MC2r modulator compounds

Abstract

The disclosures herein relate to pharmaceutical compositions comprising a compound of Formula (1): (1); or a pharmaceutically acceptable salt thereof and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with the melanocortin subtype-2 receptor (MC2R).

Description

[0001] MC2R MODULATOR COMPOUNDS

[0002] This application relates to pharmaceutical compositions comprising compounds having activity as melanocortin subtype-2 receptor (MC2R) antagonists. Pharmaceutical compositions described herein may be useful in the treatment or prevention of diseases in which MC2R is involved. This application is also directed to the manufacture and use of these compositions in the prevention or treatment of diseases in which MC2R is involved.

[0003] BACKGROUND OF THE INVENTION

[0004] Adenocorticotropic hormone (ACTH) is a 39-amino acid peptide implicated in the regulation of adrenal glucocorticoid synthesis and secretion within the hypothalamic-pituitary-adrenal (HPA) axis, and as such, plays a primary role in regulation of stress responses. ACTH is synthesized by corticotropic cells in the anterior pituitary via proteolytic cleavage of proopiomelanocortin (POMC). Upon stressful stimuli, ACTH is secreted and acts at the melanocortin 2 receptor (MC2R) in adrenal glands to regulate synthesis and secretion of glucocorticoids and androgens. The secretion of glucocorticoids provides negative feedback to both hypothalamus and anterior pituitary to reduce production and secretion of corticotropic releasing hormone (CRH) and ACTH respectively - thereby providing a fine balance in regulating stress responses. Diseases linked to ACTH dysfunction range from Cushing’s disease to congenital adrenal hyperplasia, ectopic ACTH syndrome (or ectopic Cushing’s syndrome) and polycystic ovarian syndrome (PCOS) (Microsc. Res. Tech. 61 , 275-287 (2003)).

[0005] The MC2R belongs to the melanocortin family of G protein-coupled receptors (GPCRs), of which there are five subtypes - MC1 R, MC2R, MC3R, MC4R and MC5R. MC1 R is associated with pigmentation regulation, MC2R with glucocorticoid synthesis, MC3R and MC4R with energy homeostasis and MC5R with exocrine gland physiology. MC2R is selectively activated by ACTH, while the remaining receptor subtypes also bind the melanocortin peptides a-, -, and y-melanocyte-stimulating hormone (a-MSH, p-MSH, and y-MSH) (Am. J. Physiol. Endocrinol. Metab. 284, E468-74 (2003); Life Sci. 59, 797-801 (1996)).

[0006] Another unique aspect of the MC2R relative to the other melanocortin receptors is that the accessory protein, MRAP (melanocortin 2 receptor protein), is required for MC2R expression and function. MRAP is a single transmembrane protein which forms an antiparallel homodimer with MC2R to allow trafficking of the receptor to the plasma membrane (Proc. Natl. Acad. Sci. 104, 20244 LP - 20249 (2007)) Binding of ACTH to the MC2R / MRAP complex in adrenal cortical cells activates cAMP production via the Gssignalling pathway. Increases in intracellular cAMP in turn stimulates cortisol synthesis and secretion (Microsc. Res. Tech. 61 , 275-287 (2003)).

[0007] Congenital adrenal hyperplasia (CAH) is a disorder characterised by disruption in adrenal steroidogenesis linked to excessive ACTH and CRH production. Three enzyme deficiencies arising from specific gene mutations are implicated: 21 -hydroxylase deficiency from mutations in CYP21A2 (the most common form), 3p-hydroxysteroid dehydrogenase (HSD3B2) and 11 p- hydroxylase (CYP11B1). In CAH, these enzyme deficiencies impair cortisol synthesis, resulting in a loss of cortisol negative feedback on CRH and ACTH. Excess ACTH results in steroidogenesis proximal to the deficient enzyme, leading to the hyperandrogenic pathophysiology associated with the disorder. CAH patients can present with hirsutism, acne, alopecia oligomenorrhea and infertility associated with virilization. Glucocorticoid and mineralocorticoid hormone replacement therapies are mainstay treatments, however require close monitoring to balance overtreatment and undertreatment. Further, ‘stress dosing’ is required at times of significant stress, illness or surgery ( . Pediatr. Adolesc. Gynecol. 30, 520-534 (2017)). Importantly, high doses of glucocorticoid replacement are required to inhibit ACTH production and thereby reduce adrenal androgen levels. This often means that in order to control adrenal androgen levels, patients will suffer from corticosteroid-associated side effects or Cushing’s-like symptoms. Thus, there remains a need for better treatments of CAH. As ACTH is elevated in CAH, inhibition of its activity, through antagonism of MC2R, provides an attractive means of modulating the steroidogenesis pathway.

[0008] Cushing’s disease is a rare disease associated with excess secretion of ACTH caused by adenomas of pituitary corticotropic cells. Clinical presentations include obesity, hirsutism, muscle weakness as well as cardiovascular and metabolic complications associated with hypercortisolism. Treatments for Cushing’s disease involve removal of either the ACTH- secreting tumour in the pituitary, or removal of the adrenal glands, however drug treatment is often used in addition to, or before surgery to alleviate symptoms. Current drug therapies aim to inhibit adrenal steroidogenesis, however, are not without adverse effects such as hypothyroidism and hypogonadism ( . Med. Life 9, 12-18 (2016)). Inhibition of ACTH activity via MC2R antagonism provides a potential therapeutic option in management of this disease.

[0009] In addition to CAH and Cushing’s disease, polycystic ovary syndrome (PCOS) may be amenable to MC2 modulation. PCOS is associated with abnormal regulation of steroidogenesis and excess androgen levels. In a subset of patients the androgen excess results from functional adrenal hyperandrogenism (Endocr. Rev. 37, 467-520 (2016)). Modulation of ACTH activity in these patients offers another therapeutic avenue for this multisystem disorder. Thus, antagonism of MC2R presents an important therapeutic modality for treatment of diseases associated with ACTH dysfunction. WO2019 / 23669, WO2021 / 091788, WO2021 / 126693, WO2021 / 133563 and WO2024 / 175928 disclose MC2R antagonist compounds.

[0010] Long duration of action is a widely sought after feature in drug design, enabling prolonged efficacy and simplified dosing regimes (British Journal of Pharmacology 2010, 161(3), 488- 508). In the treatment of diseases associated with ACTH dysfunction, in particular diseases with excess ACTH, inhibitors with longer residence times offer the advantage of insurmountable antagonism, whereby receptor inhibition remains in the face of high ACTH concentrations. A means of achieving these favourable drug properties involves developing a compound with slow dissociation (kOff) kinetics (Neurochemistry international 2007, 51(5), 254-260). This has been demonstrated at various targets, ranging from fevipiprant at the DP2 receptor to NKi neurokinin receptor antagonists (Mol Pharmacol 2016, 89(5), 593-605; The Journal of pharmacology and experimental therapeutics 2007, 322(3), 1286-1293).

[0011] THE INVENTION

[0012] The present invention relates to pharmaceutical compositions comprising compounds having activity as melanocortin subtype-2 receptor (MC2R) antagonists.

[0013] Provided is a pharmaceutical composition comprising a compound of Formula (1): or a pharmaceutically acceptable salt thereof, wherein the compound is present in a substantially pure stereoisomeric form. Compounds of the present invention may be used as melanocortin subtype-2 receptor (MC2R) modulators. Compounds of the present invention may be used as MC2R inhibitors. Compounds of the present invention may be used as MC2R antagonists. Compounds of the present invention may be used as MC2R antagonists with a long residence time at the receptor. Pharmaceutical compositions of the present invention may be used in the treatment of a disease or disorder associated with MC2R. Pharmaceutical compositions of the present invention may be used in the treatment of a disease or disorder that would benefit from the modulation of MC2R activity. Pharmaceutical compositions of the present invention may be used as medicaments or in the manufacture of medicaments. The pharmaceutical compositions or medicaments may be for use in treating, preventing, ameliorating, controlling or reducing the risk of diseases or disorders in which MC2R is involved. Pharmaceutical compositions of the present invention may be for use alone or in combination with one or more additional pharmaceutical agents.

[0014] Pharmaceutical compositions of the present invention may be useful in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome (or ectopic Cushing’s syndrome), polycystic ovary syndrome (PCOS), depressive illness, septic shock, and disorders or symptoms related thereto.

[0015] DETAILED DESCRIPTION OF THE INVENTION

[0016] The invention relates to compounds and pharmaceutical compositions thereof and their use as modulators of the melanocortin subtype-2 receptor (MC2R), in particular as MC2R antagonists. The invention further relates to compounds which have a long residence time at the MC2R receptor. The invention further relates to the manufacture of medicaments for use as MC2R antagonists. The invention further relates to pharmaceutical compositions and medicaments that may be useful in the treatment of a disease or disorder characterised by activation of the MC2R receptor.

[0017] Provided is a pharmaceutical composition comprising a compound of Formula (1):

[0018] or a pharmaceutically acceptable salt thereof, wherein the compound is present in a substantially pure stereoisomeric form. Also provided is a pharmaceutical composition comprising a compound which is present in a substantially pure stereoisomeric form, wherein the compound is selected from the group consisting of:

[0019] (1D) (1 E) (1 F)

[0020] or a pharmaceutically acceptable salt thereof.

[0021] Also provided is a pharmaceutical composition comprising a compound which is present in a substantially pure stereoisomeric form, wherein the compound is a compound of Formula (1 A): or a pharmaceutically acceptable salt thereof.

[0022] Also provided is a pharmaceutical composition comprising a compound of Formula (1) or a pharmaceutically acceptable salt thereof, wherein the compound is present in a stereoisomeric purity of at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5%.

[0023] Also provided is a pharmaceutical composition comprising a compound of Formula (1A) or a pharmaceutically acceptable salt thereof, wherein the compound is present in a stereoisomeric purity of at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5%.

[0024] Also provided is a pharmaceutical composition comprising a compound of Formula (1) or a pharmaceutically acceptable salt thereof, wherein the compound is present in a diastereomeric excess (de) of at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5%. Also provided is a pharmaceutical composition comprising a compound of Formula (1A) or a pharmaceutically acceptable salt thereof, wherein the compound is present in a diastereomeric excess (de) of at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5%.

[0025] Also provided is a pharmaceutical composition comprising a compound of Formula (1) or a pharmaceutically acceptable salt thereof, wherein the compound is present in an enantiomeric excess (ee) of at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5%.

[0026] Also provided is a pharmaceutical composition comprising a compound of Formula (1A) or a pharmaceutically acceptable salt thereof, wherein the compound is present in an enantiomeric excess (ee) of at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5%.

[0027] Also provided is a pharmaceutical composition comprising a compound of Formula (1) or a pharmaceutically acceptable salt thereof, wherein the compound is present in a diastereomeric excess (de) of at least 98% and an enantiomeric excess (ee) of at least 98%.

[0028] Also provided is a pharmaceutical composition comprising a compound of Formula (1) or a pharmaceutically acceptable salt thereof, wherein the compound is present in a diastereomeric excess (de) of at least 99% and an enantiomeric excess (ee) of at least 99%.

[0029] Also provided is a pharmaceutical composition comprising a compound of Formula (1) or a pharmaceutically acceptable salt thereof, wherein the compound is present in a diastereomeric excess (de) of at least 99.5% and an enantiomeric excess (ee) of at least 99.5%.

[0030] Also provided is a pharmaceutical composition comprising a compound of Formula (1A) or a pharmaceutically acceptable salt thereof, wherein the compound is present in a diastereomeric excess (de) of at least 98% and an enantiomeric excess (ee) of at least 98%.

[0031] Also provided is a pharmaceutical composition comprising a compound of Formula (1A) or a pharmaceutically acceptable salt thereof, wherein the compound is present in a diastereomeric excess (de) of at least 99% and an enantiomeric excess (ee) of at least 99%.

[0032] Also provided is a pharmaceutical composition comprising a compound of Formula (1A) or a pharmaceutically acceptable salt thereof, wherein the compound is present in a diastereomeric excess (de) of at least 99.5% and an enantiomeric excess (ee) of at least 99.5%.

[0033] Also provided is a pharmaceutical composition as described herein, wherein the compounds of Formula (1 B) to (1 H) or a pharmaceutically acceptable salt thereof are present in no more than 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1 % by weight in relation to the compound of formula (IA) or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the compound is present in the form of a pharmaceutically acceptable salt.

[0035] In some embodiments, the pharmaceutical composition described herein is formulated for administration in the form of a tablet, capsule, granules, intramuscular injection or intravenous injection. The pharmaceutical composition may be formulated for oral delivery. The pharmaceutical composition described herein may be administered in the form of a tablet, capsule, granules, intramuscular injection or intravenous injection. The pharmaceutical composition may be administered orally.

[0036] In some embodiments, the pharmaceutical composition described herein comprises at least one of a pharmaceutically acceptable diluent, carrier or excipient. The pharmaceutically acceptable diluent, carrier or excipient may be selected from: a solubilising agent, diluent, lubricant, binding agent, disaggregating agent, pigment, wetting agent, matrix polymer, carrier, shell, lipophilic liquid vehicle, semi-solid lipophilic vehicle, surfactant and an emulsifier.

[0037] The pharmaceutical composition described herein may be provided in the form of a capsule, including shells (e.g. gelatin or hydroxypropyl methylcellulose (HPMC)), solid fill capsules and liquid fill capsules, and may comprise a lipophilic liquid vehicle (e.g. refined oils, triglycerides), a semi-solid lipophilic vehicle (e.g. hydrogenated oils, cetostearyl / cetyl / stearyl alcohols, glyceryl esters, TPGS, polyoxylglycerides), a solubilizer, a surfactant or an emulsifier (e.g. Tween 80, poloxamers).

[0038] The pharmaceutical composition described herein may be provided in the form of a tablet, which may comprise a solid oral excipient, including solubilising agents (e.g. cyclodextrins or modified cyclodextrins), diluents (e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch), lubricants (e.g. silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols), binding agents (e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone), disaggregating agents (e.g. starch, alginic acid, alginates or sodium starch glycolate), pigments (e.g. iron oxides), wetting agents (e.g. lecithin, polysorbates, laurylsulphates), acid-resistant polymers or matrix polymers (e.g. hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose acetate succinate, alginate, carboxymethyl cellulose, carboxymethyl cellulose, methacrylic acid copolymers, shellac, cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate, methyl cellulose acetate phthalate, cellulose acetate isophthalate, cellulose acetate trimellitate).

[0039] The pharmaceutical composition described herein may be provided in the form of an oral liquid, which may comprise a solubilising agent (e.g. cyclodextrins or modified cyclodextrins), or carrier (e.g saccharose or saccharose with glycerine and / or mannitol and / or sorbitol, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol).

[0040] The pharmaceutical composition described herein may be provided in the form of an intramuscular injection, which may comprise a carrier (e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol) or a solubilising agent (e.g. cyclodextrins or modified cyclodextrins).

[0041] The pharmaceutical composition described herein may be provided in the form of an intravenous Injection, which may comprise a carrier (e.g. sterile water) or a solubilising agent (e.g. cyclodextrins or modified cyclodextrins).

[0042] The compound, or pharmaceutically acceptable salt thereof may be administered in any effective therapeutic amount. The compound in the pharmaceutical composition, or pharmaceutically acceptable salt thereof may be administered in any effective therapeutic amount.

[0043] The compound as a free base may be administered at a dose of 1-150 mg (for the purposes of the dose, when the compound is a salt, the mass of the active agent is only considered and so the counter ion is not considered as part of the dose mass). The compound may be administered at a dose of 5-100 mg. The compound may be administered at a dose of 5-60 mg (e.g. 5-50 mg, 5-40 mg, 5-30 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-30 mg, 20-60 mg, 20-50 mg, 20-40 mg, 20-30 mg, 30-60 mg, 30-50 mg, 30-40 mg). The compound may be administered at a dose of 20-50 mg. The compound may be administered at a dose of 0.01-3 mg / kg. The compound may be administered at a dose of 0.1-2 mg / kg. The compound may be administered at a dose of 0.2-1 mg / kg (e.g. 0.2-0.9 mg / kg, 0.2-0.8 mg / kg, 0.2-0.7 mg / kg, 0.2- 0.6 mg / kg, 0.2-0.5 mg / kg, 0.2-0.4 mg / kg, 0.2-0.3 mg / kg, 0.3-0.9 mg / kg, 0.3-0.8 mg / kg, 0.3-0.7 mg / kg, 0.3-0.6 mg / kg, 0.3-0.5 mg / kg, 0.3-0.4 mg / kg).

[0044] Further embodiments of the invention include the use of a pharmaceutical composition as described herein in therapy. Also included is the use of a pharmaceutical composition as described herein as a melanocortin subtype-2 receptor (MC2R) modulator. Pharmaceutical compositions of the present invention may be used as MC2R receptor modulators. Pharmaceutical compositions of the present invention may be used as MC2R receptor inhibitors or antagonists. Pharmaceutical compositions of the present invention may be used in the treatment of a disease or disorder characterised by activation of MC2R. Pharmaceutical compositions of the present invention may be used in the treatment of a disease or disorder associated with ACTH excess or in the treatment of a disease or disorder that would benefit from the modulation of MC2R activity. The compounds of the present invention may have a residence time at the MC2R receptor of at least 50 min, for example at least 60 min, 70 min, 80 min, 90 min, 100 min, 110 min, 120 min or 130 min.

[0045] Compounds and pharmaceutical compositions of the present invention may be used in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS), depressive illness, septic shock and disorders or symptoms related thereto.

[0046] In some embodiments, pharmaceutical compositions described herein are used as modulators of MC2R. Provided herein is a method of treating a disease in an individual comprising administering an effective amount of a pharmaceutical composition as described herein or any embodiment, variation or aspect thereof.

[0047] Compounds as MC2R modulators as disclosed herein can be useful as a prophylactic or therapeutic agent for MC2R associated diseases. In some embodiments, a pharmaceutical composition described herein may be used in a method of treating Cushing’s disease in an individual.

[0048] Also provided are combinations comprising a pharmaceutical composition of the present invention and a Corticotropin-releasing factor receptor-1 (CRFi) antagonist. In the combinations the CRFi antagonist may be selected from the group consisting of tildacerfont, crinecerfont, NBI-27914, CP-316,311 , NBI-462000, DMP696, pexacerfont, NBI-35965, ONO- 2333Ms, antalarmin, NBI-34041, DMP904, NBI-30775, SSR125543, NBI-77860, GSK876008, CRA5626 / JNJ19567470 / R317573, NBI-76169, verucerfont, and CP-154,526.

[0049] In the combinations the CRFi antagonist may be selected from:

[0050] Also provided are combinations comprising a pharmaceutical composition of the present invention and an ACTH antibody. In the combinations the ACTH antibody may be ALD1613 (Feldhaus et al. Endocrinology, Jan 2017, 158(1): 1-8).

[0051] The combinations may be used in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS), depressive illness, septic shock and disorders or symptoms related thereto.

[0052] Also provided herein are uses of a pharmaceutical composition described herein, in the manufacture of a medicament. In some embodiments, the manufacture of a medicament is for the treatment of a disorder or disease described herein. In some embodiments, the manufacture of a medicament is for the prevention and / or treatment of a disorder or disease mediated by MC2R.

[0053] In some embodiments, a pharmaceutical composition described herein may be used in a method as either a stand-alone therapy, or as a conjunctive therapy with other agents that are either palliative (e.g., agents that relieve the symptoms of the disorder to be treated), and / or agents that target the etiology of the disorder. Pharmaceutical compositions of the present invention may be used or administered in combination with a second therapeutic agent.

[0054] In some embodiments, (a) a pharmaceutical composition described herein and (b) an agent are sequentially administered, concurrently administered or simultaneously administered. In certain embodiments, (a) a pharmaceutical composition described herein and (b) an agent are administered with a time separation of about 15 minutes or less, such as about any of 10, 5, or 1 minutes or less. In certain embodiments, (a) a pharmaceutical composition described herein and (b) an agent are administered with a time separation of about 15 minutes or more, such as about any of 20, 30, 40, 50, 60, or more minutes. Either (a) a pharmaceutical composition described herein and (b) an agent may be administered first. In certain embodiments, (a) a pharmaceutical composition described herein and (b) an agent are administered simultaneously.

[0055] The compounds, pharmaceutical compositions and combinations disclosed herein may be for use in therapy.

[0056] The compounds, pharmaceutical compositions and combinations disclosed herein may be for use in the treatment of a disorder associated with ACTH excess or that would benefit from the modulation of MC2R activity.

[0057] The compounds, pharmaceutical compositions, combinations and / or dosages thereof disclosed herein may be for use in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS), depressive illness, septic shock, or disorders or symptoms related thereto.

[0058] Also provided is a method of treating a disorder associated with ACTH excess or that would benefit from the modulation of MC2R activity in a patient, comprising administering an effective amount of a pharmaceutical composition or combination as described herein or any embodiment, variation or aspect thereof.

[0059] Also provided is a method of treating congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS), depressive illness, septic shock, or disorders or symptoms related thereto in a patient, comprising administering an effective amount of a pharmaceutical composition or combination as described herein or any embodiment, variation or aspect thereof.

[0060] The compounds, pharmaceutical compositions, combinations and / or dosages thereof disclosed herein may be used in the manufacture of a medicament for the treatment of a disorder associated with ACTH excess or that would benefit from the modulation of MC2R activity. The compounds, pharmaceutical compositions and combinations disclosed herein may be used in the manufacture of a medicament for the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS), depressive illness, septic shock, or disorders or symptoms related thereto. DEFINITIONS

[0061] In this application, the following definitions apply, unless indicated otherwise.

[0062] The term “MC2R modulator” as used herein refers to any compound which binds to and modulates the function of MC2 receptors. The term “modulator” should be interpreted to include modulation by modalities including, but not limited to antagonists.

[0063] The term “treatment”, in relation to the uses of any of the compounds described herein, including those of Formula (1) and (1A) is used to describe any form of intervention where a compound is administered to a subject suffering from, or at risk of suffering from, or potentially at risk of suffering from the disease or disorder in question. Thus, the term “treatment” covers both preventative (prophylactic) treatment and treatment where measurable or detectable symptoms of the disease or disorder are being displayed.

[0064] The term “effective therapeutic amount” (for example in relation to methods of treatment of a disease or condition) refers to an amount of the compound which is effective to produce a desired therapeutic effect. For example, if the condition is pain, then the effective therapeutic amount is an amount sufficient to provide a desired level of pain relief. The desired level of pain relief may be, for example, complete removal of the pain or a reduction in the severity of the pain.

[0065] The term “enantiomeric excess” (ee) as used herein, means the excess of one enantiomer relative to another in a sample. For example, a composition comprising with 95% of one enantiomer and 5% of the other has an ee of 90%. A racemic mixture has an ee of 0%, while a single completely pure enantiomer has an ee of 100%.

[0066] The term “diastereomeric excess” (de) as used herein, means the excess of one diastereomer relative to another in a sample. For example, a composition comprising with 95% of one diastereomer and 5% of the other has a de of 90%. A racemic mixture has a de of 0%, while a single completely pure diastereomer has an de of 100%.

[0067] Chemical terms are all used in their conventional sense (e.g. as defined in the IIIPAC Gold Book), unless indicated otherwise.

[0068] Salts or pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

[0069] Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, potassium and calcium. Further examples of acid addition salts include acid addition salts formed with acetic, 2,2-dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g. benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1 ,5-disulfonic and p-toluenesulfonic), ascorbic (e.g. L- ascorbic), L-aspartic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphorsulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1 ,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g. D- glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g. (+)-L-lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g. (-)-L-malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulfonic (mesylate), 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, tartaric (e.g.(+)-L-tartaric), thiocyanic, trifluoromethanesulfonate (triflate), undecylenic and valeric acids.

[0070] Also encompassed are any solvates of the compounds and their salts. Preferred solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and DMSO. Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray crystallography.

[0071] The solvates can be stoichiometric or non-stoichiometric solvates. Particular solvates may be hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates. For a more detailed discussion of solvates and the methods used to make and characterise them, see Bryn et al, Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0072] The term “pharmaceutical composition” in the context of this invention means a composition comprising an active agent and comprising additionally one or more pharmaceutically acceptable diluents, carriers or excipients. The composition may comprise a pharmaceutically acceptable diluent, carrier or excipient as described above. The composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the mode of administration and dosage forms. The compositions may take the form, for example, of tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations. Examples of pharmaceutically acceptable excipients include carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents (e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release-controlling agents (e.g. release retarding or delaying polymers or waxes), binding agents, disintegrants, buffering agents, lubricants, preservatives, anti-fungal and antibacterial agents, antioxidants, tonicity-adjusting agents, thickening agents, flavouring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions.

[0073] The compounds of the invention may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope1H,2H (D), and3H (T). Similarly, references to carbon and oxygen include within their scope respectively12C,13C and14C and16O and18O. In an analogous manner, a reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise. For example, a reference to an alkyl group such as an ethyl group or an alkoxy group such as a methoxy group also covers variations in which one or more of the hydrogen atoms in the group is in the form of a deuterium or tritium isotope, e.g. as in an ethyl group in which all five hydrogen atoms are in the deuterium isotopic form (a perdeuteroethyl group) or a methoxy group in which all three hydrogen atoms are in the deuterium isotopic form (a trideuteromethoxy group). The isotopes may be radioactive or non-radioactive.

[0074] Therapeutic dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with the smaller dosages which are 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. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

[0075] The magnitude of an effective dose of a compound will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound and its route of administration. The selection of appropriate dosages is within the ability of one of ordinary skill in this art, without undue burden. The compound may be administered at a dose as described above. In general, daily dose ranges may be from about 10 pg to about 30 mg per kg body weight of a human and non-human animal, preferably from about 50 pg to about 1 mg per kg of body weight of a human and non-human animal, for example from about 50 pg to about 5 mg per kg of body weight of a human and non-human animal, for example from about 100 pg to about 3 mg per kg of body weight of a human and non-human animal, for example from about 100 pg to about 1 mg per kg of body weight of a human and non-human animal and most preferably from about 100 pg to about 0.5 mg per kg of body weight of a human and non-human animal.

[0076] The term “pharmaceutically acceptable” as used herein means compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

[0077] Pharmaceutical compositions containing compounds of the Formula (1) or (1 A) can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical compositions can be in any form suitable for oral, parenteral, intravenous, intramuscular, intrathecal, subcutaneous, topical, intranasal, intrabronchial, sublingual, buccal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

[0078] Tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.

[0079] Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the Gl tract.

[0080] Pharmaceutical compositions typically comprise from approximately 1 % (w / w) to approximately 95%, preferably% (w / w) active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient (for example as defined above) or combination of such excipients. Preferably, the compositions comprise from approximately 20% (w / w) to approximately 90% (w / w) active ingredient and from 80% (w / w) to 10% of a pharmaceutically acceptable excipient or combination of excipients. The pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragees, powders, tablets or capsules.

[0081] Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and / or 0-99% (w / w) fillers / or bulking agents (depending on drug dose). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, 0-5% (w / w) pigments. Slow release tablets would in addition typically contain 0-99% (w / w) release-controlling (e.g. delaying) polymers (depending on dose). The film coats of the tablet or capsule typically contain 0-10% (w / w) polymers, 0-3% (w / w) pigments, and / or 0-2% (w / w) plasticizers.

[0082] The pharmaceutical formulations may be presented to a patient in “patient packs” containing an entire course of treatment in a single package, usually a blister pack.

[0083] The compounds of the Formula (1) or (1A) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. In general, for oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically 1 milligram to 0.5 grams, for example 1 milligram to 0.2 grams, e.g. 1 milligram to 50 milligrams, of active compound.

[0084] The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective amount). The precise amounts of compound administered may be determined by a supervising physician in accordance with standard procedures.

[0085] EXAMPLES

[0086] PREPARATION OF THE COMPOUNDS OF THE INVENTION

[0087] Example 1 may be prepared in accordance with the below scheme.

[0088] Intermediate 8 Intermediate 9ExamPle 1Abbreviations & Acronyms

[0089]

[0090] Analytical HPLC method

[0091] Analytical Chrial method:

[0092] A: Column Name: WHELK (R,R), Co-Solvent: 20%, Co-Solvent Name: 0.5% Isopropyl Amine in IPA, Injected Volume: 15 pl, Flow rate: 4 mL / min, Outlet Pressure: 100 bar, 40 °C.

[0093] B: Column Name: I Cellulose Z, Co-Solvent: 30%, Co-Solvent Name: 0.5% Isopropyl Amine in IPA, Injected Volume: 15 pl, Flow rate: 4 mL / min, Outlet Pressure: 100 bar, 40 °C.

[0094] W1 : Column Name: Chiralpak AD-3, 150x4.6 mm,I.D.,3um, Co-Solvent Name: MeOH(0.2%NH3(7M in MeOH),v / v, Gradient: A:B=90:10, Injected Volume: 2.8 pl, Flow rate: 2.5 mL / min, Outlet Pressure: 2000 psi, 35 °C.

[0095] W2: Column Name: Chiralpak AD-3, 150x4.6 mm,I.D.,3um, Co-Solvent Name: MeOH, Gradient: Time A% B%, 0.0 90 10, 0.5 90 10, 3.5 50 50, 4.5 50 50, 5.0 90 10, Injected Volume: 2.8 pl, Flow rate: 2.5 mL / min, Outlet Pressure: 2000 psi, 35 °C.

[0096] W3: Column Name: Chiralpak IH-3, 50x4.6mm I.D., 3um, Co-Solvent Name: MeOH[0.2%NH3(7M in MeOH), v / v], Gradient: Gradient: A:B=85:15, Injected Volume: 2.8 pl, Flow rate: 4 mL / min, Outlet Pressure: 1800 psi, 35 °C.

[0097] W4: Chiral HPLC: Column Name: (S,S)-Whelk-O1 , 4.6x150 I.D., 3.5um, Co-Solvent Name: 0.1 % IPAm in EtOH, Gradient: Gradient: 10 to 50% B in 12.0 min, 50% B at 18.0 min, 50 to 10% B at 20.0 min, 10% 25.0 min, Injected Volume: 5 pl, Flow rate: 1 mL / min, 40 °C.

[0098] LCMS method:

[0099] Preparation of Example 1 :

[0100] A 2,000 L reactor was charged with THF (350 L) under N2 protection. 70Kg of ethyl 1-benzyl- 4-oxopiperidine-3-carboxylate hydrochloric acid was added dropwise under N2 protection at 10-25 °C. 470L of 1M t-BuOK was added dropwise under N2 protection at 10-25 °C. 55Kg (28.2L) of Ethyl iodide was added dropwise to the reactor under N2 protection. The mixture was stirred at 20-25 °C for 12 hrs. 350L of water was added under N2 protection at 20-25 °C. The reaction mixture was extracted with MTBE (700 L, 10.0 V). The layers were separated and the aqueous was extracted with MTBE (350 L, 5.00 V). Combined organic layers were washed with brine (25%, 350 L, 5.00 V). The organic phase was evaporated under vacuum and swap with HOAc (35.0 L x 3, 0.50 V x 3) to obtain ethyl 1-benzyl-3-ethyl-4-oxopiperidine- 3-carboxylate as a crude yellow oil which was used without further purification (98.5 kg, 81.0% yield, 56.0% purity).

[0101] A 500L reactor was charged with HCI (12 M, 165 L) under N2 protection. 98.5Kg of ethyl 1- benzyl-3-ethyl-4-oxopiperidine-3-carboxylate was added dropwise to the reactor under N2 protection at 10-25 °C. The reaction was heated to 100 °C and stirred at 100 °C for 12 hrs. Water was charged (220 L, 4.00 V) to reactor under N2 protection at 20-25 °C. Aqueous NaOH (30%) was added to obtain pH 8-9 at 0-20 °C. The reaction was extracted with EtOAc (275 L, 5.00 V). The aqueous was separated and extracted with EtOAc (165 L, 3.00 V). The combined organic phase was washed with water (165 L, 3.00 V). The organic phase was evaporated under vacuum and swapped with ACN (220 L x 2, 4.00 V x 2). The resulting crude 1-benzyl- 3-ethylpiperidin-4-one (58.0 kg, 82.8% yield, 59.2% purity) was obtained as a yellow oil and it was used without further purification.

[0102] A 2,000 L reactor was charged with ACN (340 L) under N2 protection. 58.0Kg of 1-benzyl-3- ethylpiperidin-4-one was added under N2 protection. ACN was charged (340 L) to reactor 2 under N2 protection. 91.5 Kg of (2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinic acid was charged to reactor 2 under N2 protection. The reactor 2 solution was added to reactor 1 under N2 protection. The reaction was heated to 40 °C. It was stirred at 40 °C for 72 hrs. It was cooled to 10-20 °C. It was stirred at 10-20 °C for 2 hrs. The mixture was filtered and the solid cake obtained was washed with ACN (100 L, 3.00 V). MTBE was charged (340 L, 10.0 V) to reactor 1 under N2 protection. The filter cake was added to reactor 1 under N2 protection. Aqueous NaHCOs (680 L, 20.0 V) was charged to reactor 1 under N2 protection. The mixture was stirred at 10-20 °C for 2 hrs. The aqueous was separated and extracted with MTBE (170 L x 2, 5.00 V x 2). The combined organic phase was washed with water (100 L, 3.00 V). The organic phase was concentrated in vacuum at 30 °C. ACN was charged (270 L, 8.00 V) to reactor 1 under N2 protection. The crude was charged to reactor 1 under N2 protection. ACN (270 L, 8.00 V) was charged to reactor 2 under N2 protection. 91.5Kg of (2R,3R)-2,3-bis((4- methylbenzoyl)oxy)succinic acid was charged to reactor 2 under N2 protection. The solution in reactor 2 was charged to reactor 1 under N2 protection. The reaction was heated to 40 °C and the mixture stirred for 12 hrs. The mixture was cooled to 10-20 °C. The mixture was stirred at 10-20 °C for 2 hrs. The mixture was filtered and the resulting solid cake was washed with ACN (80.0 L, 2.40 V) to obtain (S)-1-benzyl-3-ethylpiperidin-4-one (2R,3R)-2,3-bis((4- methylbenzoyl)oxy)succinate (Intermediate 2) (53.0 kg, 55.5% yield) as a white solid.

[0103] In a 1000L MTBE (300 L) was charged under N2 protection. 53.0 Kg of (S)-1-benzyl-3- ethylpiperidin-4-one (2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinate (Intermediate 2) was then added under N2 protection. Aqueous NaHCOs (0.83 M, 223 L) was then charged to the reactor under N2 protection. The mixture was stirred at 10-20 °C for 2 hrs. The aqueous layer was separated and extracted with MTBE (150 L x 2, 3.00 V x 2). The combined organic phase was washed with water (100 L, 2.00 V). It was then concentrated in vacuum at 30 °C to obtain freebase of (S)-1-benzyl-3-ethylpiperidin-4-one (18.8 kg, 98.5% yield) (Intermediate 2B) as yellow oil which was used in the next step without further purification.

[0104] The next step in the synthesis was performed in flow with the following procedure, illustrated in Figure 7. R1 is a 200 L three-necked flask, R2 is a 200 L three-necked flask, R3 is a 200 L three-necked flask and R4 is a 200 L three-necked flask. 18Kg of freebase of (S)-1-benzyl-3- ethylpiperidin-4-one (Intermediate 2B) were charged into R1. DME (180 L) was the charged into R1 , followed by TosMIC (16.1 kg) into R1. t-BuOK (1 M, 86.5 L, 1.10 eq) was charged into R2 and t-BuOK (1 M, 118 L, 1.50 eq) was charged into R3. t-BuOH (232 L) was further charged into R3 and 10%aq. NaCI (15.0L) was charged into R4. Pump 1 was set up at 120 mL / min for R1. Pump 2 was set up at 50 mL / min for R2. Pump 3 was set up at 190 mL / min for R3 and pump 4 was set up at 180 mL / min for R4. Pumps 5 to 9 were all set at 360 mL / min and pump 10 at 540 mL / min.

[0105] P1 and P2 were open at the same time and the mixture was collected after 6 min at FLR2. P3 was open at 6 min. The solution at FLR2 was stirred at -5 °C for 3 min. P5 was then opened. The solution at CSTR1 was stirred at 22 °C for 15 min. P6 was then opened. The solution at CSTR2 was stirred at 22 °C for 15 min. P7 was then opened. The solution at CSTR3 was stirred at 22 °C for 15 min. P8 was then opened. The solution at CSTR4 was stirred at 22 °C for 10 min. P9 and P4 was then opened. The solution at FLR4 was stirred at 10 °C for 3 min. P10 was then opened. The reaction mixture was collected after running for 67 min and until 1730 min. The reaction was quenched with brine (360 L, 10%, 20.0 V) at 20-30 °C and extracted with MTBE (360 L, 20.0 V). The organic phase was concentrated under vacuum. The resulting residue was dissolved in MTBE (360 L, 20.0 V). The reaction was extracted with citric acid (360 L, 20.0 V). MTBE (360 L, 20.0 V) was added to the citric acid aqueous phase, followed by aqueous 30% NaOH (90.0 L, 5.00V). The organic layer was separated and concentrated under vacuum to obtain (3R)-1-benzyl-3-ethylpiperidine-4-carbonitrile (Intermediate 3) (14.8 kg, 64.5 mol, 82%) as a light-yellow oil.

[0106] To a 500 L reactor THF (130 L) was charged at 20 °C under N2. 13 Kg of (3R)-1-benzyl-3- ethylpiperidine-4-carbonitrile (Intermediate 3) was then charged under N2. 14.9Kg of 6-(2- ethoxyphenyl)-3-fluoropicolinic acid (Intermediate 1) was then charged into the reactor under N2. The mixture was cooled to 0-10 °C. KHMDS (1 M solution in THF, 56.9 L) was then charged dropwise to the reactor at 0-10 °C under N2. The reaction was heated to 30 °C. KHMDS (1 M solution in THF, 85.4 L) was added dropwise to the reactor at 30-40 °C under N2. The reaction was stirred at 30-40 °C for 1 hr under N2. The reaction was cooled to 0-10 °C and then quenched with aqueous NH4CI (100 L, 10%). The organic phase was separated and washed with aqueous Na2COs (10%, 100 L) and brine (50.0 L x 2). The organic phase was concentrated in vacuum. MTBE (30.0 L) was added to a reactor, followed by heptane (120 L) and then the crude product (30 kg) was added. The mixture was stirred at 20 °C for 12 hrs. The reaction was centrifuged at 20 °C. The filter cake was washed with MTBE (10.0L) and heptane (40.0 L) to obtain sodium 3-((3R,4R)-1-benzyl-4-cyano-3-ethylpiperidin-4-yl)-6-(2- ethoxyphenyl)picolinate (24.3 kg, 4.2% yield) as a yellow solid.

[0107] The product was enantiomerically enriched using the following method:

[0108] 500 mg of rel-3-((3S,4S)-1-benzyl-4-cyano-3-ethylpiperidin-4-yl)-6-(2-ethoxyphenyl)picolinic acid (ee:10%) was purified by SFC (Method: column: ChiralPak IH, 250*30mm, 10um; mobile phase: [CC>2-MeOH];B%:40%, isocratic elution mode) to yield 3-((3S,4S)-1-benzyl-4- cyano-3-ethylpiperidin-4-yl)-6-(2-ethoxyphenyl)picolinic acid (Intermediate 4A) (240 mg as free base) and sodium 3-((3R,4R)-1-benzyl-4-cyano-3-ethylpiperidin-4-yl)-6-(2- ethoxyphenyl)picolinate (Intermediate 4) (230 mg as a salt)

[0109] Analytical data for Intermediate 4A and 4 can be found in Table 1.

[0110] The next step was performed in flow using CSTR reactors as per Figure 8.

[0111] Toluene (179 L) was charged into FLV1 at 10-15 °C. 17.9 Kg of sodium 3-((3R,4R)-1-benzyl- 4-cyano-3-ethylpiperidin-4-yl)-6-(2-ethoxyphenyl)picolinate (Intermediate 4) were charged into FLV1 at 10-15 °C. FLV1 was stirred for 0.5 hr at 10-15 °C until becoming clear solution. RedAI (44.0 kg, 70% purity) was charged into FLV2 at 10-15 °C. The bath was set at 40-45 °C. Flow rate of P1 was calibrated to 75.0 mL / min. Flow rate of P2 to was calibrated to 28.0 mL / min. The collection was started after running for 40 min and stopped at 2160 min. Potassium sodium tartrate (50%) was charged into FLV3 at 10-15 °C. The reaction was quenched with potassium sodium tartrate (50%, 89.5 L, 5.0 V) at 0-10°C. The mixture was separated and the aqueous phase was extracted with MTBE (140 L x 2, 10.0 V x 2). The combined organic phase was washed with brine (70 L, 5.00 V) and concentrated in vacuum to obtain (3R,4R)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine-4,5'-

[0112] [1.7]naphthyridine] (14.0 kg, 93.16% purity) (Intermediate 5) which was used for next step without further purification.

[0113] ACN was charged (42.0 L, 3.00 V) into the reactor 1. 14Kg of (3R,4R)-1-benzyl-2'-(2- ethoxyphenyl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridine] (Intermediate 5) was then charged into reactor 1. ACN (98.0 L, 7.00 V) was charged into the reactor 2. Maleic acid (7.73 kg, 2.10 eq) was charged into reactor 2. Reactor 2 was heated to 50 °C. Reactor 1 mixture was charged dropwise to the reactor 2 at 50 °C. The resulting mixture was stirred at 50 °C for 2 hrs. Reactor 2 was then cooled to 20 °C. MTBE (280 L, 20.0 V) was then added into reactor 2 at 20 °C. The reaction was stirred at 20 °C for 10 hrs. The mixture was filtered. The filter cake was washed with ACN (28.0 L, 2.00 V) and MTBE (56.0 L, 4.00 V). The filter cake was dried in vacuum to obtain (3R,4R)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridine] bis maleate salt (Intermediate 6) (14.0 kg, 97.7% in purity, 57% from Intermediate 4) as white solid.

[0114] 25 g of (3R,4R)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine-4,5'-

[0115] [1 .7]naphthyridine]- bis maleate salt (Intermediate 6) was dissolved in water (500 mL, 20 vol). The solution was basified with 10% aq. NaOH solution (adjust to pH~13) at 25 °C. The mixture was stirred for 30 min at 25 °C, then extracted in 2-MeTHF (250 mL, 2 x10 vol). Combined organic layers were washed with water (250 L, 10 vol) dried over sodium sulphate, filtered, and concentrated on rotavapor under reduced pressure (bath temperature 40 °C) to get 16 g of freebase (3R,4R)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine- 4,5'-[1 ,7]naphthyridine] as a pale yellow solid. Note this step is essential to avoid racemisation of the aldehyde in the next step which would be detrimental for the de of the resulting product.

[0116] 7 g of (3R,4R)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-7',8'-dihydro-6'H-spiro[piperidine-4,5'-

[0117] [1 .7]naphthyridine] and 2-MeTHF (56 mL, 8 vol) were charged into a 250 mL RB flask at 25 °C. A solution of 3.16 g of tert-butyl (R)-2-formylpyrrolidine-1 -carboxylate in 2-MeTHF (14 mL, 2 vol) (note it is essential to store reagent cold and handle material with care to avoid racemisation) was added to the reaction mixture at 0 °C. The solution was stirred under N2 for 1.5 h at 0 °C. Sodium triacetoxyborohydride (5.04 g) was added in portions to the reaction mixture. The reaction mixture was stirred for 2 h. Water (70 mL, 10 vol) was added and both layers were separated. The aqueous layer was extracted with 2-MeTHF (70 mL, 10 vol). The combined organic layer was dried over anhydrous Na2SO4 and concentrated on rotavapor (bath temperature 40 °C) to get crude solid (8.5 g). The crude was co-distilled with IPA (2 x 14 mL, 2 vol). The residue was again dissolved in IPA (35 mL, 5 vol). The solution was reversely added to cold water (70 mL, 100 vol) and stirred for 2 h at RT. The mixture was slightly basified to pH ~11 by adding 10% aq. NaOH and filtered. The wet cake was slurried in water for 30 min and then filtered. The filtered solid was dried under vacuum to yield tertbutyl (R)-2-(((3R,4R)-1-benzyl-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-

[0118] [1 ,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 7) (7.9 g).

[0119] IPA (40 mL, 4 vol) was charged into a miniclave at 25 °C. The solvent was degassed with N2 for 10 min. 20% Pd(OH)2 / C (20% w / w catalyst loading, 50% wet basis, 2 g) was charged and degassed again for 5 min. To the degassed solution, 10g of tert-butyl (R)-2-(((3R,4R)-1- benzyl-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-7'(8'H)- yl)methyl)pyrrolidine-1-carboxylate (Intermediate 7) in IPA (60 mL, 6 vol) was charged. The miniclave was evacuated and backfilled with nitrogen N2 couple of times and then with hydrogen to 75 psi. The reaction mixture was heated to 70 °C and stirred for 16. The mixture was diluted with 10% MeOH / EtOAc (0.3 L, 30 vol) and filtered through celite. The celite bed was washed with 10% MeOH / EtOAc (1.2 L, 120 vol) and concentrated to get 8.5g of tert-butyl (R)-2-(((3R,4R)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]- 7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 8) as a grey solid.

[0120] 130g of tert-butyl (R)-2-(((3R,4R)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'- [1 ,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 8) was charged into a 5 L RBF at 25 °C. IPA (1.3 L, 10 vol) was charged to the RBF and stirred for 10 min. 43 g of 2,5-dichloronicotinonitrile was added to the RBF at 25 °C. DIPEA (217 mL, 1244 mmol, 5 equiv.) was added to the reaction mixture at 25 °C. The reaction mixture was then heated to 85 °C and stirred for 12 h, then allowed to cool to RT and concentrated on rotavapor at 40 °C. The resulting residue was diluted with EtOAc (10 vol) and water (10 vol.) and stirred for 15 min. The organic layer was separated, and the aqueous layer was extracted with EtOAc (10 vol.). The combined organic layer was dried over Na2SO4, filtered, and concentrated on rotavapor (at 40 °C) to get 150g of crude tert-butyl (R)-2-(((3R,4R)-1-(5-chloro-3-cyanopyridin- 2-yl)-2'-(2-ethoxyphenyl)-3-ethyl-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-7'(8'H)- yl)methyl)pyrrolidine-1 -carboxylate (Intermediate 9) which was directly used in the next step as is. 100g of crude tert-butyl (R)-2-(((3R,4R)-1-(5-chloro-3-cyanopyridin-2-yl)-2'-(2-ethoxyphenyl)- 3-ethyl-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (Intermediate 9) was charged to a 3 L neck RB flask. 2M HCI in iPrOAc (1000 mL, 10 vol.) was charged to the RBF at 25 °C. The reaction was stirred at 25 °C for 2 h and then the stirring was stopped, and the solids settled to the bottom of the RBF. iPrOAc. HCI was decanted and fresh iPrOAc (10 vol.) was added. The mixture was stirred for 10 min and then stirring was stopped and solids allowed to settle down. iPrOAc. HCI was decanted, and this process was repeated two more times. The water (1 ,000 mL, 10 vol) was added to the residue to dissolve the solid. The aqueous solution was washed with iPrOAc (3 x 5 vol.). Charcoal (25% w / w, 25 g) was added to aqueous layer and stirred for 2 h at RT. The aqueous layer was passed through a celite bed and washed with 1.5 N aqueous HCI (10 vol). The aqueous layer was then basified with 10% NaOH solution (10 vol, pH~12-13) at 0 °C. The resulting solid was filtered and suck dried. The wet cake was slurried in water (1 ,000 mL, 10 vol.) at 25 °C for 1 h. The resulting solid was filtered and suck dried. The wet cake was slurried in hot water (60 °C, 10 vol) for 1 h, filtered, and dried to afford 55g of 5-chloro-2-((3R,4R)-2'-(2-ethoxyphenyl)-3- ethyl-7'-(((R)-pyrrolidin-2-yl)methyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]- 1-yl)nicotinonitrile (Example 1).

[0121] Analytical data for all the Intermediates and Example 1 can be found in Table 1.

[0122] Table 1: Analytical Data

[0123] intermediate 7B was made via the same route as Intermediate 7 using racemic tert-butyl (RS)-2-formylpyrrolidine-1 -carboxylate.

[0124] BIOLOGICAL ACTIVITY

[0125] Terbium labelling and preparation of SNAP-tagged MC2 membranes

[0126] Cells were labelled with 100 nM of SNAP-Lumi4-Tb and incubated for 1 h at 37 °C under 95% air / 5% CO2 atmosphere prior to harvesting and pelleting by centrifugation at 3 min at 1200 rpm. Cell pellets were homogenized using an FastPrep-24 5G homogeniser (MP Biomedicals) and subsequently centrifuged and resuspended twice at 22,000xg at 4 °C (Eppendorf Centrifuge) for 30 min. The final pellet was resuspended in 10 mM HEPES and 0.1 mM EDTA, pH 7.4, at a concentration of 5-10 mg ml’1and stored at -20°C for later use.

[0127] Fluorescent Ligand Binding Assays

[0128] All fluorescent ligand binding experiments were performed with a Cy5-labelled small molecule MC2 antagonist in 384-well Optiplate low-binding plates in 1x Tag-lite buffer (PerkinElmer), with 2% DMSO, 0.04% pluronic acid and 100pg ml’1saponin. In all cases, non-specific binding was determined in the presence of 1 pM unlabelled MC2 antagonist. Signal detection was performed on a Pherastar FSX (BMG Labtech, Germany) using standard HTRF settings and the HTRF ratios were calculated by dividing the acceptor signal (665nm) by the donor signal (620nm), and multiplying the value by 10,000. TR-FRET Competitive Equilibrium Binding Assay

[0129] To determine the equilibrium dissociation constant (K,) of competing test compounds, MC2 membranes (2pg per well) were incubated with a range of concentrations of test compounds in the presence of 50nM fluorescent tracer. HTRF ratios were obtained after overnight incubation at 25°C to ensure equilibrium had been reached.

[0130] TR-FRET Competitive Binding Kinetic Assay

[0131] To determine the association (kon) and dissociation (koff) rates of unlabelled compounds, a competitive kinetic binding assay was performed which involved the simultaneous addition of 50nM fluorescent tracer and increasing concentrations of competing ligand to MC2 membranes (2pg per well). The degree of bound fluorescent tracer at MC2 was determined at multiple timepoints by HTRF.

[0132] In parallel, the association (kon) and dissociation (kOff) rates for the fluorescent tracer were determined through incubation of increasing concentrations of fluorescent tracer with MC2 membranes in the absence and presence of 1 pM unlabelled MC2 antagonist. The degree of bound fluorescent tracer was calculated at multiple timepoints by HTRF detection and association kinetic curves were generated. The resulting data were globally fitted to the association kinetic model (Prism 8.0, GraphPad, San Diego, USA) to derive a best-fit estimate for konand kOft as described under data analysis. From these data an estimate for the equilibrium dissociation constant (Kd) could be calculated.

[0133] Competition kinetic data and fluorescent tracer kinetic parameters were fit globally to the equation first described by Motulsky and Mahan (Mol. Pharmacol., 1984, 25, 1-9) to determine unlabelled compound konand kOff.

[0134] Equilibrium and kinetic binding data cAMP Giosensor cell assay

[0135] HEK293G cells, expressing the Giosensor™ cAMP biosensor (Promega, USA), were stably transfected with human MC2 and MRAP and were maintained in DMEM cell culture medium supplemented with 10% fetal bovine serum and 1% L-glutamine. On the day of experimentation, cells were plated at 25000 cells / well in sterile tissue-culture treated white 384-well plates in HEPES-buffered saline solution (145 mM NaCI, 5 mM KCI, 1.7 mM CaCI2, 1 mM MgSO4, 10 mM HEPES, 2 mM sodium pyruvate, 1.5 mM NaHCO3, 10 mM D-glucose, pH 7.4) with 0.1% w / v bovine serum albumin (BSA) and 3% Giosensor™ cAMP reagent at 37°C for 2h. To test for compound agonism at MC2R, cells were incubated with a range of concentrations of compounds and incubated for 20 minutes at room temperature in the dark before the luminescence was measured on a Pherastar FSX plate reader. Agonist curves for each compound were calculated based on the luminescence obtained after 20 minutes. To test for compound antagonism, cells were equilibrated with a range of compound concentrations for 3h at 37°C before being challenged with an ECso concentration of ACTH 1- 24 (10nM for human MC2 in this assay). The plate was incubated at room temperature in the dark for 30 minutes before luminescence was measured with a Pherastar FSX plate reader. Antagonist curves were calculated based on these luminescence values and represented as a percentage of the luminescence obtained from 10nM ACTH 1-24 as 100%, and with buffer alone as 0%. Data ware analysed using GraphPad Prism 8.0 (USA) software to calculate IC50 values.

[0136] In this assay format, Example 1 was able to inhibit ACTH-induced cAMP in a concentrationdependent manner in cells stably expressing the human MC2R (Figure 1). cAMP accumulation assay

[0137] Chinese hamster ovary (CHO) cells, stably expressing human or rat MC2 with MRAP, were maintained in DMEM / F12 cell culture medium supplemented with 10% fetal bovine serum and 1% L-glutamine. On the day of experimentation, cells were plated at 10000 cells / well in white low-volume 384-well plates in assay buffer (Hank’s balanced salt solution containing 5 mM HEPES (pH 7.4) with 0.01% w / v BSA and 500 pM 3-isobutyl-1 -methylxanthine) before being incubated with a range of concentrations of MC2 compounds for 2h at 37C, 5% CO2. After 2h, increasing concentrations of ACTH 1 -24 were added to the cells for a set duration, before lysis and cAMP detection using the homogeneous time resolved fluorescence (HTRF) cAMP Gs HiRange kit (CisBio) according to the manufacturer’s instructions. Fluorescence resonance energy transfer (FRET) levels were detected on a PHERAstar plate reader (BMG), and data interpolated from a cAMP standard curve, and analysed using GraphPad Prism 8 (GraphPad). In this assay format, Example 1 shows a reduction in Emax of ACTH 1-24 in an in vitro cAMP accumulation assay, consistent with an insurmountable antagonist behaviour (Figure 2).

[0138] Off-Target Selectivity

[0139] A) Example 1 was tested in all the different isoforms of the melanocortin receptors MC1 R, MC3R, MC4R, or MC5R. Using the cAMP Giosensor assay, no functional antagonism was observed in MC1 R, MC3R, MC4R, or MC5R (>30uM). Example 1 showed weak agonists at the other melanocortin family receptors with greater than 1000 fold selectivity (MC1 , MC3, MC4, MC5) (Figure 3).

[0140] B) Example 1 was tested at the Eurofins DiscoverX, 78 assays in SAFETYscan @10uM. All IC5o > 10 uM, except for: ADRB1 3.7 uM (98%), ADRB2 5.9 uM (76%), CNR1 7.7 uM (59%), DRD1 4.6 uM (78%), HRH2 5.1 uM (81%), HERG 6.6 uM (69%)

[0141] Steroidogenesis Inhibition in H295RA adrenocortical cells

[0142] The H295RA (Nanba et al. 2016) is an immortalised adrenocortical cell line which expresses MC2R as well as its co-receptor MRAP. Previous work has demonstrated the ACTH- responsiveness of cortisol and aldosterone in these cells. 10nM ACTH was able to increase cortisol production 2.2-fold (n=4), aldosterone production 3.6-fold (n=4), and DHEA 3.1 -fold (n=3) over basal conditions. Example 1 was able to inhibit this ACTH-induced cortisol, aldosterone, and DHEA production to basal levels (Figure 4).

[0143] Supression of ACTH-induced corticosterone in vivo

[0144] Pharmacodynamic effects were assessed using SD Male Rats and corticosterone was used as a main pharmacological readout, as corticosterone is the main circulating glucocorticoid in rats.

[0145] Acute single dose ACTH challenge test

[0146] Rats were dosed with Example 1 via oral gavage 6 hours prior to an intravenous challenge with 10 pg / kg ACTH 1-24. Injection with 10 pg / kg ACTH 1-24 resulted in a robust increase in plasma corticosterone (to 300-400 ng / mL) within the first 15 minutes which was maintained for two hours, at which point plasma corticosterone levels had returned to baseline levels. Example 1 could inhibit this MC2R-mediated increase in plasma corticosterone in this system (Figure 5A), producing robust dose-response relationships with EC50 5 ng / mL. ACTH levels reached in this challenge (plasma ACTH concentration at 15 minutes 2114 ± 358 pg / mL, at 30 minutes 983 ± 127 pg / mL, n=20 animals) are higher than CAH patients experience in the morning surge, hence we would expect a strong inhibitory trend in CAH patients.

[0147] Chronic model with continuous pump-administartion of ACTH

[0148] The rats were dosed via oral gavage daily with Example 1 whilst being infused with 100 pg / kg / day ACTH 1-24 via an osmotic mini-pump for seven days. Example 1 was able to significantly reduce plasma corticosterone over the 7 days of the study (Figure 6A). An oral dose of 10 mg / kg of Example 1 was able to completely inhibit the adrenal hypertrophy caused by 100 pg / kg / day ACTH 1-24 for 7 days (Fig 6B and see example images of adrenal glands in Figure 6C). These results were also seen in a significant gain in bodyweight for animals treated with 10 mg / kg of Example 1 (Figure 6D). Conversely, 100 pg / kg / day ACTH 1-24 resulted in a significant reduction in bodyweight over the 7 days of the study (Figure 6D).

[0149] Brief Description of the Figures

[0150] Figure 1 : Antagonism of cAMP response from 10nM ACTH 1-24 at the human MC2R by Example 1 .

[0151] Figure 2: Antagonism of ACTH 1-24 cAMP by Example 1 at increasing concentrations over their Ki value showing functional insurmountability. Data are normalized to a percentage of the cAMP produced by 500nM ACTH 1-24. Data are mean ± SD from duplicate determinations in a single experiment.

[0152] Figure 3: cAMP produced via agonism of human isoforms of MC1 R, MC3R, MC4R, or MC5R by Example 1.

[0153] Figure 4: Antagonism of steroidogenic products (A) cortisol, (B) aldosterone, or (C) DHEA in H295RA adrenocortical cells by Example 1. Data are normalized to a percentage of the biomarker produced by 24hr incubation with 10nM ACTH 1-24. Data are combined mean ± SEM from 3 separate experiments.

[0154] Figure 5: A) Profile of plasma corticosterone produced in response to intravenous infusion of 10 pg / kg ACTH 1-24 in the absence and presence of 10mg / kg of Example 1. Example 1 was dosed orally 6 hours prior to ACTH 1-24 challenge. B) Plasma concentration response curves for Example 1 showing inhibition of ACTH-mediated corticosterone production. Data have been normalized so that each datapoint represents an individual animal and their plasma exposure of compound against the percentage of corticosterone produced after 1 hr 10 pg / kg ACTH 1-24.

[0155] Figure 6: (A) Area under the curve of plasma corticosterone produced in response to 7 days infusion of 100 pg / kg / day ACTH 1-24 in the absence and presence of 1 mg / kg or 10mg / kg of Example 1 . (B) Adrenal weight of the animals following treatment, represented as a ratio of their individual bodyweight. (C) Example images of adrenal glands from animals in (B) showing clear differences between ACTH and Example 1 treated groups. (D) Body weight of animals on day 7 expressed as a percentage of that on day 1 . *p<0.05, **p<0.01 , ***p<0.001 compared to vehicle control, one-way ANOVA.

[0156] Figure 7: Flow reaction Scheme to obtain Intermediate 3.

[0157] Figure 8: Flow reaction Scheme to obtain Intermediate 5.

Claims

1. CLAIMS1. A pharmaceutical composition comprising a compound of Formula (1):or a pharmaceutically acceptable salt thereof, wherein the compound is present in a substantially pure stereoisomeric form.The pharmaceutical composition according to claim 1, wherein the compound is selected from the group consisting of:(1D) (1 E) (1 F)or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 1, wherein the compound is a compound of Formula (1A):or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to any one of claims 1 to 3, having a stereoisomeric purity of at least 90%, 95%, 96%, 97%, 98%, 99% or 99.5%.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the compound is present in a diastereomeric excess (de) of at least 90%, 95%, 96%, 97%, 98%, 99% or 99.5%.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the compound is present in a diastereomeric excess (de) of at least 99%.

7. The pharmaceutical composition according to claim 5 or 6, wherein the compound is also present in an enantiomeric excess (ee) of at least 99%.

8. The pharmaceutical composition according to any one of claims 2 to 7, wherein the compounds of Formula (1 B) to (1 H) or a pharmaceutically acceptable salt thereof are present in no more than 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% by weight in relation to the compound of Formula (IA) or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the compound is present in the form of a pharmaceutically acceptable salt.

10. The pharmaceutical composition according to any one of claims 1 to 9, which is formulated for oral delivery.

11. The pharmaceutical composition according to any one of claims 1 to 9, which is administered in the form of a tablet, capsule, granules, intramuscular injection or intravenous injection.

12. The pharmaceutical composition according to any one of claims 1 to 11, comprising a pharmaceutically acceptable diluent, carrier or excipient.

13. The pharmaceutical composition according to claim 12, wherein the pharmaceutically acceptable diluent, carrier or excipient is selected from: a solubilising agent, diluent, lubricant, binding agent, disaggregating agent, pigment, wetting agent, matrix polymer, carrier, shell, lipophilic liquid vehicle, semi-solid lipophilic vehicle, surfactant and an emulsifier.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the compound is administered at a dose of 1-150, 10-100 or 20-50 mg.

15. A combination comprising a pharmaceutical composition according to any one of claims 1 to 14 and a CRF1 antagonist.

16. A combination comprising a pharmaceutical composition according to any one of claims 1 to 14 and an ACTH antibody.

17. The pharmaceutical composition or combination according to any one of claims 1 to 16 for use in therapy.

18. The pharmaceutical composition or combination according to any one of claims 1 to 16 for use in the treatment of a disorder associated with ACTH excess or that would benefit from the modulation of MC2R activity.

19. The pharmaceutical composition or combination according to any one of claims 1 to 16 for use in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS), depressive illness, septic shock, or disorders or symptoms related thereto.

20. A method of treating a disorder associated with ACTH excess or that would benefit from the modulation of MC2R activity in a patient, comprising administering an effective amount of a pharmaceutical composition or combination according to any one of claims 1 to 16.

21. A method of treating congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS), depressive illness, septic shock, or disorders or symptoms related thereto in a patient, comprising administering an effective amount of a pharmaceutical composition or combination according to any one of claims 1 to 16.

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