(EXTRACTED FROM WIPO PAGE)
PHARMACEUTICAL COMPOSITION OF CASR MODULATORS AND METHODS
AND USES THEREOF
CROSS REFERENCE TO THE RELATED APPLICATIONS
[1] This PCT application claims the benefit in and to Indian Provisional Patent Application Nos. 201921054138, filed December 27, 2019, and 202021006208, filed February 13, 2020, the disclosure of each of which are incorporated herein by reference in their entirety for all purposes.
FIELD
[2] This disclosure relates to solid pharmaceutical compositions comprising a pharmaceutically effective amount of one or more CaSR agonists, wherein the one or more CaSR agonists is one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), including Compound 1 to Compound 6 disclosed below, pharmaceutically acceptable salts thereof, or a combination thereof, and methods of their use for the treatment of diseases or disorders associated with the modulation of calcium sensing receptors (CaSRs), including secondary hyperparathyroidism associated with chronic kidney disease in a subject in need thereof. The solid pharmaceutical compositions can be administered orally to a subject in need thereof. This disclosure further relates to a process for the preparation of said pharmaceutical compositions.
INCORPORATION BY REFERENCE
[3] All U.S. patents, U.S. patent application publications, foreign patents, foreign and PCT published applications, articles and other documents, references and publications noted herein, and all those listed as References Cited in any patent or patents that issue herefrom, are hereby incorporated by reference in their entirety. The information incorporated is as much a part of this application as if all the text and other content was repeated in this application, and will be treated as part of the text and content of this application as filed.
BACKGROUND
[4] The following includes information that may be useful in understanding the invention. It is not an admission that any of the information, publications or documents specifically or implicitly referenced herein is prior art, or essential, to the described or claimed invention. 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.
[5] Ca2+ is known to be an intracellular second messenger, with the molecular identification of an extracellular calcium sensing receptor (CaSR). The possibility that Ca2+ might also function as a messenger outside the cells has been further opened. Information about the local changes in extracellular concentration of Ca2+ is conveyed to the interior of many types of cells through this unique receptor.
[6] Calcium- sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that signals through the activation of phospholipase C, increasing levels of inositol 1,4,5-triphosphate and cytosolic calcium. The CaSR belongs to the subfamily C of the GPCR superfamily. Structurally, CaSR has an exceptionally large amino-terminal extracellular (ECD) domain (about 600 amino acids), a feature that is shared by all of the members of the family C GPCRs.
[7] In mammals, the expression of CaSR is quite ubiquitous and its presence in the parathyroid gland plays an important role in the secretion of parathyroid hormone (PTH). PTH is involved in the homeostasis of bone metabolism by regulating the level of calcium in the blood, release of calcium from the bone, absorption of calcium from the intestine and excretion of calcium in the 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 almost 90% of patients with end stage renal disease and 40% to 60% of patients with chronic kidney disease (CKD). This results in an increase in serum phosphate and decrease in vitamin D and calcium levels, ultimatelycausing high PTH levels which can cause bone
disorders, calcification of soft tissues and blood vessels and significant risk for 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)).
[8] The reduction in serum calcium leads to the secretion of PTH. Consequently, PTH secretion leads to conservation of serum Ca2+ by increasing kidney retention and intestinal absorption of Ca2+. Also, increase in extracellular calcium levels activate the CaSR resulting in decreased PTH secretion. This happens indirectly through the PTH-induced synthesis of the active vitamin D metabolite, 25-dihydroxy vitamin D. An integrated hormonal system controls calcium transport in the gut, kidneys and bones 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)). A decrease in serum calcium inactivates the CaSR in the parathyroid glands, increasing PTH secretion which acts on the kidneys to increase calcium reabsorption and in bones to release skeletal calcium. The PTH also causes the kidneys to synthesize 1,25-dihydroxy vitamin D3, which increases calcium absorption in the gut, while decreasing further PTH secretion and increasing bone resorption. This regulation of PTH secretion by calcium 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:s377-390 (2003)). Accordingly, in chronic kidney disease patients it is important to manage intact PTH (iPTH) levels as well as those of serum calcium and phosphorus.
[9] In addition, the pulsatile action of PTH has anabolic effects on bone development and its sustained levels can lead to catabolic effects, in which the bones break down releasing Ca2+ as in the case of osteoporosis. All these systems converge in maintenance of baseline serum Ca2+ and it involves a tight regulation between serum PTH and extracellular calcium which is mediated by the remarkable receptor CaSR.
[10] In conditions such as primary and secondary hyperparathyroidism, there is excessive secretion of parathyroid hormone due to hyperplasia of the glands. The most common cause of primary hyperparathyroidism (PHPT) is parathyroid adenoma resulting from
clonal mutations (-97%) and associated hypercalcemia. In the case of secondary hyperparathyroidism (SHPT), it is most commonly seen in patients with chronic renal failure. The kidneys fail to convert enough vitamin D to its active form and also does not adequately excrete phosphorous. Excess phosphorous further depletes serum calcium forming calcium phosphate (kidney stones) leading to hypocalcemia.
[11] Small molecules that are positive allosteric modulators referred to as calcimimetics modulate and improve the receptors sensitivity to the already existing milieu of extracellular ionic calcium. This would eventually translate in lowering plasma PTH levels thereby improving conditions of hyperparathyroidism, calcium homeostasis and bone metabolism.
[12] PCT International Patent Application Publication Nos. WO 2012/127388, WO 2012/120476, WO 2012/127385, WO 2012/069421, WO 2012/069419, WO 2012/069402, US 2011/0028452, WO 2010/150837, WO 2010/136037, WO 2010/042642, WO 2010/038895, WO 2009/065406, WO 2008/059854, WO 2006/123725, WO 2004/106280, WO 2004/069793, WO 2002/012181 and US 2003/0199497 refer to compounds related to calcium sensing receptors (CaSR) for the treatment of various diseases mediated by CaSR. Kessler et al., “N1 -Bcnzoyl-N2-[ 1 -(1 -naphthyl)cthyl]-/ran.s-l ,2-diaminocyclohcxancs: 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 CaSR.
[13] As stated above, small molecules, termed “calcimimetics,” mimic (directly activate the receptor) or potentiate (positive allosteric modulators) the effects of extracellular calcium at the CaSR. Cinacalcet was the first United States Food and Drug Administration (FDA) approved calcimimetic for treating SHPT in patients with CKD receiving dialysis (Stage 5 CKD) and hypercalcaemia in patients with parathyroid carcinoma (SENSIPAR®
(Cinacalcet) Prescribing Information, Amgen Inc., revised March 2019; Padhi, D. & Harris R., “Clinical pharmacokinetic and pharmacodynamic profile of Cinacalcethydrochloride,” Clin Pharmacokinet., 48:303-311 (2009); Quarles LD, “Cinacalcet HC1: A novel treatment for secondary hyperparathyroidism in stage 5 chronic kidney disease,” Kidney Inter., 68:S24-S28
(2005)). Another calcimemetic, Etelcalcetide (PARSABIV®), approved for the treatment of SHPT in 2017 in the United States and European Union, is a second-generation calcimimetic agent for intravenous use developed to improve adherence. Among other current therapies for SHPT, phosphate binders have a risk of cardiovascular diseases and newer vitamin D sterols have a risk of hypercalcaemia and provide inefficient control. Second generation calcimimetic agents suppress PTH levels with lower calcium and phosphorus product and have a risk of hypocalcaemia, which is thought to occur after decreased mobilisation of calcium from the 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)).
[14] Current treatments for SHPT differ in duration of PTH suppression and modes of administration, and have distinctly different side effect profiles that impact patient preferences and compliance. Cinacalcet requires daily oral therapy to control SHPT, and its major side effects are nausea and vomiting and are critically responsible for low adherence and insufficient dosage (Gincherman et al., “Assessment of adherence to cinacalcet by prescription refill rates in hemodialysis patients,” Hemodialysis International, 14:68-72 (2010)). Cinacalcet, has wide variation in doses (30mg, 60 mg, 90 mg, 120 mg and 180 mg) and require a dose titration strategy in which the dose is progressively increased to the therapeutic dose for treating or managing secondary hyperparathyroidism associated with CKD in a patient on dialysis. Dose titration is generally used to enhance tolerability and efficacy, but the process can also be associated with negative outcomes. For example, the incidence of relapse or recurrence are higher in patients whose doses are titrated since there is increased patient discontinuation rate associated with titration. Patients who participate in dose titration processes experience frustration and delayed therapeutic relief due to complicated schedules and/or delays in achieving the therapeutic dosage. Such dose titration also increases healthcare costs for patients undergoing titration because they required to make more physician visits and need more prescriptions, often leading to greater use of resources and higher costs associated with physicians and laboratory monitoring. Also, patients who are far from or have transportation, mobility or financial difficulties to visit healthcare providers and/or facilities find it difficult to participate and adhere to such dose titration processes. In addition, such patients who experience side effects during a dose titration process and/or are not given an exact time of when they will reach therapeutic dosage are more likely to abandon the process altogether. Further, patients are not guaranteed that they will reach therapeutic dosage via a dose titration process.
[15] Thus, there is a need in the art to identify a novel drug for treating or controlling SHPT that can suppress PTH with minor effect on calcium and phosphate metabolism. Also, given the limitations of dose titration and observed side effects of current treatments available and the requirement of positive/favorable benefit: risk ratio therapy, there remains a significant need to develop methods of treating or managing, medicaments, compositions and kits having a simple dosage regimen that requires no dose titration, and causes fewer GI symptoms for the treatment or management of SHPT, primary hyperparathyroidism (PHPT) and hypercalcaemia in patients with parathyroid carcinoma in a patient in need thereof.
SUMMARY
[16] The inventions described and claimed herein have many attributes and aspects including, but not limited to, those set forth or described or referenced in this Summary. It is not intended to be all-inclusive and the inventions described and claimed herein are not limited to or by the features or embodiments identified in this Summary, which is included for purposes of illustration only and not restriction.
[17] This disclosure provides for a solid pharmaceutical composition suitable for the oral delivery of a pharmaceutically active agent comprising a pharmaceutically effective amount of a CaSR agonist described herein, wherein the said 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 a combination thereof, as set forth herein.
[18] A solid pharmaceutical composition comprising a pharmaceutically effective amount of one or more CaSR agonists, wherein the one or more CaSR agonists is one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI):

wherein L, Q, Z, R1, Ra, and Rb are
Q is hydrogen or

hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted haloalkyl;
Rb is selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted haloalkyl;
or Ra and Rb together attached on the same carbon form C(O) or C(S);
provided that,
when Q is

then Ra is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl and substituted or unsubstituted haloalkyl; or Ra and Rb together attached on the same carbon atom form C(O) or C(S);
when Q is hydrogen then Ra is

L is selected from a bond, — (CRcRd)m, — C(O) — , — C(S) — , — C(O)NR7 — , —
S(O)2— , — S(O)2— NR7, — C(O)CH2— , — CH2C(O)— and — C(O)O— ;
Rc and Rd, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl and substituted or unsubstituted haloalkyl;
R1 is selected from

substituted or unsubstituted alkyl, — (CReRf)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, which may be same or different at each occurrence, is independently selected from 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, — OR6, — C(O)R6, — (CReRf)0-3 — C(O)OR6, — (CReRf)i-2cycloalkylene-C(O)OR6, -cycloalkylene (CReRf)0-2 — C(O)OR6, — O(CReRf)0-3— C(O)OR6, — O-cycloalkylene-C(O)OR6, — C(O)NR7— (CReRf)i-2 — C(O)OR6, — C(O)NR7R8, — S(O)0-2R6, and — S(O)2NR7R8;
Re and Rf, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or Re and Rf, together with the carbon atom 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, which may be same or different at each occurrence, 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 same or different at each occurrence, is independently selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted haloalkyl;
R7 and R8, which may be same or different at 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 to 12 membered cyclic ring, where the cyclic ring may be substituted or unsubstituted heteroaryl or heterocyclyl;
Z is selected from — CRgRh, — C(O), and — C(S);
Rg and Rh 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, both inclusive;
‘n’ is an integer ranging from 1 to 3, both inclusive; and
‘q’ is an integer ranging from 0 to 4, both inclusive;
or pharmaceutically acceptable salt thereof;

wherein ring A, X, L, Q, R1, R9, R10, Ra, Rb, ‘p’ and ‘q’ are as follows:
Q is hydrogen or


hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted haloalkyl;
Rb is selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted haloalkyl;
or Ra and Rb together attached on the same carbon form C(O) or C(S);
provided that,
when Q is

then Ra is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl and substituted or unsubstituted haloalkyl; or
Ra and Rb together attached on the same carbon atom form C(O) or C(S);
when Q is hydrogen then Ra is

L is selected from a bond, — (CRcRd)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;
Rc and Rd, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl and substituted or unsubstituted haloalkyl;
X is selected from a bond, — (CReRf)m, — O — , — O(CReRf)m — , — (CReRf)mO — , — C(O)(CReRf)m— , — C(O)NR7— , — C(O)NR7(CReRf)m— -cycloalky lene-, and — O-cycloalkylene-;
Re and Rf, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or Re and Rf, together with the carbon atom 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, which may be same or different at each occurrence, 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 same or different at 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 same or different at 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, where the cyclic ring may be heteroaryl or heterocyclyl;
R9, which may be same or different at each occurrence, is independently selected from 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, — 0(CH2)r — C(O)OR6, — NR7R8, — C(O)NR7R8, — NR7C(O)R6, — S(O)0-2R6, — S(O)2NR7R8, and — NR7S(O)2R6;
R10, which may be same or different at each occurrence, is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, — OR6, — C(O)R6, — NR7R8, — NR7C(O)R6, — S(O)0-2R6, — S(O)2NR7R8, and — NR7S(O)2R6;
‘m’ is an integer ranging from 1 to 3, both inclusive;
‘n’ is an integer ranging from 1 to 3, both inclusive;
‘p’ is an integer ranging from 0 to 3, both inclusive;
‘q’ is an integer ranging from 0 to 4, both inclusive; and
‘r’ is an integer ranging from 1 to 3, both inclusive;
or pharmaceutically acceptable salt thereof;

wherein X, Z, R, R1, R2, R3, R4, R5, Ra, Rb, ‘m’, ‘n’, ‘p’ and ‘q’ are as follows:
Ra is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl and substituted or unsubstituted haloalkyl;
Rb, which may be same or different at each occurrence, is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted haloalkyl;
R, which may be same or different at each occurrence, is independently selected from halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, OR6, nitro, cyano, — C(O)OR6, — (CH2)r — C(O)OR6, — O — C(O)OR6, — O(CH2)r— C(O)OR6, — NR7R8, — (CH2)rNR7R8— , — C(O)R9, — C(O)NR7R8, — (CH2)r — C(O)NR7R8, — NR7C(O)R9, — S(O)O-2R6, — S(O)2NR7R8, and — NR7S(O)2R9;
X is selected from a bond, — (CRcRd)r — , — O — , — NR7 — , — NR7(CRcRd)r — , —
0(CRcRd)r— , — C(O)NR7— , — C(O)NR7(CRcRd)r— , — (CRcRd)rNR7(CRcRd)r — , — (CRcRd)rcycloalkylene-, cycloalkylene, -cycloalkylene(CRcRd)r — and — O-cycloalkylene where cycloalkylene may be substituted or unsubstituted;
Rc and Rd, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or Rc and Rd, together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring;
Z is -OR6 or — N R10R11;
R1, which may be same or different at each occurrence, is independently selected from 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)rNR7R8 — , — (CH2)r — C(O)OR6, — O— C(O)OR6, — O(CH2)r— C(O)OR6, — C(O)NR7R8, — (CH2)r— C(O)NR7R8, — NR7C(O)R9, — S(O)O-2R7, — 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 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 same or different at 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, which may be same or different at 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, may form a substituted or unsubstituted, saturated or unsaturated 3 to 12 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds;
at each occurrence, R9 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
R10 and R11 may be same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, — (CRcRd)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 R10 and R11, 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, wherein the unsaturated cyclic ring may have one or two double bonds;
‘n’ is an integer ranging from 1 to 3, both inclusive;
‘m’ is an integer ranging from 0 to 3, both inclusive;
‘p’ is an integer ranging from 0 to 4, both inclusive;
‘q’ is an integer ranging from 0 to 3, both inclusive; and
‘r’ is an integer ranging from 1 to 3, both inclusive;
or its pharmaceutically acceptable salt thereof;

wherein W, X, Z, R1, R2, R3, R4, ‘n’, ‘p’ and ‘q’ are as described below:
W is CH or N;
R1, which may be same or different at each occurrence, is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, — C(O)O R5, — (CRaRb)r — C(O)O R5, — O — C(O)O R5, — O(CRaRb)r— C(O)O R5, — NR6R7, — C(O)R8, — C(O)NR6R7, — NR6C(O)R8, — S(O)0-2 R5, — S(O)2NR6R7, and — NR6S(O)2R8;
R2 is substituted or unsubstituted aryl;
R3 is substituted or unsubstituted alkyl;
R4, which may be same or different at each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, — O R5, — NR6R7, — C(O)R8, — C(O)NR6R7, — NR6C(O)R8, — S(O)0-2 R5, — S(O)2NR6R7, and — NR5S(O)2R8;
X is selected from a bond, — (CRaRb)r — , — O — , — NR7 — , — O(CRaRb)r — , — C(O)NR7 — , — C(O)NR7(CRaRb)r — , — (CRaRb)rCycloalkylene-, cycloalky lene, cycloalkylene-(CRaRb)r — , and — O-cycloalkylene;
Ra and Rb, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or Ra and Rb, together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring;
Z is — O R5 or — NR6R7;
R5, which may be same or different at each occurrence, is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted aryl;
R6 and R7, which may be same or different at each occurrence, are independently selected from hydrogen, substituted or unsubstituted alkyl, — (CRaRb)r — C(O)O R5, 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, wherein the unsaturated cyclic ring may have one or two double bonds;
at each occurrence, R8 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
‘n’ is an integer ranging from 0 to 3, both inclusive;
‘p’ is an integer ranging from 0 to 3, both inclusive;
‘q’ is an integer ranging from 0 to 3, both inclusive; and
‘r’ is an integer ranging from 1 to 3, both inclusive;
or a pharmaceutically acceptable salt thereof;

wherein X, R1, R2, R3 and ‘n’ are as described below:
R1 is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, -(CRaRb)1-3OH, -C(O)NH-alkyl, -S(O)2- alkyl, -S(O)2NH-alkyl, -C(O)OH, -C(O)O-alkyl, -(CRaRb)1-3C(O)OH and -(CRaRb)1-3C(O)O- alkyl;
R2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl, wherein the substituents may be one or more and are independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR4, -N R5R6 and substituted or unsubstituted cycloalkyl;
X is selected from -C(O)OH, -C(O)Oalkyl, -C(O)NR5R6, -(CRaRb)1-3C(O)OH, -(CRaRb)1-3C(O)O-alkyl, -O-(CRaRb)1-3C(O)OH, -O-(CRaRb)1-3C(O)O-alkyl, -CRC=CRC-C(O)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR4 and -S(O)2-alkyl;
Ra and Rb are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or Ra and Rb , together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 6 membered saturated carbocyclic ring;
Rc is independently selected from hydrogen, halogen and substituted or unsubstituted alkyl;
R3, which may be same or different at 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
'h' is an integer ranging from 0 to 2, both inclusive; or a pharmaceutically acceptable salt thereof;

wherein 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, which may be same or different at each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C1-C6)haloalkyl, substituted or unsubstituted (C1-C6)hydroxyalkyl, — X — C(O) — Z, — OR9, — NR7R8, — NR7C(O)R6, — S(O)O-2R6, — S(O)2NR7R8, — NR7S(O)2R6, substituted or unsubstituted (C3-C12)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

X is selected from a bond, — (CRaRb)m — , — NR12 — , — O(CRaRb)m — , — (CRaRb)mO— , — C(O)NRI2— , — (CRaRb)mO— (CRaRb)m — and — C(O)NRi2(CRaRb)m— ;
Ra and Rb which may be same or different at each occurrence, 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 Ra and Rb, together with the carbon atom to which they are attached, form a substituted or unsubstituted 3 to 6 membered saturated carbocyclic ring;
Z is — OR10 or — NR7R8;
R3 is selected from hydrogen, halogen, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C1-C6)haloalkyl, — OR9, and substituted or unsubstituted (C3-C12)cycloalkyl;
R4, which may be same or different at each occurrence, 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 substituted or unsubstituted (C1-C6)alkyl;
R6 is selected from substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C3-C12)cycloalkyl and substituted or unsubstituted (C6-C14)aryl;
R7 and R8, which may be same or different at each occurrence, are independently selected from hydrogen, substituted or unsubstituted (C1-C6)alkyl, — (CRaRb)1-2R11, — (CRcRd)m — OH and substituted or unsubstituted (C3-C12)cycloalkyl;
Rc and Rd which may be same or different at each occurrence, 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-C12)cycloalkyl;
R10 is selected from hydrogen, substituted or unsubstituted (C1-C6)alkyl and — (CRaRb) 1 -2phenyl ;
Rii is substituted or unsubstituted phenyl, wherein the substituents are selected from halogen, (C1-C6)alkyl and — OR9;
R12 is hydrogen or substituted or unsubstituted (C1-C6)alkyl;
‘m’ is an integer ranging from 1 to 3, both inclusive;
‘n’ is an integer ranging from 1 to 3, both inclusive;
‘p’ is an integer ranging from 0 to 3, both inclusive; and
‘q’ is an integer ranging from 1 to 3, both inclusive;
or a pharmaceutically acceptable salt thereof,
or a combination thereof, and at least two pharmaceutically acceptable excipient, wherein the at least two pharmaceutically acceptable excipients is microcrystalline cellulose, crospovidone, starch, magnesium stearate, sodium lauryl sulfate, colloidal silicon dioxide, or a combination thereof.
[19] See also PCT International Patent Application Publication No. WO 2012/120476 Al, filed on March 9, 2012 (also published as U.S. Patent No. 9,382,216) for L, Q, Z, R1, Ra and Rb in Formula (I) above; PCT International Patent Application Publication No. WO 2012/127388 Al, filed on March 16, 2012 (also published as U.S. Patent No.
9,464,063) for ring A, X, L, Q, R1, R9, R10, Ra, Rb, ‘p’ and ‘q’ for Formula (II) above; PCT International Patent Application Publication No. WO 2013/124828 Al, filed on February 22, 2013 (also published as U.S. Patent No. 9,163,001) for X, Z, R, R1, R2, R3, R4, R5, Ra, Rb, ‘m’, ‘n’, ‘p’ and ‘q’ for Formula (III) above; PCT International Patent Application Publication No. WO 2014/033604 Al, filed on August 23, 2013 (also published as U.S. Patent No. 9,227,919) for W, X, Z, R1, R2, R3, R4, ‘n’, ‘p’ and ‘q’ for Formula (IV) above; and PCT International Patent Application Publication No. WO 2015/022631 Al, filed on August 12, 2014; PCT International Patent Application Publication No. WO 2015/028938, filed on August 26, 2014 (also published as U.S. Patent No. 9,493,396) for X, R1, R2, R3 and ‘n’ for Formula (VI) above.
[20] In another aspect, this disclosure provides for a solid pharmaceutical composition comprising a pharmaceutical effective amount of one or more CaSR agonists,
wherein the one or more CaSR agonists is one or more compounds having a 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 of 3-((S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino)methyl) morpholino)-5-(trifluoromethyl)benzoic acid, or an internal salt or hydrochloride salt thereof (“Compound 1”)

(ii) the compound of 2-methyl-5-((S)-2-(2-(((R)-l-(naphthalen-l-yl)ethyl)amino) ethyl)-2H-benzo[b][l,4]oxazin-4(3H)-yl)benzoic acid, or an internal salt or hydrochloride salt thereof (“Compound 2”)

[21] (iii) the compound of 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen- l-yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid, or an internal salt or hydrochloride salt thereof (such as 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l- yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid hydrochloride (“Compound 3”))

(iv) the compound of 3-((lR,3S)-3-((((R)-l-(4-fluoro-3-methoxyphenyl)ethyl)amino) methyl)- 1,2,3, 4-tetrahydronaphthalen-l-yl)-2, 6-dimethylbenzoic acid, or an internal salt or hydrochloride salt thereof (“Compound 4”)

(v) the compound of (R)-3-(4-fluoro-3'-(2-((l-(3-methoxy phenyl)ethyl)amino) ethoxy)-5'-(trifluoromethyl)-[l,1'-biphenyl]-3-yl)propanoic acid, or an internal salt or hydrochloride salt thereof (“Compound 5”)

(vi) the compound of (R)-N-((R)-l-(3-methoxyphenyl)ethyl)-l-(4-(4-(trifluoromethyl) phenyl)naphthalen-2-yl)propan-l -amine, or hydrochloride salt thereof (“Compound 6”)

[22] In some aspects, the compound of Formula (I) is Compound 1, 3-((S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino)methyl) morpholino)-5-(trifluoromethyl)benzoic acid, or an internal salt or hydrochloride salt thereof.
[23] In some aspects, the compound of Formula (II) is Compound 2, 2-methyl-5- ((S)-2-(2-(((R)-l-(naphthalen-l-yl)ethyl)amino) ethyl)-2H-benzo[b][l,4]oxazin-4(3H)-yl)benzoic acid, or an internal salt or hydrochloride salt thereof.
[24] In some aspects, the compound of Formula (III) is Compound 3, 2-methyl-5- ((2R,4S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid hydrochloride.
[25] In some aspects, the compound of Formula (IV) is Compound 4, 3-((lR,3S)-3-((((R)-l-(4-fluoro-3-methoxyphenyl)ethyl)amino) methyl)- 1,2,3, 4-tetrahydronaphthalen- 1-yl)-2,6-dimethylbenzoic acid, or an internal salt or hydrochloride salt thereof.
[26] In some aspects, the compound of Formula (V) is Compound 5, (R)-3-(4-fluoro-3'-(2-((l-(3-methoxy phenyl)ethyl)amino) ethoxy)-5'-(trifluoromethyl)-[l,1'-biphenyl]-3-yl)propanoic acid, or an internal salt or hydrochloride salt thereof.
[27] In some aspects, the compound of Formula (VI) is Compound 6, (R)-N-((R)-1-(3-methoxyphenyl)ethyl)- l-(4-(4-(trifluoromethyl) phenyl)naphthalen-2-yl)propan- 1 -amine, or an internal salt or hydrochloride salt thereof.
[28] In another aspect, this disclosure provides for a composition comprising one or more compounds of Formula (I) to Formula (VI), pharmaceutically acceptable salts thereof, or a combination thereof, and a pharmaceutically acceptable excipient. In some aspects, the composition is suitable for the oral delivery. In some aspects, the composition comprises a compound selected from: Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, pharmaceutically acceptable salts thereof, or a combination thereof.
[29] In another aspect, this disclosure provides for a solid oral pharmaceutical composition 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 a combination thereof in the form of a free base or a pharmaceutically acceptable salt thereof, and
(ii) at least one pharmaceutically acceptable excipient.
[30] In another aspect, this disclosure provides for 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 a combination thereof, and a pharmaceutically acceptable excipient, carrier or diluent.
[31] In another aspect, this disclosure provides for 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.
[32] In another aspect, this disclosure provides for 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.
[33] In another aspect, this disclosure provides for 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.
[34] In another aspect, this disclosure provides for 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.
[35] In another aspect, this disclosure provides for 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.
[36] In another aspect, this disclosure provides for 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.
[37] In some aspects, this disclosure provides for a pharmaceutical composition in the form of a tablet.
[38] In some aspects, this disclosure provides for a pharmaceutical composition in the form of a coated tablet.
[39] In some aspects, this disclosure provides for a film coated tablet. In some aspects, the thickness of the film coating is from about 10 microns to about 500 microns. In some aspects, the thickness of the film coating is from about 20 microns to about 100 microns. In some aspects, the film coating comprises a resistant starch, a high-amylose maize 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 ether (e.g., hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), ethyl cellulose (EC), methylcellulose, methylhydroxycellulose, methylhydroxyethylcellulose, ethylcellulose, sodium carboxymethylcellulose, or a combination thereof), vinyl polymer (e.g., polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), P VP-poly vinyl acetate copolymer, PVA-PEG copolymer), glycol (e.g., high molecular weight polyethylene glycol (PEG), polypropylene glycol), acrylic polymer (e.g., methacrylate aminoester copolymer, ethylacrylate-methylmethacrylate copolymer), 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., ester of aleurtic acid), and a combination thereof.
[40] In some aspects, this disclosure provides for a single unit dosage 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 a combination thereof, and one or more of pharmaceutically acceptable excipients.
[41] In some aspects, this disclosure provides for a single unit dosage 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 a combination thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dosage composition contains about 1 mg to about 100 mg of the one or more compounds.
[42] In some aspects, this disclosure provides for a single unit dosage 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 a combination thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dosage composition contains about 1 mg to about 50 mg of the one or more compounds.
[43] In some aspects, this disclosure provides for a single unit dosage 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 a combination thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dosage composition contains about 5 mg to about 25 mg of the one or more compounds.
[44] In some aspects, this disclosure provides for a single unit dosage 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 a combination thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dosage composition contains about 5 mg to about 10 mg of the one or more compounds.
[45] In some aspects, this disclosure provides for a single unit dosage 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 a combination thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dosage composition contains about 0.1 mg to about 200 mg of the at least one compound. In some aspects, the single unit dosage composition contains about 1 mg to about 25 mg of the one or more compounds. In some aspects, the single unit dosage 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 amounts between any of the aforementioned amounts and ranges, including, but limited to, 0.1 mg to about 200 mg.
[46] In some aspects, this disclosure provides for a single unit dosage composition in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group of Compound 1, Compound 2, Compound 3, Compound 4, Compound
5, Compound 6, and a combination thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dosage composition contains about 1 mg of the one or more compounds.
[47] In some aspects, this disclosure provides for a single unit dosage composition in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and a combination thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dosage compound contains about 2.5 mg of the one or more compounds.
[48] In some aspects, this disclosure provides for a single unit dosage composition in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound-6, and a combination thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dosage compound contains about 5 mg of the one or more compounds.
[49] In some aspects, this disclosure provides for a single unit dosage 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 a combination thereof, and at least one pharmaceutically acceptable excipient, wherein the single unit dosage compound contains about 25 mg of the one or more compounds.
[50] In some aspects, this disclosure provides for a single unit dosage composition in tablet form comprising a pharmaceutically effective amount of one or more compounds selected from the group consisting of a free base form of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and a combination thereof, wherein the single unit dosage compound contains about 1 mg to about 25 mg of the one or more compounds.
[51] In some aspects, this disclosure provides for a single unit dosage 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 a combination thereof, and at least one pharmaceutically acceptable excipient. The at least one pharmaceutically acceptable excipient selected from group consisting of a diluent, a lubricant, a disintegrant, a binder, a surfactant, a solubilizer a gladient, or a combination thereof.
[52] In another aspect, this disclosure provides for a method for treating or managing secondary hyperparathyroidism associated with chronic kidney disease (CKD) in a subject in need thereof, said method comprises 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), pharmaceutically acceptable salt(s) thereof, or a combination
thereof (such as 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid hydrochloride (Compound 3)). In some aspects, the subject can be on dialysis or not on dialysis. In some aspects, the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is a total daily dose amount 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 aspects of the invention, the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is a total daily dose amount 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 aspects, the administration of the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is about 25 mg once or twice daily, or about 20 mg once or twice daily. In some aspects of the invention, the administration is oral. In some aspects, 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), pharmaceutically acceptable salt(s) thereof, or a combination thereof to the subject.
[53] In another aspect, this disclosure provides for a pharmaceutical composition comprising one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof, as well as a kit comprising a pharmaceutical composition comprising one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof and an instructional material for use thereof.
[54] In another aspect, this disclosure provides for a method of lowering or suppressing one or more intact parathyroid hormone (iPTH) levels in a subject suffering from secondary hyperparathyroidism associated with CKD, said method comprises 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), pharmaceutically acceptable salt(s) thereof, or a combination thereof (such as 2-methyl-5-((2R,4S)-2-((((R)-l- (naphthalen-l-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound
3))•
[55] In some aspects, the subject can be on dialysis or not on dialysis. In some aspects, the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is a total daily dose amount 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 aspects, the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is a total daily dose amount 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 aspects, the administration of the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is about 25 mg once or twice daily, or about 20 mg once or twice daily. In some aspects, the administration is oral. In some aspects, administration does not require 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 salt(s) thereof, or a combination thereof to the subject.
[56] In another aspect, this disclosure provides for use of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof (such as 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l-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 the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof. In some aspects, the subject can be on dialysis or not on dialysis. In some aspects, the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is a total daily dose amount 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 aspects, the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is a total daily dose amount 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 aspects, the administration of the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is about 25 mg once or twice daily, or about 20 mg once or twice daily. In some aspects, the administration is oral. In some aspect, administration does not require 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 salt(s) thereof, or a combination thereof to the subject.
[57] In some aspects, this disclosure provides for use of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof (such as 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid hydrochloride (Compound 3)) in an oral formulation in the manufacture of a medicament for the lowering or suppression of 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 the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof. In some aspects, the subject can be on dialysis or not on dialysis. In some aspects, the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is a total daily dose amount 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 aspects, the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI),
pharmaceutically acceptable salt(s) thereof, or a combination thereof is a total daily dose amount 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 aspects, the administration of the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is about 25 mg once or twice daily, or about 20 mg once or twice daily. In some aspects, the administration is oral. In some aspects, administration does not require 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 salt(s) thereof, or a combination thereof to the subject.
[58] In another aspect, this disclosure provides for a method of treating or managing secondary hyperparathyroidism associated with CKD in a subject in need thereof, said method comprising:
(a) Identifying a subject having secondary hyperparathyroidism associated with CKD in need of treatment or management, characterized by an elevated baseline iPTH concentration level in the subject; 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), pharmaceutically acceptable salt(s) thereof, or a combination thereof.
In another aspect, the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid hydrochloride (Compound 3).
[59] In some aspects, the subject can be on dialysis or not on dialysis. In some aspects, the therapeutically effective amount of a compound selected from the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is a total daily dose amount 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 aspects, the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI),
pharmaceutically acceptable salt(s) thereof, or a combination thereof is a total daily dose amount 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 aspects, the administration of the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is about 25 mg once or twice daily, or about 20 mg once or twice daily. In some aspects, the administration is oral. In some aspects, administration does not require dose adjustment or titration of a compound selected from a compound having Formula (I)-(VI) to the subject.
[60] In another aspect, this disclosure provides for a method of treating or managing secondary hyperparathyroidism associated with CKD in a subject in need thereof, said method comprising:
(a) identifying a subject having secondary hyperparathyroidism associated with CKD in need of treatment or management, characterized by a baseline iPTH concentration level in the subject, wherein the baseline iPTH concentration level is 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), pharmaceutically acceptable salt(s) thereof, or a combination thereof.
In some aspects, the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid hydrochloride (Compound 3).
[61] In some aspects, the subject can be on dialysis or not on dialysis. In some aspects, the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is a total daily dose amount 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 aspects, the therapeutically effective amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is a total daily dose amount 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 aspects, the administration of the therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is about 25 mg once or twice daily, or about 20 mg once or twice daily. In some aspects, the administration is oral. In some aspects, 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), pharmaceutically acceptable salt(s) thereof, or a combination thereof to the subject.
[62] In another aspect, a method for treating or managing secondary hyperparathyroidism associated with CKD in a subject in need thereof, said method comprises administering to the subject a therapeutically effective amount of a calcimimetic. In some aspects, the therapeutically effective amount of the calcimimetic is a total daily dose amount 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 aspects, the therapeutically effective amount of the calcimimetic is a total daily dose amount 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 aspects, the administration of the therapeutically effective amount of the calcimimetic is about 25 mg once or twice daily, or about 20 mg once or twice daily. In some aspects, the administration is oral. In some aspects, administration does not require dose adjustment or titration of the calcimimetic to the subject. In some aspects, secondary hyperparathyroidism is treated or managed without inducing hyperphosphatemia or hypocalcemia in the subject. In some aspects, the calcimimetic comprises one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof. In some aspects, the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof is Compound 3.
[63] In some aspects, subjects with secondary hyperparathyroidism associated with CKD, include subjects diagnosed or having Stage 3b CKD, Stage 4 CKD or Stage 5 CKD.
[64] In some aspects, subjects with secondary hyperparathyroidism associated with CKD, include subjects with a baseline iPTH concentration level ranging from about 110 pg/ml to about 1500 pg/ml, or about 300 pg/ml to about 1600 pg/ml, or about 110 pg/ml to about 1350 pg/ml. Preferably, a baseline iPTH concentration level ranging from about 300 pg/ml to about 1250 pg/ml.
[65] In some aspects, in any one of the methods or uses disclosed herein, the subject’s iPTH level can be lowered by at least about 30% compared to the baseline iPTH concentration level, or at least about 15% compared to the baseline iPTH concentration level, or about 15% to about 30% compared to the baseline iPTH concentration level.
[66] In some aspects, 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 salt(s) thereof, or a combination thereof (such as 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 aspects, 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 the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof. In some aspects, the pharmaceutical composition is administered to the subject once daily, twice daily, or more than twice daily. In some aspects, the pharmaceutical composition is administered to the subject in a total daily dose amount of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof of about 10 mg to about 40 mg; most preferably, about 20 mg to about 40 mg.
[67] In some aspects, pharmaceutical composition suitable for oral administration may be presented as tablets or capsules, 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), pharmaceutically acceptable salt(s) thereof, or a combination thereof (such as Compound 3), and at least one ingredient selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant, a surfactant, glidant, and a combination thereof.
[68] In some aspects, a pharmaceutical composition for oral administration is in the form of a tablet, cachet, or capsule. In some aspects of the invention, the tablet, cachet, or capsule 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 salt(s) thereof, or a combination thereof (such as Compound 3), and at least one ingredient selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant, a surfactant, glidant, and a combination thereof. In some aspects of the invention, the tablet, cachet or each granule in a capsule is coated or scored. In some aspects of the invention, the tablet, cachet or capsule is formulated to provide an immediate release of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof (such as Compound 3), and/or other active ingredient therein. In some aspects of the invention, the tablet, cachet or each granule in a capsule is round (or circle), sphere, disc, oval, oblong, capsule-shaped, rectangle, triangle, pentagon, hexagon, octagon, bullet, diamond, or arrowhead.
[69] In some aspects, the capsule is a hard shell capsule, wherein the hard shell capsule is made of hard gelatin and/or hydroxypropyl methycellulose (HPMC). In some aspects, the size of the hard shell capsule is size 0 or size 00. In some aspects, the capsule is a push-fit capsule. In some aspects, the capsule 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 salt(s) thereof, or a combination thereof (such as Compound 3), a starch (such as starch 1500 LM), microcrystalline cellulose and crospovidone. In some aspects, the capsule comprises about 35% w/w to about 39% w/w of the one or more compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), pharmaceutically acceptable salt(s) thereof, or a combination thereof.
[70] In another aspect, the pharmaceutical composition disclosed in this 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 their complications, or a combination thereof. Uses and methods of treatment or management regarding the above are also included herein.
[71] In another aspect, the pharmaceutical composition disclosed in this application can be used to treat or manage a disease in a subject in need thereof, wherein the disease is parathyroid adenoma; parathyroid hyperplasia; parathyroid carcinoma; vascular or valvular calcification; abnormal calcium homeostasis; hypercalcemia; abnormal phosphorous homeostasis; hypophosphatemia; bone -related diseases or complications arising due to hyperparathyroidism, chronic kidney disease or parathyroid carcinoma; post-renal transplantation bone loss; osteitis fibrosa cystica; adynamic bone disease; renal bone diseases; cardiovascular complications arising due to hyperparathyroidism or chronic kidney disease; malignancies in which (Ca2+)e ions are abnormally high; cardiac, renal or intestinal dysfunctions; podocyte-related diseases; abnormal intestinal motility; diarrhea; augmenting gastrin or gastric acid secretion to directly or indirectly benefit in atrophic gastritis or to improve absorption of pharmacological compounds, drugs or supplements from gastro-intestinal tract by augmenting gastric acidity, or a combination thereof. Uses and methods of treatment or management regarding the above are also included herein.
[72] In another aspect, this disclosure provides for a single unit dosage 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 free base form of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a combination thereof, wherein the single unit dosage composition contains about 0.1% to about 50% by weight of the single unit dosage composition (w/w) of the at least one compound. In some aspects, 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 dosage composition contains the at least one compound in the amount of about 0.1% w/w to about 1% w/w, about 1% w/w to about 5% w/w, about 5% w/w to about 10% w/w, about 10% to about 15% w/w,
about 15% w/w to about 20% w/w, about 20% w/w to about 25% w/w, about 25% w/w to about 30% w/w, about 30% w/w to about 35% w/w, about 35% w/w to about 40% w/w, about 40% w/w to about 45% w/w, about 45% w/w/ to 50% w/w, or in between any of the aforementioned ranges. In some aspects, 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 dosage composition contains the at least one compound in the amount of 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, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, about 25% w/w, about 26% w/w, about 27% w/w, about 28% w/w, about 29% w/w, about 30% w/w, about 31% w/w, about 32% w/w, about 33% w/w, about 34% w/w, about 35% w/w, about 36% w/w, about 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.
[73] In some aspects, this disclosure provides for a single unit dosage 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, wherein the single unit dosage composition contains about 2% w/w to about 20% w/w of the at least one compound.
[74] In some aspects, this disclosure provides for a single unit dosage 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 a combination thereof, wherein the single unit dosage composition contains about 2% w/w to about 10% w/w of the at least one compound.
[75] In some aspects, this disclosure provides for a single unit dosage 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 a combination thereof, wherein the single unit dosage composition contains about 5% w/w to about 10% w/w of the at least one compound.
[76] In some aspects, this disclosure provides for a single unit dosage 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 a combination thereof, wherein the single unit dosage composition contains about 5% w/w of the at least one compound.
[77] In some aspects, this disclosure provides for a single unit dosage 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 a combination thereof, wherein the single unit dosage composition contains about 25% w/w of the at least one compound.

CLAIMS
What is claimed is:
1. A solid pharmaceutical composition comprising a pharmaceutically effective amount of one or more compounds, wherein the one or more compounds is selected from the group consisting of compounds having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI):

wherein
Q is

Ra is hydrogen;
Rb is hydrogen;
L is a bond or — (CRcRd)m;
Rc and R i arc independently selected from hydrogen or substituted or unsubstituted alkyl;
R1 is

ring Ar is phenyl or naphthyl;
R, which may be same or different at each occurrence, is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, —
OR6, — C(O)R6, — (CReRf)0-3— C(O)OR6, — (CReRf)i-2cycloalkylene-C(O)OR6, -cycloalkylene (CReRf)0-2 — C(O)OR6, — O(CReRf)0-3 — C(O)OR6, — O-cycloalkylene-C(O)OR6, — C(O)NR7— (CReRf)i-2— C(O)OR6, — C(O)NR7R8, — S(O)0-2R6, and — S(O)2NR7R8;
Re and Rf 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 same or different at each occurrence, is independently selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted haloalkyl;
R7 and R8, which may be same or different at each occurrence, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl;
Z is — CRgRh — ;
Rg and Rh are hydrogen;
“m” is an integer ranging from 1 to 3, both inclusive; “n” is an integer ranging from 1 to 3, both inclusive; and “q” is an integer ranging from 0 to 4, both inclusive;

wherein
Q is

Ra is hydrogen, halogen or alkyl;
Rb is selected from hydrogen, alkyl, and haloalkyl;
or Ra and Rb together attached on the same carbon form C(O);
L is a bond or — CRcRd — ;
ring A is phenyl;
Rc and Rd are independently selected from hydrogen, halogen, and alkyl;
X is selected from a bond, — (CReRf)m, — O — , — O(CReRf)m — , — (CReRf)mO — , — C(O)(CReRf)m— , — C(O)NR7— , — C(O)NR7(CReRf)m— , -cycloalky lene-, and — O-cycloalkylene-;
Re and Rf, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, alkyl, haloalkyl and cycloalkyl; or Re and Rf, together with the carbon atom to which they are attached, may 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 same or different at each occurrence, is independently selected from halogen, cyano, alkyl, haloalkyl, and cycloalkyl;
R10, which may be same or different at each occurrence, is independently selected from halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, — OR6, — C(O)R6, — NR7C(O)R6, — S(O)0-2R6, — S(O)2NR7R8, and — NR7S(O)2R6;
“m” is an integer ranging from 1 to 3, both inclusive; “n” is an integer ranging from 1 to 3, both inclusive; “p” is an integer ranging from 0 to 2, both inclusive; and “q” is an integer ranging from 0 to 1, both inclusive;

wherein Q is

Ra is hydrogen; Rb is hydrogen or alkyl;
L is a bond, or — CRcRd;
ring A is phenyl;
Rc and Rd are independently selected from hydrogen, halogen, and alkyl;
X is selected from a bond, — (CReRf)m, — O — , — O(CReRf)m — , — (CReRf)mO — , — C(O)(CReRf)m— , — C(O)NR7— , and — C(O)NR7(CReRf)m— ;
Re and Rf, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, alkyl, haloalkyl and cycloalkyl; or Re and Rf, together with the carbon atom to which they are attached, form a 3 to 7 membered saturated carbocyclic ring;
R1 is — OR6 or — NR7R8;
R2is 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;
R10, which may be same or different at each occurrence, is independently selected from halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, — OR6, — C(O)R6, — NR7R8, — NR7C(O)R6, and — (O)2NR7R8;
“m” is an integer ranging from 1 to 3, both inclusive; “n” is an integer ranging from 1 to 3, both inclusive; “p” is an integer ranging from 0 to 2, both inclusive; “q” is an integer ranging from 0 to 1, both inclusive;

wherein
Rais selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl and substituted or unsubstituted haloalkyl;
Rb, which may be same or different at each occurrence, is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted haloalkyl;
Rc which may be same or different at each occurrence, is independently selected from halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, OR6, nitro, cyano, — C(O)OR6, — (CH2)r — C(O)OR6, — O— C(O)OR6, — O(CH2)r— C(O)OR6, — NR7R8, — (CH2)rNR7R8— , — C(O)R9, — C(O)NR7R8, — (CH2)r— C(O)NR7R8, — NR7C(O)R9, — S(O)O-2R6, — S(O)2NR7R8, and — NR7S(O)2R9;
X is selected from a bond, — (CRcRd)r — , — O — , — NR7 — , — NR7(CRcRd)r — , —
0(CRcRd)r, — C(O)NR7— , — C(O)NR7(CRcRd)r, — (CRcRd)rNR7(CRcRd)r, —
(CRcRd)rCycloalkylene-, cycloalkylene, -cycloalkylene(CRcRd)r — and — O-cycloalkylene where cycloalkylene may be substituted or unsubstituted;
Rc and Rd, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or Rc and Rd, together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring;
Z is — OR6or — NR10R11;
R1, which may be same or different at each occurrence, is independently selected from 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)rNR7R8— , — (CH2)r— C(O)OR6, — O— C(O)OR6, — O(CH2)r— C(O)OR6, — C(O)NR7R8, — (CH2)r— C(O)NR7R8, — NR7C(O)R9, — S(O)o-2R7, — S(O)2NR7R8 and — NR7S(O)2R9;
R2is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl;
R3 and R4 may be 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 same or different at 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, which may be same or different at 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 R7and 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, wherein the unsaturated cyclic ring may have one or two double bonds;
at each occurrence, R9 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
R10 and R11may be same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, — (CRcRd)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 R10 and R11, 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, wherein the unsaturated cyclic ring may have one or two double bonds;
“n” is an integer ranging from 1 to 3, both inclusive; “m” is an integer ranging from 0 to 3, both inclusive; “p” is an integer ranging from 0 to 4, both inclusive; “q” is an integer ranging from 0 to 3, both inclusive; and “r” is an integer ranging from 1 to 3, both inclusive;

wherein
W is CH or N;
R1, which may be same or different at each occurrence, is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, — C(O)O R5, — (CRaRb)r — C(O)O R5, — O— C(O)O R5, — O(CRaRb)r— C(O)O R5, — NR6R7, — C(O)R8, — C(O)NR6R7, — NR6C(O)R8, — S(O)0-2 R5, — S(O)2NR6R7 and — NR6S(O)2R8;
R2 is substituted or unsubstituted aryl;
R3 is substituted or unsubstituted alkyl;
R4, which may be same or different at each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, — O R5, — NR6R7, — C(O)R8, — C(O)NR6R7, — NR6C(O)R8, — S(O)0-2 R5, — S(O)2NR6R7 and — NR5S(O)2R8;
X is selected from a bond, — (CRaRb)r — , — O — , — NR7 — , — O(CRaRb)r — , — C(O)NR7 — , — C(O)NR7(CRaRb)r — , — (CRaRb)rCycloalkylene-, cycloalky lene, cycloalkylene-(CRaRb)r — and — O-cycloalkylene;
Raand Rb, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or Raand Rb, together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring;
Z is — O R5 or — NR6R7;
R5, which may be same or different at each occurrence, is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted aryl;
R6and R7, which may be same or different at each occurrence, are independently selected from hydrogen, substituted or unsubstituted alkyl, — (CRaRb)r — C(O)O R5, 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, wherein the 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, both inclusive; “p” is an integer ranging from 0 to 3, both inclusive; “q” is an integer ranging from 0 to 3, both inclusive; and “r” is an integer ranging from 1 to 3, both inclusive;

wherein
R1 is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, -(CRaRb)1-3OH, -C(O)NH-alkyl, -S(O)2- alkyl, -S(O)2NH-alkyl, -C(O)OH, -C(O)O-alkyl, -(CRaRb)i-3C(O)OH and -(CRaRb)1-3C(O)O- alkyl;
R2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl, wherein the substituents may be one or more and are independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR4, -N R5R6 and substituted or unsubstituted cycloalkyl;
X is selected from -C(O)OH, -C(O)O-alkyl, -C(O)NR5R6, -(CRaRb)1-3C(O)OH, - C(O)O-alkyl, -O-(CRaRb)l-3C(O)OH, -O-(CRaRb)1-3C(O)O-alkyl, -CRc=CRc- -C(O)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl,- OR4 and -S(O)2-alkyl;
Ra and Rb are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or Ra and Rb , together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 6 membered saturated carbocyclic ring;
Rc is independently selected from hydrogen, halogen and substituted or unsubstituted alkyl;
R3, which may be same or different at 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, both inclusive;

ring A is phenyl or naphthyl;
R1 is hydrogen or substituted or unsubstituted (C1-C6)alkyl;
R2, which may be same or different at each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C1-C6)haloalkyl, substituted or unsubstituted (C1-C6)hydroxyalkyl, — X — C(O) — Z, — OR9, — NR7R8, — NR7C(O)R6, — S(O)0-2R6, — S(O)2NR7R8, — NR7S(O)2R6, substituted or unsubstituted (C3-C12) 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

X is selected from a bond, — (CRaRb)m — , — N R2 — , — O(CRaRb)m — , — (CRaRb)mO — , — C(O)NRI2— , — (CRaRb)mO— (CRaRb)m— and — C(O)NRi2(CRaRb)m— ;
Raand Rb which may be same or different at each occurrence, 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 Ra and Rb, together with the carbon atom to which they are attached, form a substituted or unsubstituted 3 to 6 membered saturated carbocyclic ring;
Z is — OR10 or — NR7R8;
R3 IS selected from hydrogen, halogen, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C1-C6)haloalkyl, — OR9, and substituted or unsubstituted (C3-C12)cycloalkyl;
R4, which may be same or different at each occurrence, 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 substituted or unsubstituted (C1-C6)alkyl;
R6is selected from substituted or unsubstituted (C1-Ce)alkyl, substituted or unsubstituted (C3-C12)cycloalkyl and substituted or unsubstituted (C6-C14)aryl;
R7 and R8, which may be same or different at each occurrence, are independently selected from hydrogen, substituted or unsubstituted (C1-C6)alkyl, — (CRaRt>)1-2Rii, —
(CRcRd)m — OH and substituted or unsubstituted (C3-C12)cycloalkyl;
Rcand Rd which may be same or different at each occurrence, are independently hydrogen or substituted or unsubstituted (C1-C6)alkyl;
R9is 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-C12)cycloalkyl;
R10 is selected from hydrogen, substituted or unsubstituted (C1-C6)alkyl and — (CRaRb) 1-2phenyl;
R11is substituted or unsubstituted phenyl, wherein the substituents are selected from halogen, (C1-C6)alkyl and — OR9;
R12is hydrogen or substituted or unsubstituted (C1-C6)alkyl;
“m” is an integer ranging from 1 to 3, both inclusive; “n” is an integer ranging from 1 to 3, both inclusive; “p” is an integer ranging from 0 to 3, both inclusive; and “q” is an integer ranging from 1 to 3, both inclusive;
or pharmaceutically acceptable salts thereof, or a combination thereof, and at least two pharmaceutically acceptable excipients, wherein the at least two pharmaceutically acceptable excipients is microcrystalline cellulose, crospovidone, starch, magnesium stearate, sodium lauryl sulfate, colloidal silicon dioxide, or a combination thereof.
2. The solid pharmaceutical composition of claim 1, wherein the one or more compounds is:
3-((S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino)methyl) morpholino)-5- (trifluoromethyl)benzoic acid, an internal salt or hydrochloric acid salt thereof (“Compound 1”);
2-methyl-5-((S)-2-(2-(((R)-l-(naphthalen-l-yl)ethyl)amino) ethyl)-2H- benzo[b][l,4]oxazin-4(3H)-yl)benzoic acid, an internal salt or hydrochloric acid salt thereof (“Compound 2”);
2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino) methyl)chroman-4- yl)benzoic acid hydrochloride (“Compound 3”);
3-((lR,3S)-3-((((R)-l-(4-fluoro-3-methoxyphenyl)ethyl)amino) methyl)- 1,2, 3, 4- tetrahydronaphthalen-l-yl)-2,6-dimethylbenzoic acid, an internal salt or hydrochloric acid salt thereof (“Compound 4”);
(R)-3-(4-fluoro-3'-(2-((l-(3-methoxy phenyl)ethyl)amino) ethoxy)-5'- (trifluoromethyl)-[l,1'-biphenyl]-3-yl)propanoic acid, an internal salt or hydrochloric acid salt thereof (“Compound 5”);
(R)-N-((R)-l-(3-methoxyphenyl)ethyl)-l-(4-(4-(trifluoromethyl) phenyl)naphthalen- 2-yl)propan- 1 -amine hydrochloride (“Compound 6”); or
a combination thereof.
3. The solid pharmaceutical composition of claim 1 or 2, wherein the one or more compounds is Compound 3.
4. The solid pharmaceutical composition of any one of claims 1 to 3, wherein the composition is suitable for oral administration.
5. The solid pharmaceutical composition of claim 4, wherein the composition is in the form of a tablet or capsule.
6. The solid pharmaceutical composition of claim 5, wherein the composition is in the form of a tablet, wherein the tablet is coated with a film.
7. The solid pharmaceutical composition of claim 6, wherein the film is a resistant starch, a high-amylose maize starch, Poly(methacrylic acid-co-methyl methacrylate) 1:2, Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1, Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2, 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.
8. A solid pharmaceutical composition comprising one or more compounds and one or more ingredients, wherein the one or more compounds is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, a pharmaceutical acceptable salt thereof, or a combination thereof, and wherein the one or more ingredients is:
(a) microcrystalline cellulose in the amount of about 5% to about 50% by weight of the total weight of the solid pharmaceutical composition;
(b) crospovidone in the amount of about 5% to about 20% by weight of the total weight of the solid pharmaceutical composition, or povidone in the 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 the amount of about 20% to about 50% by weight of the total weight of the solid pharmaceutical composition;
(d) magnesium stearate in the amount of about 0.5% to about 5% by weight of the total weight of the solid pharmaceutical composition, or talc in the 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 the amount of about 0.5% to about 3% by weight of the total weight of the solid pharmaceutical composition;
(f) colloidal silicon dioxide in amount of about 0.5% to about 3% by weight of the total weight of the solid pharmaceutical composition; or
(g) a combination thereof.
9. A solid pharmaceutical composition comprising 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid hydrochloride and one or more ingredients, wherein the one or more ingredients is:
(a) microcrystalline cellulose in the amount of about 5% to about 50% by weight of the total weight of the solid pharmaceutical composition;
(b) crospovidone in the amount of about 5% to about 20% by weight of the total weight of the solid pharmaceutical composition, or povidone in the 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 the amount of about 20% to about 50% by weight of the total weight of the solid pharmaceutical composition;
(d) magnesium stearate in the amount of about 0.5% to about 5% by weight of the total weight of the solid pharmaceutical composition, or talc in the 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 the amount of about 0.5% to about 3% by weight of the total weight of the solid pharmaceutical composition;
(f) colloidal silicon dioxide in amount of about 0.5% to about 3% by weight of the total weight of the solid pharmaceutical composition; or
(g) a combination thereof.
10. The solid pharmaceutical composition of any one of claims 1 to 8, wherein the one or more compounds is in the amount of about 0.1 mg to about 200 mg..
11. The solid pharmaceutical composition of any one of claims 1 to 8, wherein the one or more compounds is in the amount of about 1 mg to about 50 mg, or about 5 mg to about 25 mg.
12. The solid pharmaceutical composition of claim 9, wherein the 2-methyl-5-((2R,4S)-2- ((((R)-l-(naphthalen-l-yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid hydrochloride is in the amount of about 0.1 mg to about 200 mg, about 1 mg to about 50 mg, or about 5 mg to about 25 mg..
13. The solid pharmaceutical composition of claim 5, wherein the pharmaceutical composition is a capsule, wherein the capsule comprises about 35% w/w to about 39% w/w of the one or more compounds.
14. A method of treating secondary hyperparathyroidism associated with chronic kidney disease (CKD) in a subject in need thereof, the method comprising administering to the subject the solid pharmaceutical composition of any one of claims 1 to 13.
15. The method of claim 14, wherein the compound in the solid pharmaceutical composition is 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid hydrochloride.
16. The method of claim 14 or 15, wherein the therapeutically effective amount is a total daily dose of about 5 mg to about 50 mg.
17. The method of any one of claims 14 to 16, wherein the administration is 25 mg once or twice daily, or 20 mg once or twice daily.
18. The method of any one of claims 14 to 17, wherein the administration is oral.
19. The method of any one of claims 14 to 18, wherein the therapeutically effective amount is not dose-titrated.
20. The method of any one of claims 14 to 19, wherein the subject is not on dialysis.
21. The method of any one of claims 14 to 19, wherein the subject is on dialysis.
22. The method of any one of claims 14 to 21, wherein secondary hyperparathyroidism is treated or managed without inducing hyperphosphatemia or hypocalcemia in the subject. 23. The method of any one of claims 14 to 22, wherein the subject has been previously diagnosed or has Stage 3b CKD, Stage 4 CKD or Stage 5 CKD.
24. A method of lowering or suppressing one or more intact parathyroid hormone (iPTH) levels in a subject suffering from secondary hyperparathyroidism associated with CKD, the method comprises administering to the subject the solid pharmaceutical composition of any one of claims 1 to 13.
25. The method of claim 24, wherein the compound in the solid pharmaceutical composition is 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid hydrochloride.
26. The method of claim 24 or 25, wherein the subject is not on dialysis.
27. The method of claim 24 or 25, wherein the subject is on dialysis.
28. The method of any one of claims 24 to 27, wherein the therapeutically effective amount is a total daily dose amount of about 5 mg to about 50 mg.
29. The method of any one of claims 24 to 28, wherein the therapeutically effective amount is a total daily dose amount of about 10 mg to about 40 mg.
30. The method of claim 29, wherein the total daily dose amount is administered about 25 mg once or twice daily, or about 20 mg once or twice daily.
31. The method of any one of claims 24 to 29, wherein the administration is oral.
32. The method of any one of claims 24 to 31, wherein the administration does not require dose adjustment to the subject.
33. The method of any one of claims 24 to 32, wherein the subject’s iPTH level is reduced by at least about 30% compared to the baseline iPTH concentration level before treatment.
34. The method of any one of claims 24 to 32, wherein the subject’s iPTH level is reduced by at least about 15% compared to the baseline iPTH concentration level before treatment.
35. A solid pharmaceutical composition of 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid, hydrochloride salt for use in the treatment or management of secondary hyperparathyroidism associated with CKD.
36. A solid pharmaceutical composition of 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid hydrochloride for use in the treatment or management of secondary hyperparathyroidism associated with CKD by lowering or suppressing one or more iPTH levels.
37. A method of treating or managing secondary hyperparathyroidism associated with
CKD in a subject in need thereof, the method comprising:
(a) identifying a subject having secondary hyperparathyroidism associated with CKD in need of treatment or management, characterized by an elevated baseline iPTH concentration level in the subject; and
(b) administering to the subject the solid pharmaceutical composition of any one of claims 1 to 13.
38. The method of claim 37, wherein the one or more compounds in the solid pharmaceutical composition is 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid hydrochloride.
39. The method of claim 37 or 38, wherein the subject is on dialysis.
40. The method of claim 37 or 38, wherein the subject is not on dialysis.
41. The method of any one of claims 37 to 40, wherein the therapeutically effective amount is a total daily dose of about 5 mg to about 50 mg.
42. The method of claim 41, wherein the total daily dose is administered about 25 mg once or twice daily, or about 20 mg once or twice daily.
43. The method of any one of claims 37 to 42, wherein the administration is oral.
44. The method of any one of claims 37 to 43, wherein the therapeutically effective amount is not dose-titrated.
45. The method of any one of claims 37 to 44, wherein the baseline iPTH concentration level in the subject is in the range of about 110 pg/ml to about 1500 pg/ml, or about 300 pg/ml to about 1250 pg/ml.
46. The method of any one of claims 37 to 44, wherein the subject’s iPTH level is reduced by at least about 30% compared to the baseline iPTH concentration level before treatment.
47. The method of any one of claims 37 to 44, wherein the subject’s iPTH level is reduced by at least about 15% compared to the baseline iPTH concentration level before treatment.