MC2r modulator compounds

Abstract

The disclosures herein relate to pharmaceutically acceptable salts of a compound of Formula (1) 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 pharmaceutically acceptable salts of a compound and their use as melanocortin subtype-2 receptor (MC2R) antagonists. Such compounds may be useful in the treatment or prevention of diseases in which MC2R is involved. This application is also directed to pharmaceutical compositions comprising such compounds and the manufacture and use of these compounds and compositions in the prevention or treatment of such 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.

[0010] 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.

[0011] 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).

[0012] THE INVENTION

[0013] The present invention provides pharmaceutically acceptable salts of a compound having activity as melanocortin subtype-2 receptor (MC2R) antagonist.

[0014] Provided is a pharmaceutically acceptable salt of a compound of Formula (1):

[0015] 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. Compounds of the present invention may be used in the treatment of a disease or disorder associated with MC2R. Compounds of the present invention may be used in the treatment of a disease or disorder that would benefit from the modulation of MC2R activity. Compounds of the present invention may be used in the manufacture of medicaments. The compounds or medicaments may be for use in treating, preventing, ameliorating, controlling or reducing the risk of diseases or disorders in which MC2R is involved. Compounds of the present invention may be for use as a single agent or in combination with one or more additional pharmaceutical agents.

[0016] Compounds 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.

[0017] DETAILED DESCRIPTION OF THE INVENTION

[0018] The invention relates to pharmaceutically acceptable salts of a compound. The invention also relates to the use of such compounds as modulators of the melanocortin subtype-2 receptor (MC2R), in particular as MC2R antagonists. The invention further relates to such compounds as MC2R anatagonists which have a long residence time at the receptor. The invention further relates to the use of such compounds in the manufacture of medicaments for use as MC2R antagonists. The invention further relates to such compounds, compositions and medicaments that may be useful in the treatment of a disease or disorder characterised by activation of the MC2R receptor.

[0019] Provided is a pharmaceutically acceptable salt of a compound of Formula (1): Provided is a pharmaceutically acceptable salt of the compound: (R)-5-chloro-2-(2 -(2- ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1 ,7]naphthyridin]-1-yl)benzonitrile.

[0020] The pharmaceutically acceptable salt may be a mesylate salt.

[0021] Also provided is a pharmaceutically acceptable salt, which is a compound of Formula (1a):

[0022] Also provided is the compound: (F?)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)- 7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1-yl)benzonitrile monomethanesulfonate.

[0023] Also provided is an amorphous form of a compound of Formula (1) or (1a). Also provided is an amorphous form of (F?)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1-yl)benzonitrile. Also provided is an amorphous form of (F?)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro- 6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1-yl)benzonitrile mono-methanesulfonate.

[0024] Also provided is a crystalline form of a compound of Formula (1) or (1a). Also provided is a crystalline form of (F?)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro- 6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1-yl)benzonitrile. Also provided is a crystalline form of (F?)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1-yl)benzonitrile mono-methanesulfonate.

[0025] The crystalline form may have a powder X-ray diffraction (XRPD) pattern measured with CuKa radiation which is consistent with Figure 2. The crystalline form may have a powder X-ray diffraction (XRPD) pattern measured with CuKa radiation comprising a peak at a diffraction angle (20) of 20.59 ± 0.1 °.

[0026] The crystalline form may have a powder X-ray diffraction (XRPD) pattern measured with CuKa radiation comprising peaks at a diffraction angle (20) of 20.59 ± 0.1°; 12.89 ± 0.1 ° and 14.73 ± 0.1 °.

[0027] The crystalline form may have a powder X-ray diffraction (XRPD) pattern measured with CuKa radiation comprising peaks at a diffraction angle (20) of 20.59 ± 0.1°; 12.89 ± 0.1 °; 14.73 ± 0.1 °; 14.98 ± 0.1 °; 17.55 ± 0.1 °; 21.20 ± 0.1 °; 23.24 ± 0.1° and 24.36 ± 0.1 °.

[0028] Provided is a crystalline form of a compound of Formula (1a), wherein said crystalline form has a powder X-ray diffraction (XRPD) pattern measured with CuKa radiation comprising a peak at a diffraction angle (20) of 20.59 ± 0.1°.

[0029] Also provided is a crystalline form of a compound of Formula (1a), wherein said crystalline form has a powder X-ray diffraction (XRPD) pattern measured with CuKa radiation comprising peaks at a diffraction angle (20) of 20.59 ± 0.1 °; 12.89 ± 0.1 ° and 14.73 ± 0.1°.

[0030] Also provided is a crystalline form of a compound of Formula (1a), wherein said crystalline form has a powder X-ray diffraction (XRPD) pattern measured with CuKa radiation comprising peaks at a diffraction angle (20) of 20.59 ± 0.1°; 12.89 ± 0.1°; 14.73 ± 0.1°; 14.98 ± 0.1°; 17.55 ± 0.1°; 21.20 ± 0.1°; 23.24 ± 0.1° and 24.36 ± 0.1 °.

[0031] Provided is a crystalline form of ( )-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)- 7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1-yl)benzonitrile monomethanesulfonate, wherein said crystalline form has a powder X-ray diffraction (XRPD) pattern measured with CuKa radiation comprising a peak at a diffraction angle (20) of 20.59 ± 0.1 °.

[0032] Also provided is a crystalline form of (R)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2- ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1-yl)benzonitrile monomethanesulfonate, wherein said crystalline form has a powder X-ray diffraction (XRPD) pattern measured with CuKa radiation comprising peaks at a diffraction angle (20) of 20.59 ± 0.1 °; 12.89 ± 0.1 ° and 14.73 ± 0.1°. Also provided is a crystalline form of (F?)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2- ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-1-yl)benzonitrile monomethanesulfonate, wherein said crystalline form has a powder X-ray diffraction (XRPD) pattern measured with CuKa radiation comprising peaks at a diffraction angle (20) of 20.59 ± 0.1°; 12.89 ± 0.1°; 14.73 ± 0.1°; 14.98 ± 0.1°; 17.55 ± 0.1°; 21.20 ± 0.1°; 23.24 ± 0.1° and 24.36 ± 0.1°.

[0033] The crystalline form may have a differential scanning calorimetry (DSC) thermogram which is consistent with Figure 1.

[0034] The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset at 192.5 ± 5°C. The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset at 192.5 ± 2°C. The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset at 192.5 ± 1°C.

[0035] The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an endotherm with a peak at 198.6 ± 5°C. The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an endotherm with a peak at 198.6 ± 2°C. The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an endotherm with a peak at 198.6 ± 1°C.

[0036] The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset at 192.5 ± 5°C and a peak at 198.6 ± 5°C. The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset at 192.5 ± 2°C and a peak at 198.6 ± 2°C. The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset at 192.5 ± 1°C and a peak at 198.6 ± 1°C.

[0037] The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an exotherm with an onset at 59.7 ± 5°C. The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an exotherm with an onset at 59.7 ± 2°C. The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an exotherm with an onset at 59.7 ± 1°C. The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an exotherm with a peak at 85.1 ± 5°C. The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an exotherm with a peak at 85.1 ± 2°C.

[0038] The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an exotherm with a peak at 85.1 ± 1°C.

[0039] The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an exotherm with an onset at 59.7 ± 5°C and a peak at 85.1 ± 1 °C. The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an exotherm with an onset at 59.7 ± 2°C and a peak at 85.1 ± 1°C. The crystalline form may have a differential scanning calorimetry (DSC) thermogram comprising an exotherm with an onset at 59.7 ± 1 °C and a peak at 85.1 ± 1 °C.

[0040] The pharmaceutically acceptable salt may be present in a substantially single crystalline form. The pharmaceutically acceptable salt may be present in a substantially single polymorphic form. The crystalline form may have a purity of at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5%.

[0041] Also provided is a pharmaceutical composition comprising a compound of Formula (1) or (1a). Also provided is a pharmaceutical composition comprising a pharmaceutically acceptable salt of (F?)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1-yl)benzonitrile. Also provided is a pharmaceutical composition comprising (F?)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1-yl)benzonitrile mono-methanesulfonate. Also provided is a pharmaceutical composition comprising a crystalline form of (F?)-5-chloro- 2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1 ,7]naphthyridin]-1-yl)benzonitrile mono-methanesulfonate.

[0042] Also provided is a pharmaceutical composition comprising a compound of Formula (1) or (1a), wherein the compound is present in a stereoisomeric purity of at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5%.

[0043] Also provided is a pharmaceutical composition comprising a compound of Formula (1) or (1a), wherein the compound is present in an enantiomeric excess (ee) of at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5%. In some embodiments, the compound / pharmaceutically acceptable salt / amorphous form / crystalline form / pharmaceutical composition is formulated for administration in the form of a tablet, capsule, granules, intramuscular injection or intravenous injection. The compound / pharmaceutically acceptable salt / amorphous form / crystalline form / pharmaceutical composition may be formulated for oral delivery. The compound / pharmaceutically acceptable salt / amorphous form / crystalline form / pharmaceutical composition may be administered in the form of a tablet, capsule, granules, intramuscular injection or intravenous injection. The compound / pharmaceutically acceptable salt / amorphous form / crystalline form / pharmaceutical composition may be administered orally.

[0044] In some embodiments, the pharmaceutical composition further comprises 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.

[0045] The pharmaceutical composition 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 semisolid 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).

[0046] The pharmaceutical composition 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). The pharmaceutical composition 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).

[0047] The pharmaceutical composition 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).

[0048] The pharmaceutical composition 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).

[0049] The compound, or pharmaceutically acceptable salt thereof may be administered in any effective therapeutic amount. The pharmaceutical composition may be administered in any effective therapeutic amount.

[0050] The compound 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 50-100 mg (e.g. 50-90 mg, 50-80 mg, 50-70 mg, 50-60 mg, 60-100 mg, 60-90 mg, 60-80 mg, 60-70 mg, 70-100 mg, 70-90 mg, 70-80 mg, 80-100 mg, 80-90 mg). The compound may be administered at a dose of 60-90 mg. The compound may be administered at a dose of 0.1-3 mg / kg. The compound may be administered at a dose of 0.5-2 mg / kg. The compound may be administered at a dose of 0.5-1.5 mg / kg (e.g. 0.5-1.4 mg / kg, 0.5-1.3 mg / kg, 0.5-1.2 mg / kg, 0.5-1.1 mg / kg, 0.5-1.0 mg / kg, 0.6-1.5 mg / kg, 0.6-1.4 mg / kg, 0.6-1.3 mg / kg,

[0051] 0.6-1.2 mg / kg, 0.6-1.1 mg / kg, 0.6-1.0 mg / kg, 0.7-1.5 mg / kg, 0.7-1.4 mg / kg, 0.7-1.3 mg / kg,

[0052] 0.7-1.2 mg / kg, 0.7-1.1 mg / kg, 0.7-1.0 mg / kg, 0.8-1.5 mg / kg, 0.8-1.4 mg / kg, 0.8-1.3 mg / kg,

[0053] 0.8-1.2 mg / kg, 0.8-1.1 mg / kg, 0.8-1.0 mg / kg, 0.9-1.5 mg / kg, 0.9-1.4 mg / kg, 0.9-1.3 mg / kg,

[0054] 0.9-1.2 mg / kg, 0.9-1.1 mg / kg, 0.9-1.0 mg / kg).

[0055] Further embodiments of the invention include the use of a compound of Formula (1) or (1a) or an amorphous or crystalline form thereof or a pharmaceutical composition comprising a compound of Formula (1) or (1a) or an amorphous or crystalline form thereof in therapy. Also included is the use of a compound of Formula (1) or (1a) or an amorphous or crystalline form thereof or a pharmaceutical composition comprising a compound of Formula (1) or (1a) or an amorphous or crystalline form thereof as a melanocortin subtype-2 receptor (MC2R) modulator. Compounds of the present invention may be used as MC2R receptor modulators. Compounds of the present invention may be used as MC2R receptor inhibitors or antagonists. Compounds of the present invention may be used in the treatment of a disease or disorder characterised by activation of MC2R. Compounds of the present invention may be used in the treatment of a disease or disorder associated with MC2R or in the treatment of a disease or disorder that would benefit from the modulation of MC2R activity.

[0056] Compounds 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.

[0057] In some embodiments, compounds and compositions detailed 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 compound of Formula (1) or (1a) or any embodiment, variation or aspect thereof.

[0058] Compounds as MC2R modulators as disclosed herein can be useful as a prophylactic or therapeutic agent for MC2R associated diseases. In some embodiments, a compound or salt thereof described herein or a composition described herein may be used in a method of treating Cushing’s disease in an individual.

[0059] Also provided are combinations comprising a compound 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,

[0060] CRA5626 / JNJ19567470 / R317573, NBI-76169, verucerfont, and CP-154,526.

[0061] In the combinations the CRFi antagonist may be selected from:

[0062] Also provided are combinations comprising a compound 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).

[0063] 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.

[0064] Also provided herein are uses of a compound described herein or 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.

[0065] In some embodiments, a compound or a 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. Compounds or compositions of the present invention may be used or administered in combination with a second therapeutic agent.

[0066] In some embodiments, (a) a compound described herein or a pharmaceutical composition described herein and (b) an agent are sequentially administered, concurrently administered or simultaneously administered. In certain embodiments, (a) a compound described herein or 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 compound described herein or 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 compound described herein or a pharmaceutical composition described herein and (b) an agent may be administered first. In certain embodiments, (a) a compound described herein or a pharmaceutical composition described herein and (b) an agent are administered simultaneously.

[0067] The compounds, pharmaceutically acceptable salts, amorphous forms, crystalline forms, pharmaceutical compositions and combinations disclosed herein may be for use in therapy.

[0068] The compounds, pharmaceutically acceptable salts, amorphous forms, crystalline forms, 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.

[0069] The compounds, pharmaceutically acceptable salts, amorphous forms, crystalline forms, pharmaceutical compositions, combinations and / or doasages 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.

[0070] 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 pharmaceutically acceptable salt, amorphous form, crystalline form, pharmaceutical composition or combination as described herein or any embodiment, variation or aspect thereof.

[0071] 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 pharmaceutically acceptable salt, amorphous form, crystalline form, pharmaceutical composition or combination as described herein or any embodiment, variation or aspect thereof. The compounds, pharmaceutically acceptable salts, amorphous forms, crystalline forms, pharmaceutical compositions, combinations and / or dosages 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, pharmaceutically acceptable salts, amorphous forms, crystalline forms, 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.

[0072] DEFINITIONS

[0073] In this application, the following definitions apply, unless indicated otherwise.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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%. Chemical terms are all used in their conventional sense (e.g. as defined in the IIIPAC Gold Book), unless indicated otherwise.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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 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.

[0083] 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.

[0084] 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.

[0085] 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 10 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.

[0086] 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.

[0087] Pharmaceutical compositions containing compounds of the Formula (1) or (1a) 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] The compound 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 milligrams to 0.5 gram, for example 1 milligrams to 0.2 gram, e.g. 1 milligrams to 50 miligrams, of active compound.

[0095] 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.

[0096] EXAMPLES

[0097] The invention will now be illustrated, but not limited, by reference to the following examples.

[0098] PREPARATION OF THE COMPOUNDS OF THE INVENTION

[0099] Example 1 and Example 1.MSA may be prepared in accordance with the following scheme:

[0100]

[0101] Example 1.MSA

[0102] LCMS methods:

[0103]

[0104] HPLC method:

[0105] Abbreviations & Acroynms:

[0106] Preparation of Example 1 :

[0107] To a stirred solution of 6-chloro-3-fluoropicolinic acid (2 g, 11.39 mmol) in 1 ,4-dioxane (16 mL) and water (4 mL) at RT were added (2-ethoxyphenyl)boronic acid (2.3 g, 13.86 mmol) and potassium carbonate (3.2 g, 23.15 mmol). The reaction mixture was degassed with N2 for 5 min. Pd(amphos)Cl2 (121 mg, 0.171 mmol) was added and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was evaporated and the resulting residue diluted with water (50 mL) and washed with EtOAc (2 x 20 mL). The aqueous layer was acidified with 1 ,5N HCI to pH = 3. and extracted with 10% MeOH in DCM (2 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and evaporated to afford 6- (2-ethoxyphenyl)-3-fluoropicolinic acid (760 mg, 2.88 mmol, 25%) as a yellow gum.

[0108] LCMS:2.17 min, 262.1 (M+H)+, Method B

[0109] To a stirred solution of 6-(2-ethoxyphenyl)-3-fluoropicolinic acid (6.5 g, 24.88 mmol) in t-BuOH were added Boc-anhydride (14.44 mL, 62.2 mmol) followed by DMAP (0.304 g, 2.488 mmol) and reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was basified with 10% NaHCOs diluted with water (10 mL) and extracted with EtOAc (2 x10 mL). The combined organic layer was, dried over anhydrous sodium sulphate, evaporated and purified by flash column chromatography using EtOAc / PET-ether (0 to 30%) to afford terf-butyl 6-(2- ethoxyphenyl)-3-fluoropicolinate (6 g, 17.96 mmol, 72%) as a pale-yellow solid.

[0110] LCMS: 2.27 min, 318.1 [M+HJ+, Method W

[0111] To the stirred solution of the 1M KHMDS in THF (16.39 mL, 16.39 mmol) were added a mixture of tert-butyl 6-(2-ethoxyphenyl)-3-fluoropicolinate (4 g, 12.60 mmol) and tert-butyl 4- cyanopiperidine-1 -carboxylate (2.65 g, 12.60 mmol) in THF (30 mL) at RT and stirred at RT for 3 h. The reaction mixture was quenched cautiously with sat. NH4CI at RT and extracted with EtOAc. The combined organic layer was washed with brine, dried over sodium sulphate and purified by flash column chromatography using EtOAc-PET ether (20 to 50%) to afford tert-butyl 3-(1-(tert-butoxycarbonyl)-4-cyanopiperidin-4-yl)-6-(2-ethoxyphenyl)picolinate (5 g, 9.85 mmol, 52%) as an off white solid. LCMS: 2.55 min, 508.3 [M+H]+, Method G

[0112] To the stirred solution of the tert-butyl 3-(1-(tert-butoxycarbonyl)-4-cyanopiperidin-4-yl)-6-(2- ethoxyphenyl)picolinate (7.5 g, 14.77 mmol) in EtOH:water (230:40 mL) was added Raney Ni (12.96 g, 148 mmol) and reaction mixture was stirred at 65 °C and under 6 kg of H2 gas pressure for 48 h. The reaction mixture was filtered through celite bed and the bed was washed with 10% MeOH and DCM. Filtrate was concentrated under reduced pressure (bath temperature: 42 °C) to afford crude gum which was purified by silica flash column chromatography using 10% MeOH in DCM to obtain tert-butyl 2'-(2-ethoxyphenyl)-8'-oxo-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridine]-1-carboxylate (5.0 g, 10.74 mmol, 73%) as a white solid.

[0113] LCMS: 1.84 min, 438.2 [M+H]+, Method G

[0114] To the stirred solution of the tert-butyl 2'-(2-ethoxyphenyl)-8'-oxo-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1 ,7]naphthyridine]-1 -carboxylate (8 g, 18.28 mmol) in THF (30 mL) at 0 °C were added t-BuOK (4.10 g, 36.6 mmol) followed by benzyl chloroformate (7.77 g, 45.7 mmol) and reaction mixture was stirred at RT for 3 h. The reaction mixture was quenched cautiously with aqueous NH4CI solution (100 mL) at 0 °C and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and purified by silica flash column chromatography using 15% EtOAc in PET-ether to obtain 7'-benzyl 1 -(tert-butyl) 2'-(2-ethoxyphenyl)-8'-oxo-6'H-spiro[piperidine-4,5'- [1 ,7]naphthyridine]-1 ,7'(8'H)-dicarboxylate (8 g, 13.55 mmol, 74%) as a white solid.

[0115] LCMS: 2.37 min, 572.3 [M+H]+, Method W

[0116] To a stirred solution of 7'-benzyl 1 -(tert-butyl) 2'-(2-ethoxyphenyl)-8'-oxo-6'H-spiro[piperidine- 4,5'-[1 ,7]naphthyridine]-1 ,7'(8'H)-dicarboxylate (5 g, 8.75 mmol) in THF (25 mL) was added BH3 in THF (30.6 ml, 30.6 mmol) at 0 °C and reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched cautiously with MeOH at 0 °C and evaporated to dryness and purified by silica flash column chromatography using 30% EtOAc in PET-ether to afford 7'- benzyl 1 -(tert-butyl) 2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridine]- 1 ,7'(8'H)-dicarboxylate (4.2 g, 7.20 mmol, 82%) as an off white solid.

[0117] LCMS: 2.53 min, 558.3 [M+H]+, Method G

[0118] To the stirred solution of 7'-benzyl 1 -(tert-butyl) 2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'- [1 ,7]naphthyridine]-1 ,7'(8'H)-dicarboxylate (6.6 g, 11.83 mmol) in DCM (15 mL) was added TFA (13.49 g, 118 mmol) and reaction mixture was stirred at RT for 16 h. The reaction mixture was concentred, basified with 10% aq. NaHCOs (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate to afford benzyl 2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridine]- 7'(8'H)-carboxylate (4.2 g, 8.70 mmol, 74%) as a white solid.

[0119] LCMS: 1.46 min, 458.2 [M+HJ+, Method G

[0120] A stirred solution of benzyl 2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridine]- 7'(8'H)-carboxylate (500 mg, 1.093 mmol) and 2-bromo-5-chlorobenzonitrile (591 mg, 2.73 mmol) in Toluene (10 ml) was degassed with N2 for 15 min. NaOtBu (315 mg, 3.28 mmol), Xanthphos (126 mg, 0.219 mmol) and Pd2(dba)s (100 mg, 0.109 mmol) were added and the mixture heated at 120 °C for 24 h. The reaction mixture was then filtered through celite and the celite washed with EtOAc (3 x 50mL). The filtrate was diluted with EtOAc (100 mL), washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by silica flash column chromatography using EtOAc / PET-ether (0 to 50 %) as eluent to afford benzyl 1-(4-chloro-2- cyanophenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridine]-7'(8'H)- carboxylate (600 mg, 0.789 mmol, 72%) as a yellowish solid.

[0121] LCMS: 2.640 min, 593.3 (M+H)+, Method F

[0122] To a stirred solution of benzyl 1-(4-chloro-2-cyanophenyl)-2'-(2-ethoxyphenyl)-6'H- spiro[piperidine-4,5'-[1 ,7]naphthyridine]-7'(8'H)-carboxylate (1.1 g, 1.855 mmol) in DCM (20 mL). was added EtsN (0.402 ml, 2.78 mmol), PdCh (0.329 g, 1.855 mmol) and triethylsilane (0.924 ml, 5.56 mmol) under N2 atmosphere. The reaction mixture was stirred at 50 °C for 6 h, then filtered through celite and washed with DCM (3 x 50 mL). The filtrate was diluted with DCM, washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The resulting crude product was purified by silica flash column chromatography using MeOH / DCM (0 to 20 %) as eluent to afford 5-chloro-2-(2'-(2- ethoxyphenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1-yl)benzonitrile (400 mg, 0.871 mmol, 47%) as an off white solid.

[0123] LCMS: 1.60 min, 459.2 (M+H)+, Method F

[0124] To a stirred solution of 5-chloro-2-(2'-(2-ethoxyphenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1 ,7]naphthyridin]-1-yl)benzonitrile (470 mg, 1.024 mmol) in DCM (10 mL), was added tertbutyl (R)-2-formylpyrrolidine-1 -carboxylate (265 mg, 1.331 mmol) and the mixture stirred for 1h at RT. Na(OAc)sBH (324 mg, 1.536 mmol) was then added and the mixture stirred at RT for 24 h. The reaction mixture was concentrated under reduced pressure. 10% NaHCOs aqueous solution (5.0 mL) was added and the mixture extracted with DCM (2 times x 20 mL). The combined organic extracts were washed with brine (5.0 mL), dried over sodium sulphated, and evaporated. The resulting crude product was purified by silica flash column chromatography using EtOAC / PET-ether (0 to 50 %) as eluent to afford tert-butyl (R)-2-((1-(4- chloro-2-cyanophenyl)-2'-(2-ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]- 7'(8'H)-yl)methyl)pyrrolidine-1-carboxylate (400 mg, 0.567 mmol, 55%) as an off white solid.

[0125] LCMS: 2.19 min, 642.3 (M+H)+, Method F

[0126] To a 10 L multi neck RB flask, 300g of tert-butyl (R)-2-((1-(4-chloro-2-cyanophenyl)-2'-(2- ethoxyphenyl)-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-7'(8'H)-yl)methyl)pyrrolidine-1- carboxylate was charged. 2M HCI in iPrOAc (3 L, 10 vol) was charged to the RBF at RT. The reaction was stirred at RT for 2 h. The mixture was then stirred under nitrogen flow to remove excess HCI fumes. The mixture was concentrated on rotavapor at 45 °C. The resulting solid was diluted with water (30 L, 100 vol) and washed with EtOAc (4 x 10 vol). The layers were separated. The aqueous layer was further washed with MTBE (4 x 10 vol). The aqueous layer was then basified with 10% NaOH solution (10 vol) and extracted with DCM (2 x 20 vol). The combined organic layers were evaporated on rotavapor at 45 °C to afford 202 g of freebase (R)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H- spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1-yl)benzonitrile as fine powder (80%, 96.40% HPLC purity) (Example 1).

[0127] Preparation of Example 1.MSA:

[0128] 1M sodium methanesulfonate in IPAc (1eq) was added to a slurry of 500 mg freebase (R)-5- chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1 ,7]naphthyridin]-1-yl)benzonitrile in IPAc at 0 °C and stirred RT for 1 h. The solvent was removed under reduced pressure and the resulting crude was slurried in with IPAc (5 vol.) for 30 min. The solids were filtered and dried under vacuum to afford 400 mg of (R)-5-chloro-2- (2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-

[0129] [1 ,7]naphthyridin]-1-yl)benzonitrile mono-methanesulfonate (99.14% purity by HPLC) (Example 1.MSA). This solid was used as seed in subsequent batches.

[0130] Preparation of Example 1.MSA Form 1 :

[0131] To a 10 L multi neck RB flask, 230g of freebase (R)-5-chloro-2-(2'-(2-ethoxyphenyl)-7'- (pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1- yl)benzonitrile was charged, followed by iPrOAc (3.45 L, 15 vol.) at RT. The reaction mixture was then heated at 60 °C for 30 min. 1 M solution of methane sulfonic acid in iPrOAc (467 mL, 1.1 equiv.) was added dropwise with addition funnel during 30 min. During this addition, 500 mg of seed (prepared as described above) was added through another neck of the RBF. After 30 min, the reaction mixture was allowed to cool to RT and stir for 16 h. The reaction mixture was then transferred (small amount of sticky solid was left behind and not added) to another 20 L single neck RBF and evaporated in rotavapor at 45 °C. The resulting off-white powder was slurried in iPrOAc (2.3 L, 10 vol). 234g of crude from another reaction was added and slurried together for 2 h, the solids filtered and dried in rotavapor at 45 °C for 2 h. The resulting solid was further dried in the oven at 45 °C for 10 h to get (R)-5-chloro-2-(2'-(2-ethoxyphenyl)- 7'-(pyrrolidin-2-ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1- yl)benzonitrile mono-methanesulfonate as a fine off-white powder (400g, 73%, 97.3% HPLC purity) (Example 1.MSA Form 1).

[0132] Analytical Data

[0133] SOLID FORM CHARACTERISATION

[0134] Example 1.MSA Form 1

[0135] Differential scanning calorimetry (DSC):

[0136] The DSC thermogram of the 400g batch of Example 1.MSA Form 1 prepared as above is shown in Figure 1. Endothermic reaction / events were observed at 192.53 °C with AH = - 109.09 J / g. An exothermic event was observed at 59.65°C with AH = 65.06mJ.

[0137] Parameters: Detector: DSC-60A

[0138] Sample Weight: 2.483 mg

[0139] Cell: Aluminum Hermetic Pan Atmosphere

[0140] Nitrogen Flow Rate: 100 ml / min X-Ray Powder Diffraction (XRPD):

[0141] The XRPD diffraction pattern of the 400g batch of Example 1.MSA Form 1 prepared as above is shown in Figure 2. Scan parameters and a list of observed peaks are provided below.

[0142] Scan Parameters Peak List BIOLOGICAL ACTIVITY

[0143] Terbium labelling and preparation of SNAP-tagged MC2 membranes

[0144] 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.

[0145] Fluorescent Ligand Binding Assays

[0146] 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.

[0147] TR-FRET Competitive Eguilibrium Binding Assay

[0148] 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.

[0149] TR-FRET Competitive Binding Kinetic Assay

[0150] 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.

[0151] In parallel, the association (kon) and dissociation (kon) 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 kotf as described under data analysis. From these data an estimate for the equilibrium dissociation constant (Kd) could be calculated.

[0152] 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.

[0153] Equilibrium and kinetic binding data cAMP accumulation assay

[0154] 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 37°C, 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 3).

[0155] Brief Description of the Figures

[0156] Figure 1 : DSC thermogram of ( )-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)- 7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1-yl)benzonitrile monomethanesulfonate.

[0157] Figure 2: XRPD of final 400g of ( )-5-chloro-2-(2'-(2-ethoxyphenyl)-7'-(pyrrolidin-2-ylmethyl)- 7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1 ,7]naphthyridin]-1-yl)benzonitrile monomethanesulfonate.

[0158] Figure 3: 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.

Claims

Claims1. A pharmaceutically acceptable salt of a compound of Formula (1):

2. The pharmaceutically acceptable salt according to claim 1, which is a compound ofFormula (1a):

3. A crystalline form of the pharmaceutically acceptable salt according to claim 1 or claim2.

4. An amorphous form of the pharmaceutically acceptable salt according to claim 1 or claim 2.

5. The crystalline form according to claim 3, wherein said crystalline form has a powder X-ray diffraction (XRPD) pattern measured with CuKa radiation comprising a peak at a diffraction angle (20) of 20.59 ± 0.1°.

6. The crystalline form according to claim 3, wherein said crystalline form has a powder X-ray diffraction (XRPD) pattern measured with CuKa radiation comprising peaks at a diffraction angle (20) of 20.59 ± 0.1°; 12.89 ± 0.1° and 14.73 ± 0.1°.

7. The crystalline form according to claim 3, wherein said crystalline form has a powder X-ray diffraction (XRPD) pattern measured with CuKa radiation comprising peaks at a diffraction angle (20) of 20.59 ± 0.1°; 12.89 ± 0.1°; 14.73 ± 0.1°; 14.98 ± 0.1°; 17.55 ± 0.1°; 21.20 ± 0.1 °; 23.24 ± 0.1 ° and 24.36 ± 0.1°.

8. The crystalline form according to claims 3, 5, 6 or 7, wherein said crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an onset at 192.5 ± 1°C and a peak at 198.6 ± 1°C.

9. A substantially pure crystalline form of the pharmaceutically acceptable salt according to claims 1 , 2, 5, 6 or 7.

10. The crystalline form according to any one of claims 1 , 2, 5, 6, 7 or 8, wherein the crystalline form has a purity of at least 90%, 95%, 97%, 98% or 99%.

11. A pharmaceutical composition comprising the pharmaceutically acceptable salt, amorphous form or crystalline form according to any of claims 1 to 11 and a pharmaceutically acceptable diluent, carrier or excipient.

12. The pharmaceutical composition according to claim 11 , which is formulated for oral delivery.

13. The pharmaceutical composition according to claim 11 , which is administered in the form of tablet, capsule, granules, intramuscular injection or intravenous injection.

14. The pharmaceutical composition according to claim 11 , 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.

15. The pharmaceutically acceptable salt, amorphous form, crystalline form or pharmaceutical composition according to any one of claims 1 to 14, wherein the compound is administered at a dose of 1-150, 20-120 or 60-90 mg.

16. A combination comprising a pharmaceutically acceptable salt, amorphous form, crystalline form or pharmaceutical composition according to any one of claims 1 to 15 and a CRF1 antagonist.

17. A combination comprising a pharmaceutically acceptable salt, amorphous form, crystalline form or pharmaceutical composition according to any one of claims 1 to 15 and an ACTH antibody.

18. The pharmaceutically acceptable salt, amorphous form, crystalline form, pharmaceutical composition or combination according to any one of claims 1 to 17 for use in therapy.

19. The pharmaceutically acceptable salt, amorphous form, crystalline form, pharmaceutical composition or combination according to any one of claims 1 to 17 for use in the treatment of a disorder associated with ACTH excess or that would benefit from the modulation of MC2R activity.

20. The pharmaceutically acceptable salt, amorphous form, crystalline form, pharmaceutical composition or combination according to any one of claims 1 to 17 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.

21. 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 pharmaceutically acceptable salt, amorphous form, crystalline form, pharmaceutical composition or combination according to any one of claims 1 to 17.

22. 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 pharmaceutically acceptable salt, amorphous form, crystalline form, pharmaceutical composition or combination according to any one of claims 1 to 17.

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