Pharmaceutical compositions of CaSR modulators and methods and uses thereof

Abstract

The present invention provides compounds having the structure of Formulas (I) to (VI), including Compounds 1 to 6, their pharmaceutically acceptable salts, and compositions containing them. Additionally, the present invention includes methods of their use for the treatment of diseases or disorders associated with calcium-sensing receptor (CaSR) modulation, including secondary hyperparathyroidism associated with chronic kidney disease, in subjects in need thereof. Furthermore, the present disclosure relates to methods for the preparation of the pharmaceutical compositions.

Description

Detailed Description of the Invention

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This PCT application claims the benefit of and to Indian Provisional Patent Application Nos. 201921054138 filed December 27, 2019 and 202021006208 filed February 13, 2020, the disclosures of each of which are incorporated herein by reference in their entirety for all purposes.

[0002] [Field] The present disclosure relates to solid pharmaceutical compositions comprising a pharmaceutically effective amount of one or more CaSR agonists, wherein the one or more CaSR agonists are one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt thereof, or a combination thereof, including Compounds 1 to 6 disclosed below, and methods of use thereof for the treatment of diseases or disorders associated with calcium-sensing receptor (CaSR) modulation, including secondary hyperparathyroidism associated with chronic kidney disease, in a subject in need thereof. The solid pharmaceutical compositions can be orally administered to a subject in need thereof. Furthermore, the present disclosure relates to methods for preparing the pharmaceutical compositions.

[0003] [Incorporated by reference] All U.S. patents, U.S. patent application publications, foreign patents, foreign and PCT application publications, literature and other documents, references and publications mentioned herein, as well as all those listed as references cited in any patent(s) originating hereby are hereby incorporated by reference in their entirety. The incorporated information is part of this application and is treated as part of the text and content of this application as filed, just as if all text and other content were repeated in this application.

[0004] [background] The following contains information that may be useful in understanding the present invention. This is not an admission that any information, publication, or document referenced herein, specifically or implicitly, is prior art to or essential to the invention described or claimed. All patents, publications (including, but not limited to, books, scientific publications, and published patent applications) and products mentioned herein are hereby incorporated by reference in their entirety.

[0005] Ca 2+ It is known that Ca2+ is an intracellular second messenger, and the extracellular calcium-sensing receptor (CaSR) has been molecularly identified. Furthermore, it has become clear that Ca2+ may also function as a messenger outside the cell. 2+ Information about local changes in the extracellular concentration of is transmitted inside many types of cells via this unique receptor.

[0006] The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that signals by increasing levels of inositol 1,4,5-triphosphate and cytosolic calcium through activation of phospholipase C. CaSR belongs to subfamily C of the GPCR superfamily. Structurally, CaSR has an unusually large amino-terminal extracellular (ECD) domain (approximately 600 amino acids), a feature common to all members of family C GPCRs.

[0007] In mammals, CaSR expression is highly ubiquitous, and its presence in the parathyroid glands plays a key role in the secretion of parathyroid hormone (PTH), which is involved in the homeostasis of bone metabolism by regulating blood calcium levels, calcium release from bone, calcium absorption from the intestine, and calcium excretion in urine (Tomasello S., "Secondary hyperparathyroidism and chronic kidney disease. Diabetes Spectrum," 21:19-25 (2008)). Secondary hyperparathyroidism (SHPT) is characterized by excessive secretion of PTH (Silverberg SJ & Bilezikian JP, "The diagnosis and management of asymptomatic primary hyperparathyroidism," Nature Clin. Pract. Endocrinol. Metab., 2:494-503 (2006); Goodman WG, "Recent developments in the management of secondary hyperparathyroidism," Kidney Inter., 59:1187-1201 (2001)) and affects approximately 90% of patients with end-stage renal disease and 40%-60% of patients with chronic kidney disease (CKD). This results in increased serum phosphate and reduced vitamin D and calcium levels, ultimately leading to high PTH levels that can pose a significant risk for bone damage, soft tissue and vascular calcification, and cardiovascular morbidity (OPKO HEALTH Renal Division, "Improving people's lives by treating and preventing the clinical consequences of vitamin D insufficiency, secondary hyperparathyroidism, and hyperphosphatemia," Fact sheet CY (2015)).

[0008] A decrease in serum calcium leads to the secretion of PTH. As a result, PTH secretion is 2+ Increases serum Ca by increasing renal retention and intestinal absorption of 2+ Increased extracellular calcium levels also activate the CaSR, resulting in reduced PTH secretion. This occurs indirectly through the PTH-induced synthesis of 25-dihydroxyvitamin D, the active vitamin D metabolite. An integrated hormonal system regulates calcium transport in the gastrointestinal tract, kidney, and bone to maintain calcium homeostasis (Peacock M., "Calcium metabolism in health and disease," Clin. J. Am. Soc. Nephrol. 5:S23-S30 (2010); Carmeliet et al., "Disorders of calcium homeostasis," Best Pract. Res. Clin. Endocrinol. Metab. 17:529-546 (2003)). Reduced serum calcium inactivates the CaSR in the parathyroid gland, increasing PTH secretion, which acts on the kidney to increase calcium reabsorption and on bone to release skeletal calcium. PTH also triggers the renal synthesis of 1,25-dihydroxyvitamin D3, which increases calcium absorption in the gastrointestinal tract while reducing further PTH secretion and increasing bone resorption. This calcium regulation of PTH secretion is altered in SHPT (Carmeliet et al., "Disorders of calcium homeostasis," Best Pract. Res. Clin. Endocrinol. Metab. 17:529-546 (2003); Tfelt-Hansen et al., "The calcium-sensing receptor in human disease," Front Biosci. 8:377-390 (2003)). Therefore, it is important to manage intact PTH (iPTH) levels, along with serum calcium and phosphorus levels, in patients with chronic kidney disease.

[0009] In addition, the pulsatile action of PTH has an anabolic effect on bone development, and sustained levels can have a catabolic effect, where bone is depleted of Ca, as in osteoporosis. 2+ All these systems decay releasing baseline serum Ca 2+ This focuses on the maintenance regulation of PTH, which involves the tight regulation between serum PTH and extracellular calcium mediated by a notable receptor, the CaSR.

[0010] In conditions such as primary and secondary hyperparathyroidism, there is excessive secretion of parathyroid hormone due to glandular hyperplasia. The most common cause of primary hyperparathyroidism (PHPT) is parathyroid adenoma (approximately 97%) due to a clonal mutation and associated hypercalcemia. In the case of secondary hyperparathyroidism (SHPT), this is most commonly seen in patients with chronic renal failure. The kidneys are unable to convert sufficient vitamin D to its active form and do not adequately excrete phosphorus. Excess phosphorus further depletes serum calcium, leading to the formation of calcium phosphate (kidney stones) and hypocalcemia.

[0011] Small molecules that are positive allosteric modulators, called calcimime- ters, modulate and improve the sensitivity of the receptor to the existing extracellular ionic calcium milieu, which may ultimately translate into lower plasma PTH levels, thereby improving conditions of hyperparathyroidism, calcium homeostasis, and bone metabolism.

[0012] PCT International Patent Application Publications WO2012 / 127388, WO2012 / 120476, WO2012 / 127385, WO2012 / 069421, WO2012 / 069419, WO2012 / 069402, US2011 / 0028452, WO2010 / 150837, WO2010 / 136037, WO2010 / 042642, WO2010 / 0 38895, WO2009 / 065406, WO2008 / 059854, WO2006 / 123725, WO2004 / 106280, WO2004 / 069793, WO2002 / 012181 and US2003 / 0199497 refer to compounds related to the calcium-sensing receptor (CaSR) for the treatment of various diseases mediated by the CaSR. Kessler et al., "N1-Benzoyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes: Development of 4-Chlorophenylcarboxamide (Calhex 231) as a New Calcium Sensing Receptor Ligand Demonstrating Potent Calcilytic Activity," J. Med. Chem. (2006), 49, 5119-5128, also discloses compounds related to the CaSR.

[0013] As mentioned above, small molecules called "calcimer agonists" either mimic (directly activate the receptor) or potentiate (positive allosteric modulators) the effect of extracellular calcium at the CaSR. Cinacalcet was the first calcium receptor agonist approved by the U.S. Food and Drug Administration (FDA) to treat SHPT in patients with CKD undergoing dialysis (stage 5 CKD) and hypercalcemia in patients with parathyroid carcinoma (SENSIPAR® (cinacalcet) prescribing information, Amgen Inc., updated March 2019; Padhi, D. & Harris R., “Clinical pharmacokinetic and pharmacodynamic profile of cinacalcet hydrochloride,” Clin Pharmacokinet. 48:303-311 (2009); Quarles LD, “Cinacalcet HCl: A novel treatment for secondary hyperparathyroidism in stage 5 chronic kidney disease,” Kidney Inter. 68:S24-S28 (2005)). Another calcimimetic drug, etelcalcetide (PARSABIV®), approved for the treatment of SHPT in the United States and the European Union in 2017, is a second-generation calcimimetic drug for intravenous use developed to improve adherence. Among other current treatments for SHPT, phosphate binders carry the risk of cardiovascular disease, and newer vitamin D sterols carry the risk of hypercalcemia and result in ineffective control.Second-generation calcimimetics suppress PTH levels with lower calcium and phosphorus production and carry the risk of hypocalcemia, which is thought to occur after reduced calcium mobilization from bone caused by reduced PTH levels (Cunningham et al., "Review secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options," Clin. J. Am. Soc. Nephrol., 6:913-921 (2011)).

[0014] Current treatments for SHPT vary in duration of PTH suppression and mode of administration, and have significantly different side effect profiles that affect patient preference and compliance. Cinacalcet requires daily oral therapy to control SHPT, and its main side effects are nausea and vomiting, which are a significant cause of poor adherence and inadequate dosing (Gincherman et al., "Assessment of adherence to cinacalcet by prescription refill rates in hemodialysis patients," Hemodialysis International, Vol. 14, pp. 68-72 (2010)). Cinacalcet has a wide range of dosage variations (30 mg, 60 mg, 90 mg, 120 mg, and 180 mg) and requires a dose-titration strategy in which the dose is gradually increased to a therapeutic dose to treat or manage CKD-associated secondary hyperparathyroidism in patients undergoing dialysis. Dose escalation is commonly used to enhance tolerability and efficacy, but the method can also be associated with negative outcomes. For example, the incidence of relapse or recurrence is higher in patients whose dose is titrated, because the rate of patient discontinuation associated with titration increases.Patients who undergo dose titration methods experience dissatisfaction and delayed therapeutic effect due to complicated schedules and / or delays in reaching therapeutic dose.Such dose titration also increases the cost of health care for patients who undergo titration, because it requires more visits, requires more prescriptions, and often results in the use of more resources and higher costs related to physician and laboratory monitoring.In addition, patients who are far from medical providers and / or facilities or have transportation, travel or financial difficulties in visiting them find it difficult to receive and comply with such dose titration methods.In addition, patients who experience side effects during dose titration methods and / or are not given the exact time when they will reach therapeutic doses are more likely to abandon the method as a whole.In addition, patients are not guaranteed to reach therapeutic doses through dose titration methods.

[0015] Thus, there is a need in the art to identify new drugs for the treatment or control of SHPT that can suppress PTH while having less of an effect on calcium and phosphate metabolism. Also, given the limitations of dose escalation and observed side effects of currently available therapies, and the need for treatments with a positive / favorable benefit:risk ratio, there remains a great need to develop treatment or management methods, medicaments, compositions, and kits for the treatment or management of SHPT, primary hyperparathyroidism (PHPT), and hypercalcemia in patients with parathyroid carcinoma in patients in need thereof that have simple dosage regimens that do not require dose escalation and cause fewer GI symptoms.

[0016] [overview] The invention described and claimed herein has numerous characteristics and aspects, including but not limited to those described or illustrated or referenced in this Summary. This is not intended to be all-inclusive, and the invention described and claimed herein is not limited to or by the features or embodiments identified in this Summary, which are included for illustrative purposes only and are not limiting.

[0017] The present disclosure provides a solid pharmaceutical composition suitable for oral delivery of a pharmaceutically active agent comprising a pharmaceutically effective amount of a CaSR agonist described herein, wherein the CaSR agonist is at least one compound selected from the group consisting of compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), and combinations thereof, as described herein.

[0018] 1. A solid pharmaceutical composition comprising a pharmaceutically effective amount of one or more CaSR agonists, which are one or more compounds of the following Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or combinations thereof, and at least two pharmaceutically acceptable excipients, wherein the at least two pharmaceutically acceptable excipients are microcrystalline cellulose, crospovidone, starch, magnesium stearate, sodium lauryl sulfate, colloidal silicon dioxide, or combinations thereof:

[0019] [ka] (In formula (I), L, Q, Z, R1, R a , and R b teeth, Q is hydrogen or

[0020] [ka] and; R a teeth,

[0021] [ka] selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted haloalkyl; R b is selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted haloalkyl; Or, R bonded to the same carbon a and R b together form C(O) or C(S); however, Q is

[0022] [ka] If R a are selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted haloalkyl; or R a and R b together form C(O) or C(S); When Q is hydrogen, R a but

[0023] [ka] provided that: L is a bond, -(CR c R d ) m -C(O)-, -C(S)-, -C(O)NR7-, -S(O)2-, -S(O)2-NR7, -C(O)CH2-, -CH2C(O)-, and -C(O)O-; R c and R d may be the same or different at each occurrence and are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, and substituted or unsubstituted haloalkyl; R1 is

[0024] [ka] substituted or unsubstituted alkyl, -(CR e R f ) 1~3 -C(O)OR6, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted cycloalkenyl; Ring Ar is phenyl or naphthyl; Ring Het is heteroaryl or heterocyclyl; R may be the same or different in each occurrence and independently represents halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, -OR, -C(O)R, -(CR e R f ) 0~3 -C(O)OR6, -(CR e R f ) 1~2 Cycloalkylene-C(O)OR6, -cycloalkylene(CR e R f ) 0~2 -C(O)OR6, -O(CR e R f ) 0~3 -C(O)OR6, -O-cycloalkylene-C(O)OR6, -C(O)NR7-(CR e R f ) 1~2 -C(O)OR6, -C(O)NR7R8, -S(O) 0~2 R6 and -S(O)2NR7R8; R e and R f may be the same or different in each occurrence and are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted cycloalkyl; or R e and R f together with the carbon atoms to which they are attached form a substituted or unsubstituted 3- to 7-membered saturated carbocyclic ring; R2 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R3 and R4 may be the same or different in each occurrence and are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted cycloalkyl; R5 is substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl; R6, which may be the same or different in each occurrence, is independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted haloalkyl; R7 and R8, which may be the same or different in each occurrence, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl; or R7 and R8, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 4-12 membered cyclic ring, which may be a substituted or unsubstituted heteroaryl or heterocyclyl; Z is -CR g R h , —C(O), and —C(S); R g and R h are independently selected from hydrogen, halogen, cyano, nitro, substituted or unsubstituted alkyl, and substituted or unsubstituted haloalkyl; "m" is an integer ranging from 1 to 3 inclusive; "n" is an integer ranging from 1 to 3 inclusive; and "q" is an integer ranging from 0 to 4 inclusive); or a pharmaceutically acceptable salt thereof;

[0025] [ka] (In formula (II), rings A, X, L, Q, R1, R9, R 10 , R a , R b , "p" and "q" are as follows: Q is hydrogen or

[0026] [ka] and; R a teeth,

[0027] [ka] selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted haloalkyl; R b is selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted haloalkyl; Or, R bonded to the same carbon a and R b together form C(O) or C(S); however, Q is

[0028] [ka] If R a is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted haloalkyl; or R bonded to the same carbon atoma and R b together form C(O) or C(S); When Q is hydrogen, R a but

[0029] [ka] provided that: L is a bond, -(CR c R d ) m -C(O)-, -C(S)-, -C(O)NR7-, -S(O)2-, -S(O)2-NR7, -C(O)CH2-, -CH2C(O)-, and -C(O)O-; Ring A is aryl; R c and R d may be the same or different at each occurrence and are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, and substituted or unsubstituted haloalkyl; X is a bond, -(CR e R f ) m , -O-, -O(CR e R f ) m -, -(CR e R f ) m O-, -C(O)(CR e R f ) m -, -C(O)NR7-, -C(O)NR7(CR e R f ) m -, -cycloalkylene-, and -O-cycloalkylene-; R e and R f may be the same or different in each occurrence and are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted cycloalkyl; or R e and R ftogether with the carbon atoms to which they are attached form a substituted or unsubstituted 3- to 7-membered saturated carbocyclic ring; R1 is -OR6 or -NR7R8; R2 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R3 and R4 may be the same or different in each occurrence and are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted cycloalkyl; R5 is substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl; R6, which may be the same or different in each occurrence, is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; R7 and R8, which may be the same or different in each occurrence, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl; or R7 and R8, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 3- to 12-membered cyclic ring, which may be heteroaryl or heterocyclyl; R9 may be the same or different in each occurrence and independently represents halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, aryl, -OR6, -C(O)R6, -C(O)OR6, -(CH2) r -C(O)OR6, -O(CH2) r -C(O)OR6, -NR7R8, -C(O)NR7R8, -NR7C(O)R6, -S(O) 0~2 R6 is selected from -S(O)2NR7R8, and -NR7S(O)2R6; R 10 may be the same or different in each occurrence and independently represent halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, -OR, -C(O)R, -NR, -NRC(O)R, -S(O) 0~2 R6 is selected from -S(O)2NR7R8, and -NR7S(O)2R6; "m" is an integer ranging from 1 to 3 inclusive; "n" is an integer ranging from 1 to 3 inclusive; "p" is an integer ranging from 0 to 3 inclusive; "q" is an integer ranging from 0 to 4, inclusive; and "r" is an integer ranging from 1 to 3 inclusive; or a pharmaceutically acceptable salt thereof;

[0030] [ka] (In formula (III), X, Z, R, R1, R2, R3, R4, R5, R a , R b , "m", "n", "p" and "q" are as follows: R ais selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted haloalkyl; R b may be the same or different at each occurrence and are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted haloalkyl; R may be the same or different in each occurrence and independently represents halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, OR, nitro, cyano, -C(O)OR, -(CH) r -C(O)OR6, -OC(O)OR6, -O(CH2) r -C(O)OR6, -NR7R8, -(CH2) r NR7R8-, -C(O)R9, -C(O)NR7R8, -(CH2) r -C(O)NR7R8, -NR7C(O)R9, -S(O) 0~2 R6 is selected from -S(O)2NR7R8, and -NR7S(O)2R9; X is a bond, -(CR c R d ) r -, -O-, -NR7-, -NR7(CR c R d ) r -, -O(CR c R d ) r -, -C(O)NR7-, -C(O)NR7(CR c R d ) r -, -(CR c R d ) r NR7(CR c R d ) r -, -(CR c R d )r cycloalkylene-, cycloalkylene, -cycloalkylene (CR c R d ) r-, and -O-cycloalkylene, wherein cycloalkylene may be substituted or unsubstituted; R c and R d may be the same or different in each occurrence and are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted cycloalkyl; or R c and R d may, together with the carbon atoms to which they are attached, form a substituted or unsubstituted 3- to 7-membered saturated carbocyclic ring; Z is -OR6 or -NR 10 R 11 and; R1 may be the same or different in each occurrence and independently represents halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, -OR6, -C(O)R9, -NR7R8, -(CH2) r NR7R8-, -(CH2) r -C(O)OR6, -OC(O)OR6, -O(CH2) r -C(O)OR6, -C(O)NR7R8, -(CH2) r -C(O)NR7R8, -NR7C(O)R9, -S(O) 0~2 R7 is selected from -S(O)2NR7R8, and -NR7S(O)2R9; R2 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R3 and R4 may be the same or different and are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted cycloalkyl; R5 is substituted or unsubstituted alkyl; R6, which may be the same or different in each occurrence, is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl; R7 and R8 may be the same or different in each occurrence and are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl; or R7 and R8, together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted, saturated or unsaturated 3- to 12-membered cyclic ring, which may have one or two double bonds; R9, at each occurrence, is substituted or unsubstituted alkyl or substituted or unsubstituted aryl; R 10 and R 11 may be the same or different and independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -(CR c R d ) r -C(O)OR6, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl; or R 10 and R 11may, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted, saturated or unsaturated 3- to 12-membered cyclic ring, which unsaturated cyclic ring may have one or two double bonds; "n" is an integer ranging from 1 to 3 inclusive; "m" is an integer ranging from 0 to 3 inclusive; "p" is an integer ranging from 0 to 4, inclusive; "q" is an integer ranging from 0 to 3, inclusive; and "r" is an integer ranging from 1 to 3 inclusive; or a pharmaceutically acceptable salt thereof;

[0031] [ka] (In formula (IV), W, X, Z, R1, R2, R3, R4, "n", "p" and "q" are as described below: W is CH or N; R1 may be the same or different in each occurrence and independently represents halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, -C(O)OR5, -(CR a R b ) r -C(O)OR5, -OC(O)OR5, -O(CR a R b ) r -C(O)OR5, -NR6R7, -C(O)R8, -C(O)NR6R7, -NR6C(O)R8, -S(O) 0~2 R5 is selected from -S(O)2NR6R7, and -NR6S(O)2R8; R2 is substituted or unsubstituted aryl; R3 is substituted or unsubstituted alkyl; R4 may be the same or different in each occurrence and independently represents halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR5, -NR6R7, -C(O)R8, -C(O)NR6R7, -NR6C(O)R8, -S(O) 0~2 R5 is selected from -S(O)2NR6R7, and -NR5S(O)2R8; X is a bond, -(CR a R b ) r -, -O-, -NR7-, -O(CR a R b ) r -, -C(O)NR7-, -C(O)NR7(CR a R b ) r -, -(CR a R b ) r Cycloalkylene-, cycloalkylene, cycloalkylene-(CR a R b ) r -, and -O-cycloalkylene; R a and R b may be the same or different in each occurrence and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted cycloalkyl; or R a and R b may, together with the carbon atoms to which they are attached, form a substituted or unsubstituted 3- to 7-membered saturated carbocyclic ring; Z is -OR5 or -NR6R7; R5 may be the same or different in each occurrence and is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted aryl; R6 and R7 may be the same or different in each occurrence and independently represent hydrogen, substituted or unsubstituted alkyl, -(CR a R b ) r-C(O)OR5, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl; or R6 and R7, together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted, saturated or unsaturated 3- to 10-membered cyclic ring, which unsaturated cyclic ring may have one or two double bonds; R8, at each occurrence, is substituted or unsubstituted alkyl or substituted or unsubstituted aryl; "n" is an integer ranging from 0 to 3 inclusive; "p" is an integer ranging from 0 to 3 inclusive; "q" is an integer ranging from 0 to 3, inclusive; and "r" is an integer ranging from 1 to 3 inclusive; or a pharmaceutically acceptable salt thereof;

[0032] [ka] (In formula (V), X, R1, R2, R3 and "n" are as described below: R1 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, -(CR a R b ) 1~3 OH, -C(O)NH-alkyl, -S(O)2-alkyl, -S(O)2NH-alkyl, -C(O)OH, -C(O)O-alkyl, -(CR a R b ) 1~3 C(O)OH and -(CR a R b ) 1~3C(O)O-alkyl; R2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl, where the substituents, which may be one or more, are independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR4, -NR5R6, and substituted or unsubstituted cycloalkyl; X is -C(O)OH, -C(O)Oalkyl, -C(O)NR5R6, -(CR a R b ) 1~3 C(O)OH, -(CR a R b ) 1~3 C(O)O-alkyl, -O-(CR a R b ) 1~3 C(O)OH, -O-(CR a R b ) 1~3 selected from C(O)O-alkyl, -CRC=CRC-C(O)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR4, and -S(O)2-alkyl; R a and R b are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted cycloalkyl; or R a and R b may, together with the carbon atoms to which they are attached, form a substituted or unsubstituted 3- to 6-membered saturated carbocyclic ring; R c are independently selected from hydrogen, halogen, and substituted or unsubstituted alkyl; R3, which may be the same or different in each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and -OR4; R4 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted cycloalkyl; R5 and R6 are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; and "n" is an integer ranging from 0 to 2 inclusive); or a pharmaceutically acceptable salt thereof;

[0033] [ka] (In formula (VI), ring A, R1, R2, R3, R5, "n", "p" and "q" are as described below: Ring A is phenyl or naphthyl; R1 is hydrogen or substituted or unsubstituted (C1-C6) alkyl; R2 may be the same or different in each occurrence and independently represents halogen, cyano, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C1-C6) haloalkyl, substituted or unsubstituted (C1-C6) hydroxyalkyl, -XC(O)-Z, -OR9, -NR7R8, -NR7C(O)R6, -S(O) 0~2 R6, -S(O)2NR7R8, -NR7S(O)2R6, substituted or unsubstituted (C3-C 12 ) selected from cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted 5- to 6-membered heterocyclyl, and Ring D; Ring D is

[0034] [ka] and; X is a bond, -(CR a R b ) m -, -NR 12 -, -O(CR a R b ) m -, -(CR a R b ) m O-, -C(O)NR 12 -, -(CRa R b ) m O-(CR a R b ) m - and -C(O)NR 12 (CR a R b ) m -Selected from; R a and R b may be the same or different in each occurrence and are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C1-C6) haloalkyl, and substituted or unsubstituted (C3-C6) cycloalkyl; or R a and R b together with the carbon atoms to which they are attached form a substituted or unsubstituted 3- to 6-membered saturated carbocyclic ring; Z is -OR 10 or -NR7R8; R3 is hydrogen, halogen, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C1-C6) haloalkyl, -OR9, and substituted or unsubstituted (C3-C 12 ) cycloalkyl; R4 may be the same or different in each occurrence and is independently selected from halogen, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C1-C6) haloalkyl, substituted or unsubstituted (C1-C6) alkoxyalkyl, -SF5, and -OR9; R5 is a substituted or unsubstituted (C1-C6) alkyl; R6 is a substituted or unsubstituted (C1-C6) alkyl, a substituted or unsubstituted (C3-C 12 ) cycloalkyl and substituted or unsubstituted (C6-C 14 ) aryl; R7 and R8 may be the same or different in each occurrence and independently represent hydrogen, substituted or unsubstituted (C1-C6) alkyl, -(CR a R b ) 1~2 R 11, -(CR c R d ) m -OH and substituted or unsubstituted (C3-C 12 ) cycloalkyl; R c and R d may be the same or different in each occurrence and are independently hydrogen or substituted or unsubstituted (C1-C6) alkyl; R9 is independently selected from hydrogen, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C1-C6) haloalkyl, substituted or unsubstituted (C1-C6) alkoxyalkyl, and substituted or unsubstituted (C3-C 12 ) cycloalkyl; R 10 represents hydrogen, substituted or unsubstituted (C1-C6) alkyl, and -(CR a R b ) 1~2 phenyl; R 11 is a substituted or unsubstituted phenyl, where the substituents are selected from halogen, (C1-C6) alkyl, and -OR9; R 12 is hydrogen or substituted or unsubstituted (C1-C6) alkyl; "m" is an integer ranging from 1 to 3 inclusive; "n" is an integer ranging from 1 to 3 inclusive; "p" is an integer ranging from 0 to 3, inclusive; and "q" is an integer ranging from 1 to 3 inclusive; or a pharmaceutically acceptable salt thereof.

[0035] L, Q, Z, R1, and R in the above formula (I) a and R b Regarding the above formula (II), see PCT International Patent Application Publication WO2012 / 120476 A1 filed on March 9, 2012 (also published as U.S. Patent No. 9,382,216); 10 , Ra , R b "p" and "q" refer to PCT International Patent Application Publication WO2012 / 127388 A1 filed on March 16, 2012 (also published as U.S. Patent No. 9,464,063); X, Z, R, R, R, R, R, R, R, R, R, R a , R b , "m", "n", "p", and "q" are defined in PCT International Patent Application Publication No. WO2013 / 124828 A1 filed on February 22, 2013 (also published as U.S. Patent No. 9,163,001); W, X, Z, R1, R2, R3, R4, "n", "p", and "q" in the above formula (IV) are defined in PCT International Patent Application Publication No. WO2014 / 033604 A1 filed on August 23, 2013 (also published as U.S. Patent No. 9,227,919); and X, R1, R2, R3, and "n" in the above formula (VI) are defined in PCT International Patent Application Publication No. WO2015 / 022631 filed on August 12, 2014. A1; see also PCT International Patent Application Publication No. WO2015 / 028938, filed August 26, 2014 (also published as U.S. Patent No. 9,493,396).

[0036] In another aspect, the disclosure provides a solid pharmaceutical composition comprising a pharmaceutically effective amount of one or more CaSR agonists, wherein the one or more CaSR agonists have the structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), which has the structure of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6, respectively, as defined below: (i) The compound 3-((S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)morpholino)-5-(trifluoromethyl)benzoic acid, or its inner salt or hydrochloride salt ("Compound 1").

[0037] [ka] (ii) the compound 2-methyl-5-((S)-2-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzoic acid, or its inner salt or hydrochloride salt ("Compound 2");

[0038] [ka]

[0039] (iii) the compound 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, or an inner salt or hydrochloride thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride ("Compound 3")).

[0040] [ka] (iv) the compound 3-((1R,3S)-3-((((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dimethylbenzoic acid, or its inner salt or hydrochloride salt ("Compound 4")

[0041] [ka] (v) The compound (R)-3-(4-fluoro-3'-(2-((1-(3-methoxyphenyl)ethyl)amino)ethoxy)-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoic acid, or its inner salt or hydrochloride salt ("Compound 5").

[0042] [ka] (vi) The compound (R)—N—((R)-1-(3-methoxyphenyl)ethyl)-1-(4-(4-(trifluoromethyl)phenyl)naphthalen-2-yl)propan-1-amine, or its hydrochloride salt (“Compound 6”)

[0043] [ka]

[0044] In some embodiments, the compound of formula (I) is compound 1, 3-((S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)morpholino)-5-(trifluoromethyl)benzoic acid, or an internal salt or hydrochloride salt thereof.

[0045] In some embodiments, the compound of formula (II) is compound 2, 2-methyl-5-((S)-2-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzoic acid, or an internal salt or hydrochloride salt thereof.

[0046] In some embodiments, the compound of formula (III) is compound 3, 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride.

[0047] In some embodiments, the compound of formula (IV) is compound 4, 3-((1R,3S)-3-((((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dimethylbenzoic acid, or an inner salt or hydrochloride salt thereof.

[0048] In some embodiments, the compound of formula (V) is compound 5, (R)-3-(4-fluoro-3'-(2-((1-(3-methoxyphenyl)ethyl)amino)ethoxy)-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoic acid, or an inner salt or hydrochloride salt thereof.

[0049] In some embodiments, the compound of formula (VI) is compound 6, (R)—N—((R)-1-(3-methoxyphenyl)ethyl)-1-(4-(4-(trifluoromethyl)phenyl)naphthalen-2-yl)propan-1-amine, or an inner salt or hydrochloride salt thereof.

[0050] In another aspect, the present disclosure provides compositions comprising one or more compounds of Formula (I) to Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, and a pharmaceutically acceptable excipient. In some aspects, the compositions are suitable for oral delivery. In some aspects, the compositions comprise a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0051] In another aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: (i) a pharmaceutically effective amount of at least one compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, in the form of a free base, or a pharmaceutically acceptable salt thereof; and (ii) at least one pharmaceutically acceptable excipient A solid oral pharmaceutical composition comprising:

[0052] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0053] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically effective amount of Compound 1 and a pharmaceutically acceptable excipient, carrier, or diluent. In some aspects, the pharmaceutical composition is solid.

[0054] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically effective amount of Compound 2 and a pharmaceutically acceptable excipient, carrier, or diluent. In some aspects, the pharmaceutical composition is solid.

[0055] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically effective amount of Compound 3 and a pharmaceutically acceptable excipient, carrier, or diluent. In some aspects, the pharmaceutical composition is solid.

[0056] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically effective amount of Compound 4 and a pharmaceutically acceptable excipient, carrier, or diluent. In some aspects, the pharmaceutical composition is solid.

[0057] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically effective amount of Compound 5 and a pharmaceutically acceptable excipient, carrier, or diluent. In some aspects, the pharmaceutical composition is solid.

[0058] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically effective amount of Compound 6 and a pharmaceutically acceptable excipient, carrier, or diluent. In some aspects, the pharmaceutical composition is solid.

[0059] In some aspects, the present disclosure provides a pharmaceutical composition in the form of a tablet.

[0060] In some aspects, the present disclosure provides pharmaceutical compositions in the form of coated tablets.

[0061] In some embodiments, the present disclosure provides a pharmaceutical composition in the form of a film-coated tablet. In some embodiments, the film coating has a thickness of about 10 microns to about 500 microns. In some embodiments, the film coating has a thickness of about 20 microns to about 100 microns. In some embodiments, the film coating may be selected from the group consisting of resistant starch, high amylose corn starch, Eudragit® S polymer (poly(methacrylic acid-co-methyl methacrylate) 1:2), Eudragit® RS (poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1), Eudragit® RL (poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2), starch acetate, ethyl cellulose, Ac-Di-Sol® (croscarmellose sodium), sodium starch glycolate, cellulose ethers (e.g., hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), ethyl cellulose (EC), methyl cellulose, methylhydroxycellulose, methylhydroxyethyl ... Examples of suitable polymers include cellulose, ethylcellulose, sodium carboxymethylcellulose, or combinations thereof), vinyl polymers (e.g., polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), PVP-polyvinyl acetate copolymers, PVA-PEG copolymers), glycols (e.g., high molecular weight polyethylene glycol (PEG), polypropylene glycol), acrylic polymers (e.g., methacrylate amino ester copolymers, ethyl acrylate-methyl methacrylate copolymers), maltodextrin, polydextrose, cellulose, acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate-hypromellose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, poly(methacrylic acid-co-methyl methacrylate), shellac (e.g., esters of arachidonic acid), or combinations thereof.

[0062] In some embodiments, the present disclosure provides single unit dose compositions in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and one or more pharmaceutically acceptable excipients.

[0063] In some aspects, the present disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dose composition contains from about 1 mg to about 100 mg of the one or more compounds.

[0064] In some aspects, the present disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dose composition contains from about 1 mg to about 50 mg of the one or more compounds.

[0065] In some aspects, the present disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dose composition contains from about 5 mg to about 25 mg of the one or more compounds.

[0066] In some aspects, the present disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dose composition contains from about 5 mg to about 10 mg of the one or more compounds.

[0067] In some embodiments, the present disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dose composition contains from about 0.1 mg to about 200 mg of the at least one compound. In some embodiments, the single unit dose composition contains from about 1 mg to about 25 mg of the one or more compounds. In some embodiments, the single unit dose composition contains about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, or any amount between the aforementioned amounts and ranges, including, but not limited to, 0.1 mg to about 200 mg.

[0068] In some aspects, the present disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dose composition contains about 1 mg of the one or more compounds.

[0069] In some aspects, the present disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dose composition contains about 2.5 mg of the one or more compounds.

[0070] In some aspects, the present disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dose composition contains about 5 mg of the one or more compounds.

[0071] In some aspects, the present disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dose composition contains about 25 mg of the one or more compounds.

[0072] In some aspects, the present disclosure provides single unit dose compositions in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group consisting of the free base form of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, wherein the single unit dose composition contains from about 1 mg to about 25 mg of the one or more compounds.

[0073] In some embodiments, the present disclosure provides single unit dose compositions in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and at least one pharmaceutically acceptable excipient, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of a diluent, a lubricant, a disintegrant, a binder, a surfactant, a solubilizer, a glidant, or a combination thereof.

[0074] In another aspect, the present disclosure provides a method for treating or managing secondary hyperparathyroidism associated with chronic kidney disease (CKD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound 3)). In some aspects, the subject may or may not be undergoing dialysis. In some embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof is about 5 mg to about 50 mg, or about 10 mg to 40 mg, or about 20 mg to about 40 mg total daily dose. In some embodiments of the present invention, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg total daily dose. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof is administered in an amount of about 25 mg once or twice daily, or about 20 mg once or twice daily. In some embodiments of the present invention, the administration is oral. In some embodiments, the administration does not require dosage adjustment or titration of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, to the subject.

[0075] In another aspect, the present disclosure provides pharmaceutical compositions comprising one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof, and kits comprising pharmaceutical compositions comprising one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof, and instructional materials for their use.

[0076] In another aspect, the disclosure provides a method of reducing or suppressing one or more intact parathyroid hormone (iPTH) levels in a subject suffering from secondary hyperparathyroidism associated with CKD, comprising administering to the subject a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound 3)).

[0077] In some embodiments, the subject may be undergoing dialysis or not undergoing dialysis. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is about 5 mg to about 50 mg, or about 10 mg to 40 mg, or about 20 mg to about 40 mg total daily dose. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg total daily dose. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is administered at about 25 mg once or twice daily, or about 20 mg once or twice daily. In some embodiments, the administration is oral. In some embodiments, the administration does not require subject dosage adjustment or titration of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof.

[0078] In another aspect, the present disclosure provides the use of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound 3)) in an oral formulation, in the manufacture of a medicament for the treatment or management of secondary hyperparathyroidism associated with CKD in a subject in need thereof, wherein the oral formulation comprises a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof. In some aspects, the subject may or may not be undergoing dialysis. In some embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof is about 5 mg to about 50 mg, or about 10 mg to 40 mg, or about 20 mg to about 40 mg total daily dose. In some embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg total daily dose. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is administered at about 25 mg once or twice daily, or about 20 mg once or twice daily. In some embodiments, the administration is oral. In some embodiments, the administration does not require a subject to adjust or titrate the dose of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof.

[0079] In some aspects, the present disclosure provides the use of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound 3)) in an oral formulation in the manufacture of a medicament for reducing or suppressing one or more iPTH levels in a subject suffering from secondary hyperparathyroidism associated with CKD, wherein the oral formulation comprises a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof. In some aspects, the subject may or may not be undergoing dialysis. In some embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof is about 5 mg to about 50 mg, or about 10 mg to 40 mg, or about 20 mg to about 40 mg total daily dose. In some embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg total daily dose. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is administered at about 25 mg once or twice daily, or about 20 mg once or twice daily. In some embodiments, the administration is oral. In some embodiments, the administration does not require subject dosage adjustment or titration of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof.

[0080] In another aspect, the present disclosure provides a method of treating or managing secondary hyperparathyroidism associated with CKD in a subject in need thereof, comprising: (a) identifying subjects who have CKD-associated secondary hyperparathyroidism, characterized by elevated baseline iPTH concentration levels in the subject, and who require treatment or management; and (b) administering to the subject a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof. The present invention provides a method comprising: In another aspect, one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof is 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound 3).

[0081] In some embodiments, the subject may be undergoing dialysis or not undergoing dialysis. In some embodiments, the therapeutically effective amount of a compound selected from one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof is about 5 mg to about 50 mg, or about 10 mg to 40 mg, or about 20 mg to about 40 mg total daily dose. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg total daily dose. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof is administered in an amount of about 25 mg once or twice daily, or about 20 mg once or twice daily. In some embodiments, the administration is oral. In some embodiments, the administration does not require dose adjustment or titration of the compound selected from the compounds having Formulas (I)-(VI) to the subject.

[0082] In another aspect, the present disclosure provides a method of treating or managing secondary hyperparathyroidism associated with CKD in a subject in need thereof, comprising: (a) identifying a subject in need of treatment or management having secondary hyperparathyroidism associated with CKD, characterized by a baseline iPTH concentration level in the subject, the baseline iPTH concentration level being within the range of about 110 pg / ml to about 1500 pg / ml, or about 300 pg / ml to about 1250 pg / ml; and (b) administering to the subject a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof. The present invention provides a method comprising: In some embodiments, one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof is 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound 3).

[0083] In some embodiments, the subject may be undergoing dialysis or not undergoing dialysis. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is about 5 mg to about 50 mg, or about 10 mg to 40 mg, or about 20 mg to about 40 mg total daily dose. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg total daily dose. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is administered at about 25 mg once or twice daily, or about 20 mg once or twice daily. In some embodiments, the administration is oral. In some embodiments, the administration does not require subject dosage adjustment or titration of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof.

[0084] In another embodiment, a method for treating or managing secondary hyperparathyroidism associated with CKD in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a calcimeter. In some embodiments, the therapeutically effective amount of the calcimeter is a total daily dose of about 5 mg to about 50 mg, or about 10 mg to 40 mg, or about 20 mg to about 40 mg. In some embodiments, the therapeutically effective amount of the calcimeter is a total daily dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg. In some embodiments, the therapeutically effective amount of the calcimeter is administered at about 25 mg once or twice daily, or about 20 mg once or twice daily. In some embodiments, administration is oral. In some embodiments, administration does not require dose adjustment or titration of the calcimeter for the subject. In some embodiments, secondary hyperparathyroidism is treated or managed without inducing hyperphosphatemia or hypocalcemia in the subject. In some embodiments, the calcimimetics comprises one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof. In some embodiments, the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof is Compound 3.

[0085] In some embodiments, subjects with secondary hyperparathyroidism associated with CKD include subjects diagnosed with or with stage 3b CKD, stage 4 CKD, or stage 5 CKD.

[0086] In some embodiments, subjects with CKD-associated secondary hyperparathyroidism include subjects with baseline iPTH concentration levels ranging from about 110 pg / ml to about 1500 pg / ml, or from about 300 pg / ml to about 1600 pg / ml, or from about 110 pg / ml to about 1350 pg / ml. Preferably, the baseline iPTH concentration levels range from about 300 pg / ml to about 1250 pg / ml.

[0087] In some embodiments, any one of the methods or uses disclosed herein can reduce a subject's iPTH levels by at least about 30% compared to baseline iPTH concentration levels, or by at least about 15% compared to baseline iPTH concentration levels, or by about 15% to about 30% compared to baseline iPTH concentration levels.

[0088] In some embodiments, in any one of the methods or uses disclosed herein, one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof (e.g., Compound 3) are administered as a pharmaceutical composition. For example, the pharmaceutical composition can be in the form of a tablet or capsule. In some embodiments, the pharmaceutical composition comprises about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, or about 50 mg of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof. In some embodiments, the pharmaceutical composition is administered to a subject once daily, twice daily, or more than twice daily. In some embodiments, the pharmaceutical compositions are administered to a subject at a total daily dose of about 10 mg to about 40 mg; most preferably, about 20 mg to about 40 mg of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof.

[0089] In some embodiments, a pharmaceutical composition suitable for oral administration may be provided as a tablet or capsule, wherein the tablet comprises a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., Compound 3), and at least one component selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant, a surfactant, a glidant, and a combination thereof.

[0090] In some embodiments, the pharmaceutical composition for oral administration is in the form of a tablet, cachet, or capsule. In some embodiments of the present invention, the tablet, cachet, or capsule contains a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof (e.g., Compound 3), and at least one component selected from the group consisting of diluents, disintegrants, binders, lubricants, surfactants, glidants, and combinations thereof. In some embodiments of the present invention, each granule in the tablet, cachet, or capsule is coated or scored. In some embodiments of the present invention, the tablet, cachet, or capsule is formulated to provide immediate release of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof (e.g., Compound 3), and / or other active ingredients therein. In some embodiments of the invention, each granule in the tablet, cachet, or capsule is round (or circular), spherical, disc-shaped, oval, elliptical, capsule-shaped, oblong, triangular, pentagonal, hexagonal, octagonal, prilled, diamond-shaped, or arrowhead-shaped.

[0091] In some embodiments, the capsule is a hard-shell capsule, and the hard-shell capsule is made of hard gelatin and / or hydroxypropyl methylcellulose (HPMC). In some embodiments, the size of the hard-shell capsule is size 0 or size 00. In some embodiments, the capsule is a push-fit capsule. In some embodiments, the capsule contains a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., Compound 3), starch (e.g., starch 1500 LM), microcrystalline cellulose, and crospovidone. In some embodiments, the capsule contains about 35% w / w to about 39% w / w of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof.

[0092] In another aspect, the pharmaceutical compositions disclosed in the present application can be used to treat or manage a disease in a subject in need thereof, wherein the disease is hyperparathyroidism (including hyperparathyroidism, secondary hyperparathyroidism, or tertiary hyperparathyroidism), chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis), and complications thereof, or a combination thereof. Uses and methods of treatment or management related to the above are also included herein.

[0093] In another aspect, the pharmaceutical compositions disclosed in the present application can be used to treat or manage a disease in a subject in need thereof, including parathyroid adenoma; parathyroid hyperplasia; parathyroid carcinoma; vascular or valvular calcification; calcium dyshomeostasis; hypercalcemia; phosphorus dyshomeostasis; hypophosphatemia; bone-related diseases or complications resulting from hyperparathyroidism, chronic kidney disease, or parathyroid carcinoma; bone loss after kidney transplantation; osteitis fibrosa cysticis; adynamic bone disease; renal bone disease; cardiovascular complications resulting from hyperparathyroidism or chronic kidney disease; (Ca 2+ ) e Malignant tumors with abnormally high ions; cardiac, renal or intestinal dysfunction; podocyte-related diseases; intestinal dysmotility; diarrhea; enhancing gastrin or gastric acid secretion to directly or indirectly benefit atrophic gastritis, or improving the absorption of pharmacological compounds, drugs or supplements from the gastrointestinal tract by increasing gastric acidity, or combinations thereof. Uses and methods of treatment or management relating to the above are also included herein.

[0094] In another aspect, the disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of at least one compound, wherein the at least one compound is at least one of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a combination thereof in a free base form, wherein the single unit dose composition contains from about 0.1% to about 50% (w / w) of the at least one compound by weight of the single unit dose composition. In some embodiments, the at least one compound is the free base form of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a combination thereof, and the single unit dose composition contains from about 0.1% w / w to about 1% w / w, from about 1% w / w to about 5% w / w, from about 5% w / w to about 10% w / w, from about 10% w / w to about 15% w / w, from about 15% w / w to about 20% w / w, from about 20% w / w to about 25% w / w, from about 25% w / w to about 30% w / w, from about 30% w / w to about 35% w / w, from about 35% w / w to about 40% w / w, from about 40% w / w to about 45% w / w, from about 45% w / w to 50% w / w of the at least one compound, or an amount between any of the aforementioned ranges.In some embodiments, the at least one compound is the free base form of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a combination thereof, and the single unit dose composition comprises about 0.1% w / w, about 0.5% w / w, about 0.75% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, Approximately 21% w / w, approximately 22% w / w, approximately 23% w / w, approximately 24% w / w, approximately 25% w / w, approximately 26% w / w, approximately 27% w / w, approximately 28% w / w, approximately 29% w / w, approximately 30% w / w, approximately 31% w / w, approximately 32% w / w, approximately 33% w / w, approximately 34% w / w, approximately 35% w / w, approximately 36% w / w, approximately 37% w / w, about 38% w / w, about 39% w / w, about 40% w / w, about 41% w / w, about 42% w / w, about 43% w / w, about 44% w / w, about 45% w / w, about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, or about 50% w / w of the at least one compound.

[0095] In some aspects, the present disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of at least one compound, wherein the at least one compound is the free base form of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a combination thereof, and the single unit dose composition contains from about 2% w / w to about 20% w / w of the at least one compound.

[0096] In some aspects, the present disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of at least one compound, wherein the at least one compound is the free base form of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and the single unit dose composition contains from about 2% w / w to about 10% w / w of the at least one compound.

[0097] In some aspects, the present disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of at least one compound, wherein the at least one compound is the free base form of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and the single unit dose composition contains about 5% w / w to about 10% w / w of the at least one compound.

[0098] In some aspects, the present disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of at least one compound, wherein the at least one compound is the free base form of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and the single unit dose composition contains about 5% w / w of the at least one compound.

[0099] In some aspects, the present disclosure provides a single unit dose composition in tablet form comprising a pharmaceutically effective amount of at least one compound, wherein the at least one compound is the free base form of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and the single unit dose composition contains about 25% w / w of the at least one compound.

[0100] In another aspect, the disclosure provides a hydrochloride salt of a compound of any of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI).

[0101] In some embodiments, Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) is a free base.

[0102] In another aspect, the present disclosure provides a pharmaceutical composition comprising a tablet, wherein the tablet comprises at least one compound and at least one ingredient, wherein the at least one compound is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a combination thereof, and the at least one ingredient is: a) at least one diluent; b) at least one disintegrant; c) a binder; d) lubricants, e) surfactants, f) a lubricant, or g) combinations thereof The present invention provides a pharmaceutical composition comprising:

[0103] In another aspect, the present disclosure provides a pharmaceutical composition comprising a tablet, wherein the tablet comprises at least one compound and at least one ingredient, wherein the at least one compound is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a combination thereof, and the at least one ingredient is: a) at least one diluent; b) at least one disintegrant; c) at least one binder; d) at least one lubricant; e) at least one surfactant, or f) at least one lubricant The present invention provides a pharmaceutical composition comprising:

[0104] In another aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: At least one compound, 3-((S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)morpholino)-5-(trifluoromethyl)benzoic acid, or its inner salt or hydrochloride salt ("Compound 1"); 2-methyl-5-((S)-2-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzoic acid, or its inner salt or hydrochloride salt ("Compound 2"); 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, or its inner salt or hydrochloride salt (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride ("Compound 3"); 3-((1R,3S)-3-((((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dimethylbenzoic acid, or its inner salt or hydrochloride salt; ("Compound 4"); (R)-3-(4-fluoro-3'-(2-((1-(3-methoxyphenyl)ethyl)amino)ethoxy)-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoic acid, or an inner salt or hydrochloride salt thereof; ("Compound 5"); or (R)—N—((R)-1-(3-methoxyphenyl)ethyl)-1-(4-(4-(trifluoromethyl)phenyl)naphthalen-2-yl)propan-1-amine hydrochloride; (“Compound 6”), or at least one compound that is a combination thereof; and At least one component, (a) microcrystalline cellulose in an amount of about 5% to about 50% by weight of the total weight of the solid pharmaceutical composition; (b) crospovidone in an amount of about 5% to about 20% by weight of the total weight of the solid pharmaceutical composition, or povidone in an amount of about 3% to about 20% by weight of the total weight of the solid pharmaceutical composition, or a combination thereof; (c) pregelatinized starch in an amount of about 20% to about 50% by weight of the total weight of the solid pharmaceutical composition; (d) magnesium stearate in an amount of about 0.5% to about 5% by weight of the total weight of the solid pharmaceutical composition, or talc in an amount of about 0.5% to about 2% by weight of the total weight of the solid pharmaceutical composition, or a combination thereof; (e) sodium lauryl sulfate (SLS) in an amount of about 0.5% to about 3% by weight of the total weight of the solid pharmaceutical composition; (f) colloidal silicon dioxide in an amount of about 0.5% to about 3% by weight of the total weight of the solid pharmaceutical composition; or (g) any combination thereof The present invention provides a solid pharmaceutical composition comprising at least one component which is

[0105] In another aspect, the disclosure provides a solid pharmaceutical composition comprising 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride and at least one ingredient, wherein the at least one ingredient is: (h) microcrystalline cellulose in an amount of about 5% to about 50% by weight of the total weight of the solid pharmaceutical composition; (i) crospovidone in an amount of about 5% to about 20% by weight of the total weight of the solid pharmaceutical composition, or povidone in an amount of about 3% to about 20% by weight of the total weight of the solid pharmaceutical composition, or a combination thereof; (j) pregelatinized starch in an amount of about 20% to about 50% by weight of the total weight of the solid pharmaceutical composition; (k) magnesium stearate in an amount of about 0.5% to about 5% by weight of the total weight of the solid pharmaceutical composition, or talc in an amount of about 0.5% to about 2% by weight of the total weight of the solid pharmaceutical composition, or a combination thereof; (l) sodium lauryl sulfate (SLS) in an amount of about 0.5% to about 3% by weight of the total weight of the solid pharmaceutical composition; (m) colloidal silicon dioxide in an amount of about 0.5% to about 3% by weight of the total weight of the solid pharmaceutical composition; or (n) any combination thereof The present invention provides a solid pharmaceutical composition, wherein

[0106] In another aspect, the present disclosure provides a solid pharmaceutical composition comprising a coated tablet, wherein the coated tablet comprises at least one compound and at least one ingredient, wherein the at least one compound is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a combination thereof, and the at least one ingredient is: (a) microcrystalline cellulose (e.g., AVICEL® PH 102) in an amount of about 5% to about 50% by weight of the total weight of the coated tablet; (b) crospovidone (e.g., Kollidone® CL-SF) in an amount of about 5% to about 20% by weight of the total weight of the coated tablet, or povidone (e.g., Kollidone® K-30) in an amount of about 3% to about 20% by weight of the total weight of the coated tablet, or a combination thereof; (c) pregelatinized starch (e.g., Starch 1500®) in an amount of about 20% to about 50% by weight of the total weight of the coated tablet; (d) magnesium stearate (e.g., Hyqual®, vegetable derived) in an amount of about 0.5% to about 5% by weight of the total weight of the coated tablet, or talc (e.g., Talc, 197 Pharma) in an amount of about 0.5% to about 2% by weight of the total weight of the coated tablet, or a combination thereof; (e) sodium lauryl sulfate (SLS) in an amount of about 0.5% to about 3% by weight of the total weight of the coated tablet; (f) colloidal silicon dioxide (e.g., Aerosil® 200 Pharma) in an amount of about 0.5% to about 3% by weight of the total weight of the coated tablet; or (g) any combination thereof The present invention provides a solid pharmaceutical composition, wherein

[0107] In some embodiments, the tablet form is formulated to provide immediate release of at least one active ingredient (e.g., Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a pharmaceutically acceptable salt thereof, or a combination thereof). In some embodiments, the tablet form has at least one of the following shapes: round (or circular), spherical, disc-shaped, oval, elliptical, capsule-shaped, rectangular, triangular, pentagonal, hexagonal, octagonal, prill, diamond-shaped, or arrowhead-shaped. In some embodiments, the term "immediate release," as used herein, refers to any of the compositions or pharmaceutical compositions disclosed in the present application that do not have a rate controlling agent. In some embodiments, the term "immediate release" refers to the release of about 80% or more of at least one active ingredient (e.g., Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a pharmaceutically acceptable salt thereof, or a combination thereof) in a composition or pharmaceutical composition within 20 minutes when subjected to dissolution in 900 ml of 0.1 N HCl with 0.5% SLS using a USP apparatus Type 2 at 75 rpm and 37.5° C. In some embodiments, the term "immediate release" refers to the release of 70% or more of at least one active ingredient (e.g., Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a pharmaceutically acceptable salt thereof, or a combination thereof) in a composition or pharmaceutical composition within 10 minutes when subjected to dissolution in 900 ml of 0.1 N HCl with 0.5% SLS using a USP apparatus Type 2 at 75 rpm and 37.5° C.

[0108] In some embodiments, the pharmaceutical compositions described above can be used to treat or manage at least one disease in a subject in need thereof, wherein the at least one disease is hyperparathyroidism (including hyperparathyroidism, secondary hyperparathyroidism, or tertiary hyperparathyroidism), chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis), and complications thereof, or combinations thereof. Uses and methods of treatment or management relating to the above are also included herein.

[0109] In some embodiments, the pharmaceutical compositions described above can be used to treat or manage at least one disease in a subject in need thereof, the at least one disease being parathyroid adenoma, parathyroid hyperplasia, parathyroid carcinoma, vascular or valvular calcification, calcium dyshomeostasis, hypercalcemia, phosphorus dyshomeostasis, hypophosphatemia, hyperparathyroidism, bone-related diseases or complications resulting from chronic kidney disease or parathyroid carcinoma, bone loss after kidney transplantation, osteitis fibrosa cystica, adynamic bone disease, renal bone disease, cardiovascular complications resulting from hyperparathyroidism or chronic kidney disease, (Ca 2+ ) e The present invention relates to the treatment of malignant tumors with abnormally high ions, cardiac, renal or intestinal dysfunction, podocyte-related diseases, intestinal dysmotility, diarrhea, and atrophic gastritis by enhancing gastrin or gastric acid secretion, or by enhancing gastric acidity to improve the absorption of pharmacological compounds, drugs or supplements from the gastrointestinal tract, or a combination thereof. The above-mentioned uses and methods of treatment or management are also included herein.

[0110] In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the group consisting of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), and combinations thereof, for treating or managing at least one disease selected from the group consisting of hyperparathyroidism (including hyperparathyroidism, secondary hyperparathyroidism, or tertiary hyperparathyroidism), chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis), and complications thereof, and combinations thereof. Uses and methods of treatment or management related to the above are also included herein.

[0111] In some embodiments, a single unit dose in tablet form comprising a therapeutically effective amount of at least one compound selected from the group consisting of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), and combinations thereof, for treating or managing at least one disease selected from the group consisting of hyperparathyroidism (including hyperparathyroidism, secondary hyperparathyroidism, or tertiary hyperparathyroidism), chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis), and complications thereof, and combinations thereof. Uses and methods of treatment or management relating to the above are also included herein.

[0112] In some embodiments, the at least one disease or disorder associated with CaSR is hyperparathyroidism (including hyperparathyroidism, secondary hyperparathyroidism, or tertiary hyperparathyroidism), chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis) and complications thereof, parathyroid adenoma, parathyroid hyperplasia, parathyroid carcinoma, vascular or valvular calcification, calcium dyshomeostasis, hypercalcemia, phosphorus dyshomeostasis, hypophosphatemia, bone-related diseases or complications resulting from hyperparathyroidism, chronic kidney disease, or parathyroid carcinoma, bone loss after kidney transplantation, osteitis fibrosa cystica, adynamic bone disease, renal bone disease, cardiovascular complications resulting from hyperparathyroidism or chronic kidney disease, (Ca 2+ ) e The abnormally high ion levels are malignant tumors, cardiac, renal or intestinal dysfunction, podocyte-related diseases, intestinal motility disorders, diarrhea, or a combination thereof.

[0113] In some embodiments, methods for preparing the aforementioned pharmaceutical compositions and manufacturing tablets for the treatment or management of one or more diseases or disorders associated with CaSR. In some embodiments, methods for preparing the aforementioned pharmaceutical compositions and manufacturing coated tablets for the treatment or management of one or more diseases or disorders associated with CaSR.

[0114] In some embodiments, pharmaceutical compositions or single unit doses in tablet form comprising a pharmaceutically effective amount of at least one compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof are prepared using one or more tablet forming methods.

[0115] In some embodiments, a pharmaceutical composition or single unit dose in tablet form comprising a pharmaceutically effective amount of at least one of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof is prepared using direct compression.

[0116] In some embodiments, there is provided a method of making a tablet, comprising: i) combining one or more inactive ingredients with at least one active compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, using a combination of blending and milling to form a blended formulation; ii) compressing the blended formulation into tablets; and iii) optionally coating the tablets; A method comprising: The blending process described above includes mixing at least one active compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and combinations thereof, and at least one of the pharmaceutical excipients mentioned hereinabove in a blender, and the blended formulation is sieved; if necessary, tablet compression is performed using a tableting method (e.g., ¼ inch Standard Concave B Tooling); if necessary, tablet coating is performed using a coating (e.g., a film coating, e.g., Opadry® II).

[0117] In some embodiments, the single unit dose in tablet form has an average tablet weight ranging from about 50 mg to about 1000 mg, about 50 mg to about 200 mg, or about 100 mg to about 200 mg. The degree of error in measuring the average tablet weight can be ±20%, ±15%, ±10%, ±7%, ±5%, ±2%, or ±1%. In some embodiments, a single unit dose in tablet form has an average mass of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, and Compound 6, or a pharmaceutically acceptable salt thereof, of about 1 mg to about 100 mg, about 1 mg to about 5 mg, 5 mg to about 10 mg, 10 mg to about 20 mg, 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 60 mg, about 60 mg to about 70 mg, about 70 mg to about 80 mg, about 80 mg to about 90 mg, about 90 mg to about 100 mg, or any range between the aforementioned ranges.

[0118] In some embodiments, a single unit dose in tablet form having an average weight of 100 mg ±7% and comprising at least one hydrochloride salt of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a combination thereof is about 5.4 mg.

[0119] In some embodiments, a single unit dose in tablet form having an average weight of 500 mg ±7% and comprising at least one hydrochloride salt of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a combination thereof is about 27 mg.

[0120] In some embodiments, a pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound selected from the group consisting of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), and combinations thereof, for treating or managing a disease or disorder associated with CaSR in a subject (e.g., a mammal, including a warm-blooded animal such as a human). [Brief explanation of the drawings]

[0121] [Figure 1]1 is a bar graph showing the mean percent change in iPTH from baseline iPTH concentration levels for each dose (i.e., placebo; 10 mg QD; 25 mg QD; 20 mg BID) of a representative compound of the present disclosure, 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound 3), for patients undergoing dialysis. It also shows that iPTH levels in patients decrease by more than 30% for the 20 mg BID and 25 mg QD dose groups and 25.65% for the 10 mg QD dose group. "N" indicates the number of patients. [Figure 2] 1 is a bar graph showing the mean percent change in iPTH from baseline iPTH concentration levels for patients not undergoing dialysis for each dose of Compound 3 (i.e., placebo; 5 mg BID; 10 mg QD). It also shows that iPTH levels in patients are reduced by more than 30% for the 5 mg BID and 10 mg QD dose groups. [Figure 3] 1 is a line graph showing the mean iPTH levels at different time points (e.g., baseline (t=0); 30 days; 60 days; 90 days) and different daily doses of Compound 3 (i.e., placebo; 10 mg QD; 20 mg BID; 25 mg QD) for patients undergoing dialysis. [Figure 4] 1 is a line graph showing mean iPTH levels at different time points (e.g., baseline (t=0); 30 days; 60 days; 90 days) and different daily doses of Compound 3 (i.e., placebo; 5 mg BID; 10 mg QD) for patients not undergoing dialysis. [Figure 5] 1 is a bar graph showing the % of patients in each dose arm (or group) (i.e., placebo; 10 mg QD; 20 mg BID; 25 mg QD) using Compound 3 who achieved a 30% or greater reduction from baseline iPTH concentration levels at D90. [Figure 6]1 is a bar graph showing the mean % change in iPTH at 2-4 hours post-dose (i.e., placebo; 10 mg QD; 20 mg BID; 25 mg QD) on day 90 with Compound 3 during an exploratory analysis. DETAILED DESCRIPTION OF THE INVENTION

[0122] [Detailed explanation] The present invention is not limited to the specific compositions, methods, uses, compounds, processes, or methodologies described, as they may vary. The terminology used in this detailed description section is for the purpose of describing particular aspects or embodiments only and is not intended to limit the scope of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the embodiments, preferred methods, devices, and materials of the present invention described herein.

[0123] The pharmaceutical compositions disclosed herein are available in tablet form that are stable during long-term storage, and further provide good oral bioavailability of the disclosed compounds.

[0124] definition The following definitions will be applied for the purpose of interpreting this specification and, whenever appropriate, terms used in the singular will also include the plural and vice versa.

[0125] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0126] As used herein, the term "about" is intended to mean that the numerical value it modifies varies within a margin of error. When a specific error range (e.g., standard deviation relative to a mean) is not provided, the term "about" means plus or minus 10% of the numerical value of the number with which it is used. For example, "about 50%" means a range of 45% to 55%. Ranges may be expressed herein as "about" from one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, using the antecedent "about," it will be understood that the particular value forms a separate embodiment. It will be further understood that the endpoints of each range are significant both in relation to the other endpoint, and independently of the other endpoint.

[0127] Unless otherwise stated, the term "oxo" as used herein refers to a C(=O) group. Such oxo groups may be part of either a ring or a chain within the compounds disclosed in the present application.

[0128] The term "acyl," as used herein, refers to the group -COR, where "R" is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocyclyl, as defined herein, e.g., formyl, acetyl, trifluoroacetyl, benzoyl, piperazin-1-ylcarbonyl, and the like. When R is alkyl, it is referred to herein as alkylcarbonyl. When R is aryl, it is referred to herein as arylcarbonyl. When R is heteroaryl, it is referred to herein as heteroarylcarbonyl. When R is heterocyclyl, it is referred to herein as heterocyclylcarbonyl.

[0129] As used herein, the term "alkenyl" refers to a hydrocarbon group containing 2 to 10 carbon atoms and at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Unless stated or indicated to the contrary, all alkenyl groups described herein or in the claims can be straight-chained or branched.

[0130] The term "alkoxy," as used herein, is an alkyl group attached through an oxygen linkage. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and the like. Unless stated or indicated to the contrary, all alkoxy groups described herein or in the claims may be straight or branched.

[0131] As used herein, the term "alkoxyalkyl" refers to a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with at least one alkoxy group, as defined above, preferably one or two alkoxy groups, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0132] The term "alkoxycarbonyl" as used herein refers to a -C(O)OR group where "R" is an alkyl group as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

[0133] The term "alkyl," as used herein, refers to a hydrocarbon group derived from an alkane, containing only carbon and hydrogen atoms in the backbone, containing no unsaturation, having 1 to 6 carbon atoms, and attached to the remainder of the molecule by a single bond, such as, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), etc. Unless stated or indicated to the contrary, all alkyl groups described herein or in the claims can be straight or branched.

[0134] The term "alkylamino" as used herein refers to an -NHR group where "R" is alkyl as defined herein, e.g., methylamino, ethylamino, n-, isopropylamino, n-, iso-, tert-butylamino, and the like.

[0135] The term "alkylsulfonyl" as used herein refers to a -SO2R group where "R" is alkyl as defined herein, e.g., methylsulfonyl, ethylsulfonyl, and the like.

[0136] The term "alkylthio" as used herein refers to the group --SR where "R" is alkyl as defined herein, e.g., methylthio, ethylthio, propylthio, or butylthio, and the like.

[0137] As used herein, the term "alkynyl" refers to a hydrocarbon group containing 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, and the like. Unless stated or indicated to the contrary, all alkynyl groups described herein or in the claims can be straight-chained or branched.

[0138] As used herein, the term "amino" refers to the group --NH.sub.2.

[0139] The term "aminoalkyl," as used herein, refers to a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with at least one, and preferably one or two, -NRR', where "R" is hydrogen, alkyl, acyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocyclylalkyl, and R' is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonyl, aminosulfonyl, as defined herein, e.g., aminomethyl, methylaminoethyl, dimethylaminoethyl, 1,3-diaminopropyl, acetylaminopropyl, and the like.

[0140] The term "aryl" as used herein refers to an aromatic group having 6 to 14 carbon atoms, including monocyclic, bicyclic, and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

[0141] The term "arylalkyl" as used herein refers to an aryl group as defined above directly bonded to an alkyl group as defined above, for example, -CH2C6H5 and -C2H4C6H5.

[0142] As used herein, the term "aromatic" refers to a ring system whose constituent atoms form an unsaturated ring system and in which all atoms in the ring system are sp 2 It is hybridized and is a part where the total number of pi electrons is equal to 4n+2.

[0143] As used herein, the term "carbocyclic ring" or "carbocycle" means an optionally substituted 3- to 6-membered saturated or partially unsaturated, monocyclic, fused, bicyclic, or spirocyclic ring containing carbon atoms, for example, carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, and the like.

[0144] The term "carboxy" as used herein refers to the group --C(O)OH.

[0145] The term "cycloalkyl" refers to a non-aromatic mono- or polycyclic ring system having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of polycyclic cycloalkyl groups include, but are not limited to, perhydronaphthyl, adamantyl, and norbornyl groups, bridged cyclic or spiro bicyclic groups, such as spiro(4,4)non-2-yl, etc.

[0146] The term "cycloalkylalkyl" refers to a cycloalkyl group, as defined above, directly bonded to an alkyl group, as defined above, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, and the like.

[0147] As used herein, the term "3- to 6-membered saturated carbocyclic ring" refers to a carbocyclic ring that is a monocyclic and non-aromatic carbocyclic ring as defined herein.

[0148] The term "haloalkyl" as used herein refers to an alkyl group, as defined above, substituted with one or more halogen atoms, as defined above. Preferably, the haloalkyl may be a monohaloalkyl, dihaloalkyl, or polyhaloalkyl, including perhaloalkyl. A monohaloalkyl can have one iodine, bromine, chlorine, or fluorine atom. Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms. Preferably, polyhaloalkyl is substituted with up to 12 halogen atoms. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, and the like. As used herein, a perhaloalkyl is an alkyl in which all hydrogen atoms have been replaced with halogen atoms. Unless stated or indicated to the contrary, all haloalkyl groups described in this specification or claims may be straight-chained or branched.

[0149] The term "haloalkoxy" refers to a haloalkyl group, as defined herein, attached through an oxygen linkage. Non-limiting examples of such groups are monohaloalkoxy, dihaloalkoxy, or polyhaloalkoxy, including perhaloalkoxy. Unless stated or indicated to the contrary, all haloalkoxy groups described herein or in the claims may be straight or branched.

[0150] As used herein, the term "halogen" or "halo" refers to a group that can include, but is not limited to, fluorine, chlorine, bromine, or iodine.

[0151] As used herein, the terms "heterocyclic ring" or "heterocyclyl ring" or "heterocyclyl," unless otherwise specified, refer to a substituted or unsubstituted non-aromatic 3- to 15-membered ring consisting of carbon atoms and one or more heteroatoms independently selected from N, O, or S. The heterocyclic ring may be a monocyclic, bicyclic, or tricyclic ring system and may include fused, bridged, or spiro ring systems, and the nitrogen, carbon, oxygen, or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bonds, and one or two carbon atoms in the heterocyclic ring or heterocyclyl may be interrupted by -CF-, -C(O)-, -S(O)-, S(O)-, -C(=N-alkyl)-, or -C(=N-cycloalkyl), etc. Furthermore, the heterocyclic ring may also be fused to an aromatic ring. Non-limiting examples of heterocyclic rings include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perfluoroisopropyl benzoate, octahydro ... These include hydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinylsulfoneindoline, benzodioxole, tetrahydroquinoline, tetrahydrobenzopyran, etc. The heterocyclic ring can be attached by any atom of the heterocyclic ring that results in the creation of a stable structure.

[0152] The term "heteroaryl," as used herein, unless otherwise specified, refers to a substituted or unsubstituted 5- to 14-membered aromatic heterocyclic ring having one or more heteroatoms independently selected from N, O, or S. A heteroaryl can be a monocyclic, bicyclic, or tricyclic ring system. The heteroaryl ring can be attached by any atom of the heteroaryl ring that results in the creation of a stable structure. Non-limiting examples of heteroaryl rings include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl, and the like.

[0153] The term "heterocyclylalkyl" as used herein refers to the group -(alkylene)-R, where R is heterocyclyl as defined above, e.g., pyrrolidinylmethyl, tetrahydrofuranylethyl, pyridinylmethylpiperidinylmethyl, and the like.

[0154] As used herein, the term "heteroarylalkyl" refers to a heteroaryl ring group directly bonded to an alkyl group. The heteroarylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless otherwise indicated, the term "substituted," as used herein, refers to a group or moiety having one or more substituents attached to the structural backbone of that group or moiety. Such substituents include, but are not limited to, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclic, heterocyclylalkyl, heteroarylalkyl, -C(O)OR x, -C(O)R x , -C(S)R X , -C(O)NR x R y , -NR x C(O)NR y R z , -N(R x )S(O)R y , -N(R x )S(O)2R y , -NR x R y , -NR x C(O)R y , -NR x C(S)R y , -NR x C(S)NR y R z , -S(O)NR x R y , -OR x , -OC(O)R x , -OC(O)NR x R y , -R x C(O)OR y , -R x C(O)NR y R z , -R x C(O)R y , -SR X , and -S(O)R x where R x , R y and R z is independently selected at each occurrence from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, and aryl. The aforementioned "substituted" groups cannot be further substituted.

[0155] The compounds of the present invention may have one or more chiral centers. The absolute stereochemistry of each chiral center may be "R" or "S." The compounds of the present invention include all diastereomers and enantiomers, as well as mixtures thereof. Unless otherwise specified, a reference to one stereoisomer applies to any of the possible stereoisomers. When the stereoisomeric composition is not specified, it is understood that all possible stereoisomers are included.

[0156] As used herein, the term "stereoisomers" refers to compounds made up of the same atoms joined by the same bonds but having different three-dimensional structures that are not interchangeable. These three-dimensional structures are referred to as configurations.

[0157] As used herein, the term "enantiomers" refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0158] As used herein, the term "chiral center" is a carbon atom to which four different groups are attached.

[0159] As used herein, the term "diastereomers" are stereoisomers that are not enantiomers.

[0160] As used herein, the terms "racemate" or "racemic mixture" refer to a mixture of equal parts of enantiomers.

[0161] As used herein, the term "tautomer" refers to a compound that undergoes rapid proton transfer from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Individual tautomers as well as mixtures thereof are encompassed by the compounds of Formulas (I)-(VI).

[0162] As used herein, the term "pharmaceutically acceptable" means that the substance is generally safe, non-toxic, and free from biological or other undesirable properties and is useful in preparing pharmaceutical compositions, including acceptable for both veterinary and human medicine.

[0163] The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound of this disclosure that is pharmaceutically acceptable, as defined above, and possesses the desired pharmacological activity. Such salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or salts with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methylsulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, benzoic ... Includes acid addition salts formed with sulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.

[0164] Pharmaceutically acceptable salts also include base addition salts that can be formed when acidic protons present can react with inorganic or organic bases. Acceptable inorganic bases include, but are not limited to, sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, calcium hydroxide, etc. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.

[0165] As used herein, the terms "subject" or "patient" are understood to be interchangeable and refer to any living organism that can be treated with the methods / uses / compounds / compositions of the present invention. Accordingly, the term "subject" or "patient" can include, but is not limited to, mammals (non-human and human), primates, and other animals, such as domestic animals (e.g., pets, including cats and dogs) and non-domestic animals (e.g., wildlife). In some embodiments, a "subject" or "patient" is an adult, child, infant, or fetus. In some embodiments, the term "subject" or "patient" is a human. In some embodiments, the term "subject" or "patient" is a mammal, such as a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, primate, or human. The disclosed methods / uses / compounds / compositions of the present invention can be utilized to treat and / or prevent secondary hyperthyroidism or its symptoms in a subject in need thereof.

[0166] As used herein, the term "subject in need thereof" includes, but is not limited to, a subject having or at risk of developing a disease, illness, or disorder, such as secondary hyperthyroidism. A subject in need thereof can include a subject undergoing dialysis or a subject not undergoing dialysis.

[0167] As used herein, the terms "treat," "treating," or "treatment" of a disease, condition, or disorder include: (a) preventing or delaying the appearance of clinical symptoms of a developing disease, condition, or disorder in a subject who may have or be susceptible to the disease, condition, or disorder, but who has not yet experienced or displayed clinical or subclinical symptoms of the disease, condition, or disorder; (b) arresting the disease, condition, or disorder, i.e., preventing or reducing the onset of the disease, condition, or disorder, or at least one clinical or subclinical symptom thereof; c) ameliorating or reducing the severity of the disease, condition, or disorder, or at least one clinical or subclinical symptom thereof; or (d) alleviating the disease, condition, or disorder, i.e., causing regression of the disease, condition, or disorder, or at least one clinical or subclinical symptom thereof.

[0168] As used herein, the term "therapeutic agent" means an agent utilized to treat, combat, ameliorate, or prevent an unwanted disease, illness, or disorder in a subject.

[0169] As used herein, the terms "pharmaceutically effective amount" or "therapeutically effective amount" or "therapeutic dose" are used synonymously and interchangeably and refer to the amount of an active agent or pharmaceutical compound or composition that elicits the clinical, biological or medicinal response in a tissue, system, animal, individual or human as determined by a researcher, veterinarian, physician, or other clinical professional. A clinical, biological, or medical response can include, for example, one or more of the following: (1) preventing or delaying a disease, illness, or disorder in an individual who may be predisposed to the disease, illness, or disorder but who has not yet experienced or displayed any of the symptoms or symptoms of the disease, illness, or disorder; (2) arresting a disease, illness, or disorder or preventing further development of the symptoms and / or symptoms of the disease, illness, or disorder in an individual who is experiencing or displaying the symptoms or symptoms of the disease, illness, or disorder; (3) improving or reducing the severity of a disease, illness, or disorder in an individual who is experiencing or displaying the symptoms or symptoms of the disease, illness, or disorder, or reversing the symptoms and / or symptoms experienced or displayed by the individual; or (4) alleviating the disease, illness, or disorder in the individual, i.e., causing a regression of the disease, illness, or disorder or at least one of its clinical or subclinical symptoms. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, health and responsiveness of the subject to be treated.

[0170] As used herein, the terms "manage" or "managing" or "management" of a disease, condition, or disorder refer to a beneficial effect that a subject derives from a treatment that includes one or more prophylactic and / or therapeutic agents, which does not result in a cure of the disease, condition, or disorder. In one embodiment, a subject is administered a treatment that includes one or more prophylactic and / or therapeutic agents to "manage" a disease, condition, or disorder so as to prevent the progression or worsening of the disease, condition, or disorder.

[0171] As used herein, the term "Cmax" refers to the maximum concentration of a compound or drug achieved in a tested region of a subject after administration of the drug and before the next dose is administered. The tested region can be, for example, plasma.

[0172] As used herein, the term "Tmax" means the time from administration of a given dose of a compound or drug to a subject to the time at which Cmax is reached.

[0173] As used herein, the terms "modulate" or "modulating" or "modulation" or "modulator" refer to an increase in the quantity, quality, or effect of a specific activity or function of a receptor. Examples, but not limitations, include agonists, partial agonists, and allosteric modulators of the calcium-sensing receptor (CaSR) of the present invention. Such modulation can be associated with the occurrence of a specific event, such as activation of a signal transduction pathway.

[0174] As used herein, the term "pharmaceutically acceptable excipient" means any component of a formulation or pharmaceutical composition, other than Compounds 1 through 6, that has been approved by a regulatory agency or is generally considered safe for human or animal use. Pharmaceutically acceptable excipients include, but are not limited to, one or more diluents, disintegrants, binders, lubricants, surfactants, glidants, preservatives, buffers, chelating agents, polymers, opacifiers, colorants, gelling / viscosity enhancing agents, antioxidants, solvents, and the like.

[0175] Non-limiting examples of "binders" include one or more of alginic acid and salts thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Kiucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate; acid polysaccharides; bentonite; gelatin; polyvinylpyrrolidone / vinyl acetate; copolymers; crospovidone; povidone; starch; pregelatinized starch; dextrin; sugars such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose; natural or synthetic gums such as acacia, tragacanth, isapol bark ghatti mucilage, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabogalactan, Veegum®, polyethylene glycol, polyethylene oxide, waxes, sodium alginate, and the like. Binder usage levels in tablet formulations vary depending on whether direct compression, wet granulation, or roller compaction processes are used to manufacture the tablets and / or the types of other excipients used to manufacture the formulation, such as fillers that can themselves act as mild binders.

[0176] Non-limiting examples of "diluents" include one or more of lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, such as Avicel®; dibasic calcium phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugars, such as Di-Pac® (Amstar); hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, powdered sugar for icing; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed grain solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, etc. Diluents may be used in pharmaceutical compositions to dilute the compound of interest prior to delivery. Diluents may also be used to stabilize the compound by providing a more stable environment.

[0177] Non-limiting examples of "disintegrants" or "disintegrating agents" include one or more starches, such as natural starches, such as corn starch or potato starch, pregelatinized starches, such as National 1551 or sodium starch glycolate, such as Promogel® or Explotab®, cellulose, such as wood products, methylcrystalline cellulose, such as Avicel®, Avicel® PH101, Avicel® PH 102, Avicel® PH105, Elceme® P100, Emcocel®, Vivacel®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked cellulose such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), gums such as agar, guar, carob, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, sponge, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combined starches, and the like. Disintegrants may be used in pharmaceutical compositions to facilitate the breakdown or disintegration of the dosage form when it comes into contact with gastrointestinal fluids.

[0178] Non-limiting examples of "lubricants" and "lubricants" include one or more of stearic acid, magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate, and the like.

[0179] Non-limiting examples of "surfactants" include one or more of sodium lauryl sulfate, docusate sodium, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF), etc. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, e.g., Octoxynol 10, Octoxynol 40. Surfactants may be used in pharmaceutical compositions to enhance physical stability or for other purposes.

[0180] Non-limiting examples of "solubilizing agents" include one or more of triacetin; triethyl citrate; ethyl oleate; ethyl caprylate; sodium lauryl sulfate; docusate sodium; vitamin E TPGS; dimethylacetamide; N-hydroxyethylpyrrolidone; polyvinylpyrrolidone; organic alcohols such as ethanol, n-butanol, isopropyl alcohol, etc.; hydroxypropyl methylcellulose; hydroxypropyl beta cyclodextrins such as Captisol®; cholesterol; bile salts; propylene glycol; polyethylene glycol (e.g., PEG 200-600); glycofurol; transcutol; dimethyl isosorbide, etc.

[0181] As used herein, "hyperphosphatemia" refers to a condition in which the level of phosphate in the blood is elevated. The average serum phosphorus level in human adults typically ranges from about 2.5 to 4.5 mg / dL (about 0.81 to 1.45 mmol / L). In patients with advanced renal disease, body phosphorus overload manifests as hyperphosphatemia with serum phosphorus concentrations above normal levels, i.e., serum phosphate >4.5 mg / dL (>1.44 mmol / L).

[0182] As used herein, "hypocalcemia" refers to a decreased calcium level in the blood. A calcium level below about 9 mg / dL or 2.2 mmol / L can be a sign of hypocalcemia. Hypocalcemia is a contraindication to calcimimetic drugs, and calcimimetic drugs should not be administered to subjects with calcium levels below 8 mg / dL.

[0183] As used herein, the term "not on dialysis subject" or "subject not on dialysis" refers to a subject who has two corrected total serum calcium values obtained during the screening period, one of which is ≥ 8.8 mg / dL (2.20 mmol / L) and the lower of which is ≥ 8.4 mg / dL (2.10 mmol / L). The subject is not undergoing or has not been diagnosed with kidney dialysis.

[0184] As used herein, the term "on dialysis subject" or "subject on dialysis" refers to a subject who has two corrected total serum calcium values obtained during the screening period, one of which is ≥ 8.4 mg / dL (2.10 mmol / L) and the lower of which is ≥ 8.0 mg / dL (2 mmol / L). The subject is undergoing or has been diagnosed with kidney dialysis.

[0185] As used herein, the term "administering," when used in conjunction with a therapeutic agent, means administering the therapeutic agent directly or indirectly to a target tissue or subject, thereby causing the therapeutic agent to act locally or systemically on the tissue or subject. "Administering" a composition or pharmaceutical composition may be accomplished by oral administration, injection, infusion, inhalation, absorption, or by any method in combination with other known techniques. "Administering" can include self-administration or administration by another person, such as a healthcare provider.

[0186] Exemplary compounds and pharmaceutical compositions thereof In some embodiments, the disclosure provides pharmaceutical compositions that provide unexpectedly high oral bioavailability of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof. The pharmaceutical compositions can be solid.

[0187] In some embodiments, the compound of formula (I) has the following structure:

[0188] [ka] (in formula (I) Q is

[0189] [ka] and; R a is hydrogen; R b is hydrogen; L is a bond or -(CR c R d ) m and; R c and R d are independently selected from hydrogen or substituted or unsubstituted alkyl; R1 is

[0190] [ka] and; Ring Ar is phenyl or naphthyl; R may be the same or different in each occurrence and independently represents halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, -OR, -C(O)R, -(CRe R f ) 0~3 -C(O)OR6, -(CR e R f ) 1~2 Cycloalkylene-C(O)OR6, -cycloalkylene(CR e R f ) 0~2 -C(O)OR6, -O(CR e R f ) 0~3 -C(O)OR6, -O-cycloalkylene-C(O)OR6, -C(O)NR7-(CR e R f ) 1~2 -C(O)OR6, -C(O)NR7R8, -S(O) 0~2 R6 and -S(O)2NR7R8; R e and R f are independently hydrogen or substituted or unsubstituted alkyl; R2 is substituted or unsubstituted aryl; R3 and R4 are independently selected from hydrogen, halogen, and substituted or unsubstituted alkyl; R5 is substituted or unsubstituted alkyl or haloalkyl; R6, which may be the same or different in each occurrence, is independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted haloalkyl; R7 and R8 may be the same or different in each occurrence and are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl; Z is -CR g R h - and; R g and R h is hydrogen; "m" is an integer ranging from 1 to 3 inclusive; "n" is an integer ranging from 1 to 3 inclusive; and "q" is an integer ranging from 0 to 4 inclusive; or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, the compound of formula (II) has the following structure:

[0192] [ka] (in formula (II) Q is

[0193] [ka] and; R a is hydrogen, halogen or alkyl; R b is selected from hydrogen, alkyl and haloalkyl; Or, R bonded to the same carbon a and R b together form C(O); L is a bond or -CR c R d - and; Ring A is phenyl; R c and R d is independently selected from hydrogen, halogen, and alkyl; X is a bond, -(CR e R f ) m , -O-, -O(CR e R f ) m -, -(CR e R f ) m O-, -C(O)(CR e R f ) m -, -C(O)NR7-, -C(O)NR7(CR e R f ) m -, -cycloalkylene-, and -O-cycloalkylene-; R e and R fmay be the same or different in each occurrence and are independently selected from hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; or R e and R f may together with the carbon atoms to which they are attached form a 3- to 7-membered saturated carbocyclic ring; R1 is -OR6 or -NR7R8; R2 is substituted or unsubstituted aryl; R3 and R4 are independently selected from hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; R5 is alkyl or haloalkyl; R6 is hydrogen or alkyl; R7 and R8 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, and aryl; R9, which may be the same or different in each occurrence, is independently selected from halogen, cyano, alkyl, haloalkyl, and cycloalkyl; R 10 may be the same or different in each occurrence and independently represent halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -OR, -C(O)R, -NRC(O)R, -S(O) 0~2 R6 is selected from -S(O)2NR7R8, and -NR7S(O)2R6; "m" is an integer ranging from 1 to 3 inclusive; "n" is an integer ranging from 1 to 3 inclusive; "p" is an integer ranging from 0 to 2 inclusive; and "q" is an integer ranging from 0 to 1 inclusive; or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the compound of formula (II) has the following structure:

[0195] [ka] (In formula (II), Q is

[0196] [ka] and; R a is hydrogen; R b is hydrogen or alkyl; L is a bond or -CR c R d and; Ring A is phenyl; R c and R d is independently selected from hydrogen, halogen, and alkyl; X is a bond, -(CR e R f ) m , -O-, -O(CR e R f ) m -, -(CR e R f ) m O-, -C(O)(CR e R f ) m -, -C(O)NR7-, and -C(O)NR7(CR e R f ) m -Selected from; R e and R f may be the same or different in each occurrence and are independently selected from hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; or R e and R f form, together with the carbon atoms to which they are attached, a 3- to 7-membered saturated carbocyclic ring; R1 is -OR6 or -NR7R8; R2 is phenyl or naphthyl, wherein the phenyl is substituted with halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy; R3 and R4 are hydrogen; R5 is alkyl; R6 is hydrogen or alkyl; R7 and R8 are hydrogen or alkyl; R9 is independently selected from halogen, cyano, alkyl, haloalkyl, and cycloalkyl; R 10 may be the same or different at each occurrence and are independently selected from halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, —OR, —C(O)R, —NR, —NRC(O)R, and —(O)NR; "m" is an integer ranging from 1 to 3 inclusive; "n" is an integer ranging from 1 to 3 inclusive; "p" is an integer ranging from 0 to 2 inclusive; and "q" is an integer ranging from 0 to 1 inclusive; or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, the compound of formula (III) has the following structure:

[0198] [ka] (in formula (III) R a is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted haloalkyl; R b may be the same or different at each occurrence and are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted haloalkyl; R c may be the same or different in each occurrence and independently represent halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, OR, nitro, cyano, -C(O)OR, -(CH) r -C(O)OR6, -OC(O)OR6, -O(CH2) r-C(O)OR6, -NR7R8, -(CH2) r NR7R8-, -C(O)R9, -C(O)NR7R8, -(CH2) r -C(O)NR7R8, -NR7C(O)R9, -S(O) 0~2 R6 is selected from -S(O)2NR7R8, and -NR7S(O)2R9; X is a bond, -(CR c R d ) r -, -O-, -NR7-, -NR7(CR c R d ) r -, -O(CR c R d ) r , -C(O)NR7-, -C(O)NR7(CR c R d ) r , -(CR c R d ) r NR7(CR c R d ) r , -(CR c R d ) r Cycloalkylene-, cycloalkylene, -cycloalkylene (CR c R d ) r -, and -O-cycloalkylene, wherein cycloalkylene may be substituted or unsubstituted; R c and R d may be the same or different in each occurrence and are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted cycloalkyl; or R c and R d may, together with the carbon atoms to which they are attached, form a substituted or unsubstituted 3- to 7-membered saturated carbocyclic ring; Z is -OR6 or -NR 10 R 11 and; R1 may be the same or different in each occurrence and independently represents halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, -OR6, -C(O)R9, -NR7R8, -(CH2) r NR7R8-, -(CH2) r -C(O)OR6, -OC(O)OR6, -O(CH2) r -C(O)OR6, -C(O)NR7R8, -(CH2) r -C(O)NR7R8, -NR7C(O)R9, -S(O) 0~2 R7 is selected from -S(O)2NR7R8, and -NR7S(O)2R9; R2 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R3 and R4 may be the same or different and are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, and substituted or unsubstituted cycloalkyl; R5 is substituted or unsubstituted alkyl; R6, which may be the same or different in each occurrence, is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl; R7 and R8 may be the same or different in each occurrence and are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl; or R7 and R8, together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted, saturated or unsaturated 3- to 12-membered cyclic ring, which may have one or two double bonds; R9, at each occurrence, is substituted or unsubstituted alkyl or substituted or unsubstituted aryl; R 10 and R 11 may be the same or different and independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -(CR c R d ) r -C(O)OR6, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl; or R 10 and R 11 may, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted, saturated or unsaturated 3- to 12-membered cyclic ring, which unsaturated cyclic ring may have one or two double bonds; "n" is an integer ranging from 1 to 3 inclusive; "m" is an integer ranging from 0 to 3 inclusive; "p" is an integer ranging from 0 to 4 inclusive; "q" is an integer ranging from 0 to 3 inclusive; and "r" is an integer ranging from 1 to 3 inclusive; or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments, the compound of formula (IV) has the following structure:

[0200] [ka] (in formula (IV) W is CH or N; R1 may be the same or different in each occurrence and independently represents halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, -C(O)OR5, -(CR a R b ) r -C(O)OR5, -OC(O)OR5, -O(CR a R b ) r -C(O)OR5, -NR6R7, -C(O)R8, -C(O)NR6R7, -NR6C(O)R8, -S(O) 0~2 R5 is selected from -S(O)2NR6R7, and -NR6S(O)2R8; R2 is substituted or unsubstituted aryl; R3 is substituted or unsubstituted alkyl; R4 may be the same or different in each occurrence and independently represents halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR5, -NR6R7, -C(O)R8, -C(O)NR6R7, -NR6C(O)R8, -S(O) 0~2 R5 is selected from -S(O)2NR6R7, and -NR5S(O)2R8; X is a bond, -(CR a R b ) r-, -O-, -NR7-, -O(CR a R b ) r -, -C(O)NR7-, -C(O)NR7(CR a R b ) r -, -(CR a R b ) r Cycloalkylene-, cycloalkylene, cycloalkylene-(CR a R b ) r -, and -O-cycloalkylene; R a and R b may be the same or different in each occurrence and are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted cycloalkyl; or R a and R b may, together with the carbon atoms to which they are attached, form a substituted or unsubstituted 3- to 7-membered saturated carbocyclic ring; Z is -OR5 or -NR6R7; R5 may be the same or different in each occurrence and is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted aryl; R6 and R7 may be the same or different in each occurrence and independently represent hydrogen, substituted or unsubstituted alkyl, -(CR a R b ) r-C(O)OR5, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl; or R6 and R7, together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted, saturated or unsaturated 3- to 10-membered cyclic ring, which unsaturated cyclic ring may have one or two double bonds; R8 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl; "n" is an integer ranging from 0 to 3 inclusive; "p" is an integer ranging from 0 to 3 inclusive; "q" is an integer ranging from 0 to 3 inclusive; and "r" is an integer ranging from 1 to 3 inclusive; or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, the compound of formula (V) has the following structure:

[0202] [ka] (In formula (V) R1 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, -(CR a R b ) 1~3 OH, -C(O)NH-alkyl, -S(O)2-alkyl, -S(O)2NH-alkyl, -C(O)OH, -C(O)O-alkyl, -(CR a R b ) 1~3 C(O)OH and -(CR a R b ) 1~3 C(O)O-alkyl; R2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl, where the substituents, which may be one or more, are independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR4, -NR5R6, and substituted or unsubstituted cycloalkyl; X is -C(O)OH, -C(O)O-alkyl, -C(O)NR5R6, -(CR a R b ) 1~3 C(O)OH, -C(O)O-alkyl, -O-(CR a R b )1 ~3 C(O)OH, -O-(CR a R b ) 1~3 C(O)O-alkyl, -CR c =CR c - selected from -C(O)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR4, and -S(O)2-alkyl; R a and R b are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted cycloalkyl; or R a and R b may, together with the carbon atoms to which they are attached, form a substituted or unsubstituted 3- to 6-membered saturated carbocyclic ring; R c are independently selected from hydrogen, halogen, and substituted or unsubstituted alkyl; R3, which may be the same or different in each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and -OR4; R4 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted cycloalkyl; R5 and R6 are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; and "n" is an integer ranging from 0 to 2, inclusive; or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the compound of formula (VI) has the following structure:

[0204] [ka] (in formula (VI) Ring A is phenyl or naphthyl; R1 is hydrogen or substituted or unsubstituted (C1-C6) alkyl; R2 may be the same or different in each occurrence and independently represents halogen, cyano, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C1-C6) haloalkyl, substituted or unsubstituted (C1-C6) hydroxyalkyl, -XC(O)-Z, -OR9, -NR7R8, -NR7C(O)R6, -S(O) 0~2 R6, -S(O)2NR7R8, -NR7S(O)2R6, substituted or unsubstituted (C3-C 12 ) selected from cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted 5- to 6-membered heterocyclyl, and Ring D; Ring D is

[0205] [ka] and; X is a bond, -(CR a R b ) m -, -NR2-, -O(CR a R b ) m -, -(CR a R b ) m O-, -C(O)NR12 -, -(CR a R b ) m O-(CR a R b ) m - and -C(O)NR 12 (CR a R b ) m -Selected from; R a and R b may be the same or different in each occurrence and are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C1-C6) haloalkyl, and substituted or unsubstituted (C3-C6) cycloalkyl; or R a and R b together with the carbon atoms to which they are attached form a substituted or unsubstituted 3- to 6-membered saturated carbocyclic ring; Z is -OR 10 or -NR7R8; R3 is hydrogen, halogen, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C1-C6) haloalkyl, -OR9, and substituted or unsubstituted (C3-C 12 ) cycloalkyl; R4 may be the same or different in each occurrence and is independently selected from halogen, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C1-C6) haloalkyl, substituted or unsubstituted (C1-C6) alkoxyalkyl, -SF5, and -OR9; R5 is a substituted or unsubstituted (C1-C6) alkyl; R6 is a substituted or unsubstituted (C1-C6) alkyl, a substituted or unsubstituted (C3-C 12 ) cycloalkyl and substituted or unsubstituted (C6-C 14 ) aryl; R7 and R8 may be the same or different in each occurrence and independently represent hydrogen, substituted or unsubstituted (C1-C6) alkyl, -(CR a R b )1~2 R 11 , -(CR c R d ) m -OH and substituted or unsubstituted (C3-C 12 ) cycloalkyl; R c and R d may be the same or different in each occurrence and are independently hydrogen or substituted or unsubstituted (C1-C6) alkyl; R9 is independently selected from hydrogen, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C1-C6) haloalkyl, substituted or unsubstituted (C1-C6) alkoxyalkyl, and substituted or unsubstituted (C3-C 12 ) cycloalkyl; R 10 represents hydrogen, substituted or unsubstituted (C1-C6) alkyl, and -(CR a R b ) 1~2 phenyl; R 11 is a substituted or unsubstituted phenyl, where the substituents are selected from halogen, (C1-C6) alkyl, and -OR9; R 12 is hydrogen or substituted or unsubstituted (C1-C6) alkyl; "m" is an integer ranging from 1 to 3 inclusive; "n" is an integer ranging from 1 to 3 inclusive; "p" is an integer ranging from 0 to 3 inclusive; and "q" is an integer ranging from 1 to 3 inclusive; or a pharmaceutically acceptable salt thereof.

[0206] Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), and Formula (VI) are understood to structurally encompass all tautomers, stereoisomers, enantiomers, and diastereomers, including isotopes where applicable, and pharmaceutically acceptable salts, that may be contemplated from the general chemical structures depicted herein.

[0207] Additionally, the following compounds are disclosed in this disclosure: i) The compound 3-((S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)morpholino)-5-(trifluoromethyl)benzoic acid hydrochloride (see Compound 1)

[0208] [ka] ii) the compound 2-methyl-5-((S)-2-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzoic acid hydrochloride (see Compound 2)

[0209] [ka] iii) 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride compound (Compound 3)

[0210] [ka] iv) 3-((1R,3S)-3-((((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dimethylbenzoic acid hydrochloride compound (see Compound 4)

[0211] [ka] v) (R)-3-(4-fluoro-3'-(2-((1-(3-methoxyphenyl)ethyl)amino)ethoxy)-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoic acid (see Compound 5)

[0212] [ka] vi) (R)-N-((R)-1-(3-methoxyphenyl)ethyl)-1-(4-(4-(trifluoromethyl)phenyl)naphthalen-2-yl)propan-1-amine hydrochloride compound (see Compound 6)

[0213] [ka]

[0214] Exemplary pharmaceutical compositions comprising one or more of the compounds described above are disclosed throughout this disclosure, including, for example, in the Summary section of this disclosure and below.

[0215] [method] The present invention provides a method of treating or managing secondary hyperparathyroidism associated with chronic kidney disease (CKD) in a subject in need thereof, comprising administering a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its inner salt or hydrochloride salt ... In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof, is about 5 mg to about 50 mg. or about 10 mg to 40 mg, or about 20 mg to about 40 mg total daily dose. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 5 ... Administration of a therapeutically effective amount of a compound of Formula (I), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof is about 25 mg once or twice daily, or about 20 mg once or twice daily. In some embodiments, administration is oral. In other embodiments, administration does not require dose adjustment or titration of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof.

[0216] In another embodiment, the disclosure provides a pharmaceutical composition comprising one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its inner salt or hydrochloride salt (e.g., Compound 3)). In another embodiment, a kit includes a pharmaceutical composition comprising one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its inner salt, or hydrochloride salt (e.g., Compound 3)), and an instructional material therefor.

[0217] In another embodiment, this disclosure provides a method of reducing or suppressing one or more iPTH levels in a subject suffering from secondary hyperparathyroidism associated with CKD, comprising administering to the subject a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, or its inner salt or hydrochloride salt (e.g., Compound 3)). As will be understood by those skilled in the art, an iPTH level is measured at a single time point, and an iPTH level refers to two or more iPTH levels measured at different time points. In some embodiments, the subject may or may not be undergoing dialysis. In some embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is about 5 mg to about 50 mg, or about 10 mg to 40 mg, or about 20 mg to about 40 mg total daily dose. In some embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg total daily dose. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof, is administered in an amount of about 25 mg once or twice daily, or about 20 mg once or twice daily. In some embodiments, administration is oral. In some embodiments, administration does not require dosage adjustment or titration of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof, to the subject.

[0218] In another embodiment, the use of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its inner salt or hydrochloride salt (e.g., Compound 3)) in an oral formulation, wherein the oral formulation comprises a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof, in the manufacture of a medicament for the treatment or management of secondary hyperparathyroidism associated with CKD in a subject in need thereof. In some embodiments, the subject may or may not be undergoing dialysis. In some embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is about 5 mg to about 50 mg, or about 10 mg to 40 mg, or about 20 mg to about 40 mg total daily dose. In some embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg total daily dose. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof, is administered in an amount of about 25 mg once or twice daily, or about 20 mg once or twice daily. In some embodiments, administration is oral. In some embodiments, administration does not require dosage adjustment or titration of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof, to the subject.

[0219] In another embodiment, the use of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its inner salt or hydrochloride salt (e.g., Compound 3)) in an oral formulation, wherein the oral formulation comprises a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof, in the manufacture of a medicament for reducing or suppressing one or more iPTH levels in a subject suffering from secondary hyperparathyroidism associated with CKD. In some embodiments, the subject may or may not be undergoing dialysis. In some embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is about 5 mg to about 50 mg, or about 10 mg to 40 mg, or about 20 mg to about 40 mg total daily dose. In some embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg total daily dose. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof, is administered in an amount of about 25 mg once or twice daily, or about 20 mg once or twice daily. In some embodiments, administration is oral. In some embodiments, administration does not require dosage adjustment or titration of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof, to the subject.

[0220] In another embodiment, there is provided a method of treating or managing secondary hyperparathyroidism associated with CKD in a subject in need thereof, comprising: (a) identifying subjects who have CKD-associated secondary hyperparathyroidism, characterized by elevated baseline iPTH concentration levels in the subject, and who require treatment or management; and (b) administering to the subject a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its inner salt or hydrochloride salt (e.g., Compound 3)). A method comprising:

[0221] A patient with a baseline iPTH concentration level of about 10 pg / ml to about 65 pg / ml is considered to have a normal baseline iPTH concentration level. However, a patient with a baseline iPTH concentration level greater than about 65 pg / ml is considered to have an elevated baseline iPTH concentration level. For example, a patient undergoing dialysis with a baseline iPTH concentration level of at least about 300 pg / ml to about 1250 pg / ml is considered to have an elevated baseline iPTH concentration level. The patient's baseline iPTH concentration level is measured prior to administration of a first dose of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof. Two blood samples are collected from the patient prior to administration of the first dose, and the iPTH concentration level for each sample is determined. The higher of these two iPTH concentration level values is determined as the patient's baseline iPTH concentration level.

[0222] In some embodiments, the subject may or may not be undergoing dialysis. In other embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is a total daily dose of about 5 mg to about 50 mg, or about 10 mg to 40 mg, or about 20 mg to about 40 mg. In some embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is a total daily dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof, is administered in an amount of about 25 mg once or twice daily, or about 20 mg once or twice daily. In some embodiments, administration is oral. In some embodiments, administration does not require a subject to adjust or titrate the dose of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof.

[0223] In another embodiment, there is provided a method of treating or managing secondary hyperparathyroidism associated with CKD in a subject in need thereof, comprising: (a) identifying a subject in need of treatment or management having secondary hyperparathyroidism associated with CKD, characterized by a baseline iPTH concentration level in the subject, the baseline iPTH concentration level being in the range of about 110 pg / ml to about 1500 pg / ml, or about 300 pg / ml to about 1250 pg / ml; and (b) administering to the subject a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its inner salt or hydrochloride salt (e.g., Compound 3)). A method comprising:

[0224] In some embodiments, the subject may be undergoing dialysis or not undergoing dialysis. In some embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is a total daily dose of about 5 mg to about 50 mg, or about 10 mg to 40 mg, or about 20 mg to about 40 mg. In some embodiments, a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, is a total daily dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg. In some embodiments, the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof, is administered in a dose of about 25 mg once or twice daily, or about 20 mg once or twice daily. In some embodiments, administration is oral. In other embodiments, administration does not require a dose adjustment or titration of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salts thereof, or combinations thereof to the subject.

[0225] In another embodiment, a method for treating or managing secondary hyperparathyroidism associated with CKD in a subject in need thereof comprises administering a therapeutically effective amount of a calcimeter to the subject. In some embodiments, the therapeutically effective amount of the calcimeter is a total daily dose of about 5 mg to about 50 mg, or about 10 mg to 40 mg, or about 20 mg to about 40 mg. In some embodiments, the therapeutically effective amount of the calcimeter is a total daily dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg. In some embodiments, the therapeutically effective amount of the calcimeter is administered at about 25 mg once or twice daily, or about 20 mg once or twice daily. In some embodiments, administration is oral. In some embodiments, administration does not require dose adjustment or titration of the calcimeter for the subject. In some embodiments, secondary hyperparathyroidism is treated or managed without inducing hyperphosphatemia or hypocalcemia in the subject. In some embodiments, the calcimimetics comprises one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof, or 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, an inner salt thereof, or a hydrochloride salt thereof (e.g., Compound 3).

[0226] Subjects with secondary hyperparathyroidism associated with CKD include subjects diagnosed with or with stage 3b CKD, stage 4 CKD, or stage 5 CKD. Preferably, the subject is a patient with stage 5 CKD.

[0227] Subjects with CKD-associated secondary hyperparathyroidism include those with baseline iPTH concentration levels ranging from about 110 pg / ml to about 1500 pg / ml, or from about 300 pg / ml to about 1600 pg / ml, or from about 110 pg / ml to about 1350 pg / ml. Preferably, the baseline iPTH concentration level ranges from about 300 pg / ml to about 1250 pg / ml. Patients undergoing dialysis can have baseline iPTH concentration levels of about 300 pg / ml to about 1250 pg / ml. Patients not undergoing dialysis can have baseline iPTH concentration levels of about 110 pg / ml to about 1350 pg / ml.

[0228] In another embodiment, any one of the methods or uses disclosed herein can reduce a subject's iPTH levels by at least about 30% compared to baseline iPTH concentration levels, or by at least about 15% compared to baseline iPTH concentration levels, or by about 15% to about 30% compared to baseline iPTH concentration levels.

[0229] In another embodiment, in any one of the methods or uses disclosed herein, one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its inner salt, or hydrochloride salt (Compound 3)) is administered as a pharmaceutical composition. For example, the pharmaceutical composition can be in the form of a tablet or capsule. In some embodiments, the pharmaceutical composition comprises about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, or about 50 mg of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its inner salt or hydrochloride salt (e.g., Compound 3)). In some embodiments, the pharmaceutical composition is administered to a subject once daily, twice daily, or more than twice daily. In some embodiments, the pharmaceutical compositions are administered to a subject at a total daily dose of about 10 mg to about 40 mg; most preferably, about 20 mg to about 40 mg of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its inner salt or hydrochloride salt (e.g., Compound 3)). Preferably, the pharmaceutical compositions are administered to a subject at a total daily dose of 25 mg once daily or 20 mg twice daily of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its inner salt or hydrochloride salt (e.g., Compound 3)).

[0230] In another embodiment, pharmaceutical compositions suitable for oral administration can be presented as discrete units such as tablets, cachets, or capsules (each containing a predetermined amount of the active ingredient). The tablets, cachets, or capsules can contain one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its inner salt or hydrochloride salt (e.g., Compound 3)), and at least one component selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant, a surfactant, a glidant, and a combination thereof. The tablets or cachets can be made by compression or molding. Granules in compressed tablets, cachets, or capsules can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with diluents, disintegrants, binders, lubricants, surfactants, and / or glidants, in a suitable machine. Granules in molded tablets, cachets, or capsules can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Granules in tablets, cachets, or capsules can optionally be coated or scored. Tablets, cachets, or capsules can be formulated to provide immediate release of the active ingredient therein (e.g., Compound 3). Dyes, pigments, and / or dragee coatings can be added to tablets or cachets for identification or to characterize different doses of Compound 3. In another embodiment, each granule in the tablet, cachet, or capsule is round (or circular), disc-shaped, spherical, oval, elliptical, capsule-shaped, square, rectangular, triangular, pentagonal, hexagonal, octagonal, prilled, diamond-shaped, or arrowhead-shaped. The granules in the tablet, cachet, or capsule can be in one or more layers. For example, each granule in the tablet, cachet, or capsule can have a core layer and an outer layer outside the core layer.

[0231] In another embodiment, the pharmaceutical composition can be orally administered as a hard-shell capsule. Suitable size hard-shell capsules can be made of, for example, hard gelatin and / or hydroxypropylmethylcellulose (HPMC). The size of the hard-shell capsule can be size 0 or size 00. In another embodiment, the capsule comprises one or more compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), their pharmaceutically acceptable salts, or combinations thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its inner salt or hydrochloride salt (e.g., Compound 3)), starch (e.g., starch 1500LM), microcrystalline cellulose, and crospovidone. In another embodiment, the capsule contains about 35% to about 38% w / w of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), a pharmaceutically acceptable salt thereof, or a combination thereof (e.g., 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its inner salt or hydrochloride salt (e.g., Compound 3)).

[0232] In another embodiment, the pharmaceutical compositions can be orally administered as push-fit capsules made of gelatin. In another embodiment, the hard shell or push-fit capsules can contain at least one component selected from the group consisting of a filler (e.g., lactose), a binder (e.g., starch), and / or a lubricant (e.g., talc or magnesium stearate), a stabilizer, and combinations thereof. All formulations intended for oral administration should be in dosages suitable for such administration.

[0233] In another embodiment, the pharmaceutical compositions disclosed in the present application can be used to treat or manage a disease in a subject in need thereof, wherein the disease is hyperparathyroidism (including hyperparathyroidism, secondary hyperparathyroidism, or tertiary hyperparathyroidism), chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis), and complications thereof, or combinations thereof. Methods of use and treatment or management related to the above are also included herein.

[0234] In another embodiment, the pharmaceutical compositions disclosed herein can be used to treat or manage a disease in a subject in need thereof, wherein the disease is selected from the group consisting of parathyroid adenoma; parathyroid hyperplasia; parathyroid carcinoma; vascular or valvular calcification; calcium dyshomeostasis; hypercalcemia; phosphorus dyshomeostasis; hypophosphatemia; bone-related diseases or complications resulting from hyperparathyroidism, chronic kidney disease, or parathyroid carcinoma; bone loss after kidney transplantation; osteitis fibrosa cystica; adynamic bone disease; renal bone disease; cardiovascular complications resulting from hyperparathyroidism or chronic kidney disease; malignant tumors with abnormally high (Ca2+)e ions; cardiac, renal, or intestinal dysfunction; podocyte-related diseases; intestinal dysmotility; diarrhea; and enhancing gastrin or gastric acid secretion to directly or indirectly benefit atrophic gastritis, or improving absorption of pharmacological compounds, drugs, or supplements from the gastrointestinal tract by increasing gastric acidity. The above-related uses and methods of treatment or management are also encompassed by the present invention.

[0235] The specific methods and compositions described herein are exemplified and representative of preferred embodiments and are not intended as limitations on the scope of the invention. Other objects, embodiments, and embodiments will be apparent to those skilled in the art upon consideration of this specification and are encompassed within the spirit of the invention as defined by the appended claims. As will be readily apparent to those skilled in the art, various substitutions and modifications can be made to the invention disclosed herein without departing from the scope and spirit of the invention. The invention illustratively described herein may, where appropriate, be practiced in the absence of any one or more elements or limitations not specifically disclosed herein as essential. Thus, for example, in each instance herein, in an embodiment or example, any of the terms "comprising," "consisting essentially of," and "consisting of" may be substituted for either of the other two terms herein. Additionally, the terms "comprising," "including," "containing," etc., should be read broadly and without limitation. The methods and processes illustratively described herein may, where appropriate, be performed in a different order of steps and are not necessarily limited to the order of steps set forth in the specification or claims. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Under no circumstances shall a patent be construed as limited to the particular examples or embodiments or methods specifically disclosed herein. Under no circumstances shall a patent be construed as limited to any assertion made by any examiner or other officer or employee of the Patent and Trademark Office unless such assertion is specifically, unconditionally, and expressly acknowledged by the applicant in a responsive written response. Additionally, names, titles, and the like are provided to enhance the reader's comprehension of this document and should not be read to limit the scope of the document. Any examples of embodiments, embodiments, or components of the invention referred to herein should be considered non-limiting.

[0236] The terms and expressions which have been employed are used for purposes of description and not limitation, and there is no intention in the use of such terms and expressions to exclude any equivalents of the features shown and described or portions thereof, recognizing that various modifications are possible within the scope of the invention as set forth in the claims. Thus, while specifically disclosed in terms of preferred embodiments and optional features, it will be understood that modifications and variations of the concepts disclosed herein may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

[0237] The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the inclusive description of the invention with a condition or negative limitation excluding subject matter from the genus, whether or not the excluded matter is specifically set forth herein.

[0238] Other embodiments are within the scope of the following claims. Additionally, when features or embodiments of the invention are described as a Markush group, one skilled in the art will recognize that the invention is also described in terms of each individual member or subgroup member of that Markush group.

[0239] [Example] The compounds described herein can be prepared by methods of organic synthetic chemistry. Furthermore, although specific bases, acids, reagents, solvents, coupling reagents, etc. are described in the schemes described herein, it is understood that other bases, acids, reagents, solvents, coupling reagents, etc. can be used and are therefore within the scope of the present invention, unless otherwise specified. Variations in reaction conditions, e.g., temperature and / or reaction time, can be used as known in the art and are within the scope of the present invention. All isomers of the compounds described in these schemes are also included within the scope of the present invention, unless otherwise specified.

[0240] Example 1 - Preparation of a Representative Composition Pharmaceutical compositions in tablet form containing a total weight of 100 mg / tablet and 500 mg / tablet were manufactured on a 40 kg and 200 kg scale, respectively, with the following composition ratios shown in Table 1 below. The 100 mg tablets contained the equivalent of 5 mg of free base, while the 500 mg tablets contained the equivalent of 25 mg of free base. Both pharmaceutical compositions were prepared using the following components set forth in Table 1 below.

[0241] [Table 1]

[0242] After verifying the speed of the V-blender, half of the starch 1500 was added to the colloidal silicon dioxide and mixed in the V-blender. Next, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6, which had been previously weighed in the glove bag, was added to the V-blender. The remaining half of the starch 1500 was then added to the same glove bag, rinsed, and then added to the V-blender. Blending continued for approximately 18 minutes at 20 RPM (± 2 RPM). This premix blend was passed through Fitz-mill set-up knives with a 0.093 mm screen size at 3000 RPM, followed by approximately 1.0 kg of microcrystalline cellulose. Additionally, the remaining 11.18 kg of microcrystalline cellulose, sodium lauryl sulfate (SLS), crospovidone, Kollidon® CL-SF, povidone (Kollidon® K-30), and talc (197 Pharma) were screened through a 20 mm mesh and then added to a V-blender, followed by the milled premix blend. All of these materials were blended for 18 minutes at 20 RPM (±2 RPM). Approximately 700 g of the blended materials were then added to the magnesium stearate, mixed by hand, and passed through a 30 mm mesh hand screen. The magnesium stearate was added to the V-blender and blended for an additional 5 minutes at 20 RPM (±2 RPM). Following blending and milling, tablets were compressed according to the parameters set forth in Table 2 below using ¼ inch Standard Concave B Tooling for the production of 5 mg tablets, and B Tooling (0.6496″ x 0.2992″ Capsule Shaped).

[0243] [Table 2]

[0244] Following tablet compression, the resulting tablets were coated using standard Opadry® II (polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol 3350, yellow iron oxide, and red iron oxide) to approximately 4% of the total theoretical tablet weight using a tablet coating procedure. The compressed tablets were coated with a coating suspension containing 10% wt. solids.

[0245] Table 3 below shows a representative blend for a 90 mg capsule containing Compound 3.

[0246] [Table 3]

[0247] Male Sprague Dawley rats (weight 225 ± 25 gm; 8-10 weeks old) were orally administered the formulations. Each test compound was administered at 5 mg / kg in a dose volume of 1 mL / kg. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. The plasma concentrations of the administered compounds were analyzed and PK parameters were calculated. Plasma concentrations of the test compounds were measured by liquid chromatography with tandem mass spectrometry (LCMS-MS) using the plasma precipitation extraction method. Plasma concentration-time data were subjected to noncompartmental analysis using Phoenix WinNonlin® (version 5.3) software to evaluate pharmacokinetic parameters. Peak plasma concentration (Cmax) and time of peak plasma concentration (Tmax) were observed values. The area under the concentration-time curve (AUC) was calculated using the linear trapezoidal rule.

[0248] The pharmacokinetic parameters, such as the area under the curve (AUC) and its maximum concentration (Cmax), are summarized in Table 4 below.

[0249] [Table 4]

[0250] The results showed that when the pharmaceutical composition of the present disclosure was orally administered to a subject, it distributed the compound throughout the subject's body.

[0251] Example 3 - Therapeutic Efficacy, Pharmacokinetics (PK), Pharmacodynamics (PD) and Safety of Representative Compounds A randomized, double-blind, placebo-controlled phase 2 clinical trial was conducted to evaluate the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and safety of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound 3) as monotherapy in patients with CKD and secondary hyperparathyroidism (SHPT). Patients enrolled in the study were either undergoing dialysis or not undergoing dialysis. Patients could continue receiving calcium supplements, phosphate binders, vitamin D, vitamin D analogs, or combinations thereof (either stable or otherwise) in combination with Compound 3 for the treatment of SHPT. Patients could take at least one calcium supplement, phosphate binder, vitamin D, vitamin D analog, or combination thereof simultaneously with or together with Compound 3. Dosing of such calcium supplements, phosphate binders, vitamin D, vitamin D analogs, or combinations thereof for the treatment of SHPT can be individualized based on the patient's iPTH levels and / or can be correlated with doses currently being used for the treatment of SHPT.

[0252] The tablets investigated were in the form of a round tablet containing 5 mg of Compound 3 or a capsule-shaped tablet containing 25 mg of Compound 3, both plain-coated tablets for oral administration. Matching placebos for the 5 mg and 25 mg tablets were also provided for oral administration.

[0253] The study was conducted in two parts: a pharmacokinetic-pharmacodynamic (PK-PD) study and a pivotal study, as further discussed herein.

[0254] [A.PK-PD Study] This was an open-label, non-randomized, single-arm study enrolling 10 patients, six of whom were undergoing dialysis and four of whom were not. All patients received 25 mg of Compound 3 once daily for 8 days, followed by PK-PD assessments. All six patients (100%) in the dialysis group completed the study, while two of four patients (50%) in the nondialysis group completed the study. One objective of this study was to determine PK parameters, maximum concentration, time to maximum concentration, area under the curve (AUC) (AUC from 0 h to the last quantifiable concentration; AUC from 0 h to infinity; AUC from 0 h to 24 h), half-life, apparent clearance, and apparent volume of distribution from blood samples collected at scheduled time points. Additional objectives of this study were to determine the mean absolute change and mean percentage change in PD parameters from baseline for corrected total serum calcium and phosphorus.

[0255] [B. Main Exam] This study was a double-blind, randomized, placebo-controlled, multicenter trial with an additional non-randomized, open-label arm conducted in patients with secondary hyperparathyroidism (SHPT) associated with CKD, further stratified into dialysis and non-dialysis groups. iPTH levels in patients in the "dialysis" group ranged from 428.2 pg / ml to 1240.6 pg / ml (mean 857.76 pg / ml), while levels in patients in the "non-dialysis" group ranged from 125.0 pg / ml to 654.7 pg / ml (mean 297.83 pg / ml).

[0256] A total of 179 patients were enrolled in this study, with 108 patients receiving dialysis and 71 not receiving dialysis. Patients in the dialysis group were randomized into three subgroups enrolling 35, 36, and 18 patients, respectively, to receive 10 mg of Compound 3, 25 mg of Compound 3, or placebo once daily in a double-blind manner, and an additional non-randomized, open-label arm enrolling 19 patients and receiving 20 mg of Compound 3 twice daily. See Table 5 below. A total of 98 patients completed the study. 10 patients discontinued the study. No patients discontinued the study due to adverse drug reactions.

[0257] [Table 5]

[0258] Patients in the non-dialysis group were randomized into two treatment subgroups enrolling 37 and 18 patients, respectively, receiving 10 mg of Compound 3 or placebo once daily in a double-blind manner, and an additional non-randomized, open-label arm enrolling 16 patients and receiving 5 mg of Compound 3 twice daily. See Table 6 below. Four patients discontinued the study. No patients discontinued due to adverse drug reactions.

[0259] [Table 6]

[0260] Table 7 below shows the duration of treatment for the PK-PD study and the pivotal study.

[0261] [Table 7]

[0262] The efficacy, PK, PD, and safety of Compound 3 as monotherapy were evaluated in patients with CKD and secondary hyperparathyroidism (SHPT). One objective of the study was to evaluate the mean percentage change in iPTH from baseline at the end of 90 days. Another objective of the study was to determine the proportion of patients with a >30% decrease in iPTH from baseline at the end of 90 days. Another objective of the study was to ensure patient safety.

[0263] Regarding efficacy evaluations, the primary efficacy evaluation included measurement of iPTH, and exploratory efficacy evaluations included measurement of parathyroid gland size at planned time points. Blood samples for iPTH measurement were collected between days -30 and -1 (screening period); day 1; day 8 + / - 3 days; day 15 + / - 3 days; day 30 + / - 3 days; day 60 + / - 3 days; and day 90 + / - 3 days (EOT / early discontinuation). Two blood samples were collected during the screening period, and the higher of these two values served as the baseline value. During the treatment period of the main study, blood samples were collected on days 30, 60, and 90. If the blood sample collected on day 90 could not be analyzed for any reason, a second blood sample had to be collected within 3 days of the end of treatment (EOT). Chemiluminescence microparticles immunoassay (CMIA) (eg, Abbott's ARCHITECT® Intact PTH Assay) was used to quantitate iPTH in serum and plasma.

[0264] For exploratory efficacy assessments, parathyroid gland size was measured by ultrasound (USG) in eligible patients during screening and whenever possible at EOT (day 90).

[0265] For PK-PD evaluation, blood samples for PK assessment were collected at planned time points during the PK-PD study (screening period; Day 1 (pre-dose and post-dose); Day 2; Day 8 EOT (pre-dose and post-dose); Day 9; Day 10; and Day 15 + / - 3 days (follow-up visit)). PD profiling was performed in parallel with PK profiling during the PK-PD study. Blood samples (approximately 1 × 4 mL) for PK evaluation were collected by venipuncture or cannulation at selected time points into tubes containing dipotassium ethylenediaminetetraacetic acid (K2EDTA) anticoagulant. Collected blood samples were kept on ice until centrifugation, after which they were centrifuged at 4°C, 5000 rpm for 10 minutes, and the separated plasma was collected in two tubes / aliquots. Plasma samples were stored at -20°C or below at the clinical site until they were shipped for analysis. Blood samples (approximately 1 × 8 mL) for PD evaluation were collected at selected time points during the PK-PD study and the main study. Selected time points for the main study were screening period, day 1, day 8 + / - 3 days, day 15 + / - 3 days, day 30 + / - 3 days, day 60 + / - 3 days, and day 90 + / - 3 days (EOT / early discontinuation). Blood samples (approximately 1 x 5 mL) for PK-PD studies and exploratory PD evaluations for the main study were collected at selected time points.

[0266] For safety assessments, safety was assessed through summary of adverse events (AEs), physical examination and electrocardiogram (ECG) measurements, vital signs (e.g., blood pressure, pulse rate, respiratory rate, and temperature), body weight, and laboratory data (e.g., hematology, biochemistry, and urinalysis).

[0267] All AEs (both serious and non-serious) were based on spontaneous, voluntary patient reporting via observation and routine open-ended questioning. AE reporting extended from the date of informed consent until completion of the final visit. Any ongoing AE at the EOS visit was followed until outcome was clear, resolved, clinically stable, or a plausible explanation was found. Pre-existing diseases, including abnormal laboratory values (before study entry), were not considered AEs unless the disease worsened during the study period. Signs and symptoms clearly related to the disease being studied (including symptoms of disease progression) were reported as AEs if they were new or determined to be severe or worsening, or if worsening of disease-related signs and symptoms was directly caused by the study drug.

[0268] Physical examination, vital signs (measured after at least 3 minutes of rest in a sitting position), ECG (recorded by a qualified person after the patient rested for at least 3 minutes in a supine position), and clinical laboratory investigations were performed as part of the safety evaluation. Abnormal laboratory values / ECG / vital signs / physical examination were reported as AEs only if the abnormality was clinically relevant or significant or if it was considered necessary to report the abnormality as an AE. Any dose (and associated symptoms) administered to a patient in excess of the prescribed dose was recorded, at a minimum, as a non-serious AE in the patient file and CRF / electronic CRF. Any cases of overdose resulting in an AE or SAE had to be reported to the medical monitor in accordance with reporting requirements. In cases of inadvertent overdose, patients had to be monitored for adverse clinical events if deemed necessary.

[0269] The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines are highly practiced and referenced guidelines for the assessment and management of CKD. The targets mentioned in these guidelines are considered efficacy endpoints in this study. Furthermore, the primary and secondary endpoints selected for this study are those used during the development of calcimimetics products and are generally accepted by various regulatory agencies. Similarly, the other efficacy and safety parameters proposed are in line with traditional endpoints used in such studies (e.g., the cinacalcet phase 2 study was conducted using similar endpoints).

[0270] Changes from baseline to all measured relevant time points were calculated. Baseline values for the study were the higher of the two values obtained during the screening period for serum iPTH concentrations, corrected total serum calcium, and phosphorus. Baseline values for all other parameters were those from the last reasonable scheduled visit before the first dose of IP in the study. For continuous data, summary statistics included number, arithmetic mean, standard deviation (SD), median, minimum, and maximum. For categorical data, frequencies and percentages were presented.

[0271] A summary of the statistical analysis is shown in Table 8. Previous and concomitant medications were coded and tabulated using the World Health Organization Drug Dictionary classification. All concomitant medications administered after initiation of medication were summarized. Study compliance and degree of exposure to study medication were summarized and tabulated. All patients who discontinued treatment were listed and the reasons for discontinuation were tabulated.

[0272] [Table 8] TIFF0007720306000049.tif255163TIFF0007720306000050.tif151170

[0273] [result] In the PK-PD study, the peak effect of Compound 3 on iPTH suppression was observed within 4 hours of dosing on Day 1 (>80.0% from baseline in patients on dialysis and patients not on dialysis) and Day 8 (>70.0% and >85.0% from baseline in patients on dialysis and patients not on dialysis, respectively).

[0274] As shown in Figure 1, in the main study for patients undergoing dialysis, for patients who completed the entire study according to protocol, the mean percentage of iPTH suppression from baseline at the end of 90 days was higher in the 25 mg Compound 3 arm (-56.65%) than in the 10 mg Compound 3 arm (-25.65%) and placebo (-18.12%) arms. The difference in the mean percentage change in iPTH from baseline at the end of 90 days between the 25 mg Compound 3 and placebo arms was statistically significant (p=0.0539). As shown in Figure 6, in an exploratory analysis of peak iPTH suppression measured 2–4 hours after dosing on day 90, the mean percentage of iPTH suppression from baseline at the end of 90 days was -79.54% in the 10 mg Compound 3 arm; -85.79% in the 25 mg Compound 3 arm; and -19.29% in the placebo arm. The differences in mean percentage change in iPTH from baseline at the end of 90 days between the 10 mg Compound 3 vs. placebo arm (p=0.0293) and between the 25 mg Compound 3 vs. placebo arm (p=0.0125) were statistically significant.

[0275] As further shown in Figure 1, for iPTH suppression in the open-label arm for dialysis patients, the mean percentage of iPTH suppression from baseline at the end of 90 days was -82.42%. The difference in the mean percentage change in iPTH from baseline at the end of 90 days between the 20 mg Compound 3 BID vs. placebo arm was statistically significant (p=0.0032), and a ≥30% decrease in iPTH from baseline at the end of 90 days was seen in 93% of patients, also significant compared to placebo (p=0.0012). As shown in Figure 6, exploratory analysis also showed that the difference in the mean percentage change in iPTH from baseline at the end of 90 days between the 20 mg Compound 3 BID vs. placebo arm was statistically significant (p=0.0035), measured 2-4 hours after administration, at -93.02%.

[0276] As shown in Figure 2, for patients not undergoing dialysis, exploratory analyses showed that the mean percentage of iPTH suppression from baseline at the end of 90 days (2-4 hours post-dose) was -48.07% in the 10 mg Compound 3 arm and -5.28% in the placebo arm. The difference in the mean percentage change in iPTH from baseline at the end of 90 days between the 10 mg Compound 3 and placebo arms was statistically significant (p=0.0068). In the open-label arm administered 5 mg Compound 3, the mean percentage of iPTH suppression from baseline at the end of 90 days (2-4 hours post-dose) was -55.03% in the 5 mg Compound 3 BID arm. The difference in the mean percentage change in iPTH from baseline at the end of 90 days between the 5 mg Compound 3 BID and placebo arms was statistically significant (p=0.0006).

[0277] FIG. 3 shows the mean iPTH levels at different time points (e.g., baseline (t=0); 30 days; 60 days; 90 days) and different daily doses of Compound 3 (i.e., placebo; 10 mg QD; 20 mg BID; 25 mg QD) for patients undergoing dialysis.

[0278] FIG. 4 shows the mean iPTH levels for non-dialysis patients at different time points (e.g., baseline (t=0); 30 days; 60 days; 90 days) and different daily doses of Compound 3 (i.e., placebo; 5 mg BID; 10 mg QD).

[0279] FIG. 5 shows the % of patients in each dose arm (ie, placebo; 10 mg QD; 20 mg BID; 25 mg QD) who achieved a 30% or greater reduction from baseline iPTH concentration levels at D90.

[0280] Thus, suppression of iPTH from baseline to day 90 with Compound 3 at daily doses of 5 mg BID, 10 mg QD, 20 mg BID and 25 mg QD is significantly better than placebo.

[0281] Example 4 - Surprising Advantages of the Claimed Invention Cinacalcet, a currently approved oral calcium receptor agonist (Sensipar®), has a wide dosage range (30 mg; 60 mg; 90 mg; 120 mg; 180 mg) and requires a dose-titration strategy in which the dose is gradually increased to a therapeutic dose to treat or manage secondary hyperparathyroidism associated with CKD in patients undergoing dialysis. However, many patients are unable to titrate to the maximum therapeutically effective dose, generally because they cannot tolerate cinacalcet during or after the dose-titration strategy. Patient tolerance levels for cinacalcet vary, due in part to interindividual variability in pharmacokinetics and different susceptibility to and tolerance of gastrointestinal (GI) side effects. Furthermore, as previously mentioned, patients must expend time, money, and resources to undergo a dose-titration strategy, which are simply impossible or unwilling to commit. As a result, cinacalcet has low patient adherence to prescription instructions, and patients typically receive inadequate dosages.

[0282] 2-Methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound 3) is a novel calcimimetic drug for the treatment or management of secondary hyperparathyroidism associated with CKD in patients undergoing dialysis or not undergoing dialysis, without the need for complex dose adjustment or titration as with other approved calcimimetic drugs. Compound 3 can be administered to patients at doses of about 5 mg, about 10 mg, about 20 mg, or about 25 mg once or twice daily without the need for dose titration. Furthermore, as shown in Table 9 below, patients administered a pharmaceutical composition containing Compound 3 showed a reduction in GI-related adverse events, such as nausea, vomiting, and diarrhea, all of which were reduced in severity to mild to moderate. Table 9 also shows that GI-related adverse events were not dose-related, which provides an advantage for switching to any desired dose without the risk of experiencing GI side effects.

[0283] [Table 9]

[0284] In addition to the surprising advantages of the present invention discussed above, with regard to hypocalcemia, lowering or suppressing PTH results in a decrease in calcium levels, and the predictability of this response is crucial in preventing clinically significant hypocalcemia. Furthermore, cinacalcet exhibits a PTH-independent mechanism of action in patients, which may further contribute to hypocalcemic effects and cause complications in such patients. In contrast, as further discussed in the Examples section below, surprisingly, in a Phase 2 clinical trial using Compound 3 at a dose range of 5 mg to 50 mg, Compound 3 was found to suppress iPTH levels in CKD patients without any symptomatic hypocalcemic effects.

[0285] Additionally, the invention disclosed herein has another surprising advantage over cinacalcet. In a cinacalcet study involving CKD patients not undergoing dialysis, hyperphosphatemia occurred at week 32, showing phosphorus levels of 4.5 ± 1.0 mg / dL (+21.4%) for cinacalcet and 4.0 ± 0.7 mg / dL (+6.8%) for placebo (Chonchol et al., "A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet HCl in participants with CKD not receiving dialysis," Am. J. of Kidney Diseases, Vol. 53(2):197-207 (2009)). In contrast, surprisingly, CKD patients (either undergoing dialysis or not undergoing dialysis) administered a pharmaceutical composition containing Compound 3 did not exhibit an increase in phosphorus levels caused by administration of Compound 3 over a 90-day period.

[0286] Compound 3 also exhibited a favorable safety and tolerability profile: no trends indicating adverse treatment effects were reported in clinical laboratory assessments, vital signs, or ECGs.

[0287] Adverse events related to GI disorders in dialysis and non-dialysis patients are summarized in Table 9. Table 9 shows that when Compound 3 was administered to dialysis and non-dialysis patients, such patients showed a significant reduction in GI disorders, namely nausea, vomiting, and diarrhea, all of which were mild to moderate in severity.

[0288] Regarding hypocalcemia, a Phase 2 clinical trial of Compound 3 demonstrated that Compound 3 did not have symptomatic hypocalcemic effects when administered at doses ranging from about 5 mg to about 50 mg to suppress iPTH levels in CKD patients. Hypocalcemia occurred in three patients (one patient each in the 10 mg and 25 mg Compound 3 QD arms and one patient in the 20 mg Compound 3 BID arm), but no patients, both on dialysis and non-dialysis, discontinued the study or withheld study drug (Compound 3) for symptomatic reasons.

[0289] With regard to hyperphosphatemia, a Phase 2 clinical trial of Compound 3 in non-dialysis CKD patients showed that the differences in the mean percentage change in phosphate from baseline at the end of 90 days between the 10 mg Compound 3 vs. placebo arm and between the 5 mg Compound 3 vs. placebo arm were not significant, p=0.9222 and p=0.8559, respectively. Thus, there was no increase in phosphorus levels in non-dialysis CKD patients due to administration of Compound 3 over the 90-day period.

[0290] In CKD patients undergoing dialysis, the difference in the mean percentage change in phosphate from baseline at the end of 90 days between the 10 mg Compound 3 vs. placebo, 20 mg Compound 3 vs. placebo, and 25 mg Compound 3 vs. placebo arms was not significant, p=0.6346, p=0.9736, and p=0.9979, respectively.In CKD patients undergoing dialysis, there was also no increase in phosphorus levels due to the administration of Compound 3 over a 90-day period.

[0291] Thus, in non-dialysis and dialysis CKD patients, potent and clinically desirable suppression of iPTH can be achieved without inducing hyperphosphatemia after administration of Compound 3 in a dose range of about 5 mg to about 50 mg over a period of time.

[0292] Overall, the results demonstrate that Compound 3 reduces iPTH in dialysis and non-dialysis patients with CKD-associated SHPT. As seen in the PK-PD and pivotal studies, the peak effect of Compound 3 on mean percentage iPTH suppression was evident within 4 hours of acute and chronic dosing. In dialysis and non-dialysis patients, the efficacy of all doses of Compound 3 in terms of mean percentage iPTH suppression from baseline at peak (2-4 hours post-dose) on day 90 was clinically and statistically significant compared with placebo. In dialysis patients, a dose-response was observed between 10 mg QD, 25 mg QD, and 20 mg BID for mean percentage iPTH suppression from baseline at the end of the 90-day period, with the latter two doses of Compound 3 demonstrating greater suppression than placebo. In non-dialysis patients, no significant differences were reported in the mean percentage of iPTH suppression for Compound 3 10 mg QD and 5 mg BID doses versus placebo at the end of Day 90. However, there was significant iPTH suppression at peak (2-4 hours post-dose) on Day 90 in non-dialysis patients, suggesting a trend toward efficacy when higher doses or more frequent dosing regimens are utilized.

[0293] Compound 3 also demonstrated efficacy in a higher proportion of patients with a significant reduction in iPTH from baseline, i.e., at least 30%. Here, among patients undergoing dialysis, the proportion of patients experiencing a ≥30% reduction in iPTH from baseline at the end of 90 days was significantly higher in the 25 mg Compound 3 QD and 20 mg Compound 3 BID arms compared with placebo. The approximately 80% and 90% responder rates observed within 90 days of treatment with Compound 3 25 mg QD and 20 mg BID, respectively, are higher than those reported in longer-term studies of fully escalating doses of cinacalcet (Sensipar® [cinacalcet] prescribing information) and etelcalcetide (Parsabiv® [etelcalcetide] prescribing information).

[0294] Such higher efficacy was not associated with clinically adverse effects on calcium and phosphate levels. In our study, only 6 patients (5.7%) (including patients receiving higher doses [25 mg QD or 20 mg BID] and lower doses [10 mg QD] of Compound 3) experienced hypocalcemia TEAEs. Of these, 3 patients experienced hypocalcemia that was considered by the investigator to be related to the study drug. None of these hypocalcemia events were symptomatic. Additionally, no hyperphosphatemia adverse events were observed in the study.

[0295] In non-dialysis patients, the difference between placebo and compound 3 administered in a QD or BID dosing regimen in the proportion of patients achieving a ≥30% reduction in iPTH from baseline at the end of 90 days was not significant. The total dose administered in the QD and BID dosing regimens was 10 mg per day, which showed no significant effect compared with placebo, regardless of dialysis status. In a double-blind, randomized, placebo-controlled trial of cinacalcet in patients with CKD not undergoing dialysis, a high incidence of serum calcium levels <8.4 mg / dL and increased serum phosphorus levels was observed (ibid.). Due to this unfavorable benefit:risk ratio, cinacalcet is not approved for use in non-dialysis patients. However, none of the non-dialysis patients treated with compound 3 experienced adverse events of hypocalcemia or hyperphosphatemia, making compound 3 the first oral calcium receptor agonist to demonstrate a favorable safety profile in this population.

[0296] Adverse events were comparable between treatment arms for patients receiving dialysis and those not receiving dialysis. Compared with previous studies with cinacalcet, the incidence of hypocalcemia and gastrointestinal side effects was very low with Compound 3. None of the SAEs reported during the study were related to the study drug. No evidence of cardiovascular risk was observed after treatment with Compound 3. No differences in the incidence of adverse events were observed in patients receiving low or high doses of Compound 3, indicating a wider therapeutic window for dosing.

[0297] Thus, compound 3 is a novel calcium receptor agonist with excellent potency, efficacy, and safety profile without cytochrome P450 2D6 or human Ether-a-go-go-related gene (hERG) impairment. This molecule demonstrated an excellent PK profile in preclinical studies, leading to robust efficacy translation in vivo. No hypocalcemia was observed at preclinical effective doses. Compound 3 was found to be safe and well-tolerated in healthy subjects in first-in-human phase 1 single- and multiple-dose studies. In phase 1 studies, compound 3 demonstrated excellent PK-PD and concentration-response relationships across the dose range tested. The results of this phase 2 study demonstrated a favorable benefit:risk ratio for compound 3 in SHPT patients, regardless of dialysis status. The enhanced iPTH suppression observed with compound 3, without symptomatic hypocalcemia, hyperphosphatemia, or intolerable gastrointestinal adverse reactions, is in line with the clinically desirable profile of an ideal calcium receptor agonist.

[0298] Unless otherwise noted, all numbers used herein expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and the like, should be understood to be modified in all instances by the term "about." Accordingly, unless specifically indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0299] The recitation of ranges of values herein is merely intended to serve as a shorthand method of individually referring to each separate value falling within the range. Unless otherwise stated herein, each separate value is incorporated into this specification as if it were individually recited herein. Unless otherwise stated herein or clearly contradicted otherwise by context, all methods described herein can be performed in any suitable order. Any examples provided herein, or the use of illustrative language (e.g., "such as"), are intended only to facilitate understanding of the invention and do not impose limitations on the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0300] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limiting. Each group member may be referenced and claimed independently or in any combination with other group members or other elements found herein. It is anticipated that one or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification will be deemed to contain the group as modified, thereby satisfying all Markush group recitations in any claim ultimately claiming priority from this specification, as permitted by applicable law.

[0301] Certain embodiments of this invention are described herein, including the best mode for carrying out the invention known to the inventors. Of course, variations on these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect skilled artisans to adopt such variations as appropriate, and the inventors intend the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims which ultimately claim priority hereof, as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0302] In all of the preceding embodiments disclosed herein, it should be understood that all embodiments may be further limited by using the phrases "consisting of" or "consisting essentially of" rather than "comprising." When used, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the claim to particular materials or steps, and those that do not materially affect the basic and novel characteristics. Embodiments of the invention so claimed are essentially or expressly described and enabled herein.

[0303] The invention described and claimed herein has numerous characteristics and embodiments, including, but not limited to, those described or illustrated or referenced in this detailed description. This is not intended to be all-inclusive, and the invention described and claimed herein is not limited to or by the characteristics or embodiments specified in this detailed description, which are included for illustrative purposes only and are not limiting. Those skilled in the art will readily recognize that many of the components and parameters can be varied or modified within certain ranges or substituted with known equivalents without departing from the scope of the invention. It should be recognized that such modifications and equivalents are incorporated as if individually described herein. The invention also includes all of the steps, characteristics, compositions, and compounds referenced or indicated herein, individually or collectively, or any combination of any two or more of said steps or characteristics.

[0304] All patents, publications, scientific literature, websites, and other documents and materials referenced or mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains, and each document and material so referenced is hereby incorporated by reference in its entirety to the same extent as if individually incorporated by reference or set forth herein in its entirety. Applicant reserves the right to physically incorporate into this specification any and all materials and information from any such patents, publications, scientific literature, and other referenced materials or documents. Reference to any application, patent, and publication in this specification is not, and should not be considered as, an admission or any form of suggestion that they constitute pertinent prior art or form part of the common general knowledge in any country in the world.

Claims

1. 1. A solid pharmaceutical composition comprising a pharmaceutically effective amount of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride, and one or more ingredients, wherein the one or more ingredients are: (a) microcrystalline cellulose in an amount of 5% to 50% by weight of the total weight of the solid pharmaceutical composition; (b) crospovidone in an amount of 5% to 20% by weight of the total weight of the solid pharmaceutical composition, or povidone in an amount of 3% to 20% by weight of the total weight of the solid pharmaceutical composition, or a combination thereof; (c) pregelatinized starch in an amount of 20% to 50% by weight of the total weight of the solid pharmaceutical composition; (d) magnesium stearate in an amount of 0.5% to 5% by weight of the total weight of the solid pharmaceutical composition, or talc in an amount of 0.5% to 2% by weight of the total weight of the solid pharmaceutical composition, or a combination thereof; (e) sodium lauryl sulfate (SLS) in an amount of 0.5% to 3% by weight of the total weight of the solid pharmaceutical composition; (f) colloidal silicon dioxide in an amount of 0.5% to 3% by weight of the total weight of the solid pharmaceutical composition; or (g) combinations thereof; The solid pharmaceutical composition is suitable for oral administration and is in the form of a tablet or capsule.

2. 10. The solid pharmaceutical composition of claim 1, in the form of a tablet, said tablet being coated with a film.

3. 3. The solid pharmaceutical composition of claim 2, wherein the film is resistant starch, high amylose corn starch, starch acetate, ethyl cellulose, croscarmellose sodium, sodium starch glycolate, cellulose ether, vinyl polymer, glycol, acrylic polymer, maltodextrin, polydextrose, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate-hypromellose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, poly(methacrylic acid-co-methyl methacrylate), shellac, or a combination thereof.

4. 2. The solid pharmaceutical composition of claim 1, wherein the 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride is in an amount of 0.1 mg to 200 mg.

5. 5. The solid pharmaceutical composition of claim 4, wherein the 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride is in an amount of 1 mg to 50 mg, or 5 mg to 25 mg.

6. Use of the solid pharmaceutical composition of claim 1 in the manufacture of a medicament for the treatment of secondary hyperparathyroidism associated with chronic kidney disease in a subject.

7. The use according to claim 6, wherein the total daily dose is 5 mg to 50 mg.

8. The use described in claim 6, wherein a dose of 25 mg once or twice daily or 20 mg once or twice daily is administered to the subject.

9. The use according to claim 6, wherein the medicament is for oral administration.

10. The use of claim 6, wherein dose escalation is not required.

11. The use of claim 6, wherein the subject is not undergoing dialysis.

12. The use of claim 6, wherein the subject is undergoing dialysis.

13. 7. The use of claim 6, wherein secondary hyperparathyroidism is treated or managed without inducing hyperphosphatemia or hypocalcemia in the subject.

14. 7. The use of claim 6, wherein the subject has previously been diagnosed with or has stage 3b CKD, stage 4 CKD or stage 5 CKD.

15. 10. Use of the solid pharmaceutical composition of claim 1 in the manufacture of a medicament for the treatment or management of secondary hyperparathyroidism associated with CKD by lowering or suppressing one or more iPTH levels.

16. The use of claim 15, wherein the baseline iPTH concentration level is within the range of 110 pg / ml to 1500 pg / ml.

17. 16. The use of claim 15, wherein the iPTH level is reduced by at least 30% compared to the baseline iPTH concentration level before treatment.

18. 16. The use of claim 15, wherein the iPTH level is reduced by at least 15% compared to the baseline iPTH concentration level before treatment.

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