Solid forms of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-amine and its salts

Abstract

Disclosed are salts of the AAK1 inhibitor (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine and solid forms thereof, as well as pharmaceutical formulations containing them and methods for their preparation.

Description

[Technical field]

[0001] 1 Field of the Invention This application relates to solid forms of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, pharma- ceutically acceptable salts thereof, compositions containing them, and methods of their use. [Background technology]

[0002] 2. Background of the Invention Adaptor-associated kinase 1 (AAK1) is a member of the Ark1 / Prk1 family of serine / threonine kinases. AAK1 mRNA exists in two splice forms, termed short and long. The long form predominates and is highly expressed in brain and heart (Henderson and Conner, Mol. Biol. Cell. 2007, 18, 2698-2706). AAK1 is enriched in synaptosomal preparations and colocalizes with endocytic structures in cultured cells. AAK1 regulates clathrin-coated endocytosis, a process important for synaptic vesicle recycling and receptor-mediated endocytosis. AAK1 associates with the AP2 complex, which binds receptor cargo to the clathrin coat. Binding of clathrin to AAK1 stimulates the kinase activity of AAK1 (Conner et al., Traffic 2003, 4, 885-890; Jackson et al., J. Cell. Biol. 2003, 163, 231-236). AAK1 phosphorylates the mu-2 subunit of AP-2, which promotes binding of mu-2 to tyrosine containing sorting motifs on cargo receptors (Ricotta et al., J. Cell Bio. 2002, 156, 791-795; Conner and Schmid, J. Cell Bio. 2002, 156, 921-929). Phosphorylation of Mu2 is not required for receptor internalization, but phosphorylation increases the efficiency of internalization (Motely et al., Mol. Biol. Cell. 2006, 17, 5298-5308).

[0003] AAK1 has been identified as an inhibitor of neuregulin-1 / ErbB4 signaling in PC12 cells. Loss of AAK1 expression by RNA interference-mediated gene silencing or treatment with the kinase inhibitor K252a (which inhibits AAK1 kinase activity) enhances neurite outgrowth induced by neuregulin-1. These treatments increase ErbB4 expression and lead to its accumulation in or near the plasma membrane (Kuai et al.,Chemistry and Biology 2011,18,891-906). NRG1 and ErbB4 are putative schizophrenia susceptibility genes (Buonanno,Brain Res. Bull.2010,83,122-131). SNPs in both genes are associated with multiple schizophrenia endophenotypes (Greenwood et al.,Am.J.Psychiatry 2011,168,930-946). Neuregulin 1 and ErbB4 KO mouse models showed morphological changes and behavioral phenotypes associated with schizophrenia (Jaaro-Peled et al., Schizophrenia Bulletin 2010, 36, 301-313; Wen et al., Proc. Natl. Acad. Sci. USA. 2010, 107, 1211-1216). In addition, a single nucleotide polymorphism in an intron of the AAK1 gene has been associated with age of onset of Parkinson's disease (Latourelle et al., BMC Med. Genet. 2009, 10, 98). These results suggest that inhibition of AAK1 activity may be useful for the treatment of schizophrenia, cognitive impairment in schizophrenia, Parkinson's disease, neuropathic pain, bipolar disorder, and Alzheimer's disease.

[0004] In addition, studies with Huh-7.5 cells have shown that AAK1 kinase inhibitors may be useful for treating hepatitis C (HCV) infection. Reduction of AAK1 protein by RNA interference-mediated gene silencing, treatment with the kinase inhibitor sunitinib (a potent AAK1 inhibitor), and overexpression of a Mu2 phosphorylation site mutant (a substrate of AAK1) all reduce HCV virion assembly. Furthermore, the same treatments were shown to inhibit HCV entry, suggesting that AAK1 inhibitors can disrupt two host-dependent stages of the viral life cycle (Neveu et al. PLoS Pathog. 2012, 8, 1-16; Neveu et al., J. Virol. 2015, published online February 4). AAK1 inhibitors may also be useful against HIV and HBV (see, e.g., Boge et al., J. Biol. Chem. 1998, 273, 15773-15778).

[0005] Many AAK1 inhibitors have been disclosed in the literature. See, for example, Hartz, RA et al., J. Med. Chem., 2021 Aug 12; 64(15): 11090-11128. One example is the specific AAK1 inhibitor (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-amine, which has been prepared on a small laboratory scale. See, for example, U.S. Pat. No. 9,902,722. Unfortunately, synthetic techniques useful in laboratory settings are rarely suitable for large-scale production of pharma- ceutically acceptable substances. For example, the generation of potentially harmful reaction by-products must be minimized, and the use of toxic solvents and reagents is desirably avoided. Moreover, reaction conditions that may work well on a gram scale are often inefficient or dangerous on a larger scale.

[0006] Similarly, a solid form of a compound (e.g., an amorphous form) that may be sufficient for preclinical testing is not necessarily suitable for large-scale manufacturing or storage. Some forms may be more stable than others. For example, some forms may be more easily degraded when exposed to heat or moisture, and some forms may change to forms that have different pharmacological properties (e.g., bioavailability) than the original form. Some forms may have solubility profiles that are difficult to formulate, and some forms may be more difficult to obtain free of impurities that affect safety when administered to patients. Thus, there is a need for a solid form of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-amine, or a pharma- ceutically acceptable salt thereof, that can be prepared in commercially useful quantities, is stable, and can be easily formulated into a safe and effective dosage form. Summary of the Invention

[0007] 3. Overview of the Invention The present application relates to solid forms of adaptor associated kinase 1 (AAK1) inhibitors, (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J) and salts thereof.

[0008] Certain embodiments of the present invention encompass the solid form of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-aminium dihydrogen phosphate (Compound K): [ka]

[0009] Other embodiments of the invention include methods for preparing Compound K and pharmaceutical compositions comprising same. The invention also includes methods of its use to treat or manage diseases and disorders, including pain (e.g., neuropathic pain) and viral infections. [Brief description of the drawings]

[0010] 4. Brief Description of the Drawings [Figure 1] 1 provides a representative X-ray powder diffraction (XRPD) pattern of the crystalline solid form I of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentane-2-aminium dihydrogen phosphate (Compound K). The spectrum was obtained using a Bruker X-ray diffractometer equipped with a LYNXEYE detector (copper Kα radiation). [Diagram 2] A representative differential scanning calorimetry (DSC) thermogram of the crystalline solid form of Compound K is provided. The thermogram was obtained using a TA Instruments DSC Q2000 instrument and a sealed gold crucible filled under ambient conditions. Two scans were performed. After melting was complete in the first scan, the sample was quenched to -50°C at approximately -40K per minute and a second scan was recorded. The heating rate was 10K per minute for both scans. [Diagram 3] 1 provides a flow chart of the process used to prepare tablets containing 50 mg of Compound K. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] 5 Detailed explanation The present invention relates to (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J): [ka] and the pharma- ceutically acceptable salts thereof. Particular salts include the hydrochloride and phosphate salts.

[0012] 5.1 Definition Unless otherwise indicated, the phrases "compounds of the invention," "compounds of the disclosure," and the like refer to compounds disclosed herein.

[0013] Unless otherwise noted, the term "include" has the same meaning as "include but are not limited to," and the term "includes" has the same meaning as "includes but is not limited to." Similarly, the term "such as" has the same meaning as the term "such as, but not limited to."

[0014] Unless otherwise specified, the terms "manage," "managing," and "management" include preventing the recurrence of a particular disease or disorder in a patient already suffering from the disease or disorder and / or increasing the time that a patient suffering from a disease or disorder remains in remission. The term includes modulating the threshold, onset, and / or duration of the disease or disorder, or altering the way in which a patient responds to a disease or disorder.

[0015] Unless otherwise specified, a "therapeutically effective amount" of a compound refers to an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or an amount sufficient to delay or minimize one or more symptoms associated with a disease or condition. A "therapeutically effective amount" of a compound refers to an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment or management of a disease or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0016] Unless otherwise indicated, the terms "treat", "treating" and "treatment" contemplate actions that occur while a patient is suffering from a particular disease or disorder, and that reduce the severity of the disease or disorder or retard or slow the progression of the disease or disorder.

[0017] Unless otherwise noted, one or more adjectives immediately preceding a series of nouns are to be construed as applying to each of the nouns individually. For example, the phrase "optionally substituted alkyl, aryl, or heteroaryl" has the same meaning as "optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl."

[0018] 5.2 Salts and solid forms The present invention relates to an AAK1 inhibitor, (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J): [ka] This work is the result of extensive research and experimentation directed to discovering whether thermodynamically and chemically stable pharma- ceutically acceptable salts of the compounds of the present invention can be prepared in high purity on a large commercial scale. The work was further directed to discovering whether thermally stable crystalline solid forms of those salts can be repeatedly prepared under such conditions, and whether any of them have suitable physical (e.g., flowability, solubility) properties for use in the manufacture of pharmaceutical dosage forms.

[0019] Initially, a crystalline form of the free base of Compound J was prepared and studied, but it was found that neither it nor other solid forms of the free base exhibited sufficient stability and solubility for incorporation into a pharmaceutical dosage form.

[0020] Laboratory-scale reaction conditions were then developed that allowed for the generation and isolation of salts prepared by reacting the free base of compound J with 1.05-1.20 equivalents of various acids. Although the specific conditions required for each generation (e.g., solvent, reaction temperature, cooling cycle, filtration) varied, 12 potentially useful crystalline salts were identified: hydrochloride, hydrobromide, mesylate, citrate, fumarate, malate, phosphate, sulfate, L-tartrate, ethane 1,2-disulfonate, (+)-(1S)-camsylate, and R-(-)-mandelate. All of the resulting crystalline materials were characterized by XRPD, DSC, and TGA. Stoichiometry was determined by HPLC. Of these, six leading candidates were identified: [Table 1]

[0021] Extensive further characterization coupled with the development of a large-scale production, isolation and purification process revealed that, among all salts tested, (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-aminium dihydrogen phosphate (compound K): [ka] was found to be the most desirable.

[0022] Further investigation led to the selection of a particular crystalline form of this salt for use in large-scale manufacturing of the dosage form. This crystalline form, designated herein as Form I, has an XRPD spectrum substantially similar to that shown in Figure 1, with diffraction peaks at one or more of about 4.81, 5.99, 7.44, 7.89, 11.66, 14.85, 15.77, 19.19, 20.86, 21.65, 23.96, 24.48, or 24.73 degrees 2θ. When referring to XPRD peaks herein, the term "about" means ±0.2 degrees 2θ.

[0023] Crystalline Form I of Compound K has a melting point of about 184° C. as determined by differential scanning calorimetry (DSC) (melting endotherm) (see FIG. 2). When referring to temperatures, the terms "substantially" and "about" mean ±2° C.

[0024] Crystalline form I of compound K is the most stable form discovered for this salt. Storage for up to 4 weeks at 40°C and 75% relative humidity did not alter either the form itself, its morphology, or its purity. Furthermore, although the melting point of form I is lower than that of the hydrochloride salt of compound J (where a form with a melting point of approximately 247°C was discovered), the phosphate salt shows no associated degradation. Instead, melting of form I was observed to recrystallize into another metastable form with a melting point of approximately 172.5°C. Large-scale production and purification of form I is further aided by its water solubility, which is 26.8 mg / mL at 25°C. In comparison, the measured water solubility of the hydrochloride salt of compound J was 2.9 mg / mL at 25°C.

[0025] Despite its poor solubility, a crystalline form of the hydrochloride salt of Compound J has been prepared and was found to have a melting point (decomposition point) of about 247° C. The XRPD spectrum of that form showed peaks at about 9.2, 11.7, 13.9, 18.7, 22.2, 25.0, and 26.8 degrees 2θ.

[0026] Crystalline form I of compound K can be prepared from the free base (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (compound J), which itself can be prepared by methods known in the art. See, for example, U.S. Pat. No. 9,902,722.

[0027] In the most general sense, compound K can be prepared as follows: [ka] In this approach, compound K is prepared by contacting compound J with phosphoric acid in a solvent under conditions sufficient to form compound K. Examples of solvents include water, methanol, ethanol, n-butanol, isobutanol, t-butanol, methyl t-butyl ether, ethyl acetate, isopropyl acetate, THF, and 2-methyl THF, and mixtures thereof. A particular solvent is isopropanol.

[0028] In some embodiments of the invention, compound J is contacted with phosphoric acid at a temperature of about 0° C. to about 100° C., or about 50° C. to about 60° C. (When referring to reaction conditions, the term "about" when used to refer to temperature may be interpreted as ±10° C., unless otherwise indicated). In some embodiments, compound J is contacted with phosphoric acid for about 0.5 hours to about 24 hours, or about 2 hours to about 16 hours. (When referring to reaction conditions, the term "about" when referring to time may be interpreted as ±5% unless otherwise indicated. For example, "about 2 hours" is the same as 2 hours ±6 minutes). In some embodiments, about 0.8 to about 1.2 molar equivalents (e.g., about 1 molar equivalent) of phosphoric acid relative to compound J is utilized (Unless otherwise indicated, the term "about" when referring to molar equivalents or concentrations may be interpreted as ±5%). In some embodiments, the concentration of compound J in the solvent is about 2% to about 25%.

[0029] In another approach, compound K is prepared from compound S as shown below: [ka] Here, compound S is neutralized with a base under conditions sufficient to form compound J and contacted with phosphoric acid under conditions sufficient to form compound K. Bases suitable for neutralization include NaOH, KOH, Na2CO3, and K2CO3. A preferred base is sodium hydroxide.

[0030] Neutralization of compound S with a base may be carried out in a solvent such as water, water / MTBE, water / THF, and water / 2-MeTHF (preferred solvent is water / MTBE), and at a temperature of about 0° C. to about 60° C. (e.g., about 20° C. to about 40° C.). In some embodiments of the invention, the neutralization is carried out for about 0.5 hours to about 24 hours (e.g., about 1 hour to about 2 hours). In some embodiments, about 0.8 to about 5 molar equivalents of base relative to compound S are utilized. In some embodiments, the concentration of compound S in the solvent is about 2% to about 25%.

[0031] The exposure of compound J to phosphoric acid in the second step above is typically carried out in a solvent such as water, methanol, ethanol, n-butanol, isopropanol, isobutanol, t-butanol, methyl t-butyl ether, ethyl acetate, isopropyl acetate, THF and 2-methyl THF, or mixtures thereof. A preferred solvent is isopropanol.

[0032] In some embodiments, the exposure of compound J to phosphoric acid is carried out at a temperature of about 0° C. to about 100° C. (e.g., about 50° C. to about 60° C.). In some embodiments, the exposure of compound J to phosphoric acid is carried out for about 0.5 hours to about 24 hours (e.g., about 7 hours to about 14 hours). In some embodiments, about 0.8 to about 1.2 molar equivalents of phosphoric acid relative to compound J are utilized in the second step. In some embodiments, the concentration of compound J in the solvent is about 2% to about 25%.

[0033] Compound S can be prepared as shown below: [ka] In one embodiment, compound S is prepared by exposing compound J to hydrochloric acid in a solvent under conditions sufficient to form compound S. In some embodiments, the solvent is water, IPA, a water / IPA mixture, MeOH, MeOH / water, EtOH, EtOH / water, n-BuOH, or n-BuOH / water. A preferred solvent is isopropanol.

[0034] Exposure of compound J to hydrochloric acid is carried out at a temperature of about 0° C. to about 60° C. (e.g., about 50° C. to about 60° C.) for about 0.5 hours to about 24 hours (e.g., about 4 hours to about 8 hours). About 0.8 to about 1.2 molar equivalents of hydrochloric acid relative to compound J are typically used. In some embodiments, the concentration of compound J in the solvent is about 2% to about 25%.

[0035] 5.3 How to use One embodiment of the present invention encompasses a method of inhibiting adaptor associated kinase 1 (AAK1), both in vitro and in vivo, comprising contacting AAK1 with a compound of the present invention.

[0036] Another embodiment includes a method for treating and managing diseases and disorders mediated by AAK1 activity. Diseases and disorders mediated by AAK1 activity are diseases and disorders that have at least one symptom whose severity or expression is influenced by AAK1 activity. Examples of such diseases and disorders are believed to include Alzheimer's disease, bipolar disorder, pain, Parkinson's disease, schizophrenia (including cognitive impairment in schizophrenia), and viral infections. Certain methods include administering to a patient (human or other mammal) in need thereof a therapeutically or prophylactically effective amount of an AAK1 inhibitor (e.g., a compound disclosed herein).

[0037] Another embodiment of the present invention includes a method for treating or managing a disease or disorder, comprising administering a therapeutically or prophylactically effective amount of an AAK1 inhibitor to a patient in need thereof, wherein the disease or disorder is Alzheimer's disease, bipolar disorder, pain, Parkinson's disease, schizophrenia (including cognitive impairment in schizophrenia), or viral infection. Particular types of pain include chronic pain, acute pain, and neuropathic pain. Particular types of neuropathic pain include fibromyalgia and peripheral neuropathy (e.g., diabetic neuropathy).

[0038] The present invention is directed, in part, to methods of combating (e.g., treating) coronavirus infection. Coronaviruses are a group of related viruses that cause disease in mammals and birds. In humans, coronaviruses cause respiratory infections that can range from mild to fatal. Mild illnesses include the common cold (mainly rhinoviruses, but other causes may also be possible), while more lethal illnesses can result, such as Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and Coronavirus Disease 2019 (COVID-19).

[0039] Certain embodiments of the invention include treating patients infected with SARS-CoV2, HCoV NL63, MERS-CoV, CoV-229E, CoV-HKU1, or a virus that shares at least 95% sequence homology with SARS-CoV2, HCoV NL63, MERS-CoV, CoV-229E, or CoV-HKU1. See, e.g., International Application No. PCT / US21 / 27946, filed April 19, 2021.

[0040] When used to treat or manage a disease or disorder, the compounds of the invention are preferably administered as part of a pharmaceutical composition that includes one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0041] Pharmaceutical compositions or formulations may be presented in unit dosage forms containing a predetermined amount of active ingredient per unit dose. Dosage levels of about 0.01 to about 250 milligrams per kilogram of body weight ("mg / kg") of the compounds of the present disclosure per day, preferably about 0.05 to about 100 mg / kg of body weight per day, are typical in monotherapy for the prevention and treatment of diseases. Typically, the pharmaceutical compositions of the present disclosure are administered about 1 to about 5 times per day, or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a unit dosage form may vary depending on the disease being treated, the severity of the disease, the time of administration, the route of administration, the excretion rate of the compound employed, the duration of treatment, and the age, sex, weight, and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub-dose, or a reasonable fraction thereof, of the active ingredient, as herein above described. Treatment may be initiated with small dosages that are significantly less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. Generally, the compounds are most desirably administered at a concentration level that will generally obtain effective results without causing any harmful or deleterious side effects.

[0042] The compounds of the invention may be administered in combination with one or more additional therapeutic or prophylactic agents. For example, when used to treat pain, possible additional agents include immunosuppressants and anti-inflammatory agents.

[0043] Immunosuppressants suitable for use in the methods and compositions of the present invention include those known in the art. Examples include aminopterin, azathioprine, cyclosporine A, D-penicillamine, gold salts, hydroxychloroquine, leflunomide, methotrexate, minocycline, rapamycin, sulfasalazine, tacrolimus (FK506), and pharma- ceutically acceptable salts thereof. A particular immunosuppressant is methotrexate.

[0044] Other examples include anti-TNF antibodies, such as adalimumab, certolizumab pegol, etanercept, and infliximab. Others include interleukin-1 blockers, such as anakinra. Others include anti-B cell (CD20) antibodies, such as rituximab. Others include T cell activation blockers, such as abatacept.

[0045] Other examples include inosine monophosphate dehydrogenase inhibitors, such as mycophenolate mofetil (CellCept®) and mycophenolic acid (Myfortic®).

[0046] Anti-inflammatory agents suitable for use in the methods and compositions of the present invention include those known in the art, examples of which include glucocorticoids and NSAIDs.

[0047] Examples of glucocorticoids include aldosterone, beclomethasone, betamethasone, cortisone, deoxycorticosterone, dexamethasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and pharma- ceutically acceptable salts thereof.

[0048] Examples of NSAIDs include salicylates (e.g., aspirin, amoxiprine, benorylate, choline magnesium salicylate, diflunisal, facelamine, methyl salicylate, magnesium salicylate, salicylic acid, and pharmaceutically acceptable salts thereof), arylalkanoates (e.g., diclofenac, aceclofenac, acemetacin, bromfenac, etodolac, indomethacin, nabumetone, sulindac, tolmetin, and pharmaceutically acceptable salts thereof), arylpropionic acids (e.g., ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid, sulphonamide ... profen, and pharmaceutically acceptable salts thereof), arylanthranilic acids (e.g., meclofenamic acid, mefenamic acid, and pharmaceutically acceptable salts thereof), pyrazolidine derivatives (e.g., azapropazone, metamizole, oxyphenbutazone, phenylbutazone, sulfinprazone, and pharmaceutically acceptable salts thereof), oxicams (e.g., lornoxicam, meloxicam, piroxicam, tenoxicam, and pharmaceutically acceptable salts thereof), COX-2 inhibitors (e.g., celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, and pharmaceutically acceptable salts thereof), and sulfonanilides (e.g., nimesulide and pharmaceutically acceptable salts thereof).

[0049] Other medications used to treat pain (including, but not limited to, neuropathic pain and inflammatory pain) include medications such as pregabalin, lidocaine, duloxetine, gabapentin, carbamazepine, capsaicin, and other serotonin / norepinephrine / dopamine reuptake inhibitors, opiates (such as OxyContin, morphine, and codeine).

[0050] In treating pain caused by a known disease or condition, such as diabetes, infection (e.g., shingles or HIV infection), or cancer, the compounds of the present invention may be administered in combination with one or more additional therapeutic or prophylactic agents directed to the underlying disease or condition. For example, when used to treat diabetic neuropathy, the compounds of the present invention may be administered in combination with one or more antidiabetic agents, antihyperglycemic agents, antihyperlipidemic / lipid-lowering agents, antiobesity agents, antihypertensive agents, and appetite suppressants. Examples of antidiabetic agents include biguanides (e.g., metformin, phenformin), glucosidase inhibitors (e.g., acarbose, miglitol), insulin (insulin secretagogues, and insulin sensitizers), meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, gliclazide, chlorpropamide, and glipizide), biguanide / glyburide combinations (e.g., Glucovance), thiazolidinediones (e.g., troglitazone, loxacin), and the like. ciglitazone, and pioglitazone), PPAR-α agonists, PPAR-γ agonists, PPAR α / γ dual agonists, glycogen phosphorylase inhibitors, inhibitors of fatty acid binding protein (aP2), agonists of glucagon-like peptide-1 (GLP-1) or other GLP-1 receptors, dipeptidyl peptidase IV (DPP4) inhibitors, and sodium-glucose cotransporter 2 (SGLT2) inhibitors (e.g., dapagliflozin, canagliflozin, and LX-4211).

[0051] 5.4 Pharmaceutical Compositions The pharmaceutical formulations may be adapted for administration by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, topical, intravenous, or intradermal injection or infusion). Such formulations may be prepared by any method known in the pharmaceutical art, for example, by combining the active ingredient with the carrier(s) or excipient(s). Oral administration or administration by injection is preferred.

[0052] Pharmaceutical formulations suitable for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions.

[0053] For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral non-toxic pharma- ceutically acceptable inert carrier such as ethanol, glycerol, water, etc. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier, for example, an edible carbohydrate, such as starch or mannitol. Flavoring agents, preservatives, dispersing agents, and coloring agents can also be present.

[0054] Capsules are manufactured by preparing a powder mixture as described above and filling formed gelatin sheaths. Glidants and lubricants, such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol, can be added to the powder mixture before the filling operation. Disintegrants or solubilizers, such as agar-agar, calcium carbonate, or sodium carbonate, can also be added to improve the availability of the medicament when the capsule is ingested.

[0055] Furthermore, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (e.g., glucose or β-lactose), corn sweeteners, natural and synthetic gums (e.g., acacia, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrating agents include, but are not limited to, starch, methylcellulose, agar, betonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding lubricants and disintegrating agents, and pressing into tablets. Powder mixtures are prepared by mixing suitable comminuted compounds with diluents or bases as described above, and optionally with binders such as carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone, dissolution retarders (e.g. paraffin), resorption enhancers such as quaternary salts, and / or absorbents (e.g. betonite, kaolin, or dicalcium phosphate). The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage, or solutions of cellulosic or polymeric materials, and forcing through a sieve. Instead of granulating, the powder mixture may be passed through a tablet machine, resulting in imperfectly formed slugs being broken into granules. The granules may be lubricated by the addition of stearic acid, a stearate salt, talc, or mineral oil to prevent sticking to the tablet forming dies. The lubricated mixture is then compressed into tablets. The compounds of the present disclosure can also be combined with free-flowing inert carriers and compressed directly into tablets without the granulation or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a sugar or polymeric coating, and a polish coating of wax may be provided, and dyes may be added to these coatings to distinguish different unit dosages.

[0056] Oral liquid preparations such as solution, syrup, elixir, etc. may be prepared in dosage unit form so that a given amount contains a predetermined amount of compound.Syrup may be prepared by dissolving compound in a suitably seasoned aqueous solution, while elixir may be prepared by using non-toxic excipients.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavor additives such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners may be added.

[0057] Where appropriate, dosage unit formulations for oral administration may be microencapsulated. Formulations may also be prepared to provide extended or sustained release, for example by coating or embedding particulate matter in polymers, waxes, and the like.

[0058] The compounds of formula (I) and their pharma- ceutically acceptable salts can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0059] The compound of formula (I) and its pharma- ceutically acceptable salts may also be delivered by using monoclonal antibodies as individual carriers to which the compound molecules are bound. The compound may also be bound to a soluble polymer as a targetable drug carrier. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide polylysine substituted with palytoyl residues. In addition, the compound may be bound to a group of biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0060] Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to be in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research 1986, 3(6), 318.

[0061] Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.

[0062] Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or enemas.

[0063] Pharmaceutical formulations adapted for nasal administration where the carrier is a solid include coarse powders having a particle size, for example in the range 20 to 500 microns, which are administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose. Formulations where the carrier is a liquid, suitable for administration as a nasal spray or drops, include aqueous or oily solutions of the active ingredient.

[0064] Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered dose pressurized aerosols, nebulizers, or inhalers.

[0065] Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.

[0066] Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules or vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0067] It should be understood that in addition to the ingredients particularly mentioned above, the formulations may contain other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0068] Preferred formulations contain high purity active pharmaceutical ingredients (APIs) by synthesising potential impurities, including those shown in Table 2 below: 1 It was characterized by 1 H NMR and mass spectrometry. [Table 2] The compounds in Table 2 were observed at various stages in the laboratory scale development work leading to the methods of the present invention.

[0069] The present invention includes methods for testing the purity of compound J, or a pharma- ceutically acceptable salt thereof, by testing for the presence of one or more of the compounds listed in Table 1. Preferred methods include using mass spectrometry and / or HPLC to test for the presence of one or more compounds. EXAMPLES

[0070] 5.5 Working Example Various embodiments of the invention can be understood by consideration of the examples provided below, in which all temperatures are given in degrees Celsius and all parts and percentages are by weight unless otherwise noted. Reagents may be purchased from commercial suppliers and used without further purification unless otherwise noted. (Reagents may also be prepared according to standard literature procedures known to those skilled in the art.)

[0071] Unless otherwise specified, reactions were carried out at ambient (or room) temperature. Reactions were typically monitored by HPLC and terminated as judged by the consumption of starting material.

[0072] The structure and purity of the compound were confirmed by proton nuclear magnetic resonance ( 1 H NMR) spectroscopy, 13 The compounds were characterized by one or more of the following techniques: C NMR spectroscopy, mass spectrometry, infrared spectroscopy, melting point, X-ray crystallography, LC-MS and / or HPLC. Chemical shifts are reported in parts per million (ppm, δ) downfield from a standard, such as an internal standard, e.g., TMS. Alternatively, 1 H NMR chemical shifts were referenced to signals from residual protons in deuterated solvents, as known in the art. Peak multiplicities are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; br, broadened; and m, multiplet. Coupling constants are given in Hertz (Hz). Mass spectral (MS) data were obtained using a mass spectrometer equipped with APCI or ESI ionization.

[0073] 5.5.1 Synthesis of 6-bromo-2-(dimethoxymethyl)-3-fluoropyridine (compound L1) [ka] A solution of HCl / MeOH (10 mL of a 3.9 M solution, 0.05 eq.) was charged to a mixture of SM2 (158.5 g, 777 mmol, 1 eq.), MeOH (1585 mL, 10 V) and trimethoxymethane (166 g, 15.6 mol, 2.0 eq.). The resulting mixture was aged at 60-65 °C (reflux) until reaction completion (3-6 h) and then cooled to 10-20 °C. After concentrating to 2-3 V below 50 °C and diluting with 2-Me-THF (10 V), the reaction was quenched with 10% K2CO3 (3 V). The organic layer was separated and concentrated to 1-2 V below 50 °C. This was flushed with 2-Me-THF (5V) and further diluted with 2-Me-THF (5V) to give a 2-Me-THF solution of compound L1 (845.2g, 99% purity, 21.7% assay, 94.4% solution yield). LC-MS: LC-MS: m / z 250, 252, 220, 218 (M-OMe) 1 H NMR (400 MHz, chloroform-d) δ 7.38 (dd, J = 3.5, 8.6 Hz, 1H), 7.17-7.30 (m, 1H), 5.37-5.48 (m, 1H), 3.39 (s, 6H).

[0074] 5.5.2 Synthesis of 4-chloro-2-(dimethoxymethyl)pyridine (compound L2) [ka] HCl / MeOH (42.3 mL of a 3.9 M solution, 0.20 eq.) was charged to a mixture of SM3 (117.3 g, 819.5 mmol, 1 eq.), MeOH (1160 mL, 10 V) and trimethoxymethane (174 g, 1.64 mol, 2.0 eq.). The mixture was heated to 60-65 °C (reflux) until reaction completion (6-10 h) and then cooled to 10-20 °C. After concentration to 3-5 V and dilution with 2-Me-THF (10 V), the reaction was quenched with 10% K2CO3 (3 V, pH 8-9). The organic layer was separated, concentrated to 1-2 V, flushed with 2-Me-THF (5 V × 2), and diluted with 2-Me-THF (5 V) to obtain a 2-Me-THF solution of compound L2 (588.5 g, 99.18% purity by HPLC, 22.3% assay, 85.3% solution yield). 1 H NMR (400 MHz, chloroform-d) δ 8.42-8.57 (m, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 2.1, 5.3 Hz, 1H), 5.28-5.39 (m, 1H), 3.38 (s, 6H). LC-MS m / z 187, 156 (M-OMe).

[0075] 5.5.3 Synthesis of 2',6-bis(dimethoxymethyl)-5-fluoro-2,4'-bipyridine phosphate (compound L4-phosphate) [ka] Preparation of L3: A mixture of compound L2 (95.5 g, 1.00 eq., 5-6 V), 2-Me-THF (10 V), Pin2B2 (1.05 eq.), KOAc (3.0 eq.) and Xphos (0.02 eq.) in 2-Me-THF was degassed by sparging with N2. Pd2(dba)3 (0.01 eq.) was added and the mixture was again degassed by sparging with N2. The reaction mixture was heated to 70-80 °C and stirred until boronation of L2 was complete (16-24 h) to give L3, which was used directly in the subsequent Suzuki coupling step.

[0076] Preparation of L4 by Suzuki coupling of L3 and L1: After cooling to 15-25 °C, a solution of compound L1 in 2-Me-THF (0.96 eq., 5-6 V), Na2CO3 (2.0 eq. solid), and H2O (5 V) were added sequentially. After degassing by sparging with N2, the reaction mixture was aged at 70-80 °C until the Suzuki coupling was complete (16-24 h). After cooling to 15-25 °C, the reaction mixture was filtered through a pad of diatomaceous earth (0.5X) and the filter cake was washed with 2-Me-THF (1-2 V). The organic layer of the filtrate was separated, concentrated to 1-2 V, diluted with toluene (10 V), and washed twice with L-cysteine / NaOH (pH>10) (5X, ratio of L-cysteine / NaOH / H2O: 1 / 0.5 / 9). The organic layer was then washed with H2O (5x) and concentrated to 5 V to give a toluene solution of compound L4 free base. An analytical sample of L4 free base was obtained by crystallization in heptane / MTBE. 1 H NMR (400 MHz, chloroform-d) δ 8.66-8.77 (m, 1H), 8.06 (d, J =1.22 Hz, 1H), 7.94 (dd, J = 1.77, 5.20 Hz, 1H), 7.86 (dd, J = 3.55, 8.56 Hz, 1H), 7.51-7.60 (m, 1H), 5.63 (s, 1H), 5.44-5.48 (m, 1H), 3.54-3.60 (m, 6H), 3.43-3.49 (m, 6H);M.P. 41.8 °C (DSC peak);XRPD 2θ: 6.70, 7.61, 9.67, 13.56, 13.77, 13.99, 15.36, 19.36, 20.71, 21.81, 23.10, 26.96, 27.72, 28.02, 29.36, 31.88, 32.04, 39.09.

[0077] Preparation of L4-phosphate: A solution of 85% H3PO4 (1.6 eq. based on compound L4 free base) in MeOH (1-2 V) was added to the above L4 solution in toluene over 2 h to give a suspension. The suspension was concentrated to 3 V below 45 °C and n-heptane (10 V) was added over 2 h. The mixture was concentrated to 10 V below 45 °C and the batch temperature was adjusted to 15-25 °C. After stirring for 6-8 h, the mixture was filtered and the filter cake was washed with n-heptane (1-2 V). The wet cake was dried under reduced pressure at 40 °C with a slight N2 sweep to give 190.5 g of L4-phosphate (93.2% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.63-8.72 (m, 1H), 8.24 (dd, J = 3.6, 8.7 Hz, 1H), 8.11 (d, J = 1.1 Hz, 1H), 8.01 (dd, J = 1.8, 5.2 Hz, 1H), 7.92 (dd, J = 8.7, 9.9 Hz, 1H), 5.58 (s, 1H), 5.36 (s, 1H), 3.43 (s, 6H), 3.35 (s, 6H). LC-MS: [M+H] + 323.2; mp 124.2°C (DSC peak); XRPD 2θ: 4.87, 7.35, 9.20, 12.76, 14.66, 15.06, 15.92, 16.99, 19.56, 19.81, 20.26, 21.55, 22.12, 23.09, 23.39, 23.73, 25.61, 26.25, 27.48, 27.73, 28.26, 29.55, 30.35, 31.10, 31.82, 34.13, 34.68, 36.04, 39.48.

[0078] 5.5.4 Synthesis of 5-fluoro-[2,4'-bipyridine]-2',6-dicarboxaldehyde (Compound Q) [ka] A mixture of compound L4-phosphate (177 g, 111 g L4 free base = 1.0x), 1N hydrochloric acid (1110 mL, 10 V) and toluene (555 mL, 5 V) was stirred at 15-25 °C for 0.5-1.0 h. The organic phase was separated and the aqueous layer was stirred at 55-60 °C for 2 h. The mixture was concentrated slowly (3 h) under reduced pressure (-0.08 to -0.085 MPa) at 55-60 °C to remove the evolved MeOH, then cooled to 30-40 °C. DCM (777 V) was charged and the pH of the mixture was adjusted to 5-7 with 15% Na2CO3 (3.5-4.5x). The layers were separated and the aqueous layer was extracted with DCM (2 V). The combined organic layers were washed with H2O (5 V) and filtered through a pad of Na2SO4 (1x). The filter pad was washed with DCM (2V) and the combined filtrate was concentrated to 8-10V. The reactor walls were spray washed with 2V of DCM and n-heptane (8-10V) was charged over 2.0-5.0 h. The mixture was concentrated to 10-12V at <60°C (residual DCM in the supernatant ≤40%) under normal atmospheric pressure. The suspension was aged at 30-40°C for 1.0-2.0 h, 5-10°C for 6-8 h, and filtered. The filter cake was washed with 1:4 DCM / n-heptane (1-2V) and dried under vacuum at 40-50°C to give 80.19 g of compound Q (98% yield). LC-MS: [M+H] + 231;[M+H+H2O] + 249; 1 H NMR (400 MHz, chloroform-d) δ 10.27 (s, 1H), 10.18 (s, 1H), 8.91-9.00 (m, 1H), 8.51-8.59 (m, 1H), 8.24-8.31 (m, 1H), 8.17(dd, J = 3.5, 8.7 Hz, 1H), 7.77 (t, J = 9.0 Hz, 1H); melting point 150 °C (DSC peak).

[0079] 5.5.5 Synthesis of 2',6-bis(difluoromethyl)-5-fluoro-2,4'-bipyridine (Compound H) [ka] A solution of compound Q (30.0 g, 1.00×) and Et3N (0.044×) in dry DCM (KF≦0.02%, 20×) was cooled to 0–5°C. DAST (3.50×) was added slowly at 0–10°C, and the mixture was aged at 20–25°C until reaction completion (approximately 24 h). The reaction mixture was quenched with 15% K2CO3 (28×) at 0–20°C for 2 h and aged at 20–25°C for 0.5 h. The organic layer was separated, cooled to 10–20°C, and treated with 1 M hydrochloric acid (9.9–11.1×) at 10–25°C for 0.5–1 h. After settling for 0.5 h, the mixture was filtered through a pad of diatomaceous earth (~0.5×) followed by a brief wash with DCM (2.0–3.0×). The filtrate was allowed to settle, the organic layer was separated, washed with HO (10x), and filtered through a pad of silica gel (~1.5x). The silica pad was washed with DCM (5.0x~6.0x, 3 times) until the purity of compound H in the filtrate fractions was reduced to <90%. The combined filtrates were concentrated to approximately 2-3 V at <30 °C and co-distilled with isopropanol at 50 °C until the residual DCM was <5.0% (6-7x IPA was used in total) to a final volume of 3-4 V. The distillation residue was aged at 55-60 °C for 0.5 h, cooled to 35-40 °C, and aged for 0.5 h. Water (9.0-10.0x) was slowly added (1-3 h) at 33-40 °C, and the mixture was stirred for 0.5 h. After aging at 15-20°C, the suspension was filtered and the filter cake was washed successively with IPA / H2O (1:4, w / w, 1x) and H2O (2x). The wet cake was dried under vacuum at 40-45°C until KF < 0.3% and residual IPA < 0.1% (18-24 h) to give 30.15 g of compound H (82% yield). Melting point (mp) 75°C (DSC peak). LC-MS: [M+H] + 275.2; 1 H NMR (400 MHz, chloroform-d) δ 8.71-8.89 (m, 1H), 8.22 (s, 1H), 7.91-8.12 (m, 2H), 7.71 (t, J = 8.9 Hz, 1H), 7.00 (s, 1H), 6.87 (s, 1H), 6.82-7.05 (m, 1H), 6.59 (s, 1H), 6.73 (s, 1H).

[0080] 5.5.6 Synthesis of (S)-2-amino-2,4-dimethylpentan-1-ol benzoate (compound D-benzoate) [ka] BF3·Et2O (200 g, 2.0 eq.) was added slowly to a mixture of NaBH4 (53 g, 2.0 eq.) in THF (1.0 L) at 0–10 °C. The reaction mixture was warmed to 15 °C and (S)-(α)-methylleucine (100 g, 1.0 eq.) was added over 1 h at <25 °C. The mixture was aged at 20–25 °C for 5–8 h and then slowly quenched into 10% aqueous NaOH (750 mL) at 25–30 °C. The organic layer was separated, washed with 15% aqueous NaCl (200 mL) and diluted with n-heptane (300 mL). 2 N hydrochloric acid (ca. 300 mL) was added to the mixture until the pH reached 1–2. The organic layer was separated and extracted with 1 N hydrochloric acid (300 mL). The combined aqueous layers were basified with 30% NaOH (~500 mL) until pH > 13 and extracted with MTBE (500 mL × 3). The combined organic extracts were dried over anhydrous Na2SO4 (100–200 g), filtered, concentrated to ~200 mL, and flushed with MTBE (200–500 mL) until the water content of the concentrate was less than 0.5%. Then, a solution of amino alcohol D was added slowly (5 h) at 45–50 °C to a solution of benzoic acid (93 g, 1.1 eq.) in MTBE (500 mL). After stirring for 1 h, the mixture was cooled slowly (5–8 h) to 20–25 °C and aged for 5–8 h to obtain a suspension. The suspension was filtered, and the filter cake was washed with 1 / 1 MTBE / n-heptane (150 mL) and dried under reduced pressure at 40–50 °C to obtain compound D-benzoate in 92% yield. Melting point 125.4°C (DSC peak); 1H NMR (400 MHz, methanol-d4) δ 7.88-7.99 (m, 2H), 7.27-7.46 (m, 3H), 3.45-3.62 (m, 2H), 1.69-1.87 (m, 1H), 1.56-1.66 (m, 1H), 1.44-1.54 (m, 1H), 1.29 (s, 3H), 1.00 (d, J = 6.60 Hz, 6H); 20.32, 21.23, 22.28, 23.70, 24.09, 24.42, 26.24, 26.91, 27.49, 30.60, 32.64, 33.98, 34.98, 35.13.

[0081] 5.5.7 Synthesis of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-amine hydrochloride (Compound S) [ka] Solid t-BuOK (2.5-3.0 eq. based on compound H) was charged portionwise to a mixture of compound D-benzoate (1.2 eq. based on compound H) and THF (10.5-11.6x) at 15-20°C. The mixture was warmed to 20-25°C, stirred for 3-5 hours, and then cooled to 0-5°C. A solution of compound H (1.00x) in THF (3.6-4.5x) was added slowly (~1 hour) while maintaining the batch temperature below 20°C. The reaction mixture was aged at 20-25°C until completion (1-3 hours). MTBE (6x) was added and the mixture was cooled to 10-15°C. H2O (9.0-11.0x) was added slowly (1-3 hours) while maintaining the batch temperature below 25°C. The layers were separated and the aqueous layer was extracted with MTBE (2.2x). The combined organic layers were concentrated under reduced pressure to 2-3 V below 30° C. Free base compound J: 1H NMR (400 MHz, DMSO-d6) δ 8.70-8.84 (m, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.33 (s, 1H), 8.22 (br d, J = 5.0 Hz, 1H), 7.81 (d, J =8.8 Hz, 1H), 7.17-7.41 (m, 1H), 6.89-7.13 (m, 1H), 3.82-3.95 (m, 2H), 1.74-1.88 (m, 1H), 1.55 (br s, 2H), 1.33-1.46 (m, 2H), 1.12 (s, 3H), 0.93 (t, J = 7.1 Hz, 6H). After solvent exchange to IPA by co-distillation (6.0–6.5×) to 2–3 V, more IPA (3.8–4.2×) was added and the mixture was heated to 50–60 °C. A solution of 35% hydrochloric acid (0.44–0.47×) in IPA (1.3–1.5×) was added slowly (ca. 1 h) while keeping the batch at 50–60 °C. The resulting suspension was aged at 50–60 °C for 1.0–2.0 h, cooled to 20–30 °C in 2.0–4.0 h, stirred at 20–30 °C for 1.0–2.0 h, and then filtered. The filter cake was washed with MTBE (3.5–4.0×) and dried under reduced pressure at 40–50 °C for 16–24 h to give compound S. LC-MS m / z 386.1; mp. 246.4 °C (DSC peak), 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 5.3 Hz, 1H), 8.51 (br s, 2H), 8.45 (d, J = 8.9 Hz, 1H), 8.34 (s, 1H), 8.24 (d, J = 5.1 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.56-7.87 (m, 1H), 6.90-7.23 (m, 1H), 4.29 (s, 2H), 1.72-1.91 (m, 2H), 1.54-1.72 (m, 1H), 1.42 (s, 3H), 0.86-1.00 (m, 6H).

[0082] 5.5.8 Synthesis of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-amine phosphate (Compound K) [ka] A mixture of compound S (9.5 kg, 1.0×), MTBE (76.0 kg, 8.0×), and water (50.0 kg, 5.3×) was treated with 20% aqueous NaOH (0.95 kg NaOH solid in 4.0 kg water) at 35–40 °C until all solids were dissolved (2.0–5.0 h). The reaction mixture was cooled to 20–25 °C and stirred for 1.0–2.0 h. The organic layer was separated, washed with water (46.5 kg, 4.9×), and concentrated under reduced pressure below 30 °C to approximately 25 L (2–3×). The solvent was exchanged to IPA by co-distillation (79.0 kg IPA, 8.3×) under reduced pressure below 50 °C to a final volume of 29–38 L (3–4×), after which the distillation residue was diluted with IPA (60 kg) and heated to 50–60 °C. A solution of H3PO4 (2.8 kg, 0.29x) in IPA (5.0 kg, 0.53x) was added over 2.0-4.0 h. IPA (22.0 kg, 2.3x) was further added and the batch was stirred at 50-60 °C for 2.0-4.0 h. The batch was cooled to 15-20 °C over 2.0-4.0 h and then stirred at 15-20 °C for 1.0-2.0 h. The resulting suspension was filtered and the filter cake was washed sequentially with IPA (27.0 kg, 2.84x) and MTBE (31 kg, 3.3x). The wet cake was dried under reduced pressure at 45-55 °C for 17-24 h to obtain compound K. The salt ratio of compound J to phosphoric acid in compound K was 1:1 (two separate HPLC methods using UV and IC detectors, respectively). The purity of compound K was 98.7-99.9 area % by HPLC. The crystallinity of compound K was confirmed by XRPD and further supported by DSC. 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 5.1 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.31 (s, 1H), 8.21 (d, J = 5.1 Hz, 1H), 7.88 (brd, H), 7.47 (t, JH-C-F = 54 Hz, 1H), 7.04 (t, J H-C-F = 54 Hz, 1H), 4.03-4.29 (m, 2H), 1.72-1.87 (m, 1H), 1.60-1.69 (m, 1H), 1.49-1.59 (m, 1H), 1.33 (s, 3H), 0.92 (d, J = 6.6, 3H), 0.87 (d, J = 6.6, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 21.62, 22.74, 24.61, 24.82, 44.69 54.57, 72.80, 110.53 (t, J C-F = 237 Hz), 113.84 (t, J C-F = 238 Hz), 116.68, 122.19, 125.03, 140.07 (t, J C-F = 22 Hz), 144.13, 145.98, 150.52, 152.80 (t, J C-F = 25 Hz), 153.51. XRPD: 4.80, 5.99, 7.43, 7.88, 9.57, 11.58, 14.84, 15.21, 15.75, 17.91, 18.83, 19.17, 20.41, 20.84, 21.67, 23.23, 23.95, 24.41, 24.72, 25.27, 26.37, 30.14.

[0083] 5.5.9 Synthesis of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-amine phosphate (Compound K) [ka] To a solution of compound J (9.14 g) in IPA (100 mL) was added compound K seeds (0.18 g) at 50-60 °C. A solution of 85% phosphoric acid (2.87 g, 1.05 eq.) in IPA (7 mL) was added over 2-4 h. The suspension was aged for 2-4 h, cooled to 15-20 °C over 2-4 h, and aged for 1-2 h. The suspension was filtered and the filter cake was washed with IPA (20 mL) and then with MTBE (44 mL). The wet cake was dried under reduced pressure at 45-55 °C for 17-24 h to give 11.3 g of compound K (98% yield).

[0084] Seeding of compound K: Compound J (50.08 mg, 0.134 mmol, 1.0 eq.) was added with IPA (1.0 mL) to give a clear solution at ambient temperature, and phosphoric acid (0.156 mL, 1 M in IPA, 0.156 mmol, 1.20 eq.) was added. The mixture was stirred for 6 h to give a suspension and aged at 60 °C for 30 min. After cooling to room temperature, heptane (0.5 mL) was added and the resulting mixture was stirred for 1 h. The resulting suspension was filtered, the filter cake was washed with MTBE (0.5 mL) and dried overnight at 45-48 °C under reduced pressure to give compound K seeds (59.28 mg, 94.4% yield).

[0085] The salt ratio, purity, XRPD, DSC and TGA data are substantially identical to those obtained for compound K in Example 2.

[0086] 5.5.10 Tablet dosage form Tablets containing 10 mg, 20 mg, and 50 mg of Compound K were prepared in batches of 20,000 using the ingredients listed below: [Table 3]

[0087] The tablet manufacturing flow chart is shown in Figure 3. The same process is used for all three strengths, however the compression / coating flow chart only depicts the process for the 50 mg strength. The excipient grades, sieve sizes, and blend times depicted in the flow chart can be adjusted based on process requirements and batch size. With reference to Figure 3, the following steps were followed to prepare a solid oral dosage form of Compound K: 1. The amount of Compound K is adjusted according to the supplier's Certificate of Analysis, potency based on assay (wt%, HPLC). 2. Compound K, silicified microcrystalline cellulose, dibasic calcium phosphate anhydrous, and croscarmellose sodium are passed through a sieve into a bin blender and mixed. Note: The proportions of silicified microcrystalline cellulose and dibasic calcium phosphate anhydrous are adjusted according to the potency of Compound K determined in step 1. 3. Sift the talc and colloidal silicon dioxide into the step 2 blend and mix. 4. Add hydrogenated vegetable oil through a sieve to the blend from step 3 and mix. 5. Compress the blend from step 4. 6. The tablet cores of step 5 are then coated with an aqueous dispersion of OpaDry II White, exhibiting approximately a 4% weight gain. 7. The coated tablets from step 6 are packaged in HDPE bottles sealed with child resistant caps.

[0088] Each document (eg, patents, patent applications, and publications) cited herein is hereby incorporated by reference in its entirety.

Claims

1. A crystalline compound, wherein the compound is (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-aminium dihydrogen phosphate (Compound K): 【Chemistry 1】

2. 2. The crystalline compound of claim 1, wherein the XPRD pattern has peaks at one or more of about 4.81, 5.99, 7.44, 7.89, 11.66, 14.85, 15.77, 19.19, 20.86, 21.65, 23.96, 24.48, or 24.73 degrees 2θ.

3. 2. The crystalline compound of claim 1, having a melting point of about 184°C.

4. A composition comprising an active pharmaceutical ingredient (API), an excipient, and a lubricant, wherein the API is a crystalline compound, which is a pharma- ceutically acceptable salt of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J): 【Chemistry 2】

5. 5. The composition of claim 4, comprising less than 0.05% by weight (e.g., less than 0.01, less than 0.005, or less than 0.001) of at least one of the compounds listed in Table 2.

6. A tablet comprising the composition of claim 4.

7. The tablet according to claim 6, which is coated.

8. 7. The tablet of claim 6, comprising 10, 20 or 50 mg of a pharma- ceutically acceptable salt of Compound J.

9. 7. The composition of claim 4 or the tablet of claim 6, wherein the pharma- ceutically acceptable salt of compound J is compound K.

10. 13. A method of treating or managing pain in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

11. 13. A method of treating or managing pain in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of the formulation of claim 4.

12. 12. The method of claim 10 or 11, wherein the pain is neuropathic pain.

Images