SUBSTITUTED CHROMAN COMPOUNDS AS CALCIUM SENSING RECEPTOR MODULATORS
Related Applications
The present application claims the benefit of priority to Indian Provisional Patent
Application Nos. 0178/KOL/2012, filed on February 24, 2012 and 1030/KOL/2012, filed
on September 07, 2012. The entire provisional specifications are incorporated herein by
reference.
Field of the Invention
The present invention relates to substituted chroman compounds, pharmaceutically
acceptable salts thereof and pharmaceutical compositions for the treatment, management,
and/or lessening the severity of diseases, disorders, syndromes or conditions associated
with the modulation of calcium sensing receptors (CaSR). The invention also relates to
methods of treating, managing and/or lessening the severity of diseases disorders,
syndromes or conditions associated with the modulation of calcium sensing receptors
(CaSR). The invention also relates to processes for the preparation of the compounds of
the invention.
Background of the invention
Ca2+ is 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 Ca2+ by increasing kidney retention and
intestinal absorption of Ca2+. This happens indirectly through the PTH-induced synthesis
of the active vitamin D metabolite, 25-dihydroxyvitamin D. In addition, the pulsatile
action of PTH has anabolic effects on bone development and its sustained levels can lead
to catabolic effects, in which the bones breakdown releasing Ca2+ as in the case of
osteoporosis. All these systems converge in maintenance of baseline serum Ca2+ and it
involves a tight regulation between serum PTH and extracellular calcium which is
mediated by the remarkable receptor 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 hypocalcemia.
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 2012/127388, WO 2012/120476, WO 2012/127385, WO 2012/069421, WO
2012/069419, WO 2012/069402, US 2011/0028452, WO 2010/150837, WO
2010/136037, WO 2010/042642, WO 2010/038895, WO 2009/065406, WO
2008/059854, WO 2006/123725, WO 2004/106280, WO 2004/069793, WO 2002/012181
and US 2003/0199497 applications disclose the compounds related to calcium sensing
receptors (CaSR) for the treatment of various diseases mediated by CaSR. And also .
Med. Chem. (2006), 49, 5119-5128 discloses the compounds related to calcium sensing
receptors (CaSR).
Summary of the Invention
In accordance with one aspect, the invention provides compounds having the structure of
Formula (I),
wherein,
Ra is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano,
substituted or unsubstituted cycloalkyl and substituted or unsubstituted haloalkyl;
Rb, which may be same or different at each occurrence, is independently selected
from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted
cycloalkyl and substituted or unsubstituted haloalkyl;
R, which may be same or different at each occurrence, is independently selected
from halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted
haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted cycloalkyl, OR , nitro, cyano, -C(0)OR 6, -(CH2)r-C(0)OR 6, -
0-C(0)OR , -0(CH 2) -C(0)OR , -NR7R , -(CH2) NR7R -, -C(0)R 9, -C(0)NR 7R , -
(CH2) -C(0)NR 7R , -NR7C(0)R , -S(O)0-2R6, -S(0) 2NR7R , and -NR7S(0) 2R ;
X is selected from a bond, -(CRcRd)r-, -0-, -NR7-, -NR7(CRcRd)r-, -0(CR cRd)r-,
-C(0)NR 7-, -C(0)NR 7(CR Rd) -, -(CRcRd) NR7(CRcRd) -, -(CRcRd) cycloalkylene-,
cycloalkylene, -cycloalkylene(CRcRd) - and -O-cycloalkylene where cycloalkylene may
be substituted or unsubstituted;
Rc and Rd, which may be same or different at each occurrence, are independently
selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted
alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl;
or Rc and Rd together with the carbon atom to which they are attached, may form a
substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring;
Z is -OR6 or-NRioRii;
Ri, which may be same or different at each occurrence, is independently selected
from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted
haloalkyl, substituted or unsubstituted cycloalkyl, -OR , -C(0)Rg, -NR 7R , -
(CH2) NR7R8-, -(CH2) -C(0)OR 6, -0-C(0)OR 6, -0(CH 2) -C(0)OR 6, -C(0)NR 7R8, -
(CH2) -C(0)NR 7R , -NR7C(0)R , -S(O)0-2R7, - S(0) 2NR7R and -NR7S(0) 2R ;
R2 is selected from substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocyclyl;
R 3 and R4 may be same or different and are independently selected from hydrogen,
halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted haloalkoxy and substituted or
unsubstituted cycloalkyl;
R 5 is substituted or unsubstituted alkyl;
R6, which may be same or different at each occurrence, is independently selected
from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted
or unsubstituted aryl;
R7 and Rs, which may be same or different at each occurrence, are independently
selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or
unsubstituted heterocyclylalkyl; or R and R , together with the nitrogen atom to which
they are attached, may form a substituted or unsubstituted, saturated or unsaturated 3 to
12 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double
bonds;
at each occurrence, R is substituted or unsubstituted alkyl or substituted or
unsubstituted aryl;
Rio and may be same or different and are independently selected from
hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, -(CR cR ) -C(0)OR 6, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted
or unsubstituted heterocyclylalkyl; or Ri0 and R together with the nitrogen atom to
which they are attached, may form a substituted or unsubstituted, saturated or unsaturated
3 to 12 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two
double bonds;
'n' is an integer ranging from 1 to 3, both inclusive;
'm' is an integer ranging from 0 to 3, both inclusive;
'p' is an integer ranging from 0 to 4, both inclusive;
'q' is an integer ranging from 0 to 3, both inclusive; and
'r' is an integer ranging from 1 to 3, both inclusive;
or its pharmaceutically acceptable salt thereof.
According to one embodiment, there are provided compounds having the structure
of Formula (II):
(II)
or its pharmaceutically acceptable salt thereof;
wherein,
R2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
R, Ri, X, Z, 'p' and 'q' are as defined in Formula (I).
According to another embodiment, there are provided compounds having the
structure of Formula (III):
(III)
or its pharmaceutically acceptable salt thereof;
wherein,
R2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
R, Ri, X, Z, 'p' and 'q' are as defined in Formula (I).
According to another embodiment, there are provided compounds having the
structure of Formula (IV):
( i )q r -x-c(0)-z
(IV)
or its pharmaceutically acceptable salt thereof;
wherein,
R2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
R, Ri, X, Z, 'p' and 'q' are as defined in Formula (I).
According to another embodiment, there are provided compounds having the
structure of Formula (V):
(Ri)qir^J-X-C(0)-Z
(V)
or its pharmaceutically acceptable salt thereof;
wherein,
R2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
Ri, X, Z, 'n', and 'q' are as defined in Formula (I).
It should be understood that the Formula (I), Formula (II), Formula (III), Formula (IV)
and Formula (V) structurally encompasses all tautomers, stereoisomers, enantiomers and
diastereomers, including isotopes wherever applicable and pharmaceutically acceptable
salts that may be contemplated from the chemical structure of the genera described
herein.
The details of one or more embodiments of the invention set forth in the below are
illustrative in nature only and not intended to limit to the scope of the invention. Other
features, objects and advantages of the inventions will be apparent from the description
and claims.
According to another embodiment, there are provided compounds of Formula (I)
in which 'n' is 1.
According to another embodiment, there are provided compounds of Formula (I)
in which 'n' is 2.
According to another embodiment, there are provided compounds of Formula (I)
in which 'n' is 3.
According to another embodiment, there are provided compounds of Formula (I),
in which 'm' is 0.
According to another embodiment, there are provided compounds of Formula (I),
in which 'p' is 0.
According to another embodiment, there are provided compounds of Formulae (I),
(II), (III), (IV) and/or (V) in which Ri is selected from halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted
cycloalkyl, cyano, -O , -C(0)alkyl; wherein R is hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted haloalkyl, or substituted or unsubstituted cycloalkyl;
and 'q' is 0, l , or .
According to another embodiment, there are provided compounds of Formulae (I),
(II), (III), (IV) and/or (V) in which R2 is substituted or unsubstituted aryl, wherein the aryl
is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl. In this
embodiment the substituent(s) on R2 may be one or more and are independently selected
from halogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted
haloalkyl, and substituted or unsubstituted alkoxy.
According to another embodiment, there are provided compounds of Formulae (I), (II),
(III) , (IV) and/or (V) in which X is selected from a bond, -(CR cRd)r-, -0-, -NR 7-, -
NR7(CR Rd) -, -C CReRd , -C(0)NR 7-, -C(0)NR 7(CR Rd) -, -(CR Rd)rNR 7(CR R i)r-, -
(CR Rd)rcycloaikylene-, cycloalkylene, -cycloalkylene(CR R )r- and -O-cycloalkylene
where cycloalkylene may be substituted or unsubstituted; R7 is hydrogen or substituted or
unsubstituted alkyl; R and Rd are hydrogen or substituted or unsubstituted alkyl and 'r' is
1, 2 or 3.
According to another embodiment, there are provided compounds of Formulae (I),
(II), (III), (IV) and/or (V) in which Z is -OR wherein R is selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or
unsubstituted aryl or substituted or unsubstituted arylalkyl.
According to another embodiment, there are provided compounds of Formulae (I),
(II), (III), (IV) and/or (V) in which Z is NR10R11 wherein Ri0 and may be same or
different and are independently selected from hydrogen, substituted or unsubstituted
alkyl, -(CR cRd)r-C(0)OH, -(CR cRd)r-C(0)0-alkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl
wherein R and Rd are hydrogen or substituted or unsubstituted alkyl and 'r' is 1, 2 or 3;
or Rio and R , together with the nitrogen atom to which they are attached, may form a
saturated or unsaturated 3 to 12 membered cyclic ring, where the unsaturated cyclic ring
may have one or two double bonds.
According to another embodiment, there are provided compounds of Formula (I) in
which Ra is hydrogen; R is hydrogen; Ri is selected from halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted
cycloalkyl, cyano, -OR , -C(0)alkyl wherein R is hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted haloalkyl, or substituted or unsubstituted cycloalkyl;
'q' is 0, 1, or 2; R2 is substituted or unsubstituted aryl; R3 is hydrogen; R4 is hydrogen; R
is substituted or unsubstituted alkyl; X is selected from a bond, -(CR cRd)r, -0-, -NR 7-, -
NR7(CR cRd) -, -0(CR cRd)r-, -C(0)NR 7-, -C(0)NR7(CRcRd) - wherein R7 is hydrogen or
substituted or unsubstituted alkyl, R and Rd are hydrogen or substituted or unsubstituted
alkyl; and 'r' is 1, 2, or 3; Z is -OR or NR10R11 wherein R is selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or
unsubstituted aryl or substituted or unsubstituted arylalkyl; Rio and R may be same or
different and are independently selected from hydrogen, substituted or unsubstituted
alkyl, -(CR cRd) -C(0)OH, -(CR cRd)r-C(0)0-alkyl, substituted or unsubstituted cycloalkyl
or Rio and R together may form a substituted or unsubstituted, saturated or unsaturated 3
to 12 membered cyclic ring, where the unsaturated cyclic ring may have one or two
double bonds, 'n' is 1, 2 or 3; 'm' is 0 or 1; and 'p' is 0;
or its pharmaceutically acceptable salt thereof.
According to another embodiment, there are provided compounds of Formula (V) in
which Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, cyano, -OR , -C(0)alkyl
wherein R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted
haloalkyl, or substituted or unsubstituted cycloalkyl; 'q' is 0, 1, or 2; R2 is substituted or
unsubstituted aryl; X is selected from a bond, -(CR cRd)r-, -0-, -NR7-, -NR 7(CR cRd)r-, -
0(CR Rd)r-, -C(0)NR 7-, -C(0)NR 7(CR Rd) - wherein R7 is hydrogen or substituted or
unsubstituted alkyl, R and d are hydrogen or substituted or unsubstituted alkyl, 'r' is 1,
2, or 3; Z is -OR6 or NRioRn wherein R is selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted
aryl or substituted or unsubstituted arylalkyl; Rio and are independently selected from
hydrogen, substituted or unsubstituted alkyl, -(CRcRd)r-C(0)OH, -(CRcRd)r-C(0)0-alkyl,
substituted or unsubstituted cycloalkyl or Rio and together may form a substituted or
unsubstituted, saturated or unsaturated 3 to 12 membered cyclic ring, where the
unsaturated cyclic ring may have one or two double bonds, 'n' is 1, 2 or 3;
or its pharmaceutically acceptable salt thereof.
According to another embodiment, there are provided compounds of Formula (I)
or pharmaceutically acceptable salt; wherein the pharmaceutically acceptable salt is
hydrochloride salt.
According to another embodiment, there are provided compounds of Formula (I)
structurally encompasses stereoisomers including enantiomers and diastereomers.
Below are the representative compounds, which are illustrative in nature only and are
not intended to limit to the scope of the invention.
Methyl 2-fluoro-5-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-fluoro-5-((2 R ,45)-2-((((R )- l-(naphthalen-l-yl)ethyl)amino)methyl)chroman
-4-yl)benzoate;
Methyl-3-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)chroman-4-yl)
benzoate;
Methyl 2-methyl-3-((2 R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 3-methyl-5-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 4-methyl-3-((2 R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-ethyl-5-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-
4-yl)benzoate;
Methyl 2-ethyl-5-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)chroman-
4-yl)benzoate;
Methyl 2-isopropyl-5-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-cyclopropyl-5-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino) methyl)
chroman-4-yl)benzoate ;
Methyl 2-cyclopropyl-5-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate;
Methyl 2,6-difluoro-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 4-fluoro-2-methyl-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)
methyl)chroman-4-yl)benzoate;
Methyl 4-fluoro-2-methyl-3-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)
methyl)chroman-4-yl)benzoate;
Methyl 2,3-dimethyl-5-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 5-((2R ,45)-2-((((R )-l -(naphthalen- l-yl)ethyl)amino)methyl)chroman-4-yl)-2-
(trifluoromethyl)benzoate;
Methyl 2-methyl-5-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-methyl-5-((2R ,45)-2-((((R )- l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-fluoro-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman
-4-yl)benzoate;
Methyl 3-fluoro-5-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman
-4-yl)benzoate;
Methyl 4-fluoro-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman
-4-yl)benzoate;
Methyl 2-methoxy-5-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-methoxy-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-methoxy-3-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 4-methoxy-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-(2-methyl-5-((2R ,4 -2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate;
Methyl 2-(3-methyl-5-((2R ,4 -2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-(2-fluoro-5-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-(2-fluoro-5-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-(2-fluoro-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-(3-fluoro-5-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate;
Methyl 2-(3-fluoro-5-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-(4-fluoro-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-methyl-2-(3-((2R ,4 -2-((((R )-l -(naphthalen- l-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)propanoate;
Methyl 4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)benzoate;
Methyl 4-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)benzoate;
Methyl 2-methyl-4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-methyl-4-((2R ,45)-2-((((R )-l-(naphthalen- l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-yl)-2-
(trifluoromethyl)benzoate;
Methyl 4-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-yl)-2-
(trifluoromethyl)benzoate;
Methyl 2,6-difluoro-4-((2R ,45)-2-((((R )- l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate;
Methyl 3-methoxy-4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;m
Methyl 3-methoxy-4-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 3-fluoro-4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-fluoro-4-((2R ,45)-2-((((R )- l-(naphthalen-l-yl)ethyl)amino)methyl)chroman
-4-yl)benzoate;
Methyl 2-(4-((2R,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)phenoxy)acetate;
Methyl 2-(4-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)phenoxy)acetate ;
Methyl 2-(2-fluoro-4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-(2-fluoro-4-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-(4-((2R ,4R )-2-((((R )- l-(naphthalen-l-yl)ethyl)amino)methyl)chroman-4-
yl)phenyl)acetate;
Methyl 2-(4-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)phenyl)acetate;
Methyl 2-methyl-2-(4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenyl)propanoate ;
Methyl 2-methyl-2-(4-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenyl)propanoate ;
Methyl 3-methyl-4-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-fluoro-5-((25,4R )-2-((((R )- l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 3-((25,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)benzoate;
Methyl 2-methyl-5-((25,4R )-2-((((R )-l-(naphthalen-l -yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-methyl-5-((25,45)-2 -((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-(4-((25,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)phenoxy)acetate ;
Methyl 2-(4-((25,45)-2-((((R )-l -(naphthalen-l-yl)ethyl)amino)methyl)chroman-4-
yl)phenoxy)acetate ;
Methyl 5-((2R ,4R )-2-((((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)methyl)chroman-
4-yl)-2-methylbenzoate;
Methyl 5-((2R ,45)-2-((((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)methyl)chroman-
4-yl)-2-methylbenzoate ;
Methyl 3-((2R ,4R )-2-((((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)methyl)chroman-
4-yl)-2-methoxybenzoate ;
Methyl 3-((2R ,45)-2-((((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)methyl)chroman-
4-yl)-2-methoxybenzoate ;
Methyl 4-((2R )-2-((((R)- 1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-
4-yl)-2-methylbenzoate ;
Methyl 3-((2R )-2-((((R)- 1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-
4-yl)-2-methylbenzoate;
Methyl 5-((2R )-2-((((R)- 1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-
4-yl)-2-methylbenzoate ;
Methyl 3-((2R )-2-((((R)- 1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-
4-yl)-5-methylbenzoate ;
Methyl 3-((2R )-2-((((R)- 1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-
4-yl)-4-methylbenzoate ;
Methyl 2-fluoro-5-((25,4R )-2-(2-(((R)- 1-(naphthalen- 1-yl)ethyl)amino)ethyl)
chroman-4-yl)benzoate ;
Methyl 2-fluoro-5-((2R ,45)-2-(2-(((R)- 1-(naphthalen- 1-yl)ethyl)amino)ethyl)
chroman-4-yl)benzoate;
Methyl 2-methyl-5-((25,4R )-2-(2-(((R)- 1-(naphthalen- 1-yl)ethyl)amino)ethyl)
chroman-4-yl)benzoate ;
Methyl 2-methyl-5-((2R ,45)-2-(2-(((R)- 1-(naphthalen- 1-yl)ethyl)amino)ethyl)
chroman-4-yl)benzoate ;
Methyl 2-methoxy-3-((2R ,4R )-2-(2-(((R)- 1-(naphthalen- 1-yl)ethyl)amino)ethyl)
chroman-4-yl)benzoate ;
Methyl 5-((25,4R )-2-(2-(((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)ethyl)chroman-
4-yl)-2-methylbenzoate ;
Methyl 5-((2R ,45)-2-(2-(((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)ethyl)chroman-
4-yl)-2-methylbenzoate;
Methyl 5-((25,4R )-2-(2-(((R )-l-(4-fluoro-3-methoxyphenyl)ethyl)amino)ethyl)
chroman-4-yl)-2-methylbenzoate ;
Methyl 5-((2R ,45)-2-(2-(((R )-l-(4-fluoro-3-methoxyphenyl)ethyl)amino)ethyl)
hroman-4-yl)-2-methylbenzoate;
Methyl 2-fluoro-5-((25,45)-2-(3 -(((R )-l-(naphthalen-l-yl)ethyl)amino)propyl)
chroman-4-yl)benzoate ;
Methyl 2-fluoro-5-((2R ,4R )-2-(3-(((R )-l -(naphthalen- l-yl)ethyl)amino)propyl)
chroman-4-yl)benzoate ;
Methyl 2-methyl-5-((25,45)-2-(3 -(((R )-l-(naphthalen-l-yl)ethyl)amino)propyl)
chroman-4-yl)benzoate;
Methyl 2-methyl-5-((2 R ,4R )-2-(3 -(((R )-l -(naphthalen-l-yl)ethyl)amino)propyl)
chroman-4-yl)benzoate ;
Methyl 5-((25,45)-2-(3 -(((R )-l-(4-fluoro-3-methoxyphenyl)ethyl)amino)propyl)
chroman-4-yl)-2-methylbenzoate ;
Methyl 4-((25,45)-2-(3 -(((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)propyl)
chroman-4-yl)-3-methylbenzoate;
Methyl 4-((25,45)-2-(3 -(((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)propyl)
chroman-4-yl)benzoate ;
Methyl 5-((25,45)-2-(3 -(((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)propyl)
chroman-4-yl)-2-methylbenzoate ;
2, 6-Dimethyl-3-((2 R , 4S)-2-((((R )-l -(naphthalen- 1-yl) ethyl) amino) methyl)
chroman-4-yl)benzoic acid hydrochloride;
2,6-Dimethyl-3-((2 R ,45)-2-(2 -(((R )-l-(naphthalen-l-yl)ethyl) amino) ethyl)chroman-
4-yl) benzoic acid hydrochloride;
2,6-Dimethyl-3-((2 R ,4R )-2-(3 -(((R )-l-(naphthalen-l-yl)ethyl) amino) propyl)
chroman-4-yl)benzoic acid hydrochloride;
2,6-Dimethyl-3-((25,45)-2-(3 -(((R )-l-(naphthalen-l-yl)ethyl) amino) propyl)
chroman-4-yl)benzoic acid hydrochloride;
3-((25,45)-2-(3 -(((R )-l-(4-Fluoro-3-methoxyphenyl)ethyl) amino) propyl)chroman-4-
yl)-2,6-dimethylbenzoic acid hydrochloride;
2-Fluoro-5-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Fluoro-5-((2 R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)chroman-4-
yl)benzoic acid hydrochloride;
3-((2R ,45)-2-((((R )-l -(Naphthalen- l-yl)ethyl)amino) methyl) chroman-4-yl)benzoic
acid hydrochloride;
2-Methyl-3-((2 R ,45)-2-((((R )- l -(naphthalen- l-yl)ethyl) amino)methyl)chroman-4-
yl)benzoic acid hydrochloride;
3-Methyl-5-((2 R ,45)-2-((((R )- l -(naphthalen- l-yl)ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
4-Methyl-3-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Ethyl-5-((2R ,4R )-2-((((R )-l-(naphthalen-l-yl)ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Ethyl-5-((2R ,45)-2-((((R )-l -(naphthalen- l-yl)ethyl) amino) methyl)chroman-4-yl)
benzoic acid hydrochloride;
2-Isopropyl-5-((2R ,45)-2-((((R )-l -(naphthalen- l-yl)ethyl) amino) methyl) chroman-4-
yl)benzoic acid hydrochloride;
2-Cyclopropyl-5-((2 R ,4R )-2-((((R )-l-(naphthalen-l-yl)ethyl) amino)methyl)
chroman-4-yl)benzoic acid hydrochloride;
2-Cyclopropyl-5-((2 R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl) amino)methyl) chroman-
4-yl)benzoic acid hydrochloride;
2,6-Difluoro-3-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino)methyl) chroman-
4-yl)benzoic acid hydrochloride;
4-Fluoro-2-methyl-3-((2 R ,45)-2-((((R)- 1-(naphthalen- 1-yl) ethyl) amino)methyl)
chroman-4-yl)benzoic acid hydrochloride;
4-Fluoro-2-methyl-3-((2 R ,4R )-2-((((R )- l-(naphthalen-l-yl) ethyl) amino)methyl)
chroman-4-yl)benzoic acid hydrochloride;
2,3-Dimethyl-5-((2 R ,45)-2-((((R )-l -(naphthalen- l-yl)ethyl) amino)methyl)chroman-
4-yl)benzoic acid hydrochloride;
5-((2R ,45)-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) methyl) chroman-4-yl)-2-
(trifluoromethyl)benzoic acid hydrochloride;
2-Methyl-5-((2R ,4R )-2-((((R )-l -(naphthalen- 1-yl) ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methyl-5-((2R ,45)-2-((((R )- l -(naphthalen- l-yl)ethyl)amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Fluoro-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl) ethyl)amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
3-Fluoro-5-((2R ,45)-2-((((R )-l-(naphthalen-l-yl) ethyl)amino) methyl) chroman-4-
yl)benzoic acid hydrochloride;
4-Fluoro-3-((2 R ,4R )-2-((((R )-l -(naphthalen- 1-yl) ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methoxy-5-((2 R ,45)-2-((((R )-l -(naphthalen- 1-yl) ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methoxy-3-((2 R ,4S)-2-((((R )-l -(naphthalen- l-yl)ethyl) amino)methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methoxy-3-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino)methyl) chroman-4-
yl)benzoic acid hydrochloride;
4-Methoxy-3-((2 R ,4R )-2-((((R )-l -(naphthalen- l-yl)ethyl) amino) methyl) chroman-4-
yl) benzoic acid hydrochloride;
2-(2-Methyl-5-((2 R ,4 -2-((((R )-l -(naphthalen- l-yl)ethyl) amino)methyl) chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(3-Methyl-5-((2 R ,4 -2-((((R )-l -(naphthalen- l-yl)ethyl) amino) methyl) chroman-
4-yl)phenoxy)acetic acid hydrochloride;
2-(2-Fluoro-5-((2 R ,4R )-2-((((R )-l-(naphthalen-l-yl)ethyl) amino)methyl) chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(2-Fluoro-5-((2 R ,45)-2-((((R )-l -(naphthalen- l-yl) ethyl) amino)methyl) chroman-4-
yl) phenoxy) acetic acid hydrochloride;
2-(2-Fluoro-3-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino)methyl) chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(3-Fluoro-5-((2 R ,4R )-2-((((R )-l-(naphthalen-l-yl) ethyl) amino)methyl) chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(3-Fluoro-5-((2 R ,45)-2-((((R )-l -(naphthalen- l-yl) ethyl) amino) methyl) chroman-
4-yl) phenoxy)acetic acid hydrochloride;
2-(4-Fluoro-3-((2 R ,4R )-2-((((R )-l-(naphthalen-l-yl) ethyl) amino) methyl)chroman-4-
yl) phenoxy)acetic acid hydrochloride;
2-Methyl-2-(3-((2 R ,4 -2-((((R )-l -(naphthalen- l-yl)ethyl) amino)methyl)chroman-4-
yl)phenoxy)propanoic acid hydrochloride;
4-((2R ,4R )-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) methyl) chroman-4-yl)benzoic
acid hydrochloride;
4-((2R ,4S)-2-((((R )-l -(Naphthalen- l-yl)ethyl) amino) methyl) chroman-4-yl)benzoic
acid hydrochloride;
2-Methyl-4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methyl-4-((2 R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino) methyl)chroman-4-yl)
benzoic acid hydrochloride;
4-((2R ,4R )-2-((((R )- l -(Naphthalen- l-yl)ethyl)amino) methyl) chroman-4-yl)-2-
(trifluoromethyl)benzoic acid hydrochloride;
4-((2R ,45)-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) methyl) chroman-4-yl)-2-
(trifluoromethyl)benzoic acid hydrochloride;
2,6-Difluoro-4-((2 R ,45)-2-((((R )-l -(naphthalen- 1-yl) ethyl) amino)methyl) chroman-
4-yl)benzoic acid hydrochloride;
3-Methoxy-4-((2 R ,4R )-2-((((R )-l -(naphthalen- l-yl)ethyl) amino) methyl) chroman-4-
yl)benzoic acid hydrochloride;
3-Methoxy-4-((2 R ,4S)-2-((((R )-l -(naphthalen- 1-yl) ethyl) amino)methyl) chroman-4-
yl)benzoic acid hydrochloride;
3-Fluoro-4-((2R ,4R )-2-((((R )-l -(naphthalen- 1-yl) ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Fluoro-4-((2 R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-(4-((2R ,4R )-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) methyl)chroman-4-yl)
phenoxy)acetic acid hydrochloride;
2-(4-((2R ,45)-2-((((R)- 1-(Naphthalen- 1-yl)ethyl) amino)methyl) chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(2-Fluoro-4-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl) ethyl) amino)methyl)chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(2-Fluoro-4-((2 R ,45)-2-((((R)- 1-(naphthalen- 1-yl) ethyl) amino)methyl)chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(4-((2R ,4R )-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) methyl)chroman-4-yl)
phenyl)acetic acid hydrochloride;
2-(4-((2R ,45)-2-((((R)- 1-(Naphthalen- 1-yl)ethyl) amino) methyl)chroman-4-yl)
phenyl)acetic acid hydrochloride;
2-Methyl-2-(4-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino)methyl)chroman-4-
yl)phenyl)propanoic acid hydrochloride;
2-Methyl-2-(4-((2 R ,45)-2-((((R )- l -(naphthalen- 1-yl) ethyl) amino)methyl)chroman-4-
yl) phenyl) propanoic acid hydrochloride;
3-Methyl-4-((2R ,45)-2-((((R )- l -(naphthalen- l-yl)ethyl)amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Fluoro-5-((25,4 R )-2-((((R )-l-(naphthalen-l-yl)ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
3-((2S,4R )-2-((((R )-l -(Naphthalen- l-yl)ethyl) amino) methyl) chroman-4-yl)benzoic
acid hydrochloride;
2-Methyl-5-((25,4 R )-2-((((R )- l -(naphthalen- 1-yl) ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride
2-Methyl-5-((25,45)-2 -((((R )-l -(naphthalen- 1-yl) ethyl)amino) methyl) chroman-4-
yl)benzoic acid hydrochloride;
2-(4-((25,4R )-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) methyl) chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(4-((25,45)-2 -((((R)- 1-(Naphthalen- 1-yl)ethyl)amino)methyl) chroman-4-yl)
phenoxy)acetic acid hydrochloride;
4-((2R ,45)-2-((((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl) amino) methyl)chroman-4-
yl)-2-methylbenzoic acid hydrochloride;
3-((2R ,45)-2-((((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl) amino)methyl)chroman-4-
yl)-2-methylbenzoic acid hydrochloride;
5-((2R ,45)-2-((((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl) amino) methyl)chroman-4-
yl)-2-methyl benzoic acid hydrochloride;
3-((2R ,45)-2-((((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl) amino)methyl)chroman-4-
yl)-5-methylbenzoic acid hydrochloride;
3-((2R ,45)-2-((((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl) amino)methyl)chroman-4-
yl)-4-methylbenzoic acid hydrochloride;
5-((2R ,4R )-2-((((R )- l-(4-Fluoronaphthalen-l-yl) ethyl) amino) methyl)chroman-4-yl)-
2-methyl benzoic acid hydrochloride;
5-((2R ,4 5)-2-((((R )-l-(4-Fluoronaphthalen-l-yl) ethyl) amino) methyl)chroman-4-
yl)-2-methyl benzoic acid hydrochloride;
3-((2R ,45)-2-((((R )-l-(4-Fluoronaphthalen- l-yl)ethyl)amino) methyl)chroman-4-yl)-
2-methoxybenzoic acid hydrochloride;
3-((2R ,4R )-2-((((R)- 1-(4-Fluoronaphthalen- 1-yl)ethyl) amino) methyl)chroman-4-yl)-
2-methoxybenzoic acid hydrochloride;
2-Fluoro-5-((2S, 4R )-2-(2 -(((R )-l -(naphthalen- 1-yl) ethyl) amino) ethyl) chroman-4-
yl) benzoic acid hydrochloride;
2-Fluoro-5-((2R ,45)-2-(2 -(((R )-l -(naphthalen- l-yl)ethyl) amino) ethyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methyl-5-((25,4 R )-2-(2 -(((R )-l -(naphthalen- l-yl)ethyl) amino)ethyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methyl-5-((2 R ,45)-2-(2-(((R)- 1-(naphthalen- 1-yl)ethyl) amino)ethyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methoxy-3-((2 R ,4R )-2-(2 -(((R)- 1-(naphthalen- 1-yl)ethyl) amino)ethyl)chroman-4-
yl)benzoic acid hydrochloride;
5-((25,4R )-2-(2 -(((R )-l-(4-Huoronaphthalen-l-yl)ethyl) amino) ethyl)chroman-4-yl)-
2-methylbenzoic acid hydrochloride;
5-((2R ,45)-2-(2-(((R )-l-(4-Huoronaphthalen-l-yl)ethyl) amino) ethyl)chroman-4-yl)-
2-methylbenzoic acid hydrochloride;
5-((25,4R )-2-(2 -(((R )-l-(4-Ruoro-3-methoxy phenyl) ethyl) amino) ethyl) chroman-4-
yl)-2-methylbenzoic acid hydrochloride;
5-((2R ,45)-2-(2-(((R )-l-(4-Ruoro-3-methoxy phenyl)ethyl) amino)ethyl)chroman-4-
yl)-2-methylbenzoic acid hydrochloride;
2-Fluoro-5-((25, 45)-2-(3 -(((R )-l -(naphthalen- 1-yl) ethyl) amino) propyl) chroman-4-
yl) benzoic acid hydrochloride;
2-Fluoro-5-((2R ,4R )-2-(3 -(((R )-l -(naphthalen- 1-yl) ethyl) amino) propyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methyl-5-((25,45)-2-(3 -(((R )-l -(naphthalen- 1-yl) ethyl) amino) propyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methyl-5-((2 R ,4R )-2-(3 -(((R )-l-(naphthalen- l-yl) ethyl) amino) propyl)chroman-4-
yl)benzoic acid hydrochloride;
5-((2S,4S)-2-(3-(((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl) amino)propyl)chroman-4-
yl)-2-methylbenzoic acid hydrochloride;
4-((25,45)-2-(3 -(((R)- 1-(4-Fluoronaphthalen- 1-yl)ethyl) amino) propyl)chroman-4-
yl)-3-methylbenzoic acid hydrochloride;
4-((25,45)-2-(3 -(((R)- 1-(4-Fluoronaphthalen- 1-yl)ethyl) amino) propyl)chroman-4-
yl)benzoic acid hydrochloride;
5-((25,45)-2-(3 -(((R)- 1-(4-Fluoronaphthalen- 1-yl)ethyl) amino) propyl)chroman-4-
yl)-2-methylbenzoic acid hydrochloride;
Methyl 2-(3-((2R , 45)-2-((((R )-l-(naphthalen-l-yl) ethyl) amino) methyl) chroman-4-
yl) benzamido) acetate;
Methyl 2-(2-methyl-5-((2 R , 45)-2-((((R)- 1-(naphthalen- 1-yl) ethyl) amino) methyl)
chroman-4-yl) benzamido) acetate;
2-(3-((2R , 4 -2-((((R )-l -(Naphthalen- 1-yl) ethyl) amino) methyl) chroman-4-yl)
benzamido) acetic acid hydrochloride;
2-(2-Methyl-5-((2 R ,45)-2-((((R )- l -(naphthalen- 1-yl) ethyl) amino) methyl) chroman-
4yl) benzamido) acetic acid hydrochloride;
N , 2-Dimethyl-5-((2 R , 45)-2-((((R )- l -(naphthalen- 1-yl) ethyl) amino) methyl)
chroman-4-yl)benzamide hydrochloride ;
N,N ,2-Trimethyl-5-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino)methyl)
chroman-4-yl)benzamide hydrochloride ;
2-Methyl-5-((2 R ,45)-2-((((R )- l -(naphthalen- l-yl)ethyl) amino) methyl)chroman-4-
yl)benzamide hydrochloride;
N -Ethyl-N ,2-dimethyl-5-((2 R ,45)-2-((((R)- 1-(naphthalen- 1-yl) ethyl)amino)methyl)
chroman-4-yl)benzamide hydrochloride ;
N,N -Diethyl-2-methyl-5-((2 R ,45)-2-((((R )-l -(naphthalen-l-yl) ethyl) amino)
methyl)chroman-4-yl)benzamide hydrochloride;
(2-Methyl-5-((2R ,45)-2-((((R )- l-(naphthalen-l-yl)ethyl) amino)methyl)chroman-4-
yl)phenyl)(pyrrolidin- 1-yl)methanone hydrochloride;
2-(2-Methyl-4-(2-((((R )- l-(naphthalen- l-yl)ethyl)amino)methyl)chroman-4-
yl)phenoxy)acetic acid hydrochloride;
3-(3-(2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)phenyl)propanoic acid hydrochloride;
2-(3-(2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-yl)phenoxy)acetic
acid hydrochloride;
3-(2-Fluoro-5-(2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)phenyl)propanoic acid hydrochloride;
3-(2-(2-(((R )-l-(Naphthalen-l-yl)ethyl)amino)ethyl)chroman-4-yl)benzoic acid
hydrochloride;
3-(3-(2-(2-(((R )-l-(Naphthalen-l-yl)ethyl)amino)ethyl)chroman-4-yl)phenyl)
propanoic acid hydrochloride;
2-(2-Methyl-5-(2-(2 -(((R)- 1-(naphthalen- 1-yl)ethyl)amino)ethyl)chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(4-(2-(2-(((R )-l-(Naphthalen-l-yl)ethyl)amino)ethyl)chroman-4-yl)phenoxy)acetic
acid hydrochloride;
3-(2-(2-(((R )-l-(4-Fluoronaphthalen-l-yl)ethyl)amino)ethyl)chroman-4-yl)benzoic
acid hydrochloride;
4-(2-(3 -(((R)- 1-(Naphthalen- 1-yl)ethyl)amino)propyl)chroman-4-yl)benzoic acid
hydrochloride;
3-(2-(3 -(((R )-l-(Naphthalen-l-yl)ethyl)amino)propyl)chroman-4-yl)benzoic acid
hydrochloride;
2-Methyl-4-(2-(3-(((R )-l -(naphthalen-l-yl)ethyl)amino)propyl)chroman-4-yl)benzoic
acid hydrochloride;
3-(2-(3 -(((R )-l-(4-Fluoronaphthalen-l-yl)ethyl)amino)propyl)chroman-4-yl)benzoic
acid hydrochloride;
3-(2-((((R )-l-(4-Fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-4-yl)-2,6-
dimethylbenzoic acid hydrochloride;
2-Fluoro-3-(2-((((R )-l-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-4-
yl)-6-methylbenzoic acid hydrochloride;
2,6-Difluoro-3-(2-((((R )-l -(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-
4-yl)benzoic acid hydrochloride;
2-Fluoro-5-(2-((((R )-l-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-4-
yl)benzoic acid hydrochloride; and
2-(2-Fluoro-5-(2-((((R )-l-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-
4-yl)phenoxy)acetic acid hydrochloride;
or its pharmaceutically acceptable salt thereof.
In another aspect of the invention, there is provided a compound of Formula (I) useful in
treating, preventing, managing and/or lessening the severity of diseases, disorders,
syndromes or conditions associated with calcium sensing receptor (CaSR) modulators.
In another aspect, the invention provides a pharmaceutical composition comprising at
least one compound of Formula (I) and at least one pharmaceutically acceptable
excipient.
In another aspect, the invention provides a pharmaceutical composition of compound of
formula (I) useful in treating, preventing, managing and/or lessening the severity of 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 formula (I) or a pharmaceutically acceptable salt thereof together with a
pharmaceutically acceptable excipient.
In another aspect, there are provided processes for the preparation compounds of Formula
(lb):
(lb)
where X, R, Ri, R2, R 5 'm' , 'h' , 'p' and 'q' are as described herein above,
the process comprising the steps:
a) oxidizing a compound of Formula (15) by using suitable oxidation agents to give
compound of Formula (16) in suitable solvent(s);
b) converting a compound of Formula (16) to compound of Formula (17) using
PhNTf2 (N -phenylbis(trifluoromethanesulfonimide) in presence of KHMDS
(potassium hexamethyldisilazide) ;
c) coupling of compound of Formula (17) with suitable aryl boronic acid or aryl
boronic ester by following Suzuki coupling reaction to give compound of Formula
( 18) where Z is -OR and R is alkyl or benzyl;
( 18)
d) when Z is O-alkyl, then reducing the compound of Formula (18) with hydrog
over Palladium-Carbon to give ester compound of Formula (19) where Z is - O
alkyl;
e) converting the compound of Formula (19) obtained in step d) to the compound of
Formula (la);
( 19 ) (la)
f) hydrolyzing the ester group in compound of Formula (la) to corresponding acid
compound using suitable base and in suitable solvents;
g) converting the compound obtained in step f) to its hydrochloride salt having
Formula (lb);
(la) (lb)
h) when Z is O-benzyl in compound of Formula (18), then reducing the compound of
Formula (18) with hydrogen over Palladium-Carbon to give acid compound of
Formula (19) where Z is OH;
i) converting the compound of Formula (19) obtained in step h) to the compound of
Formula (lb);
In another aspect, there are provided processes for the preparation compounds of Formula
(Id):
wherein X, R, i , R2 , R5, R7, Rc , R 'm', 'n', 'p', 'q' and 'r' are as described in claim
1, the process comprising the steps of:
a) coupling of acid compound of Formula (lb) with suitable amines using suitable
amide coupling reagents to give compound of Formula (Ic)
when R is alkyl/benzyl etc.,
b) hydrolyzing the amido ester group, if the compound of Formula (Ic) is an ester, to
corresponding acid compound of Formula (Id) using suitable reagent and solvents.
when R is alkyl/benzyl etc.,
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 and claims, 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, 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, substituted or
unsubstituted.
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 ethenyl, 1-propenyl, 2-propenyl (allyl), wo-propenyl, 2-methyl-lpropenyl,
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, substituted
or unsubstituted.
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 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, substituted or unsubstituted.
The term "alkoxy" refers to an alkyl group attached via an oxygen linkage. Nonlimiting
examples of such groups are 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, substituted or unsubstituted.
The term "haloalkyl" refers to an alkyl group as defined above that is substituted
by one or more halogen atoms as defined above. Preferably, 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. Preferably, 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, substituted or unsubstituted.
The term "haloalkoxy" refers to a haloalkyl, defined herein, group attached via an
oxygen linkage. Preferably, the haloalkoxy may be monohaloalkoxy, dihaloalkoxy or
polyhaloalkoxy including perhaloalkoxy. Non-limiting examples of a haloalkoxy include
fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy,
trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy,
dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy, dichloroethoxy,
dichloropropoxy, dichloroisopropoxy and the like. Unless set forth or recited to the
contrary, all haloalkoxy group described or claimed herein may be straight chain or
branched, substituted or unsubstituted.
The term "cycloalkyl" refers to a non-aromatic mono or multicyclic ring system
having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
and the like. Examples of multicyclic cycloalkyl groups include, but are not limited to,
perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or
spirobicyclic groups, e.g., spiro(4,4)non-2-yl and the like. Unless set forth or recited to
the contrary, all cycloalkyl groups described or claimed herein may be substituted or
unsubstituted.
The term "cycloalkylene" refers to a saturated divalent cyclic hydrocarbon radical
that includes solely carbon and hydrogen atoms in the backbone. In particular, "C3-C7
cycloalkylene" means a saturated divalent cyclic hydrocarbon radical with 3 to 7 carbon
atoms e.g. cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and the like.
Unless set forth or recited to the contrary, all cycloalkylene groups described or claimed
herein may be substituted or unsubstituted.
The term "cycloalkenyl" refers to a non-aromatic mono or multicyclic ring system
having 3 to 12 carbon atoms and including at least one carbon-carbon double bond, such
as cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. Unless set forth or recited to
the contrary, all cycloalkenyl groups described or claimed herein may be substituted or
unsubstituted.
The term "cycloalkylalkyl" refers to a cycloalkyl group as defined above, directly
bonded to an alkyl group as defined above, e.g., cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, etc. Unless set forth or recited to
the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or
unsubstituted.
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. Unless set forth or recited to the
contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.
The term "arylalkyl" refers to an aryl group as defined above directly bonded to an
alkyl group as defined above, e.g., -CH 2C H and -C2H4C H5. Unless set forth or recited
to the contrary, all arylalkyl groups described or claimed herein may be substituted or
unsubstituted.
A "carbocyclic ring" or "carbocycle" as used herein refers to a 3- to 10- membered
saturated or unsaturated, monocyclic, fused bicyclic, spirocyclic or bridged polycyclic
ring containing carbon atoms, which may optionally be substituted, for example,
carbocyclic rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclopropylene, cyclohexanone, aryl, naphthyl, adamentyl etc. Unless set
forth or recited to the contrary, all carbocyclic groups or rings described or claimed herein
may be aromatic or non aromatic.
A "3-12 membered cyclic ring" as used herein refers to a monocyclic, bicyclic,
polycyclic heteroaryl or heterocyclic ring systems.
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 bond(s), and one or two carbon atoms(s) in the heterocyclic ring or heterocyclyl
may be interrupted with -CF2-, -C(O)-, -S(O)-, S(0) 2, -C(=N-alkyl)-, or -C(=Ncycloalkyl),
etc. In addition heterocyclic ring may also be fused with aromatic ring. Nonlimiting
examples of heterocyclic rings include azetidinyl, benzopyranyl, chromanyl,
decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl,
isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl,
perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl,
phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl,
thiazolinyl, thiazolidinyl, thiamo holinyl, thiamo holinyl sulfoxide, thiamorpholinyl
sulfone indoline, 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. Unless set forth or recited to the contrary, all
heterocyclyl groups described or claimed herein may be substituted or unsubstituted;
substituents may be on same or different ring atom.
The term "heteroaryl" unless otherwise specified, refers to a substituted or
unsubstituted 5- to 14- membered aromatic heterocyclic ring with one or more
heteroatom(s) 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, quinazolinyl,
cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl,
thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like. Unless set forth
or recited to the contrary, all heteroaryl groups described or claimed herein may be
substituted or unsubstituted.
The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded
to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at
any carbon atom in the alkyl group that results in the creation of a stable structure.
Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or
claimed herein may be substituted or unsubstituted.
The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an
alkyl group. The heteroarylalkyl radical may be attached to the main structure at any
carbon atom in the alkyl group that results in the creation of a stable structure. Unless set
forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein
may be substituted or unsubstituted.
Unless otherwise specified, the term "substituted" as used herein refers to a group
or moiety having one or more substituents attached to the structural skeleton of the group
or moiety. Such substituents include, but are not limited to hydroxy, halogen, carboxyl,
cyano, nitro, oxo (=0), thio (=S), alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl,
heteroarylalkyl, -C(0)OR , -C(0)R , -C(S)R , -C(0)NR R , -NR C(0)NR R , -
N(R )S(0)R , -N(R )S(0) 2R , -NR R , -NR C(0)R , -NR C(S)R , -NR C(S)NR R , -
S(0) 2NR R , -OR , -OC(0)R , -OC(0)NR R , -R C(0)OR , -R C(0)NR R , -R C(0)R ,
-SR , and -S(0)2R ; wherein each occurrence of R , R and R are independently selected
from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,
cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl. 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 centre 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
nonsuperimposable 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 severity of 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,
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 nondomestic
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 a sufficiently basic
compound such as an amine with a suitable acid affording a physiologically acceptable
anion.
With respect to the overall compounds described by the Formula (I), 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) disclosed herein. In particular, pharmaceutical compositions containing
a therapeutically effective amount of at least one compound of Formula (I) described
herein and at least one pharmaceutically acceptable excipient (such as a carrier or
diluent). Preferably, the contemplated pharmaceutical compositions include the
compound(s) described herein in an amount sufficient to modulate calcium sensing
receptor (CaSR) mediated diseases described herein when administered to a subject.
The subjects contemplated include, for example, a living cell and a mammal,
including human mammal. The compound of the invention may be associated with a
pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a
carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or
other container. The pharmaceutically acceptable excipient includes pharmaceutical agent
that does not itself induce the production of antibodies harmful to the individual receiving
the composition, and which may be administered without undue toxicity.
Examples of suitable carriers or exciptients 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, managing and/or lessening the severity 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
Formula (I) 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 (preosteoclast,
osteoclast, pre-osteoblast, osteoblast), juxtaglomerular kidney cell, kidney
messengial cell, glomerular kidney cell, proximal tubule kidney cell, distal tubule kidney
cell, cell of the thick ascending limb of Henle's loop and/or collecting duct, parafollicular
cell in the thyroid (C-cell), intestinal cell, platelet, vascular smooth muscle cell,
gastrointestinal tract cell, pituitary cell or hypothalamic cell. The messenger of the
calcium sensing receptor is Calcium.
The compound of Formula (I), being modulators of CaSR, is potentially useful in
treating, managing and/or lessening 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, multigland 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, managing and/or lessening 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 prevent or
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 postdialysis
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 intraglomerular
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, analgestic or anticancer agent), an
organ failure, an organ transplantation, or uropathy. In one aspect, ischemia can be sicklecell
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 gastrointestinal
tract by augmenting gastric acidity.
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-2. 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.
The compound of Formula (14) where n is , is prepared by following the
procedure as depicted in Scheme- 1, thus starting from commercially available chromone-
2-carboxylic acid is reduced to give compound of Formula (2) with hydrogen over
Palladium-Carbon. Compound of Formula (2) can be resolved by using R-(+)-lphenylpropyl
amine or (£)-(+)- 1-phenylpropyl amine (WO2007/123941) which gives
corresponding resolved acid of Formula (3). The compound of Formula (3) is reacted
with amine of Formula (a) in presence suitable reagents such as SO 2 to give compound
of Formula (4). The compound of Formula (4) undergoes reduction using suitable
reducing agents to give compound of Formula (14).
The compound of Formula (14) where n is 2, is prepared from compound of
Formula (3) thus, acid compound of Formula (3) is reacted with SO 2 to give
corresponding acid chloride of Formula (5). Further this Formula (5) undergoes onecarbon
homologation (Arndt-Eistert Synthesis) by using trimethylsilyl diazomethane
followed by silver benzoate to give compound of Formula (6). The compound of Formula
(6) reacting with amine of Formula (a) using suitable reagents such as SO 2 to give
compound of Formula (7). The compound of Formula (7) undergoes reduction using
suitable reducing agents to give compound of Formula (14).
Similarly, the compound of Formula (14) where n is 3, is prepared from Formula
(3) by reacting compound of Formula (3) with SOCI2 in presence of alcohol to give
corresponding ester. Compound of Formula (8) is reduced to give aldehyde of Formula
(9). This compound of Formula (9) undergoes Wittig reaction to give corresponding
alkenes of Formula (10). Compound of Formula (10) is reduced to give compound of
Formula (11). Further, this ester compound of Formula (11) can be hydrolyzed to give
corresponding acid of Formula (12) using suitable base such as NaOH, LiOH, etc. The
compound of Formula (12) is reacted with amine of Formula (a) using suitable reagents
for example SOCI2 to give compound of Formula (13). The compound of Formula (13)
undergoes reduction using suitable reducing agents to give compound of Formula (14).
Scheme-2
The compound of Formula (la), (lb), (Ic) or (Id) where X, R, Ri, R2, R5, R7, Rc,
R , 'm', 'n', 'p', 'q' and 'r' are as defined herein above, can be prepared by following the
procedure as depicted in Scheme-2 starting from Formula (14), which is protected with
BOC-anhydride in acetonitrile to give N-BOC protected compound of Formula (15). The
compound of Formula (15) is oxidized with suitable oxidizing agent to give compound of
Formula (16) (Chem.Eur.J.2009, 15, 3403 -3410). Compound of Formula (16) is
converted to trifluoromethanesulfonate of Formula (17) using PhNTf2 (Nphenylbis(
trifluoromethanesulfonimide) in presence of KHMDS (potassium
hexamethyldisilazide), which further undergoes carbon-carbon (C-C) coupling reaction
with corresponding boronic acid / boronic ester by following the methods known in the
art for example Suzuki coupling reaction to give compound of Formula (18) where Z is -
O 6 and 6 is alkyl or benzyl etc.,.
The double bond in compound of Formula (18) is reduced by using hydrogen over
Palladium-Carbon to give ester compound of Formula (19). But compound of Formula
(18) when Z is -OR 6 where is benzyl, is converted to give acid compound of Formula
(19) where Z is OH, by carried-out the reduction and benzyl ester hydrolysis in single
step using hydrogen over Palladium-Carbon in suitable solvent. This ester compound of
Formula (19) where Z is OH, undergoes Boc deprotection using ethereal HC1 followed by
salt preparation with hydrochloric acid in suitable solvent to give corresponding acid of
Formula (lb).
Also, compound of Formula (19) is further deprotected the BOC group using methanolic
hydrochloric acid to afford compound of Formula (la). This compound of Formula (19) is
obtained in diastereomeric mixture either in equal ratios (50:50) or obtained in different
diastereomeric ratio(s). Optionally, these diastereomeric mixture can be further separated
by known methods in the art for example chiral chromatography, crystallization technique
etc., either at this step or in any of the subsequent steps. Further, ester group in Formula
(la) can be hydrolyzed to give corresponding acid using suitable base such as NaOH,
LiOH, KOH etc., followed by salt preparation with hydrochloric acid in suitable solvent
to give corresponding acid of Formula (lb). This acid compound of Formula (lb) is
coupled with suitable amines using suitable amide coupling agents by following the
general amide coupling procedure as described in the art. Further, if the compound of
Formula (Ic) is an ester then it can be further hydrolyzed to give corresponding acid
compound Formula (Id) using suitable base such as NaOH, LiOH, KOH etc., followed by
salt preparation with hydrochloric acid in suitable solvent.
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. 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.
The aforementioned patents and patent applications are incorporated herein by reference.
Unless otherwise stated, work-up implies the following operations: distribution of
the reaction mixture between the organic and aqueous phase, separation of layers, drying
the organic layer over sodium sulfate, filtration and evaporation of the organic solvent.
Purification, unless otherwise mentioned, implies purification by silica gel
chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a
suitable polarity as the mobile phase.
Intermediates
Intermediate- 1
Chromane -2-carboxylic acid
To a suspension of commercially available chromone-2-carboxylic acid (50g,
281mmol) in methanol (500mL), slurry of (10% Pd/C wet, 5g) in water (lOmL) was
added under nitrogen atmosphere. The mixture was hydrogenated at 60 psi at room
temperature (RT) and further maintained hydrogen reservoir up to 60 psi for 2h. The
progress of reaction was monitored by TLC. Reaction mixture was filtered through celite
and the filtrate was concentrated under reduced pressure to yield chromane -2-carboxylic
acid as off-white solid (44.7 g, 95%). m/z-178.02.
Intermediate-2
(R)- (-) - Chromane- 2- carboxylic acid
To a solution of Intermediate- 1 ( 18.6g, 104mmol) in acetonitrile (91 mL), ( )-(+)-
1-phenylpropylamine (9. 14g, 67.9mmol) in methyl tert butyl ether (MTBE) (12 mL)
solution was added in dropwise manner. After about half of the total amount of the (R)-
(+)-l-phenylpropylamine solution was added. The reaction mixture was seeded with few
crystals of ((/?)-(+)- 1-phenyl propyl ammonium (R)-(-)-chromane-2-carboxylate). The
resultant thick slurry was diluted with MTBE (80 mL) and the mixture was further stirred
for 6h at RT. The salt was filtered, washed with MTBE and dried. The salt (13.7g) was
suspended in MTBE (80 mL) further aqueous HC1 solution (1:1) (88mL) was added and
the mixture was stirred in cooling to 0°C. The aqueous layer was extracted with methyl
tert-butyl ether (70 mL X 2). The extracts were combined with organic layer and the
solution was washed with 1:1 HC1 solution (40mL). The organic layer was dried over
Na2S0 4 and evaporated under reduced pressure to afford the title compound as a white
crystalline solid (6.5g); m/z-178.02.
C [ ]2 °D = - 6.8.degree (c=l in methanol)observed.
C [a] 2 D = - 6.7.degree. (c=l in methanol) reported in Patent: US6133277A1, 2000.
Intermediate-3
(R)-N-((R)- 1-(Naphthalen- 1-yl)ethyl)chroman-2-carboxamide
Thionyl chloride (11.4 mL, 156 mmol) was added in dropwise manner to a
cooled 0°C solution of Intermediate-2 (15.9g, 89mmol) in ethylene dichloride (160mL).
The reaction mixture was allowed to RT then heated to reflux and further maintained for
l h then dimethyl formamide (ldrop) was added carefully. The progress of reaction was
monitored by TLC. After reaction completion the reaction mixture was concentrated
under vacuum to get oily mass. The solution of acid chloride in dichloromethane (DCM)
(30 mL) was added to a solution of (R)-l -(naphthalen- 1-yl) ethanamine (15. 3g, 89mmol)
and triethylamine (15.5 mL, 112 mmol) in DCM (130 mL) at 0°C. The reaction was
further stirred for l h at 0°C. The progress of reaction was monitored by TLC. The
reaction mixture was diluted with water (25 mL) and extracted with DCM (50 mL X 3).
The combined organic phase was dried over Na2S0 4 and concentrated under reduced
pressure to afford the title compound (29 g, 98%). m/z-331.9.
Intermediate-4
(R)-N-((R)-Chroman-2-ylmethyl)- 1-(naphthalen- 1-yl)ethanamine
To a solution of Intermediate-3 ( 11.8g, 35.6 mmol) in tetrahydrofuran (THF) (90
mL), borane-dimethyl sulphide complex (8.9 mL, 89 mmol, 10M) was added at 0°C. The
reaction was allowed to RT then heated to 70°C and further maintained for 2h. The
progress of reaction was monitored by TLC. The reaction mixture was cooled to 0°C and
1:1 HC1 solution was added very slowly (15 mL). After quenching, the reaction was
heated to 90°C and further maintained for lh. THF was distilled off under vacuum and
the resultant residue was cooled to 0°C and basified with 2M NaOH solution. Product
was extracted with ethyl acetate (50mLX 3) and washed with water (25mL X 2) and a
brine solution (25mL). The combined organic layer was dried over Na2S0 4 and
evaporated under reduced pressure to afford the title compound as an oily mass ( 11 g, 97
). m/z-3 18.1.
Intermediate-5
ieri-Butyl ((R)-chroman-2- ) ethyl) carbamate
To a solution of Intermediate-4 (l lg, 34.7 mmol) in acetonitrile (90mL), di-tertbutyl
dicarbonate (9.7mL, 4 1.6 mmol) was added and the solution was heated to 50°C
and maintained for overnight. The progress of reaction was monitored by TLC. The
reaction was cooled to RT and the organic solvent was evaporated under reduced
pressure. The residue was dissolved in ethyl acetate (50mL X2) and washed with water
(25mL) subsequently with brine solution (20mL). The organic layer was separated and
dried over Na2S0 4 and concentrated under reduced pressure to afford the title compound
as an oily mass (13.9g, 96 ). m/z- 417.3.
Intermediate-6
r -Butyl ((R)- 1-(naphthale -1-yl)ethyl)(((R )-4-oxochroman-2-yl)methyl)carbamate
The mixture of Intermediate-5 (13.7g, 32.8mmol), magnesium sulphate (9.5g,
79mmol) in acetone (160mL) and water (80mL) was cooled to 0°C. To this, KMn0 4
(28. 5g, 180mmol) was added in portions wise for l h at 0 to 5°C. The reaction mixture
was then allowed to RT and further stirred for 16h. The progress of reaction was
monitored by TLC. The reaction mass was filtered and filtrate was extracted in ethyl
acetate (100 mL X 2). Combined organic layer was washed with saturated sodium
sulphite (30 mL) solution followed by water (50mL) and brine solution (40 mL). The
organic layer was separated and dried over Na2S0 4 and concentrated. This was further
purified by flash chromatography using a mixture of 5% ethyl acetate in hexane as eluent
to give title compound (9.6 g, 68 ). m/z- 454. 1 as Na+1 .
Intermediate-7
(2R )-2-(((ieri-Butoxycarbonyl )((R )-l -(naphthalen- l-yl)ethyl)amino)methyl)-4a,8adihydro-
2H -chromen-4-yl tri
To a solution of Intermediate-6 (0.9 g, 2.09 mmol) in THF (5 mL), potassium bis
(trimethylsilyl) amide (0.6 g, 3.13 mmol) was added at -78°C and stirred for l h at the
same temperature. l ,l ,l-trifluoro -N -phenyl-N -((trifluoromethyl)sulfonyl) methane
sulfonamide (0.89g, 2.5mmol) was added at -78 °C under nitrogen atmosphere. The
progress of reaction was monitored by TLC. To this reaction mixture water (3mL) was
added at -78°C then allowed to RT. The reaction mass extracted with diethyl ether (25
mL X 2), washed with water (25 mL X 2) followed by brine (lOmL), dried over Na2S0
and concentrated under reduced pressure to get the crude product. It was purified by flash
chromatography by using 5% ethyl acetate in hexane to get the title compound (0.9 g,
77% yield), m/z- 586. 1 as Na+1 .
Intermediate-8
(5)-Chroman-2-carboxylic acid
The title compound was resolved by following the similar procedure as described
in Intermediate-2 by taking Intermediate- 1 and (£)-(+)- 1-phenyl propyl amine as
resolving agent, m/z-178.
Intermediate-9
(5)-2-(((ieri-Butoxycarbonyl )((R )-l -(naphthalen-l-yl)ethyl)amino)methyl)-2 H -chromen-
4-yl trifluoromethanesulfonate
The title compound was prepared in five steps:
Step: 1- Intermediate-8 was reacted with (R )- l-(naphthalen-l-yl) ethanamine
by following the similar procedure as described in Intermediate-3;
Step: 2- Reduction of Step-1 Intermediate using borane dimethyl sulphide complex by
following the similar procedure as described in Intermediate-4;
Step: 3- BOC protection of Step-2 Intermediate using BOC anhydride in presence of
acetonitrile by following the similar procedure as described in Intermediate-5;
Step: 4- Oxidation of Step-3 Intermediate using KMn0 4 by following the similar
procedure as described in Intermediate-6;
Step: 5- Intermediate Step-4 treating with l ,l ,l-trifluoro -N -phenyl-N -((trifluoro methyl)
sulfonyl) methane sulfonamide in presence of KHMDS by following the similar
procedure as described in Intermediate-7; m/z- 586. 1 as Na+1 .
Intermediate- 10
(R )-2-(((ieri-Butoxycarbonyl )((R )-l-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)-
2H -chromen-4-yl trifluoromethanesulfonate
The title compound was prepared in following five steps:
Step 1: By taking Intermediate-2 and corresponding (R)- l-(4-fluoro-3-methoxyphenyl)
ethanamine hydrochloride by following the similar procedure as described in
Intermediate-3.
Step 2 : Reduction of Step-1 Intermediate using borane dimethyl sulphide complex by
following the similar procedure as described in Intermediate-4.
Step 3 : Step-2 Intermediate was protected with BOC by reacting with BOC anhydride in
presence of acetonitrile by following the similar procedure as described in Intermediate-5.
Step: 4- Oxidation of Step-3 Intermediate using KMn0 4 by following the similar
procedure as described in Intermediate-6.
Step 5 : The title compound was prepared by reacting Step-4 Intermediate with , 1, 1-
trifluoro -N -phenyl-N-((trifluoromethyl) sulfonyl) methane sulfonamide in presence of
KHMDS by following the similar procedure as described in Intermediate-7; m/z- 584. 1 as
Na+1 .
Intermediate- 11
(R)-2-(((ieri-Butoxycarbonyl) ((R )-l-(4-fluoronaphthalen-l-yl) ethyl) amino) methyl)-
2H-chromen-4-yl trifluorome
The title compound was prepared in five steps:
Step 1: Intermediate-2 was reacted with corresponding (R)-l-(4-fluoronaphthalen-l-yl)
ethanamine hydrochloride by following the similar procedure as described in
Intermediate-3.
Step 2 : Step-1 Intermediate was undergone reduction reaction using borane dimethyl
sulphide complex by following the similar procedure as described in Intermediate-4.
Step 3 : The Step-2 Intermediate was protected with BOC by reacting with BOC
anhydride in acetonitrile by following the similar procedure as described in Intermediate-
5.
Step 4 : Step-3 Intermediate was undergone oxidation reaction using KMn0 4 by following
the similar procedure as described in Intermediate-6.
Step: 5 : Step-4 Intermediate was reacted with 1, 1, l-trifluoro -N-phenyl -N-((trifluoro
methyl)sulfonyl) methane sulfonamide in presence of KHMDS by following the similar
procedure as described in Intermediate-7; m/z- 481.7(m-100).
Intermediate- 12
(5)-2-(Chroman-2-yl) acetic acid
To a solution of Intermediate- 8 (0.5g, 2.81mmol) in ethylene dichloride (10 mL),
thionyl chloride (0.35 mL, 4.77 mmol) was added in dropwise manner atO°C. The
mixture was heated to reflux and maintained for lh. The progress of reaction was
monitored by TLC. The reaction mixture was concentrated under vacuum to get oily mass
(0.55g).
To a solution of (5)-chroman-2-carbonyl chloride (0.2 g, 1.02 mmol) in dry THF
(5 mL), triethylamine (0.28 mL, 2.03 mmol) was slowly added at 0°C. After 10 minutes
trimethylsilyldiazomethane ( 1 mL, 2.03 mmol, 2M) was added. The reaction was
monitored by TLC, after completion of reaction the reaction mixture was diluted with
water (5mL) and extracted with ethyl acetate (lOmLX 3). The combined organic phase
was dried over Na2S0 4, concentrated under vacuum to get crude (5)-2-(chroman-2-yl)-2-
oxoethanediazonium (0.16 g, 77 % yield).
To a solution of silver benzoate (0.047 g, 0.20 mmol) in 1, 4-dioxane (5 mL) and
water ( 1 mL), triethylamine (0.28 mL, 2.03 mmol) was added at 0°C. After 10 minutes
(5)-2-(chroman-2-yl)-2-oxoethanediazonium (0.16 g, 0.79 mmol) was slowly added at
0°C. The reaction mixture was allowed to RT and maintained overnight. The reaction was
monitored by TLC after completion of the reaction and mixture diluted with water (5 mL)
and acidified with 1:1 HC1, extracted with ethyl acetate (lOmL X 3). The combined
organic phase was dried over Na2S0 , concentrated under vacuum to get crude product.
Further purification was carried out by using flash chromatography (20% ethyl acetate in
n-Hexane) to get title compound (60 mg, 30.7 % yield), m/z-192. 13.
Intermediate- 13
(R )-2-(2-((ieri-Butoxycarbonyl )((R)- 1-(naphthalen- 1-yl)ethyl)amino)ethyl)-2 H -chromen-
4-yl trifluoromethanesulfona
The title compound was prepared in five steps:
Step 1: Intermediate- 12 was coupled with (R )- l -(naphthalen- l-yl)ethanamine
by following the similar procedure as described in Intermediate- 3;
Step 2 : The above Step-1 Intermediate was undergone reduction reaction using borane
dimethyl sulphide complex by following the similar procedure as described in
Intermediate-4;
Step 3 : The above Step-2 Intermediate undergone BOC protection using BOC anhydride
in acetonitrile by following the similar procedure as described in Intermediate-5;
Step 4 : Step-3 Intermediate was oxidized using KMn0 4 by following the similar
procedure as described in Intermediate-6;
Step 5 : Finally, the above Step-4 Intermediate was reacted with , 1, 1-trifluoro-Nphenyl
-N -((trifluoro methyl) sulfonyl) methane sulfonamide in presence of KHMDS by
following the similar procedure as described in Intermediate-7; m/z: 478.0 (m- 100).
Intermediate- 14
(R )-2-(Chroman-2-yl) acetic acid
The title compound was prepared by following the similar procedure as described
in Intermediate- 12 by taking Intermediate-2; m/z-192. 13.
Intermediate- 15
(5)-2-(2-((ieri-Butoxycarbonyl )((R)- 1-(naphthalen- 1-yl)ethyl)amino)ethyl)-2 H -chromen-
4-yl trifluoromethanesulfonate
The title compound was prepared in five steps:
Step 1: Intermediate- 14 was coupled with (R )-l-(naphthalen-l-yl)ethanamine
by following the similar procedure as described in Intermediate- 3;
Step 2 : The above Step-1 Intermediate was undergone reduction reaction using borane
dimethyl sulphide complex by following the similar procedure as described in
Intermediate-4;
Step 3 : The above Step-2 Intermediate was undergone BOC protection using BOC
anhydride in acetonitrile by following the similar procedure as described in Intermediate-
5;
Step 4 : Step-3 Intermediate was oxidized using KMn0 4 by following the similar
procedure as described in Intermediate-6;
Step 5 : Finally, The above Step-4 Intermediate was reacted with , 1, 1-trifluoro-Nphenyl
-N -((trifluoro methyl) sulfonyl) methane sulfonamide in presence of KHMDS by
following the similar procedure as described in Intermediate-7; m/z: 478 (m-100).
Intermediate- 16
(R )-Methyl chroman-2-carboxylate
To a solution of Intermediate-2 (15 g, 84mmol) in methanol (140 mL) was added
thionyl chloride (15.36 mL,210 mmol) at 0°C and the mixture was heated to 65°C and
maintained for lh. The progress of reaction was monitored by TLC. The reaction mixture
was evaporated and quenched with saturated sodium bicarbonate solution. The aqueous
layer was extracted with ethyl acetate (50mL X 2). Combined organic layer was washed
with water (50mL) followed by brine solution (25mL). The organic layer was dried over
N a2S0 4 and evaporated under reduced pressure to give colorless oily mass (15.6 g, 96 ) ;
m/z- 192. 8.
Intermediate- 17
(R )-Chroman-2-carbaldehyde
To a solution of Intermediate- 16 (15.6 g, 81 mmol) in a mixture of dry toluene
(120mL) and DCM (30 mL), DIBAL-H (85 mL, 85 mmol, 1M) was added in dropwise
manner at -65°C and further stirred for 2 h at the same temperature. The progress of
reaction was monitored by TLC. Reaction mixture was quenched with methanol ( 15mL)
at -65°C and allowed to RT, filtered through celite, diluted with water (50mL). It was
extracted with ethyl acetate (50 mL X 2) washed with water (25 mL) and brine solution
(25mL), dried over Na2S0 4 and concentrated under reduced pressure to get the crude
product. This crude product was further purified by flash chromatography (20% ethyl
acetate in Hexane) to give the title compound (12.5 g, 95 %); m/z-1 62.94.
Intermediate- 18
(R, Z?)-Ethyl 3-(chroman-2-yl) acrylate
To solution of Intermediate- 17 ( 11.2g, 69. 1mmol) and ethyl 2-(triphenyl
phosphoranylidene) acetate (26. 5g, 76 mmol) in toluene ( 115mL) was heated to 110°C
and maintained for 3h. The progress of reaction was monitored by TLC. Reaction mixture
was allowed to RT then diluted with water (50mL) and extracted with ethyl acetate
(50mL X 3). The combined organic layer was washed with water (50mL) followed by
brine solution (50mL), dried over Na2S0 4 and concentrated to give crude product. The
crude product was further purified by flash chromatography (10% ethyl acetate in hexane)
to give title compound as colorless oily mass ( 11.lg, 69.2%); m/z-232. 11.
Intermediate- 19
(R )-Ethyl 3-(chroman-2-yl) propanoate
To a suspension of 10% palladium on carbon (2. 1g, 50% wet) in ethanol (10 mL),
Intermediate- 18 ( 11.lg, 47.8 mmol) in ethanol (lOOmL) was carefully added and the
mixture was stirred overnight under a pressure of balloon of hydrogen. The progress of
reaction was monitored by TLC. Reaction mixture was filtered through celite and the
filtrate was concentrated to get the crude product as colorless oily mass ( 11.lg, 99 %);
m/z-234.4.
Intermediate-20
(R)-3-(Chroman-2-yl)propanoic acid
To a solution of Intermediate- 19 ( 11.lg, 47.4 mmol) in THF (100 mL), methanol
(100 mL) and water (10 mL) lithium hydroxide hydrate (2.98g, 7 1.1 mmol) was added.
The reaction mixture was stirred for 2h at RT. The progress of reaction was monitored by
TLC. The reaction mixture was concentrated under vacuum then cooled to 0°C and
acidified with dilute HC1 solution. The mixture was extracted with ethyl acetate (50mL X
2), washed with water (50 mL X 2) followed by brine solution (50 mL), dried over
Na2S0 4 and concentrated under vacuum to get white solid (9.2 g, 94 %); m/z-206. 17.
Intermediate-21
(S)-2-(3-((ieri-Butoxycarbonyl )((R)- 1-(naphthalen- 1-yl)ethyl)amino)propyl)-2 Hchromen-
4-yl trifluorometha
The title compound was prepared in following five steps:
Step 1: Intermediate-20 was coupled with (R)-l -(naphthalen- 1-yl) ethanamine
by following the similar procedure as described in Intermediate- 3;
Step 2 : The above Step-1 Intermediate was undergone reduction reaction using borane
dimethyl sulphide complex by following the similar procedure as described in
Intermediate-4;
Step 3 : The above Step-2 Intermediate was undergone BOC protection using BOC
anhydride in acetonitrile by following the similar procedure as described in Intermediate-
Si
Step 4 : Step-3 Intermediate was oxidized using KMn0 4 by following the similar
procedure as described in Intermediate-6;
Step 5 : Finally, the above Step-4 Intermediate was reacted with 1, 1, 1-trifluoro-Nphenyl
-N -((trifluoro methyl) sulfonyl) methane sulfonamide in presence of KHMDS by
following the similar procedure as described in Intermediate-7; m/z : 491 .4 (M-100).
Intermediate-22
(5)-Methyl chroman-2-carboxylate
The title compound was prepared by following the similar procedure as described
in Intermediate- 16 by taking Intermediate-8; m/z- 192.2.
Intermediate-23
(5)-Chroman-2-carbaldehyde
The title compound was prepared by following the similar procedure as described
in Intermediate- 17 by taking Intermediate-22; m/z-163.
Intermediate-24
(R )-2-(3-((ieri-Butoxycarbonyl )((R)- 1-(naphthalen- 1-yl)ethyl)amino)propyl)-2 H -
chromen-4-yl trifluorometha
The title compound was prepared in following eight steps:
Step 1: Intermediate-23 was reacted with ethyl 2-(triphenyl phosphoranylidene)acetate by
following the similar procedure as described in Intermediate- 18;
Step 2 : The above Step-1 Intermediate undergone hydrogenation with 10% palladium by
following the similar procedure as described in Intermediate-19;
Step3: The above Step-2 Intermediate was hydrolyzed in presence of lithium hydroxide
by following the similar procedure as described in Intermediate-20;
Step 4 : Step-3 Intermediate was condensed with (R)-l-(naphthalen-l-yl) ethanamine by
following the similar procedure as described in Intermediate-3;
Step 5 : The above Step-4 Intermediate undergone reduction reaction using borane
dimethyl sulphide complex by following the similar procedure as described in
Intermediate-4;
Step 6 : The above Step-5 Intermediate was protected with BOC by reacting with BOC
anhydride in acetonitrile by following the similar procedure as described in Intermediate-
5.
Step 7 : Step-6 Intermediate was undergone oxidation reaction using KMh 0 4 by following
the similar procedure as described in Intermediate-6.
Step 8: Step-7 Intermediate was reacted with , 1, l-trifluoro -N -phenyl-N -((trifluoro
methyl) sulfonyl) methane sulfonamide in presence of KHMDS by following the similar
procedure as described in Intermediate-7: m/z : 491 .4 (M-100).
Intermediate-25
(5)-2-(2-((ieri-Butoxycarbonyl )((R )-l-(4-fluoronaphthalen-l-yl)ethyl)amino)ethyl)-2 Hchromen-
4-yl trifluorometh
The title compound was prepared in five steps:
Step 1: Intermediate- 14 was coupled with (R)-l-(4-fluoronaphthalen-l-yl) ethanamine
hydrochloride by following the similar procedure as described in Intermediate-3;
Step 2 : The above Step-1 Intermediate was undergone reduction reaction using borane
dimethyl sulphide complex by following the similar procedure as described in
Intermediate-4;
Step 3 : The above Step-2 Intermediate was undergone BOC protection using BOC
anhydride in acetonitrile by following the similar procedure as described in Intermediate-
Si
Step 4 : Step-3 Intermediate was oxidized using KMn0 4 by following the similar
procedure as described in Intermediate-6;
Step 5 : Finally, the above Step-4 Intermediate was reacted with , 1, 1-trifluoro-Nphenyl-
N -((trifluoro methyl) sulfonyl) methane sulfonamide in presence of KHMDS by
following the similar procedure as described in Intermediate-7; m/z: 617.8 as Na+1 .
Intermediate-26
(R )-2-(2-((ieri-Butoxycarbonyl) ((R )-l-(4-fluoronaphthalen-l-yl) ethyl) amino) ethyl)-
2H -chromen-4-yl trifluoro
The title compound was prepared in five steps:
Step 1: Intermediate- 12 was coupled with (R )-l-(4-fluoronaphthalen-l-yl) ethanamine
hydrochloride by following the similar procedure as described in Intermediate-3;
Step 2 : The above Step-1 Intermediate was undergone reduction reaction using borane
dimethyl sulphide complex by following the similar procedure as described in
Intermediate-4;
Step 3 : The above Step-2 Intermediate was undergone BOC protection using BOC
anhydride in acetonitrile by following the similar procedure as described in Intermediate-
Si
Step 4 : Step-3 Intermediate was oxidized using KMn0 4 by following the similar
procedure as described in Intermediate-6;
Step 5 : Finally, The above Step-4 Intermediate was reacted with 1, 1, 1-trifluoro-Nphenyl-
N -((trifluoro methyl) sulfonyl) methane sulfonamide in presence of KHMDS by
following the similar procedure as described in Intermediate-7; m/z: 617.8 as Na+1 .
Intermediate-27
(5)-2-(2-((ieri-Butoxycarbonyl )((R )-l-(4-fluoro-3-methoxyphenyl)ethyl)amino)ethyl)-
2H -chromen-4-yl trifluoro
The title compound was prepared in five steps:
Step 1: Intermediate- 14 was coupled with (R )-l-(4-fluoro-3-methoxyphenyl) ethanamine
hydrochloride by following the similar procedure as described in Intermediate-3;
Step 2 : The above Step-1 Intermediate was undergone reduction reaction using borane
dimethyl sulphide complex by following the similar procedure as described in
Intermediate-4;
Step 3 : The above Step-2 Intermediate was undergone BOC protection using BOC
anhydride in acetonitrile by following the similar procedure as described in Intermediate-
Si
Step 4 : Step-3 Intermediate was oxidized using KMn0 4 by following the similar
procedure as described in Intermediate-6;
Step 5 : Finally, The above Step-4 Intermediate was reacted with 1, 1, 1-trifluoro-Nphenyl-
N -((trifluoro methyl) sulfonyl) methane sulfonamide in presence of KHMDS by
following the similar procedure as described in Intermediate-7; m/z: 576.
Intermediate-28
(R )-2-(2-((ieri-Butoxycarbonyl )((R )-l -(4-fluoro-3-methoxyphenyl)ethyl)amino)ethyl)-
2H -chromen-4-yl trifluoromethanesulfonate
The title compound was prepared in five steps:
Step 1: Intermediate- 12 was coupled with (R)-l-(4-fluoro-3-methoxyphenyl) ethanamine
hydrochloride by following the similar procedure as described in Intermediate-3;
Step 2 : The above Step-1 Intermediate was undergone reduction reaction using borane
dimethyl sulphide complex by following the similar procedure as described in
Intermediate-4;
Step 3 : The above Step-2 Intermediate was undergone BOC protection using BOC
anhydride in acetonitrile by following the similar procedure as described in Intermediate-
Si
Step 4 : Step-3 Intermediate was oxidized using KMn0 4 by following the similar
procedure as described in Intermediate-6;
Step 5 : Finally, the above Step-4 Intermediate was reacted with , 1, 1-trifluoro-Nphenyl-
N -((trifluoro methyl) sulfonyl) methane sulfonamide in presence of KHMDS by
following the similar procedure as described in Intermediate-7; m/z: 576.
Intermediate-29
(5)-2-(3-((ieri-Butoxycarbonyl )((R )-l-(4-fluoronaphthalen-l-yl)ethyl)amino)propyl)-2 Hchromen-
4-yl trifluorometha
The title compound was prepared in following five steps:
Step 1: Intermediate-20 was condensed (R)-l-(4-fluoronaphthalen-l-yl) ethanamine
hydrochloride by following the similar procedure as described in Intermediate-3;
Step 2 : The above Step-1 Intermediate undergone reduction reaction using borane
dimethyl sulphide complex by following the similar procedure as described in
Intermediate-4;
Step 3 : The above Step-2 Intermediate was protected with BOC by reacting with BOC
anhydride in acetonitrile by following the similar procedure as described in Intermediate-
5.
Step 4 : Step-3 Intermediate was undergone oxidation reaction using KMh 0 4 by following
the similar procedure as described in Intermediate-6.
Step 5 : Step-4 Intermediate was reacted with , 1, l-trifluoro -N -phenyl-N -((trifluoro
methyl) sulfonyl) methane sulfonamide in presence of KHMDS by following the similar
procedure as described in Intermediate-7: m/z : 509.6 (M-100).
Intermediate-30
(5)-2-(3-((ieri-Butoxycarbonyl )((R )-l-(4-fluoro-3-methoxyphenyl)ethyl)amino)propyl)-
2H -chromen-4-yl trifluoromethanesulfonate
The title compound was prepared in following five steps:
Step 1: Intermediate-20 was condensed with (R)-l-(4-fluoro-3-methoxyphenyl)
ethanamine hydrochloride by following the similar procedure as described in
Intermediate-3;
Step 2 : The above Step-1 Intermediate undergone reduction reaction using borane
dimethyl sulphide complex by following the similar procedure as described in
Intermediate-4;
Step 3 : The above Step-2 Intermediate was protected with BOC by reacting with BOC
anhydride in acetonitrile by following the similar procedure as described in Intermediate-
5.
Step 4 : Step-3 Intermediate was undergone oxidation reaction using Mn0 4 by following
the similar procedure as described in Intermediate-6.
Step 5 : Step-4 Intermediate was reacted with 1, 1, l-trifluoro -N -phenyl-N -((trifluoro
methyl) sulfonyl) methane sulfonamide in presence of KHMDS by following the similar
procedure as described in Intermediate-7: m/z : 489.8 (M-100).
Intermediate-3 1
Methyl 5-((2R )-2-(((teri-Butoxycarbonyl )((R )-l -(naphthalen-l-yl)ethyl) amino) methyl)
chroman-4-yl)-2-fluorobenzoate
Step-1 : Methyl 5-((R )-2-(((teri-butoxycarbonyl) ((R )-l-(naphthalen- l-yl) ethyl) amino)
methyl)-2H -chromen-4-yl)-2-fluorobenzoate
Intermediate-7 (0.850g, 1.503mmol) was dissolved in toluene (5mL), ethanol (5mL) and
water (0.5mL) then (4-fluoro-3-(methoxycarbonyl) phenyl)boronic acid (0.45 g, 2.254
mmol) and Na2C0 3 (0.478 g, 4.5 1 mmol) were added under nitrogen atmosphere. After
20 minutes Tetrakis(triphenylphosphane)palladium(0) (Pd (Ph3P)4) (0.087 g, 0.075 mmol)
was added under Nitrogen purging. The reaction mixture was heated to 65°C and further
maintained for 1 h. The progress of reaction was monitored by TLC. The separated out
solid in reaction mass was filtered through Celite. The filtrate was extracted with ethyl
acetate (25 mL X 2) and washed with water (15 mL) and brine solution (15 mL). The
organic layer was dried over Na2S0 4 and concentrated under reduced pressure to get
crude product. The crude compound was purified by flash chromatography (5% ethyl
acetate in Hexane) to give title compound as solid (0.72 g, 85% yield); m/z- 467. 1.
Step-2:- Methyl 5-((2R )-2-(((teri-butoxycarbonyl) ((R )-l-(naphthalen-l-yl) ethyl)
amino) methyl) chroman-4-yl)-2-fluorobenzoate
To a stirred solution of Step-1 Intermediate (0.7 g, 1.242 mmol) in methanol
(lOmL), 10% palladium on carbon (150mg) in methanol (5 mL) was carefully added and
the mixture was stirred overnight under a pressure of balloon of hydrogen. The progress
of reaction was monitored by TLC. Reaction mixture was filtered through celite bed and
the filtrate concentrated to get the crude product (0.7 g, 100% yield). The title compound
was obtained as diastereomeric mixture having different diastereomeric ratio(s); m/z-
469.2 (M-100).
The below Intermediates 32 to 96 given in Table- 1 were prepared in two steps:
Step-1: Synthesis of chromene intermediate (C-C coupling):
where R2 is substituted or unsubstituted aryl; X, Z, i, 'n' and 'q' are as defined
herein above;
The chromene intermediate was prepared by following procedure.
Triflate intermediate for example any one of Intermediate-7, Intermediate-9 to 11,
Intermediate- 13, Intermediate- 15, Intermediate-21, or Intermediate-24 to 30 was
dissolved in mixture of toluene, ethanol and water. Then optionally substituted phenyl
boronic acid and Na2C0 3 were added under nitrogen atmosphere and stirred for 30
minutes. To this reaction mixture Pd (Ph3P) 4 was added under Nitrogen purging then
heated to 65°C and further maintained for 1 h. The progress of reaction was monitored by
TLC. The reaction mixture was cooled to RT and filtered through Celite bed. The filtrate
was extracted with ethylacetate and washed with water then with brine solution. The
organic layer was dried over Na2S0 4 and concentrated under reduced pressure to get
crude product. This crude compound was further purified by flash chromatography to
give title compound.
Step-2: Synthesis of chromane intermediate (double bond reduction):
where R2 is substituted or unsubstituted aryl; X, Z, i , 'n' and 'q' are as defined
herein above;
The chromane intermediate was prepared by following procedure.
To a stirred solution of above Step-1 Intermediate in methanol, 10% palladium on carbon
in methanol was carefully added and the mixture was stirred overnight under a pressure
of balloon of hydrogen. The progress of reaction was monitored by TLC. The reaction
mixture was filtered through celite bed and the filtrate was concentrated to get the crude
product. In this stage the title compounds of diastereomers were obtained in different
diastereomeric ratio(s).
The intermediates of 32 to 96 as mentioned in below Table- 1 were obtained as
diastereomeric mixture having different diastereomeric ratio(s) by following the
procedure as described in Step-1 and then Step-2;
Table- 1:

70

Intermediate-97
3-((2R ,45)-2-(((ieri-Butoxycarbonyl)((R )-l-(naphthalen- l-yl)ethyl)amino)methyl)
chroman-4-yl)-2,6-dimethylbenzoic acid
Step- 1: 3-((R )-2-(((ieri-Butoxycarbonyl )((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)-
2H -chromen-4-yl)-2,6-dimethylbenzoic acid
Intermediate-7 (0.32g, 0.57mmol) was dissolved in toluene (5mL), ethanol (5mL)
and water (0.5mL) then (3-((benzyloxy)carbonyl)-2,4-dimethylphenyl)boronic acid (0.2
g, 0.57 mmol) and Na2C 3 (0. 18 g, 1.7 mmol) were added under nitrogen atmosphere.
The reaction mixture was stirred for 30 minutes then added Pd (Ph 3P) 4 (0.03 g, 0.028
mmol) under nitrogen purging. The reaction mixture was heated to 65°C and further
maintained for 1 h . The progress of reaction was monitored by TLC. The reaction mixture
was cooled to RT and filtered through Celite. The filtrate was extracted with ethyl acetate
(25 mL X 2) and washed with water (15 mL) and brine solution (15 mL). The organic
layer was dried over Na2S0 4 and concentrated under reduced pressure to get crude
product. The crude compound was purified by flash chromatography (5% ethyl acetate in
Hexane) to give title compound as solid (0.25 g, 67.3% yield); m/z- 654.7.
Step-2: 3-((2 R ,4S)-2-(((teri-Butoxycarbonyl )((R)- 1-(naphthalen- 1-yl)ethyl)amino)
methyl)chroman-4-yl)-2,6-dimethylbenzoic acid
To a stirred solution of above Step-1 Intermediate (0.25 g, 0.38 mmol) in methanol
(5mL), 10% palladium on carbon (40mg) in methanol (5 mL) was carefully added and the
mixture was stirred overnight under a pressure of balloon of hydrogen. The progress of
reaction was monitored by TLC. Reaction mixture was filtered through celite bed and the
filtrate concentrated to get the crude product (0. 15 g, 69.6% yield) m/z-465.9(M-100)
The two diastereomers were separated by using following chiral preparative HPLC
method. Separation Method: LUX AMYLOSE-2, 250 x 4.6 5u; Mobile Phase: A:
Hexane/IPA (9: 1, 0.1% TFA), A=100%v/v.
The below intermediates-98 to 101 as mentioned in Table-2 were prepared by following
the similar procedure as described in Step-1 and then step-2 of Intermediate-97 in two
steps, thus the first step of C-C coupling reaction was carried out by following the similar
procedure as described in Step-1 of intermediate-97 by taking intermediate- 15,
intermediate-21, intermediate-24 or intermediate-27 and (3-((benzyloxy)carbonyl)-2,4-
dimethyl phenyl) boronic acid. In this stage the title compounds of diastereomers were
obtained in different diastereomeric ratio(s).
Further, the two diastereomers of intermediate-98 were separated by using chiral
preparative HPLC.
Separation Method: CHIRAL PA IC, 250 x 4.6 5u; Mobile Phase: A= Hexane/IPA (90:
10, v/v, 0.1%DEA), B=EtOH A: B 80/20%v/v.
Similarly, the two diastereomers of intermediate-99 to intermediate- 101 were separated
by using chiral preparative HPLC.
Separation Method: CELLULOSE-1 250 x 4.6 5u; Mobile Phase: A: Hexane/IPA (9:1,
0.1% TFA) B=IPA A=100% v/v.
Table-2:
EXAMPLES
- la, l b
Intermediate-31(0.35g, 0.614mmol) was dissolved in dichloromethane (DCM)
(5mL) and methanolic HC1 (lOmL, 3N) was added. The reaction mixture was stirred at
RT overnight. The progress of reaction was monitored by TLC. The reaction was
evaporated under reduced pressure then added saturated Na2C 3 solution (10 mL). The
mixture was extracted with ethyl acetate (10 mL X 2) and washed with water (5mL X 2)
followed by brine solution (5mL), dried over Na2S0 4 and concentrated under reduced
pressure. This was further purified by flash chromatography (15% ethyl acetate in
Hexane) to give diastereomers. Further these diastereomers were separated by chiral
preparative HPLC to give Example-la 30 mg (at RT 4.79 mins) and Example-lb 100 mg
(at RT 9.65 mins); m z -470.1.
Separation Method: CHIRAL IA 250 x 4.6 5u; Mobile Phase: A= (n-Hexane/IPA, 90/10,
0.1%DEA), B=IPA, A: B = 70 /30 %V/V.
The below Examples-2 to 44 given in Table-3 were prepared by following the similar
deprotection procedure as described in Example- la, l b by taking from corresponding
Intermediate-32 to 72, Intermediate-78 or Intermediate-79 using methanolic HC1.
The two diastereomers of Example-2 to 44 were separated by using similar chiral
preparative HPLC method as mentioned in Example-la,lb.
Table-3:
Ex.No. Interme Structure Mass
diate No. (m/z)
452.2
465.61
465.6
465.61
480.1
494.5

The below Examples-45 to 49 given in Table-4 were prepared by following the
similar deprotection procedure as described in Example- la, l b by taking corresponding
Intermediate-73 to 77 using methanolic HCl. These examples were obtained with more
than 90 % enantiomeric purity and they were directly used for ester hydrolysis without
separation by chiral HPLC.
Table-4:
Ex.No. Intermed Structure Mass (m/z)
iate-No
45 73 463.5
1
Intermediate- 80 (0.3g, 0.514mmol) was dissolved in DCM (lOmL) and methanol /
HCl (3mL, 3N).The reaction mixture was stirred at 40°C overnight. The progress of
reaction was monitored by TLC. The reaction was evaporated under reduced pressure
then added saturated Na2C0 3 solution (5mL). The mixture was extracted with ethyl
acetate (10mLx2) and washed with water (5mLx2) followed by brine solution (5mL),
dried over Na2S0 4 and concentrated under reduced pressure. This was further purified by
flash chromatography (15% Ethyl acetate in Hexane) to give diastereomers of the title
compound (190mg, 76 %). m/z - 498. Further, these diastereomers were separated by
similar chiral preparative HPLC method as mentioned in Example la, l b to give Example-
50 (80 mg); m/z: 484.3.
The below examples 5 1 to 66 given in Table-5 were prepared by following the
similar deprotection procedure as described in Example-50 by taking any one of
Intermediate-81 to 96 using methanolic HCl. Further, the diastereomers of Example-51 to
53 and 59 to 66 were separated by chiral preparative HPLC.
Method: CHIRAL IA 250 x 4.6, 5u; Mobile Phase: A= (n-Hexane/IPA, 90/10,
0.1%DEA) B=IPA, A: B = 70 /30 %V/V.
The diastereomers of Example-54 to 58 were also separated by chiral preparative
HPLC method. Method: CHIRAL PAK ID: 250mm x 4.6,5m; Mobile Phase: A=n-hexane
IPA (90/10 %v/v, 0.1 %DEA) B=IPA, A: B=95/5 %v/v.
Table-5:
Ex.No Intermedi Structure Mass
ate-No (m/z)
5 1 8 1 484.3
F O
52 82 480.05

Example- 7
2, 6-Dimethyl-3-((2R , 4S)-2-((((R )-l-(naphthalen-l-yl) ethyl) amino) methyl) chroman-4-
yl) benzoic acid hydrochloride
Intermediate-97 (0.45 g, 0.795 mmol) was dissolved in DCM (10 mL) and ethereal HCl
(lOmL) was added. The reaction mixture was stirred at RT overnight. The progress of
reaction was monitored by TLC. The reaction was evaporated under reduced pressure.
The resultant solid was washed with diethyl ether (2 mL) followed by n-pentane (2mL),
dried to get the corresponding hydrochloride salt (0.32 g, 85 % yield).
m/z: 466. 1; NM (400MHz, DMSO-d ) : d 13.21 (bs, IH), 9.80 (bs, IH), 9.48 (bs,
IH), 8.30 (d, /=8.0 Hz, IH), 8.05 (m, 3H), 7.68-7.60 (m, 3H), 7.15 (t, /=7.6Hz, IH), 7.02
(d, =7.2 Hz, IH ) , 6.89 (d, /=7.2Hz, IH), 6.82-6.78 (t, =7.6 Hz, 2H), 6.54 (m, lH),
5.47-5.46 (m, IH) 4.66 (m, IH), 4.51 (m, IH), 3.34 (m, IH), 3.16 (m, IH), 2.45 (s, 3H),
2.22 (m,lH) ,2.20 (s,3H), 1.85 (m, lH) , 1.75(d, =6.8 Hz, 3H).
The below Examples-68 to 7 1 given in Table-6 were prepared by following the similar
deprotection procedure as described in Example-67 by taking corresponding Intermediate
- 98 to 101 using ethereal HC1.
Table-6:
Ex. Intermedi Structure Mass
ate-No (m/z)
No.
68 98 2,6-Dimethyl-3-((2 R ,45)-2-(2 -(((R )-l- 480. 1
(naphthalen-l-yl)ethyl) amino) ethyl)chroman-
4-yl) benzoic acid hydrochloride
NMR (400 MHz, DMSO-d6): d 13.2 (bs,
IH), 9.60 (bs, IH), 9.20 (bs, IH), 8.27-8.25 (d,
= 8.4Hz, IH), 8.03-8.00 (m , 2H), 7.83-7.8 1
(d, = 7.6Hz, IH), 7.66-7.58 (m, 3H), 7.07-
7.00 (m, 2H), 6.76-6.69 (m, 3H), 6.60-6.50 (m,
IH) 5.43-5.40 (m, IH), 4.50-4. 10 (m, IH),
4.3 1-4.26 (m, IH), 3.32-3.20 (m, 2H), 2.33 (s,
3H), 2.22 (s, 3H), 2.09-2.07 (m, 3H), 1.80-1 .68
(m, 4H).
69 99 2,6-Dimethyl-3-((2 R ,4R )-2-(3 -(((R )-l- 494. 1
(naphthalen-l-yl)ethyl) amino)
propyl)chroman-4-yl)benzoic acid
hydrochloride
NMR (400 MHz, DMSO-d ) : d 13.20 (bs,
IH), 9.82 (bs, IH), 9.25 (bs, IH), 8.28 (d,
/=8.4 Hz, IH), 8.03-7.98 (m, 3H), 7.65-7.58
(m, 3H), 7.05-6.98 (m, 2H), 6.77-6.70 (m,
2H), 6.54 -6.38 (m, 2H), 5.33 (m, IH) , 4.46
(m, IH), 4.13 (m, IH), 3.04 (m, IH), 2.85
(m, lH), 2.32 (s,3H), 2.22 (s, 3H), 2.05 (m, lH),
1.89 (m,2H), 1.74-1 .64 (m, 6H).
70 100 2,6-Dimethyl-3-((25,45)-2-(3 -(((R)- l - 494. 1
(naphthalen-l-yl)ethyl) amino)
propyl)chroman-4-yl) benzoic acid
hydrochloride
NMR (400 MHz, DMSO-d ) : d 13.20 (bs,
IH), 9.58(bs, IH), 9.13 (bs, IH), 8.28 (d,
/=8.4Hz, IH), 8.00 (t, =8.4 Hz, 2H), 7.93 (d,
J=7.2 Hz, lH),7.65-7.58 (m, 3H), 7.07 -6.99
(m, 2H), 6.78-6.66 (m, 3H), 6.55-6.49 (m, IH),
5.34 (m, IH), 4.47 (m, IH), 4.17 (m, IH), 3.04
(m, 1H), 2.85 (m, 1H), 2.33 (s,3H), 2.22 (s,
3H), 2.05 (m, 1H), 1.92 (m, 2H), 1.73-1 .68 (m,
6H).
7 1 101 3-((25,45)-2-(3 -(((R)- l-(4-Fluoro-3- 492.42
methoxyphenyl)ethyl) amino) propyl)chroman-
4-yl)- -dimethylbenzoic acid hydrochloride
NMR (400 MHz, DMSO-d ) : 13.39 (bs,
1H), 9.40 (bs, 1H), 9.18 (bs, 1H) , 7.53 (dd
/=8.4Hz & =1.6Hz 1H), 7.30-7.25 (dd,
J= .2 Hz & =8.4 Hz, 1H), 7.12-6.99 (m, 3H),
6.80-6.71 (m, 3H), 6.50-6.48 (m, 1H), 4.47 (m,
1H), 4.36 (q, J=6A Hz, 1H), 4.16 (m, 1H), 3.84
(s, 3H) , 2.94-2.87 (m, 1H), 2.71-2.66 (m, 1H),
2.32 (s,3H), 2.20 (s, 3H), 2.07 (m,lH) ,1.85 (m,
1H), 1.72-1 .67 (m, 4H), 1.55(d =6.8 Hz, 3H).
-72a, 72b
To a solution of Example-la (O. lg, 0.21mmol) in methanol (5mL), THF (5mL) and
water (0.5mL), lithium hydroxide hydrate (0.025g, 1.07mmol) was added. The reaction
mixture was heated to 80°C and further maintained for 2h. The progress of reaction was
monitored by TLC. The reaction mixture was concentrated under vacuum then cooled to
0°C and acidified with dilute HCl solution [pH=3 to 4]. Extract the product with ethyl
acetate (lOmL X 2) washed with water (5 mL X 2) followed by brine solution (5 mL),
dried over Na2S0 4 and concentrated under vacuum to get the solid.
Preparation of hydrochloride salt:
To the above compound ethereal HCl (2 mL) was added and stirred for 10 minutes. Then
the solvent was removed and the resultant solid was washed with diethyl ether (2 mL)
followed by n-pentane (2mL), dried to get the corresponding hydrochloride salt (0.08 g,
82 % yield).
m/z- 456.1; H NMR (400 MHz, DMSO-d ) : 813.30 (bs, 1H), 9.65 (bs, 1H), 9.20 (bs,
1H), 8.21 (d, = 8.0 Hz, 1H), 8.02-7.98 (m, 2H), 7.90 (d, J =1.2 Hz, 1H), 7.65-7.59 (m,
3H), 7.46-7.44 (m, 1H), 7.34-7.22 (m, 3H), 6.99-6.89 (m, 3H), 5.40 (m, 1H), 4.37 (m,
1H), 4.24 -4.22 (m, 1H), 3.40-3.30 (m, 1H), 3.06-3.04 (m, 1H), 2.12-2.04 (m, 1H),2.00-
1.96 (m, 1H) , 1.68 (d, = 6.8 Hz, 3H).
Similarly, Example-72b was prepared from Example- l b by using the above procedure.
m/z-456.1; H NMR (400 MHz, DMSO-d ) : d 13.30 (bs, 1H), 9.76 (bs, 1H), 9.36 (bs,
1H), 8.30 (d, = 8.4 Hz, 1H), 8.05 (t, = 8.0 Hz, 2H), 7.97 (d, = 7.2 Hz, 1H), 7.68-7.61
(m, 4H), 7.46-7.44 (m,lH), 7.31-7.27 (m, 1H), 7.17(t, = 7.2Hz, 1H),6.89 (d, =8.0Hz,
1H), 6.83 (t, = 8.0 Hz, 1H), 6.58 (d, = 7.8 Hz, 1H), 5.47 (m, 1H), 4.64-4.62 (m, 1H),
4.39-4.35 (m,lH), 3.30-3.24 (m, 2H), 2.25-2.20 (m,lH), 2.08-1.89 (m, 1H), 1.75 (d, =
6.8 Hz, 3H)
The below Examples 73 to 120 given Table-5 were prepared by following the similar
ester hydrolysis procedures as described in Example-72a,72b by taking appropriate ester
compound of Example-2 to 49;
Further, HCl salt of these amino compounds were prepared by following the
similar hydrochloride salt procedure as described in Example-72a,72b;
Example- 114 to 118 diastereomers formed in more than 90% isomers were purified
by recrystallization method.
Table-7:
Ex. Ester Structure Mass
Ex. (m/z)
No.
No.
2 3-((2R ,4S)-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) 437.73
methyl) chroman-4-yl)benzoic acid hydrochloride
0
NM (400MHz, DMSO-d ) : d 12.99 (bs, IH), 9.77
(bs, IH), 9.38 (bs, IH), 8.27 (d, /=8.4Hz, IH), 8.05-7.96
(m, 3H),7.85-7.83 (m, IH), 7.74-7.61 (m, 4H), 7.48-7.46
(m, 2H), 7.15 (t, =8.0 Hz, IH) , 6.90 (d, = 8.4Hz, IH),
6.82 (t, =7.6Hz, IH), 6.56 (d, /=7.6Hz, IH), 5.48-5.46
(m, IH) , 4.66-4.62 (m, IH), 4.39-4.35 (m, IH), 3.40-
3.24 (m, 2H) , 2.27-2.22 (m, IH), 2.00-1 .91 (m, IH) ,
1.75 (d, = 6.8 Hz, 3H).
3 2-Methyl-3-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl) 451 .6
amino)methyl)chroman-4-yl)benzoic acid hydrochloride
HCI
O
NM (400MHz, DMSO-d6) : d 12.89 (bs, IH), 9.87
(bs, IH), 9.54 (bs, IH), 8.30 (d, /=8.4Hz, IH), 8.04-8.00
(m, 3H), 7.70-7.48 (m, 4H),7. 18-7. 12 (m, 2H), 7.00 (m,
IH), 6.90 (d, /=8.0Hz, IH), 6.82 (t, J=l .2 Hz, IH), 6.53
(m, IH), 5.46-5.44 (m, IH), 4.69-4.66 (m, 2H), 3.40-3.37
(m, IH), 3.29-3.22 (m, IH), 2.56 (S, 3H), 2.26-2. 19 (m,
IH), 1.95-1 .93 (m, IH), 1.75 (d, = 6.4 Hz, 3H).
4 3-Methyl-5-((2 R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl) 452. 1
amino) methyl)chroman-4-yl)benzoic acid hydrochloride
HCI
0
NMR (400 MHz, DMSO-d ) : d 12.91(bs, IH), 9.96
(bs, IH), 9.53 (bs, IH), 8.30 (d, =8.4 Hz,IH), 8.02 (t,
/=7.2 Hz, 3H), 7.68-7.59 (m, 4H), 7.54 (s, IH), 7.27 (s,
IH), 7.14 (t, =7.6 Hz, IH ), 6.88 (d, =7.6 Hz, IH ),
6.79 (t, =7.6 Hz, IH ), 6.57 (d, =7.6 Hz, IH), 5.50-
5.45 (m, IH), 4.68-4.63 (m, IH), 4.33-4.28 (m, IH), 3.40
(m,lH), 3.22-3. 16 (m, IH), 2.33 (s, 3H), 2.26-2.22 (m,
1H),1 .95- 1.92 (m, IH), 1.76 (d, = 6.8 Hz, 3H).
5 4-Methyl-3-((2 R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl) 451 .6
amino) methyl)chroman-4-yl)benzoic acid hydrochloride
1HNMR(400MHz, DMSO-d ) : d 12.80 (bs, IH), 9.90
(bs, IH), 9.48 (bs, IH), 8.27 (d, =8.4Hz, IH), 8.04-
8.01 (m, 3H), 7.72-7.59 (m, 4H), 7.49-7.39 (m, 2H), 7.15
(t, = 8.0 Hz, IH), 6.91 (d, = 8.4Hz, IH), 6.80 (t, =
8.0 Hz, IH), 6.53 (d, /=7.2 Hz,IH), 5.48 -5.44 (m, lH),
4.68 (m, IH), 4.58-4.54 (m, IH), 3.40 (m, IH), 3.21-3. 17
(m, IH), 2.50 (s, 3H), 2.26 (m, lH), 1.98- 1.88 (m, IH),
1.77 (d, = 6.8 Hz, 3H).
77a, 6a 2-Ethyl-5-((2 R ,4R )-2-((((R )-l-(naphthalen-l-yl)ethyl) 466. 1
amino) methyl)chroman-4-yl)benzoic acid hydrochloride
NMR (400 MHz, DMSO- d6): d 12.85 (bs, IH), 9.47
(bs, IH), 9.26 (bs, IH), 8.23-8.21 (d, = 8.4Hz, IH),
7.99-7.90 (m, 2H), 7.88-7.86 (d, J=6.8Hz, IH), 7.70-7.59
(m, 3H), 7.39-7.38 (d, =2Hz, IH), 7.27-7.20 (m, 2H),
7.12-7. 10 (m, IH ), 6.97-6.87 (m, 3H), 5.46-5.38 (m,
1H),4.32-4.3 1 (m, IH), 4.14-4. 12 (m, IH), 3.38-3.34 (m,
IH), 3.20-3. 19 (m, IH), 2.87-2.64 ( q, 2H), 2.08-1 .90 (m,
2H), 1.69-1 .67 (d, = 6.8Hz, 3H), 1.16-1 .13 (t, 3H).
77b 6b 2-Ethyl-5 -((2R ,45)-2 -((((R)- 1-(naphthalen- 1-yl)ethyl)
amino) methyl)chroman-4-yl)benzoic acid hydrochloride
NM (400 MHz, DMSO- d6): d 12.80 (bs, IH), 9.64
(bs, IH), 9.28 (bs, IH), 8.29-8.27 (d, = 8.4Hz, IH),
8.05 -8.01(t, = 7.2Hz, 2H), 7.95 -7.93 (d , = 7.2Hz,
IH), 7.70 -7.58 (m, 4H), 7.29 (s, 2H), 7.16-7. 13 (t,
/=7.6Hz, IH), 6.89-6.87 (d, = 7.6 Hz ,1H), 6.83-6.79
(t, J=7.6Hz, IH), 6.59-6.57 (d, = 7.6Hz , IH), 5.48 -
5.47 (m, IH), 4.63-4.61 (m, IH), 4.32-4.28 (m, IH),
3.30-3.28 (m, 2H), 2.92-2.87 (q, 2H), 2.23-2.25 (m, IH),
1.98-1 .90 (m, IH), 1.74-1 .72 (d , = 6.8Hz, 3H), 1.17-
1.13 (t, 3H).
2-Isopropyl-5-((2 R ,4S)-2-((((R )-l -(naphthalen-l- 480. 1
yl)ethyl) amino) methyl)chroman-4-yl)benzoic acid
hydrochloride
NM (400MHz, DMSO-d ) : d 13.0 (bs, IH), 9.76 (bs,
IH), 9.36 (bs, IH), 8.24-8.22 (d, = 8 Hz, IH), 8.05-7.96
(m, 3H), 7.68 -7.61 (m, 3H),7.42-7.40 (d, /=7.6Hz, 2H),
7.36-7.29 (dd, = 8Hz, IH), 7.16-7. 12 (t, = 7.6Hz, IH),
6.88-6.86 (d, = 7.2Hz, IH), 6.83-6.79 (t, = 7.6Hz,
IH) 6.59-6.57 (d, = 7.6 Hz, IH), 5.48-5.46 (m, IH),
4.63-4.55 (m, IH), 4.3 1-4.27 (m, IH), 3.78-3.66 (m,
IH), 3.39-3.34 (m, IH), 3.25-3.23 (m, IH), 2.23-2. 19 (m,
IH) , 1.97-1 .88 (m, IH), 1.75-1 .73 (d, = 6.4 Hz,
3H),1 .14- 1.12 (m, 6 H).
79a, 8a 2-Cyclopropyl-5-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1- 478. 1
yl)ethyl) amino)methyl)chroman-4-yl)benzoic acid
hydrochloride
NM (400MHz, DMSO-d6): d 12.90 (bs, IH), 9.60
(bs, IH), 9.30 (bs, IH), 8.23-8.21 (d, =8Hz, IH), 8.02-
7.97 (m, 2H), 7.86-7.84 (d, /=6.8Hz, IH), 7.65-7.57 (m,
3H), 7.3 1 -7.30 (d, =2Hz, IH), 7.24 -7.20 (t, J=8.4Hz,
IH), 7.06-7.04 (d, /=8.4Hz, IH), 6.97-6.87 (m, 4H),
5.40-5.35 (m, IH), 4.35-4. 15 (m, 2H), 3.25-3. 10 (m,
2H), 2.65-2.55 (m, IH), 2.10-1 .95 (m, 2H), 1.69- 1.67 (d,
= 6.4 Hz, 3H), 0.93-0.83 (m, 2H), 0.69-0.67 (m, 2H).
79b 8b 2-Cyclopropyl-5-((2 R ,45)-2-((((R)- 1-(naphthalen- 1- 478. 1
yl)ethyl) amino)methyl)chroman-4-yl)benzoic acid
hydrochloride
NM (400MHz, DMSO-d6): d 12.90 (bs, IH), 9.70
(bs, IH), 9.20 (bs, lH),8.29-8.27 (d, =8.8 Hz, IH), 8.05-
8.02 ( t, /=7.6Hz, 2H) , 7.94-7.92 (d , /=6.8Hz, IH),
7.69-7.64 (m, 3H) ,7.52-7.5 1 (d, =2Hz, IH), 7.25-7.22
(dd, =8.4 & 2,1H), 7.14-7. 12 (t, /=7.6Hz , IH), 6.96-
6.94 (d, /=8.4Hz, IH), 6.88-6.86 (d, /=7.2Hz , IH), 6.82
-6.78 (t, = 8.4Hz, IH), 6.59-6.57 (d, /=7.6Hz, IH),
5.50-5.40 (m, IH), 4.65-4.55 (m, IH), 4.32-4.20 (m,
IH), 3.40-3.20 (m, 2H), 2.70-2.60 (m, IH), 2.25-2. 10
(m, IH), 2.00-1 .90 (m, IH), 1.76-1 .73 (d, = 6.4 Hz, 3H),
0.97-0.94 (m, 2H), 0.69-0.65 (m, 2H).
80 9 2,6-Difluoro-3-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1- 474. 1
yl)ethyl) amino)methyl)chroman-4-yl)benzoic acid
hydrochloride
F 0
NMR (400MHz, DMSO-d ) : d 13.98 (bs, IH), 9.82
(bs, IH), 9.48 (bs, IH), 8.27 (d, = 8.4 Hz, IH), 8.05-
7.98 (m, 3H), 7.67-7.60 (m, 3H), 7.37 (s, IH), 7.21-7. 14
(m, 2H), 6.90-6.82 (d, = 7.6Hz, IH), 6.86 (t, = 8
Hz,IH), 6.63( d, =8 Hz, IH ), 5.47 (m, IH), 4.69-4.53
(m, IH), 4.57-4.55 (m, IH), 3.40-3.22 (m, 2H), 2.33-
2.22 (m, IH), 2.02-1 .96 (m, IH), 1.76 (d, = 6.4 Hz,
3H).
81a, 10a 4-Fluoro-2-methyl-3-((2 R ,45)-2-((((R)- 1-(naphthalen- 1- 470.42
yl) ethyl) amino)methyl)chroman-4-yl)benzoic acid
hydrochloride
NM (400MHz, DMSO-d6): d 12.8 1 (bs, 1H), 9.52
(bs, 1H), 9.34 (bs, 1H), 8.24-8.22 (d, =8Hz, 1H), 8.05-
7.99 (m,2H), 7.90-7.88 (d, /=7.2Hz, 1H), 7.70-7.57
(m,3H), 7.26-7. 14 (m,3H), 6.99-6.86 (m,3H), 5.39-5.38
(m,lH), 4.49-4.48 (m, lH), 4.22-4. 10 (m, lH), 3.30-
3.18(m, 2H), 2.49 (s, 3H), 2.15-1 .90 (m, 2H), 1.64-1 .62
(d, = 6.4 Hz, 3H).
4-Fluoro-2-methyl-3-((2 R ,4R )-2-((((R )-l-(naphthalen-lyl)
ethyl) amino)methyl)chroman-4-yl)benzoic acid
hydrochloride
NM (400MHz, DMSO-d6): d 12.93 (bs, 1H), 9.68
(bs, 1H), 9.29 (bs, 1H), 8.29-8.27 (d, /=8.4Hz, 1H), 8.05-
8.01 (m, 2H), 7.95-7.93 (d, /=7.2Hz, 1H),7.69-7.60 (m,
4H), 7.22-7. 14 (m, 2H), 6.90-6.88 (d, /=7.6Hz, 1H),
6.84-6.80 (t, /=7.6Hz, 1H), 6.62-6. 18 (d, /=7.6Hz, 1H),
5.48-5.46 (m, 1H), 4.66-4.57 (m, 1H), 4.56-4.55 (m, 1H),
3.24-3.21 (m, 2H), 2.49 (s, 3H), 2.23-2. 15 (m, 1H), 2.10-
1.95 (m, 1H), 1.75 -1.73 (d , = 6.8Hz, 3H).
2,3-Dimethyl-5-((2 R ,4S)-2-((((R )- l-(naphthalen-lyl)
ethyl) amino)methyl)chroman-4-yl)benzoic acid
hydrochloride
NM (400MHz, DMSO-d ) : d 12.83 (bs, IH),
9.8 1(bs, IH), 9.41 (bs, IH), 8.30 (d, /=8.4Hz, IH), 8.05-
7.98 (m, 3H), 7.68-7.60 (m, 3H), 7.36 (S, IH), 7.15-7. 11
(m, 2H), 6.87 (d, =8Hz, IH), 6.8 1 (t, /=7.6Hz, IH), 6.59
(d, =7.6 Hz, IH), 5.48-5.47 (m, IH), 4.65-4.61 (m, IH),
4.25-4.20 (m, IH), 3.40-3.24 (m, 2H), 2.35 (s, 3H), 2.24
(s, 3H), 2.22-2. 17 (m, 1H),1 .96-1 .93 (m, IH), 1.75 (d,
/=6.4Hz, 3H).
5-((2R ,45)-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino)
methyl) chroman-4-yl)-2-(trifluoromethyl)benzoic acid
hydrochloride
NMR(400MHz, DMSO-d6) : d 12.9 (bs, IH), 9.82
(bs, IH), 9.43 (bs, IH), 8.30 (d, = 8 Hz, IH), 8.04-7.98
(m, 3H), 7.82 (d, =8 Hz, IH), 7.68-7.60 (m, 4H ), 7.55
(d, =7.6 Hz, IH), 7.19-7. 12 (m, IH) , 6.91 (d, =8
Hz,IH), 6.84 (m, IH), 6.57 (d, =7.6 Hz, IH), 5.47 (m,
IH) , 4.63 (m, IH), 4.50-4.45 (m, IH) , 3.24 (m, 2H),
2.28-2.25 (m, IH), 1.98-1 .95 (m, IH), 1.75 (d, /=6.4Hz ,
3H).
84a, 13a 2-Methyl-5-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl) ethyl) 451.92
amino) methyl)chroman-4-yl)benzoic acid hydrochloride
1HNMR(400MHz, DMSO-d6) : d 12.79 (bs, IH), 9.49
(bs, IH), 9.28 (bs, IH), 8.24 (d, = 8 Hz, IH), 8.02 (t, =
8.4Hz, 2H), 7.89 (d, =7.2 Hz, IH), 7.64-7.58 (m, 3H ),
7.44 (d, J=2 Hz, IH), 7.24-7.20 (m, 2H), 7.11 (dd, =8
Hz & = 2Hz, IH), 6.97-6.88 (m, 3H), 5.40-5.38 (m,
IH), 4.33 (m, IH), 4.25-4.20 (m, IH), 3.20 (m, 2H),
2.46 (s, 3H), 2.09-2.05 (m, IH), 1.99-1 .95 (m, IH), 1.69
(d, /=6.4Hz , 3H ) .
84b 13b 2-Methyl-5-((2 R ,45)-2-((((R)- 1-(naphthalen- 1- 451.92
yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid
hydrochloride
NM (400MHz, DMSO-d ) : d 12.88 (bs, IH), 10.37
(bs, IH), 9.93 (bs, IH), 8.30 (d, /=8.8Hz, IH), 8.19 (t, =
8.4Hz, IH), 8.02 (t, /=7.2Hz, 2H), 7.66-7.57 (m, 4H),
7.23 (s, 2H), 7.13 (t, /=7.6Hz, IH), 6.86 (dd, =8Hz &
0.8Hz, IH), 6.77 (t, =8Hz, IH), 6.55 (d, /=7.6Hz, IH),
5.5 1-5.49 (m, IH), 4.76-4.74 (m, 1H),4.28-4.24 (m, IH),
3.29-3.27 (m, IH), 3.19-3. 17 (m, IH), 2.48 (s, 3H), 2.27-
2.23 (m, IH), 1.93-1 .87 (m, IH), 1.78 (d, =6.4 Hz, 3H).
85 14 2-Fluoro-3-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)
ethyl)amino) methyl)chroman-4-yl)benzoic acid
hydrochloride
NM (400 MHz, DMSO-d ) : d 13.24 (bs, IH), 9.89
(bs, IH), 9.52 (bs, IH), 8.30 (d, /=8.0Hz, IH), 8.04-8.00
(m, 3H), 7.79-7.75 (m, IH), 7.67-7.59 (m, 3H), 7.42 (m,
IH), 7.26 (t, /=7.6Hz, 1H),7. 15 (t, /=7.6Hz, IH), 6.89 (d,
=8Hz, IH), 6.82 (t, /=7.4Hz, IH), 6.61 (d, =7.6 Hz,
IH), 5.48-5.46 (m, IH), 4.72-4.68 (m, IH), 4.59-4.58
(m, IH), 3.38-3.24 (m, 2H), 2.25-2.24 (m, IH), 2.00 -
1.97 (m, IH), 1.76 (d, = 6.4Hz, 3H).
86 15 3-Fluoro-5-((2R ,45)-2-((((R )-l -(naphthalen- 1-yl)
ethyl)amino) methyl) chroman-4-yl)benzoic acid
hydrochloride
HNMR (400MHz, DMSO-d ) : d 13.34 (bs, IH), 10.07
(bs, IH), 10.00 (bs, IH), 8.30 (d, /=8.4Hz, IH), 8.04
(m,3H), 7.67-7.54 (m, 5H), 7.37 (d, =8.4 Hz, IH ), 7.18-
7.14 (t, /=7.6Hz, IH), 6.89 (d, /=7.2Hz,lH), 6.83 (t,
/=7.6Hz, lH ),6.59 (d, =8Hz, IH) , 5.49 (m, IH), 4.67-
4.63 (m, lH), 4.44-4.39 (m, IH), 3.40-3.22 (m, 2H) ,
2.29-2.24 (m, IH), 2.01 - 1.92 (m, IH), 1.76 (d, = 6.8
Hz, 3H).
4-Fluoro-3-((2R ,4R )-2-((((R )-l-(naphthalen-l-yl) ethyl)
amino) methyl)chroman-4-yl)benzoic acid hydrochloride
1HNMR(400MHz,DMSO-d ) : d 13.08 (bs, IH), 9.80 (bs,
IH), 9.4 (bs, IH), 8.29 (d, /=8.4Hz, IH), 8.05-7.97 (m,
3H), 7.93-7.89 (m, IH), 7.79-7.60 (m, 4H), 7.35 (t,
/=8.0Hz, IH), 7.17 (t, /=8.0Hz, IH), 6.90 (d, /=8.0Hz,
IH), 6.84 (t, =7Hz, IH), 6.62 (d, /=7.6Hz, IH), 5.47-
5.46 (m, IH), 4.68-4.59 (m, 2H), 3.40-3.25 (m, 2H),
2.33-2.25 (m, IH), 2.03- 1.99 (m, IH), 1.75(d, /=6.4Hz,
3H).
2-Methoxy-5-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)
ethyl) amino) methyl)chroman-4-yl)benzoic acid
hydrochloride
NM (400MHz, DMSO-d ) : d 12.62 (bs.lH), 9.95
(bs, IH), 9.54 (bs, IH), 8.29 (d, /=8.4Hz, IH), 8.04-8.00
(m, 3H), 7.67-7.61 (m,3H), 7.43 (d, /=2.4Hz, IH), 7.32
(dd, =8.8Hz & 2.4Hz, IH), 7.13-7.08 (m, 2H), 6.85 (d,
/=7.6Hz, IH), 6.79 (t, /=7.2Hz, IH), 6.57 (d, /=7.6Hz,
IH), 5.50-5.45 (m, IH), 4.67-4.63 (m, IH), 4.27-4.22 (m,
IH), 3.80 (s, 3H), 3.32-3.21 (m, 2H), 2.23-2.18 (m, IH),
1.96-1.87 (m, IH), 1.75 (d, J=6A Hz, 3H).
2-Methoxy-3-((2 R ,4S)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)
amino)methyl)chroman-4-yl)benzoic acid hydrochloride
NM (400MHz, DMSO-d ) : d 13.01 (bs, IH), 9.70
(bs, IH), 9.42 (bs, IH), 8.23 (d, /=8.4Hz, IH), 8.04-7.94
(m, 3H), 7.64-7.54 (m, 4H), 7.20 (t, /=6.8Hz, IH), 7.02
(t, /=7.6Hz, IH), 6.95-6.88 (m, 3H), 6.69 (d, /=6.4Hz,
IH), 5.50-5.45 (m, IH), 4.52-4.5 1 (m, IH), 4.30-4.26 (m,
IH), 3.84 (s, 3H), 3.33-3. 16 (m, 2H), 2.12-2.05 (m, IH),
1.96-1 .93 (m, IH), 1.69 (d, =6.4 Hz, 3H).
2-Methoxy-3-((2 R ,4R )-2-((((R - l -(naphthalen- l-yl)ethyl)
amino)methyl)chroman-4-yl)benzoic acid hydrochloride
NM (400MHz, DMSO-d ) : d 12.98 (bs, IH), 9.95
(bs, IH), 9.57 (bs, IH), 8.29 (d, /=8.4Hz, IH), 8.02 (t,
/=7.6Hz, 3H), 7.67-7.59 (m, 4H), 7.13 (t, /=7.6Hz, 3H),
6.87 (d, =8Hz, IH), 6.80 (t, =8Hz, IH), 6.57 (d,
/=7.6Hz, IH), 5.49-5.48 (m, IH), 4.72 (m, 2H), 3.79 (s,
3H), 3.37 (m, IH), 3.24 (m, IH), 2.23 (m, IH), 1.93, (m,
IH), 1.77 (d, =6.4 Hz, 3H).
19 4-Methoxy-3-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl) 468
amino) methyl)chroman-4-yl)benzoic acid hydrochloride
0
HNMR (400 MHz, DMSO-d ) : d 12.62 (bs, IH), 9.96
(bs, IH) , 9.54 (bs, IH), 8.29 (d, =8.4 Hz, IH), 8.02 (t,
/=7.6Hz, 3H), 7.67-7.61 (m, 3H), 7.43(d, =2.4 Hz, IH),
7.33 (dd, =6Hz & 2.4Hz, IH) , 7.14-7.08 (m, 2H), 6.85
(d, /=7.6Hz, IH), 6.79 (t, /=7.2Hz, IH) , 6.57 (d, =7.6
Hz, IH), 5.50-5.45 (m, IH), 4.67-4.63 (m, IH), 4.27-
4.22 (m,lH) , 3.80 (s, 3H),3.27-3.22 (m, 2H), 2.23-2. 18
(m, 1H),1 .96-1 .87 (m, 1H), 1.74 (d, /=6.4Hz,3H).
20 2-(2-Methyl-5-((2 R ,45)-2-((((R)- 1-(naphthalen- 1- 482. 1
yl)ethyl) amino)methyl)chroman-4-yl)phenoxy)acetic
acid hydrochloride
HNMR (400MHz, DMSO-d ) : d 12.93 (bs, IH), 9.95
(bs, IH), 9.56 (bs, IH), 8.23 (m, IH), 8.04-8.00 (m, 3H),
7.67-7.61 (m, 3H), 7.11-7.08 (m, 2H), 6.85 (d, /=7.6Hz,
IH), 6.77 ft, /=7.2Hz, IH), 6.68 (t, /=7.6Hz, 2H), 6.61
(d, /=7.6Hz, IH), 5.49-5.48 (m, IH), 4.68 (m, IH), 4.62
(s, 2H), 4.18-4. 14 (m, IH), 3.28 (m, 2H), 2.20 (m, IH),
2.16 (s, 3H), 1.97-1 .88 (m, IH), 1.76 (d, /=6.8Hz, 3H)
2 1 2-(3-Methyl-5-((2 R ,4S)-2-((((R)- 1-(naphthalen- 1- 481.55
yl)ethyl) amino) methyl)chroman-4-yl)phenoxy)acetic
acid hydrochloride
NM (400MHz, DMSO-d ) : d 12.96 (bs, IH), 10.09
(bs, IH), 9.67 (bs, IH), 8.29 (d, /=8.0Hz, IH), 8.08-8.00
(m, 3H), 7.67-7.59 (m, 3H), 7.11 (t, /=7.6Hz, IH), 6.84
(d, /=7.6Hz, IH), 6.78 (t, /=7.6Hz, IH), 6.62-6.57 (m,
4H), 5.49 (m, IH), 4.67 (m, IH), 4.60 (s, 2H), 4.15 (m,
IH), 3.28-3.21 (m, 2H), 2.22 (s, 3H), 2.18 (m, IH), 1.92
(m, IH), 1.77 (d, =6.8 Hz, 3H).
a, 22a 2-(2-Huoro-5-((2 R ,4R )-2-((((R )-l -(naphthalen- 1- 486.0
yl)ethyl) amino)methyl)chroman-4-yl)phenoxy)acetic
acid hydrochloride
F O
'HNMR (400 MHz, DMSO-d ) : d 13.02 (bs.lH), 9.67
(bs,lH), 9.46 (bs,lH), 8.24 (d, =8.4 Hz, 1H), 8.01-7.95
(m, 3H), 7.65-7.57 (m, 3H), 7.21-7.06 (m, 2H), 6.93-6.77
(m, 4H), 6.36 (m, 1H), 5.40 (m, 1H), 4.72 (s, 2H), 4.28-
4.22 (m, 2H), 3.39-3.29 (m, 1H), 3.13 (m,lH), 2.07-1 .97
(m, 2H) ,1.68 (d, =6.8 Hz, 3H).
b 22b 2-(2-Huoro-5-((2 R ,45)-2-((((R )-l -(naphthalen-l-yl)
ethyl) amino)methyl)chroman-4-yl) phenoxy) acetic acid
hydrochloride
1HNMR(400 MHz,DMSO-d ) : d 12.92 (bs, 1H), 9.64
(bs, 1H) , 9.43 (bs, lH), 8.29 (d, = 8.4Hz, 1H), 8.05-7.99
(m, 3H), 7.67-7.61 (m, 3H), 7.20-7. 13 (m, 2H), 6.94
(dd, =8.0 Hz & = 1.6Hz , 1H),6.85-6.72 (m, 3H), 6.58
(d, =7.6 Hz, 1H), 5.48 (m, 1H), 4.71 (s, 2H), 4.65 (m,
1H), 4.22 (m, 1H), 3.37-3.21 (m, 2H), 2.18 (m, 1H), 1.98
(m, 1H) , 1.74 (d, =6.8 Hz, 3H).
94 23 2-(2-Huoro-3-((2 R ,4R )-2-((((R )-l -(naphthalen-l - 486.0
yl)ethyl) amino)methyl)chroman-4-yl)phenoxy)acetic
acid hydrochloride

24b 2-(3-Huoro-5-((2 R,4S)-2-((((R)-l -(naphthalen-l-yl) 486.0
ethyl) amino) methyl)chroman-4-yl)phenoxy)acetic acid
hydrochloride
NM (400MHz, DMSO-d ) : d 13.05 (bs, IH), 9.95
(bs, IH), 9.55 (bs, IH), 8.29 (d, =8.0 Hz, IH), 8.04-8.00
(m, 3H), 7.67-7.59 (m, 3H), 7.14 (t, /=7.2Hz, IH), 6.86
(dd, =8.0, 0.8Hz, IH), 6.8 1 (dt, =7.6, 0.8Hz, IH),
6.71 (td, =10.8, /=2.4Hz, IH), 6.65-6.57 (m, 3H), 5.48
(m, IH), 4.68 (s, 2H), 4.62 (m, IH), 4.26 (m, IH) , 3.39-
3.3 1 (m, IH), 3.18 (m, IH), 2.22 (m, IH), 1.95 (m, IH),
1.72 (d, =6.4 Hz, 3H).
25 2-(4-Huoro-3-((2 R,4R)-2-((((R)-l -(naphthalen-l -yl) 486. 1
ethyl) amino) methyl)chroman-4-yl) phenoxy)acetic acid
hydrochloride
NM (400MHz, DMSO-d ) : d 12.97 (bs, IH), 9.87
(bs, IH), 9.49 (bs, IH), 8.29 (d, =8.4 Hz, IH), 8.04-
7.99 (m, 3H), 7.67-7.59 (m, 3H), 7.14-7. 10 (m, 2H),
6.89-6.75 (m, 4H), 6.62 (d, J=7.2 Hz, IH), 5.48 (m, IH),
4.68 (m, IH) , 4.60 (s, 2H), 4.46 (m, IH), 3.38-3.24 (m,
2H), 2.18 (m, IH), 2.08 (m, IH), 1.73 (d, J=6A Hz,
3H).
26 2-Methyl-2-(3-((2 R,4S)-2-((((R)- 1-(naphthalen- 1- 505.5
yl)ethyl) amino)methyl)chroman-4-
yl)phenoxy)propanoic acid hydrochloride
0
NM (400 MHz, DMSO-d ) : d 13.03 (bs, IH), 9.36
(bs, IH), 9.3 (bs, IH), 8.28 (d, /=8.4Hz, IH), 8.05 (t,
/=7.4Hz, IH), 7.95 (d, /=4.4Hz, IH), 7.68-7.59 (m, 3H),
7.28-7.20 (m, 2H), 7.15-7. 12 (m, IH), 7.02 (s, IH), 6.87
(d, =8Hz, IH), 6.83-6.79 (m, IH), 6.69-6.60 (m, 3H),
5.48(m, IH), 4.62 (m, IH), 4.22-4. 19 (m, IH), 3.24-
3.20 (m, 2H), 2.23-2. 19 (m, IH), 1.91-1 .85 (m, IH),
1.75 (d, = 6.4Hz, 3H), 1.38 (s, 3H), 1.22 (s, 3H).
a 27a 4-((2R,4R)-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) 437.60
methyl) chroman-4-yl)benzoic acid hydrochloride
O
HO
NMR (400MHz, DMSO-d ) : d 12.89 (bs, IH), 9.48
(bs, IH), 9.21 (bs, IH), 8.24-8.22 (d, =8.4 Hz, IH),
8.00-7.91 (m, 2H) ,7.85 -7.81 (m, 2H),7.64-7.58 (m, 3
H), 7.33-7.31 (d, = 8.4Hz, IH), 7.26 -7.21 (t, =
8.8Hz, 1 H), 7.13-7. 11 (d, = 8 Hz, 2H), 6.97-6.8 1 (m,
3H), 5.39-5.38 (m, IH), 4.37 (m, IH), 4.18-4. 1 (m,
IH), 3.37-3.30 (m, 2H), 2.15-1 .95 (m, 2 H), 1.67- 1.66 (d,
= 6.4 Hz, 3H).
98b 27b 4-((2R ,45)-2 -((((R)- 1-(Naphthalen- 1-yl)ethyl) amino) 437.60
methyl) chroman-4-yl)benzoic acid hydrochloride
NMR (400 MHz, DMSO-d ) : d 12.90 (bs, 1 H), 9.82
(bs, IH), 9.46 (bs, 1 H), 8.30-8.28 (d, =8.4Hz, IH),
8.05-7.98 (m, 3H) , 7.92 -7.90 (d, = 8.4 Hz, 2H),7.68-
7.60 (m, 3 H), 7.3 1-7.29 (d, = 8Hz, 2H), 7.17-7. 13(t,
/=7.6Hz, IH), 6.90-6.88 (d, = 7.6 Hz, IH), 6.82-6.78
(t, =7.2 Hz, IH), 6.56-6.55 (d, = 7.6 Hz , IH), 5.48-
5.47(m, 1 H), 4.67-4.63 (m, IH), 4.39-4.34 (m, IH), 3.38
-3.24 (m, 2H), 2.27-2.23 (m, 1 H), 1.98-1 .92 (m, IH),
1.76-1 .74 (d, = 6.8Hz, 3H).
99a, 28a 2-Methyl-4-((2 R ,4R )-2 -((((R)- 1-(naphthalen- 1-yl)ethyl) 452. 1
amino) methyl)chroman-4-yl)benzoic acid hydrochloride

1H),1 .75 (d, =6.4 Hz, 3H).
100a, 29a 4-((2R ,4R )-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) 505.5
methyl) chroman-4-yl)-2-(trifluoromethyl)benzoic acid
hydrochloride
NM (400MHz, DMSO-d ) : d 13.56 (bs, IH), 9.72
(bs, IH), 9.47 (bs, IH), 8.25 (d, /=8.8Hz, IH), 8.01 (m,
3H), 7.76 (d, =8Hz, IH) , 7.64-7.56 (m, 3H), 7.55 (s,
IH), 7.29-7.21 (m, 2H), 7.09-6.82 (m, 3H), 5.40-5.39 (m,
IH), 4.48 (m, IH), 4.26-4.21 (m, IH), 3.35 (m, IH),
3.18-3. 16 (m, IH), 2.14-2.04 (m, 2H), 1.71(d, =6.4 Hz ,
3H).
0b 29b 4-((2R ,4S)-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) 505.5
methyl) chroman-4-yl)-2-(trifluoromethyl)benzoic acid
hydrochloride
NM (400MHz, DMSO-d6) : d 13.57 (bs, IH), 10. 17
(bs, IH), 9.76 (bs, IH), 8.25 (d, /=8.8Hz, IH), 8.10 (d,
/=7.2Hz, IH), 8.01 (t, /=8.8Hz, 2H), 7.80 (d, =8Hz,
IH), 7.67-7.59 (m, 4H), 7.55(d, =8.4 Hz, IH), 7.17 (t,
/=7.6Hz, IH), 6.89 (d, /=7.6Hz, IH), 6.82 (t, =7.6 Hz,
IH), 6.55 (d, /=7.6Hz, IH), 5.49 (m, IH), 4.71-4.68 (m,
IH), 4.50-4.46 (m, IH), 3.27 (m, IH), 3.20-3. 16 (m,
IH), 2.3 1-2.26 (m, IH), 1.99-1.90 (m, IH), 1.76 (d,
=6.4 Hz , 3H).
101 30 2,6-Difluoro-4-((2 R ,45)-2-((((R)- 1-(naphthalen- 1-yl) 473.3
ethyl) amino)methyl)chroman-4-yl)benzoic acid
hydrochloride
NM (400 MHz, DMSO-d6): d 13.80 (bs, IH), 9.91
(bs, IH), 9.54 (bs, IH), 8.3 1-8.29 (d, = 8.4Hz, IH),
8.05-8.00 (m, 3H), 7.69 -7.60 (m, 3H), 7.19-7. 15 (t, =
7.2Hz, IH), 7.07-7.05 (m, 2H), 6.89-6.87 (d, = 8Hz,
IH), 6.85-6.8 1 (t, /=7.6Hz, IH), 6.63-6.6 1 (d, =7.6 Hz,
IH), 5.50 -5.48 (m, IH), 4.65-4.63 (m, IH), 4.40-4.35
(m, IH), 3.35-3.23 (m, 2H), 2.32-2.22 (m, IH), 2.01-1 .96
(m, IH), 1.76-1 .74 (d, = 6.8 Hz, 3H).
102a, 31a 3-Methoxy-4-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl) 468. 1
amino) methyl)chroman-4-yl)benzoic acid hydrochloride
NM (400MHz, DMSO-d6): d 13.00 (bs, IH), 9.60-
9.50 (bs, IH), 9.30-9.20 (bs, IH), 8.23-8.21 (d, =8Hz,
IH), 8.01-7.97 (m, 2H), 7.90-7.88 (d, /=6.8Hz, 1H),7.63-
7.58 (m, 3H), 7.5 1-7.50 (d, =1.6Hz, IH), 7.42-7.40 (d,
/=7.6Hz, IH), 7.23-7.21 (m, IH), 6.97-6.95 (d, =8Hz,
IH), 6.90-6.89 (m, 2H), 6.52-6.50 (d, =8Hz, IH), 5.40-
5.30 (m, IH), 4.52-4.5 1 (m, IH), 4.18-4. 15 (m, IH), 3.91
(s, 3H), 3.40-3. 16 (m, 2H), 2.07-1 .93 (m, 2H), 1.69 (d,
/=6.4Hz, 3H).
102b 31b 3-Methoxy-4-((2 R ,45)-2-((((R)- 1-(naphthalen- 1-yl) 468. 1
ethyl) amino)methyl)chroman-4-yl)benzoic acid
hydrochloride

(m, 2H), 2.28-2.23 (m,lH), 2.01- 1.98 (m, IH), 1.74-
1.73 (d, = 6.4 Hz, 3H).
2-Fluoro-4-((2 R ,4S)-2-((((R)- 1-(naphthalen- 1-yl)ethyl) 456.0
amino) methyl)chroman-4-yl)benzoic acid hydrochloride
NMR (400MHz, DMSO- d6): d 13.10 (bs, IH), 9.80
(bs, IH), 9.40 (bs, IH), 8.30-8.28 (d , = 8.8 Hz, IH),
8.05 -7.97 (m, 3H), 7.86-7.82 (t, =8Hz, IH), 7.68-7.61
(m, 3H), 7.16 -7.09 (m, 3H), 6.90-6.88 (d, /=8.4Hz, IH),
6.82-6.80 (t, /=7.6Hz, IH ), 6.60 -6.58 (d J =7.6Hz, IH),
5.48 -5.40 (m, IH), 4.64-4.60 (m, IH), 4.40-4.36 (m,
IH), 3.40-3.30 (m, 2H), 2.27-2.23 (m, 1H),2.08-I.93(m,
1H),1.75-1.73 (m, 3H).
105a, 34a 2-(4-((2R ,4R )-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) 467.8
methyl)chroman-4-yl)phenoxy)acetic acid hydrochloride
NMR(400 MHz, DMSO-d ) : d 12.99 (bs, IH), 9.55
(bs, IH), 9.35 (bs, IH), 8.25 (d, = 8.4 Hz, IH), 8.02-
7.90 (m, 3H), 7.65 -7.57 (m, 3H), 7.21-7.08 (m, 2H),
6.94-6.80 (m, 6H), 5.40(m, IH) ,4.65 (S, 2H), 4.39-4.21
(m, 2H), 3.40-3. 16 (m, 2H),2.05-2.02 (m, lH), 1.97-
1.91(m, IH), 1.69 (d, = 6.8 Hz, 3H).
105b 34b 2-(4-((2R ,45)-2-((((R)- 1-(Naphthalen- 1-yl)ethyl) 467.8
amino)methyl) chroman-4-yl)phenoxy)acetic acid
hydrochloride
H NMR (400 MHz, DMSO-d6) : d 12.84 (bs, IH), 9.77
(bs, IH), 9.41 (bs, lH), 8.30 (d, =8.4 Hz, IH), 8.05 (t,
= 8.4Hz, 2H), 7.98 (d, =7.2 Hz, IH), 7.68-7.60 (m,
3H), 7.14 -7.08 (m, 3H), 6.88-6.85 (m, 3H), 6.8 1 (t, =
6.4Hz & 1.2Hz, IH), 6.60 (d, = 7.6 Hz, IH), 5.48-5.47
(m, IH), 4.65 (s, 2H), 4.61 (m, IH), 4.22-4. 17 (m, IH) ,
3.3 1-3.24 (m, 2H), 2.20-2. 16 (m, IH), 1.95-1 .85 (m,
IH), 1.76 (d, = 6.8 Hz, 3H).
106a, 35a 2-(2-Huoro-4-((2 R ,4R )-2-((((R )-l -(naphthalen-l -yl) 486.0
ethyl) amino)methyl)chroman-4-yl)phenoxy)acetic acid
hydrochloride
NM (400MHz, DMSO-d6): d 13. 10 (bs, IH), 9.60
(bs, IH), 9.20 (bs, IH), 8.25-8.23 (d, =8Hz, IH), 8.02-
7.98 (m, 2H), 7.89-7.87 (d, = 6.8Hz, IH), 7.70-7.58 (m,
3H), 7.23-7. 19 (m, IH), 6.99 -6.85 (m, 5H), 6.67-6.65 (d,
= 8.8Hz, IH ), 5.50 -5.40 (m , IH), 4.72 (s, 2H), 4.24-
4.14 (m, 2H), 3.25-3.20 (m, 2H), 2.10-1 .90 (m, 2H),
1.69-1 .68 (d, = 6.4Hz, 3H).
106b 35b 2-(2-Huoro-4-((2 R ,45)-2-((((R )-l -(naphthalen-l-yl) 486.0
ethyl) amino)methyl)chroman-4-yl)phenoxy)acetic acid
hydrochloride
HCI
HO-^O
NM (400 MHz, DMSO-d6): d 13.09 (bs, IH), 9.67
(bs, IH), 9.34 (bs, IH) ,8.30-8.27 (d, =8.4Hz IH), 8.05-
8.01 (t, =8Hz, 2H) , 7.95-7.93 (d, =7.2Hz, IH), 7.68-
7.60 (m, 3H), 7.16-7. 12 (t, =8Hz, IH), 7.04-7.01 (m,
2H), 6.95-6.93 (d, /=8.8Hz, IH), 6.87 -6.85 (d, /=8.4Hz,
IH), 6.83-5.72 (t, /=7.6Hz, IH), 6.61-6.59 (d, =7.6H ,
IH), 5.47(m, IH), 4.75 (s, 2H), 4.60-4.58 (m, IH) , 4.15-
4.14 (m, IH), 3.37 -3.33(m, 2H), 2.21-2. 16 (m, IH)
,1.97-1 .88(m, IH), 1.74 (d, = 6.8Hz, 3H).
107a, 36a 2-(4-((2R ,4R )-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) 451.6
methyl)chroman-4-yl)phenyl) acetic acid hydrochloride
NMR (400MHz, DMSO-d ) : d 12.3 (bs, 1 H), 9.4 (bs,
IH), 9.1 (bs, 1 H), 8.24-8.22 (d, =8.4 Hz, IH), 8.02-
7.98 (m, 2H), 7.86 -7.84 (d, /=7.2Hz, 1H),7.68-7.59 (m,
3H), 7.32-7.09(m, 3H), 6.96 -6.82 (m, 5H), 5.39 (m, lH),
4.26 (m, 2H), 3.55 (s, 2H), 3.44 -3.29 (m, 2H), 2.17-2.07
(m, IH), 1.98- 1.95 (m, 1 H), 1.69 (d, J =6A Hz, 3H).
2-(4-((2R ,45)-2-((((R)- 1-(Naphthalen- 1-yl)ethyl) amino)
methyl)chroman-4-yl)phenyl) acetic acid hydrochloride
H NMR (400 MHz, DMSO-d6) : d 12.32 (bs, IH), 9.59
(bs, IH) , 9.29 (bs, IH), 8.29-8.27 (d, = 8Hz, IH),
8.05-8.01 (t, = 7.2 Hz , 2H), 7.93-7.92 (d, = 6.8 Hz,
IH) , 7.70-7.60 (m, 3H), 7.23-7.21 (d, = 8Hz, 2H) ,
7.15-7. 11(m, 3H), 6.89-6.87 (d, = 7.2Hz, IH), 6.8 1-
6.78 (t, = 7.6Hz, IH), 6.60-6.58 (d, = 7.6Hz, IH), 5.48-
5.45 (m, IH), 4.64-4.59 (m, IH), 4.26-4.22 (m, IH) ,3.55
(s, 2H), 3.44-3.29 (m, 2H), 2.22-2. 17 (m, IH), 1.97- 1.88
(m, IH), 1.72 (d, = 6.4 Hz, 3H).
2-Methyl-2-(4-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-
yl)ethyl) amino)methyl)chroman-4-yl)phenyl)propanoic
acid hydrochloride
NMR (400 MHz, DMSO-d ) : d 12.3 1 (bs, IH), 9.49
(bs, IH), 9.25 (bs, IH), 8.24-8.22 (d, = 8.4 Hz, IH),
8.00-7.88 (m, 3H), 7.70 -7.50 (m, 3H), 7.28-7. 12 (m,
3H), 6.96-6.86 (m, 5H), 5.40-5.38 (m, IH), 4.25 (m,
2H), 3.43-3.29 (m, 2H), 2.07-1 .91 (m, 2H), 1.69 (d, =
6.4 Hz, 3H),1 .46 (s, 6H).
108b 37b 2-Methyl-2-(4-((2 R ,4S)-2-((((R)- 1-(naphthalen- 1-yl)
ethyl) amino)methyl)chroman-4-yl) phenyl) propanoic
acid hydrochloride
1HNMR(400MHz, DMSO-d6) : d 12.3 1 (bs, IH), 9.80 (bs,
IH), 9.45 (bs, IH), 8.29-8.27 (d, =8.4 Hz, IH), 8.05-
7.98 (m, 2 H), 7.86-7.85 (d, =6.8Hz 1H),7.66-7.61 (m,
3H), 7.30-7.28 (d, = 8.4 Hz, 2H), 7.18-7. 12 (m, 3 H),
6.88-6.86 (d, =7.6Hz, IH), 6.81-6.77 (t, = 7.6Hz, IH),
6.59-6.57 (d, =7.6Hz, IH), 5.48-5.47 (m, IH), 4.63 (m,
IH), 4.26-4.22 (m, IH), 3.37-3.3 1 (m, IH) , 3.24 - 3.14
(m, IH), 2.18-2. 14 (m, IH), 1.93- 1.85 (m, IH), 1.75 (d,
= 6.4 Hz, 3H) ,1.44 (s, 6H).
109 I38 I 3-Methyl-4-((2 R ,45)-2-((((R )-l -(naphthalen- 1-
yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid
hydrochloride

3-((2S,4R )-2-((((R)- 1-(Naphthalen- 1-yl)ethyl) amino) 437.73
methyl) chroman-4-yl)benzoic acid hydrochloride
NMR (400MHz, DMSO -d6): d 13.05 (bs, IH), 10.08
(bs, IH), 9.28 (bs, IH), 8.28 (d, =8.4 Hz, IH), 8.04-
7.99 (m, 3H), 7.84-7.8 1 (m, IH), 7.74-7.60 (m, 4H),7.46
-7.44 (m, 2H), 7.15 (t, = 8.0 Hz, IH), 6.93 (d, = 8.0
Hz, IH), 6.8 1 (t, = 7.6 Hz, IH), 6.56 (d, = 8.0 Hz,
IH), 5.46 (m, IH), 4.63-4.58 (m, IH), 4.39-4.34 (m, IH),
3.38-3.34 (m, IH), 3.14-3. 12 (m, IH), 2.23-2. 19 (m,
1H),1 .99- I .90 (m, IH), 1.76 (d, = 6.4Hz, 3H).
112a 41a 2-Methyl-5-((25,4 R )-2-((((R)- 1-(naphthalen- 1-yl) ethyl) 451.92
amino) methyl)chroman-4-yl)benzoic acid hydrochloride
H NMR (400 MHz, DMSO-d6): d 12.85(bs, IH) , 9.9
(bs, IH) , 9.3 (bs, IH), 8.29 (d, = 8.4 Hz, IH), 8.05 (t,
=9.2 Hz & 8 Hz, IH) ,7.98 (d, =7.2 Hz, 2H),7.68-7.60
(m, 4H), 7.25 (s, 2H), 7.16 (t, =7.6 Hz & 7.2 Hz, IH),
6.92 (dd, =8.4 Hz & 1.2Hz , IH), 6.8 1 (t, =7.6 Hz &
1.2 Hz,IH) ,6.57 (d, = 7.6 Hz, IH), 5.47-5.46 (m, IH),
4.60-4.58 (m, IH), 4.32- 4.27 (m, IH), 3.34 (m, IH),
3.17-3. 13 (m, IH) ,2.49 (s, 3H),2. 17 (m, 1H),1 .95 (m,
1H) ,1.76 (d, =6.8 Hz, 3H).
112b 41b 2-Methyl-5-((25,45)-2 -((((R)- 1-(naphthalen- 1-yl) 451.92
ethyl) amino) methyl) chroman-4-yl)benzoic acid
hydrochloride
NMR (400MHz, DMSO-d6): d 12.8 (bs, IH), 9.6 (bs,
IH), 9.2 (bs, IH), 8.21(d, =8.4 Hz, IH), 8.03 (t, =8.8
Hz, 2H), 7.89 (d, = 7.2 Hz, IH), 7.66-7.58 (m, 3H),
7.45 (d, /=1.6Hz, IH), 7.26-7.21 (m, 2H) , 7.15 (dd, =8
Hz, J=2 Hz, IH), 6.98 ( t, =7.6 Hz, IH), 6.93 ( t, =7.6
Hz, 2H), 5.39 (m, IH) , 4.32 (m, IH), 4.27-4.22 (m, IH),
3.34(m, IH), 3.05-3.04 (m, IH), 2.49 (s, 3H), 2.11-2.06
(m, IH), 2.05-1 .98 (m, IH), 1.67 (d, =6.8 Hz, 3H).
113a, 42a 2-(4-((25,4 R )-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) 466.8
methyl) chroman-4-yl)phenoxy)acetic acid hydrochloride
NMR (400 MHz,DMSO-d6): 812.97 (bs, 1H), 10.04
(bs, IH), 9.23 (bs, IH), 8.28 (d, = 8.4 Hz, IH), 8.04-
7.97 (m, 3H), 7.68-7.59 (m, 3H), 7.14-7.07 (m, 3H), 6.89
-6.84 (m, 2H), 6.80 (t, =7.6Hz, 2H), 6.58 (d, =7.6 Hz,
IH), 5.45 (m, IH), 4.64 (s, 2H), 4.60-4.56 (m, 1H),4.20-
4.16 (m, IH), 3.16-3.09 (m, 2H), 2.16-2.08 (m, IH),
1.94-1 .85 (m, IH), 1.76 (d, = 6.8 Hz, 3H).
113b 42b 2-(4-((25,45)-2 -((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) 466.8
methyl) chroman-4-yl)phenoxy)acetic acid hydrochloride
NMR (400 MHz, DMSO-d6): d 12.97 (bs, IH), 9.77
(bs, IH) , 9.25 (bs, IH), 8.24 (d, = 8.4Hz, IH), 8.02-
7.89 (m, 3H) , 7.65-7.58 (m, 3H), 7.26-7. 14 (m, 2H),
6.96-6.85 (m, 6H), 5.40 (m, IH) ,4.63 (s, 2H), 4.33-4.30
(m, IH), 4.21(m, IH), 3.40-3.04 (m, 2H), 2.06- 1.96 (m,
2H), 1.68 (d, = 6.8 Hz, 3H).
4-((2R ,4S)-2-((((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl)
amino) methyl)chroman-4-yl)-2-methylbenzoic acid
hydrochloride
1HNMR(400MHz, DMSO-d ) : d 12.25 (bs, IH), 9.70
(bs, 2H), 7.8 1 (d, =8 Hz, IH), 7.61-7.60 (m, IH), 7.30
(t, =8.4 Hz, IH ), 7.15-7.08 (m, 4H), 6.91 (d, =8
Hz,IH), 6.79 (t, /=7.6Hz, IH), 6.58 (d, =7.6 Hz, IH),
4.53 (m, 2H), 4.27-4.25 (m, IH), 3.87 (s, 3H), 3.09 (m,
IH), 2.95 (m, IH), 2.46 (s, 3H), 2.23 (m, IH), 1.94-1 .85
(m,lH), 1.65 (d, = 6.8 Hz, 3H).
115 | 46 I 3-((2R ,45)-2-((((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl)
amino)methyl)chroman-4-yl)-2-methylbenzoic acid
hydrochloride
'HNMR (400MHZ , DMSO-d ) : d 12.78 (bs, IH), 9.73-
9.63 (bs, 2H),7.59-7.50 (dd, = 13.6Hz,7.2 Hz, 2H) , 7.3 1
(t, = 8.4Hz, IH), 7.21 (m, 3H), 7.02 (d, = 8Hz, IH),
6.93 (d, = 8.4Hz, IH), 6.80 (t, J=1.2 Hz ,1H), 6.53 (m,
IH), 4.55-4.47 (m, 3H), 3.83 (s, 3H), 2.95-2.93 (m, IH),
2.56-2.51 (m, IH), 2.50 (s, 3H), 2.33-2.27 (m, IH), 1.79-
1.77 (m, IH), 1.65 (d, =6.8 Hz, 3H)
47 5-((2R,4S)-2-((((R)-l-(4-Fluoro-3-methoxyphenyl) ethyl) 450. 1
amino) methyl)chroman-4-yl)-2-methyl benzoic acid
hydrochloride
1HNMR(400MHz, DMSO-d ) : d 12.84 (bs, IH), 9.78
(bs, IH), 9.70 (bs, IH), 7.65 (d, /=8.4Hz, 2H), 7.30-
7.26 (m, 3H), 7.15-7.08 (m, 2H), 6.91(d, =8Hz, IH),
6.80 (t, /=7.2Hz, IH), 6.56 (d, =7.6 Hz, IH), 4.55-4.53
(m, IH), 4.48 (m, IH), 4.29-4.25 (m, IH), 3.87 (s, 3H),
3.11-3. 10 (m, IH), 2.95 (m, IH), 2.46 (s, 3H), 2.25-2. 18
(m, IH), 1.89-1 .83 (m, IH), 1.65 (d, =6.4 Hz, 3H).
48 3-((2R,45)-2-((((R)-l-(4-Fluoro-3-methoxyphenyl) ethyl) 450. 1
amino)methyl)chroman-4-yl)-5-methylbenzoic acid
hydrochloride
^NMR^OOMHz, DMSO-d ) : 812.91 (bs, IH), 9.71-
9.66 (bs, 2H), 7.66 (s, IH), 7.63 (d, =6.8 Hz, IH), 7.54
(s, IH), 7.3 1-7.27 (m, 2H), 7.16-7.09 (m, 2H), 6.92 (d,
=8 Hz, IH), 6.8 1(t, = 7.2 Hz ,1H), 6.58 (d, /=7.6Hz ,
lH),4.55-4.48(m, 2H), 4.32-4.28 (m, IH), 3.87(s, 3H),
3.11 (m, IH), 2.97 (m, IH), 2.33 (s, 3H), 2.23 (m, IH),
1.94 (m, IH), 1.67 (d, /=6.4Hz, 3H).
3-((2R,45)-2-((((R)-l-(4-Fluoro-3-methoxyphenyl) ethyl)
amino)methyl)chroman-4-yl)-4-methylbenzoic acid
hydrochloride
NM (400MHz, DMSO-d ) : d 12.8 (bs, lH), 9.8 (bs,
IH), 9.68 (bs, IH), 7.71 (dd, /=7.2Hz, 7.6Hz, 2H), 7.45
(m, IH), 7.3 1-7.24 (m, 2H), 7.16-7. 13 (m, 2H), 6.94 (d,
=8Hz, IH), 6.80-6.76 (t, J=1.2 Hz, IH), 6.54 (d,
/=6.8Hz, IH), 4.58-4.48 (m , 3H), 3.88 (s, 3H), 3.11-3. 10
(m, IH), 2.95 (m, IH), 2.46 (s, 3H), 2.32-2.27 (m, IH)
, 1.79 (m, IH), 1.62 (d, =6.4 Hz, 3H).
5-((2R,4R)-2-((((R)-l-(4-Fluoronaphthalen-l-yl) ethyl)
amino) methyl)chroman-4-yl)-2-methyl benzoic acid
hydrochloride
NM (400 MHz, DMSO-d ) : d 12.8 1 (bs, IH), 9.45
(bs, IH), 9.23 (bs, IH), 8.33-8.30 (m, IH), 8.15-8. 13 (d,
/=8.4Hz, IH), 7.90-7.88 (m, IH), 7.80-7.73 (m, 2H),
7.55-7.43 (m, 2H), 7.23-7.21 (m, 2H), 7.11-7.09 (m,
IH), 6.97-6.90 (m, 3H), 5.40-5.36 (m, IH), 4.32 (m, IH),
4.22-4.20 (m, IH), 3.37-3. 10 (m, 2H), 2.48 (s, 3H), 2.08-
1.94 (m, 2H), 1.72-1 .68 (d, = 7.6 Hz, 3H).
5-((2R ,4 -2-((((R )-l-(4-Fluoronaphthalen-l-yl) ethyl) 470.56
amino) methyl)chroman-4-yl)-2-methyl benzoic acid
hydrochloride
NMR (400 MHz, DMSO-d ) : d 12.85 (bs, IH), 9.86
(bs, IH), 9.47 (bs, IH), 8.30-8.28 (d, = 8Hz, IH), 8.18-
8.16 (d, /=7.2Hz, IH), 7.86-7.84 (m, IH), 7.79-7.72 (m,
2H), 7.59 (s, IH), 7.5 1-7.46 (m, IH), 7.27 (s, 2H), 7.15-
7.11 (t, =8Hz, IH), 6.88-6.86 (d, =8 Hz, IH), 6.8 1-
6.76 (t, = 7.6Hz, IH), 6.55-6.53 (d, =7.6Hz, IH),
5.38-5.36 (m, IH), 4.62-4.45 (m, IH), 4.32-4.27 (m,
IH), 3.37-3.33 (m, IH), 3.24-3. 14 (m, IH), 2.48 (s,3H),
2.24-2. 19 (m, IH), 1.97- 1.88 (m, IH), 1.71-1 .70 (d, =
6.4Hz, 3H).
a 44a 3-((2R ,45)-2-((((R )-l-(4-Fluoronaphthalen-l-yl)ethyl) 485.9
amino)methyl)chroman-4-yl)-2-methoxybenzoic acid
hydrochloride
0
NMR (400 MHz, DMSO-d ) : d 13. 1 (bs, 1H), 9.76
(bs, 1H), 9.5 (bs, 1H), 8.33-8.3 1(d, = 8.4 Hz, 1H),
8.14-8. 12(d, = 7.6 Hz, 1H),8.00-7.98 (m, 1H), 7.74-7.70
(m, 2H), 7.56-7.45 (m, 2H) , 7.22-7. 12 (m, 2H), 7.04-
7.00 (t, 7.6 Hz, 1 H), 6.95-6.87 (m, 3H) , 5.36 (m, 1H),
4.5 1-4.50 (m, 1H),4.29-4.26 (m, 1H), 3.86 (s, 3H), 3.30-
3.17 (m, 2 H), 2.08-2.04 (m, 1H), 1.89-1 .85 (m, 1H),
1.76 (d, = 6.4 Hz, 3H).
b 44b 3-((2R ,4R )-2-((((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)
amino) methyl)chroman-4-yl)-2-methoxybenzoic acid
hydrochloride
NMR (400 MHz, DMSO-d ) : d 12.95 (bs, 1H), 10. 14
(bs, 1H), 9.76 (bs, 1H), 8.38-8.36 (d, = 8.0Hz, 1H),
8.17-8.09 (m, 2H), 7.77-7.70 (m, 2H), 7.61-7.58 (m,
1H), 7.53-7.48 (dd, =8.8 Hz, 1.2Hz, 1H), 7.14-7. 10 (m,
3H), 6.87-6.85 (d, = 8 Hz, 1H), 6.80-6.77 (t, = 7.6 Hz,
1H), 6.56-6.54 (d, = 7.2 Hz, 1H),5.50-5.40 (m, 1H),
4.80-4.70 (m, 2H), 3.80 (s, 3H), 3.38-3.22 (m, 2H),
2.23 (m, 1H), 1.90 (m, 1H), 1.77-1 .75 (d, = 6.4 Hz, 3H)
Example- 121
2-Fluoro-5-((2S, 4R )-2-(2 -(((R )-l-(naphthalen-l-yl) ethyl) amino) ethyl) chroman-4-yl)
benzoic acid hydrochloride
To a solution of Example-50 (0. 15 g, 0.3 1mmol) in methanol (6mL), THF (6mL)
and water ( 1 mL) lithium hydroxide monohydrate (0.026g, 0.620mmol) was added. The
reaction mixture was stirred at 65°C for 4h. The progress of reaction was monitored by
TLC. Methanol was distilled off under vacuum then cooled to 0°C and acidified with
dilute HCl solution [pH=3 to 4] . The resultant white solid was filtered, washed and dried
under vacuum to give white solid ( 110 mg, 78%).
Further, HCl salt of these amino compounds were prepared by following the
similar hydrochloride salt procedure as described in Example-72a, 72b.
m/z-470; NM (400MHz, DMSO-d ) : d 13.25 (bs, 1H), 9.98 (bs, 1H), 9.27 (bs, 1H),
8.28-8.26 (d, /=8.4Hz, 1H), 8.03-7.98 (m, 3H), 7.66-7.59 (m, 4H), 7.44-7.41 (m, 1H),
7.29-7.25 (dd, =8.8 & 2 Hz, 1H), 7.09-7.05 (t, /=7.2Hz, 1H), 6.76-6.70 (m, 2H), 6.55-
6.53 (d, = 7.6Hz, 1H), 5.38-5.36 (m, 1H), 4.33-4.26 (m, 2H), 3.30-3.24 (m, 1H), 3.10-
2.90 (m, 1H), 2.20-2. 10 (m, 3H), 1.85-1 .74 (m, 1H) , 1.69-1 .67 (d, =6.8 Hz , 3H).
The below examples 122 to 129 given Table-8 were prepared by following the similar
ester hydrolysis procedures as described in Example- 121 by taking appropriate ester
compound of Example-51 to 58.
Further, HCI salt of these amino compounds were prepared by following the
similar hydrochloride salt procedure as described in Example-72a,72b;
Table-8:
Ex. Ester Structure Mass
Ex. (m/z)
No. No.
122 51 2-Fluoro-5 -((2R ,4S)-2-(2-(((R)- 1-(naphthalen- 1-yl)ethyl) 470.42
amino) ethyl)chroman-4-yl)benzoic acid hydrochloride
H NMR (400 MHz, DMSO- d6): d 13.3-12.9 (bs, 1H), 9.40-
9.30 (bs, 1H), 9.40 (bs, 1H), 8.29-8.27 (d, = 8.4Hz, 1H),
8.03-7.95 (m, 3H), 7.70-7.50 (m, 4H), 7.45-7.40 (m, 1H),
7.30-7.20 (t, 1H), 7.10-7.06 (m , 1H), 6.77-6.6.71 (m, 2H),
6.55-6.6.53 (d, = 7.6 Hz, 1H), 5.45-5.40 (m , 1H), 4.32-4.29
(m , 2H), 3.30-3. 15 (m, 2H), 2.20-2. 10 (m , 3H), 1.80-1 .77
(m, 1H), 1.70-1 .68 (d, = 6Hz, 3H).
123 52 2-Methyl-5-((25,4 R )-2-(2 -(((R)- 1-(naphthalen- 1-yl)ethyl) 466. 10
amino)ethyl)chroman-4-yl)benzoic acid hydrochloride
NM (400MHz, DMSO-d ) : d 12.65 (bs, 1H), 9.95 (bs,
IH), 9.25 (bs, IH), 8.25-8.23 (d, /=8.4Hz, IH), 8.02-7.98 (t,
/=7.6Hz , 2H), 7.83-7.8 1 (d, /=6.8Hz, IH), 7.66-7.58 (m,
4H) , 7.27-7.22 (m, 2H), 7.08-7.04 (t, /=7.6Hz, IH), 6.75-6.69
(m, 2H), 6.53-6.52 (d, =7.6 Hz, IH) , 5.35-5.33 (m, IH),
4.26-4.02 (m, 2H), 3.29-3.23 (m, IH), 3.05-2.98 (m, IH ),
2.45 (s, 3H), 2.16-2. 11 (m, IH), 2.08-2.02 (m, 2H), 1.82-
1.73(m, IH), 1.68-1 .66 (d, =6.4 Hz , 3H)
124 53 2-Methyl-5-((2R ,4S)-2-(2-(((R)- 1-(naphthalen- 1-yl)ethyl) 466.36
amino)ethyl)chroman-4-yl)benzoic acid hydrochloride
NM (400MHz, DMSO-d6) : d 12.84 (bs, IH), 9.68 (bs,
IH), 9.16 (bs, IH), 8.29-8.27 (d, /=8.4Hz, IH), 8.03-7.99
(m, 2H), 7.85-7.93 (d, /=7.2Hz, IH), 7.67-7.59 (m, 4H),
7.27-7.26 (m, 2H), 7.09-7.05 (t, /=7.2Hz, IH), 6.75-6.70 (m,
2H), 6.55-6.53 (d, = 7.6Hz, IH) , 5.38-5.37 (m, IH), 4.28-
4.22 (m, 2H), 3.29-3.26 (m, IH), 3.24-3. 14 (m, IH), 2.46 (s,
3H), 2.16-2.07 (m, 3H), 1.84-1 .75 (m, IH) , 1.70-1 .69 (d,
=6.4 Hz, 3H)
125 54 2-Methoxy-3-((2 R ,4R )-2-(2-(((R )-l -(naphthalen- l-yl)ethyl) 482. 1
amino)ethyl)chroman-4-yl)benzoic acid hydrochloride
HNMR (400MHz, DMSO-d6): d 13.3 ( bs, IH), 9.80 (bs,
IH), 9.30 (bs, IH), 8.29-8.27 (d, = 8.4Hz, IH), 8.03-7.97
(m , 3H), 7.66-7.58 (m, 4H), 7.15-7.03 (m, 3H), 6.75-6.70
(m, 2H), 6.54-6.52 (d, =7.6Hz, IH), 5.45-5.40 (m, IH),
4.62 (m, IH), 4.40-4.32 (m, IH), 3.62 (s, 3H), 3.24-3.22
(m, IH), 3.15-3. 11 (m, IH), 2.14-2.08 (m, 3H), 1.90-1 .75
(m, IH), 1.71-1 .69 (d, = 6.8Hz, 3H)
126 55 5-((25,4R )-2-(2 -(((R )-l-(4-Fluoronaphthalen- l-yl)ethyl) 484. 1
amino) ethyl)chroman-4-yl)-2-methylbenzoic acid
hydrochloride
NMR (400 MHz, DMSO- d6): d 12.84 (bs, IH), 9.8 1 (bs,
IH), 9.20 (bs, IH), 8.37-8.35 (d, = 8.4Hz, IH), 8. 16-8. 14
(m , IH), 7.99-7.95 (m, IH), 7.77-7.70 (m , 2H) , 7.61 (s,
IH), 7.53-7.48 (m, IH), 7.25 (s, 2H), 7.08-7.04 (m, IH),
6.75-6.68 (m, 2H), 6.54-6.52 (d, = 8.0Hz, IH), 5.36-5.35
(m , IH), 4.28-4.21 (m, 2H), 3.28-3.26 (m, IH), 3.01-2.99
(m, IH), 2.49 (s, 3H), 2.17-2.06 (m, 3H), 1.85-1 .76 (m, IH),
1.70-1 .68 (d, = 6.8Hz, 3H)
127 56 5-((2R ,45)-2-(2 -(((R )-l-(4-Fluoronaphthalen- l-yl)ethyl) 484. 1
amino) ethyl)chroman-4-yl)-2-methylbenzoic acid
hydrochloride

129 58 5-((2R ,45)-2-(2 -(((R )-l-(4-Fluoro-3-methoxy phenyl)ethyl) 463.9
amino)ethyl)chroman-4-yl)-2-methylbenzoic acid
hydrochloride
NMR (400MHz, DMSO- d6): d 12.84 ( bs, 1H) , 9.7 (bs,
1H), 9.3 (bs, 1H), 7.63 (s, 1H), 7.60-7.58 (d, = 8.4 Hz, 1H),
7.3 1-7.25 (m, 3H), 7.14-7.05 (m , 2H), 6.76-6.70 (m, 2H),
6.55-6.53 (d, = 7.6Hz, 1H), 4.42-4.40 (m , 1H), 4.27-4.22
(m, 2H), 3.85 (s, 3H), 3.07-3.01 (m, 1H), 2.91-2.88 (m,
1H), 2.44 (s, 3H), 2.17-2. 12 (m, 1H), 2.07-2.01(m, 2H),
1.85-1 .76 (m, 1H), 1.59-I .57(d, = 6.4Hz, 3H)
Example- 130
2-Fluoro-5-((2S, 45)-2-(3 -(((R )- l-(naphthalen-l -yl) ethyl) amino) propyl) chroman-4-yl)
benzoic acid hydrochloride
To a solution of Example-59 (0. 120 g, 0.24 mmol) in methanol (6 mL), THF (6mL)
and water (lmL), lithium hydroxide monohydrate (0.028 g, 1.2 mmol) was added. The
reaction mixture was stirred at 65°C for 4h. The progress of reaction was monitored by
TLC. Solvent was distilled off under vacuum then cooled to 0°C and acidified with dilute
HCl solution [pH=3 to 4], the resultant solid was filtered and it was triturated with
ethereal HCl and evaporated to dryness to give title compound as off white solid.(90 mg,
70 ) .
m/z: 484.3; H NMR (400 MHz, DMSO-d6):6 13.3 (bs, IH), 9.71 (bs, IH), 9.22 (bs, IH),
8.26-8.24 (d /=8.4Hz, IH), 8.02-7.98 (m, 3H), 7.83 (m, IH), 7.65-7.57 (m, 4H), 7.44-
7.41 (m, IH), 7.30-7.25 (dd, J=8.8, 2Hz, IH), 7.09-7.05 (t, /=7.6Hz, IH), 6.69-6.67 (d,
=7.6 Hz, IH), 6.54-6.52 (d, /=7.6Hz, IH), 5.34-5.32 (m, IH), 4.30-4.27 (m, IH), 4.12-
4.11 (m, IH), 3.09-3.00 (m, IH), 2.89-2.86 (m, IH), 2.13-2.09 (m, IH), 1.88- 1.66 (m,
8H).
The below examples 131 to 137 given Table-9 were prepared by following the
above similar procedures as described in Example- 130 by taking appropriate ester
compound of Example-60 to 66.
Further, HCl salt of these amino compounds were prepared by following the
similar hydrochloride salt procedure as described in Example-72a, 72b.
Table-9:
Ex. Ester Mass
Structure (m/z)
No. Ex. No.
13 1 60 2-Fluoro-5-((2R ,4R )-2-(3 -(((R )-l-(naphthalen-l-yl) ethyl) 484.36
amino) propyl)chroman-4-yl)benzoic acid hydrochloride
NM (400MHz, DMSO-d ) : d 13.6 (bs, IH), 9.75 (bs,
IH), 9.20 (bs, IH), 8.29-8.27 (d, /=8.4Hz, IH), 8.01-7.96
(m, 3H), 7.65-7.59 (m, 4H), 7.41 -7.40 (m, IH), 7.29-7.24
(dd, =8.4 & 2Hz, IH), 7.07-7.03 (t, /=7.2Hz, IH),
6.756.71 (dd, =8.4 & 1.2Hz, IH), 6.56-6.5 1 (m, 2H),
5.34-5.32 (m, IH), 4.32-4.27 (m, IH), 4.13-4.08 (m, IH),
3.05-3.03 (m, IH), 2.89-2.86 (m, IH), 2.13-2.08 (m, IH),
1.95-1 .82 (m, 2H), 1.77- 1.65 (m , 6H).
6 1 2-Methyl-5-((2S,4S)-2-(3 -(((R )-l-(naphthalen-l-yl) ethyl) 479.3
amino) propyl)chroman-4-yl)benzoic acid hydrochloride
NM (400MHz, DMSO-d ) : d 12.84 (bs, IH), 9.95,
(bs, IH), 9.35 (bs, IH), 8.28-8.26 (d, =8Hz, IH), 8.05-
7.97 (m, 3H), 7.64-7.57 (m, 4H), 7.27-7.22 (m, 2H), 7.08-
7.03 (t, /=7.6Hz, IH), 6.74-6.67 (m, 2H), 6.53-6.5 1 (d,
/=7.6Hz, IH), 5.34-5.33 (m, IH), 4.25-4.21 (m, IH), 4.13-
4.09 (m, IH), 3.10-2.95 (m, IH), 2.90-2.75 (m, IH),
2.45(s, 3H), 2.10-2.06 (m, IH) ,1.94-1.85 (m, 2H), 1.78-
1.65 (m, 6H).
62 2-Methyl-5-((2R ,4R )-2-(3-(((R )-l-(naphthalen-l-yl) ethyl) 479.3
amino) propyl)chroman-4-yl)benzoic acid hydrochloride
NM (400MHz, DMSO-d ) : d 12.82 (bs, IH), 9.83 (bs,
IH) , 9.24 (bs, IH), 8.29-8.27 (d, /=8.4Hz, IH), 8.04-7.98
(m, 3H), 7.65-7.58 (m, 4H), 7.27-7.21 (m, 2H), 7.06-7.02
(t, /=7.2Hz, IH), 6.73-6.69 (t, J=8.4Hz, IH), 6.55-6.5 1 (m,
2H), 5.34-5.33 (m, IH), 4.25-4.20 (m, IH), 4.14 -4.08 (m,
IH), 3.1-2.91 (m, IH), 2.95-2.75 (m, IH), 2.45 (s, 3H),
2.10-2.07 (m, IH), 1.91-1 .87 (m, 2H), 1.77-1 .65 (m, 6H).
134 63 5-((25,45)-2-(3 -(((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl) 478.42
amino)propyl)chroman-4-yl) -2-methylbenzoic acid
hydrochloride
NMR (400 MHz, DMSO-d ) : d 12.84 (bs, IH), 9.45
(bs, IH), 9.25 (bs, IH) , 7.62 (s, IH), 7.55 (dd, =8.4 Hz
& =1.6 Hz, IH), 7.30-7.25 (m, 3H), 7.13-7.05 (m, 2H),
6.75-6.71 (m, 2H), 6.54 (d, = 7.6 Hz, IH), 4.38-4.36 (m,
IH), 4.28-4.23 (m, IH), 4.17-4. 12 (m, IH ), 3.84(s, 3H),
2.86 (m, IH), 2.67 (m, IH), 2.5 (s, 3H), 2.14 -2.09 (m,
IH), 1.91-1 .89 (m, IH), 1.82-1 .73 (m, 2H),1 .70-1.67 (m,
2H) ,1.58 (d, =6.8 Hz, 3H).
135 64 4-((25,45)-2-(3 -(((R)- 1-(4-Fluoronaphthalen- 1-yl)ethyl) 498.5
amino) propyl)chroman-4-yl)-3-methylbenzoic acid
hydrochloride
NM (400MHz, DMSO): d 12.81 (bs, IH), 9.77 (bs,
IH), 9.23 (bs, IH), 8.37-8.35 (d, = 8.0Hz, IH), 8.15-8. 13
(d, =7.6 Hz, 1 H), 8.01-7.98 (m, IH), 7.79-7.67 (m, 4H),
7.52-7.47 (dd, = 8.4,2 Hz , IH), 7.08-7.04 (t, =7.6 Hz,
IH), 6.94 (s, IH), 6.74-6.70 (t, = 7.6 Hz, 1 H), 6.68-
6.66 (d, = 8.4Hz, IH), 6.48-6.47 (d, = 7.2 Hz, IH),
5.32-5.30 (m, IH), 4.53-4.5 1 (m, IH), 4.16 (m, lH), 3.11-
3.00 (m,lH), 2.89-2.80 (m, IH), 2.46(s, 3H), 2.11-2.0 (m,
IH), 1.99-1 .65 (m, 3H), 1.70-1 .68 (m, 5H).
136 65 4-((25,45)-2-(3 -(((R)- 1-(4-Fluoronaphthalen- 1-yl)ethyl) 484.0
amino) propyl)chroman-4-yl)benzoic acid hydrochloride
NM (400MHz, DMSO-d ) : d 12.90 (bs, IH), 9.66 (bs,
IH), 9.20 (bs, IH), 8.37-8.35 (d, =8.0 Hz, IH), 8.15-8. 14
(d, /=7.2Hz ,1H), 7.98-7.95 (m, IH), 7.91 -7.89 (d, =8Hz,
2H), 7.76-7.68 (m, 2H), 7.52-7.48 (dd, /=8.4,2 Hz, IH),
7.29-7.27 (d, =8Hz, 2H) , 7.09-7.07 (t, /=7.2Hz, IH),
6.74-6.71 (t, /=7.6Hz, IH), 6.68-6.66 (d, =8Hz, IH),
6.52-6.50 (d, /=7.6Hz, IH), 5.32-5.3 1 (m, IH), 4.33-4.29
(m, IH), 4.15-4. 12 (m, IH), 3.15-3.00 (m, IH), 2.90-2.80
(m, IH), 2.14-2.08 (m, IH), 1.90- 1.75 (m, 3H), 1.69-1 .67
(m, 5H).
137 66 5-((25,45)-2-(3 -(((R )-l-(4-Fluoronaphthalen-l-yl)ethyl) 498.5
amino) propyl)chroman-4-yl)-2-methylbenzoic acid
hydrochloride
NMR (400 MHz,DMSO-d6): d 12.84 (bs, 1H), 9.74
(bs, 1H) , 9.24 (bs, 1 H), 8.37-8.35 (d, =8.4 Hz, 1H),
8.15-8. 13 (d, = 7.6 Hz, 1H), 8.01-7.97 (m, 1H), 7.76-7.69
(m, 2H), 7.61 (m, 1H) , 7.52 -7.47 (dd, /=8.4,2Hz, 1H),
7.27-7.22 (m, 2H), 7.07-7.04 (t, =7.2 Hz, 1 H), 6.74-6.70
(t, = 7.6Hz, 1H), 6.67-6.65 (d, = 8.0 Hz, 1H), 6.54-
6.52 (d, = 7.6 Hz, 1H), 5.32-5.31 (m, 1 H), 4.26-4.21 (m,
1H), 4.13-4. 11 (m, 1H), 3.10-3.04 (m, 1 H), 2.89-2.87
(m, 1H) , 2.46(s, 3 H), 2.08-2.03 (m, 1 H), 1.90-1 .70
(m,3H), 1.68-1 .63 (m, 5H).
Example- 138
Methyl 2-(3-((2R , 45)-2-((((R )-l-(naphthalen-l-yl) ethyl) amino) methyl) chroman-4-yl)
benzamido) acetate
To a stirred solution of Example-73 (0. 14g, 0.295mmol) in THF (lOmL), (3-
(ethyliminomethyleneamino)-N,N-dimethylpropan-l -amine) (EDC) (0.062g, 0.325
mmol), HOBT (0.05g,0.325mmol) and N,N -Diisopropylethylamine (DIPEA) (0. 153g,
1.18mmol) were added. The reaction mixture was stirred at 0°C for 15minutes. Then, to
this solution glycine methyl ester hydrochloride (0.037g, 0.295mmol) was added. The
reaction mixture was stirred at RT overnight. The progress of reaction was monitored by
TLC. The reaction mixture was diluted with water (20mL) and the compound extracted
with ethyl acetate (20 mLX2). Combined organic layer was washed with water (20 mL)
followed by brine solution (20mL). The organic layer was dried over Na2S0 4 and
concentrated under reduced pressure to give crude product (0. 14g, 93% yield); m/z-509. 1.
Example- 139
Methyl 2-(2-methyl-5-((2 R , 4S)-2-((((R)- 1-(naphthalen- 1-yl) ethyl) amino) methyl)
chroman-4-yl) benzamido) acetate
The title compound was prepared by following the similar procedure as described
in Example-138 by using corresponding acid compound of Example-84b; m/z-523. 1.
Example- 140
2-(3-((2R , 45)-2-((((R )-l -(Naphthalen- 1-yl) ethyl) amino) methyl) chroman-4-yl)
benzamido) acetic acid hydro
To a solution of Example-138 (0. 15g, 0.295mmol) in methanol (5mL), THF (5mL) and
water (2mL) lithium hydroxide monohydrate (0.035g, 1.47mmol) was added. The
reaction mixture was stirred at RT for overnight. The progress of reaction was monitored
by TLC. Solvent was distilled off under vacuum then cooled to 0°C and acidified with
dilute HC1 solution [pH=3 to 4]. Extracted the product with ethyl acetate (10mLX2),
washed with water (5 mL X2) followed by brine solution (5 mL), dried over sodium
sulfate and concentrated under vacuum to get solid. Ethereal HC1 (2mL) was added and
stirred for 10 min. The solvent was removed and the resultant solid washed with diethyl
ether (2 mL) followed by n-pentane (2 mL), dried to get product as a hydrochloride salt.
(O. lg, 64% yield);
m/z 495. 1; HNMR (400 MHz, DMSO-d ) : d 12.5 (bs, IH), 9.8 (bs, IH), 9.5 (bs, IH),
8.54-8.5 1 (m, IH), 8.30-8.28 (m, IH), 8.04-7.99 (m, 3H), 7.67-7.59 (m, 3H), 7.21-7. 11
(m, 4H), 6.85-6.77 (m, 2H), 6.63-6.61 (m, IH), 5.49 (d, /=6.4Hz, IH), 4.67 (d, /=6.3Hz,
IH), 4.27-4.25 (m, IH), 3.86 (d, J=6.2 Hz, 2H), 3.3 1 (m, 2H), 2.21-2. 19 (m, IH), 2.O.-
1.99 (m,lH), 1.76 (d, J=6A Hz ,3H).
Example- 141
2-(2-Methyl-5-((2 R, 45)-2 -((((R)-l-(naphthalen- l-yl) ethyl) amino) methyl) chroman-4yl)
benzamido) acetic acid hydro
The title compound was prepared by following the similar procedure as described in
Example -140 by using corresponding ester Example- 139 and lithium hydroxide hydrate;
m/z 509. 1; H NMR (400 MHz, DMSO-d ) : d 9.8 (bs, IH), 9.5(bs, IH), 8.54-8.5 1 (m,
IH), 8.30-8.28 (m, IH), 8.04-7.99 (m, 3H), 7.67-7.59 (m, 3H),7.21-7. 11 (m, 3H), 6.85-
6.77 (m, 2H) ,6.63-6.61 (m, IH), 5.49 (d, =6.4 H z,IH), 4.67 (d, =6.3 Hz, IH), 4.27-4.25
(m, IH), 3.86 (d, =6.24 Hz, 2H), 3.37 (m, 2H), 2.45 (s, 3H), 2.21-2. 19 (m, IH), 2.O.-
1.99 (m, IH), 1.76 (d, =6.4 Hz, 3H).
Example- 142
N, 2-Dimethyl-5-((2 R, 45)-2-((((R)-l-(naphthalen-l -yl) ethyl) amino) methyl) chroman-4-
yl) benzamide hydrochloride
To a solution of Example-84b (lOOmg, 0.205 mmol) in DMF (3 mL), 1,1'-
carbonyldiimidazole (CDI) (24.92 mg, 0.154 mmol) was added and stirred at RT for 15
minutes. To this reaction mixture methylamine hydrochloride (50 mg, 0.74 mmol) and
triethylamine (0.02 mL, 0.143 mmol) were added and heated to 60°C and further
maintained for 24 h. The reaction progress was monitored by TLC. Reaction was
quenched with ice water (3mL) the resultant solid was filtered and washed with water (5
mL X 2). Dry this solid at 45 °C. Further, HCl salt of these amino compound was
prepared by following the similar hydrochloride salt procedure as described in Example-
72a, 72b (18.5mg, 38.9 %)
m/z-464.5; ^NMR (400MHz, DMSO-d6) : 9.78 (bs, 1H), 9.43 (bs, 1H), 8.31 (d, /=8.4Hz,
1H), 8.13 (q, /=4.8Hz, 1H), 8.05 (t, /=7.6Hz, 2H), 7.99 (d, /=7.6Hz, 1H), 7.71-7.60 (m,
2H), 7.20 (t, =8Hz, 1H), 7.16-7.11 (m, 3H), 6.88 (d, =8Hz, 1H), 6.81 (t, =6.8Hz &
8.4Hz, 1H), 6.62 (d, /=7.6Hz, 1H), 5.5-5.48 (m, 1H), 4.46-4.61 (m, 1H), 4.26-4.22 (m,
1H), 3.32 (m, 1H), 3.25 (m, 1H), 2.70 (s, 3H), 2.33 (s, 3H), 2.21-2.16 (m, 1H), 1.99-1.95
(m, 1H), 1.76 (d, =6.8 Hz, 3H).
The below Examples 143 to 147 given Table- 10 were prepared by following the
above similar procedures as described in Example- 142 by taking appropriate acid
compound of Example-84b and appropriate amine;
Further, HCl salt of these amino compounds were prepared by following the
similar hydrochloride salt procedure as described in Example-72a, 72b.
Table-10:
Ex. Structure Mass
(m/z)
No.
N,N ,2-Trimethyl-5-((2R ,4S)-2-((((R)- 1-(naphthalen- 1- 478.6
yl)ethyl) amino)methyl)chroman-4-yl)benzamide
hydrochloride
NM (400 MHz, DMSO-d ) : 9.71 (bs, IH), 9.34 (bs,
IH), 8.30 (d, /=8.4 Hz, IH), 8.05 (t, /=7.6Hz & 8Hz, 2H),
7.96 (d, =7.6 Hz, IH), 7.68-7.60 (m, 3H), 7.28 (d, =8Hz,
IH) , 7.16-7. 11 (m, 2H), 6.94 (s, IH), 6.88 (d, =8Hz, IH),
6.8 1 (d, /=6.8 Hz, IH), 6.59 (d, =7.6Hz, IH), 5.49-5.47
(m, IH), 4.65-4.60 (m, IH), 4.27- 4.23 (m, IH), 3.37 (m,
2H), 2.96 (s, 3H), 2.71 (s, 3H), 2.16 (s, 3H), 2.23-2. 16 (m,
IH), 2.02-2. 11 (m, IH), 1.75 (d, =6.8 Hz, 3H).
2-Methyl-5-((2 R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl) 450.7
amino) methyl)chroman-4-yl)benzamide h drochloride
NM (400MHz, DMSO-d ) : 9.80 (bs.lH), 9.44 (bs.lH),
8.28 (d, /=8.4 Hz, H), 8.05 (m, 3H), 7.68 (m, 3H), 7.61 (bs,
IH), 7.36 (bs, IH), 7.19-7.09 (m, 4H), 6.88 (d, =6.8 Hz
&0.8 Hz, IH), 6.8 1 (t, =6.8 Hz & 0.8 Hz, IH), 6.63 (d,
=7.6 Hz, IH), 5.49-5.48 (m, IH) , 4.64 (m, IH), 4.26-4.22
(m, IH), 3.32-3.3 1 (m, IH), 3.25-3.24 (m, IH), 2.34 (s,
3H), 2.21 -2. 17 (m, IH), 1.99-1 .91 (m, IH), 1.76 (d, =6.8
Hz, 3H).
N -Ethyl-N ,2-dimethyl-5-((2R ,4S)-2-((((R)- 1-(naphthalen- 1- 493.49
yl) ethyl)amino)methyl)chroman-4-yl)benzamide
hydrochloride
NM (400 MHz, DMSO-d ) : 9.71 (bs, IH), 9.35 (bs,
IH), 8.30 (d, /=8.4 Hz, IH), 8.05 (t, /=7.6Hz & 8Hz, 2H),
7.96 (d, =7.6 Hz, IH), 7.67-7.60 (m, 3H), 7.23-7.22 (m,
IH), 7.16-7.09 (m, 2H), 6.88 (d, =8Hz, 2H), 6.8 1 (t, J =7.6
Hz & 7.2Hz, IH) 6.59 (t, =6.4 Hz & 7.2 Hz ,1H), 5.49-
5.47 (m, IH), 4.62 (m, IH), 4.26-4.24 (m, IH), 3.39-3.37
(m, 2H),2.92 (s, 2H), 2.55 (s, 3H), 2.33 (s, 3H), 2.16 (m,
IH), 1.98 (m, IH), 1.75 (d, =6.8 Hz, 3H), 1.12 (t, J=6 Hz,
3H).
N,N -Diethyl-2-methyl-5-((2 R ,45)-2-((((R)- 1-(naphthalen- 1- 493.49
yl) ethyl) amino)methyl)chroman-4-yl)benzamide
hydrochloride
NM (400 MHz, DMSO-d ) : 9.69 (bs, IH), 9.35 (bs,
IH), 8.3 0 (d, /=8.4 Hz, IH), 8.06 (t, = 8 Hz, 2H), 7.94 (d,
/=7.2 Hz, IH), 7.67-7.60 (m, 3H), 7.23 (d, =8Hz, IH),
7.21-7. 12 (m, 2H) , 6.88 (d, =7.2 Hz, 2H), 6.8 1 (t, =7.6
Hz & 7.2 Hz, 1H), 6.58 (d, =7.6 Hz, 1H), 5.48 -5.47 (m,
1H) ,4.62 (m, 1H), 4.28-4.24 (m, 1H), 3.39 (m, 4H), 3.27
(m, 1H), 3.05 (m, 1H), 2.19 (m, 1H), 2.16 (s, 3H), 1.96-
1.92 (m, 1H), 1.75 (d, =6.8 Hz, 3H), 1.14 (m, 6H).
147 (2-Methyl-5-((2 R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl) 504.6
amino)methyl)chroman-4-yl)phenyl)(pyrrolidin- 1-yl)
methanone hydrochloride
NM (400 MHz, DMSO-d ) : 9.99 (bs, 1H), 9.58 (bs,
1H), 8.30 (d, /=8.4 Hz, 1H), 8.04-8.00 (m, 3H), 7.67-7.59
(m, 3H), 7.22 (d, = 8 Hz, 1H), 7.15-7.09 (m, 2H), 6.98 (s,
1H), 6.87 (d, =7.6 Hz,IH), 6.8 1 (d, J= 2 Hz, 1H), 6.58 (d,
=7.6 Hz,IH), 5.50-5.47 (m, 1H ), 4.67 (m, 1H), 4.25-4.21
(m, 1H), 3.43-3.37 (m, 2H), 3.35-3.28 (m, 2H), 3.06-2.94
(m, 2H), 2.23-2.22 (m, 1H), 2.19 (s, 3H), 1.94-1 .9 (m, 1H),
1.78 (d, =6.8 Hz, 3H), 1.73 (m, 4H).
The below Examples 148 to 165 given Table-1 1 can be prepared by following the
similar procedures as described herein above by taking appropriately substituted
intermediates.
Table-1 1:
Ex.No. Structure Ex.No. Structure

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+] . 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
NaCi 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 CaCi 2 in 20mM HEPES base buffer. The effectiveness of the compound to
modulate receptor activity is determined by calculating the EC50 responses for that
compound in an 8-point assay and plotted using GraphPad Prism 5.
The compounds prepared were tested using the above assay procedure and the results
obtained are given below. The EC50 (nM) values of few representative compounds are set
forth in Table- 12.
The in-vitro activity data has been given in Table-12 for representative compounds.
Table- 12:
Thus, the above in-vitro assay method shows that the compounds of the invention were
found to exhibit agonistic activity for CaSR, thereby showing utility for treating diseases,
disorders associated with the modulation of CaSR.
In-vivo activity in CKD Wistar rats:
Animals were fed with 0.75% adenine diet for a period of 28 days for development of
chronic kidney disease (CKD). After measurement of plasma PTH on day 28, animals
were randomized based on plasma PTH (intact PTH) levels before using them for the
study. Overnight fasted animals were bled retro-orbitally to collect basal blood sample
(0.5 ml). Rats were dosed orally with vehicle and with test compounds where they
formulated in PEG 300:PG:Captisol (20:15:65). Six to eight animals were used in each
group then compounds of the invention were administered at 1 mg/kg dose. Post 2 h oral
dosing animals were fed with feed and water ad libitum. Post treatment blood samples
were collected by retro-orbital bleeding under light ether anesthesia at different time
points for plasma PTH estimation. Plasma PTH was measured using sandwich ELISA
kits (Immunotopics, USA). Percentage suppression of plasma PTH was calculated with
respect to individual basal untreated values by using the following Formula
Pre-treated individual value - Post-treated individual
Percent suppression = X 100
Pre-treated individual value
Compounds of the invention for example, Example No. 67, 72b, 84b, 89b, 119b, 124
were found to suppress plasma PTH levels greater than 80%.
Thus, the above in-vivo method shows that the compounds of the invention were found to
exhibit suppress plasma PTH levels, thereby showing utility for treating diseases,
disorders associated with the modulation of CaSR.
All patents, patent applications and other publications cited in this application are
hereby incorporated by reference in their entirety for all purposes to the same extent as if
each individual patent, patent application or publication were so individually denoted.
Although certain embodiments and examples have been described in detail above,
those having ordinary skill in the art will clearly understand that many modifications are
possible in the embodiments and examples without departing from the teachings thereof.
All such modifications are intended to be encompassed within the below claims of the
invention.
1. A compound of Formula (I)
wherein,
Ra is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano,
substituted or unsubstituted cycloalkyl and substituted or unsubstituted haloalkyl;
Rb, which may be same or different at each occurrence, is independently selected
from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted
cycloalkyl and substituted or unsubstituted haloalkyl;
R, which may be same or different at each occurrence, is independently selected
from halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted
haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted cycloalkyl, OR , nitro, cyano, -C(0)OR 6, -(CH2)r-C(0)OR 6, -
0-C(0)OR , -0(CH 2) -C(0)OR , -NR7R , -(CH2) NR7R -, -C(0)R 9, -C(0)NR 7R , -
(CH2) -C(0)NR 7 R8, -NR7C(0)R , -S(O)0-2R6, -S(0) 2NR7R , and -NR7S(0) 2R ;
X is selected from a bond, -(CRcR d)r-, -0-, -NR7-, -NR7(CRcRd)r-, -0(CR cRd)r-,
-C(0)NR 7-, -C(0)NR 7(CRcRd)r-, -(CRcRd)rNR7(CRcRd)r-, -(CRcR d),cycloalkylene-,
cycloalkylene, -cycloalkylene(CR cRd)r- and -O-cycloalkylene where cycloalkylene may
be substituted or unsubstituted;
Rc and Rd, which may be same or different at each occurrence, are independently
selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted
alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl;
or Rc and Rd, together with the carbon atom to which they are attached, may form a
substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring;
Z is -OR6 or-NRioRii;
Ri, which may be same or different at each occurrence, is independently selected
from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted
haloalkyl, substituted or unsubstituted cycloalkyl, -OR6, -C(0 )Rc, -NR7R8, -
(CH2) NR7R -, -(CH2) -C(0 )OR , -0 -C(0)OR , -0(CH 2) -C(0 )OR , -C(0)NR 7R , -
(CH2) -C(0 )NR 7 R8, -NR 7C(0)R , -S(O) 0-2R7, - S(0 )2NR7R and -NR 7S(0 )2R ;
R2 is selected from substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl and substituted or unsubstituted heterocyclyl;
R3 and R4 may be same or different and are independently selected from hydrogen,
halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted haloalkoxy and substituted or
unsubstituted cycloalkyl;
R is substituted or unsubstituted alkyl;
R6, which may be same or different at each occurrence, is independently selected
from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted
or unsubstituted aryl;
R and R , which may be same or different at each occurrence, are independently
selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or
unsubstituted heterocyclylalkyl; or R and R together with the nitrogen atom to which
they are attached, may form a substituted or unsubstituted, saturated or unsaturated 3 to
12 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double
bonds;
at each occurrence, R is substituted or unsubstituted alkyl or substituted or
unsubstituted aryl;
Rio and may be same or different and are independently selected from
hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, -(CRcR ) -C(0)OR 6, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted
or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted
or unsubstituted heterocyclylalkyl; or Ri0 and R together with the nitrogen atom to
which they are attached, may form a substituted or unsubstituted, saturated or unsaturated
3 to 12 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two
double bonds;
'n' is an integer ranging from 1 to 3, both inclusive;
'm' is an integer ranging from 0 to 3, both inclusive;
'p' is an integer ranging from 0 to 4, both inclusive;
'q' is an integer ranging from 0 to 3, both inclusive; and
'r' is an integer ranging from 1 to 3, both inclusive;
or its pharmaceutically acceptable salt thereof.
The compound of claim 1, having the Formula (II)
(II)
or its pharmaceutically acceptable salt thereof;
wherein,
R2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
R, Ri, X, Z, 'p' and 'q' are as defined in claim 1.
The compound of cl
(III)
or its pharmaceutically acceptable salt thereof;
wherein,
R2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
R, Ri, X, Z, 'p' and 'q' are as defined in claim 1.
4. The compound of claim 1, having the Formula (IV):
(IV)
or its pharmaceutically acceptable salt thereof;
wherein,
R2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
R, Ri, X, Z, 'p' and 'q' are as defined in claim 1.
The compound of claim 1, having the Formula (V):
(V)
or its pharmaceutically acceptable salt thereof;
wherein,
R2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
Ri, X, Z, 'n', and 'q' are as defined in claim 1.
6. The compound of claim 1, wherein 'm' is 0 or 1.
7. The compound of claim 1, wherein 'p' is 0 or 1.
8. The compound of claim 1, wherein 'q' is 0, 1 or 2.
9. The compound of claim 1 to claim 5, wherein Ri is selected from halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl,
substituted or unsubstituted cycloalkyl, cyano, -OR , -C(0)alkyl, wherein R is
hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted
haloalkyl, or substituted or unsubstituted cycloalkyl; and 'q' is 0, 1, or 2.
10. The compound of claim 1, wherein R2 is substituted or unsubstituted aryl wherein
the aryl is substituted or unsubstituted phenyl or substituted or unsubstituted
naphthyl.
11. The compound of claim 2 to 5 and claim 10, wherein the substituent(s) on phenyl
or naphthyl may be one or more and are independently selected from halogen,
hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl,
and substituted or unsubstituted alkoxy.
12. The compound of claim 1 to claim 5, wherein X is selected from a bond, -
(CR Rd) -, -0-, -NR 7-, -NR 7(CR Rd) -, -0(CR Rd) -, -C(0)NR 7-, -
C(0)NR 7(CR Rd) -, -(CR Rd) NR7(CR Rd) -, -(CR Rd) cycloalkylene-,
cycloalkylene, -cycloalkylene(CRcRd)r- and -O-cycloalkylene where
cycloalkylene may be substituted or unsubstituted; R7 is hydrogen or substituted
or unsubstituted alkyl; c and R are hydrogen or alkyl and 'r' is 1, 2 or 3.
13. The compound of claim 1 to claim 5, wherein Z is -OR wherein R is selected
from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted
haloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted
arylalkyl.
14. The compound of claim 1 to claim 5, wherein Z is NRioRn wherein Ri0 and R
may be same or different and are independently selected from hydrogen,
substituted or unsubstituted alkyl, -(CR cRd)r-C(0)OH, -(CR cRd)r-C(0)0-arkyl,
substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or
substituted or unsubstituted arylalkyl; or Ri0 and R together with the nitrogen
atom to which they are attached, may form a saturated or unsaturated 3 to 12
membered cyclic ring, where the unsaturated cyclic ring may have one or two
double bonds; wherein R and Rd are hydrogen or substituted or unsubstituted
alkyl and 'r' is 1, 2 or 3.
15. The compound of claim 1, wherein Ra is hydrogen; R is hydrogen; Ri is selected
from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted
haloalkyl, substituted or unsubstituted cycloalkyl, cyano, -OR 6, -C(0)alkyl
wherein R is hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted haloalkyl, or substituted or unsubstituted cycloalkyl; 'q' is 0, 1, or 2;
R2 is substituted or unsubstituted aryl; R3 is hydrogen; R4 is hydrogen; R is
substituted or unsubstituted alkyl; X is selected from a bond, -(CR cRd)r, -0-, -
NR7-, -NR7(CRcRd) -, -0(CRcRd) -, -C(0)NR 7-, -C(0 )NR7(CRcRd) - wherein R7 is
hydrogen or substituted or unsubstituted alkyl, R and Rd are hydrogen or
substituted or unsubstituted alkyl, 'r' is 1, 2, or 3; Z is -OR or NR10R11 wherein
R is selected from hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted haloalkyl, substituted or unsubstituted aryl or substituted or
unsubstituted arylalkyl; Ri0 and R may be same or different and are
independently selected from hydrogen, substituted or unsubstituted alkyl, -
(CR cRd)r-C(0)OH, -(CR cRd)r-C(0)0-alkyl, substituted or unsubstituted cycloalkyl
or R10 and together may form a substituted or unsubstituted, saturated or
unsaturated 3 to 12 membered cyclic ring, where the unsaturated cyclic ring may
have one or two double bonds, 'n' is 1, 2 or 3; 'm' is 0 or 1; and 'p' is 0;
or its pharmaceutically acceptable salt thereof.
16. The compound of claim 5, wherein Ri is selected from halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or
unsubstituted cycloalkyl, cyano, -OR6, -C(0)alkyl wherein R is hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, or
substituted or unsubstituted cycloalkyl; 'q' is 0, 1, or 2; R2 is substituted or
unsubstituted aryl; X is selected from a bond, -(CRcR ) -, -0-, -NR7-, -
NR CRcRd , -0(CR cRd)r-, -C(0)NR 7-, -C(0)NR 7(CRcRd) - wherein R7 is
hydrogen or substituted or unsubstituted alkyl, R and R< are hydrogen or
substituted or unsubstituted alkyl, 'r' is 1, 2, or 3; Z is -OR or NR10R11 wherein
R is selected from hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted haloalkyl, substituted or unsubstituted aryl or substituted or
unsubstituted arylalkyl; Ri0 and may be same or different and are
independently selected from hydrogen, substituted or unsubstituted alkyl, -
(CRcRd)r-C(0)OH, -(CRcRd)r-C(0)0-alkyl, substituted or unsubstituted cycloalkyl
or Rio and together may form a substituted or unsubstituted, saturated or
unsaturated 3 to 12 membered cyclic ring, where the unsaturated cyclic ring may
have one or two double bonds; and 'n' is 1, 2 or 3;
or its pharmaceutically acceptable salt thereof.
17. The compound of claim 1, which is selected from:
Methyl 2-fluoro-5-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-fluoro-5-((2 R ,45)-2-((((R )- l-(naphthalen-l-yl)ethyl)amino)methyl)chroman
-4-yl)benzoate;
Methyl-3-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)chroman-4-yl)
benzoate;
Methyl 2-methyl-3-((2 R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate;
Methyl 3-methyl-5-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 4-methyl-3-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-ethyl-5-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-
4-yl)benzoate;
Methyl 2-ethyl-5-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)chroman-
4-yl)benzoate;
Methyl 2-isopropyl-5-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate;
Methyl 2-cyclopropyl-5-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino) methyl)
chroman-4-yl)benzoate ;
Methyl 2-cyclopropyl-5-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2,6-difluoro-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 4-fluoro-2-methyl-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)
methyl)chroman-4-yl)benzoate;
Methyl 4-fluoro-2-methyl-3-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)
methyl)chroman-4-yl)benzoate;
Methyl 2,3-dimethyl-5-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 5-((2R ,45)-2-((((R )-l -(naphthalen- l-yl)ethyl)amino)methyl)chroman-4-yl)-2-
(trifluoromethyl)benzoate;
Methyl 2-methyl-5-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-methyl-5-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-fluoro-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman
-4-yl)benzoate;
Methyl 3-fluoro-5-((2R ,45)-2-((((R )- l-(naphthalen-l-yl)ethyl)amino)methyl)chroman
-4-yl)benzoate;
Methyl 4-fluoro-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman
-4-yl)benzoate;
Methyl 2-methoxy-5-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-methoxy-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-methoxy-3-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate;
Methyl 4-methoxy-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-(2-methyl-5-((2R ,4 -2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-(3-methyl-5-((2R ,4 -2-((((R )-l -(naphthalen- l-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-(2-fluoro-5-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-(2-fluoro-5-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate;
Methyl 2-(2-fluoro-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-(3-fluoro-5-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-(3-fluoro-5-((2R ,4S)-2-((((R )-l -(naphthalen- l-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-(4-fluoro-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-methyl-2-(3-((2R ,4 -2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)propanoate ;
Methyl 4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)benzoate;
Methyl 4-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)benzoate;
Methyl 2-methyl-4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-methyl-4-((2R ,45)-2-((((R )-l-(naphthalen- l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-yl)-2-
(trifluoromethyl)benzoate;
Methyl 4-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-yl)-2-
(trifluoromethyl)benzoate;
Methyl 2,6-difluoro-4-((2R ,45)-2-((((R )- l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 3-methoxy-4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;m
Methyl 3-methoxy-4-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 3-fluoro-4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate;
Methyl 2-fluoro-4-((2R ,45)-2-((((R )- l-(naphthalen-l-yl)ethyl)amino)methyl)chroman
-4-yl)benzoate;
Methyl 2-(4-((2R,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)phenoxy)acetate ;
Methyl 2-(4-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)phenoxy)acetate ;
Methyl 2-(2-fluoro-4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate ;
Methyl 2-(2-fluoro-4-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenoxy)acetate;
Methyl 2-(4-((2R ,4R )-2-((((R )- l-(naphthalen-l-yl)ethyl)amino)methyl)chroman-4-
yl)phenyl)acetate;
Methyl 2-(4-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)phenyl)acetate;
Methyl 2-methyl-2-(4-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenyl)propanoate ;
Methyl 2-methyl-2-(4-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)phenyl)propanoate ;
Methyl 3-methyl-4-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate;
Methyl 2-fluoro-5-((25,4R )-2-((((R )- l-(naphthalen-l-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 3-((25,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)benzoate;
Methyl 2-methyl-5-((25,4R )-2-((((R )-l-(naphthalen-l -yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-methyl-5-((25,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)
chroman-4-yl)benzoate ;
Methyl 2-(4-((25,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl)amino)methyl)chroman-4-
yl)phenoxy)acetate;
Methyl 2-(4-((25,45)-2-((((R )-l -(naphthalen-l-yl)ethyl)amino)methyl)chroman-4-
yl)phenoxy)acetate ;
Methyl 5-((2R ,4R )-2-((((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)methyl)chroman-
4-yl)-2-methylbenzoate ;
Methyl 5-((2R ,45)-2-((((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)methyl)chroman-
4-yl)-2-methylbenzoate ;
Methyl 3-((2R ,4R )-2-((((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)methyl)chroman-
4-yl)-2-methoxybenzoate ;
Methyl 3-((2R ,45)-2-((((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)methyl)chroman-
4-yl)-2-methoxybenzoate;
Methyl 4-((2R )-2-((((R)- 1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-
4-yl)-2-methylbenzoate ;
Methyl 3-((2R )-2-((((R)- 1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-
4-yl)-2-methylbenzoate ;
Methyl 5-((2R )-2-((((R)- 1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-
4-yl)-2-methylbenzoate ;
Methyl 3-((2R )-2-((((R)- 1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-
4-yl)-5-methylbenzoate ;
Methyl 3-((2R )-2-((((R)- 1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-
4-yl)-4-methylbenzoate;
Methyl 2-fluoro-5-((25,4R )-2-(2-(((R)- 1-(naphthalen- 1-yl)ethyl)amino)ethyl)
chroman-4-yl)benzoate ;
Methyl 2-fluoro-5-((2R ,45)-2-(2-(((R)- 1-(naphthalen- 1-yl)ethyl)amino)ethyl)
chroman-4-yl)benzoate ;
Methyl 2-methyl-5-((25,4R )-2-(2-(((R)- 1-(naphthalen- 1-yl)ethyl)amino)ethyl)
chroman-4-yl)benzoate ;
Methyl 2-methyl-5-((2R ,45)-2-(2-(((R)- 1-(naphthalen- 1-yl)ethyl)amino)ethyl)
chroman-4-yl)benzoate ;
Methyl 2-methoxy-3-((2R ,4R )-2-(2-(((R )-l -(naphthalen- l-yl)ethyl)amino)ethyl)
chroman-4-yl)benzoate;
Methyl 5-((25,4R )-2-(2-(((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)ethyl)chroman-
4-yl)-2-methylbenzoate ;
Methyl 5-((2R ,45)-2-(2-(((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)ethyl)chroman-
4-yl)-2-methylbenzoate ;
Methyl 5-((25,4R )-2-(2-(((R )-l-(4-fluoro-3-methoxyphenyl)ethyl)amino)ethyl)
chroman-4-yl)-2-methylbenzoate ;
Methyl 5-((2R ,45)-2-(2-(((R )-l-(4-fluoro-3-methoxyphenyl)ethyl)amino)ethyl)
hroman-4-yl)-2-methylbenzoate;
Methyl 2-fluoro-5-((25,45)-2-(3 -(((R )-l-(naphthalen-l-yl)ethyl)amino)propyl)
chroman-4-yl)benzoate;
Methyl 2-fluoro-5-((2R ,4R )-2-(3-(((R )-l -(naphthalen- l-yl)ethyl)amino)propyl)
chroman-4-yl)benzoate ;
Methyl 2-methyl-5-((25,45)-2-(3 -(((R )-l-(naphthalen-l-yl)ethyl)amino)propyl)
chroman-4-yl)benzoate ;
Methyl 2-methyl-5-((2R ,4R )-2-(3 -(((R )-l -(naphthalen-l-yl)ethyl)amino)propyl)
chroman-4-yl)benzoate ;
Methyl 5-((25,45)-2-(3-(((R )-l-(4-fluoro-3-methoxyphenyl)ethyl)amino)propyl)
chroman-4-yl)-2-methylbenzoate ;
Methyl 4-((25,45)-2-(3-(((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)propyl)
chroman-4-yl)-3-methylbenzoate ;
Methyl 4-((25,45)-2-(3-(((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)propyl)
chroman-4-yl)benzoate ;
Methyl 5-((25,45)-2-(3-(((R)- 1-(4-fluoronaphthalen- 1-yl)ethyl)amino)propyl)
chroman-4-yl)-2-methylbenzoate ;
2, 6-Dimethyl-3-((2R , 45)-2-((((R )-l-(naphthalen-l-yl) ethyl) amino) methyl)
chroman-4-yl)benzoic acid hydrochloride;
2,6-Dimethyl-3-((2R ,45)-2-(2-(((R )-l-(naphthalen-l-yl)ethyl) amino) ethyl)chroman-
4-yl) benzoic acid hydrochloride;
2,6-Dimethyl-3-((2R ,4R )-2-(3-(((R )-l-(naphthalen-l-yl)ethyl) amino) propyl)
chroman-4-yl)benzoic acid hydrochloride;
2,6-Dimethyl-3-((25,45)-2-(3 -(((R )-l-(naphthalen-l-yl)ethyl) amino) propyl)
chroman-4-yl)benzoic acid hydrochloride;
3-((25,45)-2-(3-(((R )-l-(4-Fluoro-3-methoxyphenyl)ethyl) amino) propyl)chroman-4-
yl)-2,6-dimethylbenzoic acid hydrochloride;
2-Fluoro-5-((2R ,4R )-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Fluoro-5-((2R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl)amino)methyl)chroman-4-
yl)benzoic acid hydrochloride;
3-((2R ,45)-2-((((R )-l-(Naphthalen-l-yl)ethyl)amino) methyl) chroman-4-yl)benzoic
acid hydrochloride;
2-Methyl-3-((2R ,45)-2-((((R )- l -(naphthalen- l-yl)ethyl) amino)methyl)chroman-4-
yl)benzoic acid hydrochloride;
3-Methyl-5-((2R ,45)-2-((((R )- l -(naphthalen- l-yl)ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
4-Methyl-3-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Ethyl-5-((2R ,4R )-2-((((R )-l-(naphthalen-l-yl)ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Ethyl-5-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino) methyl)chroman-4-yl)
benzoic acid hydrochloride;
2-Isopropyl-5-((2R ,45)-2-((((R )-l -(naphthalen- l-yl)ethyl) amino) methyl) chroman-4-
yl)benzoic acid hydrochloride;
2-Cyclopropyl-5-((2 R ,4R )-2-((((R )-l-(naphthalen-l-yl)ethyl) amino)methyl)
chroman-4-yl)benzoic acid hydrochloride;
2-Cyclopropyl-5-((2 R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl) amino)methyl) chroman-
4-yl)benzoic acid hydrochloride;
2,6-Difluoro-3-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino)methyl) chroman-
4-yl)benzoic acid hydrochloride;
4-Fluoro-2-methyl-3-((2 R ,45)-2-((((R)- 1-(naphthalen- 1-yl) ethyl) amino)methyl)
chroman-4-yl)benzoic acid hydrochloride;
4-Fluoro-2-methyl-3-((2 R ,4R )-2-((((R )- l-(naphthalen-l-yl) ethyl) amino)methyl)
chroman-4-yl)benzoic acid hydrochloride;
2,3-Dimethyl-5-((2 R ,45)-2-((((R )-l -(naphthalen- l-yl)ethyl) amino)methyl)chroman-
4-yl)benzoic acid hydrochloride;
5-((2R ,45)-2-((((R )-l -(Naphthalen- l-yl)ethyl)amino) methyl) chroman-4-yl)-2-
(trifluoromethyl)benzoic acid hydrochloride;
2-Methyl-5-((2R ,4R )-2-((((R )-l -(naphthalen- 1-yl) ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methyl-5-((2R ,45)-2-((((R )- l -(naphthalen- l-yl)ethyl)amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Fluoro-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl) ethyl)amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
3-Fluoro-5-((2R ,4S)-2-((((R )-l-(naphthalen-l-yl) ethyl)amino) methyl) chroman-4-
yl)benzoic acid hydrochloride;
4-Fluoro-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl) ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methoxy-5-((2R ,45)-2-((((R )-l -(naphthalen- 1-yl) ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methoxy-3-((2R ,45)-2-((((R )-l -(naphthalen- l-yl)ethyl) amino)methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methoxy-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino)methyl) chroman-4-
yl)benzoic acid hydrochloride;
4-Methoxy-3-((2R ,4R )-2-((((R )-l -(naphthalen- l-yl)ethyl) amino) methyl) chroman-4-
yl) benzoic acid hydrochloride;
2-(2-Methyl-5-((2R ,4 -2-((((R )- l -(naphthalen- l-yl)ethyl) amino)methyl) chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(3-Methyl-5-((2R ,4 -2-((((R )- l -(naphthalen- l-yl)ethyl) amino) methyl) chroman-
4-yl)phenoxy)acetic acid hydrochloride;
2-(2-Fluoro-5-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino)methyl) chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(2-Fluoro-5-((2R ,45)-2-((((R )-l -(naphthalen- l-yl) ethyl) amino)methyl) chroman-4-
yl) phenoxy) acetic acid hydrochloride;
2-(2-Fluoro-3-((2R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino)methyl) chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(3-Fluoro-5-((2R ,4R )-2-((((R )-l-(naphthalen-l-yl) ethyl) amino)methyl) chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(3-Fluoro-5-((2R ,45)-2-((((R )-l -(naphthalen- l-yl) ethyl) amino) methyl) chroman-
4-yl) phenoxy)acetic acid hydrochloride;
2-(4-Fluoro-3-((2R ,4R )-2-((((R )-l-(naphthalen-l-yl) ethyl) amino) methyl)chroman-4-
yl) phenoxy)acetic acid hydrochloride;
2-Methyl-2-(3-((2 R ,4 -2-((((R )- l -(naphthalen- l-yl)ethyl) amino)methyl)chroman-4-
yl)phenoxy)propanoic acid hydrochloride;
4-((2R ,4R )-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) methyl) chroman-4-yl)benzoic
acid hydrochloride;
4-((2R ,45)-2-((((R)- 1-(Naphthalen- 1-yl)ethyl) amino) methyl) chroman-4-yl)benzoic
acid hydrochloride;
2-Methyl-4-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methyl-4-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino) methyl)chroman-4-yl)
benzoic acid hydrochloride;
4-((2R ,4R )-2-((((R )- l -(Naphthalen- l-yl)ethyl)amino) methyl) chroman-4-yl)-2-
(trifluoromethyl)benzoic acid hydrochloride;
4-((2R ,45)-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) methyl) chroman-4-yl)-2-
(trifluoromethyl)benzoic acid hydrochloride;
2,6-Difluoro-4-((2 R ,4S)-2-((((R)- 1-(naphthalen- 1-yl) ethyl) amino)methyl) chroman-
4-yl)benzoic acid hydrochloride;
3-Methoxy-4-((2 R ,4R )-2-((((R )-l -(naphthalen- l-yl)ethyl) amino) methyl) chroman-4-
yl)benzoic acid hydrochloride;
3-Methoxy-4-((2 R ,4S)-2-((((R )-l -(naphthalen- 1-yl) ethyl) amino)methyl) chroman-4-
yl)benzoic acid hydrochloride;
3-Fluoro-4-((2R ,4R )-2-((((R )-l -(naphthalen- 1-yl) ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Fluoro-4-((2 R ,45)-2-((((R )-l-(naphthalen-l-yl)ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-(4-((2R ,4R )-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) methyl)chroman-4-yl)
phenoxy)acetic acid hydrochloride;
2-(4-((2R ,45)-2-((((R)- 1-(Naphthalen- 1-yl)ethyl) amino)methyl) chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(2-Fluoro-4-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl) ethyl) amino)methyl)chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(2-Fluoro-4-((2 R ,4S)-2-((((R)- 1-(naphthalen- 1-yl) ethyl) amino)methyl)chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(4-((2R ,4R )-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) methyl)chroman-4-yl)
phenyl)acetic acid hydrochloride;
2-(4-((2R ,45)-2-((((R)- 1-(Naphthalen- 1-yl)ethyl) amino) methyl)chroman-4-yl)
phenyl)acetic acid hydrochloride;
2-Methyl-2-(4-((2 R ,4R )-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino)methyl)chroman-4-
yl)phenyl)propanoic acid hydrochloride;
2-Methyl-2-(4-((2 R ,4 -2-((((R )- l -(naphthalen- 1-yl) ethyl) amino)methyl)chroman-4-
yl) phenyl) propanoic acid hydrochloride;
3-Methyl-4-((2R ,45)-2-((((R )- l -(naphthalen- l-yl)ethyl)amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Fluoro-5-((25,4 R )-2-((((R )-l-(naphthalen-l-yl)ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
3-((2S,4R )-2-((((R)- 1-(Naphthalen- 1-yl)ethyl) amino) methyl) chroman-4-yl)benzoic
acid hydrochloride;
2-Methyl-5-((25,4 R )-2-((((R )- l -(naphthalen- 1-yl) ethyl) amino) methyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methyl-5-((25,45)-2 -((((R )-l -(naphthalen- 1-yl) ethyl)amino) methyl) chroman-4-
yl)benzoic acid hydrochloride;
2-(4-((25,4R )-2-((((R)- 1-(Naphthalen- 1-yl)ethyl)amino) methyl) chroman-4-
yl)phenoxy)acetic acid hydrochloride;
2-(4-((25,45)-2 -((((R)- 1-(Naphthalen- 1-yl)ethyl)amino)methyl) chroman-4-yl)
phenoxy)acetic acid hydrochloride;
4-((2R ,45)-2-((((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl) amino) methyl)chroman-4-
yl)-2-methylbenzoic acid hydrochloride;
3-((2R ,45)-2-((((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl) amino)methyl)chroman-4-
yl)-2-methylbenzoic acid hydrochloride;
5-((2R ,45)-2-((((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl) amino) methyl)chroman-4-
yl)-2-methyl benzoic acid hydrochloride;
3-((2R ,4S)-2-((((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl) amino)methyl)chroman-4-
yl)-5-methylbenzoic acid hydrochloride;
3-((2R ,4S)-2-((((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl) amino)methyl)chroman-4-
yl)-4-methylbenzoic acid hydrochloride;
5-((2R ,4R )-2-((((R)- 1-(4-Fluoronaphthalen- 1-yl) ethyl) amino) methyl)chroman-4-yl)-
2-methyl benzoic acid hydrochloride;
5-((2R ,4 )-2-((((R )-l -(4-Fluoronaphthalen- 1-yl) ethyl) amino) methyl)chroman-4-
yl)-2-methyl benzoic acid hydrochloride;
3-((2R ,45)-2-((((R )-l-(4-Fluoronaphthalen- l-yl)ethyl)amino) methyl)chroman-4-yl)-
2-methoxybenzoic acid hydrochloride;
3-((2R ,4R )-2-((((R)- 1-(4-Fluoronaphthalen- 1-yl)ethyl) amino) methyl)chroman-4-yl)-
2-methoxybenzoic acid hydrochloride;
2-Fluoro-5-((2S, 4R )-2-(2 -(((R )-l -(naphthalen- 1-yl) ethyl) amino) ethyl) chroman-4-
yl) benzoic acid hydrochloride;
2-Fluoro-5-((2R ,45)-2-(2 -(((R )-l -(naphthalen- l-yl)ethyl) amino) ethyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methyl-5-((25,4 R )-2-(2 -(((R )-l -(naphthalen- l-yl)ethyl) amino)ethyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methyl-5-((2 R ,45)-2-(2-(((R )-l -(naphthalen- l-yl)ethyl) amino)ethyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methoxy-3-((2 R ,4R )-2-(2 -(((R)- 1-(naphthalen- 1-yl)ethyl) amino)ethyl)chroman-4-
yl)benzoic acid hydrochloride;
5-((25,4R )-2-(2 -(((R )-l-(4-Huoronaphthalen-l-yl)ethyl) amino) ethyl)chroman-4-yl)-
2-methylbenzoic acid hydrochloride;
5-((2R ,45)-2-(2-(((R )-l-(4-Huoronaphthalen-l-yl)ethyl) amino) ethyl)chroman-4-yl)-
2-methylbenzoic acid hydrochloride;
5-((25,4R )-2-(2 -(((R )-l-(4-Ruoro-3-methoxy phenyl) ethyl) amino) ethyl) chroman-4-
yl)-2-methylbenzoic acid hydrochloride;
5-((2R ,45)-2-(2-(((R )-l-(4-Ruoro-3-methoxy phenyl)ethyl) amino)ethyl)chroman-4-
yl)-2-methylbenzoic acid hydrochloride;
2-Fluoro-5-((2S, 45)-2-(3 -(((R )-l -(naphthalen- 1-yl) ethyl) amino) propyl) chroman-4-
yl) benzoic acid hydrochloride;
2-Fluoro-5-((2 R ,4R )-2-(3 -(((R )-l -(naphthalen- 1-yl) ethyl) amino) propyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methyl-5-((25,45)-2-(3 -(((R )-l -(naphthalen- 1-yl) ethyl) amino) propyl)chroman-4-
yl)benzoic acid hydrochloride;
2-Methyl-5-((2 R ,4R )-2-(3 -(((R )-l-(naphthalen- l-yl) ethyl) amino) propyl)chroman-4-
yl)benzoic acid hydrochloride;
5-((25,45)-2-(3 -(((R )-l-(4-Fluoro-3-methoxyphenyl) ethyl) amino)propyl)chroman-4-
yl)-2-methylbenzoic acid hydrochloride;
4-((25,45)-2-(3 -(((R)- 1-(4-Fluoronaphthalen- 1-yl)ethyl) amino) propyl)chroman-4-
yl)-3-methylbenzoic acid hydrochloride;
4-((25,45)-2-(3 -(((R)- 1-(4-Fluoronaphthalen- 1-yl)ethyl) amino) propyl)chroman-4-
yl)benzoic acid hydrochloride;
5-((25,45)-2-(3 -(((R )-l -(4-Fluoronaphthalen- l-yl)ethyl) amino) propyl)chroman-4-
yl)-2-methylbenzoic acid hydrochloride;
Methyl 2-(3-((2R , 45)-2-((((R )-l -(naphthalen- 1-yl) ethyl) amino) methyl) chroman-4-
yl) benzamido) acetate;
Methyl 2-(2-methyl-5-((2 R , 45)-2-((((R )- l -(naphthalen- 1-yl) ethyl) amino) methyl)
chroman-4-yl) benzamido) acetate;
2-(3-((2R , 45)-2-((((R )-l -(Naphthalen- 1-yl) ethyl) amino) methyl) chroman-4-yl)
benzamido) acetic acid hydrochloride;
2-(2-Methyl-5-((2 R ,4 -2-((((R )- l -(naphthalen- 1-yl) ethyl) amino) methyl) chroman-
4yl) benzamido) acetic acid hydrochloride;
N , 2-Dimethyl-5-((2 R , 45)-2-((((R )- l -(naphthalen- 1-yl) ethyl) amino) methyl)
chroman-4-yl) benzamide hydrochloride;
N,N ,2-Trimethyl-5-((2R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl)
amino)methyl)chroman-4-yl)benzamide hydrochloride ;
2-Methyl-5-((2 R ,45)-2-((((R)- 1-(naphthalen- 1-yl)ethyl) amino) methyl)chroman-4-
yl)benzamide hydrochloride;
N -Ethyl-N,2-dimethyl-5-((2R ,45)-2-((((R )-l -(naphthalen-l-yl) ethyl)amino)methyl)
chroman-4-yl)benzamide hydrochloride ;
N,N -Diethyl-2-methyl-5-((2R ,45)-2-((((R )-l -(naphthalen-l-yl) ethyl) amino)
methyl)chroman-4-yl)benzamide hydrochloride; and
(2-Methyl-5-((2R ,45)-2-((((R )- l-(naphthalen-l-yl)ethyl) amino)methyl)chroman-4-
yl)phenyl)(pyrrolidin- 1-yl)methanone hydrochloride;
or its pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising one or more compounds of Formula
(I) according to claim 1, and one or more pharmaceutically acceptable excipients.
19. A method of treating, managing and/or lessening the 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 of
claim 1 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.
2 1. 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 gastro-intestinal tract by
augmenting gastric acidity.
23. Use of a compound for the manufacture of a medicament for treating, managing
and/or lessening the 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 of claim 1 or a pharmaceutically
acceptable salt thereof.
24. The use of claim 23, 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.
25. The use of claim 24, wherein hyperparathyroidism is primary
hyperparathyroidism, secondary hyperparathyroidism or tertiary
hyperparathyroidism.
26. The use of claim 23, 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 gastro-intestinal tract by
augmenting gastric acidity.
27. A process for the prep mula (lb):
(lb)
wherein X, R, i, R2, R 'm' , 'h' , 'p' and 'q' are as described in claim-1 ,
the process comprising the steps of:
a) oxidizing a compound of Formula (15) by using suitable oxidation agents to
give compound of Formula (16) in suitable solvent(s);
b) converting a compound of Formula (16) to compound of Formula (17) using
PhNTf2 (N -phenylbis(trifluoromethanesulfonimide) in presence of KHMDS
(potassium hexamethyldisilazide) ;
c) coupling of compound of Formula (17) with suitable aryl boronic acid or aryl
boronic ester by following Suzuki coupling reaction to give compound of
Formula ( 18) where Z is -OR and R is alkyl or benzyl;
( 18 )
d) when Z is O-alkyl, then reducing the compound of Formula (18) with
hydrogen over Palladium-Carbon to give ester compound of Formula (19)
where Z is -O-alkyl;
e) converting the compound of Formula (19) obtained in step d) to the compound
of Formula (la);
(19) (la)
f) hydrolyzing the ester group in compound of Formula (la) to corresponding
acid compound using suitable base and in suitable solvents;
g) converting the compound obtained in step f) to its hydrochloride salt having
Formula (lb);
(la) (lb)
h) when Z is O-benzyl in compound of Formula (18), then reducing the
compound of Formula (18) with hydrogen over Palladium-Carbon to give acid
compound of Formula (19) where Z is OH;
i) converting the compound of Formula (19) obtained in step h) to the compound
of Formula (lb);
28. A process for the preparation of compound of Formula (Id):
wherein X, R, i, R2, R5, R7, Rc, R 'm', 'n', 'p', 'q' and 'r' are as described in
claim 1, the process comprising the steps of:
a) coupling of acid compound of Formula (lb) with suitable amines using
suitable amide coupling reagents to give compound of Formula (Ic);
when R is alkyl/benzyl etc.
b) hydrolyzing the amido ester group, if the compound of Formula (Ic) is an
ester, to corresponding acid compound of Formula (Id) using suitable reagent
and solvents.
when R is alkyl/benzyl etc.,