WO2017037616A1 - Arylalkylamine compounds as calcium sensing receptor modulators - Google Patents

Arylalkylamine compounds as calcium sensing receptor modulators Download PDF

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WO2017037616A1
WO2017037616A1 PCT/IB2016/055166 IB2016055166W WO2017037616A1 WO 2017037616 A1 WO2017037616 A1 WO 2017037616A1 IB 2016055166 W IB2016055166 W IB 2016055166W WO 2017037616 A1 WO2017037616 A1 WO 2017037616A1
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ethyl
methoxyphenyl
amino
alkyl
hydrogen
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PCT/IB2016/055166
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French (fr)
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Prathap Sreedharan Nair
Ganesh Bhausaheb Gudade
Mahadeo Bhaskar TRYAMBAKE
Chetan Sanjay PAWAR
Giriraj Chandrakant SHELKE
Dipak Raychand LAGAD
Sanjeev Anant Kulkarni
Venkata P. Palle
Rajender Kumar Kamboj
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Lupin Limited
Lupin Atlantis Holdings Sa
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D213/24—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
    • C07D213/54—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
    • C07D213/57—Nitriles
    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to arylalkylamine compound 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).
  • 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-dihydroxy vitamin 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 2015/028938, 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 receptor (CaSR) modulators.
  • CaSR calcium sensing receptor
  • the invention provides compounds having structure of Formula (I),
  • ring B is selected from (a) to (e):
  • G is absent, -CH 2 - or -CH 2 -CH 2 -
  • R v is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, -OR 9 and substituted or unsubstituted (C 3 - C )cycloalkyl;
  • ring A is phenyl or naphthyl;
  • each of Ri is hydrogen or substituted or unsubstituted (Ci-C 6 )alkyl;
  • R 2 which may be same or different at each occurrence, is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci- C 6 )haloalkyl, (Ci-C 6 )hydroxyalkyl, -X-C(0)-Z, -OR 9 , -NR 7 R 8 , -NR 7 C(0)R 6 , -S(0)o- 2 R 6 , - S(0) 2 NR 7 R 8 , -NR 7 S(0) 2 R 6 and substituted or unsubstituted (C 3 -C 7 )cycloalkyl;
  • R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci- C 6 )haloalkyl, -X-C(0)-Z, -OR 9 , -NR 7 R 8 , -NR 7 C(0)R 6 , -NR 7 S(0) 2 R 6 and substituted or unsubstituted (C 3 -C )cycloalkyl; at each occurrence W is independently selected from hydrogen, substituted or unsubstituted (Ci-C 6 )alkyl and -(CR a R b )o- 2 -C(0)ORi 0 ;
  • V is O or NRi
  • R a and R b which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted (Ci-C 6 )alkyl and (C 3 - C 7 )cycloalkyl;
  • R 3 is selected from hydrogen, substituted or unsubstituted (Ci-C 6 )alkyl, (Q- C 6 )haloalkyl, substituted or unsubstituted (C3-C )cycloalkyl, -(CR a R b )i-2-C(0)ORio and - (CR a Rb)i-2-ORio;
  • X is selected from a bond, -(CR a R b ) m -, -NH- and -0(CR a R b ) m -;
  • Z is -ORi 0 or -NR 7 R 8 ;
  • R 4 which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, substituted or unsubstituted (Ci-C 6 )alkoxyalkyl and -OR 9 ;
  • R5 is substituted or unsubstituted (Ci-C 6 )alkyl
  • R 6 is selected from substituted or unsubstituted (Ci-C 6 )alkyl, substituted or unsubstituted (C 3 -C )cycloalkyl and substituted or unsubstituted (C 6 -Cio)aryl;
  • R and R$ which may be same or different at each occurrence, are independently selected from hydrogen, substituted or unsubstituted (Ci-C 6 )alkyl and substituted or unsubstituted (C 3 -C )cycloalkyl;
  • R 9 is selected from hydrogen, substituted or unsubstituted (Ci-C 6 )alkyl, substituted or unsubstituted (Ci-C 6 )alkoxyalkyl and substituted or unsubstituted (C 3 -C )cycloalkyl; each of Rio is hydrogen or substituted or unsubstituted (Ci-C 6 )alkyl;
  • 'm' is an integer ranging from 1 to 3, both inclusive;
  • 'n' is an integer ranging from 0 to 3, both inclusive; and 'p' is an integer ranging from 0 to 3, both inclusive; or a pharmaceutically acceptable salt thereof or stereoisomers thereof.
  • R 2 is independently selected from halogen, cyano, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl and -X-C(0)-Z.
  • X is a bond or -(CR a Rb)i-3-.
  • Z is -ORio-
  • Rio is hydrogen or (Ci-C 6 )alkyl.
  • R a and R are hydrogen or substituted or unsubstituted (Ci- C 6 )alkyl.
  • R 4 is independently selected from halogen, substituted or unsubstituted (Ci-C 6 )alkyl and -OR9.
  • R9 is hydrogen or (Ci-C 6 )alkyl.
  • 'p' is 0, 1 or 2.
  • R3 is hydrogen, substituted or unsubstituted (Ci-C 6 )alkyl, - (CR a R b ) 1 . 2 -C(O)OR 10 and -(CR a R b ) 1 . 2 -OR 10 .
  • R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, -X-C(0)-Z and (C 3 -C 7 )cycloalkyl.
  • W is hydrogen, (Ci-C 6 )alkyl or -(CR a Rb)o- 2 -C(0)ORio-
  • R 2 which may be same or different at each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci- C 6 )haloalkyl, and -X-C(0)-Z; where X is a bond or -(CR a Rb)i- 3 -; Z is -OR10; R a and Rb are hydrogen or (Ci-C 6 )alkyl; Rio is hydrogen or (Ci-C 6 )alkyl; and n is 0, 1 or 2.
  • ring A is phenyl or naphthyl;
  • R 4 which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted (Ci-C 6 )alkyl and -OR9 where R9 is hydrogen or substituted or unsubstituted (Ci-C 6 )alkyl; and 'p' is 0, 1 or 2.
  • Ri is hydrogen or (Ci-C 6 )alkyl.
  • R5 is (Ci-C 6 )alkyl.
  • R3 is hydrogen, substituted or unsubstituted (Ci-C 6 )alkyl, - (CR a Rb)i-2-C(0)ORio and -(CR a Rb)i- 2 -ORio;
  • R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, -X-C(0)-Z and (C 3 -C 7 )cycloalkyl;
  • W is hydrogen, (Ci-C 6 )alkyl or -(CR a Rb)o-2-COORio;
  • V is O or NRi ; wherein X is a bond or - (CR a Rb)i- 3 -; Z is -OR10; R a and Rb are hydrogen or (Ci-C 6 )alkyl; Ri is hydrogen or (Ci- C 6 )alkyl; and Rio is hydrogen or (C
  • the invention provides compounds having the structure of Formula (II)
  • Ri is hydrogen or (Ci-C 6 )alkyl
  • R 2 which may be same or different at each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl and -X-C(0)-Z; where X is a bond or -(CR a R b )i-3-; Z is -ORio; R a and R are hydrogen or (Ci-C 6 )alkyl; Rio is hydrogen or (Ci-C 6 )alkyl; 'n' is 0, 1 or 2; ring A is phenyl or naphthyl; R 4 , which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted (Ci-C 6 )alkyl and -OR 9 where R9 is hydrogen or substituted or unsubstituted (Ci-C 6 )alkyl; and 'p' is 0, 1 or 2; and
  • R 5 is (Ci-C 6 )alkyl; or a pharmaceutically acceptable salt thereof or stereoisomers thereof.
  • the invention provides compounds having the structure of Formula (III)
  • G is -CH 2 - or -CH 2 -CH 2 -; ring A, ring B, R 1; R4_ R5 and 'p' are as defined herein above.
  • Ri is hydrogen or (Ci-C 6 )alkyl
  • ring A is phenyl or naphthyl
  • R 4 which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted (Ci-C 6 )alkyl and -OR 9 where R9 is hydrogen or substituted or unsubstituted (Ci-C 6 )alkyl; and 'p' is 0, 1 or 2;
  • R 5 is (Ci-C 6 )alkyl; or a pharmaceutically acceptable salt thereof or stereoisomers thereof.
  • the invention provides compounds having the structure of Formula (IV)
  • Ri is hydrogen or (Ci-C 6 )alkyl
  • R 2 which may be same or different at each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, and -X-C(0)-Z; where X is a bond or -(CR a R b )i-3-; Z is -ORio; R a and R are hydrogen or (Ci-C 6 )alkyl; Rio is hydrogen or (Ci-C 6 )alkyl; 'n' is 0, 1 or 2; ring A is phenyl or naphthyl; R 4 , which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted (Ci-C 6 )alkyl and -OR 9 where R 9 is hydrogen or substituted or unsubstituted (Ci-C 6 )alkyl; and 'p' is 0, 1 or 2; and
  • R 5 is (Ci-C 6 )alkyl; or a pharmaceutically acceptable salt thereof or stereoisomers thereof.
  • the invention provides compounds having the structure of Formula (V)
  • ring B is selected from (b) to (e):
  • Ri is hydrogen or (Ci-C 6 )alkyl
  • R 3 is hydrogen, substituted or unsubstituted (Ci-C 6 )alkyl, -(CR a R b )i-2-COORio and -(CR a R b )i_ 2 -ORio
  • R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, -X-C(0)-Z and (C 3 - C 7 )cycloalkyl
  • W is hydrogen, (Ci-C 6 )alkyl or -(CR a R b )o-2-COORio
  • V is O or NRi
  • X is a bond or -(CR a Rb)i- 3 -
  • Z is -OR10
  • R a and R b are hydrogen or (Ci-C
  • R 5 is (d-QDalkyl; or a pharmaceutically acceptable salt thereof or stereoisomers thereof.
  • R 2 is halogen, cyano, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, -X- C(0)-Z;
  • X is a bond or -(CR a R b ) m -;
  • R 3 is hydrogen, substituted or unsubstituted (Ci-C 6 )alkyl, -(CR a Rb)i-2-C(0)ORio and -(CR a Rb)i-2-ORio;
  • R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, -X-C(0)-Z and (C 3 -C 7 )cycloalkyl;
  • W is hydrogen, (Ci-C 6 )alkyl or -(CR a R b )o-2-C(0)ORio;
  • V
  • R 4 is independently selected from halogen, substituted or unsubstituted (Ci-C 6 )alkyl and -OR 9 where R 9 is hydrogen or substituted or unsubstituted (Ci-C 6 )alkyl; and 'p' is 0, 1 or 2.
  • Compounds of the invention include, for example, compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of ring A, ring B, ring E, Ri_ R4, R5 and 'p' has any of the meanings defined hereinbefore or independently in any of paragraphs (1) to (7):
  • ring A is phenyl or naphthyl.
  • ring B is selected from (a) to (e):
  • Ri is hydrogen or (Ci-C 6 )alkyl
  • R 2 is selected from halogen, cyano, (Ci- C 6 )alkyl, (Ci-C 6 )haloalkyl, (Ci-C 6 )hydroxyalkyl, -X-C(0)-Z, (C 3 -C 7 )cycloalkyl
  • 'n' is 0, 1, or 2
  • R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci- C 6 )haloalkyl, -X-C(0)-Z and substituted or unsubstituted (C 3 -C )cycloalkyl
  • X is a bond or - (CR a R b )i- 3 -
  • Z is -ORio
  • R 3 is selected from hydrogen, (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (C 3
  • G is absent, -CH 2 - or -CH 2 -CH 2 -;
  • R v is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, -OR 9 and substituted or unsubstituted (C 3 -C 7 )cycloalkyl.
  • Ri is hydrogen or substituted or unsubstituted (Ci-C 6 )alkyl.
  • R 4 which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, substituted or unsubstituted (Ci-C 6 )alkoxyalkyl and -OR 9 where R 9 is selected from hydrogen, substituted or unsubstituted (Ci-C 6 )alkyl, substituted or unsubstituted (Q- C 6 )alkoxyalkyl and substituted or unsubstituted (C 3 -C )cycloalkyl.
  • R5 is substituted or unsubstituted (Ci-C 6 )alkyl.
  • 'p' is an integer ranging from 0 to 3. According to another embodiment, there are provided compounds of Formulae (I) to (V) wherein the compound is in the free base form.
  • the provided compounds of Formulae (I) to (V) structurally encompass stereoisomers including enantiomers and diastereomers.
  • a compound of Formulae (I) to (V) 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 diseases, disorders, syndromes or conditions associated with the modulation of calcium sensing receptor are selected from hyperparathyroidism, primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyperparathyroidism, chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis) and their complications, or 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 (Ca 2+ ) e ions are abnormally high, cardiac, renal or intestinal dysfunctions, podocyte-related diseases
  • hyperparathyroidism is primary hyperparathyroidism, secondary hyperparathyroidism or tertiary hyperparathyroidism.
  • the diseases, disorders, syndromes or conditions associated with the modulation of CaSR receptors may be 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 (Ca 2+ ) 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
  • the invention provides a pharmaceutical composition comprising at least one compound of Formulae (I) to (V) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • the invention provides a pharmaceutical composition comprising a compound of Formulae (I) to (V) 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 (V) 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 -C 4 )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-C6)alkoxy,(Ci-C 4 )alkoxy, methoxy, ethoxy and 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 (C 1 -C 6 )alkoxy-(C 1 -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.
  • hydroxyalkyl refers to an alkyl group, as defined above that is substituted by one or more hydroxy groups.
  • the hydroxyalkyl is monohydroxyalkyl or dihydroxyalkyl.
  • Non-limiting examples of a hydroxyalkyl include 2-hydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, 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, trichloromethyl, 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.
  • multicycliccycloalkyl 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, tetrahydronaphthyl, 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 .
  • 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 heteroatom(s) 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.
  • the nitrogen atom may be optionally quaternized
  • the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bondfS), and one or two carbon atoms(5j in the heterocyclic ring or heterocyclyl may be interrupted with -CF 2 -, -C(O)-, - S(O)-, S(0) 2 etc.
  • heterocyclic ring may also be fused with aromatic ring.
  • heterocyclic rings include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl
  • heteroaryl refers to a substituted or unsubstituted 5- to 14- membered aromatic heterocyclic ring with one or more heteroatom(5j 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, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazohnyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl
  • substituted 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, (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, aryl(Ci-C 6 )alkyl, (C3-C )cycloalkyl, heteroaryl, heterocyclic ring, heterocyclyl(Ci-C 6 )alkyl, heteroaryl(Ci- C 6 )alkyl, -C(0)OR x , -C(0)R x , -C(S)R X , -C(0)NR x R y , -NR x C(0)NR
  • one representative group of moieties which may be a "substituent” is selected from hydroxy, halogen, cyano, nitro, (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 (C3-C 6 )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 and 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 stereoisomers 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.
  • 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 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.
  • the invention relates to pharmaceutical compositions containing the compounds of the Formula (I), or pharmaceutically acceptable salts thereof disclosed herein.
  • pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula (I) to (V) described herein and at least one pharmaceutically acceptable excipient (such as a carrier or diluent).
  • 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.
  • 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 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.
  • 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. 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.
  • 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 of 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.
  • 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 mesangial 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, para follicular 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 Formula (I), 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 hyperparathyroidism, 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+ ) e
  • 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.
  • Chronic renal insufficiency also referred to as chronic kidney disease or CKD
  • 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 hypercalciuria.
  • Tertiary hyperparathyroidism may occur after a long period of secondary hyperparathyroidism and hypercalcemia.
  • 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.
  • 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., anti -bacterial agent, anti-viral agent, anti-fungal agent, immunosuppressive agent, anti-inflammatory agent, analgesic or anticancer agent), an organ failure, an organ failure, an organ failure
  • 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.
  • the invention encompasses any of the compounds of Formulae (I) to (V), or pharmaceutically acceptable salts thereof for use in the treatment or prevention of any of the conditions disclosed herein.
  • the invention encompasses the use of any of the compounds of Formulae (I) to (V), or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prevention 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- 1 to Scheme-8.
  • 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 described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
  • the acid compound of Formula 1 is coupled with N,0-dimethylhydroxylamine hydrochloride followed by reaction using triflating reagents in presence of suitable base to give compound 3, which further undergoes reduction using suitable reducing agents such as Lithium aluminium hydride (LAH), Diisobutylaluminium hydride (DIBAL) to afford compound 4.
  • LAH Lithium aluminium hydride
  • DIBAL Diisobutylaluminium hydride
  • This compound 4 undergoes Suzuki coupling with formula la, where 'n' is 0 to 3, to provide compound 5.
  • This coupling reaction is carried-out in suitable Pd-catalyst such as Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 .DCM, Pd 2 (dba) 3 , Pd(OAc) 2 in presence of suitable base such as Na 2 C0 3 , K 2 C0 3 etc.
  • Pd-catalyst such as Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 .DCM, Pd 2 (dba) 3 , Pd(OAc) 2 in presence of suitable base such as Na 2 C0 3 , K 2 C0 3 etc.
  • suitable base such as Na 2 C0 3 , K 2 C0 3 etc.
  • Lewis acid such as Ti(0-iPr) 4 TiCl 4 etc. followed by reduction with NaBH 4 , NaBH 3 CN, NaBH(OAc) 3 etc.
  • the compound of Formula 9 (when Y is CH and M is N) is prepared by following the procedure as mentioned in Current science 1979, 48(13), p 580-581 or can be prepared from formula 8 using Grignard reagent (Ri-MgBr where Ri is alkyl) (when Y is N, and M is CH).
  • This compound of Formula 9 undergoes sequential transformations, thus, Suzuki coupling, reductive amination followed by hydrolysis as depicted in Scheme-2 to afford compound 12, where X, ring A, ring B, Y, M, R v , R 4 , R5 and 'p' are as defined herein above.
  • Scheme-3
  • the compound of Formula 9 undergoes Suzuki coupling followed by reductive amination as described Scheme-3 to afford compound 14.
  • This compound 14 is further reacted with hydrazine hydrate under microwave conditions in suitable solvent(s) to give a compound of Formula 15, where ring A, Y, M, R v , R 4 , R 5 and 'p' are as defined herein above.
  • ester compound 16 undergoes reduction with DIBAL followed by oxidation with Pyridinium chlorochromate (PCC), Dess-Martin periodinane (DMP) etc., to afford compound of Formula 18.
  • PCC Pyridinium chlorochromate
  • DMP Dess-Martin periodinane
  • This compound formula 18 undergoes sequential transformations, thus, Suzuki coupling, reductive amination followed by hydrolysis as depicted in Scheme-4 to afford compound 21, where ring A, Y, R 2i R4, R5 and 'p' are as defined herein above.
  • the compound 22 undergoes reduction with suitable reducing agents such as DIBAL followed by Grignard reaction to give compound 24.
  • This compound 24 undergoes oxidation reaction with PCC, DMP etc., to afford the compound 25.
  • the compound of Formula (25) when Ri is ethyl is also prepared from Formula (22) using trialkylaluminum, Weinreb amine and ⁇ , ⁇ '-dimethylethylenediamine in suitable solvents.
  • Compound 29 first undergoes formylation then O-benzylation to give compound 31.
  • This compound of Formula 32 is treated with inflating reagents such as triflic anhydride or N-phenyl-bis(trifluoromethanesulfonimide) in presence of suitable base such as ⁇ , ⁇ -Diisopropylethylamine (DIPEA), Triethylamine (TEA) etc. to afford compound of Formula 33.
  • DIPEA ⁇ , ⁇ -Diisopropylethylamine
  • TAA Triethylamine
  • the compound of Formula 33 is hydrogenated (H 2 /Pd/C) to give compound 34, which is further oxidized to give compound 35.
  • intermediate-40 (0.5g, 1.638 mmol), (4-(trifluoromethyl) phenyl)boronic acid (0.31 lg, 1.638 mmol) and anhydrous dioxane (5 ml) under N2 atmosphere.
  • a degassed aqueous 2M solution of sodium carbonate (2.46 ml, 4.91 mmol) was then added via syringe to the vigorously stirred reaction mixture, followed by tetrakis(triphenylphosphine)palladium (0) (0.095g, 0.082 mmol).
  • reaction mixture was stirred at 80 °C for 70 mins under microwave irradiation. TLC showed completion of reaction.
  • the reaction was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic phase were dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure. This residue was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 15% ethyl acetate in petroleum ether to afford the title compound (0.373g, 76%) as a off white solid.
  • Example-1 (R)-Methyl 2-methyl-5-(2-((( 1 -(naphthalen- 1 -yl)ethyl)amino)methyl)-5 ,6,7, 8- tetrahydroquinolin-4-yl)benzoat
  • Examples 2 and 3 given in table-2 were prepared by following same procedure as described in Example- 1 by taking appropriate aldehyde intermediate and amine intermediate.
  • Example-1 To a stirred solution of Example-1 (0.065 g, 0.140 mmol) in MeOH:THF:H 2 0 (5 ml, 2:2: 1) was added NaOH (0.034 g, 1.399 mmol) at 25 °C. Reaction mixture was then refluxed for 2 hr at 80 °C. TLC showed completion of reaction. Reaction mixture was concentrated in vaccuo to get the residue. Residue was then acidified with dil. HCl (5 ml) at 0 °C, stirred & filtered to get pure compound. Ethereal HCl (3 ml) was then added to this compound & sonicated for 2 minutes.
  • Example-7 ( 1R)- 1 -(3-methoxyphenyl)-N-(( 1 R/l S)- 1 -(8-(4-(trifluoromefhyl)phenyl)-
  • Example 8 to 14 were prepared by following the similar procedure as described in Example-7 by taking appropriate ketone intermediate and appropriate amine intermediate. Further the mixture of diastereomers (along with exo and endo) were separated by Supercritical Fluid Chromatography (SFC) as given in Example-7.
  • SFC Supercritical Fluid Chromatography
  • Example-15 Isopropyl 3-(5-(2-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)- 5,6,7,8-tetrahydroquinolin-4-yl)- -methylphenyl)propanoate
  • Example-19 3-(5-(2-((lR/lS)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)-5,6,7,8- tetrahydroquinolin-4-yl)-2-methylphenyl)propanoic acid hydrochloride
  • example- 15 (0.04 g, 0.078 mmol) in MeOH:THF:H 2 0 (5 ml, 2:2: 1) was added NaOH (4.36 mg, 0.078 mmol) at 25 °C. Reaction mixture was then refluxed for 2 hr at 80 °C. TLC showed completion of reaction. Reaction mixture was concentrated in vaccuo to get the residue. Residue was then acidified with dil. HCl (5 ml) at 0 °C, stirred & filtered to get pure compound. Ethereal HCl (3 ml) was then added to this compound & sonicated for 2 minutes.
  • Example-24 ( IR)- 1 -(Naphthalen- 1 -yl)-/V-( 1 -(4-(4-(trifluoromethyl)phenyl)quinolin-2-yl) ethyl)ethanamine hydrochloride
  • Example-26 ( 1R)- 1 -(4-Fluoro-3-methoxyphenyl)-N-(( lR/1 S)- 1 -(4-(4-(trifluoromethyl) phenyl) quinolin-2-yl)ethyl)ethan- 1 -amine hydrochloride
  • Example-28 N-((R)-l-(3-Methoxyphenyl)ethyl)-l-(4-(4-(trifluoromethyl)phenyl)quinolin- 2-yl)propan- 1 -amine hydrochloride
  • Example-29 ( IR)- 1 -(3-Methoxyphenyl)-N-( 1 -(( lR/1 S)- 1 -(4-(trifluoromethyl)phenyl) isoquinolin-3 -yl)ethyl)ethanamine hydrochloride
  • Example-31 ( 1R)- 1 -(3-Fluoro-5-methoxyphenyl)-N-(( lR/1 S)- 1 -( 1 -(4-(trifluoromethyl) phenyl)isoquinolin-3-yl)ethyl)
  • Example-33 Isopropyl 2-fluoro-5-(2-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino) ethyl)quinolin-4-yl)-3-methylbenzoate
  • Example-34 Isopropyl 3-(3-fluoro-5-(2-((lR/lS)-l-(((i?)-l-(3-methoxyphenyl)ethyl) amino) ethyl) quinolin-4-yl)phenyl)propanoate
  • Example-35 Isopropyl 3-(3-fluoro-5-(2-((lR/lS)-l-(((R)-l-(3-fluoro-5-methoxyphenyl) ethyl)amino)ethyl)quinolin-4-yl)phenyl)propanoate
  • Example-36 Isopropyl 3-(5-(2-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino) ethyl)quinolin-4-yl)-2-methylphenyl)propanoate
  • Example-37 Isopropyl 3-(3-fluoro-5-(3-((lR/lS)-l-(((i?)-l-(3-methoxyphenyl)ethyl) amino)ethyl) isoquinolin-l-yl)phenyl)propanoate hydrochloride
  • Example-38 Isopropyl 5-(3-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino) ethyl)isoquinolin- 1 -yl)-2-methylbenzoate
  • Example-39 Isopropyl 3-(2-fluoro-5-(3-(( lR/1 S)- 1 -(((R)- 1 -(3-methoxyphenyl)ethyl) amino)ethyl) isoquinolin- 1 -yl
  • Example-40 Isopropyl 3-(5-(3-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino) ethyl)isoquinolin- 1 -yl)-2-methylphenyl)propanoate
  • Example-41 5-(2-(( 1 R/l S)- 1 -(((R)- 1 -(3-Methoxyphenyl)ethyl)amino)ethyl)quinolin-4-yl)- 2-methyl benzoic acid hydrochloride
  • example-32 (0.31 g, 0.642 mmol) in MeOH: Water (3 ml, 2: 1) was added NaOH (0.128 g, 3.21 mmol) at 25 °C. Reaction mixture was then refluxed for 2 hr at 90 °C. TLC showed completion of reaction. Reaction mixture was concentrated in vacuo to get the residue. Residue was dissolved in water (2 ml) and then acidified with IN HCl (3 ml) at 0 °C, stirred and filtered the precipitated solid to get sufficiently dry and pure product. 2M ethereal HCl (3 ml) was then added to this solid compound at 0 °C and stirred for lh.
  • Example-50 (l ⁇ )-l -(3-Methoxyphenyl)-N-(( 1 R/l S)- 1 -(4-(6-(trifluoromefhyl)pyridin-3- yl)naphthalen-2-yl)ethyl)ethanamine hydrochloride
  • Example-63 Isopropyl 3-(4-(3-(( lR/1 S)- 1 -(((R)- 1 -(3-methoxyphenyl)ethyl)amino)ethyl) naphthalen- 1 -yl)- lH-pyrazol- 1 -yl)propanoate
  • the isopropyl ester formation of corresponding methyl ester can be explained on the basis of trans-esterification of methyl ester with titanium tetraisopropoxide.
  • Example-70 3-(4-(3-((lR/lS)-l-(((i?)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen- l-yl)-lH-pyrazol-l-yl)propanoic acid hydrochloride
  • Example-63 To a stirred solution of Example-63 (0.155 g, 0.319 mmol) in methanol (5 ml) was added sodium hydroxide (0.128 g, 3.19 mmol) at 25 °C. Reaction mixture was then refluxed for 2 hr at 80 °C. TLC showed completion of reaction. Reaction mixture was concentrated in vacuo to get 0.165g residue. Residue was then acidified with dil. HCl (5 ml) at 0 °C, stirred and filtered to get (0.1 lg) of pure compound.
  • Example-72 5-(3-((lR/lS)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen-l- yl)-3-methylpicolinic acid hydrochloride
  • Example-65 To a stirred solution of Example-65 (0.0 lg, 0.119 mmol) in water (5 ml) was added sodium hydroxide (28.4 mg, 1.19 mmol) at 25°C. Reaction mixture was then refluxed for 16 hr. TLC showed completion of reaction. Reaction mixture was concentrated in vacuo to get 0.165g residue. Residue was then acidified with dil. HCl (5 ml) at 0 °C, stirred and filtered to get (0.007g) of pure compound.
  • Example-74 6-(3-((lR/lS)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen-l- yl)-lH-indazol-3-amine hydrochloride
  • Step-1 2-Fluoro-4-(3-(l-(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)naphthalen-l-yl) benzonitrile
  • Step-2 6-(3-(l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen-l-yl)-lH-indazol-3- amine hydrochloride
  • Step-1 To a stirred solution of above Step-1 Intermediate (0.09g, 0.212 mmol) in ethanol (2.5 ml) was added hydrazine hydrate (0.073ml, 2.332 mmol) at 25 °C. Reaction mixture was then heated under microwave irradiation for 4 hr at 100 °C. TLC showed completion of reaction.
  • Example-75 5-(3-(( lR/1 S)- 1 -(((R)- 1 -(3-Methoxy phenyl)ethyl)amino)ethyl)naphthalen- 1 - - lH-indazol-3-amine hydrochloride
  • Step-1 2-Fluoro-5-(3-(l-(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)naphthalen-l-yl) benzonitrile
  • the tile compound was prepared by following the similar procedure as described in WO 2015/028938A1 using Intermediate-60.
  • Step-2 5-(3-( 1 -(((R)- 1 -(3-Methoxy phenyl)ethyl)amino)ethyl)naphthalen- 1 -yl)- lH-indazol- 3-amine hydrochloride
  • Example-79 Isopropyl 5-(2-(( lR/1 S)- 1 -(((R)- 1 -(3-methoxyphenyl)ethyl)amino)ethyl)- 5,6,7,8-tetrahydro quinolin -4- -2-methylbenzoate
  • Example-82 5-(2-((lR/lS)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)-5,6, 7,8- tetrahydroquinolin-4-yl)-2-methylbenzoic acid hydro chloride
  • 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.
  • compounds were found to exhibit CaSR agonistic activity thus to be particularly well suited for the treatment of the diseases or disorders as described herein above.
  • the EC 50 (nM) values of the representative compounds are set forth in Table- 12.

Abstract

The invention relates to arylalkylamine compounds of Formula (I) and their pharmaceutically acceptable salts, wherein the substituents are as described herein, and their use in medicine for the treatment of diseases, disorders associated with the modulation of calcium sensing receptor (CaSR) modulators. The invention also relates to pharmaceutical compositions containing such compounds in treating diseases disorders associated with calcium sensing receptor (CaSR) modulators.

Description

ARYLALKYLAMINE COMPOUNDS AS CALCIUM SENSING RECEPTOR
MODULATORS
Related applications
The present application claims the benefit of priority to Indian Provisional Patent Application No. 3338/MUM/2015 filed on Aug 31, 2015, 3943/MUM/2015 filed on Oct 16, 2015 and 3944/MUM/2015 filed on Oct 16, 2015 and the entire provisional specifications.
Field of the Invention
The present invention relates to arylalkylamine compound 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).
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-dihydroxy vitamin 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 2015/028938, 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 receptor (CaSR) modulators.
Summary of the Invention
In accordance with one aspect, the invention provides compounds having structure of Formula (I),
Figure imgf000005_0001
ring B is selected from (a) to (e):
Figure imgf000005_0002
(a) (b) (c) (d) (e) provided that when ring E is
Figure imgf000006_0001
ring B is (a) then one of M and Y is N;
G is absent, -CH2- or -CH2-CH2-
Rv is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted (Ci-C6)alkyl, (Ci-C6)haloalkyl, -OR9 and substituted or unsubstituted (C3- C )cycloalkyl; ring A is phenyl or naphthyl; each of Ri is hydrogen or substituted or unsubstituted (Ci-C6)alkyl;
R2, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted (Ci-C6)alkyl, (Ci- C6)haloalkyl, (Ci-C6)hydroxyalkyl, -X-C(0)-Z, -OR9, -NR7R8, -NR7C(0)R6, -S(0)o-2R6, - S(0)2NR7R8, -NR7S(0)2R6 and substituted or unsubstituted (C3-C7)cycloalkyl;
R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-C6)alkyl, (Ci- C6)haloalkyl, -X-C(0)-Z, -OR9, -NR7R8, -NR7C(0)R6, -NR7S(0)2R6 and substituted or unsubstituted (C3-C )cycloalkyl; at each occurrence W is independently selected from hydrogen, substituted or unsubstituted (Ci-C6)alkyl and -(CRaRb)o-2-C(0)ORi0;
V is O or NRi;
Ra and Rb, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted (Ci-C6)alkyl and (C3- C7)cycloalkyl; R3 is selected from hydrogen, substituted or unsubstituted (Ci-C6)alkyl, (Q- C6)haloalkyl, substituted or unsubstituted (C3-C )cycloalkyl, -(CRaRb)i-2-C(0)ORio and - (CRaRb)i-2-ORio; at each occurrence X is selected from a bond, -(CRaRb)m-, -NH- and -0(CRaRb)m-; Z is -ORi0 or -NR7R8;
R4, which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted (Ci-C6)alkyl, (Ci-C6)haloalkyl, substituted or unsubstituted (Ci-C6)alkoxyalkyl and -OR9;
R5 is substituted or unsubstituted (Ci-C6)alkyl; R6 is selected from substituted or unsubstituted (Ci-C6)alkyl, substituted or unsubstituted (C3-C )cycloalkyl and substituted or unsubstituted (C6-Cio)aryl;
R and R$, which may be same or different at each occurrence, are independently selected from hydrogen, substituted or unsubstituted (Ci-C6)alkyl and substituted or unsubstituted (C3-C )cycloalkyl; R9 is selected from hydrogen, substituted or unsubstituted (Ci-C6)alkyl, substituted or unsubstituted (Ci-C6)alkoxyalkyl and substituted or unsubstituted (C3-C )cycloalkyl; each of Rio is hydrogen or substituted or unsubstituted (Ci-C6)alkyl;
'm' is an integer ranging from 1 to 3, both inclusive;
'n' is an integer ranging from 0 to 3, both inclusive; and 'p' is an integer ranging from 0 to 3, both inclusive; or a pharmaceutically acceptable salt thereof or stereoisomers thereof. The details of one or more embodiments of the invention set forth in below are only illustrative in nature 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.
In certain embodiments, R2 is independently selected from halogen, cyano, substituted or unsubstituted (Ci-C6)alkyl, (Ci-C6)haloalkyl and -X-C(0)-Z.
In certain embodiments, X is a bond or -(CRaRb)i-3-.
In certain embodiments, Z is -ORio-
In certain embodiments, Rio is hydrogen or (Ci-C6)alkyl.
In certain embodiments, Ra and R are hydrogen or substituted or unsubstituted (Ci- C6)alkyl.
In certain embodiments, R4 is independently selected from halogen, substituted or unsubstituted (Ci-C6)alkyl and -OR9.
In certain embodiments, R9 is hydrogen or (Ci-C6)alkyl.
In certain embodiments 'p' is 0, 1 or 2.
In certain embodiments, R3 is hydrogen, substituted or unsubstituted (Ci-C6)alkyl, - (CRaRb)1.2-C(O)OR10 and -(CRaRb)1.2-OR10.
In certain embodiments, R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-C6)alkyl, (Ci-C6)haloalkyl, -X-C(0)-Z and (C3-C7)cycloalkyl.
In certain embodiments, W is hydrogen, (Ci-C6)alkyl or -(CRaRb)o-2-C(0)ORio-
In certain embodiments, R2, which may be same or different at each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted (Ci-C6)alkyl, (Ci- C6)haloalkyl, and -X-C(0)-Z; where X is a bond or -(CRaRb)i-3-; Z is -OR10; Ra and Rb are hydrogen or (Ci-C6)alkyl; Rio is hydrogen or (Ci-C6)alkyl; and n is 0, 1 or 2. In certain embodiments, ring A is phenyl or naphthyl; R4, which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted (Ci-C6)alkyl and -OR9 where R9 is hydrogen or substituted or unsubstituted (Ci-C6)alkyl; and 'p' is 0, 1 or 2.
In certain embodiments, Ri is hydrogen or (Ci-C6)alkyl.
In embodiments, R5 is (Ci-C6)alkyl.
In certain embodiments, R3 is hydrogen, substituted or unsubstituted (Ci-C6)alkyl, - (CRaRb)i-2-C(0)ORio and -(CRaRb)i-2-ORio; R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-C6)alkyl, (Ci-C6)haloalkyl, -X-C(0)-Z and (C3-C7)cycloalkyl; W is hydrogen, (Ci-C6)alkyl or -(CRaRb)o-2-COORio; V is O or NRi ; wherein X is a bond or - (CRaRb)i-3-; Z is -OR10; Ra and Rb are hydrogen or (Ci-C6)alkyl; Ri is hydrogen or (Ci- C6)alkyl; and Rio is hydrogen or (Ci-C6)alkyl.
According to one embodiment, the invention provides compounds having the structure of Formula (II)
Figure imgf000009_0001
or a pharmaceutically acceptable salt thereof or stereoisomers thereof; wherein, ring A, R1; R2 R t, R5i 'n' and 'p' are as defined herein above.
In one embodiment in Formula (II): Ri is hydrogen or (Ci-C6)alkyl;
R2, which may be same or different at each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted (Ci-C6)alkyl, (Ci-C6)haloalkyl and -X-C(0)-Z; where X is a bond or -(CRaRb)i-3-; Z is -ORio; Ra and R are hydrogen or (Ci-C6)alkyl; Rio is hydrogen or (Ci-C6)alkyl; 'n' is 0, 1 or 2; ring A is phenyl or naphthyl; R4, which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted (Ci-C6)alkyl and -OR9 where R9 is hydrogen or substituted or unsubstituted (Ci-C6)alkyl; and 'p' is 0, 1 or 2; and
R5 is (Ci-C6)alkyl; or a pharmaceutically acceptable salt thereof or stereoisomers thereof.
According to another embodiment, the invention provides compounds having the structure of Formula (III)
Figure imgf000010_0001
(III) or a pharmaceutically acceptable salt thereof or stereoisomers thereof; wherein,
G is -CH2- or -CH2-CH2-; ring A, ring B, R1; R4_ R5 and 'p' are as defined herein above.
In one embodiment in Formula (III): Ri is hydrogen or (Ci-C6)alkyl; ring A is phenyl or naphthyl; R4, which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted (Ci-C6)alkyl and -OR9 where R9 is hydrogen or substituted or unsubstituted (Ci-C6)alkyl; and 'p' is 0, 1 or 2; and
R5 is (Ci-C6)alkyl; or a pharmaceutically acceptable salt thereof or stereoisomers thereof.
According to another embodiment, the invention provides compounds having the structure of Formula (IV)
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof or stereoisomers thereof; wherein, one of M and Y is N and the other is CH; ring A, R1; R2, R4, R5, 'n' and 'p' are as defined herein above.
In one embodiment in Formula (IV):
Ri is hydrogen or (Ci-C6)alkyl;
R2, which may be same or different at each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted (Ci-C6)alkyl, (Ci-C6)haloalkyl, and -X-C(0)-Z; where X is a bond or -(CRaRb)i-3-; Z is -ORio; Ra and R are hydrogen or (Ci-C6)alkyl; Rio is hydrogen or (Ci-C6)alkyl; 'n' is 0, 1 or 2; ring A is phenyl or naphthyl; R4, which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted (Ci-C6)alkyl and -OR9 where R9 is hydrogen or substituted or unsubstituted (Ci-C6)alkyl; and 'p' is 0, 1 or 2; and
R5 is (Ci-C6)alkyl; or a pharmaceutically acceptable salt thereof or stereoisomers thereof.
According to another embodiment, the invention provides compounds having the structure of Formula (V)
Figure imgf000012_0001
(V) or a pharmaceutically acceptable salt thereof or stereoisomers thereof; wherein, one of M and Y is CH and the other is CH or N; ring B is selected from (b) to (e):
Figure imgf000012_0002
(b) (c) (d) (e) ring A, V, W, R, R1; R3, R4i R5 and 'p' as defined herein above. In one embodiment in Formula (V): ring B is selected from (b) to (e):
Figure imgf000013_0001
(b) (c) (d) (e) . wherein Ri is hydrogen or (Ci-C6)alkyl; R3 is hydrogen, substituted or unsubstituted (Ci-C6)alkyl, -(CRaRb)i-2-COORio and -(CRaRb)i_2-ORio; R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-C6)alkyl, (Ci-C6)haloalkyl, -X-C(0)-Z and (C3- C7)cycloalkyl; W is hydrogen, (Ci-C6)alkyl or -(CRaRb)o-2-COORio; V is O or NRi; wherein X is a bond or -(CRaRb)i-3-; Z is -OR10; Ra and Rb are hydrogen or (Ci-C6)alkyl; Ri is hydrogen or (Ci-C6)alkyl; Rio is hydrogen or (Ci-C6)alkyl; ring A is phenyl or naphthyl; R4, which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted (Ci-C6)alkyl and -OR9 where R9 is hydrogen or substituted or unsubstituted (Ci-C6)alkyl; and 'p' is 0, 1 or 2; and
R5 is (d-QDalkyl; or a pharmaceutically acceptable salt thereof or stereoisomers thereof.
It should be understood that the Formula (I) 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. According to another embodiment, there are provided compounds having the structure of Formula (I) wherein ring B is selected from (a) to (e):
Figure imgf000014_0001
R2 is halogen, cyano, substituted or unsubstituted (Ci-C6)alkyl, (Ci-C6)haloalkyl, -X- C(0)-Z; X is a bond or -(CRaRb)m-; R3 is hydrogen, substituted or unsubstituted (Ci-C6)alkyl, -(CRaRb)i-2-C(0)ORio and -(CRaRb)i-2-ORio; R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-C6)alkyl, (Ci-C6)haloalkyl, -X-C(0)-Z and (C3-C7)cycloalkyl; W is hydrogen, (Ci-C6)alkyl or -(CRaRb)o-2-C(0)ORio; V is O or NRi; Z is -ORi0; Ra and Rb are hydrogen or (Ci-C6)alkyl; Ri is hydrogen or (Ci-C6)alkyl; Rio is hydrogen or substituted or unsubstituted (Ci-C6)alkyl; 'n' is 0, 1 or 2; and 'm' is 1 to 3.
According to another embodiment, there are provided compound having the structure of Formulae (I), (II), (III), (IV) or (V) wherein R4 is independently selected from halogen, substituted or unsubstituted (Ci-C6)alkyl and -OR9 where R9 is hydrogen or substituted or unsubstituted (Ci-C6)alkyl; and 'p' is 0, 1 or 2. Compounds of the invention include, for example, compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of ring A, ring B, ring E, Ri_ R4, R5 and 'p' has any of the meanings defined hereinbefore or independently in any of paragraphs (1) to (7): wherein,
1) ring A is phenyl or naphthyl.
2) ring B is selected from (a) to (e):
Figure imgf000015_0001
wherein Ri is hydrogen or (Ci-C6)alkyl; R2 is selected from halogen, cyano, (Ci- C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)hydroxyalkyl, -X-C(0)-Z, (C3-C7)cycloalkyl; 'n' is 0, 1, or 2; R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-C6)alkyl, (Ci- C6)haloalkyl, -X-C(0)-Z and substituted or unsubstituted (C3-C )cycloalkyl; X is a bond or - (CRaRb)i-3-; Z is -ORio; R3 is selected from hydrogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3- C7)cycloalkyl, -(CRaRb)i-2-COORi0 and -(CRaRb)i-2-ORio; W is hydrogen, (Ci-C6)alkyl or - (CRaRb)o-2-COORi0; V is O or NRi; Ra and Rb are hydrogen; Ri is hydrogen or (Ci-C6)alkyl and Rio is hydrogen or (Ci-C6)alkyl.
Figure imgf000015_0002
where G is absent, -CH2- or -CH2-CH2-;
Rv is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted (Ci-C6)alkyl, (Ci-C6)haloalkyl, -OR9 and substituted or unsubstituted (C3-C7)cycloalkyl.
4) Ri is hydrogen or substituted or unsubstituted (Ci-C6)alkyl.
5) R4, which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted (Ci-C6)alkyl, (Ci-C6)haloalkyl, substituted or unsubstituted (Ci-C6)alkoxyalkyl and -OR9 where R9 is selected from hydrogen, substituted or unsubstituted (Ci-C6)alkyl, substituted or unsubstituted (Q- C6)alkoxyalkyl and substituted or unsubstituted (C3-C )cycloalkyl.
6) R5 is substituted or unsubstituted (Ci-C6)alkyl.
7) 'p' is an integer ranging from 0 to 3. According to another embodiment, there are provided compounds of Formulae (I) to (V) wherein the compound is in the free base form.
According to another embodiment, there are provided compounds of Formulae (I) to (V) wherein the compound is a pharmaceutically acceptable salt.
According to another embodiment, there are provided compounds of Formulae (I) to (V) wherein the pharmaceutically acceptable salt is a hydrochloride salt.
According to another embodiment, the provided compounds of Formulae (I) to (V) structurally encompass stereoisomers including enantiomers and diastereomers.
The Examples 1 to 82 given herein are the representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention.
In another aspect of the invention, there is provided a compound of Formulae (I) to (V) 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 (V) or a pharmaceutically acceptable salt thereof, for use in treating the diseases, disorders, syndromes or conditions associated with calcium sensing receptor (CaSR) modulators.
The diseases, disorders, syndromes or conditions associated with the modulation of calcium sensing receptor (CaSR) are selected from hyperparathyroidism, primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyperparathyroidism, chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis) and their complications, or 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 gastro-intestinal tract by augmenting gastric acidity. In embodiments 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.
Optionally, hyperparathyroidism is primary hyperparathyroidism, secondary hyperparathyroidism or tertiary hyperparathyroidism.
The diseases, disorders, syndromes or conditions associated with the modulation of CaSR receptors may be 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.
In another aspect, the invention provides a pharmaceutical composition comprising at least one compound of Formulae (I) to (V) 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 (V) 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 (V) 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 (V) 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. Detailed description of the invention
Definitions and Abbreviations:
Unless otherwise stated, the following terms used in the specification and claims have the meanings 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.
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 and 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 (C1-C6)alkoxy-(C1-C6)alkyl,(C1-C4)alkoxy-(C1- C4)alkyl., -CH2-0-CH3, -CH2-0-CH2CH3, -CH2CH2-0-CH3 and the like.
The term "hydroxyalkyl" refers to an alkyl group, as defined above that is substituted by one or more hydroxy groups. Preferably, the hydroxyalkyl is monohydroxyalkyl or dihydroxyalkyl. Non-limiting examples of a hydroxyalkyl include 2-hydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, 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, trichloromethyl, 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 multicycliccycloalkyl 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, tetrahydronaphthyl, 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.
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 heteroatom(s) 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 bondfS), and one or two carbon atoms(5j in the heterocyclic ring or heterocyclyl may be interrupted with -CF2-, -C(O)-, - S(O)-, S(0)2 etc. In addition, heterocyclic ring may also be fused with aromatic ring. Non- limiting Examples of heterocyclic rings include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, 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 heteroatom(5j 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, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazohnyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like.
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, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(Ci-C6)alkyl, (C3-C )cycloalkyl, heteroaryl, heterocyclic ring, heterocyclyl(Ci-C6)alkyl, heteroaryl(Ci- C6)alkyl, -C(0)ORx, -C(0)Rx, -C(S)RX, -C(0)NRxRy, -NRxC(0)NRyRz, -NRxRy, - NRxC(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-C )cycloalkyl and aryl.
For example one representative group of moieties which may be a "substituent" is selected from hydroxy, halogen, cyano, nitro, (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 and 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 stereoisomers 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 compounds described by the Formula (I) 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 Formula (I), or pharmaceutically acceptable salts thereof disclosed herein. In particular, pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula (I) to (V) 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 of 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 mesangial 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, para follicular 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 Formula (I), 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 hyperparathyroidism, 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 hyperparathyroidism 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 (V), or pharmaceutically acceptable salts thereof for use in the treatment or prevention 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 (V), or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prevention 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- 1 to Scheme-8. 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 described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
Scheme-1
Figure imgf000033_0001
The acid compound of Formula 1 is coupled with N,0-dimethylhydroxylamine hydrochloride followed by reaction using triflating reagents in presence of suitable base to give compound 3, which further undergoes reduction using suitable reducing agents such as Lithium aluminium hydride (LAH), Diisobutylaluminium hydride (DIBAL) to afford compound 4. This compound 4 undergoes Suzuki coupling with formula la, where 'n' is 0 to 3, to provide compound 5. This coupling reaction is carried-out in suitable Pd-catalyst such as Pd(PPh3)4, Pd(dppf)Cl2.DCM, Pd2(dba)3, Pd(OAc)2 in presence of suitable base such as Na2C03, K2C03 etc. Further compound of Formula 5 undergoes condensation with amino compound 2a in presence of Lewis acid such as Ti(0-iPr)4 TiCl4 etc. followed by reduction with NaBH4, NaBH3CN, NaBH(OAc)3 etc. to give compound of Formula 6. The compound of Formula 6, when R2 is ester group, undergoes ester hydrolysis using suitable base such as NaOH, KOH, LiOH etc., to give compound 7, where X, ring A, Rv, R2, R4, R5 and 'p' are as defined herein above. If the formula 6 is methyl or ethyl ester, it undergoes trans-esterification reaction to form corresponding isopropyl ester in presence of titanium tetra-isopropoxide (Lewis acid).
Scheme-2
Figure imgf000034_0001
The compound of Formula 9 (when Y is CH and M is N) is prepared by following the procedure as mentioned in Current science 1979, 48(13), p 580-581 or can be prepared from formula 8 using Grignard reagent (Ri-MgBr where Ri is alkyl) (when Y is N, and M is CH). This compound of Formula 9 undergoes sequential transformations, thus, Suzuki coupling, reductive amination followed by hydrolysis as depicted in Scheme-2 to afford compound 12, where X, ring A, ring B, Y, M, Rv, R4, R5 and 'p' are as defined herein above. Scheme-3
Figure imgf000035_0001
The compound of Formula 9 undergoes Suzuki coupling followed by reductive amination as described Scheme-3 to afford compound 14. This compound 14 is further reacted with hydrazine hydrate under microwave conditions in suitable solvent(s) to give a compound of Formula 15, where ring A, Y, M, Rv, R4, R5 and 'p' are as defined herein above.
Scheme-4
Figure imgf000035_0002
The ester compound 16 undergoes reduction with DIBAL followed by oxidation with Pyridinium chlorochromate (PCC), Dess-Martin periodinane (DMP) etc., to afford compound of Formula 18. This compound formula 18 undergoes sequential transformations, thus, Suzuki coupling, reductive amination followed by hydrolysis as depicted in Scheme-4 to afford compound 21, where ring A, Y, R2i R4, R5 and 'p' are as defined herein above.
Scheme-5
(22)
Figure imgf000036_0001
The compound 22 undergoes reduction with suitable reducing agents such as DIBAL followed by Grignard reaction to give compound 24. This compound 24 undergoes oxidation reaction with PCC, DMP etc., to afford the compound 25. But, the compound of Formula (25) when Ri is ethyl, is also prepared from Formula (22) using trialkylaluminum, Weinreb amine and Ν,Ν'-dimethylethylenediamine in suitable solvents.
Compound 25 undergoes sequential reaction transformations, thus, Suzuki coupling, reductive amination followed by hydrolysis as described herein above to afford compound 28, where ring A, Y, R2, R4, R5 and 'p' are as defined herein above. Scheme-6
Figure imgf000037_0001
37
Compound 29 first undergoes formylation then O-benzylation to give compound 31. This compound 31, on selective O-debenzylation using suitable magnesium halides, is converted to monobenzylated compound 32. This compound of Formula 32 is treated with inflating reagents such as triflic anhydride or N-phenyl-bis(trifluoromethanesulfonimide) in presence of suitable base such as Ν,Ν-Diisopropylethylamine (DIPEA), Triethylamine (TEA) etc. to afford compound of Formula 33. The compound of Formula 33 is hydrogenated (H2/Pd/C) to give compound 34, which is further oxidized to give compound 35. Compound 35 is treated with triflating reagents to afford compound 36. This compound 36 undergoes Suzuki coupling, reductive amination followed by hydrolysis as described herein above to afford compound 39 where ring A, G, X, R2i P , R5 and 'p' are as defined herein above.
Scheme-7
Figure imgf000037_0002
37a (G is -CH2-) or 40 41
37b (G is -CH2-CH2-) The conversion of compound 37a or 37b to compound 40 is carried by adding Grignard's reagent (Ri-MgBr) in suitable solvent(s) to provide corresponding alcohol, which can further be reacted with oxidizing agent such as PCC, DMP etc. Compound 40 on reductive amination as described herein above to afford compound 41 where ring A, R2, R4, R5, 'n' and 'p' are as defined herein above.
Scheme-8
Figure imgf000038_0001
The conversion of compound 36 to 43 is carried out by using Grignard's reagent (Ri-MgBr) in suitable solvents to provide corresponding alcohol, which can further be reacted with oxidizing agents such as PCC, DMP etc. This compound 43 undergoes sequential transformations, thus, Suzuki coupling, reductive amination followed by hydrolysis as depicted in Scheme-8 to afford compound 46 where ring A, ring B, G, X, R4, R5 and 'p' are as defined herein above.
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. If the compound is methyl or ethyl ester they can be transformed to corresponding isopropyl ester using the trans-esterification procedure described herein.
INTERMEDIATES
Intermediate-1: Ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydroquinoline-2- carboxylate
Figure imgf000039_0001
To a solution of ethyl 4-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxylate (500 mg, 2.260 mmol) [which was synthesized as per WO2011 159554 Al], triethylamine (0.945 ml, 6.78 mmol) in dichloromethane (5ml), was added triflic anhydride (0.496 ml, 2.94 mmol) at 0°C and stirred for 2 hrs. TLC showed completion of reaction. The residue was diluted in methylene chloride (10 ml) and washed with water (10 ml x 2). The organic phase was dried and evaporated in vacuo to get a crude compound. This solid was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 20% ethyl acetate in petroleum ether to afford title compound (0.575 g, 72 %) as a white solid. 1H NMR (400 MHz, Chloroform- d) δ 7.85 (s, 1H), 4.51 (q, J = 7.2 Hz, 2H), 3.11 (t, = 6.3 Hz, 2H), 2.88 (d, = 6.2 Hz, 2H), 2.00 - 1.85 (m, 4H), 1.45 (t, = 7.1 Hz, 3H); MS (ES+): m/z=353.09 (M+l, 100%).
Intermediate-2: 2-Formyl-5,6,7,8-tetrahydroquinolin-4-yl trifluoromethanesulfonate
Figure imgf000039_0002
A solution of intermediate- 1 (2.4g, 6.79 mmol) in dichloromefhane (5 ml) was cooled to -78 °C then the 1M solution of diisobutylaluminum hydride (13.6 ml, 13.6 mmol) in THF was added drop-wise. The reaction mixture was stirred for 1 h at same temperature then at 25 °C for 2 h. TLC showed completion of reaction. Reaction mixture was quenched by adding methanol (2 mL) then solid material was observed which was filtered through celite, the filtrate was dried over anhydrous Na2S04 and concentrated under reduced pressure to give (2-formyl-5,6,7,8-tetrahydroquinolin-4-yl trifluoromethanesulfonate (lg, 47.6 %) as a off white solid. XH NMR (400 MHz, Chloroform-JJ δ 10.01 (s, 1H), 7.68 (s, 1H), 3.19 - 3.02 (m, 2H), 2.90 (t, = 6.3 Hz, 2H), 2.03 - 1.95 (m, 2H), 1.91 (dddd, = 8.9, 6.4, 4.8, 2.5 Hz, 2H); MS (ES+): m/z=312.34 (M+l, 100%).
Intermediate-3: 2-( 1 -Hydroxyethyl)-5,6,7,8-tetrahydroquinolin-4-yl trifluoromethane sulfonate
Figure imgf000040_0001
To a solution of intermediate-2 (180 mg, 0.582 mmol) in diethyl ether (2 ml) at 0 °C was added methylmagnesium bromide (0.291 ml, 0.873 mmol) drop-wise. After stirring for 5 min at 0 °C, a saturated aqueous NH4CI (10 mL) solution was added, and the resulting mixture extracted with Et20 (10 mL x 3). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated in vacuo to give 2-(l-Hydroxyethyl)-5, 6,7,8- tetrahydroquinolin-4-yl trifluoromethanesulfonate (100 mg, 52.8 %) as a off white solid. 1H
NMR (400 MHz, DMSO-J6) δ 7.29 (s, 1H), 5.60 (d, = 4.7 Hz, 1H), 4.76 - 4.65 (m, 1H), 2.86 (t, = 6.2 Hz, 2H), 2.71 (t, = 6.1 Hz, 2H), 1.81 (tdq, = 15.0, 8.0, 4.4, 4.0 Hz, 4H), 1.35 (d, = 6.6 Hz, 3H) ; MS (ES+): m/z=326.22 (M+l, 100%).
Intermediate-4: 2-Acetyl-5,6,7,8-tetrahydroquinolin-4-yl trifluoromethanesulfonate
Figure imgf000041_0001
To a solution of intermediate-3 (lg, 3.07 mmol) in dichloromethane (25 ml) at 25 °C was added Dess-Martin periodinane (1.565, 3.69 mmol) lot-wise and stirred for 4 hrs. TLC showed completion of reaction. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (25 ml x 2). The organic phase was dried and evaporated in vacuo to get crude compound .This solid was purified by column chromatography over silica gel (100- 200 mesh) with an isocratic elution of 20% ethyl acetate in petroleum ether to afford the title compound (0.8 g, 80%) as a white solid. 1H NMR (400 MHz, DMSO-J6) δ 7.70 (s, 1H), 3.00 (t, = 6.2 Hz, 2H), 2.81 (t, = 6.1 Hz, 2H), 2.63 (s, 3H), 1.94 - 1.77 (m, 4H); MS (ES+): m/z= 324.06 (M+l , 100%).
Intermediate-5: 2-Propionyl-5,6,7,8-tetrahydroquinolin-4-yl trifluoromethanesulfonate
Figure imgf000041_0002
To a stirred solution of ethyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydroquinoline- 2-carboxylate (0.3g, 0.884 mmol) in toluene was added Nl,N2-dimethylethane-l,2-diamine (0.106 ml, 0.973 mmol) & Ν,Ο-dimethylhydroxylamine (0.054 g, 0.884 mmol) at 0 °C and stirred for 1 h at same temperature. 0.5M solution of triethylaluminum in heptane (5.48 ml, 2.74 mmol) was added at 0 °C and then heated the reaction mixture to 90 °C for 3 h. TLC showed completion of reaction. Reaction mixture was quenched with aqueous (aq.) saturated (sat.) NH4CI solution (25 ml) and extracted with ethyl acetate (25 ml). The organic phase was dried and evaporated in vacuo to get 0.25g crude compound. This residue was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 20% ethyl acetate in petroleum ether to afford the title compound (0.072g, 25%) as a white solid. 1H NMR (400 MHz, DMSO-J6) δ 7.68 (s, 1H), 3.15 (q, = 7.2 Hz, 2H), 2.98 (t, = 6.2 Hz, 2H), 2.80 (t, = 6.1 Hz, 2H), 1.85 (ttd, = 15.2, 9.5, 7.7, 4.5 Hz, 4H), 1.08 (t, = 7.2 Hz, 3H); MS (ES+): m/z=337.99 (M+l, 20%).
Intermediate-6: l-(4-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydroquinolin-2-yl)ethanone
Figure imgf000042_0001
To an oven-dried round-bottomed flask with a side-arm and condenser, was added Intermediate-4 0.42 g, 1.299 mmol), (4-(trifluoromethyl)phenyl)boronic acid (0.296 g, 1.559 mmol) and anhydrous dioxane (10 ml) under N2 atmosphere. A degassed aqueous 2M solution of sodium carbonate (1.949 ml, 3.90 mmol) was then added via syringe to the vigorously stirred reaction mixture, followed by tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.13 mmol) at 25 °C. The reaction mixture was stirred at 90 °C for 5 h. TLC showed completion of reaction. The reaction mixture was diluted with water (25 ml) and ethyl acetate (25 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 15 ml). The combined organic extract was washed with water (2 x 25 ml), brine (50 ml) and dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to get 0.7g of the crude residue. This residue was purified by column chromatography over silica gel (100- 200 mesh) with an isocratic elution of 15% ethyl acetate in petroleum ether to afford the title compound (0.401 g, 97%) as a off white solid. 1H NMR (400 MHz, DMSO-J6) δ 7.86 (d, = 8.1 Hz, 2H), 7.64 (d, = 8.0 Hz, 2H), 7.58 (s, 1H), 3.00 (t, = 6.5 Hz, 2H), 2.64 (d, = 5.2 Hz, 5H), 1.94 - 1.80 (m, 2H), 1.70 (ddd, = 9.3, 7.6, 4.7 Hz, 2H); MS (ES+): m/z= 320.03 (M+l, 100%).
Intermediate-7: l-(4-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydroquinolin-2-yl)propan- 1-one
Figure imgf000043_0001
The title compound was synthesized by procedure as described for intermediate-6 by taking intermediate-5 and 4-(trifluoromethyl)phenyl)boronic acid. MS (ES+): m/z=334.46 (M+1, 20%).
Intermediate-8: (4-Bromo-5,6,7,8-tetrahydroquinolin-2-yl)methanol
Figure imgf000043_0002
Sodium borohydride (0.268 g, 7.09 mmol) was added portion wise to a solution of methyl 4- bromo-5,6,7,8-tetrahydroquinoline-2-carboxylate (0.87 g, 3.22 mmol) ) [Synthesis reported in WO2011/159554 Al] in ethanol (5 mL) under nitrogen and the reaction mixture was stirred at 25 °C for 16 hours. The reaction was quenched by the addition of acetone (1 mL) and the reaction was stirred for 15 minutes. The solvent was evaporated and the residue partitioned between water (15 ml) and ethyl acetate (10 ml x 2). The aqueous layer was extracted with ethyl acetate (10 ml) and the combined organics were collected, dried over anhydrous sodium sulfate and the solvent evaporated to afford (4-bromo-5, 6,7,8- tetrahydroquinolin-2-yl)methanol (0.66g, 85%) as off white solid. 1H NMR DMSO-de (400MHz): 7.47(s, 1H), 5.46(t, =6.0Hz, lH), 4.46(d, =6.0Hz, 2H), 2.78(s, 2H), 2.66(s, 2 H), 1.79-7.75(m, 4H); MS (ES+): m/z=241.9, 243.9 (M+1, 100%).
Intermediate-9: 4-Bromo-5,6,7,8-tetrahydroquinoline-2-carbaldehyde
Figure imgf000043_0003
Dess-Martin Periodinane (1.034 g, 2.437 mmol) was added to a solution of intermediate-8 (0.59 g, 2.437 mmol) in dichloromefhane (10 ml) at 0 °C and the reaction mixture was stirred at 25 °C for 1 h. TLC showed completion of reaction. The residue was diluted in methylene chloride (30 ml) and washed with water (30 ml x 2). The organic phase was dried and evaporated in vacuo to get crude compound. This solid was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 20% ethyl acetate in petroleum ether to afford 4-bromo-5,6,7,8-tetrahydroquinoline-2-carbaldehyde (0.35 g, 1.458 mmol, 59.8 % yield) as a white solid. 1H NMR CDC13 (400MHz): 10.0(s, 1H), 7.98(s, 1H), 3.06-3.03(m, 2H), 2.86-2.84 (m, 2H), 1.96-1.88(m, 4H); MS (ES+): m/z=240.9,242.9 (M+l, 100%).
Intermediate-10: 5,8-Dihydroxy-l,2,3,4-tetrahydro-l,4-methanonaphthalene-6- carbaldehyde
Figure imgf000044_0001
To a solution of l,2,3,4-tetrahydro-l,4-methanonaphthalene-5,8-diol (10 g, 56.7 mmol) in dichloromethane (100 ml) was added titanium tetrachloride (18.77 ml, 170 mmol) at 25 °C. Then dichloro(methoxy)methane (9.79 g, 85 mmol) was added drop-wise under vigorous stirring and the reaction mixture was stirred for another 16 h at 25 °C. Finally 5% hydrochloric acid (100 ml) was added under ice-cooling. The organic phase was separated and the residual aqueous phase repeatedly extracted with ether (100 ml x 2). The combined organic phases were washed with saturated saline solution (100 ml), dried over sodium sulfate and evaporated under vacuum. The residue was subjected to flash chromatography on silica gel with methylenechloride/methanol 98:2 to afford pure 5,8-dihydroxy-l,2,3,4- tetrahydro- 1 ,4-methanonaphthalene-6-carbaldehyde (3.4g, 29.3%) as a pale yellow solid. 1H
NMR CDCI3 (400MHz): 10.60(s, 1H), 9.75(s, 1H), 6.79(s, 1H), 4.61(s, 1H), 3.72-3.57(m, 2H), 1.99-1.96(m, 2H), 1.95-1.76(m, 1H), 1.59-1.56(m, 1H), 1.27-1.22(m. 2H); MS (ES+): m/z=204.8 (M+l, 100%).
Intermediate-11 : 5,8-Dihydroxy- 1 ,2,3,4-tetrahydro- 1 ,4-ethanonaphthalene-6-carbaldehyde
Figure imgf000045_0001
The title compound was synthesized by procedure as described for intermediate- 10. (Is, 4s)- l,2,3,4-tetrahydro-l,4-ethanonaphthalene-5,8-diol was prepared as per WO2014/19344 Al. Yield = 57% XH NMR (400 MHz, DMSO-J6) δ 10.22 (s, 1H), 9.96 (s, 1H), 9.18 (s, 1H), 6.95 (s, 1H), 3.45-3.40 (m, 2H), 1.82 - 1.68 (m, 4H), 1.26 - 1.15 (m, 4H); MS (ES+): m/z=219.76 (M+l, 20%).
Intermediate-12 : 5 , 8-Bis(benzyloxy)- 1 ,2, 3 ,4-tetrahydro- 1 ,4-methanonaphthalene-6- carbaldehyde
Figure imgf000045_0002
To a solution of intermediate- 10 (5.1 g, 24.97 mmol) in DMF (50 ml) was added cesium carbonate (17.90 g, 54.9 mmol) at 25 °C. Then benzyl bromide (6.24 ml, 52.4 mmol) was added. The reaction mixture was then stirred under nitrogen at 25 °C for 16 h. TLC showed completion of reaction. The reaction mixture was diluted with water (25 ml) and dichloromethane (50 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 ml). The combined organic extract was washed with water (2 x 25 ml), brine (50 ml) and dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to get 11.5g of the crude residue. This residue was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 20% ethyl acetate in petroleum ether to afford 5,8-bis(benzyloxy)-l,2,3,4-tetrahydro-l,4-methanonaphthalene-6- carbaldehyde (9.1g, 95 %) as a off white solid. XH NMR (400 MHz, Chloroform-J) δ 10.22 (s, 1H), 7.48 - 7.36 (m, 10H), 7.23 (s, 1H), 5.16 - 5.03 (m, 4H), 3.74 - 3.67 (m, 2H), 1.98 (dq, = 6.2, 3.0 Hz, 2H), 1.78 (dt, = 9.0, 2.0 Hz, 1H), 1.55 (dd, = 8.9, 1.4 Hz, 1H), 1.28 - 1.24 (m, 2H); MS (ES+): m/z= 385.56 (M+l, 100%). Intermediate-13: 5,8-Bis(benzyloxy)-l,2,3,4-tetrahydro-l,4-ethanonaphthalene-6- carbaldehyde
Figure imgf000046_0001
The title compound was synthesized by procedure as described for intermediate- 12 by taking intermediate-11. Yield = 85%. 1H NMR (400 MHz, DMSO-J6) δ 10.11 (d, = 2.7 Hz, 1H), 7.51 - 7.37 (m, 10H), 5.17 (d, = 2.6 Hz, 2H), 4.98 (d, = 2.7 Hz, 2H), 3.53 (s, 1H), 3.40(s, 1H), 1.78 (d, = 8.8 Hz, 4H), 1.24 (d, = 9.4 Hz, 4H).
Intermediate-14: 8-(Benzyloxy)-5-hydroxy- 1 ,2,3,4-tetrahydro- 1 ,4-methanonaphthalene-6- carbaldehyde
Figure imgf000046_0002
To a suspension of intermediate- 12 (9 g, 23.41 mmol) in benzene/diethyl ether (7: 1, 175 ml) was added magnesium bromide diethyl etherate (7.86 g, 30.4 mmol) at 25 °C. The mixture was refluxed for 16h. TLC showed completion of reaction. After cooling to room temperature, 1 N HCl (200 ml) was added to the reaction mixture, and extracted with ethyl acetate (100 ml x 2). The organic layer was washed with saturated Na2C03 solution (200 ml) and brine (200 ml). The solvent was removed in vacuo after drying over Na2S04. The residue was purified by a silica gel (100-200 mesh) column chromatography with hexane/Ethyl acetate (9: 1) to give 8-(benzyloxy)-5-hydroxy-l,2,3,4-tetrahydro-l,4-methanonaphthalene-6- carbaldehyde (6.0g, 87 %) as a yellow liquid. 1H NMR (400 MHz, DMSO-J6) δ 10.15 (s,
1H), 10.06 (s, 1H), 7.50 - 7.28 (m, 5H), 7.15 (s, 1H), 5.17 - 5.02 (m, 2H), 3.67 (dd, = 3.2, 1.6 Hz, 1H), 3.60 - 3.54 (m, 1H), 1.89 (qd, / = 7.5, 6.2, 3.1 Hz, 2H), 1.61 (dp, = 8.2, 1.9 Hz, 1H), 1.48 (dt, = 8.9, 1.5 Hz, 1H), 1.13 - 0.93 (m, 2H); MS (ES+): m/z=295.45 (M+l, 100%). Intermediate-15: 8-(Benzyloxy)-5-hydroxy-l,2,3,4-tetrahydro-l,4-ethanonaphthalene-6- carbaldehyde
Figure imgf000047_0001
The title compound was synthesized by procedure as described for intermediate- 14 by taking intermediate- 13. Yield = 82%. 1H NMR (400 MHz, DMSO-J6) δ 10.44 (d, / = 2.5 Hz, 1H), 10.04 (d, = 2.7 Hz, 1H), 7.45 - 7.24 (m, 6H), 5.11 (s, 2H), 3.55 - 3.46 (m, 2H), 1.75 (d, = 9.8 Hz, 4H), 1.20 (d, = 10.5 Hz, 5H); MS (ES+): m/z= 309.08 (M+l, 100%).
Intermediate-16: 8-(Benzyloxy)-6-formyl-l,2,3,4-tetrahydro-l,4-methanonaphthalen-5-yl trifluoromethanesulfonate
Figure imgf000047_0002
A solution of intermediate- 14 (6 g, 20.38 mmol) and triethylamine (4.26 ml, 30.6 mmol) in dichloromethane (50 ml) was cooled to 0 °C and treated with trifluoromethanesulfonic anhydride (4.48 ml, 26.5 mmol). After 30 min, TLC showed completion of reaction. The reaction was diluted with CH2C12 (150 ml), washed successively with sat. aq. NaHC03 (150 ml) and brine (50 ml), dried over Na2S04, and concentrated in vacuo to get 7.8g of crude compound. This residue was purified by chromatography over silica (100-200 mesh) (5: 1 hexanes : ethylacetate) to afford 8-(benzyloxy)-6-formyl- 1,2,3, 4-tetrahydro- 1,4- methanonaphthalen-5-yl trifluoromethane sulfonate (6.8g, 78 %) as a white solid. XH NMR (400 MHz, DMSO-J6) δ 9.98 (s, 1H), 7.57 (s, 1H), 7.54 - 7.32 (m, 5H), 5.27 (d, = 2.2 Hz, 2H), 3.67 (d, = 3.1 Hz, 1H), 3.59 (d, = 3.1 Hz, 1H), 2.01 (pt, = 9.7, 5.1 Hz, 2H), 1.74 (dt, / = 9.4, 2.0 Hz, 1H), 1.63 (dt, / = 9.3, 1.4 Hz, 1H), 1.26 - 1.07 (m, 2H); MS (ES+): m/z = 426.97 (M+l, 100%).
Intermediate-17: 8-(Benzyloxy)-6-formyl-l,2,3,4-tetrahydro-l,4-ethanonaphthalen-5-yl trifluoromethanesulfonate
Figure imgf000048_0001
The title compound was synthesized by procedure as described for intermediate- 16 by taking intermediate- 15. Yield = 55%. 1H NMR (400 MHz, DMSO-J6) δ 10.06 (d, / = 2.3 Hz, 1H), 7.61 (d, = 2.4 Hz, 1H), 7.52 - 7.38 (m, 5H), 5.29 (s, 2H), 3.59 (s, 1H), 3.3 l(s, 1H), 1.82 (q, = 11.6, 10.1 Hz, 4H), 1.29 (q, = 11.5, 11.0 Hz, 4H); MS (ES+): m/z= 440.98 (M+l, 100%).
Intermediate-18: 7-(Hydroxymethy - 1 ,2,3,4-tetrahydro- 1 ,4-methanonaphthalen-5-ol
Figure imgf000048_0002
To a solution of intermediate- 16 (6.8 g, 15.95 mmol), diethylamine (1.999 ml, 19.14 mmol) in MeOH (70 ml), Pd/C (0.679 g, 0.638 mmol) was added at 25 °C. The reaction mixture was then stirred under hydrogen atmosphere at 25 °C for 4 h. TLC showed completion of reaction. The reaction mixture was then filtered through celite under vacuum. This filtrate was then evaporated in vacuo to get 1.98g of crude residue. This was then purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 50% ethyl acetate in petroleum ether to afford 7-(hydroxymethyl)-l,2,3,4-tetrahydro-l,4-methanonaphthalen-5- ol (1.62g, 53.4%) as a off white solid. 1H NMR DMSO-d6 (400MHz): 8.93(s, 1H), 6.58(s, 1H), 6.48(s, 1H), 4.94(t, = 6.0Hz, 1H), 4.32(d, = 5.6Hz, 2H), 3.49-3.48(m, 1H), 3.24- 3.23(m, 1H), 1.86-1.78(m, 2H), 1.53-1.51(m, 1H), 1.42-1.34(m, 1H), 1.02-0.96(m, 2H) ); MS (ES+): m/z=189.47 (M+l, 100%).
Intermediate-19: 8-Hydroxy- 1 ,2,3,4-tetrahydro- 1 ,4-ethanonaphthalene-6-carbaldehyde
Figure imgf000048_0003
The title compound was synthesized by procedure as described for intermediate- 18 by taking intermediate- 17. Yield = 20%. 1H NMR (400 MHz, DMSO-J6) δ 9.85 (s, 1H), 9.74 (s, 1H), 7.22 (d, 7 = 1.4 Hz, 1H), 7.19 (d, 7 = 1.5 Hz, 1H), 3.44 (d, 7 = 3.2 Hz, 1H), 3.06 (d, 7 = 3.3 Hz, 1H), 1.83 - 1.74 (m, 4H), 1.28 - 1.18 (m, 4H); MS (ES+): m/z= 203.04 (M+l, 50%). Intermediate-20: 8-Hydroxy- 1 ,2,3,4-tetrahydro- 1 ,4-methanonaphthalene-6-carbaldehyde
Figure imgf000049_0001
Pyridiniumchlorochromate (0.935 g, 4.34 mmol) was added to a solution of intermediate- 18 (0.75 g, 3.94 mmol) in dichloromethane (10 ml) at 0 °C and the reaction mixture was stirred at 25 °C for 1 h. TLC showed completion of reaction. This residue was diluted with methylene chloride (50 ml) and washed with water (25 ml x 2). The organic phase was dried and evaporated in vacuo to get 0.75g crude compound. This crude material was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 20% ethyl acetate in petroleum ether to afford 8-hydroxy-l,2,3,4-tetrahydro-l,4- methanonaphthalene-6-carbaldehyde (0.64 g, 3.40 mmol, 86 % yield) as a colorless liquid. 1H NMR (400 MHz, DMSO-J6) δ 9.80 (s, 1H), 9.68 (s, 1H), 7.21 (d, 7 = 1.3 Hz, 1H), 7.07 (t, 7 = 1.8 Hz, 1H), 3.59 (t, 7 = 1.8 Hz, 1H), 3.39 (q, 7 = 1.6 Hz, 1H), 1.90 (ddt, 7 = 7.2, 3.4, 1.8 Hz, 2H), 1.62 (dq, 7 = 8.7, 1.9 Hz, 1H), 1.49 (dt, 7 = 8.8, 1.5 Hz, 1H), 1.09 - 1.02 (m, 2H); MS (ES+): m/z=187.47 (M+l, 100%).
Intermediate-21 : 7-Formyl- 1 ,2,3 ,4-tetrahydro- 1 ,4-methanonaphthalen-5-yl trifluoromethane sulfonate
Figure imgf000049_0002
To a solution of intermediate-20 (0.64 g, 3.40 mmol), triethylamine (0.711 ml, 5.10 mmol) in dichloromethane (10 ml), trifluoromethanesulfonic anhydride (0.747 ml, 4.42 mmol) was added at 0 °C. The reaction mixture was then stirred under nitrogen at 0 °C for 2h. TLC showed completion of reaction. The reaction mixture was diluted with water (25 ml) and dichloromethane (25 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 ml). The combined organic extract was washed with water (2 x 25 ml), brine (50 ml) and dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to get 0.7g of the crude residue. This residue was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 20% ethyl acetate in petroleum ether to afford 7-formyl-l,2,3,4-tetrahydro-l,4-methanonaphthalen-5-yl trifluoromethane sulfonate (0.53 g, 1.655 mmol, 48.7 % yield) as a pale yellow liquid. 1H NMR CDC13 (400MHz): 9.95(s, 1H), 7.72(s, 1H), 7.51(s, 1H), 3.73-3.72(m, 1H), 3.55-3.50(m, 1H), 2.07- 2.04(m, 2H), 1.90-1.88(m, 1H), 1.87-1.66(m, 1H), 1.36-1.32(m, 2H) ; MS (ES+): m/z=321.28 (M+l, 100%).
Intermediate-22: 7-Formyl- 1 ,2,3 ,4-tetrahydro- 1 ,4-ethanonaphthalen-5-yl trifluoromethane sulfonate
Figure imgf000050_0001
The title compound was synthesized by procedure as described for intermediate-21 by taking intermediate- 19. Yield = 65%. 1H NMR (400 MHz, DMSO-J6) δ 10.02 (s, 1H), 7.90 (d, = 1.3 Hz, 1H), 7.82 (d, = 1.2 Hz, 1H), 3.31 (dt, = 8.5, 2.5 Hz, 4H), 1.98 - 1.77 (m, 4H), 1.31 (d, = 8.9 Hz, 4H); MS (ES+): m/z= 335.06 (M+l, 100%).
Intermediate-23: 7-( 1 -Hydroxyethyl)- 1 ,2,3,4-tetrahydro- 1 ,4-ethanonaphthalen-5-yl trifluoromethanesulfonate
Figure imgf000050_0002
To a solution of intermediate-22 (200 mg, 0.598 mmol) in diethyl ether (5 ml) at 0 °C was added 3M methylmagnesium bromide in diethyl ether (0.219 ml, 0.658 mmol) drop wise. Reaction mixture was stirred for 15 min at 0 °C. TLC showed completion of reaction. Reaction mixture was quenched with a saturated aqueous NH4C1 (10 mL) solution, and the resulting mixture extracted with Et20 (20 mL x 2). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated in vacuo to afford 0.2 lg of
7-( 1 -hydroxyethyl)- 1 ,2,3 ,4-tetrahydro- 1 ,4-ethanonaphthalen-5-yl trifluoromethanesulfonate as a off white solid. 1H NMR (400 MHz, DMSO-J6) δ 7.31 (d, 7 = 1.4 Hz, 1H), 7.18 (s, 1H), 5.35 (d, 7 = 4.3 Hz, 1H), 4.81 - 4.72 (m, 1H), 3.21 (s, 1H), 3.12 (s, 1H), 1.81 (d, 7 = 12.4 Hz, 4H), 1.33 (d, 7 = 6.4 Hz, 3H), 1.28 (d, 7 = 10.1 Hz, 4H); MS (ES+): m/z= 373.05 (M+23, 20%).
Intermediate-24: 7-( 1-Hydroxypropyl)- 1 ,2,3,4-tetrahydro- 1 ,4-ethanonaphthalen-5-yl trifluoromethanesulfonate
Figure imgf000051_0001
The title compound was prepared by following the similar procedure as described in intermediate-23 by taking intermediate-22 and ethylmagnesium bromide. 1H NMR (400 MHz, DMSO-Je) δ 7.28 (s, 1H), 7.15 (s, 1H), 5.31 (d, 7 = 4.4 Hz, 1H), 4.50 (q, 7 = 5.7 Hz, 1H), 3.21 (s, 1H), 3.12 (s, 1H), 1.81 (d, 7 = 12.0 Hz, 4H), 1.59 (ddt, 7 = 13.7, 9.4, 6.7 Hz, 2H), 1.29 (d, 7 = 9.9 Hz, 4H), 0.85 (t, 7 = 7.3 Hz, 3H); MS (ES+): m/z = 387 (M+23, 20%). Intermediate-25: 7-Acetyl-l,2,3,4-tetrahydro-l,4-ethanonaphthalen-5-yl trifluoromethane sulfonate
Figure imgf000051_0002
Intermediate-23 (210 mg, 0.599 mmol) was dissolved in methylene chloride (3 ml). Then PCC (142 mg, 0.659 mmol) was added lot wise over 15 min at 25 °C. The reaction mixture was stirred for 2 h at 25°C. After completion of reaction, reaction mixture was quenched by ice water (10 ml) and extracted with ethyl acetate (10 ml). Organic layer was washed with brine (10 ml) & dried over anhydrous sodium sulphate, filtered and evaporated to get 0.240g of crude compound. This residue was purified by column chromatography on silica gel (mesh 100-200) with isocratic elution of 10% ethyl acetate in petroleum ether to give 7-acetyl- l,2,3,4-tetrahydro-l,4-ethanonaphthalen-5-yl trifluoromethanesulfonate (0.14g, 67%) as a white solid. 1H NMR (400 MHz, DMSO-J6) δ 7.99 (d, = 1.4 Hz, 1H), 7.75 (d, = 1.4 Hz, 1H), 3.29 (dt, = 8.0, 2.6 Hz, 2H), 2.62 (s, 3H), 1.94 - 1.77 (m, 4H), 1.30 (d, = 10.0 Hz, 4H); MS (ES+): m/z= 349.08 (M+l, 100%).
Intermediate-26 : 7-Propionyl- 1 ,2,3 ,4-tetrahydro- 1 ,4-ethanonaphthalen-5 -yl trifluoromethan esulfonate
Figure imgf000052_0001
The title compound was prepared by following the similar procedure as described in intermediate-25 by taking intermediate-24. 1H NMR (400 MHz, DMSO-J6) δ 7.98 (s, 1H), 7.76 (s, 1H), 3.29 (d, = 8.9 Hz, 2H), 3.09 (q, J = 7.1 Hz, 2H), 1.97 - 1.79 (m, 4H), 1.33 - 1.22 (m, 4H), 1.09 (t, = 7.1 Hz, 3H); MS (ES+): m/z = 363 (M+l, 100%).
Intermediate-27: 1 -(8-(4-(Trifluoromethyl)phenyl)- 1 ,2,3 ,4-tetrahydro- 1 ,4-ethano naphthalene-6-yl)ethan- 1 -one
Figure imgf000052_0002
The title compound was prepared by following the similar procedure as described in intermediate-6 by taking intermediate-25 and (4-(trifluoromethyl)phenyl)boronic acid. MS (ES+): m/z = 345.15 (M+l, 100%).
Intermediate-28: 1 -(8-(4-(Trifluoromethyl)phenyl)- 1 ,2,3 ,4-tetrahydro- 1 ,4-ethano naphthalen-6-yl)propan- 1 -one
Figure imgf000053_0001
The title compound was prepared by following the similar procedure as described in intermediate-6 by taking intermediate-26 and (4-(trifluoromethyl)phenyl)boronic acid. 1H NMR (400 MHz, DMSO-J6) δ 7.95 - 7.84 (m, 2H), 7.78 (dd, = 17.5, 1.5 Hz, 1H), 7.73 - 7.50 (m, 2H), 3.15 (d, = 3.2 Hz, 1H), 3.12 - 3.05 (m, 2H), 1.93 - 1.71 (m, 4H), 1.32 (q, = 10.2, 9.7 Hz, 4H), 1.13 - 1.06 (m, 3H); MS (ES+): m/z = 359.08 (M+l , 100%).
Intermediate-29: Ethyl 3-(5-(7-acetyl- 1 ,2,3, 4-tetrahydro- l , 4-ethanonaphthalen-5-yl)-2- methylphenyl)propanoate
Figure imgf000053_0002
The title compound was prepared by following the similar procedure as described in intermediate-6 by taking intermediate-25 and ethyl 3-(2-methyl-5-(4,4,5,5-tetramethyl- l ,3,2- dioxaborolan-2-yl)phenyl)propanoate. Yield = 91 %. 1H NMR (400 MHz, Chloroform-J) δ 7.80 (s, 1H), 7.77 (s, 1H), 7.29 (d, = 1.8 Hz, 2H), 7.17 (d, = 4.1 Hz, 1H), 4.17 (d, = 7.3 Hz, 2H), 3.17 (s, 1H), 3.03 (t, = 8.0 Hz, 2H), 2.69 - 2.60 (m, 5H), 2.42 (s, 3H), 1.82 (dq, = 22.0, 1 1.6 Hz, 4H), 1.43 (dq, / = 23.8, 12.6 Hz, 4H), 1.27 (d, = 7.3 Hz, 3H); MS (ES+): m/z= 391.21 (M+l , 100%).
Intermediate-30: Ethyl 3-(3-(7-acetyl- 1 ,2,3, 4-tetrahydro- l , 4-ethanonaphthalen-5-yl)-5- fluorophenyl)propanoate
Figure imgf000054_0001
The title compound was prepared by following the similar procedure as described in intermediate-6 by taking intermediate-25 and ethyl 3-(3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)propanoate. Yield = 81%. 1H NMR (400 MHz, Chloroform-J) δ 7.79 (d, 7 = 2.0 Hz, 2H), 7.02 - 6.90 (m, 3H), 4.16 (t, 7 = 7.1 Hz, 2H), 3.27 (s, 1H), 3.18 (s, 1H), 3.04 (t, 7 = 7.9 Hz, 2H), 2.76 - 2.58 (m, 5H), 1.83 (p, 7 = 11.3 Hz, 4H), 1.42 (dq, 7 = 24.5, 14.0, 13.2 Hz, 4H), 1.27 (td, 7 = 7.2, 1.9 Hz, 3H); MS (ES+): m/z= 366.41 (M+l, 100%).
Intermediate-31: Ethyl 3-(5-(2-acetyl-5,6,7,8-tetrahydroquinolin-4-yl)-2-methylphenyl) propanoate
Figure imgf000054_0002
The title compound was prepared by following the similar procedure as described in intermediate-6 by taking Intermediate-4 and ethyl 3-(2-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)propanoate. Yield = 85%. 1H NMR (400 MHz, DMSO-J6) δ 7.52 (s, 1H), 7.26 (d, 7 = 7.6 Hz, 1H), 7.13 (d, 7 = 9.1 Hz, 2H), 4.05 (q, 7 = 7.1 Hz, 2H), 2.98 (t, 7 = 6.3 Hz, 2H), 2.89 (t, 7 = 7.5 Hz, 2H), 2.68 - 2.61 (m, 7H), 2.33 (s, 3H), 1.87 (q, 7 = 7.1, 6.5 Hz, 2H), 1.72 - 1.66 (m, 2H), 1.15 (q, 7 = 7.2, 5.2 Hz, 3H); MS (ES+): m/z= 366.41 (M+l, 100%).
Intermediate-32: Ethyl 3-(3-(2-acetyl-5,6,7,8-tetrahydroquinolin-4-yl)-5-fluorophenyl) propanoate
Figure imgf000055_0001
The title compound was prepared by following the similar procedure as described in intermediate-6 by taking Intermediate-4 and ethyl 3-(3-fluoro-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)phenyl)propanoate. Yield = 65%. 1H NMR (400 MHz, DMSO-J6) δ 7.54 (s, 1H), 7.22 - 7.07 (m, 3H), 4.04 (q, = 6.9 Hz, 3H), 2.92 (tt, = 24.4, 7.0 Hz, 4H), 2.73 - 2.64 (m, 4H), 2.63 (s, 4H), 1.87 (q, / = 6.7, 6.3 Hz, 2H), 1.70 (t, = 5.8 Hz, 2H), 1.15 (q, J = 7.0 Hz, 5H), 1.07 (s, 2H); MS (ES+): m/z= 370.35 (M+l, 100%).
Intermediate-33: 8-(4-(Trifluoromethyl)phenyl)- 1 ,2,3,4-tetrahydro- 1 ,4-methano naphthalene-6-carbaldehyde
Figure imgf000055_0002
The title compound was prepared by following the similar procedure as described in intermediate-6 by taking aldehyde intermediate-21 and (4-(trifluoromethyl)phenyl)boronic acid. 1H NMR (400 MHz, DMSO-J6) δ 10.00 (s, 1H), 7.90 (d, = 8.1 Hz, 2H), 7.83 - 7.72 (m, 4H), 3.54 (dd, = 13.7, 3.1 Hz, 2H), 2.03 (tdq, = 10.8, 8.3, 3.6 Hz, 2H), 1.72 (dt, = 9.0, 1.9 Hz, 1H), 1.57 (dt, 7 = 9.0, 1.4 Hz, 1H), 1.36 - 1.15 (m, 2H) ; MS (ES+): m/z=317.06 (M+l, 100%).
Intermediate-34: 1 -(8-(4-(Trifluoromethyl)phenyl)- 1 ,2,3,4-tetrahydro- 1 ,4-methano naphthalen-6-yl)ethanol
Figure imgf000056_0001
To a solution of intermediate-33 (0.46 g, 1.454 mmol) in diethyl ether (10 ml) at 0 °C was added 3M methylmagnesium bromide (0.533 ml, 1.600 mmol) drop wise. After stirring for 5 min at 0 °C, a saturated aqueous NH4C1 (10 mL) solution was added and the resulting mixture extracted with diethyl ether (10 mL x 3). The combined organic layers were washed with brine (15 ml), dried over MgS04, filtered and concentrated in vacuo to afford 0.5g of crude compound. Flash chromatography over silica gel (100-200 mesh) (ethyl acetate/hexane = 3/10) afforded title compound (0.385g, 80%) as a colorless oil. 1H NMR (400 MHz, DMSO-J6) δ 7.85 (d, 7 = 8.1 Hz, 2H), 7.67 (d, 7 = 8.0 Hz, 2H), 7.24 (dd, 7 = 9.9, 1.4 Hz, 1H), 7.14 (dd, 7 = 9.8, 1.5 Hz, 1H), 5.12 (dd, 7 = 4.1, 2.5 Hz, 1H), 4.78 - 4.66 (m, 1H), 3.43 (d, 7 = 5.7 Hz, 2H), 2.03 - 1.90 (m, 2H), 1.65 (d, 7 = 8.7 Hz, 1H), 1.50 (dt, 7 = 8.7, 1.5 Hz, 1H), 1.34 (d, 7 = 6.4 Hz, 3H), 1.29 - 1.11 (m, 2H); MS (ES+): m/z = 333.06 (M+l, 100%). Intermediate-35: 1 -(8-(4-(Trifluoromethyl)phenyl)- 1 ,2,3,4-tetrahydro- 1 ,4-methano naphthalen-6-yl)ethanone
Figure imgf000056_0002
Intermediate-34 (0.385 g, 1.158 mmol) was suspended in dichloromethane (10 ml). Then pyridinium chlorochromate (0.275 g, 1.274 mmol) was added lot- wise over 15 mins. The reaction mixture was stirred for 2 h at 25 °C. After completion of reaction, reaction mixture was quenched by ice water (25 ml) and extracted with ethyl acetate (25 ml) and then washed with brine (25 ml). Organic layer was dried over anhydrous sodium sulphate and evaporated to get 0.58g of crude compound. This residue was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 25% ethyl acetate in petroleum ether to afford 1 -(8-(4-(trifluoromethyl)phenyl)- 1 ,2,3,4-tetrahydro- 1 ,4-methanonaphthalen-6-yl) ethanone (0.355g, 93%) as a off white solid. 1H NMR (400 MHz, DMSO-J6) δ 7.89 (d, = 8.1 Hz, 2H), 7.83 (d, 7 = 1.5 Hz, 1H), 7.81 (d, 7 = 1.6 Hz, 1H), 7.75 (d, 7 = 8.0 Hz, 2H), 3.52 (d, 7 = 11.9 Hz, 2H), 2.60 (s, 3H), 2.02 (tt, 7 = 5.9, 3.0 Hz, 2H), 1.72 - 1.68 (m, 1H), 1.56 (dt, 7 = 9.0, 1.4 Hz, 1H), 1.31 - 1.16 (m, 2H) ; MS (ES+): m/z=331.12 (M+l, 100%).
Intermediate-36: Methyl 5-(7-formyl- 1 ,2,3,4-tetrahydro- 1 ,4-methanonaphthalen-5-yl)-2- methylbenzoate
Figure imgf000057_0001
The title compound was prepared by following the similar procedure as described in intermediate-6 by taking aldehyde intermediate-21 and (3-(methoxycarbonyl)-4- methylphenyl)boronic acid. 1H NMR (400 MHz, CDC13) δ 10.00(s, 1H), 8.06(s, 1H), 7.69(d, / = 1.6Hz, 2H), 7.54-7.52(m, 1H), 7.37-7.36(m, 1H), 3.94(s, 3H), 3.58-3.52(m, 2H), 2.68(s, 3H), 2.10-2.00(m, 2H), 1.85-1.75(m, 1H), 1.60-1.58(m, 1H), 1.33-1.29(m, 2H) ; MS (ES+): m/z=321.38 (M+l, 100%).
Intermediate-37: Methyl 5-(2-formyl-5,6,7,8-tetrahydroquinolin-4-yl)-2-methylbenzoate
Figure imgf000057_0002
The title compound was prepared by following the similar procedure as described in intermediate-6 by taking aldehyde intermediate-9 and (3-(methoxycarbonyl)-4- methylphenyl)boronic acid. 1H NMR (400 MHz, CDC13) δ 10.10(s, 1H), 7.88(s, 1H), 7.68(s, 1H), 7.36-7.35(m, 2H), 3.96(s, 3H), 3.15-3.12(m, 2H), 2.75-2.70(m, 2H), 2.69(s, 3H), 2.01- 1.97(m, 2H), 1.82-1.77(m, 2H) ; MS (ES+): m/z=310.00 (M+l, 100%).
Intermediate-38: 4-Hydroxy-N-methoxy-N-methylquinoline-2-carboxamide
Figure imgf000058_0001
4-Hydroxyquinoline-2-carboxylic acid hydrate (4.5 g, 21.72 mmol) was suspended in DMF (35 ml) and Ν,Ο-dimethylhydroxylamine hydrochloride (4.24 g, 43.4 mmol), HOBt (4.99 g, 32.6 mmol), EDC (6.25 g, 32.6 mmol) and triethylamine (4.54 ml, 32.6 mmol) were added. The clear solution was heated at reflux condition for 16 hrs. TLC showed completion of reaction. Solvent was evaporated in vacuo, the residue was poured in saturated NaHC03 solution (50 ml) and brine (50 ml). Product was extracted with 10% methanol in methylene chloride (50 ml x 4). The organic phase was dried and evaporated. The crude compound was purified by column chromatography on silica gel (100-200 mesh) with isocratic elution of 5% MeOH in methylene chloride to get sufficiently pure 4-hydroxy-N-methoxy-N- methylquinoline-2-carboxamide (2 g, 8.61 mmol, 39.6 % yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-J6) δ 12.11 (s, 1H), 8.09 (d, = 8.1 Hz, 1H), 7.69 (q, = 6.1, 4.2 Hz, 2H), 7.37 (d, = 7.7 Hz, 1H), 6.25 (s, 1H), 3.33 (s, 3H); MS (ES+) m/z=233.39 (M+l, 100%).
Intermediate-39: 2-(Methoxy(methyl)carbamoyl)quinolin-4-yl trifluoromethanesulfonate
Figure imgf000058_0002
To a stirred solution of intermediate-38 (2g, 8.61 mmol) and triethylamine (3.60 ml, 25.8 mmol) in dichloromethane (20 ml) was added triflic anhydride (1.891 ml, 11.20 mmol) at 0 °C and reaction mixture was stirred at 25 °C for 3h. After completion of reaction, reaction mixture quenched by using ice water (15 mL) and extracted with ethyl acetate (2 x 100 mL). Combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to get the crude compound, which was purified by column chromatography on silica gel (100-200 mesh) with isocratic elution of 10% ethyl acetate in hexane to get 2- (methoxy(methyl)carbamoyl)quinolin-4-yl trifluoromethanesulfonate (2.2 g, 6.04 mmol, 70.1 % yield) as an off white solid. 1H NMR (400 MHz, DMSO-J6) δ 8.27 (dt, = 8.6, 0.8 Hz, 1H), 8.11 (dd, = 8.3, 1.3 Hz, 1H), 8.05 (ddd, = 8.5, 7.0, 1.5 Hz, 1H), 8.00 (s, 1H), 7.96 (ddd, / = 8.2, 6.9, 1.2 Hz, 1H), 3.70 (s, 3H) ); MS (ES+) m/z=233.39 (M+l, 100%).
Intermediate-40: 2-Formylquinolin-4-yl trifluoromethanesulfonate
Figure imgf000059_0001
To a stirred solution of intermediate-39 (0.5g, 1.373 mmol) in THF (5 ml) was added DIBAL (1M in THF, 2.059 ml, 2.059 mmol) drop wise at -78°C. The resulting mixture was stirred at same temperature for lh. TLC showed completion of reaction. The reaction was quenched with aqueous NH4C1 (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic phase was dried over anhydrous Na2S04, filtered and then concentrated to give the crude product, which was purified by chromatography on silica gel (100-200 mesh) with hexane/ethyl acetate (20: 1) as the eluent to afford title compound (0.183g, 44%) as a white solid. 1H NMR (400 MHz, DMSO-J6) δ 10.11 (s, 1H), 8.41 (d, = 8.4 Hz, 1H), 8.12 (ddd, = 8.4, 6.9, 1.5 Hz, 1H), 7.97 (ddd, = 8.4, 6.9, 1.5 Hz, 1H), 7.85 (t, = 7.7 Hz, 1H), 7.80 (s, 1H) ; MS (ES+) m/z= 305.88 (M+l, 100%).
Intermediate-41 : 2- Acetylquinolin-4-yl trifluoromethanesulfonate
Figure imgf000059_0002
To a stirred solution of intermediate-39 (2.2 g, 6.04 mmol) in THF (20 ml) was added methylmagnesium bromide (2.013 ml, 6.04 mmol) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 mins. TLC showed completion of reaction. The reaction was quenched with aqueous NH4CI (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic phase was dried over anhydrous Na2S04, filtered and then concentrated to give the crude product, which was purified by chromatography on silica gel (100-200 mesh) with hexane/ethyl acetate (20: 1) as the eluent to afford title compound (1.56 g, 80%) as a white solid. 1H NMR (400 MHz, DMSO-J6) δ 8.39 (d, = 8.5 Hz, 1H), 8.20 - 8.07 (m, 3H), 8.03 (t, = 7.7 Hz, 1H), 2.81 (s, 3H) ; MS (ES+) m/z= 319.97 (M+l, 100%).
Intermediate-42: 2-(l-Hydroxypropyl)quinolin-4-yl trifluoromethanesulfonate
Figure imgf000060_0001
The title compound was prepared by following the similar procedure as described in intermediate-41 by using intermediate-40 and ethylmagnesium bromide. Yield: 25%. H NMR (400 MHz, DMSO-J6) δ 8.15 (d, = 8.4 Hz, 1H), 8.03 (d, = 8.3 Hz, 1H), 7.95 (ddd, = 8.4, 6.9, 1.4 Hz, 1H), 7.83 (t, = 7.6 Hz, 1H), 7.78 (s, 1H), 5.83 (s, 1H), 4.75 (dd, = 7.5, 4.9 Hz, 1H), 1.91 - 1.69 (m, 2H), 0.90 (t, = 7.4 Hz, 3H); MS (ES+) m/z= 336.34 (M+l, 100%).
Intermediate-43 : 2-Propionylquinolin-4-yl trifluoromethanesulfonate
Figure imgf000060_0002
To a stirred solution of intermediate-42 (0.28 g, 0.835 mmol) in methylene chloride (5 ml) was added Dess-Martin periodinane (0.425g, 1.002 mmol) dropwise at 0 °C. The resulting mixture was stirred at same temperature for 2 h. TLC showed completion of reaction. The reaction was quenched with aqueous saturated NaHC03 (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic phase was dried over anhydrous Na2S04, filtered and then concentrated to give the crude product, which was purified by chromatography on silica gel (100-200 mesh) with hexane/ethyl acetate (20: 1) as the eluent to afford title compound (0.192 g, 70%) as a white solid. 1H NMR (400 MHz, DMSO-J6) δ 8.36 (d, = 8.4 Hz, 1H), 8.16 - 8.06 (m, 3H), 8.02 (ddd, / = 8.2, 6.9, 1.2 Hz, 1H), 3.38 (q, 1.18 (t, = 7.2 Hz, 3H); MS (ES+): m/z = 334.09 (M+l , 100%).
Intermediate-44: 3-Acetylisoquinolin-l- l trifluoromethanesulfonate
Figure imgf000061_0001
The title compound was prepared by following the similar procedure as described in intermediate-39 by using l-(l-hydroxyisoquinolin-3-yl)ethan-l-one (synthesized as described in current science 1979, 48(13), p 580-581). Yield: 84%. 1H NMR (400 MHz, DMSO-Je) δ 8.75 (s, 4H), 8.46 (d, = 7.9 Hz, 4H), 8.23 (d, = 8.0 Hz, 4H), 8.09 (p, = 7.1 Hz, 8H), 2.66 (s, 12H); MS (ES+) m/z= 319.97 (M+l , 100%).
Intermediate-45: 4-(4-(Trifluoromethyl)phenyl)quinoline-2-carbaldehyde
Figure imgf000061_0002
To an oven-dried round-bottomed flask with a side-arm and condenser, was added intermediate-40 (0.5g, 1.638 mmol), (4-(trifluoromethyl) phenyl)boronic acid (0.31 lg, 1.638 mmol) and anhydrous dioxane (5 ml) under N2 atmosphere. A degassed aqueous 2M solution of sodium carbonate (2.46 ml, 4.91 mmol) was then added via syringe to the vigorously stirred reaction mixture, followed by tetrakis(triphenylphosphine)palladium (0) (0.095g, 0.082 mmol). The reaction mixture was stirred at 80 °C for 70 mins under microwave irradiation. TLC showed completion of reaction. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic phase were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. This residue was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 15% ethyl acetate in petroleum ether to afford the title compound (0.373g, 76%) as a off white solid. 1H NMR (400 MHz, DMSO-J6) δ 10.20 (s, 1H), 8.36 (d, = 8.4 Hz, 1H), 8.00 (dd, = 7.4, 5.1 Hz, 3H), 7.94 - 7.89 (m, 2H), 7.88 - 7.79 (m, 3H); MS (ES+): m/z = 302.13 (M+l, 100%).
Intermediate-46: l-(4-(4-(Trifluoromethyl)phenyl)quinolin-2-yl)ethanone
Figure imgf000062_0001
The title compound was prepared by following the similar procedure as described in intermediate-45 by using Intermediate-41 and (4-(trifluoromethyl)phenyl)boronic acid. Yield: 84%. 1H NMR (400 MHz, DMSO-J6) δ 8.30 (d, = 8.5 Hz, 1H), 8.01 - 7.92 (m, 4H), 7.88 (d, = 8.4 Hz, 1H), 7.86 - 7.73 (m, 3H), 2.82 (s, 3H) ; MS (ES+) m/z= 316.28 (M+l, 100%).
Intermediate-47: l-(4-(4-(Trifluoromethyl)phenyl)quinolin-2-yl)propan-l-one
Figure imgf000062_0002
The title compound was prepared by following the same procedure as described in intermediate-45 by using intermediate-43 and (4-(trifluoromethyl)phenyl)boronic acid. 1H NMR (400 MHz, DMSO-J6) δ 8.29 (d, = 8.5 Hz, 1H), 7.96 (q, = 8.5, 8.0 Hz, 4H), 7.84 (td, = 21.0, 8.0 Hz, 4H), 3.45 - 3.37 (m, 2H), 1.19 (t, = 7.2 Hz, 3H).
Intermediate-48: l-(l-(4-(Trifluoromethyl)phenyl)isoquinolin-3-yl)ethanone
Figure imgf000063_0001
The title compound was prepared by following the similar procedure as described in intermediate-45 by using intermediate-44 and (4-(trifluoromethyl)phenyl)boronic acid. 1H NMR (400 MHz, Chloroform- d) δ 8.54 (s, 1H), 8.12 (t, / = 8.0 Hz, 2H), 7.92 (d, = 8.1 Hz, 2H), 7.87 (d, = 8.1 Hz, 2H), 7.82 (t, J = 7.5 Hz, 1H), 7.72 (dd, / = 8.6, 6.8 Hz, 1H), 2.87 (s, 3H) ; MS (ES+) m/z= 316.28 (M+l , 100%).
Intermediate-49: Methyl 5-(2-acetylquinolin-4-yl)-2-methylbenzoate
Figure imgf000063_0002
The title compound was prepared by following the similar procedure as described in intermediate-45 by using intermediate-41 and (3-(methoxycarbonyl)-4-methylphenyl)boronic acid. XH NMR (400 MHz, DMSO-d6) δ 8.29 (dd, = 8.4, 1.3 Hz, 1H), 8.04 - 7.88 (m, 4H), 7.84 - 7.69 (m, 2H), 7.59 (d, = 7.9 Hz, 1H), 3.85 (s, 3H), 2.82 (s, 3H), 2.65 (s, 3H), 1.23 (s, 1H); MS (ES+): m/z=320.06 (M+l, 100%).
Intermediate-50: Methyl 5-(2-acetylquinolin-4-yl)-2-fluoro-3-methylbenzoate
Figure imgf000063_0003
The title compound was prepared by following the similar procedure as described in intermediate-45 by using intermediate-41 and methyl 2-fluoro-3-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate. MS (ES+): m/z=338.47 (M+1, 100%).
Intermediate-51 : Ethyl 3-(5-(2-acetylquinolin-4-yl)-2-methylphenyl)propanoate
Figure imgf000064_0001
The title compound was prepared by following the similar procedure as described in intermediate-45 by using intermediate-41 and ethyl 3-(2-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)propanoate. 1H NMR (400 MHz, DMSO-J6) δ 8.27 (d, = 8.4 Hz, 1H), 8.02 - 7.96 (m, 1H), 7.95 - 7.91 (m, 1H), 7.90 (d, = 2.2 Hz, 1H), 7.75 (ddd, = 8.3, 6.9, 1.3 Hz, 1H), 7.41 - 7.31 (m, 3H), 4.06 (q, J = 7.1 Hz, 2H), 2.96 (t, = 7.6 Hz, 2H), 2.82 (s, 3H), 2.67 (t, = 7.6 Hz, 2H), 2.40 (s, 3H), 1.13 (t, = 7.1 Hz, 3H); MS (ES+): m/z = 362.41 (M+1, 100%).
Intermediate-52: Ethyl 3-(3-(2-acetylquinolin-4-yl)-5-fluorophenyl)propanoate
Figure imgf000064_0002
The title compound was prepared by following the similar procedure as described in Intermediate-45 by using Intermediate-41 and ethyl 3-(3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)propanoate. 1H NMR (400 MHz, DMSO-J6) δ 8.29 (dd, = 8.8, 1.2 Hz, 1H), 7.99 - 7.89 (m, 3H), 7.78 (ddd, = 8.2, 6.9, 1.3 Hz, 1H), 7.37 - 7.26 (m, 3H), 4.06 (q, = 7.1 Hz, 2H), 2.99 (t, = 7.5 Hz, 2H), 2.82 (s, 3H), 2.74 (t, = 7.5 Hz, 2H), 1.29 - 1.10 (m, 3H); MS (ES+): m/z= 366.12 (M+1, 100%). Intermediate-53: Methyl 5-(3-acetyliso uinolin- l-yl)-2-methylbenzoate
Figure imgf000065_0001
The title compound was prepared by following the similar procedure as described in intermediate-45 by using intermediate-44 and (3-(methoxycarbonyl)-4-methylphenyl)boronic acid. 1H NMR (400 MHz, DMSO-J6) δ 8.57 (d, = 3.0 Hz, 1H), 8.34 (d, = 8.2 Hz, 1H), 8.18 (s, 1H), 8.09 (d, = 8.6 Hz, 1H), 7.97 - 7.87 (m, 2H), 7.83 (t, = 7.8 Hz, 1H), 7.60 (d, = 7.6 Hz, 1H), 3.87 (d, = 2.6 Hz, 3H), 2.75 (d, = 2.7 Hz, 3H), 2.67 (s, 3H), 1.24 (s, 1H); MS (ES+): m/z=320.15 (M+l, 100%).
Intermediate-54: Ethyl 3-(5-(3-acetylisoquinolin- 1 -yl)-2-methylphenyl)propanoate
Figure imgf000065_0002
The title compound was prepared by following the similar procedure as described in intermediate-45 by using intermediate-44 and ethyl 3-(2-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)propanoate. Yield = 70%. 1H NMR (400 MHz, DMSO-J6) δ 8.52 (d, = 10.1 Hz, 1H), 8.31 (d, = 8.2 Hz, 1H), 8.13 (d, = 8.5 Hz, 1H), 7.90 (t, = 7.5 Hz, 1H), 7.80 (t, = 7.7 Hz, 1H), 7.52 (d, = 9.5 Hz, 2H), 7.40 (d, = 7.7 Hz, 1H), 4.06 (q, = 7.1 Hz, 2H), 2.98 (t, = 7.5 Hz, 2H), 2.75 (s, 3H), 2.68 (t, = 7.6 Hz, 2H), 2.42 (s, 3H), 1.12 (t, = 7.1 Hz, 3H); MS (ES+): m/z= 362.41 (M+l, 100%).
Intermediate-55: Ethyl 3-(5-(3-acetylisoquinolin- 1 -yl)-2-fluorophenyl)propanoate
Figure imgf000066_0001
The title compound was prepared by following the similar procedure as described in intermediate-45 by using intermediate-44 and ethyl 3-(2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)propanoate. XH NMR (400 MHz, DMSO-J6) δ 8.54 (s, 1H), 8.33 (d, / = 8.4 Hz, 1H), 8.11 (d, = 8.5 Hz, 1H), 7.92 (s, 1H), 7.82 (t, = 8.0 Hz, 1H), 7.78 - 7.65 (m, 2H), 7.41 (t, = 9.5 Hz, 1H), 4.06 (q, = 7.6, 6.9 Hz, 2H), 3.02 (t, = 7.7 Hz, 2H), 2.80 - 2.68 (m, 5H), 1.19 - 1.06 (m, 3H); MS (ES+): m/z= 366.35 (M+l, 100%).
Intermediate-56: Ethyl 3-(3-(3-acetylisoquinolin- 1 -yl)-5-fluorophenyl)propanoate
Figure imgf000066_0002
The title compound was prepared by following the similar procedure as described in intermediate-45 by using intermediate-44 and ethyl 3-(3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)propanoate. 1H NMR (400 MHz, Chloroform-J) δ 8.50 (s, 1H), 8.17 (d, = 8.5 Hz, 1H), 8.09 (d, = 8.2 Hz, 1H), 7.80 (t, J = 7.5 Hz, 1H), 7.71 (t, 7 = 7.7 Hz, 1H), 7.41 (s, 1H), 7.36 (dd, = 9.0, 2.4 Hz, 1H), 7.13 (d, = 9.4 Hz, 1H), 4.21 - 4.15 (m, 2H), 3.11 (t, = 7.7 Hz, 2H), 2.73 (t, = 7.7 Hz, 2H), 1.27 (d, = 7.0 Hz, 3H); MS (ES+): m/z= 366.12 (M+l, 100%).
Intermediate-57: 3-Acetylnaphthalen- 1 -yl tnfluoromethanesulfonate
Figure imgf000067_0001
The title compound was prepared by following the procedure given in WO2015/028938. Intermediate-58: l-(4-(6-(Trifluoromethyl)pyridin-3-yl)naphthalen-2-yl)ethanone
Figure imgf000067_0002
Intermediate-57 (0.300 g, 0.943 mmol), (6-(trifluoromethyl)pyridin-3-yl)boronic acid (0.18g, 0.943 mmol) , anhydrous dioxane (5 ml) wad added under N2 atmosphere. A degassed aqueous solution of potassium carbonate (0.39 lg in 0.625 ml water, 2.828 mmol) was then added via syringe to the vigorously stirred reaction mixture, followed by tetrakis(triphenylphosphine)palladium(0) (0.0545 g, 0.0471 mmol). The reaction mixture was stirred at 80 °C for lh under microwave irradiation. TLC showed completion of reaction. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic phase were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. This residue was purified by column chromatography over silica gel (100- 200 mesh) with an isocratic elution of 15% ethyl acetate in petroleum ether to afford l-(4-(4- (trifluoromethyl)phenyl)quinolin-2-yl)ethanone (0.2g, 91%) as a off white solid. 1H NMR (400 MHz, DMSO-J6) δ 8.94 (d, = 2.1 Hz, 1H), 8.85 - 8.81 (m, 1H), 8.29 (ddd, = 8.4, 3.9, 2.4 Hz, 2H), 8.11 (dd, 7 = 8.1, 0.9 Hz, 1H), 7.99 (d, = 1.7 Hz, 1H), 7.81 - 7.76 (m, 1H), 7.76 - 7.65 (m, 2H), 2.76 (s, 3H); MS (ES+) m/z= 316.1 (M+l, 100%).
The below Intermediates-59 to 77 given in Table- 1 were prepared by following the similar procedures as described herein above by using appropriately substituted boronates. Table-1:
Intermediate Structure (IUPAC name) 1H NMR data; MS(ES+)
59 0 Ή NMR (400 MHz, Chloroform-d) δ 8.43
(t, = 1.3 Hz, 1H), 8.25 - 8.17 (m, 1H), 8.09 - 7.95 (m, 2H), 7.78 (d, = 0.8 Hz,
1H), 7.70 - 7.56 (m, 3H), 4.06 (s, 3H),
N-N
/ 2.76 (s, 3H). MS (ES+) m/z= 251 (M+l, l-(4-(l -Methyl- lH-pyrazol -4- 100%).
yl)naphthalen-2-yl) ethan-l-one
60 0 Ή NMR (400 MHz, DMSO-J6) δ 8.78 (d,
J = 1.1 Hz, 1H), 8.30 - 8.22 (m, 1H), 8.13 (dd, = 6.2, 2.3 Hz, 1H), 7.97 - 7.86 (m, 2H), 7.77 (dt, = 7.4, 3.2 Hz, 1H), 7.72 -
7.68 (m, 2H), 7.57 - 7.51 (m, 1H), 2.75 (s,
F 3H); MS (ES+) m/z= 290.06 (M+l,
5-(3-Acetylnaphthalen-l-yl)-2- 100%).
fluorobenzonitrile
61 0 Ή NMR (400 MHz, DMSO-J6) δ 8.78 (d,
J = 1.1 Hz, 1H), 8.30 - 8.22 (m, 1H), 8.13 (dd, = 6.2, 2.3 Hz, 1H), 7.97 - 7.86 (m, 2H), 7.77 (dt, = 7.4, 3.2 Hz, 1H), 7.72 -
7.68 (m, 2H), 7.57 - 7.51 (m, 1H), 2.75 (s,
CN 3H); MS (ES+) m/z= 290.09 (M+l,
4-(3-Acetylnaphthalen-l-yl)-2- 100%).
fluorobenzonitrile
Figure imgf000069_0001
Figure imgf000070_0001
1 -(4-( 1 -Methyl- lH-indol-5- 6.57 (d, = 3.1 Hz, 1H), 3.89 (s, 3H), 2.83 yl)quinolin-2-yl)ethan- 1 -one (s, 3H); MS (ES+): m/z= 301.05 (M+l,
100%).
0 Ή NMR (400 MHz, DMSO-J6) δ 8.33 - 8.24 (m, 1H), 8.01 - 7.89 (m, 3H), 7.83 - 7.73 (m, 1H), 7.38 - 7.25 (m, 3H), 2.82 (s, 3H); MS (ES+): m/z= 290.84 (M+l, 100%).
F
5-(2-Acetylquinolin-4-yl)-2- fluorobenzonitrile
0 Ή NMR (400 MHz, DMSO-J6) δ 8.98 (d,
= 2.1 Hz, 1H), 8.88 (t, = 1.3 Hz, 1H), 8.22 (dd, / = 7.7, 1.7 Hz, 1H), 8.05 - 7.93 (m, 3H), 7.89 - 7.76 (m, 2H), 2.83 (s, 3H); MS (ES+): m/z= 273.96 (M+l,
CN 100%).
5-(2-Acetylquinolin-4-yl)
picolinonitrile
0 *H NMR (400 MHz, DMSO-J6) δ 8.41 (s,
1H), 8.36 (dd, = 8.5, 1.4 Hz, 1H), 8.22 (dd, = 8.5, 1.3 Hz, 1H), 8.00 (d, = 1.5 Hz, 2H), 7.95 - 7.87 (m, 1H), 7.79 (ddd,
N-N
/ = 8.3, 6.9, 1.3 Hz, 1H), 3.99 (s, 3H), 2.80
1 -(4-( 1 -Methyl- lH-pyrazol-4- (s, 3H); MS (ES+): m/z= 273.96 (M+l, yl)quinolin-2-yl)ethan- 1 -one 100%). 0 Ή NMR (400 MHz, DMSO-J6) δ 8.61 (s, 1H), 8.41 - 8.32 (m, 2H), 8.20 (ddd, = 8.1, 5.3, 2.3 Hz, 1H), 8.10 (d, = 8.4 Hz, 1H), 7.95 (ddd, = 8.1, 6.9, 1.2 Hz, 1H), 7.85 (ddd, = 8.3, 6.9, 1.3 Hz, 1H), 7.79
F (t, = 9.0 Hz, 1H), 2.76 (s, 3H); MS
5-(3-Acetylisoquinolin-l-yl) -2- (ES+): m/z= 290.84 (M+l, 100%).
fluorobenzonitrile
0 Ή NMR (400 MHz, DMSO-J6) δ 8.64 (s,
1H), 8.37 (d, = 8.2 Hz, 1H), 8.19 (dd, = 8.0, 6.8 Hz, 1H), 8.10 (d, = 8.3 Hz, 1H), 8.01 - 7.92 (m, 2H), 7.89 - 7.79 (m, 2H), 2.75 (s, 3H); MS (ES+): m/z= 290.84
CN (M+l, 100%).
4-(3-Acetylisoquinolin-l-yl) -2- fluorobenzonitrile
0 Ή NMR (400 MHz, DMSO-J6) δ 9.18 (s,
1H), 8.66 (s, 1H), 8.50 (d, = 8.1 Hz, 1H), 8.40 (d, = 8.3 Hz, 1H), 8.32 (d, = 8.0 Hz, 1H), 8.11 (d, = 8.5 Hz, 1H), 7.97 (t, = 7.7 Hz, 1H), 7.88 (t, = 7.8 Hz,
CN 1H), 2.77 (d, = 1.9 Hz, 3H); MS (ES+):
5-(3-Acetylisoquinolin- 1 -yl) m/z= 274.40 (M+l, 100%).
picolinonitrile
Figure imgf000073_0001
yl)ethan-l-one
Intermediate-78: l-(8-(6-(Trifluoromethyl)pyridin-3-yl)-l,2,3,4-tetrahydro-l,4- ethanonaphthalen-6-yl)ethan- 1 -one.
Figure imgf000074_0001
The title compound was prepared by following the similar procedure as described in intermediate-6 by taking intermediate-25 and (6-(trifluoromethyl)pyridin-3-yl)boronic acid. Yield = 94%, 1H NMR (400 MHz, Chloroform-J) δ 8.77 (d, J = 2.1 Hz, 1H), 7.94 - 7.82 (m, 3H), 3.20 (dt, = 13.4, 2.7 Hz, 2H), 2.66 (s, 3H), 1.95 - 1.79 (m, 4H), 1.52 - 1.40 (m, 4H); MS (ES+): m/z = 346.11 (M+l , 100%).
Intermediate-79: l-(8-( 1-Methyl- lH-indol-5-yl)- 1 ,2,3,4-tetrahydro- 1 ,4-ethanonaphthalen-6- yl)ethan-l-one.
Figure imgf000074_0002
The title compound was prepared by following the similar procedure as described in intermediate-6 by taking intermediate-25 and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indole. Yield = 79%, MS (ES+): m/z = 330.53 (M+l, 100%).
Intermediate-80: Methyl 5-(2-acetyl-5,6,7,8-tetrahydroquinolin-4-yl)-2-methylbenzoate
Figure imgf000074_0003
The title compound was prepared by following the similar procedure as described in Intermediate-6 by taking Intermediate-4 and (3-(methoxycarbonyl)-4-methylphenyl)boronic acid. Yield = 86%; 1H NMR (400 MHz, DMSO-J6) δ 7.78 (s, 1H), 7.54 (d, / = 8.2 Hz, 2H), 7.46 (d, / = 7.9 Hz, 1H), 2.99 (t, = 6.5 Hz, 2H), 2.64 (d, = 10.3 Hz, 5H), 2.58 (s, 3H), 1.88 (p, = 6.3 Hz, 2H), 1.70 (p, J = 6.0 Hz, 2H); MS (ES+): m/z= 324.17 (M+l, 100%).
EXAMPLES
Example-1 : (R)-Methyl 2-methyl-5-(2-((( 1 -(naphthalen- 1 -yl)ethyl)amino)methyl)-5 ,6,7, 8- tetrahydroquinolin-4-yl)benzoat
Figure imgf000075_0001
Intermediate-37 (0.103 g, 0.333 mmol) was added to a solution of (R)- 1 -(naphthalen- 1- yl)ethanamine (0.057 g, 0.333 mmol) in dichloroethane (3 ml) and resulting mixture was stirred at 25 °C for 5 hrs. The reaction mixture was allowed to 0 °C and added sodium triacetoxyborohydride (0.106 g, 0.499 mmol) then allowed to 25 °C and further maintained for 16 hours. TLC showed the reaction completion. The reaction mixture was diluted with water (25 ml) and dichloromethane (25 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 5 ml). The combined organic extract was washed with water (2 x 25 ml), brine (50 ml) and dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to get 1.5g of the crude residue. This residue was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 35% ethyl acetate in petroleum ether to afford title compound (0.12g, 78%) as off white solid. 1H
NMR (400 MHz, DMSO-J6) δ 9.84(brs, 1H), 8.13-8.10(m, 1H), 8.01-7.95(m, 3H), 7.65- 7.57(m, 4H), 7.42-7.06(m, 2H), 7.06(s, 1H), 5.42(brs, 1H), 4.23-4.19(m, 2H), 3.85(s, 3H), 2.88(t, J =4.0Hz, 2H), 2.55(s, 3H), 1.85-1.82(m, 2H), 1.74(d, =6.4Hz, 3H), 1.25-1.23(m, 4H); MS (ES+): m/z=464.5 (M+l, 100%).
Examples 2 and 3 given in table-2 were prepared by following same procedure as described in Example- 1 by taking appropriate aldehyde intermediate and amine intermediate.
Table-2:
Figure imgf000076_0001
Example-4: (R)-2-Methyl-5-(2-(((l-(naphthalen-l-yl)ethyl)amino)methyl)-5,6,7,8-tetra hydroquinolin-4-yl)benzoic acid hydrochloride
Figure imgf000077_0001
To a stirred solution of Example-1 (0.065 g, 0.140 mmol) in MeOH:THF:H20 (5 ml, 2:2: 1) was added NaOH (0.034 g, 1.399 mmol) at 25 °C. Reaction mixture was then refluxed for 2 hr at 80 °C. TLC showed completion of reaction. Reaction mixture was concentrated in vaccuo to get the residue. Residue was then acidified with dil. HCl (5 ml) at 0 °C, stirred & filtered to get pure compound. Ethereal HCl (3 ml) was then added to this compound & sonicated for 2 minutes. Solvent was evaporated on rotary evaporator and resulting solid was triturated twice with n-pentane to give title compound (0.045g, 66%) as a off white solid. 1H NMR (400 MHz, DMSO-J6) δ 10.19(brs, 2H), 8.17-8.15(m, 1H), 8.03-7.96(m, 3H), 7.74(s, 1H), 7.62-7.56(m, 3H), 7.44(s, 2H), 7.39(s, 1H), 5.45(s, 1H), 4.38-4.33(m, 2H), 2.91(t, = 4.0Hz, 2H), 2.59-2.50(m, 5H), 1.83-1.82(m, 2H), 1.76(d, = 6.4Hz, 3H), 1.65-1.64(m, 2H); MS (ES+): m/z=450.9 (M+l, 100%).
The below Examples 5 and 6 given in table-3 were prepared by following the similar ester hydrolysis procedure as described in Example-4.
Table-3:
Figure imgf000078_0001
Example-7: ( 1R)- 1 -(3-methoxyphenyl)-N-(( 1 R/l S)- 1 -(8-(4-(trifluoromefhyl)phenyl)-
1 ,2,3,4-tetrahydro- 1 ,4-methanonaphthalen-6-yl)ethyl)ethan- 1 -amine hydrochloride
Figure imgf000079_0001
Intermediate-35 (0.075 g, 0.227 mmol) was added to a solution of (R)-l-(3- methoxyphenyl)ethanamine (0.086 g, 0.568 mmol) in titanium (IV) isopropoxide (0.798 ml, 2.72 mmol) at 25 °C and resulting suspension was stirred at 90 °C for 4hr. Reaction mixture was diluted with methanol (5 ml) & and cooled to 0 °C. Sodium borohydride (0.026 g, 0.681 mmol) was added lot- wise and reaction mixture was stirred at 0 °C for 10 minutes. TLC showed completion of reaction. Brine (10 ml) and ethyl acetate (20 ml) were added and precipitated solid was filtered through celite, washed with ethyl acetate (10 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (15 ml). The combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to get 0.12g of the crude residue. This residue was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 15% ethyl acetate in petroleum ether to afford pure compound (0.09g) as a sticky solid. This mixture of diastereomers (along with exo and endo) were separated by Supercritical Fluid Chromatography (SFC) to give major diastereomer (Example-7) (peak-1, Isomer-a, 0.085g) at retention time: 2.76 min, 2.90 min (mixture of exo and endo) and minor diastereomer (peak-2, isomer-b, 0.009g) at 3.17 mins, 3.29 mins (mixture of exo and endo). Method: Column: Parallel-immobilized; run time: 7 mins; total flow: 15 mins; Co-solvent: 20%; solvent: ethanol; 0.1% DEA ID-Cel-2; PDA-Chiral IE/Amyl-2.
To a stirred solution of above isomer-a or isomer-b in methylene chloride (2 ml), ethereal HCI (1 ml) was then added to this compound at 0 °C and stirred for 1 h. Solvent was evaporated on rotary evaporator at 35 °C and resulting solid was triturated twice with n- pentane to give HC1 salt of the title compound.
Isomer-a HC1 salt: 1H NMR (400 MHz, DMSO-J6) δ 9.83 (s, 1H), 9.77 (s, 2H), 7.88 (d, = 8.1 Hz, 4H), 7.69 (dd, = 17.5, 8.0 Hz, 4H), 7.42 - 7.33 (m, 2H), 7.33 - 7.22 (m, 3H), 7.15 (d, = 1.5 Hz, 1H), 7.11 - 6.91 (m, 6H), 4.00 (dd, = 26.3, 8.6 Hz, 4H), 3.73 (d, = 19.7 Hz, 6H), 3.49 (s, 2H), 3.42 (s, 4H), 2.46 (dq, = 3.6, 2.1 Hz, 6H), 2.00 (s, 3H), 1.70 (d, = 8.7 Hz, 2H), 1.57 (dtd, = 13.4, 6.7, 2.8 Hz, 13H), 1.33 - 1.05 (m, 9H); MS (ES+): m/z=466.00 (M+l, 100%).
Isomer-b HC1 salt: 1H NMR (400 MHz, DMSO-J6) δ 9.99 (s, 1H), 9.11 (s, 1H), 7.88 (d, = 8.0 Hz, 2H), 7.70 (dd, = 8.2, 3.4 Hz, 2H), 7.38 - 7.32 (m, 3H), 7.17 (dt, = 4.3, 2.0 Hz, 1H), 7.07 (d, 7 = 7.6 Hz, 1H), 6.96 (dt, / = 8.2, 2.5 Hz, 1H), 4.37 - 4.30 (m, 1H), 4.09 - 4.02 (m, 1H), 3.75 (s, 3H), 3.45 (s, 2H), 2.02 - 1.97 (m, 2H), 1.65 (s, 1H), 1.60 (td, = 6.9, 2.0 Hz, 6H), 1.53 (d, = 8.8 Hz, 1H), 1.27 (d, = 4.6 Hz, 2H) ); MS (ES+): m/z=466.00 (M+l, 100%).
The Examples 8 to 14 given in table-4 were prepared by following the similar procedure as described in Example-7 by taking appropriate ketone intermediate and appropriate amine intermediate. Further the mixture of diastereomers (along with exo and endo) were separated by Supercritical Fluid Chromatography (SFC) as given in Example-7.
Table-4:
Exampl Interme 1H NMR; MS (ES+)
Structure (Name)
e diate
8 35 Major diastereomer (Example-8): XH
NMR (400 MHz, DMSO-J6) δ 9.90
T HCI (d, = 33.0 Hz, 2H), 7.88 (d, = 8.1
Hz, 2H), 7.70 (dd, = 14.4, 8.0 Hz,
CF3 2H), 7.54 - 7.43 (m, 4H), 7.32 - 7.14
( 1 R)- 1 -(3-Chlorophenyl)-N- (m, 2H), 4.11 (ddd, = 27.6, 13.4, ((lR/lS)-l-(8-(4- 6.6 Hz, 2H), 3.49 (d, = 5.1 Hz, 2H), (trifluoromethyl) phenyl)- 2.01 (d, = 7.5 Hz, 2H), 1.70 (d, = l,2,3,4-tetrahydro-l,4- 8.8 Hz, 1H), 1.65 - 1.42 (m, 7H), methano naphthalen-6- 1.29 - 1.23 (m, 2H)); MS (ES+): yl)ethyl) ethanamine m/z=470.17 (M+l, 100%). hydrochloride Minor diastereomer: 1H NMR (400
MHz, DMSO-Je) δ 10.12 (s, 1H), 9.23 (s, 1H), 7.88 (d, = 8.0 Hz, 2H), 7.70 (dd, / = 8.1, 1.9 Hz, 2H), 7.65 - 7.59 (m, 1H), 7.52 - 7.41 (m, 3H), 7.39 - 7.29 (m, 2H), 4.41 (s, 1H), 4.13 (s, 1H), 3.50 - 3.40 (m, 2H), 1.99 (q, = 6.8 Hz, 2H), 1.75 - 1.46 (m, 8H), 1.24 (d, = 10.8 Hz, 2H))); MS (ES+): m/z=470.17 (M+l, 100%). 35 Major diastereomer (Example-9): XH
NMR (400 MHz, DMSO-J6) δ 9.88
(d, = 42.0 Hz, 2H), 7.88 (dd, =
8.4, 2.7 Hz, 2H), 7.69 (dd, = 14.7,
CF3 8.0 Hz, 2H), 7.36 - 7.14 (m, 2H),
(lR)-l-(3-Fluoro-5- 6.90 (dddd, = 16.3, 13.4, 9.3, 1.9 methoxyphenyl)-N-((lR/lS)- Hz, 3H), 4.17 - 3.97 (m, 2H), 3.75 (d,
1 -(8-(4-(trifluoromethyl) = 20.6 Hz, 3H), 3.41 (s, 2H), 2.00 phenyl)- 1 ,2,3 ,4-tetrahydro- (s, 2H), 1.70 (d, = 8.9 Hz, IH), 1.58
1 ,4-methano naphthalen-6- (ddd, = 21.4, 6.8, 3.3 Hz, 7H), 1.28 yl)ethyl) ethanamine - 1.23 (m, 2H))); MS (ES+): hydrochloride m/z=484.00 (M+l, 100%).
Minor diastereomer: 1H NMR (400 MHz, DMSO-Je) δ 9.68 (s, IH), 9.18 (s, IH), 7.89 (d, = 8.1 Hz, 3H), 7.68 (d, = 8.0 Hz, 2H), 7.33 (d, = 18.0 Hz, IH), 7.12 - 6.56 (m, 4H), 4.41 (s, IH), 4.11 (s, IH), 3.75 (s, 3H), 3.45 (s, 2H), 1.83 - 1.30 (m, 7H), 1.24 (s, 2H)))); MS (ES+): m/z=484.00 (M+l, 100%).
27 Major diastereomer (Example- 10):
1H NMR (400 MHz, DMSO-J6) δ
1 HCI 9.74 (d, = 12.9 Hz, 2H), 7.87 (d, =
7.9 Hz, 2H), 7.60 (d, = 7.9 Hz, 2H),
7.49 (d, = 3.8 Hz, 4H), 7.27 (s, IH),
CF3
7.22 (s, IH), 4.18 (dq, = 17.0, 6.2
( 1 R)- 1 -(3-Chlorophenyl)-N- Hz, 2H), 3.16 (d, = 9.4 Hz, IH), ((lR/lS)-l-(8-(4- 3.05 (s, IH), 1.78 (p, = 11.8, 10.8 (trifluoromethyl) phenyl)- Hz, 4H), 1.60 (dd, = 16.6, 6.6 Hz, l ,2,3,4-tetrahydro- l ,4- 6H), 1.34 (d, = 9.9 Hz, 4H); MS ethanonaphthalen-6- (ES+): m/z = 484.13 (M+l , 100%). yl)ethyl)ethan- 1 -amine
Minor diastereomer: 1H NMR (400 hydrochloride
MHz, DMSO-Je) δ 10.02 (s, IH), 9.25 (s, IH), 7.86 (d, = 8.0 Hz, 2H), 7.66 - 7.54 (m, 4H), 7.46 (dd, = 19.9, 4.7 Hz, 4H), 7.32 (d, = 8.8 Hz, 2H), 4.47 (s, IH), 4.1 1 (d, = 7.3 Hz, IH), 3.1 1 (s, IH), 3.05 (s, IH), 1.76 (t, = 14.6 Hz, 5H), 1.61 (dd, = 10.1 , 6.7 Hz, 7H), 1.31 (t, = 8.9 Hz, 6H), 1.24 (s, 4H), 0.87 (dd, = 10.5, 5.5 Hz, 2H); MS (ES+): m/z = 483.81 (M+ l , 100%).
28 Mixture of diastereomers: XH NMR
(400 MHz, DMSO-Je) δ 9.98 (d, =
T 7.4 Hz, IH), 7.85 (d, = 7.8 Hz, 2H), HCI
7.59 (dd, = 8.1 , 4.6 Hz, 2H), 7.39 - 7.26 (m, 2H), 7.25 - 7.14 (m, 3H), CF3 7.04 (s, IH), 7.01 - 6.86 (m, 2H),
N-((R)- 1 -(3-Methoxyphenyl)
3.80 (d, = 19.8 Hz, 2H), 3.73 (d, = ethyl)- l-(8-(4-(trifluoro
4.2 Hz, 3H), 3.14 (d, = 1 1.7 Hz, methyl )phenyl)- 1 ,2, 3,4- IH), 3.04 (d, = 9.8 Hz, IH), 1.83 - tetrahydro- 1 ,4-ethano
1.73 (m, 3H), 1.60 - 1.55 (m, 2H), naphthalen-6-yl)propan- 1 - 1.42 - 1.30 (m, 4H), 1.23 (s, 2H), amine hydrochloride
0.63 (td, = 7.4, 2.7 Hz, 3H); MS (ES+): m/z = 394.06 (M+l, 100%).
6 Major diastereomer:
1H NMR (400 MHz, DMSO-J6) δ
T HCI 9.88 (d, = 18.3 Hz, 2H), 7.88 (d, =
8.2 Hz, 2H), 7.61 (d, = 8.0 Hz, 2H), 7.53 - 7.37 (m, 4H), 7.05 (s, IH),
CF3
4.23 (s, IH), 4.12 (s, IH), 2.99 (t, =
( 1 R)- 1 -(3-Chlorophenyl)-N- 6.7 Hz, 2H), 2.61 (dt, = 8.4, 6.3 Hz, ((lR/lS)-l-(4-(4- 2H), 1.88 (p, = 6.1 Hz, 2H), 1.80 - (trifluoromethyl) phenyl)- 1.63 (m, 2H), 1.55 (dd, = 20.3, 6.7 5,6,7,8-tetrahydro quinolin-2- Hz, 5H) ; MS (ES+): m/z=459.13 yl)ethyl)ethanamine
(M+l, 100%).
hydrochloride
6 Major diastereomer:
1H NMR (400 MHz, DMSO-J6) δ
I HCI 9.87 (s, 2H), 7.88 (d, = 8.1 Hz, 2H),
7.60 (d, = 8.0 Hz, 2H), 7.51 - 7.19 (m, 2H), 7.16 - 7.02 (m, 2H), 7.00 -
CF3
( 1 R)- 1 -(3-Methoxyphenyl)-N- 6.87 (m, 2H), 4.13 (s, 2H), 3.73 (s, ((lR/lS)-l-(4-(4- 3H), 3.01 (q, = 6.1 Hz, 2H), 2.71 - (trifluoromethyl) phenyl)- 2.55 (m, 3H), 1.98 - 1.81 (m, 2H), 5,6,7,8-tetrahydro quinolin-2- 1.72 (dtt, = 9.5, 6.2, 3.4 Hz, 2H), yl)ethyl) ethanamine 1.56 (dd, = 22.7, 6.8 Hz, 6H); MS hydrochloride (ES+): m/z=455.16 (M+l, 100%). 14 Mixture of diastereomers : H NMR
(400 MHz, DMSO-J6) δ 9.99 (d, = 53.5 Hz, 2H), 7.88 (d, = 8.0 Hz, 1H), 7.61 (d, = 7.9Hz, 1H), 7.40 - 7.24 (m, 2H), 7.09 (s, 1H), 7.04 - 6.84 (m, 4H), 4.05 (s, 1H), 3.86 (dt,
N-((R)- 1 -(3-Methoxyphenyl)
= 14.4, 7.3 Ηζ,ΙΗ), 3.79 - 3.67 (m, ethyl)- 1-(4-(4- 4H), 3.01 (q, = 6.7 Hz, 1H), 2.71 - (trifluoromethyl)phenyl)- 2.57 (m, 2H), 2.09 (d, = 9.2 Hz, 5 ,6,7, 8-tetrahydroquinolin-2- 1H), 1.99 -1.84 (m, 2H), 1.72 (t, = yl)propan- 1 -amine
6.0 Hz, 2H), 1.58 (t, = 6.8 Hz, 4H), hydrochloride
1.23 (d, = 4.2 Hz, 2H), 0.67 (t, = 7.4Hz, 2H); MS (ES+): m/z = 469.06 (M+l, 100%).
Example-15: Isopropyl 3-(5-(2-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)- 5,6,7,8-tetrahydroquinolin-4-yl)- -methylphenyl)propanoate
Figure imgf000085_0001
Intermediate-31 (0.2g, 0.547 mmol) was added to a solution of (R)-l-(3- methoxyphenyl)ethanamine (0.182g, 1.204 mmol) in titanium (IV) isopropoxide (1.924 ml, 6.57 mmol) at 25 °C and resulting suspension was stirred at 90 °C for 4 hr. Reaction mixture was diluted with methanol (5 ml) & and cooled to 0 °C. Sodium borohydride (20.70 mg, 0.547 mmol) was added lot-wise and reaction mixture was stirred at 0 °C for 10 minutes. TLC showed completion of reaction. Brine (10 ml) and ethyl acetate (20 ml) were added and precipitated solid was filtered through celite, washed with ethyl acetate (10 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (15 ml). The combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to get 0.25g of the crude residue. This residue was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 15% ethyl acetate in petroleum ether to afford a pure compound (0.12g) as a sticky solid. This mixture of diastereomers was separated by SFC to give major diastereomer (Example-15) (Peak-1, 0.085g) and minor diastereomer (Peak-2, 0.009g) as a sticky solid. MS (ES+): m/z = 515.31 (M+1, 100%).
The Examples 16 to 18 given in Table-5 were prepared by following the similar procedure as described in Example-15 by taking ketone intermediate and appropriate amine intermediate.
Table-5:
Figure imgf000086_0001
Figure imgf000087_0001
Example-19: 3-(5-(2-((lR/lS)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)-5,6,7,8- tetrahydroquinolin-4-yl)-2-methylphenyl)propanoic acid hydrochloride
Figure imgf000088_0001
To a stirred solution of example- 15 (0.04 g, 0.078 mmol) in MeOH:THF:H20 (5 ml, 2:2: 1) was added NaOH (4.36 mg, 0.078 mmol) at 25 °C. Reaction mixture was then refluxed for 2 hr at 80 °C. TLC showed completion of reaction. Reaction mixture was concentrated in vaccuo to get the residue. Residue was then acidified with dil. HCl (5 ml) at 0 °C, stirred & filtered to get pure compound. Ethereal HCl (3 ml) was then added to this compound & sonicated for 2 minutes. Solvent was evaporated on rotary evaporator and resulting solid was triturated twice with n-pentane to give title compound (0.02g, 30%) as a off white solid. Major diastereomer:1H NMR (400 MHz, DMSO-J6) δ 10.36 (s, 3H), 7.62 - 7.36 (m, 3H), 7.27 (t, = 7.9 Hz, 2H), 7.15 (s, 1H), 7.01 - 6.86 (m, 2H), 4.20 (d, = 28.3 Hz, 3H), 3.72 (s, 3H), 3.00 (dd, / = 16.8, 9.7 Hz, 2H), 2.71 - 2.53 (m, 6H), 1.94 - 1.81 (m, 2H), 1.71 (d, = 7.5 Hz, 2H), 1.61 (dd, = 10.2, 6.8 Hz, 6H), 1.33 (d, = 6.2 Hz, 2H); MS (ES+): m/z = 476.31 (M+l, 100%).
The below Examples 20 and 22 given in table-6 were prepared by following the same procedure as described in Example-4.
Table-6:
Figure imgf000089_0001
Figure imgf000090_0001
Example-23: (R)-l-(3-Methoxyphenyl)-N-((4-(4-(trifluoromethyl)phenyl)quinolin-2- yl)methyl)ethan- 1 -amine hydrochloride
Figure imgf000090_0002
To a stirred solution of intermediate-45 (0.15g, 0.498 mmol) in methylene chloride (5 ml) was added (R)-l-(3-methoxyphenyl)ethanamine (0.113 g, 0.747 mmol) and sodium triacetoxyborohydride (0.264g, 1.245mmol) at 0 °C and resulting solution was stirred at 25 °C for 16 hrs. TLC showed completion of reaction. Aqueous sat. NaHC03 (10 ml) and methylene chloride (10 ml) were added and phases were separated. The combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to get 0.2g of the crude residue. This residue was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 15% ethyl acetate in petroleum ether afford title to compound (0.2g, 92%) as a off white solid. To a stirred solution of above compound in methylene chloride (2 ml), ethereal HCI (1 ml) was then added to this compound at 0 °C and stirred for 1 h. Solvent was evaporated on rotary evaporator at 35 °C and resulting solid was triturated twice with n-pentane to give pure HCI salt as a off white solid. HCI salt. 1H NMR (400 MHz, DMSO-J6) δ 8.19 (d, = 8.4 Hz, 1H), 7.99 (d, = 8.0 Hz, 2H), 7.94 - 7.84 (m, 2H), 7.81 (d, = 8.0 Hz, 2H), 7.74 - 7.65 (m, 2H), 7.40 - 7.30 (m, 2H), 7.20 (d, = 7.6 Hz, 1H), 6.96 (dd, = 8.2, 2.5 Hz, 1H), 4.57 (q, = 6.4 Hz, 1H), 4.45 (dt, = 14.0, 5.4 Hz, 1H), 4.24 (dt, 7 = 15.2, 5.7 Hz, 1H), 3.76 (s, 3H), 1.72 (d, = 6.7 Hz, 3H); MS (ES+): m/z = 437.37 (M+l, 100%).
Example-24: ( IR)- 1 -(Naphthalen- 1 -yl)-/V-( 1 -(4-(4-(trifluoromethyl)phenyl)quinolin-2-yl) ethyl)ethanamine hydrochloride
Figure imgf000091_0001
Intermediate-46 (0.125 g, 0.396 mmol) was added to a solution of (R)- 1 -(naphthalen- 1- yl)ethanamine (0.136 g, 0.793 mmol) in titanium tetraisopropoxide (1.75 ml, 5.95 mmol) at 25 °C and resulting suspension was stirred at 90 °C for 16 hrs. Reaction mixture was diluted with methanol (5 ml) and cooled to 0 °C. Sodium borohydride (0.045 g, 1.189 mmol) was added lot-wise and reaction mixture was stirred at 0 °C for 10 mins. TLC showed completion of reaction. Brine (10 ml) and ethyl acetate (20 ml) were added and precipitated solid was filtered through celite, washed with ethyl acetate (10 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (15 ml). The combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to get 0.12g of the crude residue. This residue was purified by column chromatography over silica gel ( 100-200 mesh) with an isocratic elution of 15% ethyl acetate in petroleum ether to afford a pure compound (0.09g) as a sticky solid.
To a stirred solution of above compound (mixture of diastereomers) in methylene chloride (2 ml), ethereal HCl ( 1 ml) was then added to this compound at 0 °C and stirred for 1 h. Solvent was evaporated on rotary evaporator at 35 °C and resulting solid was triturated twice with n- pentane to give pure HCl salt as a off white solid. HCl salt: 1H NMR (400 MHz, DMSO-J6) δ 10.28 (s, 2H), 10.13 (s, 1H), 8.20 (d, = 8.3 Hz, 2H), 8.03 - 7.86 (m, 10H), 7.86 - 7.76 (m, 6H), 7.75 - 7.59 (m, 6H), 7.57 - 7.34 (m, 23H), 4.36 (d, = 8.0 Hz, 4H), 4.01 (d, = 10.3 Hz, 3H), 2.15 (s, 2H), 1.73 - 1.54 (m, 22H), 1.50 (d, = 6.6 Hz, 2H), 1.38 - 1.25 (m, 4H), 1.23 (s, 4H), 1.09 (t, = 7.0 Hz, 2H), 0.86 (t, = 6.6 Hz, 3H); MS (ES+): m/z=455.1 1 ( 100%).
Example-25: ( 1R) - 1 -(3-Chlorophenyl)-N-(( 1R/1S)- l-(4-(4-(trifluoromethyl)phenyl)quinolin- 2-yl) ethyl)ethanamine hydrochloride
Figure imgf000092_0001
The title compound was prepared by following the same procedure as described in example- 24 by using intermediate-46 and (R)- l-(3-Chlorophenyl)ethanamine. Hydrochloride salt (Major diastereomer): 1H NMR (400 MHz, DMSO-J6) δ 10.50 - 10.15 (m, 3H), 8.27 - 8.13 (m, 3H), 8.09 - 7.85 (m, 9H), 7.77 (dt, = 8.2, 4.2 Hz, 3H), 7.67 (dt, = 15.2, 7.5 Hz, 4H), 7.54 (ddt, 7 = 21.1 , 15.4, 7.3 Hz, 3H), 7.39 (dd, J = 18.0, 7.9 Hz, 2H), 7.21 (q, J = 7.5 Hz, 2H), 7.02 (s, 1H), 6.99 - 6.80 (m, 2H), 5.30 (s, 1H), 5.14 (d, J = 9.4 Hz, 1H), 4.96 (d, J = 10.1 Hz, 1H), 4.37 (s, 1H), 1.82 - 1.65 (m, 9H); MS (ES+): m/z=300.34 ( 100%).
Example-26: ( 1R)- 1 -(4-Fluoro-3-methoxyphenyl)-N-(( lR/1 S)- 1 -(4-(4-(trifluoromethyl) phenyl) quinolin-2-yl)ethyl)ethan- 1 -amine hydrochloride
Figure imgf000093_0001
The title compound was prepared by following the same procedure as described in example- 24 by using intermediate-46 and (R)-l-(4-fluoro-3-methoxyphenyl)ethan-l -amine. Major diastereomer: 1H NMR (400 MHz, DMSO-J6) δ 10.08 (s, 2H), 8.21 (d, = 8.4 Hz, 1H), 8.00 (d, / = 8.0 Hz, 2H), 7.95 - 7.89 (m, 1H), 7.86 (d, = 8.3 Hz, 1H), 7.78 (dd, = 8.4, 4.0 Hz, 3H), 7.70 (dd, / = 8.6, 6.6 Hz, 1H), 7.51 (s, 1H), 6.91 (dd, / = 8.8, 2.5 Hz, 1H), 6.75 (dd, 7 = 12.4, 2.6 Hz, 1H), 4.58 (s, 1H), 4.38 (q, J = 6.4 Hz, 1H), 3.75 (s, 3H), 1.65 (dd, = 6.8, 2.5 Hz, 6H); MS (ES+): m/z = 469.07 (M+l, 100%).
Example-27: ( 1R)- 1 -(3-fluoro-5-methoxyphenyl)-N-(( 1R/1S)- 1 -(4-(4-(trifluoromethyl) phenyl) quinolin-2-yl)ethyl)etha - 1 -amine hydrochloride
Figure imgf000093_0002
The title compound was prepared by following the same procedure as described in example- 24 by using intermediate-46 and (R)-l-(3-fluoro-5-methoxyphenyl)ethan-l-amine. Major diastereomer: 1H NMR (400 MHz, DMSO-J6) δ 10.20 (d, J = 86.1 Hz, 2H), 8.20 (d, = 8.4 Hz, 1H), 8.00 (d, = 7.9 Hz, 2H), 7.96 - 7.84 (m, 2H), 7.78 (d, = 7.9 Hz, 2H), 7.71 (t, = 7.6 Hz, 1H), 7.55 (d, = 2.3 Hz, 1H), 6.92 (d, = 9.4 Hz, 1H), 6.84 (s, 2H), 4.45 - 4.21 (m, 2H), 1.65 (dd, = 10.2, 6.7 Hz, 6H); MS (ES+): m/z = 469.06 (100%).
Example-28: N-((R)-l-(3-Methoxyphenyl)ethyl)-l-(4-(4-(trifluoromethyl)phenyl)quinolin- 2-yl)propan- 1 -amine hydrochloride
Figure imgf000094_0001
The title compound was prepared by following the same procedure as described in example- 24 by using intermediate-47 and (R)-l-(3-methoxyphenyl)ethan-l -amine. Mixture of diastereomers: 1H NMR (400 MHz, DMSO-J6) δ 10.30 (s, 1H), 10.05 (s, 1H), 8.20 (d, = 8.4 Hz, 1H), 7.99 (d, = 8.0 Hz, 2H), 7.91 (dd, = 17.0, 8.2 Hz, 2H), 7.79 (d, = 7.9 Hz, 2H), 7.71 (dd, = 8.7, 6.8 Hz, 1H), 7.52 (s, 1H), 7.27 (t, = 7.9 Hz, 1H), 7.01 (t, = 2.0 Hz, 1H), 6.92 (dd, = 8.1, 2.1 Hz, 2H), 4.11 (d, = 23.6 Hz, 2H), 3.67 (s, 3H), 2.26 (ddd, = 12.7, 7.4, 4.7 Hz, 1H), 2.09 (tq, = 13.4, 7.3 Hz, 1H), 1.65 (t, = 6.9 Hz, 3H), 0.71 (q, = 7.4, 6.9 Hz, 3H); MS (ES+): m/z = 466.30 (M+l, 100%).
Example-29: ( IR)- 1 -(3-Methoxyphenyl)-N-( 1 -(( lR/1 S)- 1 -(4-(trifluoromethyl)phenyl) isoquinolin-3 -yl)ethyl)ethanamine hydrochloride
Figure imgf000094_0002
The title compound was prepared by following the same procedure as described in example- 24 by using intermediate-48 and (i?)-l-(3-methoxyphenyl)ethanamine. Hydrochloride salt (Major diastereomer): 1H NMR (400 MHz, DMSO-J6) δ 10.04 (d, = 16.2 Hz, 1H), 9.70 (s, 1H), 8.13 - 7.94 (m, 4H), 7.90 (d, = 7.4 Hz, 1H), 7.85 (d, = 14.9 Hz, 1H), 7.74 (t, = 7.6 Hz, 1H), 7.30 (t, = 7.9 Hz, 1H), 7.09 (d, = 5.5 Hz, 1H), 7.01 - 6.87 (m, 2H), 4.27 (s, 1H), 4.16 (s, 1H), 3.72 (d, = 28.0 Hz, 3H), 1.61 (dd, = 25.6, 6.5 Hz, 6H) ; MS (ES+): m/z=300.34 (100%). Example-30: ( 1 R)- 1 -(3-Chlorophenyl)-N-(( 1 R/ 1 S)- 1 -( 1 -(4-(trifluoromethyl)phenyl) isoquinolin-3-yl)ethyl)ethan-l -
Figure imgf000095_0001
The title compound was prepared by following the same procedure as described in example- 24 by using intermediate-48 and (R)-l-(3-chlorophenyl)ethan-l -amine. Major diastereomer: 1H NMR (400 MHz, DMSO-J6) δ 8.02 (d, / = 15.5 Hz, 5H), 7.89 (t, 7 = 7.7 Hz, 1H), 7.82 (s, 1H), 7.74 (t, = 7.9 Hz, 1H), 7.43 (dd, = 16.0, 10.8 Hz, 4H), 4.31 (dd, = 22.7, 7.1 Hz, 2H), 1.63 (d, = 6.7 Hz, 3H), 1.56 (d, = 6.8 Hz, 3H); MS (ES+): m/z = 455.09 (100%). Example-31 : ( 1R)- 1 -(3-Fluoro-5-methoxyphenyl)-N-(( lR/1 S)- 1 -( 1 -(4-(trifluoromethyl) phenyl)isoquinolin-3-yl)ethyl)
Figure imgf000095_0002
The title compound was prepared by following the same procedure as described in example- 24 by using intermediate-48 and (R)-l-(3-fluoro-5-methoxyphenyl)ethan-l-amine. Major diastereomer: 1H NMR (400 MHz, DMSO-J6) δ 10.25 (s, 1H), 9.82 (s, 1H), 8.10 - 7.95 (m, 6H), 7.88 (d, = 7.5 Hz, 2H), 7.74 (t, = 7.7 Hz, 1H), 6.94 (d, = 13.9 Hz, 3H), 6.84 (s, 1H), 4.32 (s, 1H), 4.18 (s, 1H), 3.69 (d, = 2.4 Hz, 3H), 1.67 (d, = 6.6 Hz, 3H), 1.57 (d, = 6.7 Hz, 5H); MS (ES+): m/z=469.18 (M+l, 100%).
Example-32: Isopropyl 5-(2-((lR/lS)-l-(((i?)-l-(3-methoxyphenyl)ethyl)amino)ethyl) quinolin-4-yl)-2-methylbenzoate
Figure imgf000096_0001
Intermediate-49 (0.4 lg, 1.284 mmol) was added to a solution of (R)-l-(3- methoxyphenyl)efhanamine (0.482g, 3.19 mmol) in titanium tetraisopropoxide (5.6 ml, 19.11 mmol) at 25 °C and resulting suspension was stirred at 90 °C for 16 hrs. Reaction mixture was diluted with methanol (5 ml) and cooled to 0 °C. Sodium borohydride (0.145 g, 3.82 mmol) was added lot-wise and reaction mixture was stirred at 0 °C for 10 mins. TLC showed completion of reaction. Brine (20 ml) and ethyl acetate (20 ml) were added and precipitated solid was filtered through celite, washed with ethyl acetate (10 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (15 ml). The combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to get 0.62g of the crude residue. This residue was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 15% ethyl acetate in petroleum ether to afford a major diastereomer (0.3 lOg, 50.4%) as a sticky solid. XH NMR (400 MHz, DMSO- de) δ 8.04 - 8.00 (m, 1H), 7.93 (d, = 2.0 Hz, 1H), 7.84 - 7.80 (m, 1H), 7.79 - 7.73 (m, 1H), 7.71 (dd, = 7.8, 2.0 Hz, 1H), 7.66 (s, 1H), 7.61 - 7.53 (m, 2H), 7.21 (t, = 7.8 Hz, 1H), 6.89 - 6.82 (m, 2H), 6.78 (dd, 7 = 8.1, 2.6 Hz, 1H), 5.17 (p, = 6.3 Hz, 2H), 3.73 (s, 3H), 2.96 (s, 1H), 1.32 (d, = 6.2 Hz, 7H), 1.25 - 1.20 (m, 5H) ); MS (ES+): m/z=483.20 (M+l, 100%).
The isopropyl ester formation of corresponding methyl ester was explained on the basis of trans-esterification of methyl ester with titanium tetraisopropoxide.
Example-33: Isopropyl 2-fluoro-5-(2-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino) ethyl)quinolin-4-yl)-3-methylbenzoate
Figure imgf000097_0001
The title compound was prepared by following the same procedure as described in example- 32 by using intermediate-50 and (R)-l-(3-methoxyphenyl)ethanamine. Major diastereomer: MS(ES+): m/z= 501.06 (M+l, 100%).
Example-34: Isopropyl 3-(3-fluoro-5-(2-((lR/lS)-l-(((i?)-l-(3-methoxyphenyl)ethyl) amino) ethyl) quinolin-4-yl)phenyl)propanoate
Figure imgf000097_0002
The title compound was prepared by following the same procedure as described in example- 32 by using intermediate-52 and (R)-l-(3-methoxyphenyl)ethanamine. Major diastereomer: MS(ES+): m/z= 515.22 (M+l, 100%).
Example-35: Isopropyl 3-(3-fluoro-5-(2-((lR/lS)-l-(((R)-l-(3-fluoro-5-methoxyphenyl) ethyl)amino)ethyl)quinolin-4-yl)phenyl)propanoate
Figure imgf000097_0003
The title compound was prepared by following the same procedure as described in example- 32 by using intermediate-52 and (R)-l-(3-fluoro-5-methoxyphenyl)ethan-l-amine. Major diastereomer: MS(ES+): m/z= 533.16 (M+l, 100%).
Example-36: Isopropyl 3-(5-(2-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino) ethyl)quinolin-4-yl)-2-methylphenyl)propanoate
Figure imgf000098_0001
The title compound was prepared by following the same procedure as described in example- 32 by using intermediate-51 and (R)-l-(3-methoxyphenyl)ethanamine. Major diastereomer: MS(ES+): m/z= 511.21 (M+l, 100%).
Example-37: Isopropyl 3-(3-fluoro-5-(3-((lR/lS)-l-(((i?)-l-(3-methoxyphenyl)ethyl) amino)ethyl) isoquinolin-l-yl)phenyl)propanoate hydrochloride
Figure imgf000098_0002
The title compound was prepared by following the same procedure as described in example- 32 by using Intermediate-56 and (i?)-l-(3-methoxyphenyl)ethanamine. Hydrochloride salt (Major diastereomer). 1H NMR (400 MHz, DMSO-J6) δ 10.01 (d, = 20.0 Hz, 1H), 9.66 (d, = 10.9 Hz, 1H), 8.05 (dd, = 27.6, 8.2 Hz, 2H), 7.87 (t, = 7.4 Hz, 1H), 7.75 (d, = 19.5 Hz, 2H), 7.48 (d, = 13.8 Hz, 2H), 7.31 (dt, = 12.1, 8.1 Hz, 3H), 7.07 (d, = 10.5 Hz, 2H), 6.93 (dt, / = 18.1, 8.5 Hz, 4H), 4.89 (p, = 6.2 Hz, 1H), 4.25 (s, 1H), 4.14 (s, 1H), 3.87 (d, = 6.8 Hz, 1H), 3.76 (d, = 6.2 Hz, 3H), 3.69 (s, 3H), 3.00 (t, = 7.4 Hz, 2H), 2.72 (t, = 7.4 Hz, 2H), 1.66 - 1.51 (m, 8H), 1.23 (d, = 3.8 Hz, 1H), 1.14 (d, / = 6.2 Hz, 7H); MS(ES+): m/z= 515.19 (M+l, 100%).
Example-38: Isopropyl 5-(3-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino) ethyl)isoquinolin- 1 -yl)-2-methylbenzoate
Figure imgf000099_0001
The title compound was prepared by following the same procedure as described in example- 32 by using intermediate-53 and (R)-l-(3-methoxyphenyl)ethanamine. Major diastereomer: MS(ES+): m/z= 483.21 (M+l, 100%).
Example-39: Isopropyl 3-(2-fluoro-5-(3-(( lR/1 S)- 1 -(((R)- 1 -(3-methoxyphenyl)ethyl) amino)ethyl) isoquinolin- 1 -yl
Figure imgf000099_0002
The title compound was prepared by following the same procedure as described in example- 32 by using intermediate-55 and (R)-l-(3-methoxyphenyl)ethanamine. Major diastereomer: MS(ES+): m/z= 515.24 (M+l, 100%).
Example-40: Isopropyl 3-(5-(3-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino) ethyl)isoquinolin- 1 -yl)-2-methylphenyl)propanoate
Figure imgf000100_0001
The title compound was prepared by following the same procedure as described in example- 32 by using intermediate-54 and (R)-l-(3-methoxyphenyl)ethanamine. Major diastereomer: MS(ES+): m/z= 511.21 (M+l, 100%).
Example-41 : 5-(2-(( 1 R/l S)- 1 -(((R)- 1 -(3-Methoxyphenyl)ethyl)amino)ethyl)quinolin-4-yl)- 2-methyl benzoic acid hydrochloride
Figure imgf000100_0002
To a stirred solution of example-32 (0.31 g, 0.642 mmol) in MeOH: Water (3 ml, 2: 1) was added NaOH (0.128 g, 3.21 mmol) at 25 °C. Reaction mixture was then refluxed for 2 hr at 90 °C. TLC showed completion of reaction. Reaction mixture was concentrated in vacuo to get the residue. Residue was dissolved in water (2 ml) and then acidified with IN HCl (3 ml) at 0 °C, stirred and filtered the precipitated solid to get sufficiently dry and pure product. 2M ethereal HCl (3 ml) was then added to this solid compound at 0 °C and stirred for lh. Solvent was evaporated on a rotary evaporator at 30 °C and resulting solid triturated twice with n- pentane to give hydrochloride salt of a title compound (0.153 g, 53%) as an off white solid. HCl salt (Major diastereomer): 1H NMR (400 MHz, DMSO-J6) δ 10.28 (s, 1H), 9.97 (s, 1H), 8.22 - 8.17 (m, 1H), 7.95 (d, / = 2.0 Hz, 1H), 7.93 - 7.87 (m, 2H), 7.69 (td, / = 7.4, 7.0, 1.3 Hz, 1H), 7.63 (dd, = 7.8, 2.0 Hz, 1H), 7.55 (d, = 7.9 Hz, 1H), 7.45 (s, 1H), 7.27 (t, = 7.9 Hz, 1H), 7.04 (t, = 2.0 Hz, 1H), 6.94 - 6.88 (m, 2H), 4.30 (dq, = 18.6, 6.6 Hz, 2H), 3.67 (s, 3H), 2.64 (s, 3H), 1.71 - 1.59 (m, 6H); MS (ES+): m/z= 441.11 (M+l, 100%). The below Examples 42 to 49 given in Table-7 were prepared by following the similar procedures as described herein above by using appropriately substituted ester examples.
Table-7:
Example Structure (IUPAC name) Example ¾ NMR data; MS(ES+) used
42 33 HCI salt (Major diastereomer): 1H NMR (400
I HCI MHz, DMSO-Je) δ 10.05 (d,
= 91.1 Hz, 2H), 8.22 - 8.16 (m, 1H), 7.96 - 7.87 (m, 2H),
F 0
7.79 (dd, = 6.4, 2.3 Hz, 1H),
2-Fluoro-5-(2-((lR/lS)-l- 7.71 (dt, / = 6.5, 4.1 Hz, 2H), (((R)- 1 -(3-methoxyphenyl) 7.45 (s, 1H), 7.29 (t, = 7.9 ethyl)amino )ethyl)quinolin-4- Hz, 1H), 7.02 (t, = 2.1 Hz, yl)-3 -methyl benzoic acid 1H), 6.96 - 6.87 (m, 2H), 4.33 hydrochloride (d, = 7.6 Hz, 2H), 3.69 (s,
3H), 2.39 (d, = 2.1 Hz, 3H), 1.64 (dd, = 6.8, 2.7 Hz, 6H); m/z= 459.21 (M+l , 100%).
43 34 HCI salt (Major diastereomer): 1H NMR (400
I HCI MHz, DMSO-Je) δ 10.27 (s,
1H), 9.99 (s, 1H), 8.16 (s, 1H), 7.90 (s, 2H), 7.68 (s,
0
1H), 7.48 (s, 1H), 7.41 - 7.17
3-(3-Fluoro-5-(2-(( lR/lS)-l- (m, 4H), 6.96 (d, = 38.1 Hz, (((R)- 1 -(3-methoxyphenyl) 3H), 4.27 (s, 2H), 3.70 (s, ethyl)amino) ethyl)quinolin-4- 3H), 2.96 (t, = 7.6 Hz, 2H),
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
2-methyl phenyl)propanoic 7.29 (t, 7 = 7.9 Hz, 1H), 7.11 acid hydrochloride (t, = 2.0 Hz, 1H), 6.94 (td,
= 7.5, 6.7, 4.4 Hz, 2H), 4.25 (d, / = 6.8 Hz, 1H), 4.17 (d, = 8.0 Hz, 1H), 3.70 (s, 3H), 2.96 (t, = 7.7 Hz, 2H), 2.62 (t, = 7.7 Hz, 2H), 2.42 (s, 3H), 1.65 (d, = 6.7 Hz, 3H), 1.60 (d, = 6.8 Hz, 3H); MS (ES+): m/z = 469.06 (M+l, 100%).
Example-50: (l^)-l -(3-Methoxyphenyl)-N-(( 1 R/l S)- 1 -(4-(6-(trifluoromefhyl)pyridin-3- yl)naphthalen-2-yl)ethyl)ethanamine hydrochloride
Figure imgf000105_0001
Intermediate-58 (0.2g, 0.634 mmol) was added to a solution of (R)-l-(3- methoxyphenyl)ethanamine (0.24g, 1.586 mmol) in titanium tetraisopropoxide (2.79 ml, 9.52 mmol) at 25 °C and resulting suspension was stirred at 90 °C for 16 hrs. Reaction mixture was diluted with methanol (5 ml) and cooled to 0 °C. Sodium borohydride (0.072 g, 1.903 mmol) was added lot-wise and reaction mixture was stirred at 0 °C for 10 mins. TLC showed completion of reaction. Brine (10 ml) and ethyl acetate (20 ml) were added and precipitated solid was filtered through celite, washed with ethyl acetate (10 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (15 ml). The combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to get 0.5g of the crude residue. This residue was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 15% ethyl acetate in petroleum ether to afford a mixture of diastereomer (0.29g) as a sticky solid. This mixture of diastereomer was separated by reverse phase preparative HPLC to afford 0.09g of (> 90% purity) Major diastereomer. This mixture was separated by chiral preparative HPLC to provide 0.06g of pure major diastereomer.
Method for reverse phase preparative HPLC: Column: KINETEX C18, 50 X 2.1 mm, 1.7μ; Mobile phase: A: water: ACN (90: 10 V/V%)+0.1% formic acid; B : ACN: water (90: 10 V/V%) + 0.08% formic acid.
Method for chiral preparative HPLC: Column: Amylose-2, flow: 1ML/MIN; Mobile Phase : A= Hex (0.1 %DEA) , B= EtOH A=B 97/3 % V/V
To a stirred solution of major diastereomer in methylene chloride (2 ml), ethereal HC1 (1 ml) was then added to this compound at 0 °C and stirred for 1 h. Solvent was evaporated on rotary evaporator at 35 °C and resulting solid was triturated twice with n-pentane to give pure HC1 salt as a off white solid. HC1 salt: 1H NMR (400 MHz, DMSO-J6) δ 10.14 (dt, 7 = 43.3, 11.2 Hz, 2H), 8.96 (d, 7 = 2.1 Hz, 1H), 8.29 (dd, 7 = 8.2, 2.1 Hz, 1H), 8.14 (d, 7 = 8.1 Hz, 1H), 8.00 (d, 7 = 7.8 Hz, 2H), 7.81 (d, 7 = 8.0 Hz, 1H), 7.76 - 7.55 (m, 3H), 7.34 (t, 7 = 7.9 Hz, 1H), 7.16 - 7.03 (m, 1H), 7.03 - 6.92 (m, 2H), 4.30 - 4.14 (m, 1H), 4.03 (td, 7 = 10.2, 9.7, 4.7 Hz, 1H), 3.71 (s, 3H), 1.71 (d, 7 = 6.7 Hz, 3H), 1.59 (d, 7 = 6.7 Hz, 3H); MS (ES+): m/z=451 (M+1,100%).
The below Examples-51 to 62 given in Table-8 were prepared by following the similar procedures as described in Example-50 by using appropriately substituted amines.
Table-8:
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
yl)isoquinolin-3-yl)ethyl)ethan- Hz, 1H), 7.52 (d, = 2.2 Hz, 1 -amine hydrochloride 1H), 7.43 (d, = 7.2 Hz, 2H),
4.30 (dd, = 19.9, 11.9 Hz, 2H), 1.68 (d, = 6.7 Hz, 3H), 1.59 (d, = 6.7 Hz, 3H); MS (ES+): m/z = 456.03 (M+1, 100%).
Example-63: Isopropyl 3-(4-(3-(( lR/1 S)- 1 -(((R)- 1 -(3-methoxyphenyl)ethyl)amino)ethyl) naphthalen- 1 -yl)- lH-pyrazol- 1 -yl)propanoate
Figure imgf000113_0001
Intermediate-62 (0.375 g, 1.163 mmol) was added to a solution of (R)-l-(3- Methoxyphenyl)ethanamine (0.440 g, 2.91 mmol) in titanium(iv) isopropoxide (4.09 ml, 13.96 mmol) at 25 °C and resulting suspension was stirred at 90 °C for 16 hrs. TLC showed completion of reaction. Reaction mixture was diluted with methanol (10 ml) and cooled to 0 °C, sodium borohydride (0.132 g, 3.49 mmol) was added lot-wise and reaction mixture was stirred at 0 °C for 10 mins. TLC showed completion of reaction. Brine (10 ml) and ethyl acetate (20 ml) were added and precipitated solid was filtered through celite, washed with ethyl acetate (10 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (5 ml). The combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to get 0.42g of the crude residue. This residue was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 10% ethyl acetate in petroleum ether to afford a pure compound (0.32g) as a sticky solid. This mixture of diastereomers were separated by reverse phase preparative HPLC to give major diastereomer 0.15g (>95% purity) as a sticky solids. This mixture of diastereomer was purified by chiral preparative HPLC separately to get a pure major diastereomer (Example-63) (0.09g) as a sticky solid. MS (ES+): m/z=486.29 (M+1, 100%).
The isopropyl ester formation of corresponding methyl ester can be explained on the basis of trans-esterification of methyl ester with titanium tetraisopropoxide.
Method for reverse phase preparative HPLC:
Column: YMC TRIART_C18, 50 X 2.1 mm, 1.9μ; Mobile phase: A: water: ACN (90: 10 V/V%)+0.1% Ammonium Hydroxide B : ACN: water (90: 10 V/V%)+0.1% Ammonium hydroxide.
Method for chiral preparative HPLC: Column: CHIRAL PAK 1C, 250 x 4.6 5u; Mobile Phase: A: N-HEX_0.1% DEA, B:EtOH) A:B 95/5%v/v Flow = 1.2 ml/min.
The below Examples-64 to 69 given in Table-9 were prepared by following the similar procedures as described herein above by using appropriately substituted amines.
Table-9:
Example Intermediate Structure (IUPAC name) MS(ES+)
64 63 Major diastereomer: MS(ES+):
m/z= 521.94 (M+1, 100%).
Isopropyl 5-(3-((lR/lS)-l- (((/?)- l-(3-methoxyphenyl)
ethyl)amino)ethyl)naphthalen
- 1 -yl)-3-methylbenzofuran-2- carboxylate
Figure imgf000115_0001
Figure imgf000116_0001
Example-70: 3-(4-(3-((lR/lS)-l-(((i?)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen- l-yl)-lH-pyrazol-l-yl)propanoic acid hydrochloride
Figure imgf000116_0002
To a stirred solution of Example-63 (0.155 g, 0.319 mmol) in methanol (5 ml) was added sodium hydroxide (0.128 g, 3.19 mmol) at 25 °C. Reaction mixture was then refluxed for 2 hr at 80 °C. TLC showed completion of reaction. Reaction mixture was concentrated in vacuo to get 0.165g residue. Residue was then acidified with dil. HCl (5 ml) at 0 °C, stirred and filtered to get (0.1 lg) of pure compound.
Ethereal HCl (3 ml) was then added to this compound at 0 °C and stirred for 1 h. Solvent was evaporated on rotary evaporator at 35 °C and resulting solid was triturated twice with n- pentane to give pure HCl salt of 3-(4-(3-((R)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino) ethyl)naphthalen-l-yl)-lH-pyrazol-l-yl)propanoic acid (0.1 g, 0.225 mmol, 70.6 % yield) as a off white solid. Major diastereomer: 1H NMR (400 MHz, DMSO-J6) δ 10.03 (t, / = 11.8 Hz, 2H), 8.20 (dt, / = 6.8, 3.6 Hz, 1H), 8.15 (s, 1H), 7.94 - 7.87 (m, 1H), 7.82 (s, 1H), 7.74 (d, = 1.8 Hz, 1H), 7.67 (d, = 1.8 Hz, 1H), 7.61 (dt, = 6.4, 3.4 Hz, 2H), 7.36 (t, = 7.9 Hz, 1H), 7.09 - 7.05 (m, 1H), 7.02 - 6.93 (m, 2H), 4.45 (t, = 6.7 Hz, 3H), 4.17 - 4.07 (m, 1H), 3.96 (d, = 8.8 Hz, 1H), 3.72 (s, 3H), 2.91 (t, = 6.8 Hz, 2H), 1.69 (d, = 6.7 Hz, 3H), 1.57 (d, = 6.6 Hz, 3H); MS (ES+): m/z = 444.21 (M+1,100%).
Example-71: 5-(3-((lR/lS)-l-(((i?)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen-l- yl)-3-methylbenzofuran-2-carboxylic acid hydrochloride
Figure imgf000117_0001
The title compound was prepared by following the same ester hydrolysis procedure as described in Example-70 by using example-64. HCl salt (major diastereomer): XH NMR
(400 MHz, DMSO-J6) δ 13.57 (s, 1H), 10.02 (s, 2H), 8.06 - 7.88 (m, 3H), 7.84 (dd, / = 8.6, 6.6 Hz, 2H), 7.73 - 7.46 (m, 4H), 7.35 (t, = 7.9 Hz, 1H), 7.09 (t, = 2.0 Hz, 1H), 6.98 (dd, 7 = 8.1, 2.2 Hz, 2H), 4.21 (m, 1H), 4.0 (m, 1H), 3.71 (s, 3H), 2.60 (s, 3H), 1.71 (d, = 6.7 Hz, 3H), 1.59 (d, = 6.7 Hz, 3H).MS (ES+): m/z = 480 (M+1,100%).
Example-72: 5-(3-((lR/lS)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen-l- yl)-3-methylpicolinic acid hydrochloride
Figure imgf000118_0001
To a stirred solution of Example-65 (0.0 lg, 0.119 mmol) in water (5 ml) was added sodium hydroxide (28.4 mg, 1.19 mmol) at 25°C. Reaction mixture was then refluxed for 16 hr. TLC showed completion of reaction. Reaction mixture was concentrated in vacuo to get 0.165g residue. Residue was then acidified with dil. HCl (5 ml) at 0 °C, stirred and filtered to get (0.007g) of pure compound.
Ethereal HCl (3 ml) was then added to this compound at 0 °C and stirred for 1 h. Solvent was evaporated on rotary evaporator at 35°C and resulting solid was triturated twice with n- pentane to give pure HCl salt of the title compound (0.005g,) as a off white solid. Major diastereomer: MS (ES+): m/z = 441.09 (M+, 100%).
Example-73: 5-(2-((lR/lS)-l-(((R)-l-(3-Chlorophenyl)ethyl)amino)ethyl)quinolin-4-yl) picolinic acid hydrochloride
Figure imgf000118_0002
The title compound was prepared by following the same procedure as described in example- 72 by using Example-66. Major diastereomer: 1H NMR (400 MHz, DMSO-J6) δ 10.34 (d, 90.9 Hz, 2H), 8.89 (s, 1H), 8.31 - 8.17 (m, 3H), 7.98 - 7.85 (m, 2H), 7.75 - 7.64 (m, 2H), 7.52 - 7.39 (m, 4H), 4.36 (s, 2H), 1.67 (dd, = 10.0, 6.7 Hz, 6H); MS (ES+): m/z = 432.15 (M+ 1,100%).
Example-74: 6-(3-((lR/lS)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen-l- yl)-lH-indazol-3-amine hydrochloride
Figure imgf000119_0001
Step-1: 2-Fluoro-4-(3-(l-(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)naphthalen-l-yl) benzonitrile
The title compound was prepared by following the similar procedure as described in WO 2015/028938A1 using Intermediate-61. Major diastereomer: 1H NMR (400 MHz, DMSO-J6) δ 8.11 (s, 1H), 7.98 (d, / = 8.0 Hz, 1H), 7.74 (d, / = 11.0 Hz, 3H), 7.62 - 7.43 (m, 4H), 7.23 (s, 1H), 6.82 (d, = 15.8 Hz, 3H), 3.73 (s, 3H), 3.60 (s, 1H), 1.24 (s, 3H), 1.17 (dd, / = 14.4, 7.2 Hz, 3H); MS(ES+): m/z= 425.10 (M+l, 100%).
Step-2: 6-(3-(l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen-l-yl)-lH-indazol-3- amine hydrochloride
To a stirred solution of above Step-1 Intermediate (0.09g, 0.212 mmol) in ethanol (2.5 ml) was added hydrazine hydrate (0.073ml, 2.332 mmol) at 25 °C. Reaction mixture was then heated under microwave irradiation for 4 hr at 100 °C. TLC showed completion of reaction.
Reaction mixture was concentrated in vacuo to get 0.165g residue. This residue was purified by column chromatography over silica gel (100-200 mesh) with an isocratic elution of 2% methanol in methylene chloride to afford a pure compound (0.06mg, 65%) as a off white solid.
Ethereal HCl (3 ml) was then added to this compound at 0 °C and stirred for 1 h. Solvent was evaporated on rotary evaporator at 35 °C and resulting solid was triturated twice with n- pentane to give pure HCl salt title compound (0.1 g, 0.225 mmol, 70.6 % yield) as a off white solid. Major diastereomer: 1H NMR (400 MHz, DMSO-J6) δ 13.04 (s, 1H), 10.25 (d, = 15.3 Hz, 2H), 8.13 (d, = 8.4 Hz, 1H), 7.96 (d, = 8.4 Hz, 2H), 7.85 (d, = 8.3 Hz, 1H), 7.59 (dd, = 25.5, 8.4 Hz, 4H), 7.41 - 7.26 (m, 2H), 7.14 (s, 1H), 6.97 (d, = 7.8 Hz, 2H), 4.17 (s, 1H), 3.72 (d, 7 = 2.6 Hz, 3H), 2.09 (d, / = 2.6 Hz, 2H), 1.72 (d, = 6.6 Hz, 3H), 1.60 (d, = 6.6 Hz, 3H); MS (ES+): m/z = 437.10 (M+1, 100%).
Example-75: 5-(3-(( lR/1 S)- 1 -(((R)- 1 -(3-Methoxy phenyl)ethyl)amino)ethyl)naphthalen- 1 - - lH-indazol-3-amine hydrochloride
Figure imgf000120_0001
Step-1: 2-Fluoro-5-(3-(l-(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)naphthalen-l-yl) benzonitrile
The tile compound was prepared by following the similar procedure as described in WO 2015/028938A1 using Intermediate-60. Major diastereomer: 1H NMR (400 MHz, DMSO-J6) δ 8.19 - 8.02 (m, 1H), 8.01 - 7.81 (m, 2H), 7.78 - 7.61 (m, 3H), 7.58 - 7.39 (m, 3H), 7.22 (t, = 7.9 Hz, 1H), 6.80 (dd, = 15.1, 7.5 Hz, 3H), 3.72 (d, = 2.7 Hz, 3H), 3.58 (s, 1H), 1.31 (d, = 6.8 Hz, 3H), 1.20 (d, = 8.4 Hz, 3H); MS(ES+): m/z= 425.10 (M+l, 100%).
Step-2: 5-(3-( 1 -(((R)- 1 -(3-Methoxy phenyl)ethyl)amino)ethyl)naphthalen- 1 -yl)- lH-indazol- 3-amine hydrochloride
The title compound was prepared by following the similar procedure as described in Step-2 of Example-74 using the above Step-1 intermediate. Major diastereomer: 1H NMR (400 MHz, DMSO-Je) δ 10.16 (s, 1H), 8.11 (s, 1H), 8.00 - 7.83 (m, 3H), 7.61 (h, = 8.3, 7.4 Hz, 5H), 7.35 (t, = 8.0 Hz, 1H), 7.13 (s, 1H), 7.01 - 6.93 (m, 2H), 4.19 (s, 1H), 4.02 (s, 1H), 3.71 (s, 3H), 1.72 (d, = 6.6 Hz, 3H), 1.59 (d, = 6.6 Hz, 3H), 1.24 (s, 1H); MS (ES+): m/z = 437.10 (M+1,100%).
The Examples-76 to 78 given in Table- 10 were prepared by following the similar procedure as described in Step-2 of Example-74 Table-10:
Figure imgf000121_0001
Figure imgf000122_0001
Example-79: Isopropyl 5-(2-(( lR/1 S)- 1 -(((R)- 1 -(3-methoxyphenyl)ethyl)amino)ethyl)- 5,6,7,8-tetrahydro quinolin -4- -2-methylbenzoate
Figure imgf000122_0002
The title compound was prepared by following the similar procedure as described in Example-15 by using Intermediate-80 and (R)-l-(3-methoxyphenyl)ethanamine. Major diastereomer: MS (ES+): m/z = 487.06 (M+l, 100%). The Examples 80 to 81 given in table- 11 were prepared by following the similar procedure as described in Example-7 by taking appropriate ketone intermediate and appropriate amine intermediate Table-11:
Interme ¾ NMR; MS (ES+)
Example Structure (Name)
diate
80 78 Mixture of diastereomers: XH NMR
(400 MHz, DMSO-Je) δ 9.86 (s,
T HCI 1H), 8.79 (d, / = 2.1 Hz, 1H), 8.13 - 8.02 (m, 2H), 7.43 - 7.26 (m, 3H), 7.07 (s, 1H), 6.97 (dt, = 12.1, 9.0 CF3
Hz, 2H), 4.06 (p, = 6.8 Hz, 2H),
(lR)-l-(3-Methoxyphenyl)-N- 3.80 - 3.73 (m, 3H), 3.08 (d, = (l-(8-(6-(trifluoromethyl)
14.1 Hz, 2H), 1.80 (dq, = 21.7, pyridin-3-yl)-l,2,3,4-tetra
13.2 Hz, 4H), 1.61 (dt, / = 17.2, 6.5 hydro- 1 ,4-ethanonaphthalen-6- Hz, 6H), 1.39 - 1.27 (m, 5H), 1.24 yl)ethyl)ethan- 1 -amine
(q, = 4.2, 3.8 Hz, 2H); MS (ES+): m/z = 481.18 (M+l, 100%).
81 79 Mixture of diastereomers: XH NMR
(400 MHz, DMSO-J6) δ 9.92 (s,
T HCI 3H), 7.56 (d, = 8.5 Hz, 1H), 7.51
(t, = 6.8 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.24 (dt, = 13.5, 5.6 Hz, 2H),
\ 7.18 - 7.05 (m, 4H), 7.02 (d, = 7.4
( 1R)- l-(3-Methoxyphenyl)-N- Hz, 1H), 6.97 (d, = 7.7 Hz, 1H), ( 1 -(8-( 1 -methyl- 1 H-indol-5 - 6.90 (d, = 7.3 Hz, 1H), 3.85 (d, = yl)- 1 ,2,3,4-tetrahydro- 1 ,4- 5.1 Hz, 2H), 3.75 (d, = 6.6 Hz, ethanonaphthalen-6- 3H), 3.69 (d, = 3.8 Hz, 3H), 3.28 yl)ethyl)ethan- 1 -amine (s, 2H), 2.98 (dd, = 22.8, 15.0 Hz,
2H), 2.64 (d, / = 6.6 Hz, 2H), 1.61 - 1.55 (m, 6H), 1.37 - 1.24 (m, 4H); MS (ES+): m/z 465.18 (M+l, 20%).
Example-82: 5-(2-((lR/lS)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)-5,6, 7,8- tetrahydroquinolin-4-yl)-2-methylbenzoic acid hydro chloride
Figure imgf000124_0001
The title compound was prepared by following the similar procedure as described in Example-4 by using Example-79. Major diastereomer: 1H NMR (400 MHz, DMSO-Je) δ 10.36 (s, 3H), 7.62 - 7.36 (m, 3H), 7.27 (t, = 7.9 Hz, 2H), 7.15 (s, 1H), 7.01 - 6.86 (m, 2H), 4.20 (d, = 28.3 Hz, 3H), 3.72 (s, 3H), 3.00 (dd, / = 16.8, 9.7 Hz, 2H), 2.71 - 2.53 (m, 6H), 1.94 - 1.81 (m, 2H), 1.71 (d, = 7.5 Hz, 2H), 1.61 (dd, = 10.2, 6.8 Hz, 6H), 1.33 (d, = 6.2 Hz, 2H); MS (ES+): m/z = 445.13 (M+l, 100%). 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. Through the use of the above described assay procedure, compounds were found to exhibit CaSR agonistic activity thus to be particularly well suited for the treatment of the diseases or disorders as described herein above. The EC50 (nM) values of the representative compounds are set forth in Table- 12.
The in-vitro activity data has been given below. Table-12:
Example No. ECso (nM) Example EC50
No. (nM)
4 122 46 100
6 125 47 8
7 21 48 45
8 16 49 16
9 34 50 47
11 20 51 20
12 5.1 52 41
13 8.3 53 27
14 32 55 71
19 33 56 23
20 57 57 34
21 100 58 65
22 104 59 11
23 35 60 51
24 11 61 71 25 10 62 100
26 300 70 36
27 42 71 36
28 40 74 300
29 13 75 147
30 33 76 100
31 53 77 86
41 100 78 67
42 100 80 300
43 5.2 81 115
44 27 82 45
45 42

Claims

1. A compound having the Formula (I):
Figure imgf000127_0001
wherein.
one of M and Y is CH and other is CH or N:
r
Figure imgf000127_0002
ing E is
ring B is selected from (a) to (e):
Figure imgf000127_0003
(a) (b) (c) (d) (e)
provided that when ring E is
Figure imgf000127_0004
, ring B is (a) then one of M and Y is N;
G is absent, -CH2- or -CH2-CH2-; Rv is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, -OR9 and substituted or unsubstituted (C3- Cv)cycloalkyl; ring A is phenyl or naphthyl; each of Ri is hydrogen or substituted or unsubstituted (Ci-Ce)alkyl;
R2, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted (Ci-Ce)alkyl, (Ci- C6)haloalkyl, (Ci-C6)hydroxyalkyl, -X-C(0)-Z, -OR9, -NRyRs, -NR7C(0)R6, -S(0)o-2Re, - S(0)2NR7R8, -NR7S(0)2R6 and substituted or unsubstituted (C3-C7)cycloalkyl;
R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-Ce)alkyl, (Ci- C6)haloalkyl, -X-C(0)-Z, -OR9, -NR7Rs, -NR7C(0)R6, -NR7S(0)2R6 and substituted or unsubstituted (C3-C7)cycloalkyl; at each occurrence W is independently selected from hydrogen, substituted or unsubstituted (Ci-Ce)alkyl or -(CRaRb)o-2-C(0)ORio;
V is O or NRi;
Ra and Rb, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted (Ci-Ce)alkyl and (C3- C7)cycloalkyl;
R3 is selected from hydrogen, substituted or unsubstituted (Ci-Ce)alkyl, (Ci- C6)haloalkyl, substituted or unsubstituted (C3-C7)cycloalkyl, -(CRaRb)i-2-C(0)ORio and - (CRaRb)i-2-ORio; at each occurrence X is selected from a bond, -(CRaRb)m-, -NH- and -0(CRaRb)m-; Z is -OR10 or -NR7Rs; R4, which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, substituted or unsubstituted (Ci-Ce)alkoxyalkyl and -OR9;
R5 is substituted or unsubstituted (Ci-Ce)alkyl;
R6 is selected from substituted or unsubstituted (Ci-Ce)alkyl, substituted or unsubstituted (C3-C?)cycloalkyl and substituted or unsubstituted (C6-Cio)aryl;
R7 and R8, which may be same or different at each occurrence, are independently selected from hydrogen, substituted or unsubstituted (Ci-Ce)alkyl and substituted or unsubstituted (C3-C?)cycloalkyl;
R9 is selected from hydrogen, substituted or unsubstituted (Ci-Ce)alkyl, substituted or unsubstituted (Ci-Ce)alkoxyalkyl and substituted or unsubstituted (C3-C?)cycloalkyl; each of Rio is hydrogen or substituted or unsubstituted (Ci-Ce)alkyl;
'm' is an integer ranging from 1 to 3, both inclusive;
'n' is an integer ranging from 0 to 3, both inclusive; and
'p' is an integer ranging from 0 to 3, both inclusive; or a pharmaceutically acceptable salt thereof or stereoisomers thereof.
2. The compound of claim 1 having the Formula (II):
Figure imgf000129_0001
or a pharmaceutically acceptable salt thereof; wherein,
ring A, Ri, R2. R4. R5, 'n' and 'p' as defined in claim-1.
3. The compound of claim 1 havin the Formula (III):
Figure imgf000130_0001
(III)
or a pharmaceutically acceptable salt thereof or stereoisomers thereof; wherein,
G is -CH2- or -CH2-CH2-;
ring A, ring B, Ri, R4 R5 and 'p' are as defined in claim-1.
4. The compound of claim 1 havin the Formula (IV):
or a pharmaceutically acceptable salt thereof;
wherein,
one of M and Y is N and the other is CH;
ring A, Ri, R2, Ri. Rs, 'n' and 'p' as defined in claim-1.
5. The compound of claim 1 having the Formula (V):
Figure imgf000131_0001
(V) or a pharmaceutically acceptable salt thereof; wherein, one of M and Y is CH and the other is CH or N; ring B is selected from (b) to (e):
Figure imgf000131_0002
(b) (c) (d) (e) ring A, V, W, R, Ri, R3, Ri. Rs and 'p' as defined in claim- 1.
6. The compounds of claims 1 to 4 wherein R2 is selected from halogen, cyano, substituted or unsubstituted (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, and -X-C(0)-Z; where X is a bond or -(CRaRb)i-3-; Z is -OR10; Ra and Rb are hydrogen or (Ci-Ce)alkyl; Rio is hydrogen or (Ci-Ce)alkyl; and n is 0, 1 or 2.
7. The compounds of claim 1 or claim 5 wherein R3 is hydrogen, substituted or unsubstituted (Ci-C6)alkyl, -(CRaRb)i-2-C(0)ORio and -(CRaRb)i-2-ORio where Ra and Rb are hydrogen or (Ci-Ce)alkyl; and Rio is hydrogen or (Ci-Ce)alkyl.
8. The compounds of claim 1 or claim 5 wherein R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, -X-C(0)-Z and (C3- Cv)cycloalkyl; where X is a bond or -(CRaRb)i-3-; Z is -ORio; Ra and R are hydrogen or (Ci-Ce)alkyl; and Rio is hydrogen or (Ci-C6)alkyl.
9. The compounds of claim 1 or claim 5 wherein W is hydrogen, (Ci-Ce)alkyl or - (CRaRb)o-2-COORio; V is O or NRi; where R, and Rb are hydrogen or (Ci-C6)alkyl; Ri is hydrogen or (Ci-Ce)alkyl and Rio is hydrogen or (Ci-Ce)alkyl.
10. The compounds of claim 1 wherein Ri is hydrogen or (Ci-Ce)alkyl.
11. The compound of claim- 1 wherein ring B is selected from (a) to (e)
Figure imgf000132_0001
R2 is halogen, cyano, substituted or unsubstituted (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, -X- C(0)-Z; X is a bond or -(CRaRb)m-; R3 is hydrogen, substituted or unsubstituted (Ci-Ce)alkyl, -(CRaRb)i-2-C(0)ORio and -(CRaRb)i-2-ORio; R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-C6)alkyl, (Ci-C6)haloalkyl, -X-C(0)-Z and (C3-C?)cycloalkyl; W is hydrogen, (Ci-C6)alkyl or -(CRaRb)o-2-C(0)ORio; V is O or NRi; Z is -ORio; R, and Rb are hydrogen or (Ci-Ce)alkyl; Ri is hydrogen or (Ci-Ce)alkyl; Rio is hydrogen or substituted or unsubstituted (Ci-Ce)alkyl; 'n' is 0, 1 or 2; and 'm' is 1 to 3.
12. The compound of Claim- 1 wherein ring B is selected from (b) to (e):
Figure imgf000132_0002
wherein Ri is hydrogen or (Ci-Ce)alkyl; R3 is hydrogen, substituted or unsubstituted (Ci-C6)alkyl, -(CRaRb)i-2-COORio and -(CRaRb)i-2-ORio; R is selected from hydrogen, cyano, substituted or unsubstituted (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, -X-C(0)-Z and (C3- Cv)cycloalkyl; W is hydrogen, (Ci-C6)alkyl or -(CRaRb)o-2-COORio; V is O or NRi; wherein X is a bond or -(CRaRb)i-3-; Z is -OR10; Ra and Rb are hydrogen or (Ci-Ce)alkyl; Ri is hydrogen or (Ci-Ce)alkyl; Rio is hydrogen or (Ci-Ce)alkyl.
13. The compound of claim- 1 wherein ring A is phenyl or naphthyl.
14. The compound of any preceding claim, wherein R4 is selected from halogen, substituted or unsubstituted (Ci-Ce)alkyl and -OR9 where R9 is hydrogen or substituted or unsubstituted (Ci-Ce)alkyl; and 'p' is 0, 1 or 2.
15. A compound of which is selected from:
(i?)-Methyl-2-methyl-5-(2-(((l-(naphthalen-l-yl)ethyl)amino)methyl)-5,6,7,8- tetrahydroquinolin-4-yl)benzoate;
(R)-Methyl-5-(2-(((l-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)-5,6,7,8-tetrahydro quinolin-4-yl)-2-methylbenzoate;
Methyl-5-(7-((((R)-l-(3-methoxyphenyl)ethyl)amino)methyl)-l,2,3,4-tetrahydro-l,4- methanonaphthalen-5-yl)-2-methylbenzoate;
(R)-2-Methyl-5-(2-(((l-(naphthalen-l-yl)ethyl)amino)methyl)-5,6,7,8-tetra
hydroquinolin-4-yl)benzoic acid hydrochloride;
(R)-5-(2-(((l-(4-Fluoro-3-methoxyphenyl)ethyl)amino)methyl)-5,6,7,8-tetrahydro quinolin-4-yl)-2-methyl benzoic acid hydrochloride;
5-(7-((((R)-l -(3-Methoxyphenyl)ethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 ,4- methanonaphthalen-5-yl)-2-methylbenzoic acid hydrochloride; (lR)-l-(3-Methoxyphenyl)-N-((lR/lS)-l-(8-(4-(trifluoromethyl)phenyl)-l,2,3,4- tetrahydro- 1 ,4-methanonaphthalen-6-yl)ethyl)ethan- 1 -amine hydrochloride;
(1 R)- 1 -(3 -Chlorophenyl)-N-((l R/l S)- 1 -(8-(4-(tnfluoromethyl)phenyl)- 1 ,2,3,4- tetrahydro-l,4-methano naphthalen-6-yl)ethyl) ethanamine hydrochloride;
(lR)-l-(3-Fluoro-5-methoxyphenyl)-N-((lR/lS)-l-(8-(4-(trifluoromethyl)phenyl)- l,2,3,4-tetrahydro-l,4-methano naphthalen-6-yl)ethyl) ethanamine hydrochloride;
(1 R)- 1 -(3 -Chlorophenyl)-N-((l R/l S)- 1 -(8-(4-(tnfluoromethyl)phenyl)- 1 ,2,3,4- tetrahydro- 1 ,4-ethanonaphthalen-6-yl)ethyl)ethan- 1 -amine hydrochloride;
N-((R)-l-(3-Methoxyphenyl) ethyl)-l-(8-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro- 1,4-ethano naphthalen-6-yl)propan-l -amine hydrochloride;
(1R)-1 -(3-Chlorophenyl)-N-((lR/l S)-l -(4-(4-(tnfluoromethyl)phenyl)-5,6,7,8-tetrahydro quinolin-2-yl)ethyl)ethanamine hydrochloride;
(lR)-l-(3-Methoxyphenyl)-N-((lR/lS)-l-(4-(4-(trifluoromethyl)phenyl)-5,6,7,8- tetrahydro quinolin-2-yl)ethyl) ethanamine hydrochloride;
N-((R)-l-(3-Methoxyphenyl)ethyl)-l-(4-(4-(trifluoromethyl)phenyl)-5,6,7,8- tetrahydroquinolin-2-yl)propan-l -amine hydrochloride;
Isopropyl-3-(5-(2-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)-5,6,7,8- tetrahydroquinolin-4-yl)-2-methylphenyl)propanoate;
Isopropyl-3-(3-fluoro-5-(2-((lR/l S)-l-(((R)-l-(3-methoxyphenyl) ethyl) amino)ethyl)- 5,6,7,8-tetra hydro quinolin-4-yl)phenyl)propanoate;
Isopropyl-3-(5-(7-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)-l,2,3,4-tetra hydro- 1,4-ethano naphthalen-5-yl)-2-methylphenyl)propanoate;
Isopropyl-3-(3-fluoro-5-(7-((lR/l S)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)- 1, 2,3, 4-tetrahydro- 1,4-ethano naphthalen-5-yl)phenyl)propanoate; 3-(5-(2-((lR/l S)-l -(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)-5,6,7,8- tetrahydroquinolin-4-yl)-2-methylphenyl)propanoic acid hydrochloride;
3-(3-Fluoro-5-(2-((lR/l S)-l -(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)-5,6,7,8- tetrahydro quinolin-4-yl)phenyl)propanoic acid hydrochloride;
3 -(5-(7-(( 1 R/l S)- 1 -(((R)- 1 -(3 -Methoxyphenyl)ethyl)amino)ethyl)- 1 ,2,3 ,4-tetrahydro- 1 ,4- ethanonaphthalen-5-yl)-2-methylphenyl)propanoic acid hydrochloride;
3-(3-Fluoro-5-(7-((lR/l S)-l -(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)-l,2,3,4- tetrahydro-l,4-ethanonaphthalen-5-yl)phenyl) propanoic acid hydrochloride;
(R)-l-(3-Methoxyphenyl)-N-((4-(4-(trifluoromethyl)phenyl)quinolin-2-yl)methyl)ethan- 1 -amine hydrochloride;
(li?)-l -(Naphthalen-l-yl)-N-(l-(4-(4-(trifluoromethyl)phenyl)quinolin-2-yl)
ethyl) ethanamine hydrochloride;
(li?)-l -(3-Chlorophenyl)-N-((lR/l S)-l-(4-(4-(trifluoromethyl)phenyl)quinolin-2-yl) ethyl) ethanamine hydrochloride;
(lR)-l -(4-Fluoro-3-methoxyphenyl)-N-((lR/l S)-l-(4-(4-(trifluoromethyl)phenyl) quinolin-2-yl)ethyl)ethan-l -amine hydrochloride;
(lR)-l -(3-Fluoro-5-methoxyphenyl)-N-((lR/l S)-l-(4-(4-(trifluoromethyl)phenyl) quinolin-2-yl)ethyl)ethan-l -amine hydrochloride;
N-((R)-l -(3-Methoxyphenyl)ethyl)-l-(4-(4-(trifluoromethyl)phenyl)quinolin-2- yl)propan-l -amine hydrochloride;
(IR)-1 -(3-Methoxyphenyl)-N-(l -((lR/1 S)-l -(4-(trifluoromethyl)phenyl) isoquinolin-3- yl)ethyl)ethanamine hydrochloride;
(1 R)- 1 -(3 -Chlorophenyl)-N-(( 1 R/l S)- 1 -( 1 -(4-(tnfluoromethyl)phenyl) isoquinolin-3 - yl)ethyl)ethan-l -amine hydrochloride; (lR)-l-(3-Fluoro-5-methoxyphenyl)-N-((lR/lS)-l-(l-(4-(trifluoromethyl)
phenyl)isoquinolin-3-yl)ethyl)ethan-l -amine hydrochloride;
Isopropyl 5-(2-((lR/lS)-l-(((i?)-l-(3-methoxyphenyl)ethyl)amino)ethyl)quinolin-4-yl)-2 methylbenzoate;
Isopropyl-2-fluoro-5-(2-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl) quinolin-4-yl)-3-methylbenzoate;
Isopropyl-3-(3-fluoro-5-(2-((lR/l S)-l-(((i?)-l-(3-methoxyphenyl)ethyl)amino)ethyl) quinolin-4-yl)phenyl)propanoate;
Isopropyl-3 -(3 -fluoro-5 -(2-(( 1 R/l S)- 1 -(((R)- 1 -(3 -fluoro-5 -methoxyphenyl)ethyl) amino)ethyl)quinolin-4-yl)phenyl)propanoate;
Isopropyl-3-(5-(2-((lR/l S)-l -(((R)-l -(3-methoxyphenyl)ethyl)amino)ethyl)quinolin-4- yl)-2-methylphenyl)propanoate;
Isopropyl-3-(3-fluoro-5-(3-((lR/l S)-l-(((i?)-l-(3-methoxyphenyl)ethyl)amino)ethyl) isoquinolin- 1 -yl)phenyl)propanoate hydrochloride;
Isopropyl-5-(3-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)isoquinolin-l- yl)-2-methylbenzoate;
Isopropyl-3-(2-fluoro-5-(3-((lR/l S)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl) isoquinolin- 1 -yl)phenyl)propanoate;
Isopropyl-3-(5-(3-((lR/l S)-l -(((R)-l -(3-methoxyphenyl)ethyl)amino)ethyl)isoquinolin-
1- yl)-2-methylphenyl)propanoate;
5-(2-((lR/l S)-l-(((i?)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)quinolin-4-yl)-2-methyl benzoic acid hydrochloride;
2- Fluoro-5-(2-((lR/lS)-l-(((R)-l-(3-methoxyphenyl) ethyl)amino)ethyl)quinolin-4-yl)-3 methyl benzoic acid hydrochloride; 3-(3-Fluoro-5-(2-((lR/l S)-l -(((R)-l-(3-methoxyphenyl) ethyl)amino)ethyl)quinolin-4-yl) phenyl) propanoic acid hydrochloride;
3-(3-Fluoro-5-(2-((lR/l S)-l -(((R)-l-(3-fluoro-5-methoxyphenyl)ethyl)amino)ethyl) quinolin-4-yl) phenyl) propanoic acid hydrochloride;
3-(5-(2-((lR/l S)-l -(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)quinolin-4-yl)-2- methylphenyl)propanoic acid hydrochloride;
5-(3-((lR/l S)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)isoquinolin-l-yl)-2-methyl benzoic acid hydrochloride;
3-(3-Fluoro-5-(3-((lR/l S)-l -(((i?)-l-(3-methoxyphenyl) ethyl) amino) ethyl)isoquinolin- 1 -yl)phenyl) propanoic acid hydrochloride;
3-(2-Fluoro-5-(3-((lR/l S)-l -(((R)-l-(3-methoxyphenyl) ethyl)amino) ethyl)isoquinolin- 1 -yl)phenyl) propanoic acid hydrochloride;
3-(5-(3-((lR/l S)-l -(((R)-l-(3-Methoxy phenyl)ethyl) amino)ethyl) isoquinolin-l-yl)-2- methyl phenyl)propanoic acid hydrochloride;
(li?)-l -(3-Methoxyphenyl)-N-((lR/l S)-l-(4-(6-(trifluoromethyl)pyridin-3-yl)naphthalen- 2-yl)ethyl)ethanamine hydrochloride;
(1R)-1 -(3-Methoxyphenyl)-N-((lR/l S)-l -(4-(l -methyl- lH-pyrazol-4-yl)naphthalen-2- yl)ethyl)ethan-l -amine hydrochloride;
5-(3-((lR/l S)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen-l - yl)picolinonitrile hydrochloride;
2-(4-(3 -(( 1 R/l S)- 1 -(((R)- 1 -(3 -Methoxyphenyl)ethyl)amino)ethyl)naphthalen- 1 -yl)- 1 H- pyrazol-l-yl) ethan-l -ol hydrochloride;
(1R)-1 -(3-Methoxyphenyl)-N-((lR/l S)-l -(4-(l -methyl-lH-indol-5-yl)naphthalen-2- yl)ethyl)ethan-l -amine hydrochloride; (1 R) - 1 -(3 -Methoxyphenyl)-N-(( 1 R/l S)-l-(4-(l -methyl- 1 H-indol-5 -yl)quinolin-2- yl)ethyl)ethan-l -amine hydrochloride;
(1R)-1 -(3-Methoxyphenyl)-N-((lR/l S)-l -(4-(l -methyl- lH-pyrazol-4-yl)quinolin-2- yl)ethyl)ethan-l -amine hydrochloride;
5-(2-((lR/l S)- 1 -(((R)-l -(3-Methoxyphenyl)ethyl)amino)ethyl)quinolin-4- yl)picolinonitrile hydrochloride;
5-(3-((lR/l S)- 1 -(((R)-l -(3-Methoxyphenyl)ethyl)amino)ethyl)isoquinolin-l - yl)picolinonitrile hydrochloride;
5-(3 - (( 1 R/l S) - 1 - (((R) - 1 -(3 -Chlorophenyl)ethyl)amino)ethyl)isoquinolin- 1 - yl)picolinonitrile hydrochloride;
2-(4-(3 - (( 1 R/l S) - 1 -(((R)- 1 -(3 -Methoxy phenyl)ethyl)amino)ethyl)isoquinolm- 1 -yl)-l H- pyrazol-l-yl) ethan-l-ol hydrochloride;
(lR)-l-(3-Methoxyphenyl)-N-((lR/lS)-l-(l-(l-methyl-lH-indol-5-yl)isoquinolin-3- yl)ethyl)ethan-l -amine hydrochloride;
(1 R) - 1 -(3 -Chlorophenyl)-N-(( 1 R/l S) - 1 -( 1 -(6-(trifluoromethyl)pyndin-3 -yl)isoquinolin-3 - yl)ethyl)ethan-l -amine hydrochloride;
Isopropyl-3-(4-(3-((lR/l S)-l -(((/?)- 1 -(3-methoxyphenyl)ethyl)amino)ethyl) naphthalen- 1 -yl)- lH-pyrazol- 1 -yl)propanoate;
Isopropyl-5-(3-((lR/lS)-l-(((i?)-l-(3-methoxyphenyl)ethyl)amino)ethyl)naphthalen-l- yl)-3-methylbenzofuran-2-carboxylate;
5-(3-((lR/l S)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen-l-yl)-3- methylpicolinonitrile;
5-(2-((lR/l S)-l-(((R)-l-(3-Chlorophenyl)ethyl)amino)ethyl)quinolin-4-yl)picolinonitrile; 2-Fluoro-4-(3-((lR/l S)-l -(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)isoquinolin-l- yl)benzonitrile;
2-Fluoro-5-(3-((lR/l S)-l -(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)isoquinolin-l- yl)benzonitrile;
2- Fluoro-5-(2-((lR/l S)-l -(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)quinolin-4- yl)benzonitrile;
3- (4-(3-((lR/l S)-l -(((i?)-l -(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen-l -yl)-lH- pyrazol-l-yl)propanoic acid hydrochloride;
5-(3-((lR/l S)- 1 -(((R)- 1 -(3 -Methoxyphenyl)ethyl)amino)ethyl)naphthalen- 1 -yl)-3 - methylbenzofuran-2-carboxylic acid hydrochloride;
5-(3-((lR/l S)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen-l -yl)-3- methylpicolinic acid hydrochloride;
5- (2-((lR/l S)-l-(((R)-l-(3-Chlorophenyl)ethyl)amino)ethyl)quinolin-4-yl)picolinic acid hydrochloride;
6- (3-((lR/l S)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen-l -yl)-m- indazol-3 -amine hydrochloride;
5- (3-((lR/l S)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)naphthalen-l -yl)-m- indazol-3 -amine hydrochloride;
6- (3-((lR/l S)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino) ethyl)isoquinolm-l -yl)-lH- indazol-3 -amine hydrochloride;
5-(3-((lR/l S)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)isoquinolin-l-yl)-lH- indazol-3 -amine hydrochloride;
5-(2-((lR/l S)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)quinolin-4-yl)-lH-indazol- 3 -amine hydrochloride; Isopropyl-5-(2-((lR/lS)-l-(((R)-l-(3-methoxyphenyl)ethyl)amino)ethyl)-5,6,7,8- tetrahydroquinolin -4-yl)-2-methylbenzoate;
(1 R) - 1 -(3 -Methoxyphenyl)-N-( 1 -(8-(6-(trifluoromethyl)pyridin-3 -yl)- 1 ,2,3 ,4-tetra hydro- 1 ,4-ethanonaphthalen-6-yl)ethyl)ethan- 1 -amine;
(1 R) - 1 -(3 -Methoxyphenyl)-N-( 1 -(8-( 1 -methyl- 1 H-indol-5 -yl)- 1 ,2,3 ,4-tetrahydro- 1 ,4- ethanonaphthalen-6-yl)ethyl)ethan- 1 -amine and
5-(2-((lR/l S)-l-(((R)-l-(3-Methoxyphenyl)ethyl)amino)ethyl)-5,6,7,8-tetrahydro quinolin-4-yl)-2-methylbenzoic acid hydrochloride or a free base thereof or a pharmaceutically acceptable salt thereof or stereoisomers thereof.
16. The compound of any one of the preceding claims, wherein the pharmaceutically acceptable salt is an acid addition salt.
17. The compound of claim 16, wherein the pharmaceutically acceptable salt is hydrochloride salt.
18. A pharmaceutical composition comprising one or more compounds according to any one of the preceding claims, and one or more pharmaceutically acceptable excipients.
19. 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 15, or a pharmaceutically acceptable salt thereof.
20. The method of claim 19, 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.
21. The method of claim 20, wherein hyperparathyroidism is primary hyperparathyroidism, secondary hyperparathyroidism or tertiary hyperparathyroidism.
22. The method of claim 19, 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.
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Citations (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002012181A1 (en) 2000-08-08 2002-02-14 Centre National De La Recherche Scientifique (Cnrs) Novel diamines having a casr modulating activity
US20030199497A1 (en) 2000-05-24 2003-10-23 Martial Ruat Novel calcium receptor active molecules and method for preparing same
WO2003099776A1 (en) * 2002-05-23 2003-12-04 Amgen Inc. Calcium receptor modulating arylalkylamines
WO2004069793A2 (en) 2003-01-28 2004-08-19 Bristol-Myers Squibb Company Novel 2-substituted cyclic amines as calcium sensing receptor modulators
WO2004106280A1 (en) 2003-05-28 2004-12-09 Japan Tobacco Inc. CaSR ANTAGONIST
WO2006123725A1 (en) 2005-05-19 2006-11-23 Astellas Pharma Inc. Pyrrolidine derivative or salt thereof
WO2008057282A1 (en) * 2006-10-26 2008-05-15 Amgen Inc. Calcium receptor modulating agents
WO2008059854A1 (en) 2006-11-16 2008-05-22 Astellas Pharma Inc. Piperidine derivatives or salts thereof
WO2009065406A2 (en) 2007-11-23 2009-05-28 Leo Pharma A/S Novel cyclic hydrocarbon compounds for the treatment of diseases
WO2010038895A1 (en) 2008-10-03 2010-04-08 味の素株式会社 Casr agonist
WO2010042642A1 (en) 2008-10-08 2010-04-15 Amgen Inc. Calcium receptor modulating agents
WO2010136037A1 (en) 2009-05-27 2010-12-02 Leo Pharma A/S Novel calcium sensing receptor modulating compounds and pharmaceutical use thereof
WO2010150837A1 (en) 2009-06-25 2010-12-29 第一三共株式会社 Indoline derivative
US20110028452A1 (en) 2006-10-04 2011-02-03 Pfizer Inc PYRIDO[4,3-d]PYRIMIDIN-4(3H)-ONE DERIVATIVES AS CALCIUM RECEPTOR ANTAGONISTS
WO2011159554A1 (en) 2010-06-15 2011-12-22 Merck Sharp & Dohme Corp. Tetrahydroquinoline amide m1 receptor positive allosteric modulators
WO2012069419A1 (en) 2010-11-26 2012-05-31 Leo Pharma A/S Calcium-sensing receptor-active compounds
WO2012069402A1 (en) 2010-11-26 2012-05-31 Leo Pharma A/S Substituted cyclopentyl - azines as casr- active compounds
WO2012069421A1 (en) 2010-11-26 2012-05-31 Leo Pharma A/S Calcium-sensing receptor-active compounds
WO2012120476A1 (en) 2011-03-10 2012-09-13 Lupin Limited Substituted morpholines as modulators for the calcium sensing receptor
WO2012127385A1 (en) 2011-03-18 2012-09-27 Lupin Limited Benzo [b] [1, 4] oxazin derivatives as calcium sensing receptor modulators
WO2013002329A1 (en) 2011-06-28 2013-01-03 味の素株式会社 Method for producing lanthionine derivative
WO2013124828A1 (en) 2012-02-24 2013-08-29 Lupin Limited Substituted chroman compounds as calcium sensing receptor modulators
WO2013136288A1 (en) 2012-03-16 2013-09-19 Lupin Limited Substituted 3,4-dihydro-2h-benzo[b] [1,4]oxazine compounds as calcium sensing receptor modulators
WO2014019344A1 (en) 2012-08-03 2014-02-06 Sunshine Lake Pharma Co., Ltd. Bridged ring compounds as hepatitis c virus (hcv) inhibitors and pharmaceutical applications thereof
US20140080770A1 (en) 2004-05-28 2014-03-20 Mitsubishi Tanabe Pharma Corporation Arylalkylamine compound and process for preparing the same
US20140155416A1 (en) 2002-08-26 2014-06-05 Takeda Pharmaceutical Company Limited Substituted pyrazolo[1,5-a] pyrimidines as calcium receptor modulating agents
WO2015028938A1 (en) 2013-08-28 2015-03-05 Lupin Limited Substituted naphthalene compounds as calcium sensing receptor modulators

Patent Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030199497A1 (en) 2000-05-24 2003-10-23 Martial Ruat Novel calcium receptor active molecules and method for preparing same
WO2002012181A1 (en) 2000-08-08 2002-02-14 Centre National De La Recherche Scientifique (Cnrs) Novel diamines having a casr modulating activity
WO2003099776A1 (en) * 2002-05-23 2003-12-04 Amgen Inc. Calcium receptor modulating arylalkylamines
US20140155416A1 (en) 2002-08-26 2014-06-05 Takeda Pharmaceutical Company Limited Substituted pyrazolo[1,5-a] pyrimidines as calcium receptor modulating agents
WO2004069793A2 (en) 2003-01-28 2004-08-19 Bristol-Myers Squibb Company Novel 2-substituted cyclic amines as calcium sensing receptor modulators
WO2004106280A1 (en) 2003-05-28 2004-12-09 Japan Tobacco Inc. CaSR ANTAGONIST
US20140080770A1 (en) 2004-05-28 2014-03-20 Mitsubishi Tanabe Pharma Corporation Arylalkylamine compound and process for preparing the same
WO2006123725A1 (en) 2005-05-19 2006-11-23 Astellas Pharma Inc. Pyrrolidine derivative or salt thereof
US20110028452A1 (en) 2006-10-04 2011-02-03 Pfizer Inc PYRIDO[4,3-d]PYRIMIDIN-4(3H)-ONE DERIVATIVES AS CALCIUM RECEPTOR ANTAGONISTS
WO2008057282A1 (en) * 2006-10-26 2008-05-15 Amgen Inc. Calcium receptor modulating agents
WO2008059854A1 (en) 2006-11-16 2008-05-22 Astellas Pharma Inc. Piperidine derivatives or salts thereof
WO2009065406A2 (en) 2007-11-23 2009-05-28 Leo Pharma A/S Novel cyclic hydrocarbon compounds for the treatment of diseases
WO2010038895A1 (en) 2008-10-03 2010-04-08 味の素株式会社 Casr agonist
WO2010042642A1 (en) 2008-10-08 2010-04-15 Amgen Inc. Calcium receptor modulating agents
WO2010136037A1 (en) 2009-05-27 2010-12-02 Leo Pharma A/S Novel calcium sensing receptor modulating compounds and pharmaceutical use thereof
WO2010150837A1 (en) 2009-06-25 2010-12-29 第一三共株式会社 Indoline derivative
WO2011159554A1 (en) 2010-06-15 2011-12-22 Merck Sharp & Dohme Corp. Tetrahydroquinoline amide m1 receptor positive allosteric modulators
WO2012069421A1 (en) 2010-11-26 2012-05-31 Leo Pharma A/S Calcium-sensing receptor-active compounds
WO2012069402A1 (en) 2010-11-26 2012-05-31 Leo Pharma A/S Substituted cyclopentyl - azines as casr- active compounds
WO2012069419A1 (en) 2010-11-26 2012-05-31 Leo Pharma A/S Calcium-sensing receptor-active compounds
WO2012120476A1 (en) 2011-03-10 2012-09-13 Lupin Limited Substituted morpholines as modulators for the calcium sensing receptor
WO2012127385A1 (en) 2011-03-18 2012-09-27 Lupin Limited Benzo [b] [1, 4] oxazin derivatives as calcium sensing receptor modulators
WO2012127388A1 (en) 2011-03-18 2012-09-27 Lupin Limited Benzo [b] [1, 4] oxazin derivatives as calcium sensing receptor modulators
WO2013002329A1 (en) 2011-06-28 2013-01-03 味の素株式会社 Method for producing lanthionine derivative
WO2013124828A1 (en) 2012-02-24 2013-08-29 Lupin Limited Substituted chroman compounds as calcium sensing receptor modulators
WO2013136288A1 (en) 2012-03-16 2013-09-19 Lupin Limited Substituted 3,4-dihydro-2h-benzo[b] [1,4]oxazine compounds as calcium sensing receptor modulators
WO2014019344A1 (en) 2012-08-03 2014-02-06 Sunshine Lake Pharma Co., Ltd. Bridged ring compounds as hepatitis c virus (hcv) inhibitors and pharmaceutical applications thereof
WO2015028938A1 (en) 2013-08-28 2015-03-05 Lupin Limited Substituted naphthalene compounds as calcium sensing receptor modulators

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CURRENT SCIENCE, vol. 48, no. 13, 1979, pages 580 - 581
J. MED. CHEM., vol. 49, 2006, pages 5119 - 5128

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