WO2015162538A1 - Heterocyclic compounds as calcium sensing receptor modulators for the treatment of hyperparathyroidism, chronic renal failure and chronic kidney disease - Google Patents

Heterocyclic compounds as calcium sensing receptor modulators for the treatment of hyperparathyroidism, chronic renal failure and chronic kidney disease Download PDF

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WO2015162538A1
WO2015162538A1 PCT/IB2015/052868 IB2015052868W WO2015162538A1 WO 2015162538 A1 WO2015162538 A1 WO 2015162538A1 IB 2015052868 W IB2015052868 W IB 2015052868W WO 2015162538 A1 WO2015162538 A1 WO 2015162538A1
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substituted
unsubstituted
alkyl
ethyl
compound
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Sachin MADAN
Prashant Vitthalrao TALE
Seema Prabhakar ZADE
Amolsing Dattu PATIL
Sanjeev Anant Kulkarni
Venkata P. Palle
Rajender Kumar Kamboj
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Lupin Limited
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to substituted heterocyclic compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions for treating the diseases, disorders, syndromes or conditions associated with the modulation of calcium sensing receptors (CaSR).
  • the invention also relates to methods of treating the diseases disorders, syndromes or conditions associated with the modulation of calcium sensing receptors (CaSR).
  • the invention also relates to process for the preparation of the compounds of the invention.
  • Ca 2+ has been known to be an intracellular second messenger, with the molecular identification of an extracellular calcium sensing receptor (CaSR), it has further opened the possibility that Ca 2+ might also function as a messenger outside the cells. Information about the local changes in extracellular concentration of Ca 2+ is conveyed to the interior of many types of cells through this unique receptor.
  • CaSR extracellular calcium sensing receptor
  • CaSR Calcium-sensing receptor
  • GPCR G-protein-coupled receptor
  • 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.
  • ECD extracellular
  • PTH parathyroid hormone
  • PTH secretion leads to conservation of serum Ca + by increasing kidney retention and intestinal absorption of Ca 2+ . This happens indirectly through the PTH-induced synthesis of the active vitamin D metabolite, 2,5-dihydroxyvitamin D.
  • the pulsatile action of PTH has anabolic effects on bone development and its sustained levels can lead to catabolic effects, in which the bones breakdown releasing Ca 2+ as in the case of osteoporosis. All these systems converge in maintenance of baseline serum Ca 2+ and it involves a tight regulation between serum PTH and extracellular calcium which is mediated by the remarkable CaSR.
  • PHPT primary hyperparathyroidism
  • SHPT secondary hyperparathyroidism
  • 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.
  • WO 2013/124828, WO 2013/002329, WO 2013/136288, US 2014/0080770, US 2014/01554161, 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 applications disclose the compounds related to calcium sensing receptors (CaSR) for the treatment of various diseases mediated by CaSR. And also . Med. Chem. (2006), 49, 5119-5128 discloses the compounds related to calcium sensing receptors (CaSR).
  • CaSR calcium sensing receptors
  • the invention provides compounds having the structure of Formula (I),
  • ring A is selected from oxazole, isooxazole, imidazole, pyrazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzoxadiazole, chromene, quinazoline, quinoline, indole, pyrimidine and pyridine;
  • Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, -C(0)OH, -C(0)0-alkyl, -C(0)NH-alkyl, -S(0) 2 -alkyl, -S(0) 2 NH-alkyl, -(CR a R b )i_ 3 C(0)OH, and -(CR a R b )i_ 3 C(0)0-alkyl;
  • R 2 is substituted or unsubstituted aryl; wherein the aryl is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
  • R a and R which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or R a and R , together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 6 membered saturated carbocyclic ring;
  • R 4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl;
  • R5 and R 6 are same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl;
  • R is substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl
  • R y which may be same or different at each occurrence, is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; and
  • R z which may be same or different at each occurrence, is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; or R x and R z together with the nitrogen atom to which they are attached form a substituted or unsubstituted, saturated or unsaturated 4 to 8 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds; or pharmaceutically acceptable salt thereof.
  • the invention provides compounds having the structure of Formula (I),
  • ring A is heteroaryl selected from oxazole, isooxazole, imidazole, pyrazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole and benzoxadiazole;
  • Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, -C(0)OH, -C(0)0-alkyl, -C(0)NH-alkyl, -S(0) 2 -alkyl, -S(0) 2 NH-alkyl, -(CR a R b )i_ 3 C(0)OH, and -(CR a R b )i_ 3 C(0)0-alkyl;
  • R 2 is substituted or unsubstituted aryl; wherein the aryl is substituted or
  • R 3i which may be same or different at each occurrence, is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, -CN, -C(0)OH, -C(0)0-alkyl, -OR 4 , -NR 5 R 6 , and -NR 6 C(0)R 7 -, C(0)NR 5 R 6 , -S(0) 2 -alkyl, -S(0) 2 NH-alkyl, -(CR a R b )i_ 3 C(0)OH, and -(CR a R b )i_ 3 C(0)0- alkyl;
  • R a and R b which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or R a and R bi together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 6 membered saturated carbocyclic ring;
  • R 4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted cycloalkyl;
  • R5 and R 6 are same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl;
  • R is substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl
  • 'n' is an integer ranging from 0 to 3, both inclusive; or pharmaceutically acceptable salt thereof.
  • the invention provides compounds having the structure of Formula (II)
  • ring A is heterocyclyl selected from isooxazole, benzofuran, benzothiophene, benzothiazole, chromene, quinazoline, quinoline, indole, pyrimidine and pyridine;
  • Ri is halogen, substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl;
  • R 2 is substituted or unsubstituted phenyl
  • R 4 is substituted or unsubstituted alkyl
  • R y which may be same or different at each occurrence, is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; and
  • R z which may be same or different at each occurrence, is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; or R x and R z together with the nitrogen atom to which they are attached form a substituted or unsubstituted, saturated or unsaturated 4 to 8 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds; or pharmaceutically acceptable salt thereof.
  • ring A is selected from benzofuran, benzothiophene, benzothiazole, chromene, and quinazoline;
  • R 4 is substituted or unsubstituted alkyl
  • 'n' is an integer ranging from 0 to 3, both inclusive; or pharmaceutically acceptable salt thereof.
  • ring A is selected from quinazoline, quinoline, pyrimidine and pyridine;
  • R 3i which may be same or different at each occurrence, is independently selected from substituted or unsubstituted alkyl, -C(0)OH, -OR 4 ; substituted or unsubstituted alkyl; and
  • 'n' is an integer ranging from 0 to 2, both inclusive; or pharmaceutically acceptable salt thereof.
  • Ri is selected from halogen (e.g. F) and substituted or unsubstituted haloalkyl (e.g. CF 3 ).
  • compounds having the structure of Formula (I) wherein 'n' is 0 to 3; R 3 , same or different at each occurrence, are independently selected from substituted or unsubstituted alkyl (e.g. methyl), -C(0)OH, and -OR 4 or two R 3 groups together with the carbon atom to which they are attached form oxo (C 0); R 4 is substituted or unsubstituted alkyl (e.g. methyl).
  • ring A is Ri is halogen (e.g. F) and substituted or unsubstituted haloalkyl (e.g. CF 3 ); R 2 is substituted or unsubstituted phenyl; R 3 is selected from substituted or unsubstituted alkyl (e.g. methyl) and -OR 4 ; R 4 is substituted or unsubstituted alkyl (e.g. methyl); n is 0 to 2.
  • Ri is halogen (e.g. F) and substituted or unsubstituted haloalkyl (e.g. CF 3 );
  • R 2 is substituted or unsubstituted phenyl;
  • R 3 is selected from substituted or unsubstituted alkyl (e.g. methyl) and -OR 4 ;
  • R 4 is substituted or unsubstituted alkyl (e.g. methyl);
  • n is 0 to 2.
  • Formula (I), Formula (II), Formula (III) and/or Formula (IV) structurally encompasses all tautomers, stereoisomers, enantiomers and diastereomers, including isotopes wherever applicable and pharmaceutically acceptable salts that may be contemplated from the chemical structures generally described herein.
  • Compounds of the invention include, for example, compounds of the Formula (I), (II), (III) or (IV) or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of ring A, R 1; R 2 , R3, and 'n' has any of the meanings defined hereinbefore or independently in any of paragraphs (1) to (5): 1) ring A is isooxazole, benzofuran, benzothiophene, benzothiazole, chromene, quinazoline, quinoline, indole, pyrimidine and pyridine;
  • Ri is halogen, substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl
  • R 2 is substituted or unsubstituted phenyl
  • 'n' is an integer ranging from 0 to 3, both inclusive.
  • ring A is isooxazole, benzofuran, benzothiophene, benzothiazole, chromene, quinazoline, quinoline, indole, pyrimidine and pyridine;
  • Ri is halogen, substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl;
  • R 2 is substituted or unsubstituted phenyl;
  • R 4 is substituted or unsubstituted alkyl; 'n' is 0 to 3.
  • a compound of Formulae (I) to (IV) or a pharmaceutically acceptable salt thereof for use in treating the diseases, disorders, syndromes or conditions associated with calcium sensing receptor (CaSR) modulators.
  • CaSR calcium sensing receptor
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of Formulae (I) to (IV) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formulae (I) to (IV), or a pharmaceutically acceptable salt thereof, for use in treating, the diseases disorders, syndromes or conditions associated with calcium sensing receptor (CaSR) modulators in a subject, in need thereof by administering to the subject, one or more compounds described herein in a therapeutically effective amount to cause modulation of such receptor.
  • CaSR calcium sensing receptor
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formulae (I) to (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable stereoisomer, thereof together with a pharmaceutically acceptable excipient.
  • halogen or halo means fluorine, chlorine, bromine, or iodine.
  • alkyl refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molecule by a single bond, for example (Ci- C 6 )alkyl or (Ci-C4)alkyl, representative groups include e.g., methyl, ethyl, n-propyl, 1- methylethyl (isopropyl), n-butyl, n-pentyl, 1, 1-dimethylethyl (t-butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched.
  • alkenyl refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond.
  • alkenyl groups include, for example (C 2 -C 6 )alkenyl, (C 2 -C4)alkenyl, ethenyl, 1-propenyl, 2-propenyl (allyl), zso-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched.
  • alkynyl refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon- carbon triple bond.
  • alkynyl groups include, for example (C 2 -C 6 )alkynyl, (C 2 -C 4 ) alkynyl, ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched.
  • alkoxy refers to an alkyl group attached via an oxygen linkage.
  • Non-limiting examples of such groups include, for example (Ci-C 6 )alkoxy, (Ci-C4)alkoxy, methoxy, ethoxy, propoxy and the like. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.
  • alkoxyalkyl refers to an alkoxy group as defined above directly bonded to an alkyl group as defined above, for example (Ci-C6)alkoxy-(Ci-C 6 )alkyl, (C 1 -C 4 )alkoxy-(C 1 - C 4 )alkyl, -CH 2 -0-CH 3 , -CH 2 -0-CH 2 CH 3 , -CH 2 CH 2 -0-CH 3 and the like.
  • haloalkyl refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above.
  • the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl.
  • a monohaloalkyl can have one iodine, bromine, chlorine or fluorine atom.
  • Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms.
  • a polyhaloalkyl is substituted with up to 12 halogen atoms.
  • a haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloro methyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like.
  • a perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms. Unless set forth or recited to the contrary, all haloalkyl groups described or claimed herein may be straight chain or branched.
  • cycloalkyl refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, such as (C 3 -Cio)cycloalkyl, (C 3 -C 6 )cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • multicyclic-cycloalkyl groups include, but are not limited to, perhydronaphththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g. spiro(4,4)non-2-yl and the like.
  • aryl refers to an aromatic radical having 6- to 14- carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydro naphthyl, indanyl, and biphenyl and the like.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g. -CH 2 C 6 H 5 and -C 2 H 4 C 6 H 5 .
  • 3 to 6 membered saturated carbocyclic ring refers to a carbocyclic ring which is a monocyclic and non-aromatic carbocyclic ring as defined herein.
  • a “carbocyclic ring” or “carbocycle” as used herein refers to a 3- to 6-membered saturated or partially unsaturated, monocyclic, fused bicyclic or spirocyclic ring containing carbon atoms, which may optionally be substituted, e.g. carbocyclic rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, etc.
  • heterocyclic ring or “heterocyclyl ring” or “heterocyclyl”, unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consists of carbon atoms and with one or more heteroatomfS) independently selected from N, O or S.
  • the heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro-ring systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states.
  • heterocyclic ring may also be fused with aromatic ring.
  • heterocyclic rings include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxo piperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydro isoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, pheno thiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetra
  • heteroaryl refers to a substituted or unsubstituted 5- to 14-membered aromatic heterocyclic ring with one or more heteroatomfS) independently selected from N, O or S.
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring may be attached by any atom of the heteroaryl ring that results in the creation of a stable structure.
  • Non-limiting examples of a heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzo thiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridiny
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an (Ci- C 6 )alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an (Ci- C 6 )alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • substituted refers to a group or moiety having one or more substituents attached to the structural skeleton of the group or moiety.
  • one representative group of moieties which may be a "substituent” is selected from hydroxy, halogen, cyano, nitro, oxo, thio, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl, (C 3 - C 7 )cycloalkyl, -C(0)OR x , -C(0)R x , -C(0)NR x R y , -NR x R y , -NR x C(0)R y , -S(0) 2 NR x R y , -OR x , -OC(0)R x , -SR X and -S(0) 2 R x ; wherein each occurrence of R x and R y are independently selected from hydrogen, halogen, (Ci-C 4 )alkyl, (Ci-C 4 )haloalkyl and (C 3 -C6)cycloalkyl.
  • the compounds of the present invention may have one or more chiral centers.
  • the absolute stereochemistry at each chiral center may be 'R' or 'S'.
  • the compounds of the invention include all diastereomers, enantiomers and mixtures thereof. Unless specifically mentioned otherwise, reference to one stereoisomer applies to any of the possible stereoisomers. Whenever the stereoisomeric composition is unspecified, it is to be understood that all possible stereoisomers are included.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations.
  • enantiomer refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
  • chiral center refers to a carbon atom to which four different groups are attached.
  • diastereomers refers to stereo isomers which are not enantiomers.
  • racemate or “racemic mixture” refer to a mixture of equal parts of enantiomers.
  • a “tautomer” refers to a compound that undergoes rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula (I).
  • treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; (c) lessening the a disease disorder or condition or at least one of its clinical or subclinical symptoms or (d) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • modulate refers to an increase in the amount, quality, or effect of a particular activity or function of the receptor.
  • it includes agonists, partial agonists and allosteric modulators of calcium sensing receptor (CaSR) of the present invention.
  • Such modulation may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway.
  • allosteric modulators of calcium-sensing receptor refers to the ability of a compound that binds to calcium sensing receptors and induces a conformational change that reduces the threshold for calcium sensing receptor activation by the endogenous ligand Ca 2+ depending on the concentration of the compound exposed to the calcium-sensing receptor.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a disease, disorder, syndrome or condition, is sufficient to cause the effect in the subject which is the purpose of the administration.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • the compounds of the invention may form salts with acid or base.
  • the compounds of invention may be sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate.
  • Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic acid addition salts formed by addition of acids including hydrochloride salts.
  • Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic base addition salts formed by addition of bases.
  • the compounds of the invention may also form salts with amino acids. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for Example by reacting sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • the invention extends to these stereoisomeric forms and to mixtures thereof.
  • the different stereoisomeric forms of the invention may be separated from one another by a method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis or chiral HPLC (high performance liquid chromatography. Tautomeric forms and mixtures of compounds described herein are also contemplated.
  • compositions containing the compounds of the Formulae (I) to (III), or pharmaceutically acceptable salts thereof disclosed herein.
  • the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to modulate calcium sensing receptor (CaSR) mediated diseases described herein when administered to a subject.
  • CaSR calcium sensing receptor
  • the subjects contemplated include, for Example, a living cell and a mammal, including human mammal.
  • the compound of the invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient includes pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
  • suitable carriers or excipients include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing.
  • the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • the pharmaceutical compositions described herein may be prepared by conventional techniques known in the art.
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container, for Example, in a sachet.
  • the pharmaceutical compositions may be in conventional forms, for Example, capsules, tablets, caplets, orally disintegrating tablets, aerosols, solutions, suspensions or products for topical application.
  • the route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • Solid oral Formulations include, but are not limited to, tablets, caplets, capsules (soft or hard gelatin), orally disintegrating tablets, dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Liquid Formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as pocketed tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, caplet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the total daily dose of the compounds of the invention depends, of course, on the mode of administration.
  • oral administration may require a higher total daily dose, than an intravenous (direct into blood).
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg according to the potency of the active component or mode of administration.
  • Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in subject based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects for the patient.
  • the daily dosage of the CaSR modulator can range from about 0.1 to about 30.0 mg kg.
  • Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the invention.
  • the invention provides compounds and pharmaceutical compositions thereof that are useful in treating the diseases, disorders, syndromes or conditions modulated by calcium sensing receptor (CaSR).
  • CaSR calcium sensing receptor
  • the invention further provides method of treating diseases, disorders, syndromes or conditions modulated by CaSR in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the invention.
  • the methods provided are also useful for diagnosis of conditions that can be treated by modulating CaSR for determining if a patient will be responsible to therapeutic agents.
  • the invention provides a method for the treatment of diseases, disorders or conditions through modulating CaSR.
  • a subject in need of such treatment is administered a therapeutically effective amount of a compound of Formulae (I) to (V), or a pharmaceutically acceptable salt thereof described herein.
  • the compound and pharmaceutical composition of the present invention is useful to a subject in need of the treatment having a disease, disorder, syndrome or condition characterized by one or more of the following: (a) abnormal calcium ion homeostasis, (b) an abnormal level of a messenger whose production or secretion is affected by the calcium sensing receptor (CaSR) activity or (c) an abnormal level of activity of a messenger whose function is affected by the calcium sensing receptor activity.
  • a disease, disorder, syndrome or condition characterized by one or more of the following: (a) abnormal calcium ion homeostasis, (b) an abnormal level of a messenger whose production or secretion is affected by the calcium sensing receptor (CaSR) activity or (c) an abnormal level of activity of a messenger whose function is affected by the calcium sensing receptor activity.
  • CaSR calcium sensing receptor
  • the patient has a disease, disorder, syndrome or condition characterized by an abnormal level of one or more calcium sensing receptor-regulated components and the compound is active on a CaSR of a cell including parathyroid cell, bone cells (pre-osteoclast, osteoclast, pre-osteoblast, osteoblast), juxtaglomerular kidney cell, kidney messengial cell, glomerular kidney cell, proximal tubule kidney cell, distal tubule kidney cell, cell of the thick ascending limb of Henle's loop and/or collecting duct, parafollicular cell in the thyroid (C-cell), intestinal cell, platelet, vascular smooth muscle cell, gastrointestinal tract cell, pituitary cell or hypothalamic cell.
  • the messenger of the calcium sensing receptor is Calcium.
  • the compounds of Formulae (I) to (IV), or a pharmaceutically acceptable salts thereof, being modulators of CaSR is potentially useful in treating the severity, morbidity/mortality or complications of diseases, disorders, syndromes or conditions include but are not limited to primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyper parathyroidism, chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis) parathyroid adenoma, parathyroid hyperplasia, parathyroid carcinoma, vascular & valvular calcification, abnormal calcium homeostasis such as hypercalcemia, abnormal phosphorous homeostasis such as hypophosphatemia, bone related diseases or complications arising due to hyperparathyroidism, chronic kidney disease or parathyroid carcinoma, bone loss post renal transplantation, osteitis fibrosa cystica, adynamic bone disease, renal bone diseases, cardiovascular complications arising due to hyperparathyroidism or chronic kidney disease, certain malignancies in which (Ca 2+
  • Primary hyperparathyroidism is a disorder of one or more of the parathyroid glands, resulting from a hyper function of the parathyroid glands themselves (acquired sporadically or familial) resulting in PTH over secretion which could be due to single or double adenoma, hyperplasia, multi-gland disease or rarely, carcinoma of the parathyroid glands.
  • the blood calcium rises to a level that is higher than normal (called hypercalcemia). This elevated calcium level can cause many short-term and long-term complications.
  • Secondary hyperparathyroidism occurs when a decrease in circulating levels of Ca 2+ level stimulates PTH secretion.
  • One cause of secondary hyperparathyroidism is chronic renal insufficiency (also referred to as chronic kidney disease or CKD), such as that in renal polycystic disease or chronic pyelonephritis, or chronic renal failure, such as that in hemodialysis patients (also referred to as end stage renal disease or ESRD).
  • CKD chronic kidney disease
  • CKD chronic kidney disease
  • CKD chronic kidney disease
  • CKD chronic kidney disease
  • CKD chronic kidney disease
  • CKD chronic kidney disease
  • CKD chronic kidney disease
  • CKD chronic kidney disease
  • CKD chronic kidney disease
  • CKD chronic kidney disease
  • ESRD end stage renal disease
  • Excess PTH may be produced in response to hypocalcemia resulting from low calcium intake, GI disorders, renal insufficiency, vitamin D deficiency, magnesium deficiency and renal hyper
  • the compound and composition of the present invention can be used in treating the vascular or valvular calcification in a subject.
  • administration of the compound of the invention retards or reverses the formation, growth or deposition of extracellular matrix hydroxyapatite crystal deposits.
  • administration of the compound of the invention prevents the formation, growth or deposition of extracellular matrix hydroxyapatite crystal deposits.
  • the compounds of the invention may also be used to treat atherosclerotic calcification and medial calcification and other conditions characterized by vascular calcification.
  • vascular calcification may be associated with chronic renal insufficiency or end-stage renal disease or excess calcium or PTH itself.
  • vascular calcification may be associated with pre- or post-dialysis or uremia.
  • vascular calcification may be associated with diabetes mellitus I or II.
  • vascular calcification may be associated with a cardiovascular disorder.
  • Abnormal calcium homeostasis such as hyperparathyroidism related diseases can be characterized as described in standard medical textbooks, but not limited to Harrison's Principles of Internal Medicine.
  • the compound and composition of the present invention can be used, in particular, to participate in a reduction of the serum levels in the parathyroid hormone known as PTH: these products could thus be useful for the treatment of diseases such as hyperparathyroidism.
  • Abnormal phosphorous homeostasis such as hypophosphatemia can be characterized as described in standard medical textbooks, but not limited to Harrison's Principles of Internal Medicine.
  • the compound and composition of the present invention can be used, in particular, to participate in a reduction of the serum levels in the parathyroid hormone known as PTH: these products could thus be useful for the treatment of diseases such as hypophosphatemia.
  • the podocyte diseases or disorders treated by methods of the present invention stem from the perturbations in one or more functions of podocytes.
  • functions of podocytes include: (i) a size barrier to protein; (ii) charge barrier to protein; (iii) maintenance of the capillary loop shape; (iv) counteracting the intra- glomerular pressure; (v) synthesis and maintenance of the glomerular basement membrane (GMB); (vi) production and secretion of vascular endothelial growth factor (VEGF) required for the glomerular endothelial cell (GEN) integrity.
  • VEGF vascular endothelial growth factor
  • Such disorders or diseases include but are not limited to loss of podocytes (podocytopenia), podocyte mutation, an increase in foot process width, or a decrease in slit diaphragm length.
  • the podocyte-related disease or disorder can be effacement or a diminution of podocyte density.
  • the diminution of podocyte density could be due to a decrease in a podocyte number, for example, due to apoptosis, detachment, lack of proliferation, DNA damage or hypertrophy.
  • the podocyte-related disease or disorder can be due to a podocyte injury.
  • the podocyte injury can be due to mechanical stress such as high blood pressure, hypertension, or ischemia, lack of oxygen supply, a toxic substance, an endocrinologic disorder, an infection, a contrast agent, a mechanical trauma, a cytotoxic agent (cis-platinum, adriamycin, puromycin), calcineurin inhibitors, an inflammation (e.g., due to an infection, a trauma, anoxia, obstruction, or ischemia), radiation, an infection (e.g., bacterial, fungal, or viral), a dysfunction of the immune system (e.g., an autoimmune disease, a systemic disease, or IgA nephropathy), a genetic disorder, a medication (e.g.
  • ischemia can be sickle-cell anemia, thrombosis, transplantation, obstruction, shock or blood loss.
  • the genetic disorders may include congenital nephritic syndrome of the Finnish type, the fetal membranous nephropathy or mutations in podocyte-specific proteins.
  • the compounds of the invention can be used for treating abnormal intestinal motilities disorders such as diarrhea.
  • the methods of the invention comprise administering to the subject a therapeutically effective amount of the compounds of Formula I.
  • diarrhea can be exudative diarrhea, i.e., resulting from direct damage to the small or large intestinal mucosa. This type of diarrhea can be caused by infectious or inflammatory disorders of the gut.
  • exudative diarrhea can be associated with gastrointestinal or abdominal surgery, chemotherapy, radiation treatment, inflammation or toxic traumatic injury.
  • diarrhea can be secretary, means that there is an increase in the active secretion, or there is an inhibition of absorption. There is little to no structural damage. The most common cause of this type of diarrhea is cholera.
  • diarrhea can be due to acceleration of intestinal transit (rapid transit diarrhea). Such condition may occur because the rapid flow-through impairs the ability of the gut to absorb water.
  • the compound and composition of the present invention can be used, in particular, to participate in an augmenting gastrin or gastric acid secretion to directly or indirectly benefit certain medical conditions such as but not limited to atrophic gastritis or to improve absorption of pharmacological compounds, drugs or supplements from gastro-intestinal tract by augmenting gastric acidity. It is to be understood that the invention encompasses any of the compounds of Formulae (I) to (IV), or pharmaceutically acceptable salts thereof for use in the treatment of any of the conditions disclosed herein.
  • the invention encompasses the use of any of the compounds of Formulae (I) to (IV), or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of any of the conditions disclosed herein.
  • the compounds described herein may be prepared by techniques known in the art.
  • the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme- lto Scheme-3. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the scope of the present invention.
  • Variations in reaction conditions, for Example, temperature and/or duration of the reaction which may be used as known in the art, are also within the scope of the present invention. All the isomers of the compounds in described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
  • the compound of Formula- 1 is reacted with 2-bromoethanol to afford compound of Formula-2, which is treated with methane sulfonyl chloride (MsCl) in presence of base to give compound of Formula-3.
  • MsCl methane sulfonyl chloride
  • the compound of Formula-3 reacts with (R)- l -(3- methoxyphenyl) ethanamine (Formula-4) (wherein X is H or F) to give compound of Formula-5.
  • Compound of Formula-5 is reacted with compound of Formula-6 to give compound of formula-7 which is hydrolysed in the presence of LiOH to give compound of Formula- 1 a.
  • the compound of formula- lb is prepared as shown in scheme-2.
  • the compound of formula- 1 is reacted with j?-methoxybenzylchloride and CS 2 CO 3 to give compound of formula-8.
  • Compound of formula-8 is treated with BISPIN and PdCl 2 (dppf) to give compound of formula-9.
  • Compound of formula-9 undergoes Suzuki coupling reaction with compound of formula- 10 in presence of PdCl 2 (dppf) to give compound of formula- 1 1.
  • Debenzylation of formula- 1 1 using Pd-c and ammonium formate to give compound of formula- 12.
  • Compound of formula- 12 is reacted with 2-bromoethanol followed by methanesulfonyl chloride to afford compound of formula- 13.
  • the compound of Formula-Ic is prepared by using scheme-3.
  • the compound of Formula 15 is reacted with compound of Formula- 16 in the presence of Pd catalyst to give compound of Formula- 17.
  • This compound of Formula- 17 is reacted with 2-bromoethanol to give compound of formula- 18.
  • Compound of formula- 18 then reacted with MsCl to afford compound of formula- 19.
  • the compound of formula- 19 is reacted with compound of Formula-4 to give compound of formula-20 which is hydrolyzed to give compound of Formula-Ic.
  • Step-2 2-(3-Bromo-5-(trifluoromethyl)phenoxy)ethyl methanesulfonate
  • Step-3 (i?)-2-(3-bromo-5-(trifluoromethyl)phenoxy)-N-( 1 -(3-bromo-5-methoxy phenyl) ethyl)ethanamine
  • the titled compound was prepared as described in Bioorg. Med. chem. Lett. (2005), 15, 4961-4966.
  • Step-1 To a well stirred solution of the above Step-1 (1.0 g, 3.3 mmol) in DMF (10 mL) was added, DBU (1.1 equiv) under nitrogen and the mixture was stirred for 5 h at 140 °C. Progress of the reaction was monitored by TLC. It was then cooled, slowly quenched with ice cold water and extracted with Ethyl acetate (50 mL X 2). The organic phase was separated, dried, concentrated under vacuum and purified by flash column chromatography to afford the desired bicyclic titled compound (0.35 g, 37%) as an off white solid.
  • Step-3 Ethyl 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-2- carboxylate
  • Step-3 compound (220 mg, 0.78 mmol), Potassium acetate (230 mg, 2.3 mmol), BISPIN (296 mg, 1.2 mmol) in 1,4-dioxane (5 mL) were charged under nitrogen and degassed for 20 min.
  • PdCl 2 (dppf) 28.4 mg, 0.04 mmol was added and the reaction mixture was heated to 100 °C for 4 h. Progress of the reaction was monitored by TLC after that it was diluted with Ethyl acetate (50 mL) and filtered. The filtrate was then concentrated under reduced pressure and purified by flash column chromatography using Ethyl acetate-Hexanes to give titled compound (0.2 g, 78%).
  • Step-2 Methyl 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo [&]thiophene- 2-carboxylate
  • Methyl 5-bromo-3-methylbenzo[&]thiophene-2-carboxylate (0.95 g, 3.3 mmol)
  • Potassium acetate 1.0 g, 10 mmol
  • 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.27 g, 5.0 mmol)
  • 1,4-dioxane 25 mL
  • Step-2 Ethyl 3-methyl-4-oxo-6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-4H- chromene-2-Carboxylate
  • the titled compound was prepared as described in Org.Lett.,(2003), 5, 3753-3754.
  • Step-2 l-(5-Bromo-2-hydroxy-3-methylphenyl)propan-l-one
  • the formed precipitate was filtered, dissolved in water, separated, acidified to pH ⁇ 2 and extracted with DCM (2 X 100 mL). The combined extracts were dried and evaporated to give the crude compound that was purified by column chromatography to give titled compound (1.88 g, 48%) as an off-white solid.
  • Step-4 Ethyl 3,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4H- chromene-2-carboxylate
  • the titled compound was prepared as described in Tetrahedron Letters (2003), 44, 1755- 1758.
  • Step- 1 5 -Bromo-2- ( 1 -iminoethyl)phenol
  • Step-2 7-Bromo-4-methyl-2-oxo-2H-chromene-3-carboxylic acid
  • Step-1 compound (1.85 g, 8.6 mmol) was dissolved in Ethanol (10 mL) and to this, 2,2- dimethyl-l,3-dioxane-4,6-dione (1.56 g, 10.8 mmol) was added.
  • the reaction mixture was stirred for 5 h under reflux. Then, it was cooled, concentrated, and proportioned between 5% NaHC0 3 (25 mL) and Ethyl acetate (50 mL).
  • the aqueous phase was acidified (IN HCl) to afford white precipitate that was filtered and dried to give titled compound (1.45 g, 59%) as a white solid.
  • Step-4 Methyl 4-methyl-2-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H- chromene-3-carboxylate
  • step-3 compound 0.6 g, 2.0 mmol
  • BISPIN 0.77 g, 3.0 mmol
  • Potassium acetate 0.6 g, 6.0 mmol
  • 1,4-dioxane 10 mL
  • the mixture was degassed for 10 min, and PdCl 2 (dppf) (75 mg, 0.1 mmol) was added to it, and heated to 100 °C for 2 h. Progress of the reaction was monitored by TLC. It was diluted with Ethyl acetate (50 mL), filtered, concentrated and purified by column chromatography using Ethyl acetate:Hexanes to furnish titled compound (0.4 g, 59%) as pale yellow oil.
  • Step-2 Ethyl 3-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline-2- carboxylate
  • Step-1 Ethyl 5-bromo-l -methyl- l -indole-2-carboxylate
  • Step-2 Ethyl l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole-2- carboxylate
  • Step-2 Ethyl 5-bromobenzo[d]oxazole-2-carboxylate
  • Step-3 Ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[d]oxazole-2-carboxylate
  • Step-1 Methyl 5-bromobenzofuran-2-carboxylate To a solution of 4-bromobenzofuran-2-carboxylic acid (0.5 g, 2.1 mmol) in Methanol (10 mL) was added, SOCl 2 (0.2 mL, 3.1 mmol) at 0 °C drop-wise and the reaction mixture was heated to 60 °C for 4 h. After completion (TLC), it was concentrated and diluted with ice cold water. The aqueous layer was extracted with Ethyl acetate (3 X 10 mL), washed with water, dried and concentrated under reduced pressure to give titled compound (0.4 g, 76%). Step-2: Methyl 5-(4,4,5,5-tetrameth l-l,3,2-dioxaborolan-2-yl)benzofuran-2-carboxylate
  • Step-1 Ethyl 6-bromobenzo[JJthiazole-2-carbox late
  • Step-2 Ethyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[JJthiazole-2- carboxylate
  • Step-4 Methyl 3-methyl-6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzo [&]thiophene- 2-carboxylate
  • methyl 6-bromo-3-methylbenzo[&]thiophene-2- carboxylate 0.4 g, 1.4 mmol
  • BISPIN 0.5 g, 2.1 mmol
  • Potassium acetate 0.4 g, 4.2 mmol
  • 1,4-dioxane 10 ml
  • Step-2 Ethyl 6-bromo-4-oxo-4H-chromene-2-carboxylate
  • Step-3 Ethyl 4-oxo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4H-chromene-2- carboxylate
  • ethyl 6-bromo-4-oxo-4H-chromene-2-carboxylate 0.5 g, 1.75 mmol
  • 4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxa borolan-2-yl)- 1,3,2-dioxaborolane 0.7 g, 2.6 mmol
  • Potassium acetate 0.515 g, 5.25 mmol
  • 1,4- dioxane 10 mL).
  • Step-2 Methyl 6-bromo-4-oxo-l,4-dihydroquinoline-2-carboxylate
  • Step-4 Methyl 4-methoxy-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline-2- carboxylate
  • methyl 6-bromo-4-methoxyquinoline-2-carboxylate (0.2 g, 0.7 mmol), BISPIN (0.26 g, 1.0 mmol), Potassium acetate (0.2 g, 2.0 mmol) and 1,4-dioxane (10 mL) were charged under nitrogen and the mixture was degassed for 20 min. Then, PdCl 2 (dppf) (0.02 g, 0.03 mmol) was added to it. The reaction was heated to 100 °C for 2 h.
  • the titled compound was prepared as described in . Org. Chem. (2007), 72, 4276-4279.
  • Step-2 6-Bromo-l-methyl-4-oxo-l,4-dihydroquinoline-2-carboxylate
  • Step-3 Methyl 1 -methyl-4-oxo-6-(4,4,5 ,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 ,4-dihydro quinoline-2-carboxylate
  • Step-2 l-(3-Fluoro-5-methoxyphenyl)ethanone
  • Step-3 (E)-l-(3-Fluoro-5-methoxyphenyl)ethanone (9-benzyl oxime
  • Step-4 l-(3-Fluoro-5-methoxyphenyl)ethanamine
  • Step-1 l-Bromo-3-((4-methoxybenzyl)oxy)-5-(trifluoromethyl)benzene
  • Step-2 2-(3-((4-Methoxybenzyl)oxy)-5-(trifluoromethyl)phenyl)-4,4,5,5-tetra methyl- 1,3,2- dioxaborolane
  • Step-3 To a stirred solution of Step-3 (1.1 g, 2.5 mmol) in Methanol (20 mL) were added, ammonium formate (0.8 g, 12.7 mmol), Pd-C (0.14 g, 1.3 mmol) and the reaction mixture was allowed to heat to 60 °C and stirred for 3 h. After completion, the mixture was cooled to RT, diluted with Ethyl acetate (100 mL) and filtered. The filtrate was collected, concentrated and purified by flash chromatography to yield the titled compound (0.6 g, 76%) as an oil.
  • Step-4 To a stirred solution of Step-4 (0.4 g, 1.3 mmol) in DMF (10 mL) was added, Cs 2 C0 3 (1.7 g, 5.1 mmol) and the mixture was heated to 70 °C for 1 h. Then, 2-bromoethanol (0.3 g, 2.6 mmol) was added and the reaction mixture was further heated to 70 °C overnight. After completion of reaction (TLC), it was diluted with ice water (50 mL), extracted with Ethyl acetate (75 mL X 2), washed with water, and brine. The combined organic layers were dried, filtered and concentrated under reduced pressure to give crude product that was purified by flash column chromatography to give the desired alcohol derivative (0.33 g, 72%) as off white solid.
  • Step-6 Methyl 3-methyl-6-(3-(2-((methylsulfonyl)oxy)ethoxy)-5-(trifluoromethyl)phenyl) picolinate
  • step 5 To a stirred solution of the alcohol derivative (step-5) (0.25 g, 0.7 mmol) and DIPEA (0.4 mL, 2.1 mmol) in DCM (10 mL) was slowly added, MsCl (0.08 mL, 1.1 mmol) at 0 °C and the reaction mixture was stirred for 2 h while allowing it to attain RT. After completion (TLC), it was diluted with DCM (100 mL), washed with water and brine. The organic layers were separated, dried, filtered and concentrated to afford the titled compound (0.25 g, 82%) as yellow solid.
  • the titled compound was prepared by following a procedure as described in scheme-3 using Intermediate-35a.
  • Example-1 (i?)-5-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl) phenyl)-3 -methyl benzofuran-2-carboxylic acid
  • Example- 18 (i?)- l-(3-Methoxyphenyl)-N-(2-(3-(quinolin-6-yl)-5-(trifluoromethyl)phenoxy) ethyl)ethanamine
  • Example-20 l-(3-Fluoro-5-methoxyphenyl)-N-(2-(3-(2-methoxypyrimidin-5-yl)-5-(trifluoro methyl)phenoxy)ethyl)ethanamine
  • Example-21 (i?)-6-(3-(2-((l-(3-Fluoro-5-methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoro methyl)phenyl)-3-methylpicolinic acid
  • Example-22 (Z?)-7-(3-(2-((l-(3-Methoxy phenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl) phenyl)-3-methylbenzo[&]thiophene-2-carboxylic acid
  • Certain illustrative compounds within the scope of the invention are screened for CaSR activity according to the procedure given below.
  • the screening of the compounds may also be carried by other methods and procedures known to skilled in the art.
  • the ability of the compounds to modulate Calcium sensing receptor is determined by measuring an increase in intracellular calcium [Ca 2+ ]i.
  • Stably transfected HEK293 cells expressing hCaSR_pTriEx-3 hygro vector are developed. Cells are grown overnight on a 96- well plate to 80% confluency in Ham's F12 containing 20% FBS at 37°C, 5% C0 2 . Subsequently, cells are washed extensively with 20mM HEPES buffer containing 126mM NaCl 2 , ImM MgCl 2 and 4mM KC1 to remove serum components that might interfere with the assay.
  • Cells are loaded with calcium sensing Fluo4NW dye in HEPES base buffer containing 0.1% BSA and lmg/ml glucose for 30 minutes to measure changes in intracellular calcium.
  • the activities of the compounds are measured in FLIPR using 0.3mM CaCl 2 in 20mM HEPES base buffer.
  • the effectiveness of the compound to modulate receptor activity is determined by calculating the EC 50 responses for that compound in an 8-point assay and plotted using GraphPad Prism 5.
  • the compounds prepared were tested using the above assay procedure and the results obtained are given below.
  • the EC 50 (nM) values of few representative compounds are set forth in Table- 12.
  • the above in-vitro assay method shows that the compounds of the invention were found to exhibit agonistic activity for CaSR, thereby showing utility for treating diseases, disorders associated with the modulation of CaSR.
  • mice were fed with 0.75% adenine diet for a period of 28 days for development of chronic kidney disease (CKD). After measurement of plasma PTH on day 28, animals were randomized based on plasma PTH (intact PTH) levels before using them for the study. Overnight fasted animals were bled retro-orbitally to collect basal blood sample (0.5 ml). Rats were dosed orally with vehicle and with test compounds Formulated in PEG 300:PG:Captisol (20: 15:65). Six to eight animals were used in each group then compounds of the invention were administered at 1 mg/kg dose. Post 2 h oral dosing animals were fed with feed and water ad libitum.
  • CKD chronic kidney disease
  • Plasma PTH was measured using sandwich ELISA kits (Immunotopics, USA). Percentage suppression of plasma PTH was calculated with respect to individual basal untreated values by using the following Formula
  • the above in-vivo method shows that the compounds of the invention were found to exhibit suppress plasma PTH levels, thereby showing utility for treating diseases, disorders associated with the modulation of CaSR.

Abstract

The invention relates to heterocyclic compounds of Formula (I) and their pharmaceutically acceptable salts, wherein the substituents are as described herein, and their pharmaceutical compositions for use in medicine for the treatment of diseases or disorders associated with the modulation of calcium sensing receptor modulators (CaSR), like e.g. hyperparathyroidism, chronic renal failure and chronic kidney disease and their complications.

Description

HETEROCYCLIC COMPOUNDS AS CALCIUM SENSING RECEPTOR MODULATORS FOR THE TREATMENT OF HYPERPARATHYROIDISM, CHRONIC RENAL FAILURE AND CHRONIC KIDNEY DISEASE
Related applications
The present application claims the benefit of priority to Indian Provisional Patent Application No. 1428/MUM/2014 filed on April 21, 2014 and the entire provisional specifications are incorporated herein by reference.
Field of the Invention
The present invention relates to substituted heterocyclic compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions for treating the diseases, disorders, syndromes or conditions associated with the modulation of calcium sensing receptors (CaSR). The invention also relates to methods of treating the diseases disorders, syndromes or conditions associated with the modulation of calcium sensing receptors (CaSR). The invention also relates to process for the preparation of the compounds of the invention.
Background of the invention
Ca2+ has been known to be an intracellular second messenger, with the molecular identification of an extracellular calcium sensing receptor (CaSR), it has further opened the possibility that Ca2+ might also function as a messenger outside the cells. Information about the local changes in extracellular concentration of Ca2+ is conveyed to the interior of many types of cells through this unique receptor.
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. 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). The reduction in serum calcium leads to the secretion of PTH. Consequently, PTH secretion leads to conservation of serum Ca + by increasing kidney retention and intestinal absorption of Ca2+. This happens indirectly through the PTH-induced synthesis of the active vitamin D metabolite, 2,5-dihydroxyvitamin D. 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 breakdown 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 CaSR.
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 hypocalcaemia.
Small molecules that are positive allosteric modulators called 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.
WO 2013/124828, WO 2013/002329, WO 2013/136288, US 2014/0080770, US 2014/01554161, 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 applications disclose the compounds related to calcium sensing receptors (CaSR) for the treatment of various diseases mediated by CaSR. And also . Med. Chem. (2006), 49, 5119-5128 discloses the compounds related to calcium sensing receptors (CaSR).
Summary of the Invention
In accordance with one aspect, the invention provides compounds having the structure of Formula (I),
Figure imgf000005_0001
wherein, ring A is selected from oxazole, isooxazole, imidazole, pyrazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzoxadiazole, chromene, quinazoline, quinoline, indole, pyrimidine and pyridine;
Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, -C(0)OH, -C(0)0-alkyl, -C(0)NH-alkyl, -S(0)2-alkyl, -S(0)2NH-alkyl, -(CRaRb)i_ 3C(0)OH, and -(CRaRb)i_3C(0)0-alkyl; R2 is substituted or unsubstituted aryl; wherein the aryl is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
R3 which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, -CN, -C(0)OH, -C(0)0-alkyl, -OR4, -NR5R6, and - NR6C(0)R7-, C(0)NR5R6, -S(0)2-alkyl, -S(0)2NH-alkyl, -(CRaRb)i_3C(0)OH and -(CRaRb)i_ 3C(0)0-alkyl or two R3 groups together with the carbon atom to which they are attached form oxo (C=0);
Ra and R , which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or Ra and R , together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 6 membered saturated carbocyclic ring;
R4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; R5 and R6 are same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl;
R is substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl;
'n' is an integer ranging from 0 to 3, both inclusive; wherein the substituents for substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted haloalkyl are one or more same or different and independently selected from the group consisting of hydroxy, halogen, carboxy, cyano, nitro, oxo (=0), thio (=S), alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroaryl alkyl, -C(0)ORx, -C(0)Ry, -C(S)Ry, -C(0)NRxRz, -NRxC(0)NRxRz, - N(Rx)S(0)2Ry, -NRXRZ, -NRxC(0)Ry, -NRxC(S)Ry, -NRXC(S)NRXRZ, -S(0)2NRxRz, -ORx, - OC(0)Ry, -C(RaRb)i-3 C(0)ORx, -C(RaRb)i-3C(0)NRxRz, -OC(RaRb)2-3-ORx, -OC(RaRb)2-3- NRXRZ, -OC(RaRb)2-3 S(O)0-2Ry, - C(RaRb)i-3-NRxRz, -C(RaRb)i-3-S(O)0-2Ry, -OC(RaRb)i-3- C(0)NRxRz, -OC(RaRb)i-3-C(0)ORx, and -S(O)0-2Ry; Rx, which may be same or different at each occurrence, is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl;
Ry, which may be same or different at each occurrence, is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; and
Rz, which may be same or different at each occurrence, is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; or Rx and Rz together with the nitrogen atom to which they are attached form a substituted or unsubstituted, saturated or unsaturated 4 to 8 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds; or pharmaceutically acceptable salt thereof.
In accordance with another aspect, the invention provides compounds having the structure of Formula (I),
Figure imgf000007_0001
wherein, ring A is heteroaryl selected from oxazole, isooxazole, imidazole, pyrazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole and benzoxadiazole; Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, -C(0)OH, -C(0)0-alkyl, -C(0)NH-alkyl, -S(0)2-alkyl, -S(0)2NH-alkyl, -(CRaRb)i_3C(0)OH, and -(CRaRb)i_3C(0)0-alkyl; R2 is substituted or unsubstituted aryl; wherein the aryl is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
R3i which may be same or different at each occurrence, is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, -CN, -C(0)OH, -C(0)0-alkyl, -OR4, -NR5R6, and -NR6C(0)R7-, C(0)NR5R6, -S(0)2-alkyl, -S(0)2NH-alkyl, -(CRaRb)i_3C(0)OH, and -(CRaRb)i_3C(0)0- alkyl;
Ra and Rb, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or Ra and Rbi together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 6 membered saturated carbocyclic ring;
R4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and substituted or unsubstituted cycloalkyl;
R5 and R6 are same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl;
R is substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; and
'n' is an integer ranging from 0 to 3, both inclusive; or pharmaceutically acceptable salt thereof.
In accordance with one embodiment, the invention provides compounds having the structure of Formula (II)
Figure imgf000009_0001
wherein, ring A is heterocyclyl selected from isooxazole, benzofuran, benzothiophene, benzothiazole, chromene, quinazoline, quinoline, indole, pyrimidine and pyridine; Ri is halogen, substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl;
R2 is substituted or unsubstituted phenyl;
R3 which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted alkyl, -C(0)OH, -OR4 or two R3 groups together with the carbon atom to which they are attached form oxo (C=0);
R4 is substituted or unsubstituted alkyl;
'n' is an integer ranging from 0 to 3, both inclusive; and wherein the substituents for substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted haloalkyl are one or more same or different and independently selected from the group consisting of hydroxy, halogen, carboxy, cyano, nitro, oxo (=0), thio (=S), alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroaryl alkyl, -C(0)ORx, -C(0)Ry, -C(S)Ry, -C(0)NRxRz, -NRxC(0)NRxRz, - N(Rx)S(0)2Ry, -NRXRZ, -NRxC(0)Ry, -NRxC(S)Ry, -NRXC(S)NRXRZ, -S(0)2NRxRz, -ORx, - OC(0)Ry, -C(RaRb)i_3 C(0)ORx, -C(RaRb)i_3C(0)NRxRz, -OC(RaRb)2_3-ORx, -OC(RaRb)2_3- NRXRZ, -OC(RaRb)2_3 S(O)0-2Ry, - C(RaRb)i_3-NRxRz, -C(RaRb)i_3-S(O)0-2Ry, -OC(RaRb)i_3- C(0)NRxRz, -OC(RaRb)i_3-C(0)ORx, and -S(O)0-2Ry; Rx, which may be same or different at each occurrence, is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl;
Ry, which may be same or different at each occurrence, is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; and
Rz, which may be same or different at each occurrence, is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; or Rx and Rz together with the nitrogen atom to which they are attached form a substituted or unsubstituted, saturated or unsaturated 4 to 8 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds; or pharmaceutically acceptable salt thereof.
According to another embodiment, there are provided compounds having the structure of Formula (III)
Figure imgf000010_0001
wherein, ring A is selected from benzofuran, benzothiophene, benzothiazole, chromene, and quinazoline;
R3 which may be same or different at each occurrence, is independently selected from substituted or unsubstituted alkyl, -C(0)OH,-OR4 or two R3 groups together with the carbon atom to which they are attached form oxo (C=0);
R4 is substituted or unsubstituted alkyl; and
'n' is an integer ranging from 0 to 3, both inclusive; or pharmaceutically acceptable salt thereof.
According to one embodiment, there are provided compounds having the structure of Formula (IV),
Figure imgf000011_0001
(IV) wherein, ring A is selected from quinazoline, quinoline, pyrimidine and pyridine;
R3i which may be same or different at each occurrence, is independently selected from substituted or unsubstituted alkyl, -C(0)OH, -OR4; substituted or unsubstituted alkyl; and
'n' is an integer ranging from 0 to 2, both inclusive; or pharmaceutically acceptable salt thereof. According to another embodiment, there are provided compounds having the structure of Formula (I) wherein ring A is selected from:
Figure imgf000012_0001
According to another embodiment, there are provided compounds having the structure of Formula (I) wherein Ri is selected from halogen (e.g. F) and substituted or unsubstituted haloalkyl (e.g. CF3).
According to another embodiment, there are provided compounds having the structure of Formula (I) wherein R2 is selected from substituted or unsubstituted phenyl.
According to another embodiment, there are provided compounds having the structure of Formula (I) wherein 'n' is 0 to 3; R3, same or different at each occurrence, are independently selected from substituted or unsubstituted alkyl (e.g. methyl), -C(0)OH, and -OR4 or two R3 groups together with the carbon atom to which they are attached form oxo (C=0); R4 is substituted or unsubstituted alkyl (e.g. methyl).
According to another embodiment, there are provided compound having the structure of Formula (I) wherein 'n' is 0-3.
According to another embodiment, there are provided compounds having the structure of
Formula (I) wherein, ring A is
Figure imgf000012_0002
Ri is halogen (e.g. F) and substituted or unsubstituted haloalkyl (e.g. CF3); R2 is substituted or unsubstituted phenyl; R3 is selected from substituted or unsubstituted alkyl (e.g. methyl) and -OR4; R4 is substituted or unsubstituted alkyl (e.g. methyl); n is 0 to 2.
It should be understood that the Formula (I), Formula (II), Formula (III) and/or Formula (IV) structurally encompasses all tautomers, stereoisomers, enantiomers and diastereomers, including isotopes wherever applicable and pharmaceutically acceptable salts that may be contemplated from the chemical structures generally described herein.
The details of one or more embodiments of the invention set forth in the below are illustrative in nature only and not intended to limit to the scope of the invention. Other features, objects and advantages of the inventions will be apparent from the description and claims.
Compounds of the invention include, for example, compounds of the Formula (I), (II), (III) or (IV) or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of ring A, R1; R2, R3, and 'n' has any of the meanings defined hereinbefore or independently in any of paragraphs (1) to (5): 1) ring A is isooxazole, benzofuran, benzothiophene, benzothiazole, chromene, quinazoline, quinoline, indole, pyrimidine and pyridine;
2) Ri is halogen, substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl;
3) R2 is substituted or unsubstituted phenyl;
4) R3 which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted alkyl, -C(0)OH and -OR4 or two R3 groups together with the carbon atom to which they are attached form oxo (C=0);
5) 'n' is an integer ranging from 0 to 3, both inclusive.
According to another embodiment, there are provided compounds having the structure of Formula (I):
Figure imgf000014_0001
Wherein ring A is isooxazole, benzofuran, benzothiophene, benzothiazole, chromene, quinazoline, quinoline, indole, pyrimidine and pyridine; Ri is halogen, substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl; R2 is substituted or unsubstituted phenyl; R3 which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted alkyl, -C(0)OH and -OR4 or two R3 groups together with the carbon atom to which they are attached form oxo (C=0); R4 is substituted or unsubstituted alkyl; 'n' is 0 to 3.
Below are the representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention:
(i?)-5-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-3- methylbenzofuran-2-carboxylic acid,
(i?)-5-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-3- methylbenzo[&]thiophene-2-carboxylic acid, (i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-3- methyl-4-oxo-4H-chromene-2-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-3,8- dimethyl-4-oxo-4H-chromene-2-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-4- methylquinazoline-2-carboxylic acid, (i?)-7-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-4- methyl-2-oxo-2H-chromene-3-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-3- methylquinoline-2-carboxylic acid,
(i?)-5-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-l- methyl- lH-indole-2-carboxylic acid,
(i?)-5-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)benzo [JJoxazole-2-carboxylic acid,
(i?)-5-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)benzo furan-2-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)benzo [JJthiazole-2-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-3- methylbenzo[&]thiophene-2-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-4- oxo-4H-chromene-2-carboxylic acid,
(i?)-4-Methoxy-6-(3-(2-(( l-(3-methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl) phenyl)quinoline-2-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-l- methyl-4-oxo- 1 ,4-dihydroquinoline-2-carboxylic acid,
6-(3-(2-((l-(3-fluoro-5-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)- 4-methylquinazoline-2-carboxylic acid,
(i?)-2-(3-(3,5-Dimethylisoxazol-4-yl)-5-fluorophenoxy)-N-(l-(3-methoxyphenyl)ethyl) ethanamine, (i?)- l-(3-Methoxyphenyl)-N-(2-(3-(quinolin-6-yl)-5-(trifluoromethyl)phenoxy)ethyl) ethanamine, l-(3-Fluoro-5-methoxyphenyl)-N-(2-(3-(quinolin-6-yl)-5-(trifluoromethyl)phenoxy) ethyl)ethanamine, l-(3-Fluoro-5-methoxyphenyl)-N-(2-(3-(2-methoxypyrimidin-5-yl)-5-(trifluoromethyl) phenoxy)ethyl)ethanamine,
(i?)-6-(3-(2-(( l-(3-Fluoro-5-methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl) phenyl)-3-methylpicolinic acid and
(i?)-7-(3-(2-(( l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-3- methylbenzo[&]thiophene-2-carboxylic acid or pharmaceutically acceptable salt thereof.
In another aspect of the invention, there is provided a compound of Formulae (I) to (IV) or a pharmaceutically acceptable salt thereof for use as a medicament.
In another aspect of the invention, there is provided a compound of Formulae (I) to (IV) or a pharmaceutically acceptable salt thereof, for use in treating the diseases, disorders, syndromes or conditions associated with calcium sensing receptor (CaSR) modulators.
In another aspect, the invention provides a pharmaceutical composition comprising at least one compound of Formulae (I) to (IV) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of Formulae (I) to (IV), or a pharmaceutically acceptable salt thereof, for use in treating, the diseases disorders, syndromes or conditions associated with calcium sensing receptor (CaSR) modulators in a subject, in need thereof by administering to the subject, one or more compounds described herein in a therapeutically effective amount to cause modulation of such receptor.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of Formulae (I) to (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable stereoisomer, thereof together with a pharmaceutically acceptable excipient.
In another aspect of the invention, there is provided use of a compound of Formulae (I) to (IV), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating, the diseases, disorders, syndromes or conditions associated with calcium sensing receptor (CaSR) modulators.
In another aspect, there are provided process for the preparation of compounds of Formula
(la):
Figure imgf000017_0001
la wherein ring A is as defined herein above and X is H or F; the process comprising the steps of: a) reacting the compound of Formula-3 with compound of Formula-4 (wherein X is H or F) to give compound of Formula-5
Figure imgf000017_0002
3 X=H/F 5 b) reacting the compound of Formula-5 with compound of Formula-6 to give compound of formula-7,
Figure imgf000018_0001
7 c) hydrolyzing the compound of formula-7 in the presence of LiOH to give compound of Formula-la.
Figure imgf000018_0002
7 la
Detailed description of the invention
Definitions and Abbreviations: Unless otherwise stated, the following terms used in the specification and claims have the meanings as given below.
For purposes of interpreting the specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.
The terms "halogen" or "halo" means fluorine, chlorine, bromine, or iodine.
Unless otherwise stated, in the present application "oxo" means C=0 group. Such an oxo group may be a part of either a cycle or a chain in the compounds of the present invention.
The term "alkyl" refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molecule by a single bond, for example (Ci- C6)alkyl or (Ci-C4)alkyl, representative groups include e.g., methyl, ethyl, n-propyl, 1- methylethyl (isopropyl), n-butyl, n-pentyl, 1, 1-dimethylethyl (t-butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched.
The term "alkenyl" refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Non-limiting Examples of alkenyl groups include, for example (C2-C6)alkenyl, (C2-C4)alkenyl, ethenyl, 1-propenyl, 2-propenyl (allyl), zso-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched. The term "alkynyl" refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon- carbon triple bond. Non- limiting Examples of alkynyl groups include, for example (C2-C6)alkynyl, (C2-C4) alkynyl, ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched. The term "alkoxy" refers to an alkyl group attached via an oxygen linkage. Non-limiting Examples of such groups include, for example (Ci-C6)alkoxy, (Ci-C4)alkoxy, methoxy, ethoxy, propoxy and the like. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.
The term "alkoxyalkyl" refers to an alkoxy group as defined above directly bonded to an alkyl group as defined above, for example (Ci-C6)alkoxy-(Ci-C6)alkyl, (C1-C4)alkoxy-(C1- C4)alkyl, -CH2-0-CH3, -CH2-0-CH2CH3, -CH2CH2-0-CH3 and the like.
The term "haloalkyl" refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above. For example (Ci-C6)haloalkyl or (Ci-C4)haloalkyl. Suitably, the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodine, bromine, chlorine or fluorine atom. Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms. Suitably, a polyhaloalkyl is substituted with up to 12 halogen atoms. Non-limiting examples of a haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloro methyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. A perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms. Unless set forth or recited to the contrary, all haloalkyl groups described or claimed herein may be straight chain or branched.
The term "cycloalkyl" refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, such as (C3-Cio)cycloalkyl, (C3-C6)cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of multicyclic-cycloalkyl groups include, but are not limited to, perhydronaphththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g. spiro(4,4)non-2-yl and the like.
The term "aryl" refers to an aromatic radical having 6- to 14- carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydro naphthyl, indanyl, and biphenyl and the like. The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g. -CH2C6H5 and -C2H4C6H5.
"3 to 6 membered saturated carbocyclic ring" refers to a carbocyclic ring which is a monocyclic and non-aromatic carbocyclic ring as defined herein.
A "carbocyclic ring" or "carbocycle" as used herein refers to a 3- to 6-membered saturated or partially unsaturated, monocyclic, fused bicyclic or spirocyclic ring containing carbon atoms, which may optionally be substituted, e.g. carbocyclic rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, etc.
The term "heterocyclic ring" or "heterocyclyl ring" or "heterocyclyl", unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consists of carbon atoms and with one or more heteroatomfS) independently selected from N, O or S. The heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro-ring systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(S), and one or two carbon atomsfS) in the heterocyclic ring or heterocyclyl may be interrupted with -CF2-, -C(O)-, -S(O)-, S(0)2, - C(=N-(Ci-C6)alkyl)-, or -C(=N-(C3-C12) cycloalkyl), etc. In addition heterocyclic ring may also be fused with aromatic ring. Non-limiting Examples of heterocyclic rings include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxo piperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydro isoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, pheno thiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydro pyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfoneindoline, benzodioxole, tetrahydroquinoline, tetrahydrobenzopyran and the like. The heterocyclic ring may be attached by any atom of the heterocyclic ring that results in the creation of a stable structure.
The term "heteroaryl" unless otherwise specified, refers to a substituted or unsubstituted 5- to 14-membered aromatic heterocyclic ring with one or more heteroatomfS) independently selected from N, O or S. The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring may be attached by any atom of the heteroaryl ring that results in the creation of a stable structure. Non-limiting examples of a heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzo thiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like.
The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an (Ci- C6)alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an (Ci- C6)alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
Unless otherwise specified, the term "substituted" as used herein refers to a group or moiety having one or more substituents attached to the structural skeleton of the group or moiety. Such substituents include, but are not limited to hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(Ci-C6)alkyl, (C3-Ci2)cycloalkyl, heteroaryl, heterocyclic ring, heterocyclyl(Ci-C6)alkyl, hetero aryl(Ci-C6)alkyl, -C(0)ORx, -C(0)Rx, -C(S)RX, -C(0)NRxRy, -NRxC(0)NRyRz, - NRxRy, -N RxC(0)Ry, - S(0)2NRxRy, -ORx, -OC(0)Rx, -OC(0)NRxRy, RxC(0)Ry, -SRX, and -S(0)2Rx; wherein each occurrence of Rx, Ry and Rz are independently selected from hydrogen, halogen, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C3-Ci2)cycloalkyl and aryl.
For example one representative group of moieties which may be a "substituent" is selected from hydroxy, halogen, cyano, nitro, oxo, thio, (Ci-C4)alkyl, (Ci-C4)haloalkyl, (C3- C7)cycloalkyl, -C(0)ORx, -C(0)Rx, -C(0)NRxRy, -NRxRy, -NRxC(0)Ry, -S(0)2NRxRy, -ORx, -OC(0)Rx, -SRX and -S(0)2Rx; wherein each occurrence of Rx and Ry are independently selected from hydrogen, halogen, (Ci-C4)alkyl, (Ci-C4)haloalkyl and (C3-C6)cycloalkyl.
It is to be understood that the aforementioned "substituted" groups cannot be further substituted. For Example, when the substituent on "substituted alkyl" is "aryl" or "alkenyl", the aryl or alkenyl cannot be substituted aryl or substituted alkenyl respectively.
The compounds of the present invention may have one or more chiral centers. The absolute stereochemistry at each chiral center may be 'R' or 'S'. The compounds of the invention include all diastereomers, enantiomers and mixtures thereof. Unless specifically mentioned otherwise, reference to one stereoisomer applies to any of the possible stereoisomers. Whenever the stereoisomeric composition is unspecified, it is to be understood that all possible stereoisomers are included. The term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" refers to stereo isomers which are not enantiomers. The terms "racemate" or "racemic mixture" refer to a mixture of equal parts of enantiomers.
A "tautomer" refers to a compound that undergoes rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula (I).
The term "treating" or "treatment" of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; (c) lessening the a disease disorder or condition or at least one of its clinical or subclinical symptoms or (d) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
The term "modulate" or "modulating" or "modulation" or "modulator" refers to an increase in the amount, quality, or effect of a particular activity or function of the receptor. By way of illustration and not limitation, it includes agonists, partial agonists and allosteric modulators of calcium sensing receptor (CaSR) of the present invention. Such modulation may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway. The term "allosteric modulators of calcium-sensing receptor", refers to the ability of a compound that binds to calcium sensing receptors and induces a conformational change that reduces the threshold for calcium sensing receptor activation by the endogenous ligand Ca2+ depending on the concentration of the compound exposed to the calcium-sensing receptor. The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease, disorder, syndrome or condition, is sufficient to cause the effect in the subject which is the purpose of the administration. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
Pharmaceutically Acceptable Salts:
The compounds of the invention may form salts with acid or base. The compounds of invention may be sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic acid addition salts formed by addition of acids including hydrochloride salts. Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic base addition salts formed by addition of bases. The compounds of the invention may also form salts with amino acids. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for Example by reacting sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. With respect to the overall compounds described by the Formulae (I) to (V) herein, the invention extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the invention may be separated from one another by a method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis or chiral HPLC (high performance liquid chromatography. Tautomeric forms and mixtures of compounds described herein are also contemplated.
Screening of compounds of invention for calcium sensing receptor (CaSR) modulation activity can be achieved by using various in vitro and in vivo protocols mentioned herein below or methods known in the art.
Pharmaceutical Compositions The invention relates to pharmaceutical compositions containing the compounds of the Formulae (I) to (III), or pharmaceutically acceptable salts thereof disclosed herein. In particular, pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula (I) described herein and at least one pharmaceutically acceptable excipient (such as a carrier or diluent). Preferably, the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to modulate calcium sensing receptor (CaSR) mediated diseases described herein when administered to a subject.
The subjects contemplated include, for Example, a living cell and a mammal, including human mammal. The compound of the invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. The pharmaceutically acceptable excipient includes pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity. Examples of suitable carriers or excipients include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
The pharmaceutical compositions described herein may be prepared by conventional techniques known in the art. For Example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for Example, in a sachet. The pharmaceutical compositions may be in conventional forms, for Example, capsules, tablets, caplets, orally disintegrating tablets, aerosols, solutions, suspensions or products for topical application.
The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
Solid oral Formulations include, but are not limited to, tablets, caplets, capsules (soft or hard gelatin), orally disintegrating tablets, dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Liquid Formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as pocketed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, caplet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
For administration to subject patients, the total daily dose of the compounds of the invention depends, of course, on the mode of administration. For Example, oral administration may require a higher total daily dose, than an intravenous (direct into blood). The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg according to the potency of the active component or mode of administration.
Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in subject based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects for the patient. For Example, the daily dosage of the CaSR modulator can range from about 0.1 to about 30.0 mg kg. Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the invention.
Methods of Treatment
In another aspect, the invention provides compounds and pharmaceutical compositions thereof that are useful in treating the diseases, disorders, syndromes or conditions modulated by calcium sensing receptor (CaSR). The invention further provides method of treating diseases, disorders, syndromes or conditions modulated by CaSR in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the invention.
In another aspect of the invention, the methods provided are also useful for diagnosis of conditions that can be treated by modulating CaSR for determining if a patient will be responsible to therapeutic agents.
In another aspect, the invention provides a method for the treatment of diseases, disorders or conditions through modulating CaSR. In this method, a subject in need of such treatment is administered a therapeutically effective amount of a compound of Formulae (I) to (V), or a pharmaceutically acceptable salt thereof described herein.
The compound and pharmaceutical composition of the present invention is useful to a subject in need of the treatment having a disease, disorder, syndrome or condition characterized by one or more of the following: (a) abnormal calcium ion homeostasis, (b) an abnormal level of a messenger whose production or secretion is affected by the calcium sensing receptor (CaSR) activity or (c) an abnormal level of activity of a messenger whose function is affected by the calcium sensing receptor activity. In one aspect, the patient has a disease, disorder, syndrome or condition characterized by an abnormal level of one or more calcium sensing receptor-regulated components and the compound is active on a CaSR of a cell including parathyroid cell, bone cells (pre-osteoclast, osteoclast, pre-osteoblast, osteoblast), juxtaglomerular kidney cell, kidney messengial cell, glomerular kidney cell, proximal tubule kidney cell, distal tubule kidney cell, cell of the thick ascending limb of Henle's loop and/or collecting duct, parafollicular cell in the thyroid (C-cell), intestinal cell, platelet, vascular smooth muscle cell, gastrointestinal tract cell, pituitary cell or hypothalamic cell. The messenger of the calcium sensing receptor is Calcium.
The compounds of Formulae (I) to (IV), or a pharmaceutically acceptable salts thereof, being modulators of CaSR, is potentially useful in treating the severity, morbidity/mortality or complications of diseases, disorders, syndromes or conditions include but are not limited to primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyper parathyroidism, chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis) parathyroid adenoma, parathyroid hyperplasia, parathyroid carcinoma, vascular & valvular calcification, abnormal calcium homeostasis such as hypercalcemia, abnormal phosphorous homeostasis such as hypophosphatemia, bone related diseases or complications arising due to hyperparathyroidism, chronic kidney disease or parathyroid carcinoma, bone loss post renal transplantation, osteitis fibrosa cystica, adynamic bone disease, renal bone diseases, cardiovascular complications arising due to hyperparathyroidism or chronic kidney disease, certain 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. Primary hyperparathyroidism, is a disorder of one or more of the parathyroid glands, resulting from a hyper function of the parathyroid glands themselves (acquired sporadically or familial) resulting in PTH over secretion which could be due to single or double adenoma, hyperplasia, multi-gland disease or rarely, carcinoma of the parathyroid glands. As a result, the blood calcium rises to a level that is higher than normal (called hypercalcemia). This elevated calcium level can cause many short-term and long-term complications.
Secondary hyperparathyroidism occurs when a decrease in circulating levels of Ca2+ level stimulates PTH secretion. One cause of secondary hyperparathyroidism is chronic renal insufficiency (also referred to as chronic kidney disease or CKD), such as that in renal polycystic disease or chronic pyelonephritis, or chronic renal failure, such as that in hemodialysis patients (also referred to as end stage renal disease or ESRD). Excess PTH may be produced in response to hypocalcemia resulting from low calcium intake, GI disorders, renal insufficiency, vitamin D deficiency, magnesium deficiency and renal hypercalciuria. Tertiary hyperparathyroidism may occur after a long period of secondary hype parathyroidism and hypercalcemia.
In one aspect, the compound and composition of the present invention can be used in treating the vascular or valvular calcification in a subject. In one aspect, administration of the compound of the invention retards or reverses the formation, growth or deposition of extracellular matrix hydroxyapatite crystal deposits. In another aspect of the invention, administration of the compound of the invention prevents the formation, growth or deposition of extracellular matrix hydroxyapatite crystal deposits. In one aspect, the compounds of the invention may also be used to treat atherosclerotic calcification and medial calcification and other conditions characterized by vascular calcification. In one aspect, vascular calcification may be associated with chronic renal insufficiency or end-stage renal disease or excess calcium or PTH itself. In another aspect, vascular calcification may be associated with pre- or post-dialysis or uremia. In a further aspect, vascular calcification may be associated with diabetes mellitus I or II. In yet another aspect, vascular calcification may be associated with a cardiovascular disorder. Abnormal calcium homeostasis such as hyperparathyroidism related diseases can be characterized as described in standard medical textbooks, but not limited to Harrison's Principles of Internal Medicine. The compound and composition of the present invention can be used, in particular, to participate in a reduction of the serum levels in the parathyroid hormone known as PTH: these products could thus be useful for the treatment of diseases such as hyperparathyroidism.
Abnormal phosphorous homeostasis such as hypophosphatemia can be characterized as described in standard medical textbooks, but not limited to Harrison's Principles of Internal Medicine. The compound and composition of the present invention can be used, in particular, to participate in a reduction of the serum levels in the parathyroid hormone known as PTH: these products could thus be useful for the treatment of diseases such as hypophosphatemia.
In one aspect, the podocyte diseases or disorders treated by methods of the present invention stem from the perturbations in one or more functions of podocytes. These functions of podocytes include: (i) a size barrier to protein; (ii) charge barrier to protein; (iii) maintenance of the capillary loop shape; (iv) counteracting the intra- glomerular pressure; (v) synthesis and maintenance of the glomerular basement membrane (GMB); (vi) production and secretion of vascular endothelial growth factor (VEGF) required for the glomerular endothelial cell (GEN) integrity. Such disorders or diseases include but are not limited to loss of podocytes (podocytopenia), podocyte mutation, an increase in foot process width, or a decrease in slit diaphragm length. In one aspect, the podocyte-related disease or disorder can be effacement or a diminution of podocyte density. In one aspect, the diminution of podocyte density could be due to a decrease in a podocyte number, for example, due to apoptosis, detachment, lack of proliferation, DNA damage or hypertrophy.
In one aspect, the podocyte-related disease or disorder can be due to a podocyte injury. In one aspect, the podocyte injury can be due to mechanical stress such as high blood pressure, hypertension, or ischemia, lack of oxygen supply, a toxic substance, an endocrinologic disorder, an infection, a contrast agent, a mechanical trauma, a cytotoxic agent (cis-platinum, adriamycin, puromycin), calcineurin inhibitors, an inflammation (e.g., due to an infection, a trauma, anoxia, obstruction, or ischemia), radiation, an infection (e.g., bacterial, fungal, or viral), a dysfunction of the immune system (e.g., an autoimmune disease, a systemic disease, or IgA nephropathy), a genetic disorder, a medication (e.g. anti-bacterial agent, anti-viral agent, anti-fungal agent, immunosuppressive agent, anti-inflammatory agent, analgesic or anticancer agent), an organ failure, an organ transplantation, or uropathy. In one aspect, ischemia can be sickle-cell anemia, thrombosis, transplantation, obstruction, shock or blood loss. In one aspect, the genetic disorders may include congenital nephritic syndrome of the Finnish type, the fetal membranous nephropathy or mutations in podocyte-specific proteins.
In one aspect, the compounds of the invention can be used for treating abnormal intestinal motilities disorders such as diarrhea. The methods of the invention comprise administering to the subject a therapeutically effective amount of the compounds of Formula I. In a further aspect, diarrhea can be exudative diarrhea, i.e., resulting from direct damage to the small or large intestinal mucosa. This type of diarrhea can be caused by infectious or inflammatory disorders of the gut. In one aspect, exudative diarrhea can be associated with gastrointestinal or abdominal surgery, chemotherapy, radiation treatment, inflammation or toxic traumatic injury. In another aspect, diarrhea can be secretary, means that there is an increase in the active secretion, or there is an inhibition of absorption. There is little to no structural damage. The most common cause of this type of diarrhea is cholera. In another aspect, diarrhea can be due to acceleration of intestinal transit (rapid transit diarrhea). Such condition may occur because the rapid flow-through impairs the ability of the gut to absorb water.
The compound and composition of the present invention can be used, in particular, to participate in an augmenting gastrin or gastric acid secretion to directly or indirectly benefit certain medical conditions such as but not limited to atrophic gastritis or to improve absorption of pharmacological compounds, drugs or supplements from gastro-intestinal tract by augmenting gastric acidity. It is to be understood that the invention encompasses any of the compounds of Formulae (I) to (IV), or pharmaceutically acceptable salts thereof for use in the treatment of any of the conditions disclosed herein.
It is to be understood that the invention encompasses the use of any of the compounds of Formulae (I) to (IV), or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of any of the conditions disclosed herein.
All of the patent, patent application and non-patent publications referred to in this specification are incorporated herein by reference in their entireties.
General Methods of Preparation The compounds described herein may be prepared by techniques known in the art. In addition, the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme- lto Scheme-3. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the scope of the present invention. Variations in reaction conditions, for Example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the isomers of the compounds in described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
Scheme-1
Figure imgf000034_0001
The compound of Formula- 1 is reacted with 2-bromoethanol to afford compound of Formula-2, which is treated with methane sulfonyl chloride (MsCl) in presence of base to give compound of Formula-3. The compound of Formula-3 reacts with (R)- l -(3- methoxyphenyl) ethanamine (Formula-4) (wherein X is H or F) to give compound of Formula-5. Compound of Formula-5 is reacted with compound of Formula-6 to give compound of formula-7 which is hydrolysed in the presence of LiOH to give compound of Formula- 1 a.
Scheme-2
Figure imgf000035_0001
Figure imgf000035_0002
The compound of formula- lb is prepared as shown in scheme-2. The compound of formula- 1 is reacted with j?-methoxybenzylchloride and CS2CO3 to give compound of formula-8. Compound of formula-8 is treated with BISPIN and PdCl2(dppf) to give compound of formula-9. Compound of formula-9 undergoes Suzuki coupling reaction with compound of formula- 10 in presence of PdCl2(dppf) to give compound of formula- 1 1. Debenzylation of formula- 1 1 using Pd-c and ammonium formate to give compound of formula- 12. Compound of formula- 12 is reacted with 2-bromoethanol followed by methanesulfonyl chloride to afford compound of formula- 13. The compound of formula- 13 is reacted with (R)- l -(3- fluoro-5-methoxyphenyl)ethanamine (Formula-4, X = F) followed by hydrolysis using LiOH to give compound of formula-lb.
Scheme-3
Figure imgf000036_0001
The compound of Formula-Ic is prepared by using scheme-3. The compound of Formula 15 is reacted with compound of Formula- 16 in the presence of Pd catalyst to give compound of Formula- 17. This compound of Formula- 17 is reacted with 2-bromoethanol to give compound of formula- 18. Compound of formula- 18 then reacted with MsCl to afford compound of formula- 19. The compound of formula- 19 is reacted with compound of Formula-4 to give compound of formula-20 which is hydrolyzed to give compound of Formula-Ic.
Experimental
The invention is further illustrated by the following Examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. The Examples set forth below demonstrate the synthetic procedures for the preparation of the representative compounds. It is to be understood by the skilled person in the art that one of the major or minor diastereomers mentioned herein is R, R isomer and the other is R, S isomer. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention. It is to be understood that the examples of hydrochloride salts were prepared by using the similar hydrochloride salt procedure by adding HCl in suitable solvent to a corresponding free base as mentioned herein or any other procedure known in the art. The aforementioned patents and patent applications are incorporated herein by reference.
INTERMEDIATES
Intermediate-l:(i?)-2-(3-bromo-5-(trifluoromethyl)phenoxy)-N-(l-(3-bromo-5-methoxy phenyl)ethyl)ethan amine
Figure imgf000037_0001
Step-1: 2-(3-Bromo-5-(trifluoromethyl)phenoxy)ethanol
Figure imgf000037_0002
To a stirred solution of 3-bromo-5-(trifluoromethyl)phenol (5.0 g, 20.7 mmol) in DMF (50 mL) was added, CS2CO3 (13.5 g, 41.5 mmol) and the mixture was heated to 50°C for 30 min. It was cooled to RT, and then 2-bromoethanol (2.85 g, 22.8 mmol) was added and the reaction mixture was heated to 50°C overnight. After completion of reaction (TLC), it was quenched with water and extracted with Ethyl acetate (100 mL X 2). The organic layer was washed with water (50 mL), dried (Na2S04) and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using Ethyl acetate-Hexanes to furnish the desired compound (2.7g, 45%).
Step-2: 2-(3-Bromo-5-(trifluoromethyl)phenoxy)ethyl methanesulfonate
Figure imgf000037_0003
To a solution of 2-(3-bromo-5-(trifluoromethyl)phenoxy)ethanol (Intermediate 1) (2.7 g, 9.47 mmol) in DCM (20 mL) was added, DIPEA (6.62 mL, 37.9 mmol) at 0°C and the mixture was stirred for 10 min. To this, MsCl (1.1 mL, 14.2 mmol) was added and the reaction was stirred at 0°C for 2 h. TLC showed complete conversion of starting material, it was quenched with water and extracted with DCM (50 ml X 2). The organic layer was washed with water (20 mL), dried (Na2S04) and concentrated under reduced pressure to give titled compound (2.6 g, 76%).
Step-3: (i?)-2-(3-bromo-5-(trifluoromethyl)phenoxy)-N-( 1 -(3-bromo-5-methoxy phenyl) ethyl)ethanamine
To a stirred solution of 2-(3-bromo-5-(trifluoromethyl)phenoxy)ethyl methane sulfonate (Intermediate-2) (2.6 g, 7.16 mmol) in DMF (20 mL) was added, corresponding (R)-l-(3- methoxyphenyl)ethanamine (2 eq) and Na2C03 (1.5 equiv) and the reaction mixture was heated to 1 10 °C overnight. After complete conversion (TLC), it was quenched with water and extracted with DCM (50 ml X 2). The organic layer was washed with water (20 mL X 2), dried (Na2S04), concentrated and purified by column chromatography using Ethyl acetate- Hexanes to give the corresponding bromo derivative in 50-60% yield.
Intermediate-2: Ethyl 3-methyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzofuran- 2-carboxylate
Figure imgf000038_0001
The titled compound was prepared as described in Bioorg. Med. chem. Lett. (2005), 15, 4961-4966.
Step-1: Ethyl 2-(2-acetyl-4-bromophenoxy)acetate
Figure imgf000038_0002
To a mixture of l-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.3 mmol) and K2CO3 (2.6 g, 18.6 mmol) in DMF (20 mL) was added, ethyl 2-bromoacetate (1.3 mL, 11.6 mmol) under nitrogen and the reaction mixture was stirred at room temperature (RT) overnight. After completion, the mixture was poured into ice cold water, filtered and dried to furnish the titled compound (2.75 g, 98%) as pale brown solid.
Step-2: Ethyl 5-bromo-3-methylbe
Figure imgf000039_0001
To a well stirred solution of the above Step-1 (1.0 g, 3.3 mmol) in DMF (10 mL) was added, DBU (1.1 equiv) under nitrogen and the mixture was stirred for 5 h at 140 °C. Progress of the reaction was monitored by TLC. It was then cooled, slowly quenched with ice cold water and extracted with Ethyl acetate (50 mL X 2). The organic phase was separated, dried, concentrated under vacuum and purified by flash column chromatography to afford the desired bicyclic titled compound (0.35 g, 37%) as an off white solid.
Step-3: Ethyl 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-2- carboxylate
In a 50 mL sealed tube, Step-3 compound (220 mg, 0.78 mmol), Potassium acetate (230 mg, 2.3 mmol), BISPIN (296 mg, 1.2 mmol) in 1,4-dioxane (5 mL) were charged under nitrogen and degassed for 20 min. To this mixture, PdCl2(dppf) (28.4 mg, 0.04 mmol) was added and the reaction mixture was heated to 100 °C for 4 h. Progress of the reaction was monitored by TLC after that it was diluted with Ethyl acetate (50 mL) and filtered. The filtrate was then concentrated under reduced pressure and purified by flash column chromatography using Ethyl acetate-Hexanes to give titled compound (0.2 g, 78%).
Intermediate-3: Methyl 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[&] thiophene-2-carboxylate
Figure imgf000040_0001
The titled compound was prepared as described in Bioorg. Med. chem. Lett. (2012), 22, 2922-2926. Step-1: Methyl 5-bromo-3-methylbenzo[b]thiophene-2-carboxylate
Figure imgf000040_0002
Methyl 2-mercaptoacetate (2 mL, 18.4 mmol) was added drop-wise to a stirred solution of DMAP (5.6 g, 46.1 mmol) in 1,4-dioxane (25 mL) and the mixture was stirred for 15 min at RT. To this, l-(5-bromo-2-fluorophenyl)ethanone (2.0 g, 9.2 mmol) dissolved in 1,4-dioxane (10 mL) was added drop-wise and the reaction was heated to 125°C overnight. After completion, the reaction was cooled to RT, quenched with ice cold water and extracted with Ethyl acetate (100 mL X 2). The organic phase was separated, dried, concentrated and purified by column chromatography to give the desired bromo compound (0.97 g, 36%) as a white solid.
Step-2: Methyl 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo [&]thiophene- 2-carboxylate
In a 50 mL sealed tube, Methyl 5-bromo-3-methylbenzo[&]thiophene-2-carboxylate (0.95 g, 3.3 mmol), Potassium acetate (1.0 g, 10 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.27 g, 5.0 mmol), 1,4-dioxane (25 mL) were charged and the mixture was degassed with nitrogen for 20 min. To this, PdCl2(dppf) (120 mg, 0.17 mmol) was added and the reaction mixture was heated to 100 °C for 4 h. After completion (TLC), it was diluted with Ethyl acetate (50 mL) and filtered through celite pad. The filtrate was concentrated under reduced pressure and purified by column chromatography using Ethyl acetate:Hexanes to give the titled compound (0.85 g, 77%) as a white solid. Intermediate-4: Ethyl 3-methyl-4-oxo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4H- chromene-2-carboxylate
Figure imgf000041_0001
Step-1: Ethyl 6-bromo-3-methyl-4-oxo-4H-chromene-2-carboxylate
Figure imgf000041_0002
To a mixture of l-(5-bromo-2-hydroxyphenyl)propan-l-one (1.0 g, 4.4 mmol) in pyridine (3.5 mL, 43.7 mmol) was added, ethyl 2-chloro-2-oxoacetate (0.7 mL, 6.5 mmol) and the reaction mixture was heated to 100 °C overnight. It was cooled to RT, acidified (IN HCl) and extracted with DCM (2 X 50 mL). The organic layers were combined, dried and concentrated to yield crude product that was purified by column chromatography to give titled compound (0.49 g, 36%) as an off white semi-solid.
Step-2: Ethyl 3-methyl-4-oxo-6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-4H- chromene-2-Carboxylate
A 30 mL sealed tube was charged with ethyl 6-bromo-3-methyl-4-oxo-4H-chromene-2- carboxylate (0.48 g, 1.5 mmol), Potassium acetate (0.45 g, 4.6 mmol), 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetra methyl-l ,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (0.6 g, 2.3 mmol) and 1,4-dioxane (10 mL) and the mixture was degassed for 10 min. Then, PdCi2(dppf) (57 mg, 0.08 mmol) was added, and the sealed tube was heated to 100 °C for 2 h. Progress of the reaction was monitored by TLC. It was diluted with Ethyl acetate (50 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography using Ethyl acetate:Hexanes to furnish titled compound (0.38 g, 69%) as an off-white solid. Intermediate-5: Ethyl 3,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)- 4H-chromene-2-carboxylate
Figure imgf000042_0001
The titled compound was prepared as described in Org.Lett.,(2003), 5, 3753-3754.
Step-1: 4-Bromo-2-methylphenyl propionate
Figure imgf000042_0002
To a well stirred solution of 4-bromo-2-methylphenol (3.1 g, 16.6 mmol), DMAP (2.0 g, 16.6 mmol) and triethylamine (3.5 mL, 24.9 mmol) in DCM (30 mL) was added, propionyl chloride (1.8 mL, 20.7 mmol) drop-wise at 0°C under nitrogen atmosphere. After addition, reaction was allowed to stir at RT for 2 h and the progress of the reaction was monitored by TLC. It was then diluted with DCM (100 mL), washed with IN HC1 (50 mL X 3) and brine (50 mL). The organic phase was separated, dried (Na2S04) and concentrated under reduced pressure to give titled compound (3.92 g, 97%) as pale yellow oil. Step-2: l-(5-Bromo-2-hydroxy-3-methylphenyl)propan-l-one
Figure imgf000042_0003
A mixture of 4-bromo-2-methylphenyl propionate (3.9 g, 16.04 mmol) and anhydrous A1C13 (3.21 g, 24.06 mmol) was heated to 140-150 °C for 2 h. Progress of the reaction was monitored by TLC. It was cooled to RT, quenched with 5% HC1 (40 mL) and the mixture was again heated to 100 °C until the solid material dissolved. After cooling to RT, the precipitated brown oil was extracted with DCM (3 X 100 mL) and the organic layer was treated with 5N Sodium hydroxide (40 mL). The formed precipitate was filtered, dissolved in water, separated, acidified to pH ~ 2 and extracted with DCM (2 X 100 mL). The combined extracts were dried and evaporated to give the crude compound that was purified by column chromatography to give titled compound (1.88 g, 48%) as an off-white solid.
Step-3: Ethyl 6-bromo-3,8-dimethyl-4-oxo-4H-chromene-2-carboxylate
Figure imgf000043_0001
To a solution of l-(5-bromo-2-hydroxy-3-methylphenyl)propan-l-one (1.25 g, 5.14 mmol) in pyridine (20 mL) was added, ethyl 2-chloro-2-oxoacetate (1.7 mL, 15.4 mmol) at RT and the reaction mixture was allowed to heat to 100 °C for 6 h. It was cooled to RT, acidified with IN HC1 and extracted with DCM (2 X 50 mL). The organic layers were combined, dried, and concentrated to yield the crude product that was purified by column chromatography using Ethyl acetate:Hexanes system to afford titled compound (0.88 g, 52%) as white solid.
Step-4: Ethyl 3,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4H- chromene-2-carboxylate
Figure imgf000043_0002
A 50 mL sealed tube was charged with ethyl 6-bromo-3,8-dimethyl-4-oxo-4H-chromene-2- carboxylate (0.87 g, 2.7 mmol), BISPIN (1.0 g, 4.0 mmol), Potassium acetate (0.8 g, 8.0 mmol), and 1,4-dioxane (10 mL) under nitrogen. The mixture was degassed for 10 min and then, PdCi2(dppf) (0.1 g, 0.13 mmol) was added, and the reaction was heated to 100 °C for 2 h. Progress of the reaction was monitored by TLC. It was then diluted with Ethyl acetate (50 mL), filtered, concentrated and purified by column chromatography using Ethyl acetate: Hexanes system to give titled compound (0.71 g, 71 %) as an off white solid.
Intermediate-6: Ethyl 4-methyl-6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)quinazoline- 2-carboxylate
Figure imgf000044_0001
The titled compound was prepared as described in Bioorg. Med. chem. Lett. (2011), 21, 1206-1213. Step-1: Ethyl 2-((2-acetyl-4-bromophenyl)amino)-2-oxoacetate
Figure imgf000044_0002
Ethyl 2-chloro-2-oxoacetate (0.5 mL, 4.5 mmol) was added to a stirred solution of l-(2- amino-5-bromophenyl)ethanone (0.75 g, 3.5 mmol) and pyridine (0.6 mL, 7.7 mmol) in DCM (20 mL) at 0 °C under nitrogen and the reaction mixture was allowed to attain RT while stirring for 3 h. Progress of the reaction was monitored by TLC. It was concentrated, diluted with Ethyl acetate (10 mL), washed with 10% citric acid, 5% NaHC03 solution, and then brine. The organic layer was separated, dried, filtered, concentrated and purified by column chromatography to give titled compound (0.86 g, 78%) as a white solid.
Step-2: Ethyl 6-bromo-4-methylq
Figure imgf000044_0003
Ammonium acetate (2.1 g, 27.1 mmol) was added to ethyl 2-((2-acetyl-4- bromophenyl)amino)-2-oxoacetate (0.85 g, 2.7 mmol) in Acetic acid (20 mL) at RT and the reaction mixture was heated to reflux for 3 h. Progress of the reaction was monitored by TLC. After completion, it was cooled to RT and concentrated under reduced pressure. The crude product was treated with 5% NaHC03 solution and extracted with Ethyl acetate (100 mL X 3). The combined organic layers were separated, dried, filtered, concentrated and purified by column chromatography to give titled compound (0.36 g, 45%) as a pale yellow solid. Step-3: Ethyl 4-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinazoline-2- carboxylate
To a 50 mL sealed tube, ethyl 6-bromo-4-methylquinazoline-2-carboxylate (0.35 g, 1.2 mmol), BISPIN (0.45 g, 1.8 mmol), Potassium acetate (0.35 g, 3.5 mmol) and 1,4-dioxane (10 mL) were added and the mixture was degassed for 10 min. Then, PdCl2(dppf) (43 mg, 0.06 mmol) was added, and the reaction was heated to 100 °C for 2 h. Progress of the reaction was monitored by TLC. It was then diluted with Ethyl acetate (50 mL), filtered, concentrated and purified by column chromatography to afford titled compound (0.19 g, 46%) as pale yellow oil. Intermediate-7: Methyl 4-methyl-2-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 2H-chromene-3-carboxylate
Figure imgf000045_0001
The titled compound was prepared as described in Tetrahedron Letters (2003), 44, 1755- 1758.
Step- 1 : 5 -Bromo-2- ( 1 -iminoethyl)phenol
Figure imgf000045_0002
Ammonia in Methanol (2.7 mL, 18.6 mmol) was added to a well stirred solution of 4-bromo- 2-hydroxyacetophenone (2.0 g, 9.3 mmol) in Methanol (10 mL) at RT and the reaction mixture was stirred at RT overnight. It concentrated to afford titled compound (1.87 g, 94%) as yellow solid that was used as such in the next step without any purification.
Step-2: 7-Bromo-4-methyl-2-oxo-2H-chromene-3-carboxylic acid
Figure imgf000045_0003
Step-1 compound (1.85 g, 8.6 mmol) was dissolved in Ethanol (10 mL) and to this, 2,2- dimethyl-l,3-dioxane-4,6-dione (1.56 g, 10.8 mmol) was added. The reaction mixture was stirred for 5 h under reflux. Then, it was cooled, concentrated, and proportioned between 5% NaHC03 (25 mL) and Ethyl acetate (50 mL). The aqueous phase was acidified (IN HCl) to afford white precipitate that was filtered and dried to give titled compound (1.45 g, 59%) as a white solid.
Step-3: Methyl 7-bromo-4-methyl-2- 3-carboxylate
Figure imgf000046_0001
Thionyl chloride (0.6 mL, 8.1 mmol) was added drop-wise to a stirred solution of 7-bromo-4- methyl-2-oxo-2H-chromene-3-carboxylic acid ( 1.15 g, 4.1 mmol) in Methanol (25 mL) under nitrogen at RT and the reaction mixture was allowed to stir at 70 °C for 6 h. Progress of the reaction was monitored by TLC. After solvent removal, the product was diluted with water and filtered to afford titled compound (0.75 g, 62%) as an off-white solid.
Step-4: Methyl 4-methyl-2-oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H- chromene-3-carboxylate
A 50 mL sealed tube was charged with step-3 compound (0.6 g, 2.0 mmol), BISPIN (0.77 g, 3.0 mmol), Potassium acetate (0.6 g, 6.0 mmol), and 1,4-dioxane (10 mL) under nitrogen. The mixture was degassed for 10 min, and PdCl2(dppf) (75 mg, 0.1 mmol) was added to it, and heated to 100 °C for 2 h. Progress of the reaction was monitored by TLC. It was diluted with Ethyl acetate (50 mL), filtered, concentrated and purified by column chromatography using Ethyl acetate:Hexanes to furnish titled compound (0.4 g, 59%) as pale yellow oil.
Intermediate-8: Ethyl 3-methyl-6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)quinoline-2- carboxylate
Figure imgf000046_0002
The titled compound was prepared as described in heterocycles (2005), 66, 611-619. Step-1: Ethyl 6-bromo-3-methylquinoline-2-carboxylate
Figure imgf000047_0001
To a well stirred solution of 4-bromoaniline (3.0 g, 17.4 mmol) in DMSO (20 mL) was added, ethyl 2-oxoacetate (5.3 g, 26.2 mmol) and the mixture was stirred at RT for 1 h. To this, ytterbium(III)trifluromethanesulfonate (0.11 g, 0.17 mmol) was added and the reaction was heated to 90 °C overnight. After completion, it was cooled to RT, quenched with ice cold water and extracted with Ethyl acetate (100 mL X 2). The organic phase was separated, dried, concentrated and purified by column chromatography to give titled compound (0.35 g, 6.8%) as pale yellow oil.
Step-2: Ethyl 3-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline-2- carboxylate
Figure imgf000047_0002
To a well stirred solution of ethyl 6-bromo-3-methylquinoline-2-carboxylate (0.2 g, 0.7 mmol) in 1,4-dioxane (10 mL) was added, BISPIN (0.26 g, 1.0 mmol), and Potassium acetate (0.2 g, 2.0 mmol). The mixture was degassed for 10 min and then PdCl2(dppf) (0.025 g, 0.034 mmol) was added and the reaction mixture was heated to 100 °C for 3 h. After completion (TLC), it was filtered through celite, washed with Ethyl acetate (2 X 10 mL), concentrated and purified by column chromatography to afford titled compound (0.16 g, 69%) as an oil.
Intermediate-9: Ethyl l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole- 2-carboxylate
Figure imgf000048_0001
Step-1: Ethyl 5-bromo-l -methyl- l -indole-2-carboxylate
Figure imgf000048_0002
Ethyl 5-bromo-lH-indole-2-carboxylate (1.0 g, 3.7 mmol), K2CO3 (1.4 g, 10.1 mmol) and Mel (0.3 mL, 4.5 mmol) were dissolved in DMF (3 mL) and the reaction mixture was heated to 50 °C overnight. After completion, it was cooled to RT, quenched with ice cold water and extracted with Ethyl acetate (100 ml X 2). The organic phase was separated, dried, concentrated and purified by column chromatography to give titled compound (0.8 g, 76%) as pale yellow oil.
Step-2: Ethyl l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole-2- carboxylate
To a solution of ethyl 5-bromo-l -methyl- lH-indole-2-carboxylate (0.3 g, 1.0 mmol) in 1,4- dioxane (10 mL) in a 30 mL sealed tube was added, BISPIN (0.4 g, 1.6 mmol) and Potassium acetate (0.21 g, 2.1 mmol) and the mixture was degassed for 10 min. To this, PdCi2(dppf) (31 mg, 0.04 mmol) was added and the reaction was heated to 100°C for 3 h. It was then diluted with Ethyl acetate (50 mL), filtered, washed again with Ethyl acetate (2 X 10 mL). The organic layer was concentrated and purified by column chromatography using Ethyl acetate:Hexanes to afford the desired titled compound (0.32 g, 91%) as pale yellow oil.
Intermediate-10: Ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[d]oxazole-2- carboxylate
Figure imgf000048_0003
Step-1: 5-Bromobenzo[d]oxazole
Figure imgf000049_0001
A solution of 2-amino-4-bromophenol (6.0 g, 32 mmol) in triethylorthoformate (120 mL, 720 mmol) was refluxed for 1.5 h. The mixture was then cooled and the organic solvent was removed under reduced pressure to give the crude product 5.5 g that was purified by column chromatography using Ethyl acetate:Hexanes to furnish the desired titled compound (5.0 g, 79%) as pale brown solid.
Step-2: Ethyl 5-bromobenzo[d]oxazole-2-carboxylate
Figure imgf000049_0002
To a well stirred solution of 5-bromobenzo[JJoxazole (2.5 g, 12.6 mmol) in dry THF (25 mL) was added, 1M LiHMDS solution in THF (20.2 mL, 20.2 mmol) at -40 °C dropwise and the mixture was stirred for 20 mins. To this, ethyl carbonocyanidate (1.9 g, 18.9 mmol) dissolved in THF (10 mL) was added slowly so as to attain a temperature of 0 °C over a period of 1.5 h. It was again cooled to -40 °C and aq. NH4C1 solution was added. The crude product was then extracted with Ethyl acetate (2 X 100 mL), dried, concentrated and purified by column chromatography to give titled compound (0.6 g, 17.6%) as pale yellow oil.
Step-3: Ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[d]oxazole-2-carboxylate
To a solution of ethyl 5-bromobenzo[JJoxazole-2-carboxylate (0.6 g, 2.2 mmol) in 1,4- dioxane (10 mL) was added, BISPIN (0.85 g, 3.3 mmol), Potassium acetate (0.65 g, 6.7 mmol) and the mixture was degassed for 10 min. To this, PdCi2(dppf) (0.08 g, 0.1 mmol) was added and the reaction was heated to 100 °C for 2 h. The crude product was filtered, washed with Ethyl acetate (2 X 20 mL), evaporated and purified by column chromatography using Ethyl acetate:Hexanes to afford titled compound (0.52 g, 73.8%) as pale yellow oil. Intermediate-11: Methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-2- carboxylate
Step-1: Methyl 5-bromobenzofuran-2-carboxylate
Figure imgf000050_0001
To a solution of 4-bromobenzofuran-2-carboxylic acid (0.5 g, 2.1 mmol) in Methanol (10 mL) was added, SOCl2 (0.2 mL, 3.1 mmol) at 0 °C drop-wise and the reaction mixture was heated to 60 °C for 4 h. After completion (TLC), it was concentrated and diluted with ice cold water. The aqueous layer was extracted with Ethyl acetate (3 X 10 mL), washed with water, dried and concentrated under reduced pressure to give titled compound (0.4 g, 76%). Step-2: Methyl 5-(4,4,5,5-tetrameth l-l,3,2-dioxaborolan-2-yl)benzofuran-2-carboxylate
Figure imgf000050_0002
In a 30 mL sealed tube, methyl 5-bromobenzofuran-2-carboxylate (0.3 g, 1.2 mmol), BISPIN (0.45 g, 1.7 mmol), Potassium acetate (0.35 g, 3.5 mmol), and 1,4-dioxane (10 mL) were charged and the mixture was degassed 20 min. To this, PdCl2(dppf) (35 mg, 0.05 mmol) was added and the reaction mixture was heated to 100 °C for 2 h. TLC showed complete conversion hence it was diluted with Ethyl acetate (20 mL) and filtered through celite. The filtrate was concentrated and purified by column chromatography using Ethyl acetate:Hexanes to furnish titled compound (0.2 g, 56.3%) as white solid.
Intermediate-12: Ethyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[JJthiazole-2- carboxylate
Figure imgf000050_0003
Step-1: Ethyl 6-bromobenzo[JJthiazole-2-carbox late
Figure imgf000051_0001
To a solution of 6-bromobenzo[JJthiazole (0.5 g, 2.3 mmol) in dry THF (15 mL) at -78 °C was added, LiHMDS (3.27 mL, 3.3 mmol) drop-wise and the mixture was stirred at -78 °C 30 min. To this, ethyl carbonocyanidate (0.35 g, 3.5 mmol) was added drop-wise over a period of 5 min. The reaction was stirred for additional 30 min at -78 °C. After completion (TLC), it was quenched with aq. NH4C1 solution (10 mL) and allowed to attain RT. Then it was extracted with Ethyl acetate (3 X 10 mL) and the combined organic layers were dried and concentrated. The crude product obtained was purified by column chromatography to give the titled compound (0.28 g, 42%).
Step-2: Ethyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[JJthiazole-2- carboxylate
Figure imgf000051_0002
To a 30 mL sealed tube, ethyl 6-bromobenzo[JJthiazole-2-carboxylate (0.27 g, 0.9 mmol), BISPIN (0.33 g, 1.4 mmol), Potassium acetate (0.28 g, 2.8 mmol) and 1,4-dioxane (10 mL) were added and the mixture was degassed for 20 min. To this, PdCl2(dppf) (0.03 g, 0.04 mmol) was added and the reaction was heated to 100 °C for 2 h. TLC showed complete conversion of starting material so it was diluted with Ethyl acetate (15 mL) and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography to afford titled compound (0.18 g, 57%).
Intermediate-13: Methyl 3-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo [&]thiophene-2-carboxylate
Figure imgf000052_0001
The titled compound was prepared as described in Bioorg. Med. Chem. Lett. (2012), 22, 2922-2926. Step-1: 4-Bromo-2-fluoro-N-methoxy-N-methylbenzamide
Figure imgf000052_0002
To a stirred solution of 4-bromo-2-fluorobenzoic acid (1.0 g, 4.6 mmol) in DMF (10 mL) were added, HOBT (1.0 g, 6.85 mmol), DIPEA (4 mL, 22.8 mmol) and EDC (1.3 g, 6.85 mmol) under nitrogen at RT and the mixture was stirred for 10 min. Then, N,(9-dimethyl hydroxylamine hydrochloride (0.45 g, 4.6 mmol) was added and the reaction was stirred at RT overnight. After complete conversion (TLC), it was quenched with water (20 mL) and extracted with Ethyl acetate (3 X 20 mL). The organic layer was washed with water (20 mL), dried, and concentrated. The crude product obtained was then purified by column chromatography to furnish the titled compound (1.0 g, 84%). Step-2: l-(4-Bromo-2-fluorophenyl)ethanone
Figure imgf000052_0003
To a solution of 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide (0.8 g, 3.05 mmol) in dry THF (10 mL) at 0 °C was added, MeMgBr (2.0 mL, 6.1 mmol) drop- wise and the reaction was stirred at RT for 3 h. After completion (TLC), it was cooled to 0°C, slowly quenched with aq. NaHC03 solution (10 mL) and extracted with Ethyl acetate (3 X 20 mL). The combined organic layers were dried, concentrated and purified by column chromatography using Ethyl acetate:Hexanes as solvent system to afford titled compound (0.4 g, 60.4%).
Step-3: Methyl 6-bromo-3-methylbenzo[&]thiophene-2-carboxylate
Figure imgf000053_0001
Methyl 2-mercaptoacetate (0.24 mL, 2.3 mmol) was added drop-wise to a well stirred solution of DMAP (0.9 g, 7.4 mmol) in DMF (5 mL) at RT and the mixture was stirred for 15 min. To this, l-(4-bromo-2-fluorophenyl)ethanone (0.4 g, 1.8 mmol) in DMF (5 mL) was added drop-wise and the reaction was heated to 100 °C for 8 h. TLC showed complete conversion of starting material. It was cooled to 0 °C, slowly diluted with ice cold water (10 mL) and extracted with Ethyl acetate (3 X 10 mL). The combined organic layers were dried, concentrated and the crude product obtained was purified by column chromatography to give titled compound (0.4 g, 76%).
Step-4: Methyl 3-methyl-6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzo [&]thiophene- 2-carboxylate A 30 mL sealed tube was charged with methyl 6-bromo-3-methylbenzo[&]thiophene-2- carboxylate (0.4 g, 1.4 mmol), BISPIN (0.5 g, 2.1 mmol), Potassium acetate (0.4 g, 4.2 mmol) and 1,4-dioxane (10 ml) and the mixture was degassed with nitrogen for 20 min. To this, PdCl2(dppf) (0.04 g, 0.056 mmol) was added and the reaction was heated to 100 °C for 2 h. After TLC showed complete conversion, it was diluted with Ethyl acetate (50 mL), filtered, concentrated and purified by column chromatography to furnish desired compound (0.4 g, 86%) as white semi-solid.
Intermediate-14: Ethyl 4-oxo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4H- chromene-2-carboxylate
Figure imgf000054_0001
The titled compound was prepared as described in Tetrahedron (2005), 61(31), 7366-7377. Step-1: Ethyl 4-(5-bromo-2-hydroxyphenyl)-2,4-dioxobutanoate
Figure imgf000054_0002
To a solution of diethyl oxalate (1.9 mL, 13.9 mmol) in Ethanol (20 mL) was added, l-(5- bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.3 mmol), followed by portion-wise addition of NaOEt (1.9 g, 27.9 mmol) and the reaction was heated to 70 °C overnight. It was cooled to RT, solvent was evaporated, water was added, acidified with HCl (2 N) and extracted with Ethyl acetate (100 mL X 2). The organic layer was separated, washed with brine, dried (Na2S04), and concentrated to give crude product that was purified by column chromatography to give titled compound (0.81 g, 27%) as yellow semi-solid.
Step-2: Ethyl 6-bromo-4-oxo-4H-chromene-2-carboxylate
Figure imgf000054_0003
H2SO4 (0.96 mL, 18.1 mmol) was added drop-wise to ethyl 4-(5-bromo-2-hydroxy phenyl)- 2,4-dioxobutanoate (1.9 g, 6.0 mmol) and the mixture was heated to 70 °C for 30 min. Progress of the reaction was monitored by TLC. It was cooled to RT, poured into ice water and then extracted with Ethyl acetate (100 mL X 3). The combined organic layers were dried and concentrated to yield the crude product that was purified by column chromatography using Ethyl acetate:Hexanes to afford titled compound (0.53 g, 29%) as an off-white solid.
Step-3: Ethyl 4-oxo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4H-chromene-2- carboxylate A 50 mL sealed tube was charged with ethyl 6-bromo-4-oxo-4H-chromene-2-carboxylate (0.5 g, 1.75 mmol), 4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxa borolan-2-yl)- 1,3,2-dioxaborolane (0.7 g, 2.6 mmol), Potassium acetate (0.515 g, 5.25 mmol), and 1,4- dioxane (10 mL). The mixture was degassed for 10 mins and then, PdCl2(dppf) (0.06 g, 0.09 mmol) was added. The reaction mixture was heated to 110 °C for 4 h. It was then diluted with Ethyl acetate (50 mL), filtered, concentrated and purified by column chromatography to yield titled compound (0.5 g, 91%) as pale yellow oil.
Intermediate-15: Methyl 4-methoxy-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) quinoline -2-carboxylate
Figure imgf000055_0001
The titled compound was prepared as described in . Org. Chem. (2007), 72, 4276-4279. Step-1: Dimethyl 2-((4-bromophenyl)amino)but-2-enedioate
Figure imgf000055_0002
To a solution of 4-bromoaniline (2.0 g, 11.6 mmol) in Methanol (20 mL) was added dimethyl but-2-ynedioate (1.65 g, 11.6 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h. TLC showed complete conversion and the crude product was concentrated under reduced pressure that was used as such in the next step (3.0 g, 82%).
Step-2: Methyl 6-bromo-4-oxo-l,4-dihydroquinoline-2-carboxylate
Figure imgf000055_0003
Eaton's reagent (15 ml, 9.5 mmol) was added to dimethyl 2-((4-bromophenyl)amino)but-2- enedioate (3.0 g, 9.5 mmol) and reaction was heated to 50 °C for 2 h r. TLC showed complete conversion and the mixture was cooled to 0 °C, quenched with aq. Na2C03 solution to give solid compound that was filtered and dried under vacuum to give titled compound (2.5 g, 93%).
Step-3: Methyl 6-bromo-4-methoxyquinoline-2-carbox late
Figure imgf000056_0001
To a solution of methyl 6-bromo-4-oxo- 1 ,4-dihydroquinoline-2-carboxylate (0.6 g, 2.1 mmol) in DMF (25 mL) at 0 °C was added, NaH (0.18 g, 7.4 mmol) and the mixture was stirred at 0 °C for 10 min. Then, methyl iodide (0.16 mL, 2.5 mmol) was added to it and the reaction was stirred at 0 °C for 3 h. TLC showed complete conversion, it was quenched with ice water (25 mL) and extracted with Ethyl acetate (3 X 20 mL). The organic layer was washed with brine, dried, concentrated and by column chromatography to give desired compound (0.2 g, 33%). Step-4: Methyl 4-methoxy-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline-2- carboxylate
To a 30 mL sealed tube, methyl 6-bromo-4-methoxyquinoline-2-carboxylate (0.2 g, 0.7 mmol), BISPIN (0.26 g, 1.0 mmol), Potassium acetate (0.2 g, 2.0 mmol) and 1,4-dioxane (10 mL) were charged under nitrogen and the mixture was degassed for 20 min. Then, PdCl2(dppf) (0.02 g, 0.03 mmol) was added to it. The reaction was heated to 100 °C for 2 h. TLC showed complete conversion therefore it was diluted with Ethyl acetate (20 mL), filtered, concentrated and purified by column chromatography to give titled compound (0.2 g, 86%). Intermediate-16: Methyl l-methyl-4-oxo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- l,4-dihydroquinoline-2-carboxylate
Figure imgf000057_0001
The titled compound was prepared as described in . Org. Chem. (2007), 72, 4276-4279.
Step-1: Dimethyl 2-((4-bromophenyl)(methyl)amino)but-2-enedioate
Figure imgf000057_0002
To a solution of 4-bromo-N-methylaniline (1.0 g, 5.4 mmol) in Methanol (10 mL) at 0 °C was added, dimethyl but-2-ynedioate (0.7 g, 5.4 mmol) and the reaction was stirred at RT for 2 h. TLC showed complete conversion hence it was concentrated under reduced pressure. The crude product obtained was used as such used in next step (1.5 g, 85%).
Step-2: 6-Bromo-l-methyl-4-oxo-l,4-dihydroquinoline-2-carboxylate
Figure imgf000057_0003
Eaton's reagent (1.8 mL, 4.6 mmol) was added to dimethyl 2-((4-bromophenyl) (methyl)amino)but-2-enedioate (1.5 g, 4.6 mmol) and the reaction mixture was heated to 50 °C for 2 h. TLC showed complete starting material so it was cooled to 0 °C and quenched with saturated NaHC03 solution. Aq. layer was then extracted with Ethyl acetate (3 X 10 mL). The combined organic layers were dried, and concentrated under reduced pressure. The crude product obtained was purified by column chromatography to furnish titled compound (0.8 g, 46%).
Step-3: Methyl 1 -methyl-4-oxo-6-(4,4,5 ,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 ,4-dihydro quinoline-2-carboxylate
A 30 mL sealed tube was charged with methyl 6-bromo-l-methyl-4-oxo-l,4- dihydroquinoline-2-carboxylate (0.29 g, 0.98 mmol), BISPIN (0.37 g, 1.5 mmol), Potassium acetate (0.3 g, 2.9 mmol) and 1,4-dioxane (10 ml) and the mixture was degassed for 20 min. To this, PdCl2(dppf) (0.039 g, 0.04 mmol) was added and the reaction was heated to 100 °C for 2 h. After complete conversion (TLC), it was diluted with Ethyl acetate (50 mL) and filtered through celite. The filtrate was collected, concentrated and purified by column chromatography using Ethyl acetate :Hexanes to afford titled compound (0.2 g, 59.5%).
Intermediate-17: (i?)-Methyl 5-(3-(2-((l-(3-methoxyphenyl)ethyl)amino)ethoxy)-5- (trifluoro methyl)phenyl)-3-methylbenzofuran-2-carboxylate
Figure imgf000058_0001
In a 50 mL sealed tube, Intermediate- 1 (150 mg, 0.36 mmol), Na2C03 (95 mg, 0.9 mmol), ethyl 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-2-carboxylate (Intermediate-2) (178 mg, 0.54 mmol), 1,4-dioxane (5 mL), and H20 (0.5 mL) were charged and degassed with nitrogen for 20 min. Then, PdCl2(dppf) (13 mg, 0.018 mmol) was added, and the reaction mixture was heated to 100 °C overnight. TLC showed complete conversion, and the mixture was filtered through celite and washed by Ethyl acetate (20 mL X 3). Filtrate collected was concentrated and purified by flash column chromatography to give the desired ester derivative of Intermediate-17 (0.19 g, 98%) as pale yellow oil. Intermediates 18 to 32 given in Table- 1 were prepared by following the similar procedure as described in Intermediate -17.
Table-1:
Figure imgf000059_0001
Figure imgf000060_0001
Intermediate- 10
Intermediate- 13
Figure imgf000062_0001
Intermediate-6
Intermediate-33a: l-(3-Fluoro-5-methoxyphenyl)ethanamine
Figure imgf000063_0001
Step-1: 3-Fluoro-N,5-dimethoxy-N-methylbenzamide
Figure imgf000063_0002
To a stirred solution of 3-fluoro-5-methoxybenzoic acid (2.0 g, 11.8 mmol) in DMF (20 mL) were added, HOBT (2.7 g, 17.6 mmol), DIPEA (10.3 ml, 59 mmol), EDC (3.4 g, 17.6 mmol) under nitrogen and the mixture was stirred at RT for 10 min. To this, Ν,Ο- dimethylhydroxylamine hydrochloride (1.4 g, 14.1 mmol) was added and the reaction was stirred for 4 hr at RT. TLC showed complete conversion so it was quenched with water and extracted with Ethyl acetate (3 X 10 mL). The organic layer was washed with water, dried and concentrated under reduced pressure to afford the titled compound (2.0 g, 80%).
Step-2: l-(3-Fluoro-5-methoxyphenyl)ethanone
Figure imgf000063_0003
To a solution of 3-fluoro-N,5-dimethoxy-N-methylbenzamide (2.0 g, 9.4 mmol) in dry THF (30 mL) at 0 °C was added, methylmagnesium bromide (9.4 ml, 28 mmol) dropwise and the reaction mixture was stirred at RT overnight. After TLC showed complete conversion, it was cooled to 0 °C and slowly quenched with aq. NH4C1 chloride solution (50 mL). The organic layer was separated and extracted with Ethyl acetate (3 X 20 mL), dried, concentrated, and purified by column chromatography to yield titled compound (1.4 g, 89%).
Step-3: (E)-l-(3-Fluoro-5-methoxyphenyl)ethanone (9-benzyl oxime
Figure imgf000064_0001
To a solution of l-(3-fluoro-5-methoxyphenyl)ethanone (1.4 g, 8.3 mmol) in Ethanol (10 mL) and water (2 mL) was added, Sodium acetate (0.75 g, 9.2 mmol), (9-benzylhydroxyl amine hydrochloride (2.0 g, 12.5 mmol) and the reaction mixture was heated to 80 °C for 3 h. After complete conversion (TLC), it was concentrated. The aqueous layer was extracted with Ethyl acetate (3 X 5 mL) and washed with brine, dried and concentrated under reduced pressure to give crude product that was used as such in the next step (2.0 g, 88%).
Step-4: l-(3-Fluoro-5-methoxyphenyl)ethanamine
Figure imgf000064_0002
To a solution of (E)- l-(3-fluoro-5-methoxyphenyl)ethanone-0-benzyl oxime (2.0 g, 7.3 mmol) in dry THF (20 mL) was added, BH3.DMS (12.8 ml, 25.6 mmol) and the reaction mixture was stirred at RT overnight. After TLC showed complete reaction, it was diluted with (1 : 1 , HC1:H20; 25 mL) and the reaction was heated to 50 °C for 1 h. Then it was cooled to 0 °C and pH was adjusted to 10 with 2N Sodium hydroxide solution. Aqueous layer was extracted with Ethyl acetate (3 X 10 mL), dried and concentrated under reduced pressure. The crude product was then purified by column chromatography to furnish titled compound (0.98 g, 79%).
Intermediate-33b: Methyl 3-methyl-6-(3-(2-((methylsulfonyl)oxy)ethoxy)-5-(trifluoro methyl)phenyl)picolinate
Figure imgf000065_0001
Step-1: l-Bromo-3-((4-methoxybenzyl)oxy)-5-(trifluoromethyl)benzene
Figure imgf000065_0002
To a stirred solution of 3-bromo-5-(trifluoromethyl)phenol (3.0 g, 12.45 mmol) in DMF (30 mL) was added, potassium carbonate (6.9 g, 49.8 mmol) and the mixture was stirred for 10 mins. Then, l-(chloromethyl)-4-methoxybenzene (2.5 mL, 18.7 mmol) was added and the reaction mixture was heated to 60 °C overnight. After completion, the mixture was diluted with ice water (100 mL), extracted with Ethyl acetate (250 mL X 2), washed with water, brine and the combined organic layers were dried and filtered. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography to furnish the titled compound (4.1 g, 91%) as colorless oil.
Step-2: 2-(3-((4-Methoxybenzyl)oxy)-5-(trifluoromethyl)phenyl)-4,4,5,5-tetra methyl- 1,3,2- dioxaborolane
Figure imgf000065_0003
To a stirred solution of (4.0 g, 11.1 mmol) in 1,4-Dioxane (10 mL) were added, BISPIN (4.2 g, 16.6 mmol), potassium acetate (3.26 g, 33.2 mmol) and the mixture was degassed for 10 mins. To this, PdC12(dppf) was added (0.24 g, 0.33 mmol) and the reaction mixture was heated to 100 °C for 2 h. It was diluted with Ethyl acetate (100 mL), filtered, concentrated and purified by flash chromatography to give titled compound (4.0 g, 88%) as white solid. Step-3: Methyl 6-(3-((4-methoxybenzyl)oxy)-5-(trifluoromethyl)phenyl)-3-methyl picolinate
Figure imgf000066_0001
To a stirred solution of methyl 6-chloro-3-methylpicolinate (1.0 g, 5.4 mmol) in 1,4-Dioxane (20 mL) were added, 2-(3-((4-Methoxybenzyl)oxy)-5-(trifluoromethyl)phenyl)-4,4,5,5-tetra methyl- 1, 3, 2-dioxaborolane (3.5 g, 8.6 mmol), Na2C03 (1.7 g, 16.2 mmol) in H20 (2 mL) and the mixture was degassed for 10 mins. To this, PdCl2(dppf) (0.16 g, 0.22 mmol) was added and the reaction mixture was heated to 100 °C overnight. After completion (TLC), it was diluted with Ethyl acetate (50 mL) and filtered through a pad of celite. The filtrate was collected, concentrated and purified by flash chromatography using Ethyl acetate: Hexanes to afford the titled compound (1.2 g, 51%) as white solid.
Step-4: Methyl 6-(3-hydroxy-5-(trifluoromethyl)phenyl)-3-methylpicolinate
Figure imgf000066_0002
To a stirred solution of Step-3 (1.1 g, 2.5 mmol) in Methanol (20 mL) were added, ammonium formate (0.8 g, 12.7 mmol), Pd-C (0.14 g, 1.3 mmol) and the reaction mixture was allowed to heat to 60 °C and stirred for 3 h. After completion, the mixture was cooled to RT, diluted with Ethyl acetate (100 mL) and filtered. The filtrate was collected, concentrated and purified by flash chromatography to yield the titled compound (0.6 g, 76%) as an oil.
Step-5: Methyl 6-(3-(2-hydroxyethoxy)-5-(trifluoromethyl)phenyl)-3-methyl picolinate
Figure imgf000067_0001
To a stirred solution of Step-4 (0.4 g, 1.3 mmol) in DMF (10 mL) was added, Cs2C03 (1.7 g, 5.1 mmol) and the mixture was heated to 70 °C for 1 h. Then, 2-bromoethanol (0.3 g, 2.6 mmol) was added and the reaction mixture was further heated to 70 °C overnight. After completion of reaction (TLC), it was diluted with ice water (50 mL), extracted with Ethyl acetate (75 mL X 2), washed with water, and brine. The combined organic layers were dried, filtered and concentrated under reduced pressure to give crude product that was purified by flash column chromatography to give the desired alcohol derivative (0.33 g, 72%) as off white solid.
Step-6: Methyl 3-methyl-6-(3-(2-((methylsulfonyl)oxy)ethoxy)-5-(trifluoromethyl)phenyl) picolinate
Figure imgf000067_0002
To a stirred solution of the alcohol derivative (step-5) (0.25 g, 0.7 mmol) and DIPEA (0.4 mL, 2.1 mmol) in DCM (10 mL) was slowly added, MsCl (0.08 mL, 1.1 mmol) at 0 °C and the reaction mixture was stirred for 2 h while allowing it to attain RT. After completion (TLC), it was diluted with DCM (100 mL), washed with water and brine. The organic layers were separated, dried, filtered and concentrated to afford the titled compound (0.25 g, 82%) as yellow solid.
Intermediate-33: (i?)-Methyl 6-(3-(2-(( 1 -(3-fluoro-5-methoxyphenyl)ethyl)amino)ethoxy)- 5-(trifluoromethyl)phenyl)-3-methylpicolinate
Figure imgf000068_0001
Mixture of Intermediate-33b (0.08 g, 0.18 mmol) and (i?)-l-(3-fluoro-5-methoxyphenyl) ethanamine (Intermediate-33a) (0.05 g, 0.3 mmol) was heated to 110 °C for 8 h. The reaction was cooled to RT, diluted with CHC13 (25 mL) and again heated to 75 °C for 30 min. It was again cooled, diluted with chloroform (75 mL) and washed with water. The organic phase was separated, dried and concentrated. The crude product obtained was purified by column chromatography using Ethyl acetate; Hexanes to afford the Intermediate-33 (45 mg, 48%) as pale yellow oil.
Intermediate-34 : 6-(4,4, 5 ,5 -Tetrameth l- 1 , 3 ,2-dioxaborolan-2-yl)quinoline
Figure imgf000068_0002
In a 30 mL sealed tube, 6-bromoquinoline (1.0 g, 4.8 mmol), BISPIN (1.8 g, 7.2 mmol), Potassium acetate (1.4 g, 14.4 mmol) and 1,4-dioxane (10 mL) were charged and the mixture was degassed for 20 min. To this, PdCi2(dppf) (0.14 g, 0.19 mmol) was added and the reaction was heated to 100 °C for 2 h. TLC showed complete conversion hence it was diluted with Ethyl acetate (50 mL), filtered, concentrated and purified by column chromatography to give desired titled compound (1.0 g, 82%).
Intermediate-35a: Methyl 7-bromo-3-methylbenzo[&]thiophene-2-carboxylate
Figure imgf000068_0003
The titled compound was prepared as described in Bioorg. Med. Chem. Lett. (2012),22, 2922-2969. Intermediate-35b: (Z?)-methyl 7-(3-(2-((l-(3-methoxyphenyl)ethyl)amino)ethoxy)-5-(tri fluoromethyl)phenyl)-3-methylbenzo[&]thiophene-2-carboxylate
Figure imgf000069_0001
The titled compound was prepared by following a procedure as described in scheme-3 using Intermediate-35a.
EXAMPLES
Example-1: (i?)-5-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl) phenyl)-3 -methyl benzofuran-2-carboxylic acid
Figure imgf000069_0002
To a stirred solution of Intermediate- 17 (0.18 g, 0.33 mmol) in THF:H20 (5 mL, 10: 1) was added, LiOH (7 mg, 1 mmol) and the reaction mixture was stirred at RT for 2 days. After completion (TLC), it was concentrated, diluted with water (2 mL) and washed with diethyl ether (5 mL X 2). The aqueous phase was separated, acidified with 10% citric acid and filtered to give the title compound (65 mg, 38%) as white solid; XH NMR (400 MHz, dMSO- d6) δ 8.00 (d, = 1.9 Hz, 1H), 7.72 (dd, = 8.7 & 1.9 Hz, 1H), 7.65-7.48 (m, 3H), 7.30 (t, = 7.9 Hz, 1H), 7.23 (t, = 1.9 Hz, 1H), 7.14-7.02 (m, 2H), 6.87 (dd, = 8.3 & 2.5 Hz, 1H), 4.30 (t, = 5.6 Hz, 2H), 4.12 (q, = 6.7 Hz, 1H), 3.75 (s, 3H), 3.03 (dt, = 11.3 & 5.1 Hz, 1H), 2.93-2.80 (m, 1H), 2.54 (s, 3H), 1.46 (d, = 6.5 Hz, 3H); m/z: 514 (M+l)+. The below Examples 2 to 16 were prepared by following the similar ester hydrolysis procedure as described in Example- 1 using corresponding ester intermediate
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
F3C Ή NMR (400 MHz, DMSO-d6) δ
8.55 (d, = 2.0 Hz, 1H), 8.37 (dd, = 8.8 & 2.0 Hz, 1H), 8.10 (d, = 8.8 Hz, 1H), 7.87-7.67 (m, 2H), 7.32 (s, 1H), 6.91-6.83 (m, 2H), 6.69 (dt, / =
16 32 1 1.0 & 2.3 Hz, 1H), 4.26 (t, = 5.5
Hz, 2H), 3.92 (q, = 6.5 Hz, 1H),
6-(3-(2-(( l -(3-Fluoro-5-methoxy 3.75 (s, 3H), 3.03 (s, 3H), 2.89 (dt, phenyl)ethyl)amino)ethoxy)-5-(tri = 1 1.5 & 5.4 Hz, 1H), 2.79 (dt, = fluoromethyl)phenyl)-4-methyl 12.1 & 5.5 Hz, 1H), 1.34 (d, = 6.5 quinazoline-2-carboxylic acid Hz, 3H); m/z: 544 (M+l )+
(i?)-2-(3-(3,5-Dimethylisoxazol-4-yl)-5-fluorophenoxy)-N-( l-(3-methoxy
Figure imgf000075_0001
The title compound was prepared by following the similar procedure as described in Intermediate- 17 using Intermediate- 1 and 3,5-dimethylisoxazol-4-yl)boronic acid. 1H NMR (400 MHz, CDCls) δ 6.97 (d, = 10.2 Hz, 2H), 6.83 (ddd, = 8.2, 2.7 & 0.9 Hz, 1H), 6.62 (dt, = 10.5 & 2.3 Hz, 1H), 6.58 (d, = 2.3 Hz, 2H), 6.55 (dd, = 2.3 & 1.4 Hz, 1H), 4.16- 4.06 (m, 2H), 3.97-3.88 (m, 1H), 3.83 (s, 3H), 2.94 (ddt, = 25.9, 13.2 & 6.4 Hz, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 1.48 (d, = 6.5 Hz, 3H); m/z: 385 (M+l )+.
Example- 18: (i?)- l-(3-Methoxyphenyl)-N-(2-(3-(quinolin-6-yl)-5-(trifluoromethyl)phenoxy) ethyl)ethanamine
Figure imgf000076_0001
Titled compound were prepared by following similar procedure as described in Intermediate- 17 using Intermediate- 1 and Intermediate-34. 1H NMR (400 MHz, DMSO-J6) δ 8.95 (dd, = 4.2, 1.7 Hz, 1H), 8.51-8.41 (m, 2H), 8.22-8.09 (m, 2H), 7.76-7.66 (m, 2H), 7.60 (dd, = 8.3 & 4.2 Hz, 1H), 7.30 (s, 1H), 7.22 (t, = 7.8 Hz, 1H), 7.00-6.90 (m, 2H), 6.77 (ddd, 7 = 8.1, 2.6 & 1.0 Hz, 1H), 4.20 (t, = 5.6 Hz, 2H), 3.77 (q, = 6.5 Hz, 1H), 3.73 (s, 3H), 2.76 (dp, = 23.8, 6.6 & 6.0 Hz, 2H), 1.27 (d, = 6.5 Hz, 3H); m/z: 467 (M+l)+. l-(3-Fluoro-5-methoxyphenyl)-N-(2-(3-(quinolin-6-yl)-5-(trifluoromethyl)
Figure imgf000076_0002
Titled compound were prepared by following similar procedure as described in Intermediate- 17 using Intermediate-34. XH NMR (400 MHz, DMSO-J6) δ 8.95 (dd, = 4.2, 1.7 Hz, 1H), 8.50-8.41 (m, 2H), 8.18 (dd, = 8.8 & 2.1 Hz, 1H), 8.12 (d, = 8.8 Hz, 1H), 7.72 (s, 1H), 7.68 (t, = 1.9 Hz, 1H), 7.61 (dd, = 8.3 & 4.2 Hz, 1H), 7.29 (t, = 1.9 Hz, 1H), 6.80 (dd, = 8.5 & 2.2 Hz, 2H), 6.65 (dt, J = 11.0, 2.4 Hz, 1H), 4.20 (t, = 5.6 Hz, 2H), 3.78 (q, = 6.6 Hz, 1H), 3.74 (s, 3H), 2.83-2.65 (m, 2H), 1.26 (d, = 6.6 Hz, 3H); m/z: 485 (M+l)+.
Example-20: l-(3-Fluoro-5-methoxyphenyl)-N-(2-(3-(2-methoxypyrimidin-5-yl)-5-(trifluoro methyl)phenoxy)ethyl)ethanamine
Figure imgf000077_0001
Titled compound were prepared by following similar procedure as described in Intermediate- 17 using 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) pyrimidine. XH NMR (400 MHz, DMSO-Je) δ 9.03 (s, 2H), 7.65 (s, 1H), 7.59 (t, = 1.9 Hz, 1H), 7.27 (t, = 1.8 Hz, 1H), 6.78 (dd, = 8.6, 2.2 Hz, 2H), 6.64 (dt, = 11.0 & 2.4 Hz, 1H), 4.16 (t, = 5.6 Hz, 2H), 3.98 (s, 3H), 3.77 (t, = 6.6 Hz, 1H), 3.74 (s, 3H), 2.80-2.64 (m, 2H), 1.23 (d, = 3.2 Hz, 3H); m/z: 466 (M+l)+.
Example-21 : (i?)-6-(3-(2-((l-(3-Fluoro-5-methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoro methyl)phenyl)-3-methylpicolinic acid
Figure imgf000077_0002
Titled compound were prepared by following similar procedure as described in Example- 1 using Intermediate-33. XH NMR (400 MHz, DMSO-J6) δ 8.13 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 34.0 Hz, 2H), 7.85 (d, J = 8.1 Hz, 1H), 7.30 (s, 1H), 6.83 (d, J = 10.2 Hz, 2H), 6.67 (d, J = 11.0 Hz, 1H), 4.25 - 4.15 (m, 2H), 3.88 - 3.84 (m, 1H), 3.75 (s, 3H), 2.85 - 2.73 (m, 2H), 2.47 (s, 3H), 1.29 (d, J = 6.4 Hz, 3H); m/z: 493 (M+l)+.
Example-22: (Z?)-7-(3-(2-((l-(3-Methoxy phenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl) phenyl)-3-methylbenzo[&]thiophene-2-carboxylic acid
Figure imgf000078_0001
Titled compound were prepared by following similar procedure as described in Example- 1 using Intermediate-35b. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.96 (d, = 8.4 Hz, 1H), 7.82-7.7 (m, 1H), 7.60 (d, / = 24.1 Hz, 2H), 7.30-7.2 (m, 2H), 7.05-6.91 (m, 2H), 6.80 (dd, = 8.3, 2.6 Hz, 1H), 4.20 (t, = 5.7 Hz, 2H), 3.86 (d, = 6.7 Hz, 1H), 3.75 (s, 3H), 2.87-2.65 (m, 5H), 1.33 (t, = 6.6 Hz, 3H); m/z: 530 (M+l)+.
In-vitro Pharmacological activity
Certain illustrative compounds within the scope of the invention are screened for CaSR activity according to the procedure given below. The screening of the compounds may also be carried by other methods and procedures known to skilled in the art.
In-vitro assay method of Calcimimetics through modulation of Calcium Sensing Receptor (CaSR):
The ability of the compounds to modulate Calcium sensing receptor is determined by measuring an increase in intracellular calcium [Ca2+]i. Stably transfected HEK293 cells expressing hCaSR_pTriEx-3 hygro vector are developed. Cells are grown overnight on a 96- well plate to 80% confluency in Ham's F12 containing 20% FBS at 37°C, 5% C02. Subsequently, cells are washed extensively with 20mM HEPES buffer containing 126mM NaCl2, ImM MgCl2 and 4mM KC1 to remove serum components that might interfere with the assay. Cells are loaded with calcium sensing Fluo4NW dye in HEPES base buffer containing 0.1% BSA and lmg/ml glucose for 30 minutes to measure changes in intracellular calcium. The activities of the compounds are measured in FLIPR using 0.3mM CaCl2 in 20mM HEPES base buffer. The effectiveness of the compound to modulate receptor activity is determined by calculating the EC50 responses for that compound in an 8-point assay and plotted using GraphPad Prism 5. The compounds prepared were tested using the above assay procedure and the results obtained are given below. The EC50 (nM) values of few representative compounds are set forth in Table- 12.
The in-vitro activity data has been given in the following Table for representative compounds.
Table:
Figure imgf000079_0001
Thus, the above in-vitro assay method shows that the compounds of the invention were found to exhibit agonistic activity for CaSR, thereby showing utility for treating diseases, disorders associated with the modulation of CaSR.
In- vivo activity in CKD Wistar rats:
Animals were fed with 0.75% adenine diet for a period of 28 days for development of chronic kidney disease (CKD). After measurement of plasma PTH on day 28, animals were randomized based on plasma PTH (intact PTH) levels before using them for the study. Overnight fasted animals were bled retro-orbitally to collect basal blood sample (0.5 ml). Rats were dosed orally with vehicle and with test compounds Formulated in PEG 300:PG:Captisol (20: 15:65). Six to eight animals were used in each group then compounds of the invention were administered at 1 mg/kg dose. Post 2 h oral dosing animals were fed with feed and water ad libitum. Post treatment blood samples were collected by retro-orbital bleeding under light ether anesthesia at different time points for plasma PTH estimation. Plasma PTH was measured using sandwich ELISA kits (Immunotopics, USA). Percentage suppression of plasma PTH was calculated with respect to individual basal untreated values by using the following Formula
Pre-treated individual value - Post-treated individual
Percent suppression = X 100
Pre-treated individual value
Thus, the above in-vivo method shows that the compounds of the invention were found to exhibit suppress plasma PTH levels, thereby showing utility for treating diseases, disorders associated with the modulation of CaSR.
Although certain embodiments and examples have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments and examples without departing from the teachings thereof. All such modifications are intended to be encompassed within the below claims of the invention.

Claims

1. A compound having the Formula (I):
Figure imgf000081_0001
wherein, ring A is selected from oxazole, isooxazole, imidazole, pyrazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzoxadiazole, chromene, quinazoline, quinoline, indole, pyrimidine and pyridine;
Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, -C(0)OH, -C(0)0-alkyl, -C(0)NH-alkyl, -S(0)2-alkyl, -S(0)2NH-alkyl, -(CRaRb)i_ 3C(0)OH, and -(CRaRb)i_3C(0)0-alkyl;
R2 is substituted or unsubstituted aryl; wherein the aryl is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
R3 which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, -CN, -C(0)OH, -C(0)0-alkyl, -OR4, -NR5R6, and - NR6C(0)R7-, C(0)NR5R6, -S(0)2-alkyl, -S(0)2NH-alkyl, -(CRaRb)i-3C(0)OH and -(CRaRb)i_ 3C(0)0-alkyl or two R3 groups together with the carbon atom to which they are attached form oxo (C=0); Ra and R , which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or Ra and R , together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 6 membered saturated carbocyclic ring;
R4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl;
R5 and R6 are same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl; R is substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl;
'n' is an integer ranging from 0 to 3, both inclusive; wherein the substituents for substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted haloalkyl are one or more same or different and independently selected from the group consisting of hydroxy, halogen, carboxy, cyano, nitro, oxo (=0), thio (=S), alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroaryl alkyl, -C(0)ORx, -C(0)Ry, -C(S)Ry, -C(0)NRxRz, -NRxC(0)NRxRz, - N(Rx)S(0)2Ry, -NRXRZ, -NRxC(0)Ry, -NRxC(S)Ry, -NRXC(S)NRXRZ, -S(0)2NRxRz, -ORx, - OC(0)Ry, -C(RaRb)i-3 C(0)ORx, -C(RaRb)i-3C(0)NRxRz, -OC(RaRb)2-3-ORx, -OC(RaRb)2-3- NRXRZ, -OC(RaRb)2-3 S(O)0-2Ry, - C(RaRb)i-3-NRxRz, -C(RaRb)i-3-S(O)0-2Ry, -OC(RaRb)i-3- C(0)NRxRz, -OC(RaRb)i-3-C(0)ORx, and -S(O)0-2Ry; Rx, which may be same or different at each occurrence, is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl;
Ry, which may be same or different at each occurrence, is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; and
Rz, which may be same or different at each occurrence, is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; or Rx and Rz together with the nitrogen atom to which they are attached form a substituted or unsubstituted, saturated or unsaturated 4 to 8 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds; or pharmaceutically acceptable salt thereof.
2. The compound of claim 1 having the Formula (II):
Figure imgf000083_0001
(Π) wherein, ring A is heterocyclyl selected from isooxazole, benzofuran, benzothiophene, benzothiazole, chromene, quinazoline, quinoline, indole, pyrimidine and pyridine; Ri is halogen, substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl;
R2 is substituted or unsubstituted phenyl;
R3i which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted alkyl, -C(0)OH and -OR4 or two R3 groups together with the carbon atom to which they are attached form oxo (C=0);
R4 is substituted or unsubstituted alkyl;
'n' is an integer ranging from 0 to 3, both inclusive; wherein the substituents for substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted haloalkyl are one or more same or different and independently selected from the group consisting of hydroxy, halogen, carboxy, cyano, nitro, oxo (=0), thio (=S), alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroaryl alkyl, -C(0)ORx, -C(0)Ry, -C(S)Ry, -C(0)NRxRz, -NRxC(0)NRxRz, - N(Rx)S(0)2Ry, -NRXRZ, -NRxC(0)Ry, -NRxC(S)Ry, -NRXC(S)NRXRZ, -S(0)2NRxRz, -ORx, - OC(0)Ry, -QRaRb)!., C(0)ORx, -C(RaRb)1.3C(0)NRxRz, -OC(RaRb)2_3-ORx, -OC(RaRb)2_3- NRXRZ, -OC(RaRb)2_3 S(O)0-2Ry, - C(RaRb)i_3-NRxRz, -C(RaRb)i_3-S(O)0-2Ry, -OC(RaRb)i_3- C(0)NRxRz, -OC(RaRb)i_3-C(0)ORx, and -S(O)0-2Ry;
Rx, which may be same or different at each occurrence, is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; Ry, which may be same or different at each occurrence, is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; and
Rz, which may be same or different at each occurrence, is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; or Rx and Rz together with the nitrogen atom to which they are attached form a substituted or unsubstituted, saturated or unsaturated 4 to 8 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds; or pharmaceutically acceptable salt thereof.
3. The compound of claim 1
Figure imgf000085_0001
(III) wherein, ring A is selected from benzofuran, benzothiophene, benzothiazole, chromene, and quinazoline;
R3i which may be same or different at each occurrence, is independently selected from substituted or unsubstituted alkyl, -C(0)OH and -OR4 or two R3 groups together with the carbon atom to which they are attached form oxo (C=0);
R4 is substituted or unsubstituted alkyl; and
'n' is an integer ranging from 0 to 3, both inclusive; or pharmaceutically acceptable salt thereof.
4. The compound of claim 1 having the Formula (IV):
Figure imgf000086_0001
wherein, ring A is selected from quinazoline, quinoline, pyrimidine and pyridine;
R3i which may be same or different at each occurrence, is independently selected from substituted or unsubstituted alkyl, -C(0)OH and -OR4;
R4 is substituted or unsubstituted alkyl; and
'n' is an integer ranging from 0 to 2, both inclusive; or pharmaceutically acceptable salt thereof.
5. The compound of claim 1 wherein ring A is oxazole, isooxazole, imidazole, pyrazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzoxadiazole, chromene, quinazoline, quinoline, indole, pyrimidine and pyridine.
6. The compound of claim 1 wherein Ri is halogen or substituted or unsubstituted haloalkyl.
7. The compound of claim 1 wherein R2 is selected from substituted or unsubstituted aryl.
8. The compound of claim 7 wherein substituted or unsubstituted aryl is substituted or unsubstituted phenyl.
9. The compound of claim 1 wherein 'n' is 0 to 3; R3 is selected from substituted or unsubstituted alkyl, -C(0)OH, and -OR4 or two R3 groups together with the carbon atom to which they are attached form oxo (C=0); R4 is substituted or unsubstituted alkyl.
10. The compound of claim 1 which is selected from:
(i?)-5-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-3- methylbenzofuran-2-carboxylic acid,
(i?)-5-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-3- methylbenzo[&]thiophene-2-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-3- methyl-4-oxo-4H-chromene-2-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-3,8- dimethyl-4-oxo-4H-chromene-2-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-4- methylquinazoline-2-carboxylic acid,
(i?)-7-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-4- methyl-2-oxo-2H-chromene-3-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-3- methylquinoline-2-carboxylic acid,
(i?)-5-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-l- methyl- lH-indole-2-carboxylic acid,
(i?)-5-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)benzo [JJoxazole-2-carboxylic acid, (i?)-5-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)benzo furan-2-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)benzo [JJthiazole-2-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-3- methylbenzo[&]thiophene-2-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-4- oxo-4H-chromene-2-carboxylic acid,
(i?)-4-Methoxy-6-(3-(2-(( l-(3-methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl) phenyl)quinoline-2-carboxylic acid,
(i?)-6-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-l- methyl-4-oxo- 1 ,4-dihydroquinoline-2-carboxylic acid,
6-(3-(2-((l-(3-fluoro-5-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)- 4-methylquinazoline-2-carboxylic acid,
(i?)-2-(3-(3,5-Dimethylisoxazol-4-yl)-5-fluorophenoxy)-N-(l-(3-methoxyphenyl)ethyl) ethanamine,
(i?)-l-(3-Methoxyphenyl)-N-(2-(3-(quinolin-6-yl)-5-(trifluoromethyl)phenoxy)ethyl) ethanamine, l-(3-Fluoro-5-methoxyphenyl)-N-(2-(3-(quinolin-6-yl)-5-(trifluoromethyl)phenoxy) ethyl)ethanamine, l-(3-Fluoro-5-methoxyphenyl)-N-(2-(3-(2-methoxypyrimidin-5-yl)-5-(trifluoromethyl) phenoxy)ethyl)ethanamine,
(i?)-6-(3-(2-((l-(3-Fluoro-5-methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl) phenyl)-3-methylpicolinic acid and (i?)-7-(3-(2-((l-(3-Methoxyphenyl)ethyl)amino)ethoxy)-5-(trifluoromethyl)phenyl)-3- methylbenzo[&]thiophene-2-carboxylic acid or pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.
12. A method of treating diseases or disorders, syndromes or conditions associated with the modulation of calcium sensing receptor (CaSR) in a subject in need thereof wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to any of claims 1 to 11, or a pharmaceutically acceptable salt thereof.
13. The method of claim 12, wherein the diseases, disorders, syndromes or conditions associated with the modulation of calcium sensing receptor (CaSR) are selected from hyperparathyroidism, chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis) and their complications.
14. The method of claim 13, wherein hyperparathyroidism is primary hyperparathyroidism, secondary hyperparathyroidism or tertiary hyperparathyroidism.
15. The method of claim 13, wherein the diseases, disorders, syndromes or conditions associated with the modulation of CaSR receptors are selected from the group consisting of parathyroid adenoma, parathyroid hyperplasia, parathyroid carcinoma, vascular & 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, bone loss post renal transplantation, osteitis fibrosa cystica, adynamic bone disease, renal bone diseases, cardiovascular complications arising due to hyperparathyroidism or chronic kidney disease, certain 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 gastrointestinal tract by augmenting gastric acidity.
16. A process for the preparation of compound of Formula (la):
Figure imgf000090_0001
la wherein ring A is as defined herein above and X is H or F; the process comprising the steps of: a) reacting the compound of Formula-3 with compound of Formula-4 (wherein X is H or F) to give compound of Formula-5
Figure imgf000090_0002
b) reacting the compound of Formula-5 with compound of Formula-6 to give compound of Formula-7 89
Figure imgf000091_0001
Figure imgf000091_0002
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