of patients in need thereof.

[0014] U.S. Patent No. 9,663,467 discloses compounds that can be used to treat diseases and disorders associated with the regulation of IL-12, IL-23 and / or IFNa, such as autoimmune diseases and inflammatory diseases. This reference has been assigned to the assignee of the present invention and is incorporated herein by reference in its entirety.

[0015] The following compounds are disclosed

[0016]

[0017] Activity against the target has been shown.

[0018] U.S. Patent No. 9,505,748 also discloses compounds that can be used for treating diseases and disorders associated with the regulation of IL-12, IL-23 and / or IFNa such as autoimmune diseases and inflammatory diseases. This reference has been transferred to the assignee of the present invention and is incorporated herein by reference in its entirety.

[0019] The following compounds are disclosed

[0020]

[0021] Activity against the target has been shown.

[0022] As can be appreciated, there remains a need to improve the delivery of the above compounds to patients.

[0023] Applicants have discovered prodrugs of compounds (I) and (II) that can be used for administration of compounds (I) and (II), respectively. The prodrugs have better solubility at physiologically important pH values ​​than compounds (I) and (II) and surprisingly allow compounds (I) and (II) to be administered in a wider dosage range and / or a wider range of pharmaceutical formulations. The prodrug compounds provided are useful as medicaments having desirable stability, bioavailability, therapeutic index, and toxicity values ​​important for their pharmaceutical usability. Summary of the invention

[0024] The present invention relates to prodrugs of compounds (I) and (II), which can be used as modulators of IL-12, IL-23 and / or IFNa by inhibiting Tyk2-mediated signal transduction.

[0025] The present invention also provides methods and intermediates for preparing the compounds of the present invention.

[0026] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention.

[0027] The present invention also provides a method for regulating IL-12, IL-23 and / or IFNa by inhibiting Tyk-2 mediated signal transduction, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention.

[0028] The present invention also provides a method for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention.

[0029] A preferred embodiment is a method for treating inflammatory and autoimmune diseases or disorders.For purposes of the present invention, inflammatory and autoimmune diseases or disorders include any disease with an inflammatory or autoimmune component.

[0030] An alternative preferred embodiment is a method of treating metabolic diseases including type 2 diabetes and atherosclerosis.

[0031] The present invention also provides use of the compound of the present invention in the manufacture of a medicament for treating cancer.

[0032] The present invention also provides a compound of the invention for use in therapy.

[0033] These and other features of the present invention will be set forth in expanded form as the disclosure proceeds. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The present invention is explained by referring to the drawings described below.

[0035] Figure 1 The PK of the prodrug of Compound I is shown. Rats were orally dosed using the following doses with the following notation: (◇)-5 mpk, (D)-25 mpk, and (◇)-150 mpk. The maximum circulating prodrug observed was <0.05% of the parent (150 mpk dose). DETAILED DESCRIPTION

[0036] The first aspect of the present invention provides a prodrug of compounds (I) and (II) as shown below

[0037]

[0038] In a second aspect of the present invention, the following compounds of the present invention are provided:

[0039]

[0040]

[0041]

[0042] or a salt thereof.

[0043] In the third aspect of the present invention, there is provided a prodrug of compound (I) as shown below

[0044]

[0045] or a salt thereof.

[0046] In a fourth aspect of the present invention, there is provided a prodrug of compound (II) as shown below

[0047]

[0048]

[0049] or a salt thereof.

[0050] In another aspect, the present invention provides a compound selected from the illustrative examples within the scope of the first aspect, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0051] In another aspect, the invention provides a compound selected from any subset of the list of compounds within the scope of any of the above aspects.

[0052] In another embodiment, a pharmaceutical composition is provided, comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier or diluent.

[0053] The present invention also relates to a pharmaceutical composition that can be used to treat diseases associated with the regulation of IL-12, IL-23 and / or IFNa by acting on Tyk-2 to cause signal transduction inhibition, comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0054] The present invention further relates to a method for treating diseases associated with the regulation of IL-12, IL-23 and / or IFNa, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to formula I.

[0055] The present invention also provides methods and intermediates for preparing the compounds of the present invention.

[0056] The present invention also provides a method for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases (or the use of the compounds of the present invention for the manufacture of a medicament for treating these diseases), comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention.

[0057] The present invention also provides a method for treating inflammatory diseases or autoimmune diseases (or the use of the compounds of the present invention for manufacturing medicaments for treating these diseases), which comprises administering a therapeutically effective amount of a compound of formula I to a patient in need of such treatment.

[0058] The present invention also provides a method for treating a disease (or the use of the compounds of the present invention for the manufacture of a medicament for treating these diseases), comprising administering a therapeutically effective amount of a compound of formula I to a patient in need of such treatment, wherein the disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, inflammatory bowel disease, psoriasis, Crohn's disease, psoriatic arthritis, Sjogren's syndrome, systemic sclerosis, ulcerative colitis, Graves' disease, discoid lupus erythematosus, adult-onset Still's disease, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis, type 1 diabetes, insulin-dependent diabetes, sepsis, infectious Shock, shigellosis, 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, Kawasaki disease, chronic inflammatory demyelinating polyneuropathy (CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome, autoimmune lung inflammation, autoimmune thyroiditis, autoimmune inflammatory eye disease, and chronic demyelinating polyneuropathy.

[0059] The present invention also provides a method for treating an inflammatory disease or an autoimmune disease (or the use of a compound of the present invention for the manufacture of a medicament for treating the disease), comprising administering a therapeutically effective amount of a compound of formula I to a patient in need of such treatment, wherein the disease is selected from systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, Crohn's disease, ulcerative colitis, type 1 diabetes, psoriasis, rheumatoid arthritis, systemic onset juvenile idiopathic arthritis, ankylosing spondylitis, and multiple sclerosis.

[0060] The present invention also provides a method for treating rheumatoid arthritis (or the use of the compound of the present invention for manufacturing a medicament for treating rheumatoid arthritis), which comprises administering a therapeutically effective amount of a compound of formula I to a patient in need of such treatment.

[0061] In addition, the present invention also provides a method for treating a disease (or the use of the compounds of the present invention for the manufacture of a medicament for treating these diseases), comprising administering a therapeutically effective amount of a compound of formula I to a patient in need of such treatment, wherein the disease is selected from acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, solid tumors, ocular neovascularization, and infantile hemangioma, B-cell lymphoma, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, polyangiitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type I diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and hot agglutinin disease, Evans syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), sarcoidosis, Sjogren's syndrome, peripheral neuropathy, pemphigus vulgaris and asthma.

[0062] The present invention also provides a method for treating IL-12, IL-23 and / or IFNa mediated diseases (or the use of the compounds of the present invention for the manufacture of medicaments for treating these diseases), which comprises administering a therapeutically effective amount of a compound of formula I to a patient in need of such treatment.

[0063] The present invention also provides a method for treating diseases mediated by IL-12, IL-23 and / or IFNa (or the use of the compounds of the present invention for the manufacture of medicaments for treating these diseases), which comprises administering a therapeutically effective amount of a compound of formula I to a patient in need of such treatment, wherein the IL-12, IL-23 and / or IFNa-mediated disease is a disease regulated by IL-12, IL-23 and / or IFNa.

[0064] The present invention also provides a method of treating a disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I in combination with other therapeutic agents.

[0065] The present invention also provides a compound of the invention for use in therapy.

[0066] In another embodiment, the compound of Formula I is selected from the exemplified compounds or a combination of exemplified compounds or other embodiments herein.

[0067] In another embodiment, there is provided an IC in at least one of the following assays: 50 Compounds at <1000 nM.

[0068] The present invention can be implemented in other specific forms without departing from its spirit or basic attributes. The present invention encompasses all combinations of preferred aspects of the present invention and / or embodiments indicated herein. It should be understood that any and all embodiments of the present invention can be combined with any other one or more embodiments to describe other more preferred embodiments. It should also be understood that each individual element of the preferred embodiment is its own independent preferred embodiment. In addition, any element of the embodiment is intended to describe other embodiments with any and all other element combinations from any embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0070] The following are definitions of terms used in this specification and the appended claims. Unless otherwise indicated, the initial definitions provided herein for a group or term apply to that group or term (alone or as part of another group) throughout the specification and claims.

[0071] The compounds of the present invention may have one or more asymmetric centers. Unless otherwise indicated, all chirality (enantiomers and diastereomers) and racemic forms of the compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C=N double bonds, etc. may also be present in the compounds, and all such stable isomers are considered in the present invention. The cis and trans geometric isomers of the compounds of the present invention are described, and they can be separated as a mixture of isomers or as separated isomeric forms. The compounds of the present invention can be separated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by splitting racemic forms or by synthesizing from optically active starting materials. Unless a specific stereochemistry or isomeric form is specifically indicated, all chirality (enantiomers and diastereomers) and racemic forms and all geometric isomeric forms of the structure are meant.

[0072] When any variable (e.g., R 3 ) occurs more than once in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is represented by 0-2 R 3 substituted, the group may optionally be replaced by up to two R 3 group substituted, and R 3 In each occurrence, independently selected from R 3 Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0073] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0074] In the case of nitrogen atoms (e.g., amines) present on the compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and / or hydrogen peroxide) to obtain other compounds of the invention. Therefore, all nitrogen atoms shown and claimed are considered to include both the nitrogen shown and its N-oxide (N→O) derivative.

[0075] According to the convention used in the art,

[00136] Used in structural formulae herein to depict a bond that serves as the point of attachment of a moiety or substituent to a core or backbone structure.

[0076] 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.

[0077] The compound of formula I can exist in free form (without ionization) or can form a salt, which is also within the scope of the present invention. Unless otherwise specified, reference to the compound of the present invention should be understood to include reference to the free form and its salt. The term "one or more salts" means acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, the term "one or more salts" can include zwitterions (inner salts), for example, when the compound of formula I contains a basic part (such as an amine or pyridine or imidazole ring) and an acidic part (such as a carboxylic acid). Pharmaceutically acceptable (i.e., non-toxic physiologically acceptable) salts are preferred, such as acceptable metal salts and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts can be used, for example, in separation or purification steps that can be used during preparation, and are therefore covered within the scope of the present invention. The salt of the compound of formula I can be, for example, by reacting the compound of formula I with a certain amount of acid or base (such as an equivalent) in a medium (such as a medium in which the salt is precipitated) or in an aqueous medium, followed by freeze-drying and forming.

[0078] Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acids (e.g., trifluoroacetic acid)), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), hydrobromide (formed with hydrogen bromide), hydroiodide, 2-hydroxyethanesulfonate,

[0013] The invention also includes but is not limited to bis(opyrates), lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates (such as tosylate), undecanoates, and the like.

[0079] Exemplary basic salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc and aluminum salts; salts with organic bases (e.g., organic amines) such as trialkylamines (such as triethylamine), procaine, dibenzylamine, N-benzyl-β-phenylethylamine, 1-diphenylhydroxymethylamine (ephenamine), N,N'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically acceptable amines; and salts with amino acids (such as arginine, lysine, etc.). Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (e.g., sulfates of dimethyl, diethyl, dibutyl and diamyl), long chain halides (e.g., chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl), aralkyl halides (e.g., bromides of benzyl and phenethyl), and other agents. Preferred salts include monohydrochlorides, bisulfates, methanesulfonates, phosphates or nitrates.

[0080] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0081] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and basic or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, 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, and 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, and isethionic acids, and the like.

[0082] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing basic or acidic moieties. Typically, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of an appropriate base or acid in water or in an organic solvent or in a mixture of the two; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts is found in Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is hereby incorporated by reference.

[0083] If applicable, all stereoisomers of the compounds of the present invention are considered, either in mixtures or in pure or substantially pure form. Stereoisomers can include compounds that are optical isomers by having one or more chiral atoms, as well as compounds that are optical isomers (atropisomers) by limited rotation around one or more bonds. The definition of the compounds according to the present invention encompasses all possible stereoisomers and mixtures thereof. It very specifically encompasses racemic forms and separated optical isomers with a specified activity. The racemic form can be split by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates of conventional methods, such as salt formation with optically active acids, followed by crystallization.

[0084] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0085] The compounds of formula I and their salts can exist in their tautomeric forms, wherein hydrogen atoms are transposed to other parts of the molecule, and thus the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all tautomeric forms, as long as they may exist, are included in the present invention. In addition, the compounds of the present invention can have trans and cis isomers.

[0086] It should also be understood that solvates (eg, hydrates) of the compounds of Formula I are also within the scope of the present invention. Solvation methods are generally known in the art.

[0087] utility

[0088] The compounds of the invention regulate IL-23-stimulated and IFNa-stimulated cell functions, including gene transcription. Other types of cell functions that can be regulated by the compounds of the invention include, but are not limited to, IL-12-stimulated responses.

[0089] Therefore, the compounds of Formula I are useful in treating disorders related to the regulation of the function of IL-23 or IFNa, and in particular, the selective inhibition of the function of IL-23, IL-12 and / or IFNa by acting on Tyk2 to mediate signal transduction. Such disorders include IL-23, IL-12 or IFNa related diseases, wherein the pathogenesis is mediated by these cytokines.

[0090] As used herein, the terms "treating" or "treatment" encompass treatment of a disease state in a mammal, particularly a human, and include: (a) preventing or delaying the onset of a disease state in a mammal, particularly when the mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state; (b) inhibiting the disease state, i.e., arresting its development; and / or (c) achieving a complete or partial reduction in the symptoms or disease state and / or alleviation, amelioration, alleviation or cure of the disease or disorder and / or its symptoms.

[0091] In view of their activity as modulators of IL-23, IL-12 and IFNa stimulated cellular responses, the compounds of Formula I can be used to treat IL-23, IL-12 or IFNa related 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; autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, psoriasis; autoinflammatory diseases including CAPS, TRAPS, FMF, adult-onset Still's disease, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis; Metabolic diseases, including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders, such as bone resorption diseases, osteoarthritis, osteoporosis, multiple myeloma-related bone disorders; proliferative disorders, such as acute myeloid leukemia, chronic myeloid leukemia; angiogenic disorders, such as angiogenic disorders including solid tumors, ocular neovascularization and infantile hemangioma; infectious diseases, such as sepsis, septic shock and shigellosis; neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury, tumors and viral diseases, such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma, as well as HIV infection and CMV retinitis, AIDS.

[0092] More specifically, specific conditions or diseases that may be treated with the compounds of the present invention include, but are not limited to, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, severe Myasthenia, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, inflammatory reactions caused by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases , allograft rejection, fever and myalgia due to infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, febrile illness, 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 traumatic injury; angiogenesis disorders, including solid tumors, ocular neovascularization, and infantile angiogenesis Tumor; viral diseases, including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignant tumors and herpes; stroke, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia [this should be hypoxia], angiogenesis, heart and kidney reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, disorders associated with prostaglandin endoperoxidase synthase-2, and pemphigus vulgaris. Preferred treatment methods are those in which the disorder is selected from Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris. Alternatively, preferred treatment methods are those in which the disorder is selected from ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury caused by stroke and myocardial ischemia-reperfusion injury caused by myocardial infarction. Another preferred method of treatment is one wherein the disorder is multiple myeloma.

[0093] When the terms "IL-23, IL-12 and / or IFNa-associated disorders" or "IL-23, IL-12 and / or IFNa-associated diseases or disorders" are used herein, each of the terms is intended to encompass all of the disorders identified above, as if repeated in detail, as well as any other disorder affected by IL-23, IL-12 and / or IFNa.

[0094] Therefore, the present invention provides a method for treating such disorders, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula I or a salt thereof. "Therapeutically effective amount" is intended to include an amount of a compound of the present invention that effectively inhibits IL-23, IL-12 and / or IFNa function and / or treats a disease when administered alone or in combination.

[0095] Methods for treating IL-23, IL-12 and / or IFNa-related disorders may include administering the compounds of Formula I alone or in combination with each other and / or in combination with other suitable therapeutic agents for treating such disorders. Therefore, "therapeutically effective amount" is also intended to include the amount of the claimed combination of compounds that effectively inhibits IL-23, IL-12 and / or IFNa function and / or treats diseases associated with IL-23, IL-12 and / or IFNa.

[0096] Examples of such other therapeutic agents include corticosteroids, rolipram, carvstatin, cytokine suppressive anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide and other immunosuppressants; nuclear translocation inhibitors such as deoxyspergualin (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, ); antimalarials such as hydroxychloroquine; cytotoxic drugs such as azathioprine and cyclophosphamide; TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptors, and rapamycins (sirolimus or ) or its derivatives.

[0097] When used in combination with the compounds of the present invention, the above other therapeutic agents can be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by those of ordinary skill in the art. In the methods of the present invention, such one or more other therapeutic agents can be administered before, simultaneously or after the compounds of the present invention are administered. The present invention also provides pharmaceutical compositions that can treat IL-23, IL-12 and / or IFNa-related disorders by inhibiting Tyk2-mediated signal transduction, the disorders including IL-23, IL-12 and / or IFNa-mediated diseases, as described above.

[0098] The compositions of the present invention may contain other therapeutic agents as described above, and may be formulated, for example, by using conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type suitable for the desired mode of administration (e.g., excipients, binders, preservatives, stabilizers, flavoring agents, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.

[0099] Therefore, the present invention further includes compositions comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier.

[0100] "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering a biologically active agent to an animal, particularly a mammal. Pharmaceutically acceptable carriers are formulated according to many factors well within the knowledge of those of ordinary skill in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated; the subject to be administered the composition containing the agent; 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 semisolid dosage forms. Such carriers may include many different ingredients and additives in addition to the active agent, and such additional ingredients are included in the formulation for a variety of reasons well known to those of ordinary skill in the art (e.g., stabilizing the active agent, adhesives, etc.). Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection are found in a variety of readily available sources (e.g., such as Remington's Pharmaceutical Sciences, 17th edition (1985)), which are incorporated herein by reference in their entirety.

[0101] The compound of formula I can be applied by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or the amount of drug to be delivered. Topical application is generally preferred for skin-related diseases, and systemic treatment is preferred for cancerous or precancerous conditions, but other modes of delivery are also considered. For example, the compound can be delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; local delivery, such as in the form of solutions, suspensions, gels or ointments; sublingual delivery; buccal delivery; parenteral delivery, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion technology (e.g., as a sterile injectable aqueous or non-aqueous solution or suspension); nasal delivery, such as by inhalation spray; local delivery, such as in the form of creams or ointments; rectal delivery, such as in the form of suppositories; or liposome delivery. A dosage unit formulation containing a nontoxic pharmaceutically acceptable vehicle or diluent can be applied. The compound can be applied in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved using suitable pharmaceutical compositions or, particularly in the case of extended release, using devices such as subcutaneous implants or osmotic pumps.

[0102] Exemplary compositions for topical administration include a topical carrier such as (Mineral oil gelled with polyethylene).

[0103] Exemplary compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for imparting volume, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavorings, such as those known in the art; and immediate release tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants, such as those known in the art. The compounds of the present invention may also be delivered orally by sublingual and / or buccal administration, for example, in molded, compressed or freeze-dried tablets. Exemplary compositions may include rapidly dissolving diluents, such as mannitol, lactose, sucrose and / or cyclodextrins. High molecular weight excipients, such as cellulose, may also be included in such formulations. or polyethylene glycol (PEG); excipients that aid mucoadhesion, such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC), and / or maleic anhydride copolymers (e.g., ); and controlled release agents, such as polyacrylic acid copolymers (e.g., CARBOPOL ). In order to facilitate manufacturing and use, lubricants, glidants, flavoring agents, colorants and stabilizers may also be added.

[0104] Exemplary compositions for nasal aerosol or inhalation administration include solutions that may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and / or bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0105] Exemplary compositions for parenteral administration include injectable solutions or suspensions that may contain, for example, suitable nontoxic parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution or other suitable dispersing or wetting agents and suspending agents, including synthetic mono- or diglycerides and fatty acids including oleic acid.

[0106] Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides or polyethylene glycols which are solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release the drug.

[0107] The therapeutically effective amount of the compound of the present invention can be determined by one of ordinary skill in the art, and includes exemplary dosages of about 0.05 to 1000 mg / kg, 1-1000 mg / kg, 1-50 mg / kg, 5-250 mg / kg, 250-1000 mg / kg body weight of active compound per day for mammals, which can be administered in a single dose or in the form of separate divided doses (such as 1 to 4 times per day). It should be understood that the specific dose level and dose frequency of any particular subject can vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, the species, age, weight, overall health, sex and diet of the subject, the mode and time of administration, excretion rate, drug combination, and the severity of the specific condition. Preferred subjects for treatment include animals, most preferably mammalian species, such as humans; and livestock, such as dogs, cats, horses, etc. Thus, when the term "patient" is used herein, the term is intended to include all subjects, most preferably mammalian species, that are affected by modulation of IL-23, IL-12 and / or IFNα-mediated functions.

[0108] Preparation method

[0109] The compounds of the present invention can be synthesized by a variety of 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 are not intended to limit the possible techniques that those skilled in the art may use to prepare compounds disclosed herein. The different methods for preparing the compounds of the present invention are clear to those skilled in the art. In addition, the various steps in the synthesis can be carried out in an alternating order to obtain the desired one or more compounds. Examples of the compounds of the present invention prepared by the methods described in the general scheme are given in the preparation and examples sections listed below.

[0110] Example

[0111] The preparation of compounds of formula (I) and intermediates for preparing compounds of formula (I) can be prepared using the procedures and related procedures shown in the following examples. The methods and conditions used in these examples, as well as the actual compounds prepared in these examples are not intended to be limiting, but are intended to show how compounds of formula (I) can be prepared. When not by the method procedures described herein, the starting materials and reagents used in these examples are generally commercially available, or reported in the chemical literature, or can be prepared by using the procedures described in the chemical literature.

[0112] In the examples given, the phrase "dried and concentrated" generally refers to drying a solution in an organic solvent over sodium sulfate or magnesium sulfate, followed by filtration and removal of the solvent from the filtrate (usually under reduced pressure and at a temperature suitable for the stability of the material being prepared). Column chromatography was performed using an Isco medium pressure chromatography apparatus (Teledyne Corporation) with a pre-packed silica gel column, eluting with the indicated solvent or solvent mixture. Chemical names were determined using ChemDraw Ultra, Version 9.0.5 (CambridgeSoft). The following abbreviations may be used:

[0113] abbreviation

[0114]

[0115]

[0116] The analytical purity of the compounds was determined by using the following method:

[0117] Analytical HPLC method A: SUNFIRE C18 [150x4.6 mm] column; 0.05% trifluoroacetic acid in water at 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);

[0118] Analytical HPLC method B: XBridge Phenyl C18 [150x4.6 mm] column; 0.05% trifluoroacetic acid in water at 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);

[0119] 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 to 1 min); 98% B (1 min to 1.5 min); 98%-2% B (1.5 min to 1.6 min). Gradient time (total) = 1.6 min. Analysis time = 2.2 min. Flow rate: 0.8 mL / min. Detector: UV and MS (ESI+) at 254 nM

[0120] Example 1

[0121]

[0122] Step 1:

[0123] 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 combined in a 500 mL flask with 260 mL acetonitrile (commercial grade anhydrous). The slurry was stirred at room temperature for 30 minutes, and then sodium iodide (11.63 g, 78 mmol) and di-tert-butyl (chloromethyl) phosphate (27.3 wt % in MeCN, density = 0.824 g / mL, 89 mL, 78 mmol) were added. The vessel was equipped with a water-cooled condenser and heated to 50° C. for 18 hours. The reaction was cooled to room temperature and filtered through celite, eluting with approximately 800 mL DCM:MeOH (1:1). The filtrate was concentrated and continued. Dialkylation (major): LC retention time 0.92 [C]. MS (E+) m / z: 870.7 (MH + ). Monoalkylation (regional isomer unknown): LC retention time 0.82 [C]. MS (E+) m / z: 648.5 (MH + ).

[0124] Step 2:

[0125] The crude product of step 1 is dissolved in acetic acid (28.8mL) and water (14mL), and the solution is homogeneous at first, but becomes slurry when product is formed. Once the desired material is converted, water (-200mL) is added. The slurry is subjected to ultrasound treatment and then stirred at room temperature. The vessel is briefly cooled in a refrigerator until the solution is below room temperature, at which time the precipitate is filtered out and rinsed with water (15mL). The filter cake is air-dried and then washed with ether (1L). The solid is collected, ultrasound treated in DCM (20mL), and then filtered to collect the resulting solid (4.6g). LC retention time 0.59[C]. MS (E+) m / z: 536.1 (MH + ).

[0126] Step 3:

[0127] The free acid (6.75 g, by HPLC, -90% pure) was suspended in MeCN (25 mL) and DDI water (90 mL). 1M NaOH (aqueous solution, 27.7 mL, 27.7 mmol) was added thereto over -1 min. The thick brown suspension became a fine milky suspension. After stirring for 5 minutes, the solution was filtered through two intermediate glass frits, providing a slightly turbid yellow solution. Water (200 mL) was added to produce an almost uniform solution. Acetone was added thereto until the total volume was about 3 L, at which time seed crystals were added and fine white crystals were immediately formed, which increased rapidly in amount. After 15 minutes, a fine suspension was predominant. After another 30 minutes, additional acetone (total volume = 4 L) was added and the suspension was stored at 8 ° C overnight. The solid was collected by filtration and rinsed with acetone. The solid was collected and then ground and sonicated in about 200 mL of acetone. The product was collected by filtration and dried under vacuum (<0.1 Torr) overnight to provide 4.75 g of small yellow crystals (72% yield, 8.12 mmol). 13 C 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 H NMR (500 MHz, deuterium oxide) δ8.43 (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)

[0128] LC retention time 0.59[C]. MS(E+)m / z:536.1(MH + ).

[0129] Example 2

[0130]

[0131] Step 1

[0132] To a suspension of 6-(cyclopropanecarboxamido)-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 batch 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 continued for another 24 hours. Water was added to the reaction mixture and the product was extracted with ethyl acetate (x2), the combined organic layers were washed with water and brine, and then dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was continued as recovered. LC retention time 0.77 [C]. MS (E+) m / z: 648.5 (MH + ).

[0133] Step 2

[0134] The crude mixture from step 1 is dissolved in acetone (4mL) and water (4mL), and solution is heated to 50 ℃, until the reaction is complete (1 hour).The reaction is concentrated under reduced pressure using rotary evaporator and room temperature heating bath.The crude product is diluted with water (total volume=60mL), and then washed with DCM (about 500mL x2).The water layer is directly loaded on reversed phase (gold) isco 50g cartridge, and water (DDI, no buffer) / MeCN (no buffer) gradient (0-40%MeCN:H o) is used to purify. 1H NMR (400 MHz, 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 by analogy with Example 1 and also by small molecule crystal structures of decomposition products resulting from long term exposure in sodium hydroxide:

[0135] Di-tert-butyl (chloromethyl) phosphate

[0136]

[0137] Prepare di-tert-butyl phosphate potassium salt (8.5g, 34.2mmol), sodium bicarbonate (11.50g, 137mmol) and tetrabutylammonium hydrogen sulfate (1.162g, 3.42mmol) solution in DCM (104mL) and water (124mL) and stir 15 minutes at 0 ℃.Add chloromethyl chlorosulfonate (6.93mL, 68.5mmol) thereto and make reaction mixture reach room temperature, stir overnight.Reaction mixture is diluted with DCM (100ml) and washed with water (4x 200mL) and then with salt water washing.Organic layer is dried over anhydrous sodium sulfate, filtered and concentrated (temperature maintenance is lower than 25 ℃) to obtain colorless liquid in a vacuum without heating.

[0138] 1 H NMR (500 MHz, CHLOROFORM-d) δ 5.58 (d, J = 14.8 Hz, 2H), 1.46 (d, J = 0.8 Hz, 18H).

[0139] Example 3

[0140]

[0141] Step 1

[0142] (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

[0143]

[0144] 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 room temperature for 30 min and then chloromethyl methyl sulfide (0.977 mL, 11.84 mmol) and sodium iodide (0.887 g, 5.92 mmol) were added. The mixture was stirred at 50 °C under nitrogen for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 50 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 (150 x 21.2 mm; 5 microns), mobile phase A: 10 mM ammonium acetate at 4.5 pH, 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 light yellow solid. 1 H NMR(400MHz, DMSO-d6)δ0.64-0.76(m,4H),1.45-1.56(m,1H),2.26(s,3H),2.82(d,J=4.02Hz,3H),3.74(s,3H),4.46(s,3H),5 .21(s,2H),7.36(br.s,1H),7.66(br.s,2H),8.00(br.s,1H),8.50(s,1H),8.55-8.69(br.s,1H); LC-MS(ES): m / z=483.2[M+H] +

[0145] Step 2

[0146] (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

[0147]

[0148] 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) at 0°C was added sulfuryl chloride (0.084 mL, 1.036 mmol). The mixture was stirred at 0°C for 30 min 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] +

[0149] Step 3

[0150] (E)-3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoic acid (2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-(methylcarbamoyl)pyridin-1(2H)-yl)methyl ester

[0151]

[0152] 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) at 0° C. was added 3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoic acid (0.169 g, 0.350 mmol). The mixture was stirred at room temperature 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 (250 x 19 mm; 5 microns), mobile phase A: 10 mM ammonium acetate in water at 4.5 pH, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 30, 15 / 80) gave the title compound (0.115 g, 0.119 mmol, 50.8% yield) as an off-white solid. 1H NMR(300MHz,DMSO-d6)δ0.55-0.69(m,4H),1.49(s,7H),2.01-2.08(s,3H),2.39(s,3H),2. 77(d,J=4.15Hz,3H),2.91(s,2H),3.72(s,3H),4.46(s,3H),5.11(d,J=8.31Hz,4H),5.88(b r.s,2H),6.64(s,1H),6.88(s,1H),7.23-7.40(m,10H),7.51-7.60(m,1H),7.66(br.s,1H), 7.90(br.s,1H),8.30(s,1H),8.49-8.58(m,1H),10.79(s,1H); LC-MS(ES):m / z=917.4[M+H] +

[0153] Step 4

[0154] (E)-3-(2,4-dimethyl-6-(phosphonooxy)phenyl)-3-methylbutanoic acid (2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-(methylcarbamoyl)pyridin-1(2H)-yl)methyl ester

[0155]

[0156] 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) at 0° C. was added TFA (0.756 mL, 9.82 mmol) and anisole (0.536 mL, 4.91 mmol). After stirring at 50° C. for 1 h, the solvent was removed under vacuum to give the crude product. After RP HPLC purification (preparative column: Sunfire C18 (150 x 19 mm; 5 microns), mobile phase A: 10 mM ammonium acetate in water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 10, 25 / 100), the title compound was obtained as an off-white solid (0.015 g, 0.020 mmol, 20.52% yield). 1H NMR(400MHz,DMSO-d6)δ0.73-0.97(m,4H),1.31-1.67(m,6H),1.83-1.95(m,3H),2.0 9-2.29(m,4H),2.73-3.00(m,3H),3.09-3.21(m,2H),3.72-3.83(m,3H),4.35-4.54( m,3H),5.79-5.96(m,2H),6.17-6.27(m,1H),6.97-7.06(m,1H),7.43-7.52(m,2H),7 .59-7.70(m,1H),7.81-7.92(m,1H),8.71-8.79(m,1H).LC-MS(ES):m / z=737.2[M+H] + ; HPLC retention time and purity: 6.410 min and 98.91% (method A) and 7.749 min and 98.89% (method B).

[0157] Example 4

[0158]

[0159] Step-1

[0160] €-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

[0161]

[0162] 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 methyl sulfide (0.970 mL, 11.75 mmol) and sodium iodide (0.881 g, 5.88 mmol). After stirring at 50 °C under nitrogen for 16 h, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude product. RP-HPLC purification of the crude product (preparative column: Sunfire C18 (150 x 4.6 mm; 5 microns), mobile phase A: 10 mM ammonium acetate, mobile phase B: acetonitrile, flow rate: 1.0 mL / min, gradient: 0 / 10, 20 / 100) gave the title compound (0.210 g, 0.424 mmol, 36.1% yield) as a light yellow solid. 1 H NMR (300MHz, DMSO-d6) δ0.58-0.79(m,4H),1.52-1.58(m,1H),2.07(s,3H),3.74(s,3H),4.46(s,3H),5.21(s,2H),7.35(t,J=7.80Hz,1H),7.6 0(br.S,1H),7.66(d,J=7.93Hz,1H),7.90-8.04(br.S,1H),8.49(s,1H),8.56-8.65(br.S,1H),10.71(br.S,1H); LC-MS(ES):m / z=486.2[M+H] +

[0163] Step 2

[0164] €-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

[0165]

[0166] To a solution of €-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) at 0°C was added sulfuryl chloride (0.083 mL, 1.030 mmol). The mixture was stirred at 0°C for 30 min. 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 as is in the next step. LC-MS (ES): m / z=474.2 [M+H] + Step 3

[0167] €-3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoic acid (2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-1(2H)-yl)methyl ester

[0168]

[0169] To a solution of €-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) at 0° C. was added 3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoic acid (0.144 g, 0.298 mmol). After stirring at room temperature for 3 h, the reaction mixture was concentrated in vacuo at 30° C. The residue was purified by RP-HPLC purification (preparative column: kinetex C18 (150x4.6 mm; 5 microns), 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. 1H NMR(300MHz,DMSO-d6)δ0.55-0.69(m,4H),1.49(s,7H),2.05(s,3H),2.39(s,3H),2.91 (s,2H),3.73(s,3H),4.46(s,3H),5.09(s,2H),5.12(s,2H),5.89(br.S,2H),6.64(s,1H ),6.87(s,1H),7.23-7.41(m,10H),7.57(d,J=6.00Hz,1H),7.68(d,J=7.20Hz,1H),7.91 (br.S,1H),8.30(s,1H),8.50(br.S,1H),10.79(br.S,1H); LC-MS(ES):m / z=920.4[M+H] +

[0170] Step 4

[0171] €-3-(2,4-dimethyl-6-(phosphonooxy)phenyl)-3-methylbutanoic acid (2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-1(2H)-yl)methyl ester

[0172]

[0173] To a solution of (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) at 0° C., TFA (0.377 mL, 4.89 mmol) and anisole (0.267 mL, 2.446 mmol) were added. The mixture was stirred at 50° C. for 1 h. The reaction mixture was concentrated under vacuum to give a crude product. RP-HPLC purification (preparative column: Sunfire C18 (150 x 19 mm; 5 microns), mobile phase A: 0.1% HCOOH in water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 30, 10 / 45) gave the title compound (0.014 g, 0.018 mmol, 37.5% yield) as an off-white solid. 1HNMR(400MHz,DMSO-d6)δ0.79-0.88(m,4H),1.50(s,6H),1.95(s,3H),2.12(br.S, 1H),2.32(s,3H),3.16(br.S,2H),3.78(s,3H),4.48(s,3H),5.90(s,2H),6.30(s,1 H),7.05(s,1H),7.48(d,J=8.03Hz,2H),7.66(d,J=8.03Hz,1H),7.86(d,J=6.53Hz ,1H),8.80(s,1H),10.10(br.S,1H),11.67(br.S,1H); LC-MS(ES):m / z=740.4[M+H] + ; HPLC retention time and purity: 6.386 min and 97.03% (method A) and 7.746 min and 97.45% (method B).

[0174] Example 5

[0175]

[0176] Step 1

[0177] Methyl 4-((Bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate

[0178]

[0179] To 4-hydroxy-3-methoxybenzoic acid methyl ester (3.000g, 16.47mmol) in the solution of dichloromethane (30mL), add N, N-diisopropyl dibenzyl phosphoramidate (8.30mL, 24.70mmol), then add 1H-tetrazole (73.0mL, 24.70mmol) (0.45M in acetonitrile), and the mixture is stirred to 8h at room temperature.Reaction is cooled at 0 ℃.Add H o (5.05mL, 165mmol).After stirring at room temperature for 2h, reaction mixture is concentrated to remove acetonitrile, and remaining water layer is diluted with water and extracted with ethyl acetate (3x 100mL).By the organic layer salt water washing merged, through anhydrous sodium sulfate drying, filter and concentrate.Crude material is passed through ISCO purification [silica gel 60-120 mesh, column size 80g, ethyl acetate in hexane as eluent]. The product eluted into 30% ethyl acetate in hexanes to give the title compound as a colorless oil (8.200 g, 15.94 mmol, 97% yield). 1H NMR (400MHz, CDCl3) δ3.84(s,3H),3.91(s,3H),5.16(s,2H),5.18(s,2H),7.25(d,J=8 .00Hz, 1H), 7.31-7.37 (m, 10H), 7.57 (d, J=9.20Hz, 2H).; LC-MS (ES): m / z=443.2[M+H] +

[0180] Step 2

[0181] 4-((Bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoic acid

[0182]

[0183] 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 for 1 h at 0°C, the mixture was extracted with ethyl acetate (2 x 100 mL). The aqueous layer was acidified with 1.5N HCl solution (pH about 1) and extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine solution, 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 (400MHz, DMSO-d6) δ3.80 (s, 3H), 5.17 (s, 2H), 5.20 (s, 2H), 6.85 (dd, J = 2.40, 6.40Hz, 1H), 7.40-7. 52(m,10H),7.53(dd,J=2.00,8.40Hz,1H),7.59(s,1H),12.60(br.s,1H).LC-MS(ES):m / z=429.0[M+H] +

[0184] Step 3

[0185] (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

[0186]

[0187] 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 room temperature 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 (150 x 19 mm; 5 microns), mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 10, 10 / 45) gave 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] +

[0188] Step 4

[0189] (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

[0190]

[0191] 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) at 0° C. was added TFA (0.623 mL, 8.08 mmol) followed by anisole (0.442 mL, 4.04 mmol). The mixture was stirred at 50° C. for 2 h and then concentrated under vacuum to give the crude product as a brown gum. RP-HPLC purification (preparative column: Sunfire C18 (150 x 19 mm; 5 microns), mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 10, 10 / 35) gave the title compound (0.026 g, 0.038 mmol, 46.4% yield) as an off-white solid. 1 H NMR(400MHz, DMSO-d6)δ0.66-0.81(m,4H),1.71(br.s,1H),3.74(s,3H),3.81(s,3H),4.46(s,3H),6.27(br.s,2H),7.38(t,J=7.60H z,1H),7.48-7.56(m,3H),7.61-7.68(m,1H),7.71-7.86(m,2H),8.74-8.93(m,2H),11.01-11.03(m,1H); LC-MS(ES):m / z=686.2[M+H] + ; HPLC retention time and purity: 10.082 min and 99.31% (method A) and 11.877 min and 98.83% (method B).

[0192] Example 6

[0193]

[0194] (E)-1-Hydroxycyclopropane-1-carboxylic acid (2-((cyclopropanecarbonyl)imino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-1(2H)-yl)methyl ester

[0195]

[0196] 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) at 0°C was added 1-hydroxycyclopropanecarboxylic acid (3.88 mg, 0.038 mmol). After stirring at room temperature for 3 h, the reaction mixture was concentrated in vacuo at 30°C to give the crude product. RP-HPLC purification (preparative column: Sunfire (150 x 4.6 mm; 5 microns), mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile, flow rate: 1.0 mL / min, gradient: 0 / 10, 20 / 100) gave the title compound (0.011 g, 0.019 mmol, 59.9% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ0.86-0.94(m,4H),1.04-1.09(m,2H),1.19-1.24(m ,2H),2.07(m,1H),3.74(s,3H),4.46(s,3H),6.19(br.s,2H),6.42(br.s,1 H),7.41-7.50(m,1H),7.64(s,1H),7.90(br.s,1H),9.01(br.s,1H),9.09( br.s,1H),10.94(br.s,1H),11.51(br.s,1H); LC-MS(ES):m / z=540.2[M+H] + ; HPLC retention time and purity: 10.047 min and 93.15% (method A) and 12.826 min and 91.08% (method B).

[0197] Example 7

[0198]

[0199] ((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) hydrogen phosphate

[0200]

[0201] 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 eq.) in DMF (0.5 mL) was added 2-(2-methoxyethoxy)ethanol (8.08 mg, 0.067 mmol, 1.200 eq.), EDC (10.74 mg, 0.056 mmol). The mixture was stirred at room temperature for 16 h. The crude product was purified using RP HPLC (preparative column: Sunfire C18 (19 x 250 mm; 5 microns), mobile phase A: 10 mM ammonium acetate in water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 20, 10 / 35). The fractions were concentrated using 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 h to give the title compound (15.6 mg, 0.024 mmol, 43.4% yield) as a light yellow solid. 1 H NMR(400MHz,D2O)δ8.43(s,1H),7.83(br.s,1H),7.68(d,J=8.03Hz,1H),7.49(dd,J=8.03,1.51Hz,1H),7.34(t,J=7.78Hz,1H),6.03(d,J=12.0 5Hz,2H),3.92-3.98(m,5H),3.55-3.63(m,7H),3.48-3.52(m,2H),3.29 (s,3H),1.91(br.s,1H),0.98-1.02(m,4H).LC-MS(ES):m / z=638.2[M+H] + ; HPLC retention time and purity: 5.74 min and 99.51% (method A) and 5.90 min and 99.44% (method B).

[0202] Example 8

[0203]

[0204] (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

[0205]

[0206] 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 iodomethyl pivalate (81 mg, 0.336 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was directly purified using RP HPLC (preparative column: Kinetex (21.2 x 150 mm; 5 microns), mobile phase A: 0.1% formic acid, mobile phase B: acetonitrile, flow rate: 20 mL / min). The fractions were concentrated using 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 light yellow solid. 1 HNMR(400MHz,D2O)δ8.38(s,1H),7.77(s,1H),7.70(d,J=7.72Hz,1H),7.45(dd,J=7.97,1.51Hz,1H),7.33-7.38(m,1H),6.05(d,J=13.1 1Hz,2H),5.41(d,J=13.55Hz,2H),3.97(s,3H),3.51(s,3H),1.82(bs,1H),1.07(s,9H),0.93-1.01(m,4H).LC-MS(ES):m / z=650.2[M+H] + ; HPLC retention time and purity: 7.045 min and 95.58% (method A) and 6.85 min and 95.71% (method B).

[0207] Example 9

[0208]

[0209] Step 14, 6-dichloro-N-(methyl-d3)-N-((methylthio)methyl)nicotinamide

[0210]

[0211] 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 methyl sulfide (230 mg, 2.379 mmol) was added and the reaction mixture was allowed to reach room temperature and stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with H2O (1 x 10 mL) and saturated NaCl (1 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. 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 in petroleum ether. The desired fractions were evaporated under reduced pressure to afford the title compound (350 mg, 1.109 mmol, 46.2% yield) as a brown oil. 1 H NMR (300MHz, DMSO-d6) δ2.17 (s, 3H), 4.37 (s, 1H), 4.68 (br.s 1H), 7.96 (d, J = 10.80Hz, 1H), 8.48 (d, J = 6.90Hz, 1H). LC-MS (ES): m / z = 268.0 [M+H] +

[0212] Step 26-Chloro-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)-N-((methylthio)methyl)nicotinamide

[0213]

[0214] 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 (3.17 mL, 3.17 mmol) in THF 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 (2 x 50 mL). The organic layer was washed with H2O (1 x 30 mL) and saturated NaCl solution (1 x 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (550 mg, 1.032 mmol, 81% yield) as a brown semi-solid. LC-MS (ES): m / z = 437.2 [M+H]+

[0215] Step 3 6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)-N-((methylthio)methyl)nicotinamide

[0216]

[0217] 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) in a sealed tube was purged with nitrogen and then sealed. The mixture was stirred at 110 °C overnight. The reaction mixture was allowed to cool 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 provide a 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 in chloroform. The desired fractions were evaporated under reduced pressure to afford the title compound (500 mg, 0.875 mmol, 69.5% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ0.63-0.77(m,4H),1.97-1.99(m,1H),2.07(br.s,3H),3.70(s,3H),4.45(s,3H),4.67(s,2H),7.32( t,J=7.78Hz,1H),7.60-7.63(m,2H),8.00(s,1H),8.16(s,1H),8.48-8.51(m,1H),10.76(s,1H); LC-MS(ES):m / z=486.2[M+H] +

[0218] Step 4

[0219] (6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)nicotinamido)methyl dihydrogen phosphate

[0220]

[0221] To 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)-N-((methylthio)methyl)

[0222] Nicotinamide (100 mg, 0.206 mmol) was added to a stirred solution of powdered molecular sieves (15 mg) and NIS (93 mg, 0.412 mmol) in anhydrous THF (5 mL). The reaction mixture was stirred at room temperature for 5 min and phosphoric acid (605 mg, 6.18 mmol) was added in one go. The reaction mixture was stirred for 5 min and cooled to 0 ° C. MeOH (1 mL) was added and then the pH was adjusted to about 8 by adding saturated Na2CO3 solution. The reaction mixture was filtered through a diatomaceous earth bed and the bed was washed with THF (20 mL). The filtrate was concentrated under high vacuum at 30 ° C to obtain a semi-solid crude product. The crude compound was purified in reverse phase preparative HPLC (preparative column: INERTSIL ODS (250 x 19 mm; 3.5 microns), mobile phase A: water, mobile phase B: acetonitrile, flow rate: 17 mL / min, gradient: 0 / 0, 12 / 20). 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 the solution was lyophilized for 24 h to afford the title compound as an off-white solid (40 mg, 0.068 mmol, 33.1% yield). 1 H NMR(400MHz,D2O)δ0.89-0.98(m,4H),1.83(m,1H),3.63-3.67(m,3H),4.45-4.49(m,3H),5.04-5.13(m,2H ),7.36-7.46(m,1H),7.54-7.63(m,2H),7.71-7.81(m,1H),8.24-8.31(m,1H).LC-MS(ES):m / z=536.2[M+H] + ; HPLC retention time and purity: 5.918 min and 99.73% (method A) and 5.748 min and 99.68% (method B).

[0223] Example 10

[0224]

[0225] Step 1

[0226] N-(tert-Butoxycarbonyl)-N-methylglycine (2-(methylamino)pyridin-3-yl)methyl ester

[0227]

[0228] 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)

[0229] The mixture was stirred at room temperature for 16 h and then 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 reduced pressure. The residue was purified using CombiFlash (12 g silica gel column; 40% ethyl acetate in petroleum ether) to provide the title compound (210 mg, 0.563 mmol, 78% yield) in a brown semi-solid. 1 H NMR (400MHz, DMSO-d6) δ1.16-1.40(m,9H),2.82-2.87(m,6H),4.00(m,2H),4.99(d,J=14.56Hz,2H),6.18(br.s,1 H),6.51(dd,J=7.03,5.02Hz,1H),7.37-7.43(m,1H),8.03(dd,J=5.02,1.51Hz,1H); LC-MS(ES):m / z=310.2[M+H] +

[0230] Step 2

[0231] N-(tert-Butyloxycarbonyl)-N-methylglycine (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl ester

[0232]

[0233] 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 reduced pressure. The residue was purified using CombiFlash (12 g silica gel column; 30% ethyl acetate in petroleum ether) to provide the title compound (200 mg, 0.428 mmol, 60.2% yield) as a yellow semisolid. LC-MS (ES): m / z=402.2 [M+H] +

[0234] Step 3

[0235] (E)-Methylglycine (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 ester trifluoroacetic acid acetate

[0236]

[0237] 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 KCO (147 mg, 1.065 mmol), (2-(((chloromethoxy)carbonyl)(methyl)amino)acetic acid (428 mg, 1.065 mmol) and then sodium iodide (186 mg, 1.243 mmol). The reaction mixture was heated to 80 °C and stirred under nitrogen for 30 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with H0 and saturated NaCl, dried over anhydrous NaSO, filtered and concentrated under reduced pressure to provide the crude compound as a mixture of mono- and di-alkylated products as a brown semi-solid. 4M HCl (5mL, 20.00mmol) in dioxane was added to this crude mixture (400mg, 0.170mmol) in anhydrous DCM (5mL) at 0°C. After stirring for 15min, the reaction mixture was concentrated to dryness. The crude compound was purified by reverse phase preparative HPLC (preparative column: Symmetry C8 (300x 19mm; 7 microns), mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, flow rate: 18mL / min, gradient: 0 / 10, 5 / 20). The preparative 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 provide the title compound (20mg, 0.024mmol, 13.94% yield) as an off-white solid. 1 H NMR(400MHz,MeOH-d4)δ0.95-1.02(m,4H)1.92-2.02(m,1H)2.77(s,3H)2. 99(s,3H)3.37-3.45(m,3H)3.84(s,3H)4.04-4.11(m,2H)4.49(s,3H)5.14- 5.34(m,2H)6.09-6.38(m,2H)7.42-7.56(m,2H)7.65-7.80(m,2H)7.99-8. 09(m,2H)8.45-8.57(m,1H)8.70-8.94(m,1H).LC-MS(ES):m / z=688.2[M+H] + ; HPLC retention time and purity: 8.827 min and 99.49% (method A) and 11.610 min and 95.18% (method B).

[0238] Embodiment 11

[0239]

[0240] Step 14: Methyl 4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoate

[0241]

[0242] 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 dibenzyl diisopropyl phosphoramidate (4.16 g, 12.04 mmol) at room temperature.

[0243] After stirring for 16h, the reaction mixture was cooled to 0°C, and H2O2 (2.108mL, 24.07mmol) was added dropwise. After stirring for 20min at 0°C, the mixture was quenched with a 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 under reduced pressure. The residue was purified using CombiFlash (40g silica gel column; 25% ethyl acetate in petroleum ether as eluent). The desired fraction was evaporated under reduced pressure to provide the title compound (3.0g, 5.63mmol, 46.8% yield) in a brown semi-solid. 1 H NMR (300MHz, CDCl3) δ3.92 (s, 3H), 4.99-5.08 (m, 6H), 7.29-7.38 (m, 10H), 7.42 (dd, J = 5.70, 7.50Hz, 2H), 7.45-8.05 (m, 2H).

[0244] Step 2 4-(((Bis(benzyloxy)phosphoryl)oxy)methyl)benzoic acid

[0245]

[0246] 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, a solution of LiOH (0.112 g, 4.69 mmol) in water (10 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was cooled to 0°C and treated with 1.5N 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 under reduced pressure to provide the title compound (600 mg, 0.757 mmol, 32.3% yield) as a brown solid. The crude product was used as is. 1H NMR (400MHz, 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).

[0247] Step 3

[0248] (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

[0249]

[0250] 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).

[0251] The reaction mixture is stirred at 0 ° C for 2h. Then the mixture is diluted with water (5mL) and extracted with ethyl acetate (2x25mL). The organic layer is washed with H2O (1x 10mL) and saturated NaCl (1x 10mL). The organic layer is dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound is purified in reverse phase preparative HPLC (preparative column: SUNFIRE C18 (150x 19mm; 5 microns), mobile phase A: 10mM ammonium acetate in water, mobile phase B: acetonitrile, flow rate: 18mL / min, gradient: 0 / 30, 10 / 70). The preparation fraction containing the desired product is concentrated at 30 ° C under high vacuum. The residue is dissolved in a mixture of acetonitrile and water and lyophilized for 24h to provide the title compound (20mg, 0.023mmol, 21.80% yield) in an off-white solid. 1H NMR(400MHz,MeOH-d4)δ0.69-714(m,2H),0.91-093(m,2H),1.61-1.7(m,1H),2 .94(s,3H),3.82(s,3H),4.45(s,3H),5.02(s,2H),5.05(s,2H),5.07(s,2H),6 .32(s,2H),7.31-7.40(m,11H),7.40(d,J=9.04Hz,3H),7.70(d,J=7.53Hz,1H) ,7.79(s,2H),7.99(d,J=8.03Hz,2H),8.52(s,1H); LC-MS(ES):m / z=847.2[M+H] +

[0252] Step 4

[0253] (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

[0254]

[0255] 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 pL, 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 in reverse phase preparative HPLC (preparative column: Xbridgephenyl (250 x 19 mm; 5 microns), mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 20, 6 / 30). 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, which was lyophilized for 24 h to provide the title compound (10 mg, 0.015 mmol, 62.2% yield) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ0.55-0.74(m,4H),1.45-1.51m,1H),2.82(d,J=4.52Hz,3H),3 .75(br.s,3H),4.46(s,3H),4.96(d,J=7.53Hz,2H),6.26(br.s,2H),7.37(br.s,1H),7 .54(d,J=8.53Hz,2H),7.64(br.s,1H),7.70(br.s,1H),7.92(br.s,1H),7.97(d,J=8. 03Hz,2H),8.65(s,1H),8.73(br.s,1H),10.77(br.s,1H); LC-MS(ES):m / z=667.2[M+H] + ; HPLC retention time and purity: 4.675 min and 98.23% (method A) and 6.088 min and 98.58% (method B).

[0256] Example 12

[0257] Step 1

[0258] 3-((Bis(benzyloxy)phosphoryl)oxy)-4-methoxybenzoic acid

[0259]

[0260] 1H-TETRAZOLE (91mg, 2.68mmol) is added to the stirring solution of 3-hydroxy-4-methoxybenzoic acid (300mg, 1.784mmol) in anhydrous acetonitrile (10mL) at 0°C, then dibenzyl diisopropyl phosphoramidate (678mg, 1.963mmol) is added dropwise. After interpolation, the reaction mixture is made to reach room temperature and stir for 16h. The mixture is cooled to 0°C, and H is added dropwise o (0.312mL, 3.57mmol). After stirring for 20min, the reaction mixture is extracted with ethyl acetate (2x 25mL). By organic layer H o ​​(1x 10mL) and saturated NaCl (1x 10mL) washing, through anhydrous Na sO dry, filter and concentrate under reduced pressure. Crude compound is purified in reverse phase preparation HPLC. (Preparative column: SUNFIRE C18 (150 x 19 mm; 5 microns), mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 10, 10 / 55). The preparative fractions containing the desired product were concentrated under high vacuum at 30 °C to afford the title compound (350 mg, 0.809 mmol, 45.3% yield) as a light yellow oil.1 H NMR(300MHz,DMSO-d6)δ3.85(s,3H),5.16(s,2H),5.19(s,2H),7.22(d,J=8.31Hz,1H),7 .75-7.77(m,10H),7.80(d,J=8.69Hz,2H),12.88(br.s,1H); LC-MS(ES):m / z=429.0[M+H] +

[0261] Step 2

[0262] (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

[0263]

[0264] 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 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with H2O (1 x 10 mL) and saturated NaCl (1 x 10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (80 mg, 0.046 mmol, 72.8% yield) as a brown semisolid. The crude product was used as is in the next reaction. LC-MS (ES): m / z=863.5 [M+H] +

[0265] Step 3

[0266] (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

[0267]

[0268] 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) and then 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 in reverse phase preparative HPLC. (Preparative column: Kinetex C18 (150 x 19 mm; 5 microns), mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 10, 10 / 35). The preparative 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 h to afford the title compound (10 mg, 0.014 mmol, 31.0% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ0.80-0.82(m,4H),1.99-2.00(m,1H),2.83(d,J=4.52Hz,3H),3.75(s,3H),3.86(s,3H),4.46(s,3H),6.38(br.s,2 H),7.03-7.45(m,4H),7.66-7.73(m,2H),7.84(br.s,1H),8.03(s.,1H),9.03-9.24(m,1H),11.35(br.s,1H); LC-MS(ES): m / z=683.2[M+H] + ; HPLC retention time and purity: 10.551 min and 98.75% (method A) and 12.137 min and 98.30% (method B).

[0269] Example 13

[0270]

[0271] Step 1

[0272] (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

[0273]

[0274] 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 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with H2O (1 x 10 mL) and saturated NaCl (1 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified in reverse phase preparative HPLC (preparative column: X-bridge phenyl (250 x 19 mm; 5 microns), mobile phase A: 10 mM ammonium acetate in water, mobile phase B: acetonitrile, flow rate: 18 mL / min, gradient: 0 / 30, 10 / 67). 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 the solution was lyophilized for 24 h to provide 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] +

[0275] Step 2

[0276] (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

[0277]

[0278] 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) and then 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 in reverse phase preparative HPLC using formic acid as a buffer. 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 the solution was lyophilized for 24 h to afford the title compound (10 mg, 0.015 mmol, 41.5% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ0.62-0.82(m,4H),1.65-1.75(m,1H),3.75(s,3H),4.46(s,3H),4.98(d,J=7.53Hz,2H),6.33(br.s,2H),7.28(s,1H),7.41 (d,J=8.03Hz,1H),7.55(d,J=8.03Hz,2H),7.77(br.s,2H),7.99(d,J=8.03Hz,2H),8.85(br.s,2H),11.05(br.s,1H); LC-MS(ES): m / z=670.2[M+H] + ; HPLC retention time and purity: 11.080 min and 98.35% (method A) and 11.919 min and 98.66% (method B).

[0279] Embodiment 14

[0280] Table 1

[0281]

[0282] As shown in Table 1 above, the compound of Example 1 was orally administered to rats to determine if there was any circulating prodrug after administration. It was found that at therapeutic doses (5 and 25 mpk), no exposure of the prodrug was seen. It was also shown that less than 0.05% of the prodrug was observed at the 150 mpk dose. Therefore, this shows that the prodrug is converted to the parent drug in vivo.

Claims

1. A compound having the formula:

2. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

3. Use of the compound according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating a disease associated with the regulation of IL-12, IL-23 and / or IFNα, wherein the disease is an inflammatory disease or an autoimmune disease.

4. The use according to claim 3, wherein the inflammatory disease or autoimmune disease is multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Sjogren's syndrome or scleroderma.

5. The use according to claim 3, wherein the inflammatory disease or autoimmune disease is Crohn's disease.

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