Process of making TYK2 inhibitors and uses thereof

Abstract

The disclosure provides a process for the preparation of compounds, for example, a compound of Formula I, contemplated to have activity against, e.g., tyrosine kinase 2 (TYK2).

Description

Attorney Docket No.: ESK-028WOPROCESS OF MAKING TYK2 INHIBITORS AND USES THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Application No. 63 / 733,074 filed on December 12, 2024; the content of which is hereby incorporated by reference herein in its entirety.BACKGROUND

[0002] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases. The mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are integral to cytokine signaling. TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g., IFN-a, IFN-P, IFN-K, IFN-6, IFN-s, IFN-T, IFN-CD, and IFN- (also known as limitin), and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, L-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). The activated TYK2 then goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0003] TYK2 activation by IL-23, has been linked to inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. A genome- wide association study of 2,622 individuals with psoriasis identified associations between disease susceptibility and TYK2. Knockout or tyrphostin inhibition of TYK2 significantly reduces both IL-23 and IL-22-induced dermatitis. TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucous hypersecretion is mediated by IL-13-induced activation of TYK2, which in turn activates STAT6. Decreased TYK2 activity leads to protection of joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. Mechanistically, decreased Tyk2 activity reduced the production of Thl / Thl 7-related cytokines and matrix metalloproteases, and other key markers of inflammation.Attorney Docket No.: ESK-028WO

[0004] TYK2 knockout mice showed complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)), with no infdtration of CD4 T cells in the spinal cord, as compared to controls, suggesting that TYK2 is essential to pathogenic CD4-mediated disease development in MS. This corroborates earlier studies linking increased TYK2 expression with MS susceptibility. Loss of function mutation in TYK2, leads to decreased demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders.

[0005] TYK2 is the sole signaling messenger common to both IL-12 and IL-23. TYK2 knockout reduced methylated B SA injection-induced footpad thickness, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice. Joint linkage and association studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder), showed a strong, and significant correlation between loss of function mutations to TYK2 and decreased prevalence of SLE in families with affected members. Genome-wide association studies of individuals with SLE versus an unaffected cohort showed highly significant correlation between the TYK2 locus and SLE. TYK2 has been shown to play an important role in maintaining tumor surveillance and TYK2 knockout mice showed compromised cytotoxic T cell response, and accelerated tumor development. However, these effects were linked to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be highly suitable for the treatment of autoimmune disorders or transplant rejection. Although other JAK family members such as JAK3 have similar roles in the immune system, TYK2 has been suggested as a superior target because of its involvement in fewer and more closely related signaling pathways, leading to fewer off-target effects.

[0006] Studies in T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL is highly dependent on IL-10 via TYK2 via STATl-mediated signal transduction to maintain cancer cell survival through upregulation of anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell growth. Specific activating mutations to TYK2 that promote cancer cell survival include those to the FERM domain (G36D, S47N, and R425H), the JH2 domain (V73 II), and the kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is required for increased cancer cell survival, as TYK2 enzymes featuring kinase-dead mutations (M978Y or M978F) in addition to an activatingAttorney Docket No.: ESK-028WO mutation (E957D) resulted in failure to transform. Thus, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL- 10 and / or BCL2-addicted tumors, such as 70% of adult T-cell leukemia cases. TYK2 mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-P (A ) peptide. Decreased TYK2 phosphorylation of STAT3 following A0 administration lead to decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's patients. Inhibition of JAK-STAT signaling pathways is also implicated in hair growth, and the reversal of the hair loss associated with alopecia areata.

[0007] Accordingly, effective processes for making compounds capable of inhibiting TYK2 are needed to address the treatment of TYK2-mediated disorders, without the side-effects associated with the inhibition of JAK2.SUMMARY

[0008] The present disclosure is directed, at least in part, to processes for the preparation of compounds which may be inhibitors of TYK.2. For example, disclosed herein is a process for preparing a compound of Formula (I):

[0009] Also disclosed herein, for example is a process for preparing a compound of Formula (Ila):

[0010] In addition, disclosed herein, for example, is a process for preparing a compound of Formula (III):Attorney Docket No.: ESK-028WODETAILED DESCRIPTION

[0011] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise. As used herein, the words “a” and “an” are meant to include one or more unless otherwise specified. For example, the term “an agent” encompasses both a single agent and a combination of two or more agents. Where the use of the term “about” or “approximately” is before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” or “approximately” refers to a ± 10% variation from the nominal value unless otherwise indicated or inferred.Processes

[0012] The present disclosure is directed, at least in part, to processes for the preparation of compounds which may be inhibitors of TYK2. For example, disclosed herein is a process for preparing a compound of Formula (I):wherein the process comprises the following steps:(1) activating a compound of the following formula: o xHOAAN x, wherein each X is independently halogen,Attorney Docket No.: ESK-028WO in the presence of an activating agent to provide a compound of the following formula: o x; wherein L is a leaving group;(2) condensing the compound provided in step (1) with diethyl 2-(methyl-<73)malonate, to provide a compound of the following formula:or an enol tautomer thereof;(3) decarboxylating the compound provided in step (2), to provide a compound of the following formula:(4) cross-coupling the compound provided in step (3) with cyclopropanecarboxamide, to provide a compound of Formula (II):(5) coupling the compound of Formula (II) with a compound of Formula (III):to provide the compound of Formula (I).Attorney Docket No.: ESK-028WO

[0013] In some embodiments, for example, X is independently, e.g., chloro or bromo. In other embodiments, each X is, e.g., chloro. In additional embodiments, the activating agent is, for example, carbonyldiimidazole. In further embodiments, L is, for example, imidazolyl.

[0014] In some embodiments, a process for preparing the compound of Formula (I) contemplated herein comprises the steps of:(1) activating a compound of the following formula:in the presence of carbonyldiimidazole, to provide a compound of the following formula:(2) condensing the compound provided in step (1) with diethyl 2-(methyl- 3)malonate, to provide a compound of the following formula:or an enol tautomer thereof;(3) decarboxylating the compound provided in step (2), to provide a compound of the following formula:(4) cross-coupling the compound provided in step (3) with cyclopropanecarboxamide, to provide a compound of Formula (Ila):Attorney Docket No.: ESK-028WO(5) coupling the compound of Formula (Tla) with a compound of Formula (ITT):to provide the compound of Formula (I).

[0015] For example, disclosed herein is a process for preparing a compound of Formula(I): wherein the process comprises the following steps:(1) activating a compound of the following formula:in the presence of carbonyldiimidazole, to provide a compound of the following formula:(2) condensing the compound provided in step (1) with diethyl 2-(methyl-t / 3)malonate, to provide a compound of the following formula:or an enol tautomer thereof;(3) decarboxylating the compound provided in step (2), to provide a compound of the following formula:Attorney Docket No.: ESK-028WO(4) cross-coupling the compound provided in step (3) with cyclopropanecarboxamide, to provide a compound of Formula (Ila):(5) coupling the compound of Formula (Ila) with a compound of Formula (III):to provide the compound of Formula (I).

[0016] In some embodiments, activating occurs, for example, at about 25 °C to about 35 °C. In other embodiments, condensing occurs in in the presence of a Lewis acid and an amine base. For example, in certain embodiments condensing occurs in the presence of MgCh and N,N-diisopropylethylamine. In further embodiments, condensing occurs, for example, at about 75 °C to about 85 °C.

[0017] In some embodiments, decarboxylating occurs in the presence of a polar aprotic solvent. For example, in some embodiments decarboxylating occurs in the presence of a polar aprotic solvent and water. In certain embodiments, for example, decarboxylating occurs in the presence of, e.g., N-methylpyrrolidine and water. In other embodiments, decarboxylating occurs, for example, at about 110 °C to about 120 °C. In still other embodiments, decarboxylating optionally occurs in the presence of a Lewis acid. In additional embodiments, decarboxylating optionally occurs in the presence of, for example, MgCh.

[0018] In other embodiments, cross-coupling occurs in the presence of a palladium catalyst. For example, in some embodiments cross-coupling occurs in the presence of a palladium catalyst, a base, and a phosphine ligand. In certain embodiments, cross-coupling occurs in the presence of, for example, Pd(OAc)2, K2CO3, and DIPPF. In further embodiments, cross-coupling occurs, or example, at about 75 °C to about 85 °C.Attorney Docket No.: ESK-028WO

[0019] Tn still other embodiments, coupling occurs in the presence of a catalytic amount of HC1. In further embodiments, coupling occurs, for example, at about 75 °C to about 85 °C.

[0020] In additional embodiments, a process disclosed herein further comprises purifying the compound of Formula (I) by recrystallizing the compound. For example, a process disclosed herein further comprises purifying the compound of Formula (I) by recrystallizing the compound in aqueous 1 -propanol or 2-propanol in the presence of a catalytic amount of HC1. In some embodiments, the compound of Formula (1) is provided, for example, in greater than 97% purity as determined by HPLC. In other embodiments, the compound of Formula (I) is provided, for example, in greater than 98% purity as determined by HPLC. In other embodiments, the compound of Formula (I) is provided, for example, in greater than 99% purity as determined by HPLC.

[0021] Also disclosed herein is a process for preparing a compound of Formula (I):wherein the process comprises the following steps:(1) cross-coupling a compound of the following formula:, wherein Y is halogen, with a bis-boronic ester to provide a compound of the following formula:Attorney Docket No.: ESK-028WO wherein R1and R2are each independently Ci-Cgalkyl, or R1and R2, together with the atoms to which they are attached, may be joined together to form a 5-6 membered ring;(2) cross-coupling the compound provided in step (1) with a compound of the following formula:to provide a compound of Formula (III):(3) coupling the compound of Formula (III) with a compound of Formula (II):wherein X is halogen; to provide the compound of Formula (I).

[0022] In some embodiments, X and Y are each independently, for example, chloro or bromo. In other embodiments, X is chloro and is Y bromo. In additional embodiments, the bis- boronic ester is, for example, bis(pinacolato)diboron. For example, in certain embodiments wherein the compound provided in step

[0023] In some embodiments, for example, a process for preparing the compound of Formula (I) contemplated herein comprises the steps of:(1) cross-coupling a compound of the following formula:Attorney Docket No.: ESK-028WO with bis(pinacolato)diboron to provide a compound of the following formula:(2) cross-coupling the compound provided in step (1) with a compound of the following formula:to provide a compound of Formula (III):(3) coupling the compound of Formula (III) with a compound of Formula (Ila):to provide the compound of Formula (I).

[0024] For example, disclosed herein is a process for preparing a compound of Formula(I):wherein the process comprises the following steps:Attorney Docket No.: ESK-028WO(1) cross-coupling a compound of the following formula:with bis(pinacolato)diboron to provide a compound of the following formula:(2) cross-coupling the compound provided in step (1) with a compound of the following formula:to provide a compound of Formula (III):(3) coupling the compound of Formula (III) with a compound of Formula (Ila):to provide the compound of Formula (I).

[0025] In some embodiments, the cross-coupling of step (1) occurs in the presence of a palladium catalyst. In other embodiments, the cross-coupling of step (1) occurs in the presence of a palladium catalyst, a base, and a phosphine ligand. For example, in certain embodiments the cross-coupling of step (1) occurs in the presence of Pd2(dba)s, KO Ac, and di(adamantan-l- yl)(butyl)phosphane. In further embodiments, the cross-coupling of step (1) occurs, for example, at about 90 °C to about 100 °C.Attorney Docket No.: ESK-028WO

[0026] In other embodiments, the cross-coupling of step (2) occurs in the presence of a palladium catalyst. In some embodiments, the cross-coupling of step (2) occurs in the presence of a palladium catalyst, a base, and a phosphine ligand. For example, in certain embodiments the cross-coupling of step (2) occurs in the presence of Pd2(dba)3, aqueous K3PO4, and di(adamantan-l-yl)(butyl)phosphane. In further embodiments, the cross-coupling of step (2) occurs at about 90 °C to about 100 °C.

[0027] In still other embodiments, coupling occurs in the presence of a catalytic amount of HC1. In further embodiments, coupling occurs, for example, at about 75 °C to about 85 °C.

[0028] In additional embodiments, a process disclosed herein further comprises purifying the compound of Formula (I) by recrystallizing the compound. For example, a process disclosed herein further comprises purifying the compound of Formula (I) by recrystallizing the compound in aqueous 1 -propanol or 2-propanol in the presence of a catalytic amount of HC1. In some embodiments, the compound of Formula (I) is provided, for example, in greater than 97% purity as determined by HPLC. In other embodiments, the compound of Formula (I) is provided, for example, in greater than 98% purity as determined by HPLC. In other embodiments, the compound of Formula (1) is provided, for example, in greater than 99% purity as determined by HPLC.

[0029] Further disclosed herein, for example, is a process for preparing a compound of Formula (Ila):wherein the process comprises the following steps:(1) activating a compound of the following formula:, wherein X is halogen, in the presence of an activating agent to provide a compound of the following formula:Attorney Docket No.: ESK-028WOO Cl, wherein L is a leaving group;(2) condensing the compound provided in step (1) with diethyl 2-(methyl-t73)mal onate, to provide a compound of the following formula:or an enol tautomer thereof;(3) decarboxylating the compound provided in step (2), to provide a compound of the following formula:(4) cross-coupling the compound provided in step (3) with cyclopropanecarboxamide, to provide the compound of Formula (Ila).

[0030] In some embodiments, X is, for example, chloro or bromo. In other embodiments, X is chloro. In further embodiments, the activating agent is, for example, carbonyldiimidazole. In additional embodiments, L is, for example, imidazolyl.

[0031] In some embodiments, for example, a process for preparing the compound of Formula (Ila) contemplated herein comprises the steps of:(1) activating a compound of the following formula:in the presence of carbonyldiimidazole, to provide a compound of the following formula:Attorney Docket No.: ESK-028WO(2) condensing the compound provided in step (1) with diethyl 2-(methyl-<73)malonate, to provide a compound of the following formula:or an enol tautomer thereof;(3) decarboxylating the compound provided in step (2), to provide a compound of the following formula:(4) cross-coupling the compound provided in step (3) with cyclopropanecarboxamide, to provide the compound of Formula (Ila).

[0032] For example, disclosed herein is a process for preparing a compound of Formula (Ila):wherein the process comprises the following steps:(1) activating a compound of the following formula:in the presence of carbonyldiimidazole, to provide a compound of the following formula:(2) condensing the compound provided in step (1) with diethyl 2-(methyl-t / 3)malonate, to provide a compound of the following formula:Attorney Docket No.: ESK-028WOor an enol tautomer thereof;(3) decarboxylating the compound provided in step (2), to provide a compound of the following formula:(4) cross-coupling the compound provided in step (3) with cyclopropanecarboxamide, to provide the compound of Formula (Ila).

[0033] In some embodiments, activating occurs, for example, at about 25 °C to about 35 °C. In other embodiments, condensing occurs in in the presence of a Lewis acid and an amine base. For example, in certain embodiments condensing occurs in the presence of MgCh and N,N-diisopropylethylamine. In further embodiments, condensing occurs, for example, at about 75 °C to about 85 °C.

[0034] In some embodiments, decarboxylating occurs in the presence of a polar aprotic solvent. For example, in some embodiments decarboxylating occurs in the presence of a polar aprotic solvent and water. In certain embodiments, for example, decarboxylating occurs in the presence of, e.g., N-methylpyrrolidine and water. In other embodiments, decarboxylating occurs, for example, at about 110 °C to about 120 °C. In still other embodiments, decarboxylating optionally occurs in the presence of a Lewis acid. In additional embodiments, decarboxylating optionally occurs in the presence of, for example, MgCh.

[0035] In other embodiments, cross-coupling occurs in the presence of a palladium catalyst. For example, in some embodiments cross-coupling occurs in the presence of a palladium catalyst, a base, and a phosphine ligand. In certain embodiments, cross-coupling occurs in the presence of, for example, Pd(OAc)2, K2CO3, and DIPPF. In further embodiments, cross-coupling occurs, or example, at about 75 °C to about 85 °C.

[0036] In addition, disclosed herein, for example, is a process for preparing a compound of Formula (III):Attorney Docket No.: ESK-028WOwherein the process comprises the following steps:(1) cross-coupling a compound of the following formula:, wherein Y is halogen, with a bis-boronic ester to provide a compound of the following formula:wherein R1and R2are each independently Ci-Cealkyl, or R1and R2, together with the atoms to which they are attached, may be joined together to form a 5-6 membered ring; and (2) cross-coupling the compound provided in step (1) with a compound of the following formula:to provide a compound of Formula (III).

[0037] In some embodiments, for example, X is chloro and is Y bromo. In other embodiments, the bis-boronic ester is, for example, bis(pinacolato)diboron. For example, in certain embodiments the compound provided in step

[0038] In some embodiments, for example, a process for preparing the compound of Formula (III) contemplated herein comprises the steps of:(1) cross-coupling a compound of the following formula:Attorney Docket No.: ESK-028WOwith bis(pinacolato)diboron to provide a compound of the following formula:(2) cross-coupling the compound provided in step (1) with a compound of the following formula:to provide the compound of Formula (III).

[0039] For example, disclosed herein is a process for preparing a compound of Formula(III):wherein the process comprises the following steps:(1) cross-coupling a compound of the following formula:with bis(pinacolato)diboron to provide a compound of the following formula:Attorney Docket No.: ESK-028WO(2) cross-coupling the compound provided in step (1) with a compound of the following formula:to provide the compound of Formula (III).

[0040] In some embodiments, the cross-coupling of step (1) occurs in the presence of a palladium catalyst. In other embodiments, the cross-coupling of step (1) occurs in the presence of a palladium catalyst, a base, and a phosphine ligand. For example, in certain embodiments the cross-coupling of step (1) occurs in the presence of Pd2(dba)3, KOAc, and di(adamantan-l- yl)(butyl)phosphane. In further embodiments, the cross-coupling of step (1) occurs, for example, at about 90 °C to about 100 °C.

[0041] In other embodiments, the cross-coupling of step (2) occurs in the presence of a palladium catalyst. In some embodiments, the cross-coupling of step (2) occurs in the presence of a palladium catalyst, a base, and a phosphine ligand. For example, in certain embodiments the cross-coupling of step (2) occurs in the presence of Pd2(dba)3, aqueous K3PO4, and di(adamantan-l-yl)(butyl)phosphane. In further embodiments, the cross-coupling of step (2) occurs at about 90 °C to about 100 °C.

[0042] Further disclosed herein, for example, is a process for preparing a compound of Formula (I):wherein the process comprises the following steps:(1) coupling a compound of Formula (Ila):Attorney Docket No.: ESK-028WOwith a compound of Formula (III):in the presence of a catalytic amount of an acid, to provide the compound of Formula (I); and(2) purifying the compound of Formula (I) by recrystallizing the compound; wherein the compound of Formula (I) is provided in greater than 99% purity.

[0043] In some embodiments, coupling occurs, for example, in the presence of a catalytic amount of HC1. In other embodiments, coupling occurs in 1 -propanol or 2-propanol. In certain embodiments, coupling occurs, for example, at about 75 °C to about 85 °C. In some embodiments, recrystallizing the compound of Formula (I) occurs, for example, in aqueous 1 - propanol or 2-propanol in the presence of a catalytic amount of HC1.

[0044] In addition, disclosed herein, for example, is a process for preparing a compound of Formula (IV):wherein the process comprises the following steps:(1) alkylating a compound of the following formula:in the presence of a base and CD3X, wherein X is tosylate or halogen, to provide a compound of the following formula:Attorney Docket No.: ESK-028WO(2) reducing the compound provided in step (1) to provide the compound of Formula (IV).

[0045] In some embodiments, CD3X is, for example, CD3OTS. In other embodiments, the base is an inorganic base selected from the group consisting of, for example, K3PO4 and K2CO3. In still other embodiments, reducing comprises reducing by, for example, hydrogenolysis. For example, in certain embodiments reducing comprises reducing by hydrogenolysis in the presence of catalytic Pt / C and H2. In other embodiments, reducing comprises reducing by debromination in the presence of a reducing agent, for example, sodium sulfite. For example, in certain embodiments reducing comprises contacting the compound provided in step (1) with sodium sulfite. In further embodiments, reducing comprises reducing by debromination in the presence of a reducing agent, for example, triphenylphosphine. For example, in certain embodiments reducing comprises contacting the compound provided in step (1) with triphenylphosphine. In additional embodiments, reducing comprises reducing by debromination in the presence of a reducing agent, for example, trimethylphosphite. For example, in certain embodiments reducing comprises contacting the compound provided in step (1) with trimethylphosphite.

[0046] Also disclosed herein is a process for preparing a compound of Formula (V):wherein R1is Ci-C4alkyl; wherein the process comprises the following steps:(1) providing a compound Formula (VI): o o R2O / ^X^^OR2(VI), wherein R2is Ci-C4alkyl; wherein when R1and R2are identical, the process further comprises the step of:(2) alkylating the compound of Formula (VI) in the presence of a base and CD3X, wherein X is tosylate or halogen, to provide a compound of Formula (V); orAttorney Docket No.: ESK-028WO wherein when R1and R2are not identical, the process further comprises the step of(2) alkylating the compound of Formula (VI) in the presence of a base and CD3X, wherein X is tosylate or halogen, to provide a compound of Formula (VII):(3) hydrolyzing the compound of Formula (VII) to provide a compound of Formula(VIII):(4) esterifying the compound of Formula (VII) to provide the compound of Formula (V).

[0047] In some embodiments, R1and R2are each independently selected from the group consisting of, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tertbutyl. In some embodiments, R1and R2may be the same. For example, in some embodiments R1and R2are each methyl. In some embodiments, R1and R2are each ethyl. In some embodiments, R1and R2are each tert-butyl. In still other embodiments, R1and R2may be different. For example, in some embodiments R1is -CH2CH3 and R2is tert-butyl.

[0048] In some embodiments, for example, a process for preparing the compound of Formula (V) contemplated herein comprises the steps of:(1) alkylating a compound of the following formula:in the presence of a base and CD3X, wherein X is tosylate or halogen, to provide a compound of the following formula:Attorney Docket No.: ESK-028WO(2) hydrolyzing the compound provided in step (1) to provide a compound of the following formula:(3) esterifying the compound provided in step (2) to provide the compound of the following formula:

[0049] For example, disclosed herein is a process for preparing a compound of Formula(IX):wherein the process comprises the following steps:(1) alkylating a compound of the following formula:in the presence of a base and CD3X, wherein X is tosylate or halogen, to provide a compound of the following formula:(2) hydrolyzing the compound provided in step (1) to provide a compound of the following formula:; and(3) esterifying the compound provided in step (2) to provide the compound of Formula (IX).Attorney Docket No.: ESK-028WO

[0050] In some embodiments, CD3X is selected from the group consisting of, for example, CD3I and CD3OTS. In other embodiments, the base is an inorganic base selected from the group consisting of, for example, potassium hydroxide and sodium hydroxide. In further embodiments, alkylating occurs in the presence of CD3I and potassium hydroxide. In certain embodiments, alkylating occurs in the presence of, for example, CD3OTS, a catalytic amount of KI, and aqueous sodium hydroxide. In some embodiments, hydrolyzing occurs in the presence of concentrated HC1. In other embodiments, esterifying occurs in the presence of, for example, anhydrous ethanol and acetyl chloride.

[0051] The compounds prepared in the processes disclosed herein are useful for treating a TYK2-mediated disease or disorder in a patient in need thereof. In some embodiments, the disease or disorder is an autoimmune disorder, e.g., type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease. In some embodiments, the disease or disorder is an inflammatory disorder, e.g., rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory bowel disease. In some embodiments, the disease or disorder is an inflammatory or allergic condition of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0052] For example, the compounds prepared in the processes disclosed herein are useful for treating a TYK2 -mediated diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven- Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis andAttorney Docket No.: ESK-028WOCrohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.Attorney Docket No.: ESK-028WOEXAMPLES

[0053] The procedures disclosed herein can be conducted in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. The following non-limiting examples illustrate the disclosure.Preparation of (4,6-dichloropyridin-3-yl)(l / / -imidazol-l-yl)methanone:

[0054] 4, 6-di chloronicotinic acid (1 equivalent) and acetonitrile (approximately 9 V) are charged, the temperature is adjusted to approximately 25 °C and agitated. Carbonyldiimidazole (approximately 1.2 equivalence) is charged while maintaining the internal temperature at approximately 35 °C. The reaction mixture is agitated at approximately 25 °C until the reaction is completed.Preparation of ethyl 2-(4,6-dichloronicotinoyl)propanoate-3,3,3-

[0055] Once the reaction is complete, diethyl 2-(methyl-d3)malonate, (approximately 1.1 equiv.), magnesium chloride (approximately 2.0 equiv.) and / ' / -diisopropylethylamine (approximately 2.0 equiv.) are charged and then the reaction mixture is heated to reflux. OnceAttorney Docket No.: ESK-028WO the reaction is completed, the reaction mixture is adjusted to approximately 35 °C and ethyl acetate (approximately 8 V) is charged while maintaining the internal temperature of no more than 40 °C. Aqueous hydrochloric acid (approximately 8 V, 3N) is added while maintaining the internal temperature of at least 40 °C and then the mixture is agitated for approximately 15 minutes before allowing the layers to separate. The aqueous layer is discarded, and the organic layer is washed with aqueous hydrochloric acid (approximately 8 V, IN). The organic layer is further washed with aqueous sodium bicarbonate solution (approximately 8 V, 5%) and aqueous sodium chloride solution (approximately 8 V, 5%) and then concentrated to approximately 5 V under vacuum. N-methypyrrolidine (approximately 5 V) is charged and concentrated to approximately 6 V under vacuum.Preparation of l-(4,6-dichloropyridin-3-yl)propan-l-one-3,3,3-

[0056] Purified water (approximately 5 equiv.) is charged to the N-methypyrrolidine solution containing ethyl 2-(4,6-dichloronicotinoyl)propanoate-3,3,3-<A. The mixture is adjusted to approximately 115 °C and agitated until the reaction is completed. Once the reaction is completed, the reaction mixture is cooled to approximately 25 °C and tert-butyl methyl ether (approximately 5 V) is charged. The mixture is washed with an aqueous sodium bicarbonate (approximately 10 V, 3%) while maintaining the internal temperature no more than 35 °C. The layers are separated, and the aqueous layer is back extracted with tert-butyl methyl ether (approximately 5 V). To the combined organic layer, aqueous sodium hydroxide solution (approximately 5 V, IN) is charged then agitated for at least 3 hours at 20 - 30 °C . The layers are separated, then the organic layer is washed with an aqueous sodium chloride solution (approximately 5 V, 5%) and an aqueous sodium chloride solution (approximately 5 V, 10%). The organic layer is treated with activated carbon and then fdtered and rinsed with tert-butyl methyl ether (approximately 2 V). The tert-butyl methyl ether solution is concentrated to approximately 2 V under vacuum and methanol (approximately 8 V) is charged then concentrated to approximately 2 V under vacuum. Methanol (approximately 1.5 V) is charged then purified water (approximately 3.5 V) is slowly charged for no less than 6 hours at 25 °C.Attorney Docket No.: ESK-028WOThe resulting slurry is slowly cooled to 0 - 5 °C for at least 2 hours and then agitated for at least 12 hours. The solid is fdtered and rinsed with pre-cooled purified water (0 - 5 °C, 5 V). The wet cake is dried under a vacuum.Preparation of A-(4-chloro-5-(propanoyl-3,3,3- pyridin-2-yl)cyclopropanecarboxamide:

[0057] Potassium carbonate (approximately 3 equiv.), l-(4,6-dichloropyridin-3- yl)propan-l-one-3,3,3-d3 (approximately 1 equiv.), and cyclopropanecarboxamide (approximately 1 equiv.) are charged into a reactor. 2-Methyltetrahydrofuran (approximately 14 V) is charged. Palladium(II) acetate (approximately 0.005 equiv.) and 1,1'- Bis(diisopropylphosphino)ferrocene (DIPPF, approximately 0.02 equiv.) are charged. The reaction mixture is adjusted to approximately 80 °C and agitated until the reaction is completed. Once the reaction is completed, the reaction mixture is adjusted to approximately 20 °C - 30 °C then filtered and rinsed with 2-methyltetrahydrofuran (approximately 5 V). The 2- methyltetrahydrofuran solution is washed with aqueous sodium chloride solutions (approximately 10 V and approximately 5 V) and then concentrated to approximately 5 V under vacuum. Toluene (approximately 5 V) and activated carbon are charged and the mixture is adjusted to approximately 50 °C then agitated for at least 2 hours. The mixture is filtered and rinsed with 2-methyltetrahydrofuran (approximately 4 V). The filtrate is concentrated to approximately 4 V under vacuum and then toluene (approximately 5 V) is charged. The mixture is concentrated to approximately 4 V under vacuum and toluene is charged to adjust to approximately 5 V. The content is adjusted to at least 80 °C. The mixture is agitated until all solid is dissolved then adjusted to 0 - 5 °C. The slurry is agitated then the solid is filtered and the wet cake is rinsed with pre-cooled toluene (0 - 5 °C, approximately 3 V). The wet cake is dried with heat under vacuum.Preparation of 2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline:Attorney Docket No.: ESK-028WO

[0058] 3 -bromo-2-methoxyaniline (1.0 equiv.) and 2-methyl-2 -butanol (10 V) are charged into a reactor then agitated for at least 15 minutes at 20- 30 °C. Under nitrogen 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-l,3,2-dioxaborolane (approximately 2.0 equiv.) and potassium acetate (approximately 3.0 equiv) are charged. Tris(dibenzylideneacetone) dipalladium(O) (approximately 0.0025 equiv.) and di(adamantan-l-yl)(butyl)phosphane (approximately 0.015 equiv.) are charged under nitrogen. The reaction mixture is adjusted to approximately 95 °C and agitated for at least 4 hours until the reaction is completed. Once the reaction is completed, the reaction mixture is adjusted to 20 - 30 °C and purified water is charged and agitated for at least 30 minutes. Then aqueous 1 M aqueous potassium phosphate tribasic solution (approximately 3 equiv. K3PO4 in approximately 14 V water) is charged and agitated for no less than 1 hour. After the phase separation, sparging of the organic layer is performed subsurface with nitrogen gas for at least 30 minutes.Preparation of 2-Methoxy-3-(l-(methyl- -lH-l,2,4-triazol-3-yl)aniline:

[0059] Aqueous potassium phosphate tribasic solution (approximately 3.3 equiv. K3PO4 in approximately 3.4 V water) and 3-bromo-l-(methyl-d3)-lH-l,2,4-triazole (approximately 1.1 equiv.) in 2-methyl-2-butanol (approximately 5 volumes) solution are charged into another reactor under nitrogen. tris(dibenzylideneacetone)dipalladium(0) (approximately 0.005 equiv) and di(adamantan-l-yl)(butyl)phosphane (approximately 0.03 equiv.) are charged under nitrogen. The reaction mixture is adjusted to approximately 95 °C and the 2 -m ethoxy-3 -(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline solution prepared above is slowly transferred to the reaction mixture over at least 5 hours while maintaining an internal temperature of at least 90 °CAttorney Docket No.: ESK-028WOThen, the reaction mixture is agitated at approximately 95 °C for least 12 hours until the reaction is completed. Once the reaction is completed, the reaction mixture is adjusted to approximately 55 °C. Then purified water is charged is agitated for approximately 15 minutes before allowing the layers to phase separate. The organic layer is concentrated to approximately 3 V under vacuum and the solvents is exchanged to acetonitrile (approximately 13 V). Activated carbon is charged and the mixture is agitated for at least 2 hours at 20 °C - 30 °C. The mixture is filtered and rinsed with acetonitrile (approximately 5 V). The filtrate is concentrated to approximately 3 V under vacuum and then 1 -propanol (approximately 8 V) is charged, followed by concentration to approximately 3 V under vacuum. After the distillation is completed, the slurry is adjusted to at least 65 °C and held for at least 30 minutes. The reaction mixture is cooled to 15 °C - 25 °C over approximately 1 hour then n-heptane (approximately 6 V) is charged over approximately 1 hour at 15 °C - 25 °C. The slurry is agitated for at least 12 hours then the solid is filtered and the cake is rinsed with 1-propanol / n-heptane (approximately 1:2) (approximately 3 V). The wet product is dried under vacuum with heat at approximately 45 °C.Preparation of A-(4-((2-Methoxy-3-(l-(methyl- -lH-l,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-<A)pyridin-2-yl)cyclopropanecarboxamide Hydrochloride:

[0060] 2-Methoxy-3-(l-(methyl-d3)-lH-l,2,4-triazol-3-yl)aniline (1.0 equiv.), N-(4- chloro-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (approximately 1.05 equiv.), and 1-propanol (approximately 14.7 V) are charged and agitated at 25 °C. Concentrated hydrochloric (approximately 0.2 equiv.) is slowly charged at 20 °C - 30 °C then the reaction mixture is heated to approximately 80 °C. The reaction mixture is agitated at the same temperature until the reaction is complete. The reaction mixture is cooled to 25 °C for no less than 3 hours and agitated for no less than 2 hours at 25 °C. The slurry is filtered and isolatedAttorney Docket No.: ESK-028WO solids are rinsed with 1 -propanol (approximately 6 V). The wet product is dried at with heat under vacuum.Preparation of V-(4-((2-Methoxy-3-(l-(methyl- -lH-l,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3- pyridin-2-yl)cyclopropanecarboxamide Hydrochloride Crystal Form 1 :

[0061] N-(4-((2-methoxy-3-(l-(methyl-d3)-lH-l,2,4-triazol-3-yl)phenyl)amino)-5- (propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide hydrochloride, 1 -propanol (approximately 15 V) and purified water (approximately 2.2 V) are charged and agitated. Concentrated hydrochloric acid (approximately 0.2 equiv.) is slowly charged while maintaining an internal temperature to no more than 30 °C. The mixture is then heated to 60 °C - 70 °C with agitation until the solids are fully dissolved and the solution is filtered. The filtrate is adjusted to approximately 65 °C then cooled to approximately 40 °C over at least 30 minutes. V-(4-((2- methoxy-3-(l-(methyl-d3)-lH-l,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2- yl)cyclopropanecarboxamide hydrochloride crystal form 1 seed material (approximately 5 wt%) is charged and agitated for approximately 1 hour at approximately 40 °C then cooled the contents to approximately 20 °C over approximately 2 hours. The slurry is agitated for approximately 10 hours at approximately 20 °C and concentrated to approximately 8.5 V under reduced pressure at a jacket temperature of approximately 50 °C. The slurry is cooled to approximately 20 °C and 1- propanol (approximately 10 V) is charged, concentrated to approximately 7.5 V under reduced pressure at a jacket temperature of approximately 50 °C. 1 -Propanol is charged to adjust to approximately 8.5 V and slurry is cooled to approximately 20 °C over approximately 2 hours and agitated for approximately 2 hours at approximately 20 °C. The suspension is filtration and the wet product is rinsed with 1 -propanol (approximately 4 V). The wet product is dried under vacuum and heat.Preparation of 2-(methyl- / )malonic acid:Attorney Docket No.: ESK-028WO1 45% N OH

[0062] To the reactor is charged di- / c77-butyl malonate (approximately 1.0 equiv., limiting reagent) and sulfolane (approximately 1.5 vol.) and with agitation the internal temperature is adjusted to approximately 10-15 °C. lodomethane-da (approximately 1.0 equiv.) is charged followed by the slow addition of potassium hydroxide (approximately 1.3 equiv.) maintaining an internal temperature less than 20 °C. The mixture is the is then heated to approximately 25-35 °C and stirred for at least 2 hours. After the reaction is determined to be complete it is diluted with water (approximately 7 vol.) and methyl / c77-butyl ether (approximately 12 vol.). After agitation, the phases are separated, and the aqueous phase is extracted with methyl tert-butyl ether (approximately 6 vol.). The combined organic phase is then washed twice with water (approximately 4 vol. ea.) and then concentrated under vacuum at elevated temperature until no more solvent is removed. The reaction temperature is adjusted to approximately 30 °C and concentrated hydrochloric acid is added. The mixture is then warmed to approximately 55-65 °C and stirred for at least 2 hours then warmed 60-70 °C and stirred for at least 2 hours. Once the reaction is determined to be complete the reaction mixture is cooled to approximately 44-55 °C and the reaction is concentrated under vacuum. Once the concentration is complete the reaction mixture is cooled to 25-35 °C and methylene chloride (approximately 2.5 vol.) is then charged with agitation and the solvent again removed by distilled under vacuum. The methylene chloride (approximately 2.5 vol. ea.) charged and distillation is repeated two more times. Once the distillations are completed, a final addition of methylene chloride (approximately 2.5 vol.) is charged to the V2002. The temperature is adjusted to 35-40 °C and stirred for at least 2 hours then cooled to 10-15 °C and then stirred for at least 2 hours. The product is then isolated by filtration and the cake is rinsed with methylene chloride (approximately 0.5 vol.) and dried under vacuum at approximately 45-50 °C for no less than 12 h, providing 2-(methyl-t / 3)malonic acid in approximately 67% yield.Preparation of m ethyl -c / ?, 4-m ethylbenzenesulfonate:Attorney Docket No.: ESK-028WO

[0063] Charge to reactor #1 p-toluenesulfonyl chloride (approximately 1.1 equiv.) toluene (approximately 13.5 vol.), 45% aqueous sodium hydroxide (approximately 3.6 equiv.) and methanol-d3 (1.0 equiv., limiting reagent). To reactor #2 charge Toluene (approximately 11.1 vol.). Slowly charge the contents of reactor #2 into reactor #1, maintaining a solution temperature of no more than 30 °C. Rince reactor #2 with additional toluene (approximately 0.58 vol.) and warm the reaction mixture in reactor #1 to 35-45 °C and agitate for NLT 10 hours. The reaction mixture is then warmed to 45-55 °C for no less than 2 hours.

[0064] When the reaction is complete the reaction mixture is cooled to approximately 30 °C and water (approximately 17 vol.) is charged to the reactor. After agitation, the phases are separated, and the aqueous phase is discharged to waste. Water (approximately 8.5 vol) is charged to the organic phase in the reactor and after agitation the phases are separated, and the aqueous phase is discharged to waste. Again water (approximately 8.5 volumes) is charged to the organic phase and after agitation phases are separated and the aqueous phase is discharged to waste. The organic phased in then concentrated under vacuum until no more solvent can be removed, yielding the product m ethyl -t / 3 4-methylbenzenesulfonate as a low melting solid in approximately 90% yield.Preparation of 2-(methyl- malonic acid:

[0065] To the reactor is charged di-tert-butyl malonate (1.0 equivalence, limiting reagent), THF (approximately 4.45 vol), methyl-d3 4-methylbenzenesulfonate (approximately 1.05 eq.), and 4.6 g KI (0.02 eq.). The mixture is then cooled to approximately 5-15 °C and with agitation 45% aqueous sodium hydroxide (1.2 eq) is slowly added to the reaction mixture maintaining an internal temperature of no more than 20 °C and agitated for no less than 1 hour. The reaction mixture is then heated to approximately 40 °C and stirred for no more than 4 house then cooled to approximately 20-30 °C and agitated for no mor than 12 hours. After the reaction is complete charge cyclohexane (approximately 1.56 vol.) and water (approximately 2 vol.) and adjust the reaction temperature to approximately 20-30 °C with agitation. The phases are separated, and the aqueous phase is sent to waste. To the organic phase is added morpholineAttorney Docket No.: ESK-028WO(approximately 0.4 equiv.) and the mixture is warmed to approximately 40 °C and agitated for no less than 4 hours to remove residual m ethyl -t / 3 4-methylbenzenesulfonate.

[0066] To the solution is added 10% aqueous sodium thiosulfate pentahydrate solution (approximately 0.17 equiv.) and the mixture is adjusted to approximately 20-35 °C with agitation. The phases separated and the lower aqueous phase sent to waste.

[0067] The organic phase is then washed with water (approximately 2 vol), then by 11% aqueous hydrochloric acid (approximately 1.3 vol.), then again by water (approximately 2 vol). The organic phase is then concentrated under vacuum until no more solvent can be removed yielding the product di- / c’ / 7-butyl 2-(methyl-d3)malonate as an oil. To the di- / c77-butyl 2-(methyl- d3)malonate prepared above is added 32% hydrochloric acid (approximately 1.2 equiv.) and heated to approximately 70 °C. After heating for approximately 2 hours the tert-butyl chloride side product is removed by distillation.

[0068] After confirming the reaction is complete cyclohexane (approximately 3.0 Vol) is charged and mixture is heated to reflux, and residual water and hydrochloric acid are removed by azeotrope. The mixture is then cooled to approximately 20-35°C, agitated for greater than 1 hour, and the product is isolated by filtration. The filter cake is then washed with cyclohexane (approximately 2.0 vol), dried under vacuum with heat providing 2-(methyl-t / 3)malonic acid in approximately 80% yield.Preparation of diethyl 2-(m ethyl - / 3 )m al onate:

[0069] To the reactor containing absolute ethanol (approximately 4.0 vol) cooled to approximately 0 °C acetyl chloride (approximately 2.24 equiv.) is added with agitation maintaining the temperature less than 20 °C. The mixture is warmed to approximately 15-20 °C stirred for no less than 60 min. To the solution is slowly added 2-(methyl-t / 3)malonic acid (approximately 1 equiv., limiting reagent) maintaining an internal temperature of approximately 15-20 °C and stirred for no less than 14 hours. After the reaction is determined to be complete it is diluted with cyclohexane (approximately 4.0 vol.) and cooled to less than 10 °C and cold water (approximately 6.0 vol.) charged slowly maintaining the internal temperature no more than 10Attorney Docket No.: ESK-028WO°C. After agitation, the phases are separated, and the aqueous phase is back extracted with cyclohexane (approximately 4 vol.). The combined organic phase is washed with 5% aqueous sodium bicarbonate (approximately 0.29 equiv.) and water (approximately 4.0 vol.) then concentrated to an oil under vacuum at elevated temperature. The product is then purified by fractional distillation providing diethyl 2-(methyl-r / )malonate in approximately 83% yield.Preparation of 3,5-dibromo-l-(methyl- -lH-l,2,4-triazole:,

[0070] Potassium phosphate tribasic (approximately 1.6 equiv.) is charged to the reactor1.4-dioxane (approximately 8 vol.) is then charged and agitation is started. 3,5-dibromo-17 / -1.2.4-triazole (approximately 1 equiv., limiting reagent) is charged to the reactor and the reaction is adjusted to approximately 25-30 °C. M ethyl -t / 3 4-methylbenzenesulfonate (approximately 0.95 equiv.) and 1,4-dioxane (approximately 8 vol.) are charged. The reaction mixture is then heated to 50-60 °C and stirred for at least 12 hours. After the reaction is complete, the reaction is cooled to 25-35 °C and filtered to remove salts. The reaction mixture is then concentrated under vacuum and elevated temperature. After concentration, the reaction is adjusted to 45-50 °C and warm water (approximately 2.2 vol.) is gradually added with agitation. The suspension is then stirred at approximately 40-45 °C for at least 5 hours, then cooled to approximately 3O-35°C over at least1 hour. The suspension is filtered, and the cake rinsed with cold water (approximately 2 vol.). The solids are dried under vacuum providing 3,5-dibromo- l -(methyl-<A)- l / 7- l ,2.4-triazole in approximately 65% yield.Preparation of 3,5-dibromo-l-(methyl- -lH-l,2,4-triazole:

[0071] Reactor #! is charged 3,5-dibromo-lH-l,2,4-triazole (approximately 1 equiv., limiting regent), tetrahydrofuran (approximately 2.8 vol.), agitated until a solution. To the reaction is added 40% aqueous potassium carbonate (approximately 0.55 equiv.). Methyl-d3 4-Attorney Docket No.: ESK-028WO methylbenzenesulfonate (approximately 1 .0 equiv.) is washed into the reactor with tetrahydrofuran (approximately 0.22 vol.). The reaction is then agitated at approximately 25°C for at least 2 hours then warmed to 50 °C for at least 6 hours. When the reaction is complete the reaction is cooled to approximately 20-30 °C and transferred to reactor #2 and reactor #1 is rinsed with water (approximately 0.50 vol.) and tetrahydrofuran (approximately 0.56 vol.) into reactor #2. The reaction is then concentrated under vacuum and heat until no distillates are observed. To the residue is added toluene (approximately 3.5 vol.) and water (approximately 3 vol.). After agitation, the phases are separated and the aqueous phase extracted twice with toluene (approximately 1.73 vol. ea.). The combined organic phase is then concentrated until no distillate is observed. Water (approximately 0.50 vol.) is then charged to the reactor and the mixture is then heated to approximately 60 °C and concentrate until no distillates are observed. Cool the reaction mixture to approximately 50 °C and charge 98% acetic acid (approximately 0.40 vol.). To the mixture is added water (approximately 4.0 vol.) maintaining an internal temperature of approximately 50 °C and stir for at least 60 minutes. The suspension is then cooled to approximately 37-42 °C and agitated for at least 60 minutes, then cooled to 0-5 °C and agitated for at least two hours. The product is then isolated by filtration and the wet cake is washed with cold water (approximately 2.0 vol.). The product is then dried in vacuo with heat providing 3,5-dibromo-l-(methyl-t73)-1 / -l,2,4-triazole in approximately 66% yield.Preparation of 3-bromo-l-(methyl-r / 3)-1 / -l,2,4-triazole:

[0072] To the hydrogenation reactor are added 3,5-dibromo-l-(methyl-<73)-177-l,2,4- triazole (approximately 1 equiv., limiting reagent), methanol (approximately 15.2 vol.), tri ethylamine (approximately 2.0 equiv.), and 5% platinum on carbon (approximately 0.01 wt.). The reactor is purged with nitrogen then hydrogen. The reaction mixture is then hydrogenated at under a hydrogen pressure of 5-6 kg / cm2and 25-35 °C until hydrogen is no longer consumed, and the reaction is complete. The reaction is filtered and the hydrogenator and filter washed two times with methanol (approximately 3.2 vol., ea.). To the filtrate is charged 45% aqueous sodium hydroxide (approximately 1.05 equiv.) maintaining an internal temperature less than 30 °C. TheAttorney Docket No.: ESK-028WO reaction mixture is then concentrated until approximately 12.6 volumes of solvent are removed. To the reaction mixture methanol (approximately 3.2 vol) is charged and the reaction mixture is concentrated under vacuum at elevated temperature until no more solvent is removed. Methanol (approximately 3.2 vol.) is charged to the reaction mixture and again the reaction mixture is concentrated under vacuum at elevated temperature until no more solvent is removed. With agitation the product mixture is dissolved in water (approximately 2.5 vol) and 32% hydrochloric acid (approximately 0.50 equiv.) and dichloromethane (approximately 4.5 vol.) is added. The mixture is agitated then the phases separated, and the aqueous layer is extracted two times with dichloromethane (approximately 4.5 vol., ea.). The organic phase is then washed with 18% sodium chloride (approximately 4 vol.) and the aqueous phase is extracted dichloromethane (approximately 1.5 vol). The organic phase is then concentrated to an oil, and the product is then purified by fractional distillation providing 34Dro o-l -(methyl-tA)-! / 7-1 ,2,4-triazole in approximately 87% yield.INCORPORATION BY REFERENCE

[0073] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.EQUIVALENTS

[0074] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0075] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims areAttorney Docket No.: ESK-028WO approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

[0076] What is claimed is:

Claims

Attorney Docket No.: ESK-028WOCLAIMS1. A process for preparing a compound of Formula (I):wherein the process comprises the following steps:(1) activating a compound of the following formula: o xHOAN x, wherein each X is independently halogen, in the presence of an activating agent to provide a compound of the following formula: o x; wherein L is a leaving group;(2) condensing the compound provided in step (1) with diethyl 2-(methyl-t6)malonate, to provide a compound of the following formula:or an enol tautomer thereof;(3) decarboxylating the compound provided in step (2), to provide a compound of the following formula:Attorney Docket No.: ESK-028WO(4) cross-coupling the compound provided in step (3) with cyclopropanecarboxamide, to provide a compound of Formula (II):(5) coupling the compound of Formula (II) with a compound of Formula (III):to provide the compound of Formula (I).

2. The process of claim 1, wherein each X is independently chloro or bromo.

3. The process of claim 1 or 2, wherein each X is chloro.

4. The process of any one of claims 1-3, wherein the activating agent is carbonyldiimidazole.

5. The process of any one of claims 1-4, wherein L is imidazolyl.

6. The process of claim 1, wherein the process comprises the following steps:(1) activating a compound of the following formula:in the presence of carbonyldiimidazole, to provide a compound of the following formula:(2) condensing the compound provided in step (1) with diethyl 2-(methyl-<73)malonate, to provide a compound of the following formula:Attorney Docket No.: ESK-028WOor an enol tautomer thereof;(3) decarboxylating the compound provided in step (2), to provide a compound of the following formula:(4) cross-coupling the compound provided in step (3) with cyclopropanecarboxamide, to provide a compound of Formula (Ila):(5) coupling the compound of Formula (Ila) with a compound of Formula (III):to provide the compound of Formula (I).

7. The process of any one of claims 1-6, wherein activating occurs at about 25 °C to about 358. The process of any one of claims 1-7, wherein condensing occurs in in the presence of a Lewis acid and an amine base.

9. The process of any one of claims 1-8, wherein condensing occurs in the presence of MgCL and N,N-diisopropylethylamine.

10. The process of any one of claims 1-9, wherein condensing occurs at about 75 °C to about 85Attorney Docket No.: ESK-028WO11 . The process of any one of claims 1-10, wherein decarboxylating occurs in the presence of a polar aprotic solvent.

12. The process of any one of claims 1-11, wherein decarboxylating occurs in the presence of a polar aprotic solvent and water.

13. The process of any one of claims 1-12, wherein decarboxylating occurs in the presence of N- methylpyrrolidine and water.

14. The process of any one of claims 1-13, wherein decarboxylating occurs at about 110 °C to about 120 °C.

15. The process of any one of claims 1-13, wherein decarboxylating optionally occurs in the presence of a Lewis acid.

16. The process of claim 15, wherein decarboxylating optionally occurs in the presence of MgCh.

17. The process of any one of claims 1-16, wherein cross-coupling occurs in the presence of a palladium catalyst.

18. The process of any one of claims 1-17, wherein cross-coupling occurs in the presence of a palladium catalyst, a base, and a phosphine ligand.

19. The process of any one of claims 1-18, wherein cross-coupling occurs in the presence of Pd(OAc)2, K2CO3, and DIPPF.

20. The process of any one of claims 1-19, wherein cross-coupling occurs at about 75 °C to about 85 °C.

21. The process of any one of claims 1-20, wherein coupling occurs in the presence of a catalytic amount of HC1.

22. The process of any one of claims 1-21, wherein coupling occurs at about 75 °C to about 85 °C.

23. The process of any one of claims 1-22, further comprising purifying the compound of Formula (I) by recrystallizing the compound.Attorney Docket No.: ESK-028WO24. The process of any one of claims 1-23, further comprising purifying the compound of Formula (I) by recrystallizing the compound in aqueous 1 -propanol or 2-propanol in the presence of a catalytic amount of HC1.

25. The process of any one of claims 1-21, wherein the compound of Formula (I) is provided in greater than 97% purity as determined by HPLC.

26. The process of any one of claims 1-22, wherein the compound of Formula (I) is provided in greater than 98% purity as determined by HPLC.

27. The process of any one of claims 1-26, wherein the compound of Formula (I) is provided in greater than 99% purity as determined by HPLC.

28. A process for preparing a compound of Formula (I):wherein the process comprises the following steps:(1) cross-coupling a compound of the following formula:, wherein Y is halogen, with a bis-boronic ester to provide a compound of the following formula:wherein R1and R2are each independently Ci-Cealkyl, or R1and R2, together with the atoms to which they are attached, may be joined together to form a 5-6 membered ring;Attorney Docket No.: ESK-028WO(2) cross-coupling the compound provided in step (1) with a compound of the following formula:to provide a compound of Formula (III):(3) coupling the compound of Formula (III) with a compound of Formula (II):wherein X is halogen; to provide the compound of Formula (I).

29. The process of claim 27, wherein X and Y are each independently chloro or bromo.

30. The process of claim 28 or 29, wherein X is chloro and is Y bromo.

31. The process of any one of claims 28-30, wherein the bis-boronic ester is bis(pinacolato)diboron.

32. The process of any one of claims 28-31, wherein the compound provided in step (1) is33. The process of claim 28, wherein the process comprises the following steps:(1) cross-coupling a compound of the following formula:Attorney Docket No.: ESK-028WO with bis(pinacolato)diboron to provide a compound of the following formula:(2) cross-coupling the compound provided in step (1) with a compound of the following formula:to provide a compound of Formula (III):(3) coupling the compound of Formula (III) with a compound of Formula (Ila):to provide the compound of Formula (I).

34. The process of any one of claims 28-33, wherein the cross-coupling of step (1) occurs in the presence of a palladium catalyst.

35. The process of any one of claims 28-34, wherein the cross-coupling of step (1) occurs in the presence of a palladium catalyst, a base, and a phosphine ligand.

36. The process of any one of claims 28-35, wherein the cross-coupling of step (1) occurs in the presence of Pd2(dba)s, KO Ac, and di(adamantan-l-yl)(butyl)phosphane.

37. The process of any one of claims 28-36, wherein the cross-coupling of step (1) occurs at about 90 °C to about 100 °C.Attorney Docket No.: ESK-028WO38. The process of any one of claims 28-37, wherein the cross-coupling of step (2) occurs in the presence of a palladium catalyst.

39. The process of any one of claims 28-38, wherein the cross-coupling of step (2) occurs in the presence of a palladium catalyst, a base, and a phosphine ligand.

40. The process of any one of claims 28-39, wherein the cross-coupling of step (2) occurs in the presence of Pd2(dba)a, aqueous K3PO4, and di(adamantan-l-yl)(butyl)phosphane.

41. The process of any one of claims 28-40, wherein the cross-coupling of step (2) occurs at about 90 °C to about 100 °C.

42. The process of any one of claims 28-41, wherein coupling occurs in the presence of a catalytic amount of HC1.

43. The process of any one of claims 28-42, wherein coupling occurs at about 75 °C to about 8544. The process of any one of claims 28-43, further comprising purifying the compound of Formula (I) by recrystallizing the compound.

45. The process of any one of claims 28-44, further comprising purifying the compound of Formula (I) by recrystallizing the compound in aqueous 1 -propanol or 2-propanol in the presence of a catalytic amount of HC1.

46. The process of any one of claims 28-45, wherein the compound of Formula (I) is provided in greater than 97% purity as determined by HPLC.

47. The process of any one of claims 28-46, wherein the compound of Formula (I) is provided in greater than 98% purity as determined by HPLC.

48. The process of any one of claims 28-47, wherein the compound of Formula (I) is provided in greater than 99% purity as determined by HPLC.

49. A process for preparing a compound of Formula (Ila):Attorney Docket No.: ESK-028WO wherein the process comprises the following steps:(1) activating a compound of the following formula: o ciHOAAN x, wherein X is halogen, in the presence of an activating agent to provide a compound of the following formula:, wherein L is a leaving group;(2) condensing the compound provided in step (1) with diethyl 2-(methyl-6fe)malonate, to provide a compound of the following formula:or an enol tautomer thereof;(3) decarboxylating the compound provided in step (2), to provide a compound of the following formula:(4) cross-coupling the compound provided in step (3) with cyclopropanecarboxamide, to provide the compound of Formula (Ila).

50. The process of claim 49, wherein X is chloro.

51. The process of any claim 49 or 50, wherein the activating agent is carbonyldiimidazole.

52. The process of any one of claims 49-51, wherein L is imidazolyl.

53. The process of claim 49, wherein the process comprises the following steps:(1) activating a compound of the following formula:Attorney Docket No.: ESK-028WOin the presence of carbonyldiimidazole, to provide a compound of the following formula:(2) condensing the compound provided in step (1) with diethyl 2-(methyl-t / 3)mal onate, to provide a compound of the following formula:or an enol tautomer thereof;(3) decarboxylating the compound provided in step (2), to provide a compound of the following formula:(4) cross-coupling the compound provided in step (3) with cyclopropanecarboxamide, to provide the compound of Formula (Ila).

54. The process of any one of claims 49-53, wherein activating occurs at about 25 °C to about 35 °C.

55. The process of any one of claims 49-54, wherein condensing occurs in in the presence of a Lewis acid and an amine base.

56. The process of any one of claims 49-55, wherein condensing occurs in the presence of MgCh and N,N-diisopropylethylamine.

57. The process of any one of claims 49-56, wherein condensing occurs at about 75 °C to about 85 °C.Attorney Docket No.: ESK-028WO58. The process of any one of claims 49-57, wherein decarboxylating occurs in the presence of a polar aprotic solvent.

59. The process of any one of claims 49-58, wherein decarboxylating occurs in the presence of a polar aprotic solvent and water.

60. The process of any one of claims 49-59, wherein decarboxylating occurs in the presence of N-methylpyrrolidine and water.

61. The process of any one of claims 49-60, wherein decarboxylating occurs at about 110 °C to about 120 °C.

62. The process of any one of claims 49-60, wherein decarboxylating optionally occurs in the presence of a Lewis acid.

63. The process of claim 62, wherein decarboxylating optionally occurs in the presence ofMgCl2.

64. The process of any one of claims 49-63, wherein cross-coupling occurs in the presence of a palladium catalyst.

65. The process of any one of claims 49-64, wherein cross-coupling occurs in the presence of a palladium catalyst, a base, and a phosphine ligand.

66. The process of any one of claims 49-65, wherein cross-coupling occurs in the presence of Pd(OAc)2, K2CO3, and DIPPF.

67. The process of any one of claims 49-66, wherein cross-coupling occurs at about 75 °C to about 85 °C.

68. A process for preparing a compound of Formula (III):wherein the process comprises the following steps:(1) cross-coupling a compound of the following formula:Attorney Docket No.: ESK-028WO, wherein Y is halogen, with a bis-boronic ester to provide a compound of the following formula:wherein R1and R2are each independently Ci-Cealkyl, or R1and R2, together with the atoms to which they are attached, may be joined together to form a 5-6 membered ring; and(2) cross-coupling the compound provided in step (1) with a compound of the following formula:to provide a compound of Formula (III).

69. The process of claim 68, wherein X is chloro and is Y bromo.

70. The process of claim 68 or 69, wherein the bis-boronic ester is bis(pinacolato)diboron.

71. The process of any one of claims 68-70, wherein the compound provided in step (1) is72. The process of claim 68, wherein the process comprises the following steps:(1) cross-coupling a compound of the following formula:with bis(pinacolato)diboron to provide a compound of the following formula:Attorney Docket No.: ESK-028WO(2) cross-coupling the compound provided in step (1) with a compound of the following formula:to provide the compound of Formula (III).

73. The process of any one of claims 68-72, wherein the cross-coupling of step (1) occurs in the presence of a palladium catalyst.

74. The process of any one of claims 68-73, wherein the cross-coupling of step (1) occurs in the presence of a palladium catalyst, a base, and a phosphine ligand.

75. The process of any one of claims 68-74, wherein the cross-coupling of step (1) occurs in the presence of Pd2(dba)s, KO Ac, and di(adamantan-l-yl)(butyl)phosphane.

76. The process of any one of claims 68-75, wherein the cross-coupling of step (1) occurs at about 90 °C to about 100 °C.

77. The process of any one of claims 68-76, wherein the cross-coupling of step (2) occurs in the presence of a palladium catalyst.

78. The process of any one of claims 68-77, wherein the cross-coupling of step (2) occurs in the presence of a palladium catalyst, a base, and a phosphine ligand.

79. The process of any one of claims 68-78, wherein the cross-coupling of step (2) occurs in the presence of Pd2(dba)s, aqueous K3PO4, and di(adamantan-l-yl)(butyl)phosphane.

80. The process of any one of claims 68-79, wherein the cross-coupling of step (2) occurs at about 90 °C to about 100 °C.

81. A process for preparing a compound of Formula (I):Attorney Docket No.: ESK-028WOwherein the process comprises the following steps:(1) coupling a compound of Formula (Ila):with a compound of Formula (III):in the presence of a catalytic amount of an acid, to provide the compound of Formula (I); and(2) purifying the compound of Formula (I) by recrystallizing the compound; wherein the compound of Formula (I) is provided in greater than 99% purity.

82. The process of claim 81, wherein coupling occurs in the presence of a catalytic amount of HC1.

83. The process of claim 81 or 82, wherein coupling occurs in 1 -propanol or 2-propanol.

84. The process of any one of claims 81-83, wherein coupling occurs at about 75 °C to about 85 °C.

85. The process of any one of claims 81-84, wherein recrystallizing the compound of Formula(I) occurs in aqueous 1-propanol or 2-propanol in the presence of a catalytic amount of HC1.

86. A process for preparing a compound of Formula (IV):Attorney Docket No.: ESK-028WOwherein the process comprises the following steps:(1) alkylating a compound of the following formula:in the presence of a base and CD3X, wherein X is tosylate or halogen, to provide a compound of the following formula:(2) reducing the compound provided in step (1) to provide the compound of Formula (IV).

87. The process of claim 86, wherein CD3X is CD3OTS.

88. The process of claim 86 or 87, wherein the base is an inorganic base selected from the group consisting of K3PO4 and K2CO3.

89. The process of any one of claims 86-88, wherein reducing comprises reducing by hydrogenolysis.

90. The process of any one of claims 86-89, wherein reducing comprises reducing by hydrogenolysis in the presence of catalytic Pt / C and H2.

91. The process of any one of claims 86-88, wherein reducing comprises contacting the compound provided in step (1) with a reducing agent selected from the group consisting of sodium sulfite, triphenylphosphine, and trimethylphosphite.

92. A process for preparing a compound of Formula (V):wherein R1is Ci-C4alkyl; wherein the process comprises the following steps:Attorney Docket No.: ESK-028WO(1) providing a compound Formula (VI):wherein R2is Ci-C4alkyl; wherein when R1and R2are identical, the process further comprises the step of:(2) alkylating the compound of Formula (VI) in the presence of a base and CD3X, wherein X is tosylate or halogen, to provide a compound of Formula (V); or wherein when R1and R2are not identical, the process further comprises the step of:(2) alkylating the compound of Formula (VI) in the presence of a base and CD3X, wherein X is tosylate or halogen, to provide a compound of Formula (VII):(3) hydrolyzing the compound of Formula (VII) to provide a compound of Formula(VIII):(4) esterifying the compound of Formula (VIII) to provide the compound of Formula (V).

93. The process of claim 92, wherein R1is -CH2CH3 and R2is / c / 7-butyl.

94. The process of claim 92 or 93, wherein the process comprises the following steps:(1) alkylating a compound of the following formula:in the presence of a base and CD3X, wherein X is tosylate or halogen, to provide a compound of the following formula:Attorney Docket No.: ESK-028WO(2) hydrolyzing the compound provided in step (1) to provide a compound of the following formula:(3) esterifying the compound provided in step (2) to provide the compound of the following formula:

95. The process of any one of claims 92-94, wherein CD3X is selected from the group consisting of CD3I and CD3OTS.

96. The process of any one of claims 92-95, wherein the base is an inorganic base selected from the group consisting of potassium hydroxide and sodium hydroxide.

97. The process of any one of claims 92-96, wherein alkylating occurs in the presence of CD3I and potassium hydroxide.

98. The process of any one of claims 92-97, wherein alkylating occurs in the presence of CD3OTS, a catalytic amount of KI, and aqueous sodium hydroxide.

99. The process of any one of claims 93-98, wherein hydrolyzing occurs in the presence of concentrated HC1.

100. The process of any one of claims 93-99, wherein esterifying occurs in the presence of an anhydrous ethanol and acetyl chloride.

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