OA17086A

OA17086A - Substituted chroman compounds as calcium sensing receptor modulators.

Info

Publication number: OA17086A
Application number: OA1201400388
Authority: OA
Inventors: Manojkumar Ramprasad SHUKLA; Ankush Gangaram Sarde; Rajeshkumar Maganlal Loriya; VipuI Dilip PACHPUTE; Navnath Bajirao WALKE; Talha Hussain KHAN; Sanjeev Anant Kulkarni; Venkata P. Palle; Rajender Kumar Kamboj
Original assignee: Lupin Limited
Priority date: 2012-02-24
Filing date: 2013-02-22
Publication date: 2016-03-23

Abstract

The present invention provides calcium sensing receptor modulators (CaSR). In particular, the compounds described herein are useful for treating, managing, and/or lessening the severity of diseases, disorders, syndromes and/or conditions associated with the modulation of calcium sensing receptors (CaSR). The invention also provides herein the pharmaceutical compositions thereof, and methods for treating, managing, and/or lessening the severity of diseases, disorders, syndromes and/or conditions associated with the modulation of CaSR. The invention also relates to process for the preparation of the compounds of the invention.

Description

Related Applications

The présent 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 spécifications are Incorporated herein by reference.

Field of the Invention

The présent Invention relates to substituted chroman compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions for the treatment, management, and/or lessenlng 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 lessenlng 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 préparation of the compounds of the invention.

Background of the Invention

Ca²* Is known to be an întracellular second messenger, with the molecular Identification of an extracellular calcium sensing receptor (CaSR), it has further opened the possibllity that Ca²* might also function as a messenger outslde the cells. Information about the local changes in extraceilular concentration of Ca²* Is conveyed to the interior of many types of cells through this unique receptor.

Calcîum-sensing receptor (CaSR) is a G-protein-coupied receptor (GPCR) that signais through the activation of phospholipase C, Increasing levels of inositol 1,4,5-triphosphate and cytosoiic calcium. The CaSR beiongs to the subfamily C of the GPCR superfamily. Structuraily, CaSR has an exceptionaliy large amino-terminal extraceilular (ECD) domain (about 600 amino acids), a feature that is shared by ali 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 roie în the sécrétion of parathyroid hormone (PTH). The réduction in sérum calcium leads to the sécrétion of PTH. Consequently, PTH sécrétion leads to conservation of sérum Ca²* by increasing kldney rétention and intestinal absorption of Ca²*. This happens indlrectly through the PTH-induced synthesis of the active vitamin D métabolite, 25-dihydroxyvitamin D. In addition, the pulsatile action of PTH has anabolic effects on bone development and its sustalned levels can lead to catabolic effects, in which the bones breakdown releasing Ca²* as in the case of osteoporosis. Ail these Systems converge In maintenance of baseline sérum Ca²* and it invoives a tight régulation between sérum PTH and extracellular calcium which is mediated by the remarkable receptor CaSR.

ln conditions such as primary and secondary hyperparathyroidism, there is excessive sécrétion of parathyroid hormone due to hyperplasia of the giands. The most common cause of primary hyperparathyroidism (PHPT) Is parathyroid adenoma resulting from cional mutations (—97%) and associated hypercaicemia. ln the case of secondary hyperparathyroidism (SHPT), it is most commonly seen in patients with chronic rénal faliure. The kidneys fail to convert enough vitamin D to its active form and also does not adequateiy excrete phosphorous. Excess phosphorous further depletes sérum calcium forming calcium phosphate (kidney stones) leading to hypocalcémie.

Smali molécules that are positive aliosteric modulators called calcimimetics modulate and improve the receptors sensitivity to the already existing milieu of extraceliular ionic calcium. This would eventualiy translate in lowering plasma PTH ieveis 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 J. Med. Chem. (2006), 49, 5119-5128 discloses the compounds reiated to calcium sensing receptors (CaSR).

Summarv of the Invention ln accordance with one aspect, the invention provides compounds having the structure of Formula (I),

Rs (I) wherein,

R, is selected from hydrogen, halogen, substituted or unsubstituted aikyl, cyano, substituted or unsubstituted cycloalkyl and substituted or unsubstituted haioalkyl;

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, ls 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, ORe, nitro, cyano, -C(O)ORe, -(CH^r-CiOJORe, -O-C(O)ORe, -O(CH₂)rC(O)ORe, -NR₇Re, -ÎCH₂)_tNR₇Re-, -C(O)R₉, -C(O)NR₇Re, -ÎC^X-CiOJNR.Re, -NR₇C(O)Re, S(0)o.₂Re, -SÎOfeNRTRe, and -NR₇S(O)₂R9;

X is selected from a bond, -(CRcRJr, -O-, -NR_r, -NR₇(CRcRd)r, -O(CRcRd)r-, C(O)NR_r, -CiOïNRXCRcRdJr» -(CRcRdîrNRKCRcRdJr. -(CRcRdXcycloalkylene-, cycloalkylene, cycloalkylene(CRcRd)_r and -O-cycloalkylene where cycloalkylene may be substituted or unsubstituted;

Rc and Rj, 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 R< 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 -OReor-NRioRn!

R_b which may be same or different at each occurrence, ls 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 cydoalkyl, -ORe, -C(O)R₉, -NR₇Re, -(CH₂)_rNR₇Re-, -(CH^rCÎOÏORe, -OC(O)ORe, -O(CH₂)r-C(O)ORe, -C(O)NR₇Re, -(CH₂)_rC(O)NR₇Re. -NR₇C(O)R₉, -S(O)q.₂R₇, S(O)₂NR₇Re and -NR₇S(O)2R₉;

R₂ Is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl;

R₃ and R4 may be same or different and are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haioalkoxy and substituted or unsubstituted cycloalkyl;

R₃ is substituted or unsubstituted alkyl;

Re, which may be same or different at each occurrence, ls Independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryk

R₇ and Ra, 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 heterocyclylalkyt; or R₇ and Re. 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 hâve one or two double bonds;

at each occurrence, R₉ Is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;

Rio and R_t1 may be same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -(CRcRuJr-CXOjORe, 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 heterocyclylalkyt; or Rio and Rn. 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 hâve 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* ls an integer ranging from 0 to 3, both inclusive; and 'f is an integer ranging from 1 to 3, both inclusive; or Its pharmaceutically acceptable sait thereof.

According to one embodiment, there are provided compounds having the structure of Formula (II):

or its pharmaceutically acceptable sait 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 (1).

According to another embodiment, there are provided compounds having the structure of Formula (III):

or its pharmaceutically acceptable sait thereof;

wherein,

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):

or its pharmaceutically acceptable sait thereof; wherein,

R_z 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):

çh₃

or its pharmaceutically acceptable sait thereof;

wherein,

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 ail tautomers, stereoisomers, enantiomers and diastereomers, including isotopes wherever applicable and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the généra described herein.

The details of one or more embodiments of the invention set forth ln the below are Illustrative in nature oniy and not intended to timit 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 (1) in which ’rï 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 (l) 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 (!), in which *p’ is 0.

According to another embodiment, there are provided compounds of Formulae (l), (li), (III), (IV) and/or (V) in which R! is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, cyano, -ORe, C(O)alkyi; wherein Re is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, or substituted or unsubstituted cycloalkyl: and ’q' is 0,1, or 2.

According to another embodiment, there are provided compounds of Formulae (I), (il), (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. ln 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), (lll), (IV) and/or (V) ln which X is selected from a bond, -(CRcRd)r-. -O-· -NRr. *NRT(CRcRd)r-. -O(CRcRe)r . -C(O)NRr. -(XOJNRTÎCRcRdïr-. -(CRcRdJrNRXCRcRdJr-, -(CRcRdJrCycloalkylene-, cycloalkylene, -cycloalkyiene(CRcR<j)r- and -O-cycloalkylene where cycloalkylene may be substituted or unsubstituted; R7 is hydrogen or substituted or unsubstituted alkyl; Rc and Re 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), (lll), (IV) and/or (V) ln which Z is -ORe wherein Re 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 NR₁₀Rn wherein Ri_Oand Rn may be same or different and are Independently selected from hydrogen, substituted or unsubstîtuted alkyl, -(CR_cR_d)_r-C(O)OH, (CRcRd)rC(O)O-alkyl, substituted or unsubstîtuted cycloalkyl, substituted or unsubstîtuted aryl or substituted or unsubstîtuted arylalky! whereln R< and Rd are hydrogen or substituted or unsubstîtuted alkyl and T* Is 1, 2 or 3; or R₁₀ and Ru. 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 hâve one or two double bonds.

According to another embodiment, there are provided compounds of Formula (I) In which R. is hydrogen; Rt> Is hydrogen; Ri is selected from halogen, substituted or unsubstîtuted alkyl, substituted or unsubstîtuted haloalkyl, substituted or unsubstîtuted cycloalkyl, cyano, -ORe, C(O)alky! wherein Re Is hydrogen, substituted or unsubstîtuted alkyl, substituted or unsubstîtuted haloalkyl, or substituted or unsubstîtuted cycloalkyl; ’q’ Is 0, 1. or 2; R₂ Is substituted or unsubstîtuted aryl; Rj Is hydrogen; R< is hydrogen; R5 Is substituted or unsubstîtuted alkyl; X Is selected from a bond, -(CRcRdjr. -O-, -NRr, -NR^CR^),-. O(CRcR<j)r-. -C(0)NRn -CiOJNRXCRcRJr whereln R₇ Is hydrogen or substituted or unsubstîtuted alkyl, R< and Rd are hydrogen or substituted or unsubstîtuted alkyl; and T is 1, 2, or 3; Z Is -ORe or NR₁₀Rn whereln Re Is selected from hydrogen, substituted or unsubstîtuted alkyl, substituted or unsubstîtuted haloalkyl, substituted or unsubstîtuted aryl or substituted or unsubstîtuted arylalky!; R₁₀ and Rn may be same or different and are Independently selected from hydrogen, substituted or unsubstîtuted alkyl, -(CRcRdîr-CiOjOH, -(CRçRdîrCiOJO-alkyl, substituted or unsubstîtuted cycloalkyl or Rio and Rn together may form a substituted or unsubstîtuted, saturated or unsaturated 3 to 12 membered cyclic ring, where the unsaturated cyclic ring may hâve one or two double bonds, ’n’ is 1,2 or 3; ’m’ is 0 or 1; and ’p’ is 0;

or its pharmaceutically acceptable sait thereof.

According to another embodiment, there are provided compounds of Formula (V) In which Ri Is selected from halogen, substituted or unsubstîtuted alkyl, substituted or unsubstîtuted haloalkyl, substituted or unsubstîtuted cycloalkyl, cyano, -ORe, -C(O)alky! wherein Re Is hydrogen, substituted or unsubstîtuted alkyl, substituted or unsubstîtuted haloalkyl, or substituted or unsubstîtuted cycloalkyl; 'q' is 0, 1, or 2; R₂ is substituted or unsubstîtuted aryl; X Is selected from a bond. -(CRcRdJr. -O-, -NRr, -NR₇(CRcR<j)r, -OiCRcRJr. -C(O)NR_r. -CtOJNR^CRçRd),wherein R₇ is hydrogen or substituted or unsubstîtuted alkyl, Rc and Re are hydrogen or substituted or unsubstîtuted alkyl, ’r* is 1, 2, or 3; Z is -ORe or NR10R11 wherein Rels selected from hydrogen, substituted or unsubstîtuted alkyl, substituted or unsubstîtuted haloalkyl, substituted or unsubstituted aryl or substituted or unsubstîtuted arylalky!; Rio and Rn are

Independently selected from hydrogen, substituted or unsubstituted alkyl, -(CRcR^r-CÎOJOH, (CRcR<i}rC(O)O-alkyl, substituted or unsubstituted cycloalkyl or R_t0 and Ru together may form a substituted or unsubstituted, saturated or unsaturated 3 to 12 membered cyclic ring, where the unsaturated cyclic ring may hâve one or two double bonds, ‘n’ is 1,2 or 3;

or its pharmaceutically acceptable sait thereof.

According to another embodiment, there are provided compounds of Formula (i) or pharmaceutically acceptable sait; wherein the pharmaceutically acceptable sait is hydrochloride sait.

According to another embodiment, there are provided compounds of Formula (I) structurally encompasses stereoisomers Including enantlomers and diastereomers.

Below are the représentative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention.

Methyl 2-fluoro-5-((2R,4R)-2«((((R)-1 -(naphthalen-1«yl)ethyl)amino)methyl) chroman-4yl)benzoate;

Methyl 2-fluoro-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chfoman-4yljbenzoate;

Methyl-3-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl) benzoate; Methyl 2-methyl-3-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amlno)methyl)chroman-4yljbenzoate;

Methyl 3-methyl-5«((2R_l4S)-2-((((R)-1'(naphthalen-1-yl}ethyl)amino)methyl} chroman-4yljbenzoate;

Methyl 4-methyl-3-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yljbenzoate;

Methyl 2-ethyl-5-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yljbenzoate;

Methyl 2-ethyl-5-((2R,4S)-2«((((R)-1-(naphthalen-1’yl}ethyl)amino)methyl}chroman-4yljbenzoate;

Methyl 2-isopropyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yljbenzoate;

Methyl 2-cyclopropyl-5-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino) methyl) chroman4-yl)benzoate;

ίο

Methyl 2-cyclopropyl-5-((2R,4S)-2’((((R)-1-(^naPhthalen-1-yl)ethyl)amino)methyl) chroman-4yl)benzoate;

Methyl 2,6-difluoro-3-((2R.4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amlno)methyl)chroman-4yl)benzoate;

Methyl 4-fluoro-2-methyl-3-((2R,4R)-2-((((R)-1 -(naphtha!en-1 -yl)ethyl)amlno) methyl )chroman-4-yl)benzoate:

Methyl 4-fluoro-2-methyl-3-((2i?,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino) methyl)chroman-4-yl)benzoate;

Methyl 2,3-dimethyl-5-((2R₍4S>2-((((i?)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl)benzoate;

Methyl 5-((2R₍4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2(trifl uoromethyl)benzoate;

Methyl 2-methyl-5-((2/^:?_l4/^:?)'2-((((/?F1*(naphtha!en-1-yl)ethyl)amino)methyl) chroma n-4yl)benzoate;

Methyl 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl)benzoate;

Methyl 2-fluoro-3-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amlno)methyl)chroman -4yljbenzoate;

Methyl 3-fluoro-5-((2i?,4S)-2-((((R)-1 -(naphthalen-1 -yl)ethyl)amlno)methyl)chroman -4yl)benzoate;

Methyl 4-fluoro-3-((2R_l4i?)-2-((((R)-1-(naphtha!en-1-yl)ethyl)amino)methyl)chroman-4yl)benzoate;

Methyl 2-methoxy-5-((2R,4S)-2-((((R)-1 -(naphtha!en-1 -yl)ethyl)amino)methyl) chroman-4yljbenzoate;

Methyl 2-methoxy-3-((2R,4R)-2-((((R)-1-(naphtha!en-1-yl)ethyl)amino)methyl) chroman-4yl)benzoate;

Methyl 2-methoxy-3-((2F?, 4SJ-2-((((F?>-1 -(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yl)benzoate;

Methyl 4-methoxy-3-((2R4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl)benzoate;

Methyl 2-(2-rnethyl-5-((2Æ?,4S)-2-((((/^:?>-1 -(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl)phenoxy)acetate;

Methyl 2-( 3-methyl-5-((2R,4 S)-2-( ( ( ( R)-1 -(naphthalen-1 -yl)ethyl)amino)methyl) chroman-4yl)phenoxy)acetate;

Methyl 2-(2-fluoro-5-((2R,4R)-2-((((R)-1 -(naphthalen-1-yl)ethyl)amino)methy!) chroman-4yl)phenoxy)acetate;

Methyl 2-(2-fluoro-5-((2R_l4S)-2-((((R)-1-(naphthalen-1-yl)ethy!)amino)methyl) chroman-4yl)phenoxy)acetate;

Methyl 2-(2-fluoro-3-((2R_l4R)-2-Î(((R)-1-Înaphthalen-1-yl)ethy!)amino)methy!) chroman-4y!)phenoxy)acetate;

Methyl 2-(3-fluoro-5-((2R,4R)-2-((((R)-1-(naphthalen-1 -y!)ethy!)amino)methyl) chroman-4y!)phenoxy)acetate;

Methyl 2-{3-fluoro-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl)phenoxy)acetate;

Methyl 2-(4-fluoro-3-((2R,4R)-2-((((R)-1-(naphthaien-1-y!)ethyl)arnino)rnethyl) chroman-4yl)phenoxy)acetate;

Methyl 2-methy!-2-(3-((2R.4S)-2-((((R)-1 -(naphthalen-1 -y!)ethyl)amino)methy!) chroman-4y!)phenoxy)propanoate;

Methyl 4-((2R,4R)-2-((((R)-1-(naphthalen-1-y!)ethy!)amino)methy!)chroman-4-y!)benzoate;

Methyl 4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate;

Methyl 2-methyl-4-((2R,4R)-2-((((R)-1 -(naphthalen-1-y!)ethy!)amlno)methyl) chroman-4yljbenzoate;

Methyl 2-methyl-4-((2R_l4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl)benzoate;

Methyl 4-((2R,4R)-2-((((R)-1 -(naphthalen-1 -y!)ethy!)amino)methyl)chroman-4-yl)-2(trifluoromethyl)benzoate;

Methyl 4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2(trifluoromethyl)benzoate;

Methyl 2,6-difluoro-4-((2R,4S)-2-((((R)-1 -(naphthalen-1 -y!)ethy!)amino)methyl)chroman-4y!)benzoate;

Methyl 3-methoxy-4-((2R,4R)-2-((((R)-1-(naphthalen-1-y!)ethyl)amlno)methyl) chroman-4yl)benzoate;m

Methyl 3-methoxy-4-((2R,4S)-2-((((R)-1-(naphthaien-1-yl)ethy!)amino)methy!)chroman-4y!)benzoate;

Methyl 3-fluoro-4-((2R,4R)-2-((((R)-1-(naphthalen-1-y!)ethyl)amino)methy!) chroman-4y!)benzoate;

Methyl 2-fluoro-4-((2R_l4S)-2-((((R)-1-(naphthalen-1 -yl)ethy!)amino)methyl)chroman -4y!)benzoate;

Methyl 2-(4-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amlno)methyl)chronian-4yl)phenoxy)acetate;

Methyl 2-(4-((2R,4S)-2-((((R)-1 -(naphthalen-1 -yl)ethyl)anilno)methyl)chroman-4yl)phenoxy)acetate;

Methyl 2-(2-fluoro-4-((2R,4/?)-2-((((R)-1-(naphthalen-1 -yl)ethyl)amlno)methyl) chroman-4yl)phenoxy)acetate;

Methyl 2-(2-fluoro-4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)aniino)methyl) chroman-4yl)phenoxy)acetate;

Methyl 2-(4-((2R,4R)-2-((((R)-1 -(naphthalen-1 -yl)ethyl)amino)methyl)chroman-4yl)phenyl)acetate;

Methyl 2-(4-((2R,4S)-2-((((/?)-1 -(naphthalen-1 -yl)ethyl)amlno)methyl)chroman-4yl)phenyl)acetate:

Methyl 2-methyl-2-(4-((2F?,4F?)-2-((((f?)-1-(naphthalen-1-yl)ethyl)aniino)niethyl) chroman-4yl)phenyl)propanoate;

Methyl 2-methyl-2-(4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl)phenyl)propanoate;

Methyl 3-methyl-4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amlno)niethyl) chroman-4yl)benzoate;

Methyl 2-fluoro-5-((2S,4F?)-2-((((/?)-1 -(naphthalen-1 -yl)ethyl)amino)methyl) chroman-4yl)benzoate;

Methyl 3-((2S,4R)-2-((((R)-1 -(naphthalen-1 -yl)ethyl)amlno)methyl)chroman-4-yl)benzoate;

Methyl 2-methyl-5-((2S,4R)-2-((((R)-1 -(naphthalen-1-yl)ethyl)anilno)methyl) chroman-4yl)benzoate;

Methyl 2-methyl-5-((2S,4S)-2-((((/?)-1 -(naphthalen-1 -yl)ethyl)amlno)methyl) chroman-4yl)benzoate;

Methyl 2-(4-((2S,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yl)phenoxy)acetate;

Methyl 2-(4-((2S.4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yl)phenoxy)acetate;

Methyl 5-((2R,4R)-2-((((R)-1 -(4-fluoronaphthalen-1 -yl)ethyl)amino)methyl)chroman-4-yl)-2methylbenzoate;

Methyl 5-((2/?,4S)-2-((((F?)-1-(4-fluoronaphthalen-1-yl)ethyl)aniÎno)methyl)chroman-4-yl)-2methylbenzoate;

Methyl 3-((2R,4R)-2-((((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2methoxybenzoate;

Methyl 3-((2 R, 4S)-2-((«R)-1 -(4-fluoronaphthalen-1 -y1)ethy1)amÎno)methy1)chroman'4-yl)'2methoxybenzoate;

Methyl 4-((2R)-2-((((R)-1-(4’fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-4-yl)-2methylbenzoate;

Methyl 3-{(2R)-2-((((R)’1-(44luoiO-3-methoxyphenyl)ethyl)aniino)methyl)chroman-4-yl)-2methylbenzoate;

Methyl 5-((2R)-2-((((R)-1-(4-fluoiO-3-methoxyphenyl)ethyl)amino)methyl)chroman-4-yl)-2methylbenzoate;

Methyl 3-((2R)-24(((R)-144’fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-4-yl)’5methylbenzoate;

Methyl 3-{(2R)-2-((((R)-1-(4’fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-4-yl)-4methylbenzoate;

Methyl 2-fluoro-5-((2S,4R)-2-(2-(((R)-1-(naphthalen-1-yl)ethyl)aniino)ethyl) chroman-4yl)benzoate;

Methyl 2-fluoro-&((2R,4S)’2-(2-(((R)’1-(naphthalen-1-yl)ethyl)amino)ethyl) chroman-4yl)benzoate;

Methyl 2-methyl-5-((2S_l4R)-2-(2-(((R)-1-{naphthalen-1-yl)ethyl)amino)ethyl)chroman’4yl)benzoate;

Methyl 2-methyl-5-{(2R,4S)’2-(2-(((R)-1-(naphthalen-1-yl)ethyl)amÎno)ethyl) chroman-4yljbenzoate;

Methyl 2-methoxy-3-((2R_l4R)’2-(2-{((R)’1-{naphthalen-1-yl)ethyl)amino)ethyl) chroman-4yl)benzoate;

Methyl 5-{(2S,4R)’2-(2-(((R)’1-{4-fluoronaphthalen-1-yl)ethyl)amino)ethyl)chroman-4-yl)-2methylbenzoate;

Methyl 5-((2R,4S)-2-(2-{((R)-1-{4’fluoronaphthalen-1-yl)ethyl)aniino)ethyl)chroman-4-yl)-2methylbenzoate;

Methyl 5^(2S,4R)-2-(2-(((R)-1-(4-fluoro-3-methoxypheny1)ethy1)amino)ethyl) chroman-4-yl)2-methylbenzoate;

Methyl 5-((2R,4S)-2-(2-(((R)-1-(4’fluoro-3-methoxyphenyl)ethyl)amlno)ethyl) hroman-4-yl)-2methylbenzoate;

Methyl 2-fluoro-54(2S,4S)-2-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl) chroman-4y1)benzoate;

Methyl 2-fluoro-5-((2R_l4R)-2-(3-{((R)-1-(ⁿaphthal^en-1 -yl)ethyl)amino)propyl) chroman-4yijbenzoate;

Methyl 2-methyl-5-((2S,4S)-2-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl) chroman-4yljbenzoate;

Methyl 2-methyl-54(2R,4R)-2-(3-(((R)-1-(naphthalen-1-yl)ethyl)amlno)propyl) chroman-4yl)benzoate;

Methyl 5-i(2S,4S)-2-(3-(((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)amino)propyl)chroman-4yl)-2-methylbenzoate;

Methyl 4-[(2S,4S)-2-(3-(((R)-1-(4-fliioronaphthalen-1-yl)ethyl)amino)propyi) chroman-4-yl)-3methylbenzoate;

Methyl 4-i(2S,4S)-2-(3-(((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)propyl) chroman-4yl)benzoate;

Methyl 5-i(2S.4S)-2-(3-(((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)propyl) chroman-4-yl)-2methylbenzoate;

2, 6-Dimethyl-3-((2R, 4S)-2-<(((R)-1 -(naphthalen-1-yl) ethyi) amino) methyl) chroman-4yljbenzoic acid hydrochloride;

2.6- Dimethyl-3-((2R,4S)-2-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino) ethyl)chroman-4-yl) benzoic acid hydrochloride;

2.6- Dimethyl-3-((2R,4R)-2-(3-(((R)-1-(naphthalen-1-yl)ethyl) amino) propyi) chroman-4yljbenzoic acid hydrochloride;

2.6- Dimethyi-3-((2S,4S)-2-(3-(((R)-1-{naphthalen-1-yl)ethyi) amino) propyi) chroman-4y!)benzoic acid hydrochloride;

3-((2S,4S)-2-(3-(((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino) propyi)chroman-4-yl)-2,6dimethylbenzoic acid hydrochloride;

2-Fluoro-5-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride;

2- Fluoro-5-((2R,4S)-2-{(((R)-1-{naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride;

3- ((2R,4S)-2-{(((R)-1-(Naphthalen-1-yl)ethyi)amino) methyl) chroman-4-yl)benzoic acid hydrochloride;

2- Methyl-3-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride;

3- Methyi-5-((2R,4S)-2-((((R)-1-(naphthalen’1-yl)ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride;

4- Methyl-3-((2R,4S)-2-((((R)-1-{naphthalen’1-yljethyl) amino) methyl )chroman-4-yl)benzoic acid hydrochloride;

2-Ethyl-5-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride;

2-Ethyl-5-((2/î,4S)-2-((((/î)-1-(naphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl) benzoic acid hydrochloride;

Σ-ΙδορΓορ^-δ-ί^/ΐ^δϊ-Σ-ίίίίΚΗ-ίηθρΗΙΐΊθΙβη-Ι-γΙίβΙΐΊγΙ) amino) methyl) chroman-4yl)benzoic acid hydrochloride;

2-Cyclopro pyt-5-(( 2R,4R)-2-(((( R)-1 -(naphthalen-1 -yl)ethyl) amino)methyl) chroman-4yljbenzoic acid hydrochloride;

2-Cyclopropyl-5-((2/î,4S)-2-((((/?)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yljbenzoic acid hydrochloride;

2,6-Difluoro-3-((2/î,4/?)-2-((((/?)-1-(naphthalen-1-yl)ethyl) amino)methyl) chroman-4yl)benzolc acid hydrochloride;

4-Fluoro-2-methyl-3-((2/?,4S)-2-((((R)-1-(naphthaien-1-yl) ethyl) amlno)methyl) chroman-4yl)benzoic acid hydrochloride;

4- Fluoro-2-methyl-3-((2/?,4/?)-2-((((/î)-1-(naphthalen-1-yl) ethyl) amlno)methyl) chroman-4yl)benzoic acid hydrochloride;

2,3-Dimethyl-5-((2R_l4S)-2-((((R)-1-(naphthalen-1-yl)ethy!)amino)methyl)chroman-4yl)benzoic acid hydrochloride;

5- ((2/?,4S)-2-((((/?)-1-(Naphthalen-1-yl)ethyl)amino) methyl) chroman-4-yl)-2(trifluoromethyl)benzoic acid hydrochloride;

2-Methyl-5-((2/?_>4/î)-2-((((R)-1-(naphthalen-1-y!) ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride;

2-Methyl-5-((2/?.4S)-2-((((/?)-1 -(naphthalen-1 -yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid hydrochloride;

2- Fluoro-3-((2R,4R)-2-((((R)-1-(naphthalen-1-yl) ethyl)amlno) methy!)chroman-4-yl)benzoic acid hydrochloride;

3- Fluoro-5-((2/?,4S)-2-((((/?)-1-(naphthalen-1-yl) ethyl)amino) methyl) chroman-4-yl)benzoic acid hydrochloride;

4- Fluoro-3-((2/?,4/?)-2-((((/?)-1-(naphthalen-1-yl) ethyl) amino) methyl)chroman-4-yl)benzolc acid hydrochloride;

2-Methoxy-5-((2/?_l4S)-2-((((/?)-1-(naphthalen-1-yl) ethyl) amino) methyl)chroman-4yl)benzoic acid hydrochloride;

2-Methoxy-3-((2/?,4S)-2-((((/?)-1-(naphthalen-1-yl)ethyl) amino)methyl)chroman-4-yl)benzolc acid hydrochloride;

2-Methoxy-3-((2R,4R)-2-((((R)-1 -(naphthalen-1 -yl)ethyl) aminojmethy!) chroman-4yljbenzoic acid hydrochloride;

4-Methoxy-3-((2R,4R)-2-((((R)-1-(naphthalen-1-y! )ethyl) amino) methyl) chroman-4-yl) benzoic acid hydrochloride;

2-(2-Methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amlno)methyl) chroman-4yl)phenoxy)acetlc acid hydrochloride;

2-(3-Methyl-5-((2R_l4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl) chroman-4yl)phenoxy)acetic acid hydrochloride;

2-(2-Fluoro-5-((2F?,4R)-2-((((R)-1 -(naphthalen-1 -yl)ethyl) amino)methyl) chroman-4yl)phenoxy)acetic acid hydrochloride;

2-(2-Fluoro-5-((2R,4S)-2-((((R)-1-(naphthalen-1-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-4y!)phenoxy)acetic acid hydrochloride;

2-(3-Fluoro-5-((2R,4R)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino)methyl) chroman-4yl)phenoxy)acetic acid hydrochloride;

2-(3-Fluoro-5-i(2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyl) chroman-4-yl) phenoxy)acetic acid hydrochloride;

2-(4-Fluoro-3-((2R,4R)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyi)chroman-4-yl) phenoxy)acetic acid hydrochloride;

2-Methyl-2-(3-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yl)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)-1-(Naphthalen-1-yl)ethy!) amino) methyl) chroman-4-yl)benzolc acid hydrochloride;

2-Methyl-4-((2R,4R)-2-((((R)-1 -(naphthalen-1 -yijethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride;

2-Methy!-4-((2R_l4S)-2-((((R)-1 -(naphthalen-1 -yijethyl) amino) methyl)chroman-4-yl) benzoic acid hydrochloride;

4-((2R,4R)-2-((((R)-1 -(Naphthalen-1 -yi)ethyl)amino) methyl) chroman-4-yl)-2(trifluoromethyl)benzoic acid hydrochloride;

4-((2R,4S)-2-((((R)-1-(Naphthalen-1-yl)ethyl)amino) methyl) chroman-4-yl)-2(trifluoromethyl)benzoic acid hydrochloride;

2,6-Difluoro-4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) aminojmethyl) chroman-4yljbenzoic acid hydrochloride;

3-Methoxy-4-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl) chroman-4yl)benzoic acid hydrochloride;

3-Methoxy-4-({2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino)methyl) chroman-4yl)benzoic acid hydrochloride;

3-Fluoro-4-((2R,4R)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride;

2-Fluoro-4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino) methyl)chroman-4-yl)benzoîc acid hydrochloride;

244-((2R,4R)-2-((((R)-1-(Naphthalen-1-yl)ethyl)amino) methyl)chroman-4-yl) phenoxy)acetic acid hydrochloride;

2-(4-((2R,4S)-2-((((R)-1-(Naphthalen-1-yl)ethyl) amino)methyl) chroman-4-yl)phenoxy)acetic acid hydrochloride;

2-(2-Fluoro-4-((2R_l4R)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino)methyl)chroman-4yl)phenoxy)acetic acid hydrochloride;

2-(2-Fluoro-4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino)methyl)chroman-4yl)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,4S)-2-((((R)-1-(Naphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl) phenyljacetîc acid hydrochloride;

2-Methyl-2-(4-((2R_l4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yl)phenyl)propanoic acid hydrochloride;

2- Methyl-2-(4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino)methyl)chroman-4-yl) phenyl) propanoic acid hydrochloride;

3- Methyl-4-((2R_l4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amlno) methyl)chroman-4-yl)benzoic acid hydrochloride;

2- Fluoro-5-((2S,4R)-2-((((R)-1-(naphthalen-1-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-((2S,4R)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride

2-Methyl-5-((2S_l4S)-2-{(((R>-1-(naphthalen-1-yl) ethyl)amino) methyl) chroman-4-yl)benzoic acid hydrochloride;

2-{4-{(2S,4R)-2-((((R)-1-(Naphthalen-1-yl)ethyl)amino) methyl) chroman-4-yl)phenoxy)acetic acid hydrochloride;

2- {4-{(2S,4S)-2-((((R)-1-(Naphthalen-1-yl)ethyl)amlno)methyl)chroman-4-yl) phenoxy)acetic acid hydrochloride;

4- ((2R,4S)-2-((((R)-1-(4-Fluoro-3-methoxyphenyl) ethyl) amino) methyl)chroman-4-yl)-2methylbenzolc acid hydrochloride;

3- ((2R,4S)-2-((((R)-1-(4-Fluoro-3-methoxyphenyl) ethyl) amino)methyl)chroman-4-yl)-2methylbenzolc acid hydrochloride;

5- Î(2R,4S)-2-{(((R)-1-{4-Fluoro-3-methoxyphenyl) ethyl) amino) methyl)chroman-4-yl)-2methyl benzolc acid hydrochloride;

3-((2R,4S)-2-((((R)-1-{4-Fluoro-3-methoxyphenyl) ethyl) amino)methyl)chroman-4-yl)-5methylbenzoic acid hydrochloride;

3-{(2R,4S)-2-{(((R)-1-(4-Fluoro-3-methoxyphenyl) ethyl) amino)methyl)chroman-4-yl)-4methylbenzoic acid hydrochloride;

5-{(2R,4R)-2-((((R)-1-(4-Fluoronaphthalen-1-yl) ethyl) amino) methyl)chroman-4-yl)-2-methyl benzolc acid hydrochloride;

5-((2R,4 S)-2-((((R)-1-(4-Fluoronaphthalen-1-yl) ethyl) amino) methyl)chroman-4-yl)-2methyl benzolc acid hydrochloride;

3-{(2R,4S)-2-((((R)-1-{4-Fluoronaphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2methoxybenzolc acid hydrochloride;

3-f(2R,4R)-2-((((R)-1 -{4-Fluoronaphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl)-2methoxybenzoic acid hydrochloride;

2-Fluoro-5-((2S, 4R)-2-(2-(((R)-1-{naphthalen-1-yl) ethyl) amino) ethyl) chroman-4-yl) benzoic acid hydrochloride;

2-Fluoro-5-((2R,4S)-2-{2-(((R)-1 -(naphthalen-1 -yl)ethyl) amino) ethyl)chroman-4-yl)benzoic acid hydrochloride;

2-Methyl-5-((2S,4R)-2-{2-(((R)-1-(naphthalen-1-yl)ethyl) amino)ethyl)chroman-4-yl)benzoic acid hydrochloride;

2-Methyl-5-((2R,4S)-2-(2-(((R)-1 -{naphthalen-1 -yl)ethyl ) amino)ethyl)chroman-4-yl)benzolc acid hydrochloride;

2-Methoxy-3-((2R,4R)-2-(2-(((R)-1 -(naphthalen-1 -yl)ethyl) amlno)ethyl)chroman-4-yl)benzoic acid hydrochloride;

5-((2S,4i?)-2-(2-(((i?)-1-(4-Fluoronaphthalen-1-yl)ethyl) amino) ethyl)chroman-4-yl)-2methylbenzoic acid hydrochloride;

5-((2R,4S)-2-(2-(((R)-1-(4-Fluoronaphthalen-1-yl)ethyl) amino) ethyl)chroman-4-yl)-2methylbenzoic acid hydrochloride;

5-f(2S,4R)-2-(2-(((R)-1-(4-Fluoro-3-methoxy phenyl) ethyl) amino) ethyl) chroman-4-yl)-2methylbenzoic acid hydrochloride;

5-((2R,4S)-2-(2-(((R)-1-(4-Fluoro-3-methoxy phenyl)ethyl)amino)ethyl)chroman-4-yl)-2methylbenzoic acid hydrochloride;

2-Fluoro-5-((2S, 4S)-2-(3-(((R)-1-(naphthalen-1-yl) ethyl) amino) propyl) chroman-4-yl) benzolc acid hydrochloride;

2-Fluoro-5-{(2R,4R)-2-(3-(((R)-1 -(naphthalen-1 -yl) ethyl) amino) propyl)chroman-4yl)benzolc acid hydrochloride;

2-Methyl-5-((2S,4S)-2-(3-(((R)-1-(naphthalen-1-yl) ethyl) amino) propyl)chroman-4yl)benzoic acid hydrochloride;

2-Methyl-5-((2R,4R)-2-(3-(((R)-1-(naphthalen-1-yl) ethyl) amino) propyl)chroman-4yl)benzoic acid hydrochloride;

5-((2S,4S)-2-(3-(((R)-1-(4-Fluoro-3-methoxypheny!)ethy!)amino)propyl)chroman-4-yl)-2methylbenzoic acid hydrochloride;

4-f(2S,4S)-2-(3-(((i?)-1-(4-Fluoronaphthalen-1-yl)ethyl)amlno) propyl)chroman-4-yl)-3methylbenzolc acid hydrochloride;

4- {(2S,4S)-2-(3-(((R)-1-(4-Fluoronaphthalen-1-yl)ethyl) amino) propyl)chroman-4-yl)benzoic acid hydrochloride;

5- ((2S,4S)-2-(3-(((R)-1-(4-Fluoronaphthalen-1-yl)ethyl) amino) propyl)chroman-4-yl)-2methylbenzoic acid hydrochloride;

Methyl 2-(3-((2/7, 4S)-2-((((R)-1 -(naphthalen-1-yl) ethyl) amino) methyl) chroman-4-yl) benzamido) acetate;

Methyl 2-(2-methyl-5-((2R₁ 4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyl) chroman-

4-yl) benzamido) acetate;

2-(3-((2/7,4S)-2-((«F?)-1 -(Naphthalen-1 -yl) ethyl) amino) methyl) chroman-4-yl) benzamido) acetic acid hydrochloride;

2-(2-Methy!-5-((2F?,4S)-2-«((F?)-1 -(naphthalen-1 -y!) ethyl) amino) methyl) chroman-4yl) benzamido) acetic acid hydrochloride;

N, 2-Dimethyl-5-((2/7, 4S)-2-((((R)-1-(naphthalen-1-y!) ethyl) amino) methyl) chroman-4yl)benzamide hydrochloride;

N,N.2-Trimethyl-5-({2R,4S)-2-(({(R)-1-(naphthalen-1-yl)ethyl) amino)methyl) chroman-4yl)benzamide hydrochloride;

2-Methyl-5-((2R,4S)-2-((((R)-1 -(naphthalen-l-yljethyl) amino) methyl)chroman-4yl)benzamide hydrochloride;

M-Ethyl-N_l2-dimethyl-5-((2R_l4S)-2-((((R)-1-(naphthaien-1-yl) ethyl)amino)methyl) chroman-

4-yl)benzamide hydrochloride;

N,N-Diethyl-2-methyl-5-((2R4S)-2-((((R)-1-(riaphthaien-1-yl) ethyl) amino) methyl)chroman-

4-yl)benzamide hydrochloride;

{2-Methyl-5-((2R,4S)-2-(«(R)-1-(naphthaien-1-yl)ethyl) amino)methyl)chroman-4yl)phenyl)(pyrrolidin-1 -yl)methanone hydrochloride;

2- (2-Methyl-4-(2-((((R)-1-(naphthalen-1-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-(naphthaien-1-yl)ethyl)amino)methyl)chroman-4yl)phenyl)propanoic acid hydrochloride;

3-(2-(2-(((R)-1-{Naphthalen-1-yl)ethyl)amino)ethyl)chroman-4-yl)benzoic add hydrochloride;

3-{3-(2-(2-(((R)-1-(Naphthalen-1-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)-1-(Naphthaien-1-yl)ethyl)amino)ethyl)chroman-4-yl)phenoxy)acetic add hydrochloride;

3- (2-(2-(((R)-1-(4-Fiuoronaphthalen-1-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-1-yl)ethy1)amino)propyl)chroman-4-yl)benzoic acid hydrochloride;

2- Methyl-4-(2-(3-(((R)-1-(naphthalen-1-y1)ethy1)amino)propyl)chroman-4-y1)benzoic acid hydrochloride;

3- (2-(3-(((R)-1-(4-Fluoronaphthalen-1-yl)ethyl)amino)propy1)chroman-4-yl)benzoic acid hydrochloride;

3-(2-((((R)-1-(4-Fluoro-3-methoxypheny!)ethyl)amino)methy1)chroman-4-yl)-2,6dimethylbenzolc acid hydrochloride;

2-F!uoro-3-(2-((((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-4-yl)-6methylbenzoic acid hydrochloride;

2,6-Difluoro-3424(((R)-1-(⁴-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-4yljbenzoic acid hydrochloride;

2-Fluoro-5-(2-((((R)-1-(4-fluoro-3-methoxypheny1)ethy1)amino)methy1)chroman-4-y1)benzoic acid hydrochloride; and

2-(2-Fluoro-5-(2-((((R)-1-(4-fluoro-3-methoxyphenyl)ethy1)amino)methy1)chroman-4y1)phenoxy)acetic acid hydrochloride;

or Its pharmaceutically acceptable sait thereof.

ln another aspect of the Invention, there is provided a compound of Formula (I) useful ln treating, preventing, managing and/or lessenlng the severity of diseases, disorders, syndromes or conditions associated with calcium sensing receptor (CaSR) modulators.

ln another aspect, the invention provides a pharmaceutical composition comprising at least one compound of Formula (I) and at least one pharmaceutically acceptable excipient.

ln another aspect, the invention provides a pharmaceutical composition of compound of formula (I) useful in treating, preventing, managing and/or lessenlng the severity of the diseases disorders, syndromes or conditions associated with calcium sensing receptor (CaSR) modulators in a subject, ln 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 sait thereof together with a pharmaceutically acceptable excipient.

In another aspect, there are provided processes for the préparation compounds of Formula (Ib):

R₂

Rs (ib) where X, R, R_1t R₂, R₅‘m’. ‘n*. *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 10 compound of Formula (16) In suitable solvent(s):

b) converting a compound of Formula (16) to compound of Formula (17) using PhNTf₂ (N- phenylbls(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 réaction to give compound of Formula (18) where Z is -OR« and R« is alkyl or benzyl;

d) when Z is 0-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)

MeOH/HCl

DCM

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 sait having Formula (ib);

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 ls OH;

I) converting the compound of Formula (19) obtained in step h) to the compound of Formula (Ib);


^(R,p£ JL J A r₂ r_s	i) etherial.HCI	^(R)pUjJ	^Ri HCl
A^X-C(O)-Z	ii) DCM/Et₂O-HCI	« X-C(O)OH
(19)		(Ib)

In another aspect, there are provided processes for the préparation compounds of Formula (Id):

wherein X, R, R_b R₂, R_s, R₇₁ Rc. Rd'm’, *n’, *p’, ‘q’ and Y are as described in claim 1, the process comprising the steps of:

a) coupling of acid compound of Formula (Ib) with suitable amines using suitable amide coupling reagents to give compound of Formula (le)

(lb)

RjRd (le) when R« Is alkyl/bertzyl etc.,

b) hydralyzing the amido ester group, if the compound of Formula (le) 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

Définitions and Abbreviations:

Unless otherwise stated, the following terms used in the spécification and claims hâve the meanings given below.

For purposes of interpreting the spécification and claims, the following définitions 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 molécule 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, ail 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-limlting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), /so-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2butenyl and the like. Unless set forth or recited to the contrary, ail alkenyl groups described or clalmed herein may be stralght chain or branched, substituted or unsubstituted.

The term aikynyf refera to a hydrocarbon radical containing 2 to 10 carbon atoms and Including at ieast 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, ail alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term alkoxy refera to an alkyl group attached via an oxygen linkage. Non-iimiting examples of such groups are methoxy, ethoxy and propoxy and the like. Unless set forth or recited to the contrary, ali alkoxy groups described or claimed herein may be stralght chain or branched, substituted or unsubstituted.

The term haloalkyl” refera 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, di haloalkyl or polyhaloalkyl Including perhaloalkyl. A monohaloalkyl can hâve one lodine, 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-iimiting examples of a haloalkyl Include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. A perhaloalkyl refera to an alkyl having ail hydrogen atoms replaced with halogen atoms. Unless set forth or recited to the contrary, ail haloalkyl groups described or clalmed herein may be straight chain or branched, substituted or unsubstituted.

The term haloalkoxy refera to a haloalkyl, defined herein, group attached via an oxygen linkage. Preferably, the haloalkoxy may be monohaloalkoxy, dihaloalkoxy or polyhaloalkoxy Including perhaloalkoxy. Non-iimiting examples of a haloalkoxy include fluoromethoxy, dlfluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dîchlorofluoromethoxy, difluoroethoxy, difluoropropoxy, dichloroethoxy, dichloropropoxy, dichloroisopropoxy and the like. Unless set forth or recited to the contrary, ail haloalkoxy group described or claimed herein may be stralght chain or branched, substituted or unsubstituted.

The term cycloalkyT refera 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 inciude, but are not limited to, perhydronapththyl, adamantyl and norbomyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spîro(4,4)non-2-yl and the like. Unless set forth or recited to the contrary, ail 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, ail 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, ail 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., cydopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexyfethyl, etc. Unless set forth or recited to the contrary, ail 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 bipheny! and the like. Unless set forth or recited to the contrary, ail 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., -CH₂CçH₅ and -C2H₄CeH_s. Unless set forth or recited to the contrary, ail 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 inciude but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, aryl, naphthyl, adamentyl etc. Unless set forth or recited to the contrary, ail carbocyclic groups or rings described or claimed herein may be aromatic or non aromatic.

A 3-12 membered cyclic ring as used herein refera to a monocyclic, bicyclic, polycyclic heteroaryl or heterocyclic ring Systems.

The term heterocyclic ring or heterocydyl ring or heterocydyl, 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-, bl- 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 oxldized to various oxidation states. In addition, the nitrogen atom may be optionally quatemized, the heterocyclic ring or heterocydyl may optionally contain one or more olefinic bond(s), and one or two carbon atoms(s) in the heterocyclic ring or heterocydyl may be interrupted with -CF2-, -S(O)-, S(O)2, -C(=N-alky!)-, or -C(=Ncycloalkyl), etc. In addition heterocyclic ring may also be fused with aromatic ring. Non-limiting examples of heterocyclic rings include azetîdinyl, benzopyranyl, chromanyl, decahydrolsoquinolyl, indanyl, Indolinyl, Isoindolinyl, Isochromanyl, Isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidlnyl, 2-oxopiperazinyl, 2-oxoplperidinyl, 2oxopyrrolidinyl, 2-oxoazepinyl, octahydrolndolyl, octahydroisoindolyl, perhydroazeplnyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, plperidinyl, phenothlazinyl, phenoxazinyl, quinuclidinyl, tetrahydrolsquinolyl, tetrahydrofuryl, tetrahydropyranyl, thlazolinyl, thiazolidinyl, thlamorpholinyl, thlamorpholinyl sulfoxlde, thlamorpholinyl sulfone Indoline, benzodioxole, tetrahydroqulnoline, tetrahydrobenzopyran and the like. The heterocyclic ring may be attached by any atom of the heterocyclic ring that results In the création of a stable structure. Unless set forth or reclted to the contrary, ail heterocydyl groups described or clalmed 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-, bl- or tricyclic ring system. The heteroaryl ring may be attached by any atom of the heteroaryl ring that results in the création of a stable structure. Non-limiting examples of a heteroaryl ring include oxazolyl, isoxazolyl, Imldazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thlazolyl, Isothlazolyl, pyridyl, pyrimidinyl, pyrazlnyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothlenyl, carbazolyl, quinolinyl, Isoqulnolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, qulnoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, Indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like. Unless set forth or recited to the contrary, ail heteroaryl groups described or clalmed herein may be substituted or unsubstituted.

The term heterocyclylalkyt refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyt radical may be attached to the main structure at any carbon atom In the alkyl group that results In the création of a stable structure. Unless set forth or recited to the contrary, all heterocyclylalkyt groups described or claimed herein may be substituted or unsubstîtuted.

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 alkyt group that results In the création of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstîtuted.

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), alkyt, haloalkyl, aikenyl, alkynyl, aryl, arylalky!, cycloalkyl, cycloalkytalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyt, heteroarylalkyl, C(0)0R^x, -C(O)R^X, -C(S)R^X, -C(0)NRW, -NR‘C(O)NR^VR^Z, -N(R^x)S(0)R^y, -N(R^x)S(0)2R^y. NR^xR^y, -NR^xC(0)R^y, -NR^xC(S)R^y, -NR^xC(S)NR^yR^I, - S(0)2NR^xR^y, -OR^X, -0C(0)R^x, 0C(0)NR^xR^y, -R^xC(0)0R^y, -R^xC(0)NR^yR^I, -R^xC(0)R^y, -SR^X, and -S(O)₂R^X; whereln each occurrence of R^x, R^y and R¹ are independently selected from hydrogen, halogen, alkyl, haloalkyl, aikenyl, alkynyl, aryl, arylalkyî, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclytalkyl and heteroarylalkyl. The aforementioned substituted groups cannot be further substituted. For example, when the substituent on substituted alkyl Is aryl or aikenyl, the aryl or aikenyl cannot be substituted aryl or substituted aikenyl, respectively.

The compounds of the présent invention may hâve one or more chiral centers. The absolute stereochemistry at each chiral centre may be *R‘ or 'S‘. The compounds of the invention Include all dlastereomers and enantiomers and mixtures thereof. Unless specifically mentioned otherwise, reference to one stereolsomer applies to any of the possible stereolsomers. Whenever the stereoisomeric composition Is unspecified, it Is to be understood that all possible stereolsomers are Included.

The term stereolsomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimenslonal structures which are not Interchangeable. The three-dimensional structures are called configurations. As used herein, the term enantlomer refers to two stereolsomers whose molécules 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 enantlomers. 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 Individuel 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 clinicai symptoms of the state, disorder or condition developing ln a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet expérience or display ciinical 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 ciinical or subclinical symptom thereof; c) lessening the severity of a disease disorder or condition or at least one of its ciinical or subclinical symptoms or (d) relieving the disease, I.e., causing régression of the state, disorder or condition or at least one of Its ciinical or subclinical symptoms.

The term modulate or “modulating or modulation or “moduiator 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, aliosteric modulators of calcium sensing receptor (CaSR) of the présent invention. Such modulation may be contingent on the occurrence of a spécifie event, such as activation of a signal transduction pathway.

The term aliosteric 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 indudes mammals (especlally humans) and other animais, such as domestic animais (e.g., household pets including cats and dogs) and non- domestic animais (such as wildllfe).

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 sufficîent to cause the effect ln 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 âge, weight, physlcal 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 baslc or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable sait 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 exemples 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 sufficientiy 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 séparation 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 stereospecifïc 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 mammai, Including human mammai. 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 toxlcity.

Exemples of suitable carriers or exciptients Include, but are not limited to, water, sait solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnésium carbonate, sugar, cyclodextrin, amylose, magnésium stéarate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, saiicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritoi fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrroiidone.

The pharmaceutical composition may also Include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for Influenclng 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 ingrédient 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 conventîonal forms, for example, capsules, tablets, caplets, orally disintegrating tablets, aérosols, solutions, suspensions or products for toplcal 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, Intrademnal, transdermal, parentéral, 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 ingrédient 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, émulsions, suspensions, solutions, soft gelatin and stérile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions. For parentéral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissoived in polyhydroxylated castor oil.

The pharmaceutical préparation Is preferably in unit dosage form. In such form the préparation Is subdivided Into unit doses containing appropriate quantifies of the active component. The unit dosage form can be a packaged préparation, the package containing discrète quantifies of préparation, 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 dépends, 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 préparation 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 ln treating the diseases and disorders described herein can be determined by those skilled ln the relevant art. Therapeutic doses are generally Identified through a dose ranging study in subject based on preliminary evidence derived from the animal studios. Doses must be sufficient to resuit ln a desired therapeutic benefit without causlng 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. Ail changes and modifications are envisioned within the scope of the invention.

Methods of Treatment ln 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 wili be responsible to therapeutic agents.

ln 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 présent invention is useful to a subject ln 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 sécrétion is affected by the caicium sensing receptor (CaSR) activity or (c) an abnormal level of activity of a messenger whose function is affected by the calcium sensing receptor activity. ln 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 parathyrold cell, bone cells (pre-osteoclast, osteoclast, pre-osteoblast, osteoblast), juxtaglomerular kldney cell, kldney messenglal cell, glomerular kldney cell, proximal tubule kidney cell, distal tubule kldney cell, cell of the thlck ascending limb of Henle's loop and/or collectlng duct, parafollicular cell In the thyrold (C-cell), Intestinal cell, platelet, vascular smooth muscle cell, gastrointestlnal tract cell, pltuîtary cell or hypothalamlc cell. The messenger of the calcium senslng receptor ls Calcium.

The compound of Formula (i), being modulators of CaSR, is potentially useful in treating, managing and/or iessenlng the severity, morbidity/mortality or complications of diseases, disorders, syndromes or conditions Include but are not limited to primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyperparathyroidism, chronlc rénal failure (with or without dialysis), chronlc kldney disease (with or without dialysis) parathyroid adenoma, parathyrold hyperplasla, parathyrold carclnoma, vascular & valvular calcification, abnormal calcium homeostasls such as hypercalcemla, abnormal phosphorous homeostasls such as hypophosphatemla, bone related diseases or complications arising due to hyperparathyroidism, chronlc kldney disease or parathyrold carclnoma, bone loss post rénal transplantation, osteitis fibrosa cystica, adynamie bone disease, rénal bone diseases, cardiovascuiar complications arislng due to hyperparathyroidism or chronlc kldney disease, certain malignancles In which (Ca²*)_e ions are abnormally high, cardiac, rénal or intestinal dysfonctions, podocyte-related diseases, abnormal intestinal motility, diarrhea, augmentlng gastrin or gastric acid sécrétion to directly or indireetîy benefit In atrophie gastritis or to Improve absorption of pharmacologicai compounds, drugs or suppléments from gastro-intestinal tract by augmentlng gastric acîdity.

Primary hyperparathyroidism, is a disorder of one or more of the parathyroid glands, resulting from a hyper fonction of the parathyrold glands themselves (acquired sporadically or familial) resulting In PTH over sécrétion which could be due to single or double adenoma, hyperplasla, multigland disease or rarely, carclnoma of the parathyrold glands. As a resuit, the blood calcium rises to a level that is higher than normal (called hypercalcemla). This elevated calcium ievei can cause many short-term and long-term complications.

Secondary hyperparathyroidism occurs when a decrease In circulating Ievels of Ca²* Ievei stimulâtes PTH sécrétion. One cause of secondary hyperparathyroidism is chronic rénal Insufficlency (also referred to as chronlc kldney disease or CKD), such as that In rénal polycystic disease or chronic pyelonephritis, or chronlc rénal failure, such as that in hemodialysls patients (also referred to as end stage rénal disease or ESRD). Excess PTH may be produced in response to hypocalcemla resulting from iow calcium Intake, Gl disorders, rénal Insufficiency, vitamin D deficiency, magnésium deficiency and rénal hypercalciuria. Tertiary hyperparathyroidism may occur after a long period of secondary hyperparathyroidism and hypercalcémie.

In one aspect, the compound and composition of the présent 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 déposition of extracellular matrix hydroxyapatite crystal deposits. In another aspect of the invention, administration of the compound of the invention prevents the formation, growth or déposition 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 médial calcification and other conditions characterized by vascular calcification. In one aspect, vascular calcification may be associated with chronic rénal insufficiency or end-stage rénal disease or excess calcium or PTH I tse If. In another aspect, vascular calcification may be associated with pre- or post-dialysis or uremla. In a further aspect, vascular calcification may be associated with diabètes 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 Internai Medicine. The compound and composition of the présent invention can be used, In particular, to particlpate in a réduction of the sérum levels in the parathyrold hormone known as PTH: these products could thus be useful for the treatment of diseases such as hyperparathyroidism.

Abnormal phosphorous homeostasis such as hypophosphatémie can be characterized as described In standard medical textbooks, but not limited to Harrison's Principles of Internai Medicine. The compound and composition of the présent Invention can be used, in particular, to particlpate In a réduction of the sérum levels In the parathyrold hormone known as PTH: these products could thus be useful for the treatment of diseases such as hypophosphatémie.

In one aspect, the podocyte diseases or disorders treated by methods of the présent Invention stem from the perturbations In one or more functions of podocytes. These functions of podocytes Inciude: (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 sécrétion of vascular endothélial growth factor (VEGF) required for the glomerular endothélial 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 prolifération, 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 endocrinologie disorder, an infection, a contrast agent, a mechanical trauma, a cytotoxic agent (cis-piatinum, adriamycin, puromycin), calcineurin inhibitors, an inflammation (e.g., due to an Infection, a trauma, anoxia, obstruction, or ischemia), radiation, an infection (e.g., bacterial, fungai, or virai), a dysfonction of the immune system (e.g., an autoimmune disease, a systemlc disease, or IgA nephropathy), a genetic disorder, a médication (e.g., anti-bacterial agent, antiviral agent, anti-fongal agent, Immunosuppressive agent, anti-inflammatory agent, analgestic or anticancer agent), an organ failure, an organ transplantation, or uropathy. In one aspect, ischemia can be sickle-cell anémia, thrombosis, transplantation, obstruction, shock or blood loss. In one aspect, the genetic disorders may include congénital nephritlc syndrome of the Finnlsh type, the fêtai membranous nephropathy or mutations In podocyte-speciflc proteins.

In one aspect, the compounds of the Invention can be used for treating abnormal intestinal motilities disorders such as dîarrhea. 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 dîarrhea, 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 sécrétion, or there is an inhibition of absorption. There is little to no structural damage. The most common cause of this type of diarrhea is choiera, in another aspect, diarrhea can be due to accélération 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 présent invention can be used, In particular, to participate In an augmenting gastrin or gastric acid sécrétion to directly or Indirectly benefit certain medical conditions such as but not limited to atrophie gastritis or to improve absorption of pharmacologlcai compounds, drugs or suppléments from gastro-intestinal tract by 5 augmenting gastric acidity.

Ali of the patent, patent application and non-patent publications referred to In this spécification are incorporated herein by reference in their entireties.

General Methods of Préparation

The compounds described herein may be prepared by techniques known in the art. in addition, 10 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 spécifie 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 présent invention. Variations In reaction 15 conditions, for example, température and/or duration of the reaction, which may be used as known in the art, are also within the scope of the présent Invention. Ail the isomers of the compounds described In these schemes, unless otherwise specified, are also encompassed within the scope of this Invention.

Scheme-1

The compound of Formula (14) where n is 1, is prepared by following the procedure as depicted in Scheme-1, thus starting from commercially available chromone-2-carboxylic acid is 5 reduced to give compound of Formula (2) with hydrogen over Palladium-Carbon. Compound of Formula (2) can be resoived by using R-(+)-1-phenylpropyl amine or (S)-(+)-1-pheny!propy! amine (W02007/123941) which gives corresponding resoived acid of Formula (3). The compound of Formula (3) is reacted with amine of Formula (a) in presence suitable reagents such as SOCI₂ to give compound of Formula (4). The compound of Formula (4) undergoes 10 réduction 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 SOCI₂ to give corresponding acid chloride of Formula (5). Further this Formula (5) undergoes one-carbon homologation (Amdt-Eistert Synthesis) by using trimethylsiiy! diazomethane foilowed by silver benzoate to give compound of 15 Formula (6). The compound of Formula (6) reacting with amine of Formula (a) using suitable reagents such as SOCI₂ to give compound of Formula (7), The compound of Formula (7) undergoes réduction 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 aldéhyde 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 SOCI₂to give compound of Formula (13). The compound of Formula (13) undergoes réduction using suitable reducing agents to give 10 compound of Formula (14).

Scheme-2 (R)c

(BOCfaO

R,--------- (R)

(15)

KMnCWoSO» Rj---------»

Acetone/Water

Rs

KHMDS/PhNTfï (18)

HyPd/C ^(R)p

when Z is O-alkyl, '—' X-C(D)-Z (1S)

BOC „ D MeOH/HCI

Ri Rs _________ ^Me0H (Ri).

when Z is OH;

i) ethereal HCl; (11) DCM/EtiO- HCl

when R* Is atkyVbensyl etc,

Ester Hydrolysls

DCM/EtjO- HCl

Rs

The compound of Formula (la), (1b), (le) or (Id) where X, R, Ri, R₂, Rs. Rz. Rc. Rd. ‘m’, ‘n‘, 5 ’p’, ’q’ and *r* are as defined herein above, can be prepared by following the procedure as depicted in Scheme-2 startïng 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.EurJ.2009, 15, 3403 -3410). Compound of Formula (16) is converted to trifluoromethanesulfonate of 10 Formula (17) using PhNTf₂ (N-phenylbÎs(trifluoromethanesulfonimide) in presence of KHMDS (potassium hexamethyldisilazide), which further undergoes carbon-carbon (C-C) coupling reaction with corresponding boronlc 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 -OR«and Re Is alkyl or benzyl etc.,.

The double bond in compound of Formula (18) is reduced by using hydrogen over PalladiumCarbon to give ester compound of Formula (19). But compound of Formula (18) when Z Is -ORe where Re is benzyl, is converted to give acid compound of Formula (19) where Z Is OH, by carried-out the réduction and benzyl ester hydroiysls 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 HCl followed by sait préparation with hydrochioric acid in suitable solvent to give corresponding acid of Formula (Ib).

Also, compound of Formula (19) Is further deprotected the BOC group using methanoiic hydrochioric 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 subséquent 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 sait préparation with hydrochioric acid In suitable solvent to give corresponding acid of Formula (Ib). This acid compound of Formula (Ib) 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 (le) 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 sait préparation with hydrochioric 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 llmit the scope of the invention. The examples set forth below demonstrate the synthetic procedures for the préparation of the représentative compounds. Certain modifications and équivalents 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 référencé.

Uniess otherwise stated, work-up implies the following operations: distribution of the reaction mixture between the organic and aqueous phase, séparation of layers, drying the organic layer over sodium sulfate, filtration and évaporation of the organic solvent. Purification, unless otherwise mentioned, implles purification by silica gel chromatographie techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase.

Intermediates lntermedîate-1

Chromane -2-carboxylic acid

To a suspension of commerclaliy availabie chromone-2-carboxylic acid (50g, 281 mmol) ln methanol (500mL), slurry of (10% Pd/C wet, 5g) in water (10mL) was added under nitrogen atmosphère. The mixture was hydrogenated at 60 psi at room température (RT) and further maintained hydrogen réservoir 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/z178.02.

lntermediate-2 (R)- (-) - Chromane- 2- carboxylic acid

To a solution of lntermediate-1 (18.6g, 104mmol) in acetonîtrile (91 mL), (RH⁺)-¹* phenylpropylamlne (9.14g, 67.9mmol) in methyl tert butyl ether (MTBE) (12 mL) solution was added ln dropwlse manner. After about half of the total amount of the (RH⁺)-1phenylpropylamine solution was added. The reaction mixture was seeded with few crystals of ((RX+)-1-phenyl propyl ammonium (R)-(-)-chromane-2-carboxylate). The résultant thick slurry was diluted with MTBE (80 mL) and the mixture was further stirred for 6h at RT. The sait was filtered, washed with MTBE and dried. The sait (13.7g) was suspended in MTBE (80 mL) further aqueous HCl solution (1:1 ) (88mL) was added and the mixture was stirred ln 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 HCl solution (40mL). The organic layer was dried over Na₂SO₄ and evaporated under reduced pressure to afford the title compound as a white crystalline solid (6.5g); m/z-178.02.

C [a]^Mo - - 6.8.degree (c=1% In methanoi)observed.

C [α]^Μο = - 6.7.degree. (c=1% In methanol) reported in Patent: US6133277 A1, 2000.

lntermedlate-3 (R)-N-((R)-1-(Naphthalen-1-yl)ethy1)chroman-2-carboxamlde

Thionyi chloride (11.4 mL, 156 mmol) was added ln dropwise manner to a cooled O’C solution of lntermediate-2 (15.9g, 89mmol) in ethylene dichloride (160mL). The reaction mixture was allowed to RT then heated to reflux and further maintained for 1h then dimethyl formamide (1drop) was added carefully. The progress of reaction was monitored by TLC. After reaction completion the reaction mixture was concentrated under vacuum to get oliy mass. The solution of acid chloride ln dîchloromethane (DCM) (30 mL) was added to a solution of (R)-1(naphthalen-1-yl) ethanamine (15.3g, 89mmol) and triethylamine (15.5 mL, 112 mmol) in DCM (130 mL) at O’C. The reaction was further stirred for 1 h at O’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 Na₂SO₄ and concentrated under reduced pressure to afford the title compound (29 g, 98%). m/z-331.9.

lntermediate-4 (R)-N-((R)-Chroman-2-y1methy1)-1 -(naphthalen-1 -yljethanamine

To a solution of lntermediate-3 (11.8g, 35.6 mmol) ln tetrahydrofuran (THF) (90 mL), borane-dimethyl sulphide complex (8.9 mL, 89 mmol, 10M) was added at 0°C. The réaction 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 O’C and 1:1 HCl solution was added very slowiy (15 mL). After quenching, the reaction was heated to 90’C and further maintained for 1h. THF was distilled off under vacuum and the résultant residue was cooled to O’C and basified with 2M NaOH solution. Product was extracted with ethyi acetate (50mLX 3) and washed with water (25mL X 2) and a brine solution (25mL). The combined organic layer was dried over Na₂SO₄ and evaporated under reduced pressure to afford the title compound as an oily mass (11 g, 97%). m/z-318.1.

lntermediate-5 fert-Butyl ((RJ-chroman-2-ylmethyl) ((R)-1-(naphthalen-1-yl) ethyi) carbamate

To a solution of lntermediate-4 (11g, 34.7 mmol) in acetonitrile (90mL), di-fert-butyl dicarbonate (9.7mL, 41.6 mmol) was added and the solution was heated to 50^eC and maintained for ovemight. The progress of reaction was monitored by TLC. The reaction was cooled to RT and the organic soivent 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 Na₂SO₄ and concentrated under reduced pressure to afford the title compound as an oily mass (13.9g, 96 %). m/z- 417.3.

lntermedîate-6 tert-Butyl ((R)-1-(naphthalen-1-y1)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate

The mixture of lntermediate-5 (13.7g, 32.8mmol), magnésium sulphate (9.5g, 79mmol) in acetone (160mL) and water (80mL) was cooled to 0°C. To this, KMnO₄ (28.5g, 180mmol) was added in portions wise for 1h at 0 to 5^eC. 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 Na₂SO₄ 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.

lntermediate-7 (2R)-2-(((fert-Butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-4a,8a-dihydro-2Hchromen-4-yl trifluoromethanesulfonate

OTf

To a solution of lntermediate-6 (0.9 g. 2.09 mmol) In THF (5 mL). potassium bis (trimethylsilyl) amlde (0.6 g, 3.13 mmol) was added at -78^eC and stirred for 1h at the same température. 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl) methane sulfonamide (0.89g, 2.5mmol) was added at -78’C under nitrogen atmosphère. 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 (10mL), dried over Na₂SO< and concentrated under reduced pressure to get the crude product. It was purified by flash chromatography by using 5% ethyi acetate In hexane to get the title compound (0.9 g, 77% yield). m/z- 586.1 as Na+1.

lntermediate-8 (S)-Chroman-2-carboxylIc acid

ΌΗ

The title compound was resolved by following the similar procedure as described In lntermediate-2 by taking intermediate-1 and (SX+)-1-phenyl propyi amine as resolving agent. m/z-178.

lntermediate-9 (S)-2-(((fert-Butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate

The title compound was prepared in five steps:

Step: 1- lntermediate-8 was reacted with (R)-1-(naphthalen-1-yl) ethanamine by following the similar procedure as described in lntermediate-3;

Step: 2- Réduction of Step-1 Intermediate using borane dimethyl sulphide complex by following the similar procedure as described in lntermediate-4;

Step: 3- BOC protection of Step-2 Intermediate using BOC anhydride In presence of acetonitrile by following the similar procedure as described in lntermediate-5;

Step: 4- Oxidatîon of Step-3 Intermediate using KMnO< by following the similar procedure as described in lntermediate-6;

Step: 5- Intermediate Step-4 treating with 1,1,1-trifluoro-N-phenyl-N-((trifluoro methyl) sulfonyl) methane sulfonamide In presence of KHMDS by foliowing the similar procedure as described in lntermediate-7; m/z- 586.1 as Na+1.

lntermediate-10 (R)-2-(((tert-Butoxycarbonyl)((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)-2H-chromen4-yl trifluoromethanesulfonate

The title compound was prepared in foliowing five steps:

Step 1: By taking lntermediate-2 and corresponding (R)-1-(4-fluoro-3-methoxyphenyl) ethanamine hydrochloride by following the slmiiar procedure as described ln lntermediate-3.

Step 2: Réduction of Step-1 Intermediate using borane dimethyl sulphide compiex by following the similar procedure as described in lntermediate-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 lntermediate-5.

Step: 4- Oxidatîon of Step-3 Intermediate using KMnO< by foilowing the simliar procedure as described in lntermediate-6.

Step 5: The title compound was prepared by reacting Step-4 Intermediate with 1.1.1-trifluoroN-phenyl-N-((trifluoromethyl) sulfonyl) methane sulfonamide in presence of KHMDS by following the simiiar procedure as described in lntermediate-7; m/z- 584.1 as Na+1.

lntermediate-11 (R)-2-(((fert-Butoxycarbonyl) ((R)-1-(4-fluoronaphthalen-1-yl) ethyl) amino) methyl)-2H-chromen4-yl trifluoromethanesulfonate

The title compound was prepared In five steps:

Step 1: lntermediate-2 was reacted with corresponding (R)-1-(4-fluoronaphthalen-1-yl) ethanamine hydrochloride by following the similar procedure as described in lntermediate-3.

Step 2: Step-1 Intermediate was undergone réduction reaction using borane dimethyl sulphide complex by following the similar procedure as described in lntermediate*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 lntermediate-5.

Step 4: Step-3 Intermediate was undergone oxidation reaction using KMnO< by following the similar procedure as described in lntermediate-6.

Step: 5: Step-4 Intermediate was reacted with 1, 1, 1-trifluoro-N-phenyl-/V-((trifluoro methyt)sulfonyl) methane sulfonamide in presence of KHMDS by following the similar procedure as described In lntermediate-7; m/z- 481.7(m-100).

lntermediate-12 (S)-2-(Chroman-2-yl) acetic acid

To a solution of lntermediate-8 (0,5g, 2.81 mmol) in ethylene dichioride (10 mL), thlonyl chloride (0.35 mL, 4.77 mmol) was added In dropwise manner atO’C. The mixture was heated to reflux and maintained for 1h. 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 (S)-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 (10mLX 3). The combined organic phase was dried over Na₂SO₄, concentrated under vacuum to get crude (S)-2-(chroman-2-yl)-2-oxoethanediazonlum (0.16 g, 77 % yieid).

To a solution of siiver 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 (S)-2-(chroman-2yl)-2-oxoethanediazonlum (0.16 g, 0.79 mmol) was slowly added at 0’C. The reaction mixture was allowed to RT and maintained ovemight. The reaction was monitored by TLC after completion of the reaction and mixture diluted with water (5 mL) and acldified with 1:1 HCl, extracted with ethyl acetate (10mL X 3). The combined organic phase was dried over Na₂SO4, 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 % yieid). m/z-192.13.

intermediate-13 (R)-2-{2-{(fert-ButoxycarbonylX(R)-1-(naphthalen-1-yl}ethyl)amino)ethyl)-2H-chromen-4-yl trifluoromethanesulfonate

OTf

The titie compound was prepared In five steps:

Step 1: lntermediate-12 was coupled with (R)-1-(naphthalen-1-yl}ethanamIne by following the similar procedure as described in lntermediate-3:

Step 2: The above Step-1 Intermediate was undergone réduction 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 lntermediate-5;

Step 4: Step-3 Intermediate was oxidized using KMnO₄ by following the similar procedure as described ln lntermediate-6;

Step 5: Finally, the above Step-4 Intermediate was reacted with 1,1, 1-trifluoro-N-phenyl-N((trifluoro methyl) sulfonyl) methane sulfonamlde in presence of KHMDS by following the similar procedure as described in lntermediate-7; m/z: 478.0 (m-100).

lntermediate-14 (R)-2-(Chroman-2-yl) acetic acid

The titie compound was prepared by following the similar procedure as described in lntermediate-12 by taking lntermediate-2; m/z-192.13.

lntermediate-15 (S)-2-(2-((terf-Butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-2H-chromen-4-yl trifluoromethanesulfonate

OTf

The title compound was prepared In five steps:

Step 1: lntermediate-14 was coupled with (R)-1-(naphthalen-1-yljethanamine by following the similar procedure as described in lntermediate-3;

Step 2: The above Step-1 Intermediate was undergone réduction reaction using borane dim ethyl sulphide complex by following the similar procedure as described in lntermediate-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 lntermediate-5;

Step 4: Step-3 Intermediate was oxidized using KMnO< by following the similar procedure as described in lntermediate-6;

Step 5: Finalîy, The above Step-4 Intermediate was reacted with 1,1, 1-trifluoro-N-phenyl-N((trifluoro methyl) sulfonyl) methane sulfonamide In presence of KHMDS by following the similar procedure as described In lntermediate-7; m/z: 478 (m-100).

lntermediate-16 (R)-Methyl chroman-2-carboxylate

O

To a solution of lntermediate-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 malntained for 1 h. 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 Na₂SO< and evaporated under reduced pressure to give coloriess oily mass (15.6 g. 96 %); m/z-192.8.

lntermediate-17 (R)-Chroman-2-carbaldehyde

To a solution of Intermedia te-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 température. The progress of reaction was monitored by TLC. Réaction 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 Na₂SO₄ 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/z162.94.

lntermediate-18 (R, E)-Ethyl 3-(chroman-2-yl) acrylate

To solution of lntermediate-17

69.1 mmol) 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. Réaction 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 Na₂SO₄ 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 (11.1g, 69.2%); m/z-232.11.

lntermedlate-19 (R)-Ethyl 3-(chroman-2-yl) propanoate

To a suspension of 10% palladium on carbon (2.1g, 50% wet) in éthanol (10 mL), lntermediate-18 (11.1g, 47.8 mmol) in éthanol (100mL) was carefully added and the mixture was stirred ovemight 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 (11.1g, 99 %); m/z-234.4.

lntermediate-20

To a solution of lntermediate-19 (11.1g, 47.4 mmol) in THF (100 mL), methanol (100 mL) and water (10 mL) lithium hydroxide hydrate (2.98g, 71.1 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 HCl 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 Na₂SO₄ and concentrated under vacuum to get white solid (9.2 g, 94 %); m/z-206.17.

lntermediate-21 (S)-2-(3-((ter1-Butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-2H-chromen-4-yl trifluoromethanesulfonate

OTf

The titie compound was prepared In following five steps:

Step 1 : lntermediate-20 was coupled with (R)-1-(naphthalen-1-yl) ethanamine by following the similar procedure as described in lntermediate-3;

Step 2: The above Step-1 Intermediate was undergone réduction reaction using borane dimethyl sulphide complex by following the similar procedure as described in lntermediate-4;

Step 4: Step-3 Intermediate was oxidized using KMnO₄ by following the similar procedure as described in lntermediate-6;

Step 5: Finaily, the above Step-4 Intermediate was reacted with 1, 1, 1-trifluoro-/V-phenyl-/V((trifluoro methyl) sulfonyl) methane sulfonamide in presence of KHMDS by following the similar procedure as described in lntermediate-7; m/z : 491.4 (M-100).

lntermediate-22 (S)-Methyl chroman-2-carboxylate

The title compound was prepared by following the similar procedure as described In lntermediate-16 bytaking lntermediate-8; m/z-192.2.

lntermediate-23 (S)-Chroman-2-carbaldehyde

The title compound was prepared by following the similar procedure as described in lntermediate-17 by taking lntermediate-22; m/z-163.

lntermediate-24 (R)-2-(3-((fert-Butoxycarbonyl)((R)-1-{naphthalen-1-yl)ethyl)amino)propyl)-2H-chromen’4-yl trifl uorometha nés u Ifona te

OTf

The title compound was prepared In following eight steps:

Step 1: lntermediate-23 was reacted with ethyl 2-(triphenyl phosphoranylidene)acetate by following the similar procedure as described In lntermediate-18;

Step 2: The above Step-1 Intermediate undergone hydrogénation with 10% palladium by following the similar procedure as described in lntermediate-19;

Step3: The above Step-2 Intermediate was hydrolyzed In presence of lithium hydroxide by following the similar procedure as described In lntermediate-20;

Step 4: Step-3 Intermediate was condensed with (R)-1-(naphthalen-1-yl) ethanamlne by following the similar procedure as described in lntermediate-3;

Step 5: The above Step-4 Intermediate undergone réduction réaction using borane dimethyl sulphide complex by following the similar procedure as described In lntermediate-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 lntermediate-5.

Step 7: Step-6 Intermediate was undergone oxidation reaction using KMnO₄ by following the similar procedure as described in lntermediate-6.

Step 8: Step-7 Intermediate was reacted with 1, 1, 1-trifluoro-N-phenyl-N-((trifluoro methyl) sulfonyl) methane sulfonamide in presence of KHMDS by following the similar procedure as 5 described in lntermediate-7: m/z : 491.4 (M-100).

lntermediate-25 (S)-2-(2-((tert-Butoxycarbonyl)((R)-1-(4-fluoronaphthalen-1-y!)ethy!)amino)ethy!)-2H-chromen-4-

yl trifluoromethanesuifonate	Çoc
frX	I T il
	¹ M
OTf
10 The title compound was prepared in five steps:

Step 1: lntermediate-14 was coupled with (R)-1-(4-fluoronaphthalen-1-yl) ethanamine hydrochloride by foilowing the similar procedure as described in lntermediate-3;

Step 2: The above Step-1 Intermediate was undergone réduction reaction using borane dimethy! sulphide complex by following the similar procedure as described in lntermediate-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 oxidlzed using KMnO₄ by following the similar procedure as described in lntermediate-6:

Step 5: Finally, the above Step-4 Intermediate was reacted with 1, 1, 1-trifluoro-N-phenyl-N20 ((trifluoro methyl) sulfonyl) methane sulfonamide in presence of KHMDS by following the similar procedure as described in lntermediate-7; m/z: 617.8 as Na+1.

lntermediate-26 (R)-2-(2-((tert-Butoxycarbonyl) ((R)-1-(4-fluoronaphthalen-1-yl) ethyl) amino) ethy1>2Hchromen-4-yl trifluoromethanesulfonate

OTf

The title compound was prepared In five steps:

Step 1: lntermediate-12 was coupled with (R)-1-(4-fluoronaphthalen-1-y1) ethanamine hydrochloride by following the similar procedure as described In lntermediate-3;

Step 2: The above Step-1 Intermediate was undergone réduction reaction using borane dimethyl sulphlde complex by following the similar procedure as described In lntermediate-4;

Step 4: Step-3 intermediate was oxldized using KMnO₄ by following the similar procedure as described In lntermediate-6;

Step 5: Flnally, The above Step-4 Intermediate was reacted with 1,1, 1-trifluoro-N-phenyl-A/((trifluoro methyi) sulfonyl) methane sulfonamide in presence of KHMDS by following the similar procedure as described in lntermediate-7; m/z: 617.8 as Na+1.

lntermediate-27 (S)-2-(2-((tert-Butoxycarbonyl)((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)amlno)ethy1)-2H-chromen-

The title compound was prepared In five steps:

Step 1: lntermediate-14 was coupled with (R)-1-(4-fluoro-3-methoxyphenyl) ethanamine hydrochloride by following the similar procedure as described in lntermediate-3;

Step 4: Step-3 Intermediate was oxidlzed using KMnO₄ by following the similar procedure as described ln lntermediate-6;

Step 5: Flnally, The above Step-4 Intermediate was reacted with 1,1, 1-trifluoro-N-phenyl-N((trifluoro methyl) sulfonyl) methane sulfonamlde ln presence of KHMDS by following the similar procedure as described In lntermediate-7; m/z: 576.

lntermediate-28 (R)-2-(2-((tert-Butoxycarbonyl)((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)amino)ethyl)-2H-chromen4-yl trifluoromethanesulfonate

OTf

The tltle compound was prepared ln five steps:

Step 1: intermediate-12 was coupled with (R)-1-(4-fluoro-3-methoxyphenyl) ethanamine hydrochloride by following the similar procedure as described in lntermediate-3;

Step 2: The above Step-1 Intermediate was undergone réduction reaction using borane dimethyl sulphlde complex by following the similar procedure as described ln lntermediate-4;

Step 3: The above Step-2 Intermediate was undergone BOC protection using BOC anhydride In acetonitrile by following the similar procedure as described ln lntermediate-5;

Step 5: Finally, the above Step-4 Intermediate was reacted with 1, 1, 1-trifluoro-N-phenyl-N((trifluoro methyl) sulfonyl) methane sulfonamlde In presence of KHMDS by following the similar procedure as described ln lntermediate-7; m/z: 576.

lntermediate-29 (S)-2-(3-((tert-Butoxycarbonyl)((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amlno)propyl)-2H-chromen-

4-yl trifluoromethanesulfonate
rVT	I A
ULU	Boc φφρ
OTf

The title compound was prepared In following five steps:

Step 1: lntermediate-20 was condensed (R)-1-(4-fluoronaphthalen-1-yl) ethanamine hydrochloride by following the similar procedure as described In lntermediate-3;

Step 2: The above Step-1 Intermediate undergone réduction reaction using borane dimethyl sulphide complex by following the similar procedure as described In lntermediate-4;

Step 3: The above Step-2 Intermediate was protected with BOC by reacting with BOC anhydride In acetonitrile by foilowing the similar procedure as described in lntermediate-5.

Step 4: Step-3 Intermediate was undergone oxidation reaction using KMnO₄ by following the similar procedure as described In lntermediate-6.

Step 5: Step-4 Intermediate was reacted with 1, 1, 1-trifluoro-N-phenyl-N-((trifluoro methyl) sulfonyl) methane sulfonamide In presence of KHMDS by following the similar procedure as described In lntermediate-7: m/z : 509.6 (M-100).

lntemriediate-30 (S)-2-(3-((tert-Butoxycarbonyl)((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)amino)propyl)-2Hchromen-4-yl trifluoromethanesulfonate

OTf

The title compound was prepared In following five steps:

Step 1: lntermediate-20 was condensed with (R)-1-(4-fluoro-3-methoxyphenyl) ethanamine hydrochloride by following the similar procedure as described In lntermediate-3;

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 lntermediate-5.

Step 5: Step-4 Intermediate was reacted with 1, 1, 1-trifluoro-/V-phenyl-/V-((trifluoro methyl) sulfonyl) methane sulfonamide in presence of KHMDS by following the similar procedure as described In lntermediate-7: m/z : 489.8 (M-100).

lntermediate-31

Methyl 5-((2R)-2-(((tert-Butoxycarbonyl)((R)-1-(naphthaien-1-yl)ethyl) amino) methyl) chroman4-yl)-2-fluorobenzoate

Step-1: Methyl 5-((R)-2-(((tert-butoxycarbonyl) ((R)-1-(naphthalen-1-yl) ethyl) amino) methyl)2H-chromen-4-yl)-2-fluorobenzoate lntermediate-7 (0.850g, 1.503mmol) was dissolved in toluene (5mL), éthanol (5mL) and water (0.5mL) then (4-fluoro-3-(methoxycarbonyl) phenyl)boronic acid (0.45 g, 2.254 mmol) and Na₂CO₃ (0.478 g, 4.51 mmol) were added under nitrogen atmosphère. 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 Na₂SO₄ 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% yleld); m/z- 467.1.

Step-2:- Methyl 5-((2R)-2-(((tert-butoxycarbonyl) ((R)-1-(naphthalen-1-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 (10mL), 10% palladium on carbon (150mg) In methanol (5 mL) was carefully added and the mixture was stirred ovemight 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% yleld). 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, Ri, ’n’ and ‘q‘ are as defined herein above;

The chromene intermediate was prepared by following procedure.

Triflate Intermediate for example any one of lntermediate-7, intermediate-9 to 11, Intermediate13, lntermediate-15, lntermediate-21, or lntermediate-24 to 30 was dissolved In mixture of toluene, éthanol and water. Then optionally substituted phenyl boronic acid and Na₂CO₃ were added under nitrogen atmosphère 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 réaction was monitored by TLC. The réaction 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 Na₂SO4 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 réduction):

where R₂ is substituted or unsubstituted aryl; X, Z, '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 ovemight under a pressure of balloon of hydrogen. The progress of reaction was monitored by TLC. The réaction 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 Step1 and then Step-2;

Table-1:

Interme dlate	Structure Mass(m/z)	Interme dlate	Structure Mass (m/z)
32		ï (^>1	33			I	Π
		ry X A JJ r y n
	Y	UoA>V		A-	II	cAcA
		A ^x			r	r
		kJyA			A	T°^x
		0				0
		452.2(M-100)			509.69(M-55)
34		- AA	35			-	n
		cl A JL J îrT ΝτΨ			A	aay	1 Ij XX
	A	OAoC*			II		.Jÿj
		A			rï	X
					U	Ύ°^ν
		0				0
		509.69(M-55)			509.69( M-55)
36		- AA	37			-
		o .x aA/			,O_X	A^N'Ari'	I 1] xx
	kx	VAU		C	Γ	AJ	A
		Λ Ά			rï	A
		Tïï ^Οχ			LJ	<xA
		x °				0
		479.56(M-100)				594.5
38			39			-	aa
					y		i y X>X
	Az·	XAaAJ			ΪΓ	AJ
		a ^x			r	f A
		γγθ_χ			ly	ïï°^x
		A ⁰			F	0
		591.95			488.1(M-100)

40	0 R	u 484.	-y Y⁰'' 0 2(M-100)	n	41	zX· x^.	CO0 Ύγ (xo jA 4tY⁰^ 480.1 (M-100)	n xx V
42			-	Aïl	43		-	Aïi
	X'''	.0. il T		1 1] XX			/aA	I H Ύ-χ
		Il 1	cAoX	Y		U	[ T j (i XX CrTi
		Q	X Y°				A A tY⁰'
		CF,					I 0
			620				463.1 (M-100)
44			-	Aïi	45		-	Ai
				1 J			r°<A	1 l\| Xx
	C	Γ T	j l 0^0	«A		^5x	44 qAo
		UlT	F xA				O
		UC	Y°^			F'	XXo_x
			0
		470.2(M-100)				470.2(M-100)
46			-	n	47		*	Ail
				JL 11 XX			_rVx	1 H •χχ
	Y,	Jl I	cAc4			X^	ÇOv
	R	rïi	X				A
		M¹	Y⁰^				tY⁰^
			0				A o
		470.2(M-100)
							480.68(M-100)

48	Μ,	-	49	cXxxxîj vy o^o 0 480.68(M-100)
.0. if 0 480	QX> Y°^ 0 .68(M-100)
50			;	51		= y->
	X''	.CL
	Μχ	J]	WU		UU	_or_o LJ
		A	A		lil	X
		M			MM	'Ύ'
			0			O
		496(M-100)		496.1 (M-100)
52			-	53
		o.	i 1 IJ		_____	i 1 IJ
	X				r^Y >
		Il	₀A>V		UU	A> V
		ri	Y		A	_r ^F X
		LM	M⁰'		LM	M⁰'
		F	0			0
		500 (M-100)		500 (M-100)
54			-	55		: Î^jl
	ί^<ί?Χ	O_x	ΧνΎΑυ		rr⁰'	M'nMAt
	Mz	Γ	oAjU'		UU	oA Y
		ri	A		y	1
	F'	JU	Μλ 0		M	M⁰' 0
		500 (M-100)		500 (M-100)

56	νγ o^o y A⁴· Οχ. 555.2 (M-55)	Π y	57	oxû Ύ'Χ) 511.9 (M-39)	JÛ
58	-		59	—
		I n		ΑτΥΛ	JL B ^ZÏ%!Y
	L JL J j h			L1 J à L o^o ^k
	ôk			ÛL

	'O'X)			Ύ'Χ)
	466.2(M-100)			620.1
60	*	Î^il	61	-
		1 J\|			1 I]
	ΟΟλΑ			UUoAA
	rïl			^Yi Ÿ
	^FV^F			J
	Ύ'Χ)			(Yo'
	488.1 (M-100)			581.33
62	-		63	*
	n ''ύ	1 1]		r'W'-N'Sr	1 l\|
	L JL J j T Y\z o^o			L JL J j 1 Vy (Λθ	y
	nr^F X			y

	^Χ(Αθ
	469.3(M-100)			569.32

Μ

64	ς) χ° 526 (M-69)	n	65	[Xf°X^NXY XX^ ₀X 4 A A 500 (M-100)
66		O	67
	UU„m	JL JJ As/		OÔXu
	ό			ip
				^χΟγν
	^°yJ			0
	0			494.1 (M-100)
	466.1 (M-100)
68	: :	x	69	- fXi
	x/ÿ	X		,//VôV UJaV Λ ^x
	^χθΧ)			TT⁰'
				F 0
	563.3			469.2(M-100)
70			71	:
				ίΧΧΧΧιι
	L 1 J Y l X°X	Y		LY ₀X X fX
	UL^X			ΤΠ
	0			I 0
	451.7(M-100)			463.1 (M-100)

72	oô;ù9 ç ' x° ^χο^Λο 526 (M-69)	73	οαάχ (Ao I 463.6 (M-100)
74	T	75	î
	oçœcc		ooxcc
			cXoA
	ΜγΟχ.		I 0
	0
			463.6(M-100)
	463.6 (M-100)
76	Ξ	77	»
	ooxœ		oœçcc
			OL A
	o		\|\|
			0
	463.6(M-100)		463.6(M-100)
78		79
	UkJ _oa_o Uk_F		^ΎΊΐ
	A		zOA AAf
	τπ °^x		^°γΜ *U
	I 0		0
			500 (M-100)
	\| 484.29 (M-100)		I

80	ψ	81	Ψ ο Y^j F 0 484.1 (Μ-100)
F 0 484.1 (Μ-10	υ 0)
82	ψ		83	Ψ
	Ο_γΟ	η Τ 1		₀ JYjp.
				Il I I I I II

				[
	II
	τπ °^χ			I II
	I ο			ΤΠ
	480.1 (Μ-100)		I ο
				480.1 (Μ-100)
84	Ψ		85	ψ
	ο^ο			^ογ°ίΥ
		XI		[ίΥΥ^Ύγΐ]
	ί\| Ι*^ Ι	T U
				0Γ
	I η			γΊ1
				1 \|Ι ι-ι

	Μγ<\			1 0
	ο
				497.7 (Μ-100)
	495
86	ψ		87	Y υ
	oyo	rf		°γ°Ϋ
	γύ°τ^^ντ	T il
	Μγ ¹	Μ		υγ *
	ΓΙ)			ril
	ττ^ο			ΤΠ
	1 0			I 0
	497.7 (Μ-100)		600 (Na+1)

88	Ύ A) <γ> cçHA τϊ^Οχ ' 0 600(Na+1)	JF	89	0	φγγγ X χ ττ⁰^ F 0 498.56 (Μ-100)	η ^Υ
90	-	ίΥΐ	91		-	ίΥΐ
		1 Ι\|				I π
	OQ οΑΑ			υ	ψ «aJ	^Υ
	Λ χ				A ^χ
	τϊ°^χ				ΤΥ°^
	F 0				I 0
	498.56 (Μ-100)				493.2 (Μ-100)
92		rX	93		f
	Η J J j Η Λ	1 I] Ύ		ο
	ΤΤ				I ô
	I 0
	493.2 (Μ-100)				492.56 (Μ-100)
94	=	ΓΊ	95		ί	Π
	ΑΎθγ*'—ΑΧ
	Ο0“ οΑΛ			υ	Ο οΑΛ
					Λ
	φτ				Y
	ΟΧ 511.8( Μ-100)			<	497.7(Μ-100)
96	j	ίΠ
	<Υ^°Υ*^^χ^'Ν^>Λγ	Άγ
	CU οΑΛ
	Ττ^Οχ
	I 0
	511 (Μ-100)

lntermediate-97

3-((2R,4S)-2-(((fert-Butoxycarbonyi)((R)-1-(naphthalen-1-yi)ethyi)amino)methyl) chroman-4-yl)2,6-dimethylbenzoic acid

Step-1:3-((R)-2-(((fert-Butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2Hchromen-4-yl)-2,6-dimethylbenzolc acid lntermediate-7 (0.32g, 0.57mmoi) was dissolved in toluene (5mL), éthanol (5mL) and water (0.5mL) then (3-((benzyloxy)carbonyi)-2,4-dimethylphenyl)boronic acid (0.2 g, 0.57 mmoi) and Na₂CO₃ (0.18 g, 1.7 mmol) were added under nitrogen atmosphère. The reaction mixture 10 was stirred for 30 minutes then added Pd (Ph₃P)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 réaction mixture was cooled to RT and fiitered through Celite. The filtrate was extracted with ethyi acetate (25 mL X 2) and washed with water (15 mL) and brine solution (15 mL). The organic iayer was dried over Na₂SO₄and concentrated under 15 reduced pressure to get crude product. The crude compound was purified by flash chromatography (5% ethyi acetate in Hexane) to give title compound as solid (0.25 g, 67.3% yield); m/z-654.7.

Step-2: 3-((2R,4S)-2-(((fert-Butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyi)amino) methyl)chroman-4-yi)-2,6-dÎmethylbenzoicacid

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 carefuliy added and the mixture was stirred ovemight under a pressure of balloon of hydrogen. The progress of réaction 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 préparative HPLC method. Séparation 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 lntermediate-97 in two steps, thus 30 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 taklng intermediate-15, intermediate-21, intermediate17086 «9 or intermediate-27 and (3-((benzy1oxy)carbonyl)-2,4-dimethyl phenyl) boronic acid, ln this stage the title compounds of diastereomers were obtained in different diastereomerlc ratio(s).

Further, the two diastereomers of intermediate-98 were separated by using chiral préparative HPLC.

Séparation Method: CHIRAL PAK 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.

Similariy, the two diastereomers of intermediate-99 to intermediate-101 were separated by using chiral préparative HPLC.

Séparation Method: CELLULOSE-1 250 x 4.6 5u; Mobile Phase: A: Hexane/IPA (9:1, 0.1%

TFA)B=IPAA=100% v/v.

Table-2:

Interme	Structure	Interme	Structure
diate	Mass(m/z)	diate	Mass(m/z)
98	Ψ ₀	99	CO'Xï?
	UkJ M
			Vv^0H
	tïï°^h		IJ
	I o
	479.7(M-100)		493.5(M-100)
100	n	101	T
	ŒT <aV ksJL^OH		cœçxÿx? L^A,OH
	I Q		I O
	493.5(M-100)		492.56(M-100)

EXAMPLES

Example-1a,1b

lntermediate-31 (0.35g, 0.614mmol) was dissolved in dichloromethane (DCM) (5mL) and methanolic HCl (10mL, 3N) was added. The reaction mixture was stirred at RT ovemight. The progress of reaction was monitored by TLC. The reaction was evaporated under reduced pressure then added saturated Na₂CO₃ 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 Na₂SO₄ and concentrated under reduced pressure. This was further purified by flash chromatography (15% ethyl acetate in Hexane) to give diastereomers. Further these dlastereomers were separated by chiral préparative HPLC to give Example-1 a 30 mg (at RT 4.79 mins) and Example-1 b 100 mg (at RT 9.65 mlns); m/z -470.1.

Séparation 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 foliowing the similar deprotection procedure as described in Example-1 a,1b by taking from corresponding lntermedlate-32 to 72, lntermediate-78 or lntermediate-79 using methanolic HCl.

The two diastereomers of Example-2 to 44 were separated by using similar chiral préparative HPLC method as mentioned In Example-1 a, 1b.

Table-3:

Ex.No.	Intermed late No.	Structure	Mass (m/z)
2	32			-		452.2
			o		1 D
		f\			ΙΊ
				H \|	M
			Λ
			M
				O
3	33			τ		465.61
			ï J	ro

			ri
			U	T ^x
				O
4	34			ï	lAl	465.6
		i*’''	χ/θχ \|Γ		JL 11
			II	1 h 11
			ri
			JU	T
				0

5	35	Z' k^	KJ U	00 y°x 0	0 sJ	465.61
6a,6b	36			.					τ	0	480.1
		10		El i	1 Ί		jf J		‘0	iY
					sJ	Xïx				XJ
			λ i
							ΓΪ1
			Z	Y°^x			XJ		,0^
			X					0
7	37					r		il			494.5
				f'	T T	00	iiT	1]
				Y	1 J		M
					γΊι
					M	Y°^
						o
8a,8b	38			-	Z'	Ί1					491.9
		s?'·				JJ	0,.		:	1 ]
			Γ		T				n0	iT
		k^			XJ		LJ		H	J
			7			Xsx·

			Γ				10
			T				LJ		.0^
			A					0
9	39					-		Ίΐ			487.73
				(Z'	_.CK Γ J	00	ÎJ	y
				k^			XJ

					riî
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10a,10	40			.	Z'	\|ï			:		484.1
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23	53	Z^	Xk, ΓΊΓ δ	^¼³ ,F 0	500.1
24a,24	54		X		î]	_t		500
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28a ,28	58		»	X	T]	:		465.61
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29a,29 b	59	OCr· à,. ^νΟ^ΛΟ	? ru ? M Oôpn ^cAo	A CT	520.44
30	60		= _Π		488.1
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			γΊι
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31a,31	61		? fUi -		481.86
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32	62		: n		469.9
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40	70	00 0° 0	1 JÛ V	452.2
41a,41 b	71	Y	0. I 0	465.61
42a,42 b	72	oûô? Φ x°	r°	482.2
43a,43 b	78	Û00 0-	I 0	484.3
44a,44 b	79	QT u, ά 0	0	500.43

The below Examples-45 to 49 given In Table-4 were prepared by following the similar deprotectlon procedure as described In Example-1a,1b by taklng corresponding lntermediate-73 to 77 using methanolic HCl. These examples were obtained with more than 90 % enantiomeric 5 purity and they were directly used for ester hydrolysls without séparation by chiral HPLC.

Table-4:

Ex.No.	Intermedl ate-No	Structure	Mass (m/z)
45	73	οτπχ °S	463.5
46	74	000? o	463.5
47	75	OO0X ' 0	463.5
48	76	η O /	463.5
49	77	C00? 0	463.5

Examole-50

lntermediate-80 (0.3g, 0.514mmol) was dissolved in DCM (10mL) and methanol / HCl (3mL, 3N).The reaction mixture was stirred at 40°C ovemight. The progress of reaction was monltored by TLC. The reaction was evaporated under reduced pressure then added saturated Na₂CO₃ solution (5mL). The mixture was extracted with ethyl acetate (10mLx2) and washed with water (5mLx2) followed by brine solution (5mL), dried over Na₂SO₄ and concentrated under reduced pressure. This was further purified by flash chromatography (15% Ethyl acetate ln Hexane) to give diastereomers of the title compound (190mg, 76 %). m/z - 498. Further, these diastereomers were separated by similar chiral préparative HPLC method as mentioned In Examplela, 1b to give Example-50 (80 mg); m/z: 484.3.

The below examples 51 to 66 given ln Table-5 were prepared by following the similar deprotection procedure as described ln Example-50 by taking any one of lntermediate-81 to 96 using methanolic HCl. Further, the diastereomers of Example-51 to 53 and 59 to 66 were separated by chiral préparative 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 préparative HPLC method. Method: CHIRAL PAK ID: 250mm x 4.6,5μ; Mobile Phase: A=n-hexane IPA (90/10 %v/v, 0.1 %DEA) B=lPA, A: B=95/5 %v/v.

Table-5:

Ex.No	Intermedl ate-No	Structure	Mass (m/z)
51	81	F O	484.3
52	82	CQ Φτ	480.05
53	83		480
54	84	0	481.51
55	85	cô'~-*Æ> Φτ	497.8

56	86		497.8
57	87	Y	478.48
58	88		478.48
59	89	Y	498.49
60	90	cç~A9 Y	498.49
61	91	^IÎq	494

62	92	Φϊ'	494
63	93	' 0	492.49
64	94		512.56
65	95		498
66	96		512

Example-67

2, 6-Dimethyl-3-((2R, 4S)-2-((((R)-1-(naphthalen-1-yl) ethyi) amino) methyl) chroman-4-yl) benzolc acid hydrochloride

lntermediate-97 (0.45 g, 0.795 mmol) was dissolved in DCM (10 mL) and ethereal HCl (10mL) was added. The reaction mixture was stirred at RT ovemight. The progress of reaction was monitored by TLC. The reaction was evaporated under reduced pressure.

The résultant solid was washed with diethyl ether (2 mL) followed by n-pentane (2mL), dried to get the corresponding hydrochloride sait (0.32 g, 65 % yield).

m/z: 466.1; ’HNMR (400MHz, DMSO-d_e): δ 13.21 (bs, 1H), 9.80 (bs, 1H), 9.48 (bs, 1H), 8.30 (d, J=8.0 Hz, 1 H). 8.05 (m, 3H), 7.68-7.60 (m, 3H), 7.15 (t, J=7.6Hz, 1H), 7.02 (d, J=7.2 Hz, 1H ) , 6.89 (d, J=7.2Hz, 1 H). 6.82-6.78 (t, J=7.6 Hz, 2H), 6.54 (m,1H), 5.47-5.46 (m, 1H) 4.66 (m, 10 1H), 4.51 (m, 1 H). 3.34 (m, 1H), 3.16 (m, 1H), 2.45 (s, 3H), 2.22 (m.1H) ,2.20 (s,3H), 1.85 (m,1H), 1.75(d, J=6.8 Hz, 3H).

The below Examples-68 to 71 glven ln Table-6 were prepared by following the similar deprotection procedure as described ln Example-67 by taking corresponding Intermediate - 98 to 101 using ethereal HCl.

Table-6:

Ex. No.	Intermedia te-No	Structure	Mass (m/z)
68	98	2,6-Dimethyl-3-((2R,4S)-2-(2-(((R)-1(naphthalen-l-yl)ethy!) amino) ethyljchroman4-yl) benzolc acid hydrochloride	480.1

		LaJ * M

		AJAoh
		1 O
		¹H NMR (400 MHz, DMSO-d6):nnn13.2 (bs, 1H), 9.60 (bs. 1 H), 9.20 (bs, 1H), 8.27-8.25 (d, J ~ 8.4Hz, 1H), 8.03-8.00 (m , 2H), 7.83-7.81 (d, J = 7.6Hz, 1H), 7.66-7.58 (m, 3H), 7.07-7.00

		(m. 2H), 6.76-6.69 (m, 3H), 6.60-6.50 (m, 1H) 5.43-5.40 (m, 1H). 4.50-4.10 (m, 1H). 4.31-4.26 (m, 1H), 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-Dlmethyl-3-((2R_l4R)-2-(3-(((R)-1 (naphthalen-1-yl)ethyl) amino) propyl)chroman4-yl)benzoic acid hydrochloride cQ'Yd? ÇÇ°H ¹H NMR (400 MHz, DMSO-d_e): δ 13.20 (bs, 1H), 9.82 (bs, 1H),9.25(bs, 1H), 8.28 (d, J=8.4 Hz, 1H), 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, 1H), 4.46 (m, 1H), 4.13(m, 1H). 3.04 (m, 1H), 2.85(m,1H), 2.32 (s,3H), 2.22 (s, 3H), 2.05 (rn.lH). 1.89 (m,2H), 1.74-1.64 (m, 6H).	494.1
70	100	2.6-Dimethyl-3-((2S,4S)-2-(3-(((R)-1(naphthalen-1-yl)ethyl) amino) propyl)chroman4-yl) benzoic acid hydrochloride YXzOH I O ¹H NMR (400 MHz, DMSO-d_e): δ 13.20 (bs, 1 H), 9.58(bs, 1H), 9.13 (bs, 1H), 8.28 (d, J=8.4Hz, 1H), 8.00 (t, J=8.4 Hz, 2H). 7.93 (d, J=7.2 Hz, 1H),7.65-7.58 (m, 3H), 7.07 -6.99 (m, 2H), 6.78-6.66 (m. 3H). 6.55-6.49 (m, 1H),	494.1

8«

		5.34 (m, 1H), 4.47 (m, 1 H), 4.17 (m, 1H), 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).
71	101	3- ((2S,4S)-2-(3-(((R)-1-(4-Fluoro-3methoxyphenyl)ethyl) amino) propyl)chroman- 4- yl)-2,6-dimethylbenzoic actd hydrochloride	492.42
		ccoôcc


		I 0
		’H NMR (400 MHz, DMSO-d_e): 13.39 (bs, 1H), 9.40 (bs, 1 H), 9.18 (bs, 1 H), 7.53 (dd J=8.4Hz &J=1.6Hz 1 H), 7.30-7.25 (dd, J=11.2 Hz & J=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=6.4 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,1H) ,1.85 (m, 1H), 1.72-1.67 (m, 4H), 1.55(d J=6.8 Hz, 3H).

Example-72a, 72b

To a solution of Example-1a (0.1g, 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 80C 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 4J. Extract the product with ethyl acetate (10mL X 2) washed with water (5 mL X 2) followed by brine solution (5 mL), dried over Na₂SO₄ and concentrated under vacuum to get the solid.

Préparation of hydrochloride sait

To the above compound ethereal HCl (2 mL) was added and stirred for 10 minutes. Then the solvent was removed and the résultant solid was washed with diethy! ether (2 mL) followed by n-pentane (2mL), dried to get the corresponding hydrochloride sait (0.08 g, 82 % yield).

m/z- 456.1; ¹H NMR (400 MHz, DMSO-d_e): 513.30 (bs, 1H), 9.65 (bs, 1H), 9.20 (bs, 1H), 8.21 (d, J - 8.0 Hz, 1H), 8.02-7.98 (m. 2H), 7.90 (d, J =7.2 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, 1 H), 4.37 (m, 1H), 4.24 -4.22 (m, 1H), 3.403.30 (m, 1 H), 3.06-3.04 (m, 1H), 2.12-2.04 (m, 1 H),2.00-1.96 (m, 1H), 1.68 (d, J = 6.8 Hz, 3H). Similarly, Example-72b was prepared from Example-1 b by using the above procedure.

m/z-456,1; Ή NMR (400 MHz, DMSO-d_e): δ 13.30 (bs, 1H), 9.76 (bs, 1H), 9,36 (bs, 1H), 8.30 (d, J = 8.4 Hz, 1H). 8.05 (t, J = 8.0 Hz, 2H), 7.97 (d, J = 7.2 Hz, 1H). 7.68-7.61 (m, 4H), 7.467.44 (m,1H), 7.31-7.27 (m, 1H). 7.17(t, J = 7.2Hz, 1H),6.89 (d, J =8.0Hz, 1 H), 6.83 (t, J = 8.0 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1 H), 5.47 (m, 1H), 4.64-4.62 (m, 1 H), 4.39-4.35 (m,1H), 3.30-3.24 (m, 2H). 2.25-2.20 (m,1H), 2.08-1.89 (m, 1H), 1.75 (d, J= 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 taklng appropriate ester compound of Example-2 to 49;

Further, HCl sait of these amino compounds were prepared by following the similar hydrochloride sait 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. No.	Ester Ex. No.	Structure	Mass (m/z)
73	2	3-((2R,4S)-2-((((R)-1-(Naphthalen-1-yl)ethy!)amino) methyl) chroman-4-yi)benzoic acid hydrochloride	437.73

		OCO^u HCl LJAoH 0
		’HNMR (400MHz, DMSO-d_e): 5 12.99 (bs, 1H), 9.77 (bs, 1H), 9.38 (bs, 1H), 8.27 (d. J^8.4Hz, 1H), 8.05-7.96 (m, 3H),7.85-7.83 (m, 1H), 7.74-7.61 (m, 4H), 7.48-7.46 (m, 2H), 7.15 (t, J=8.0 Hz, 1H), 6.90 (d, J = 8.4Hz, 1 H>, 6.82 (t, J =7.6Hz, 1H), 6.56 (d, J=7.6Hz, 1H), 5.48-5.46 (m, 1H), 4.66-4.62 (m, 1H), 4.39-4.35 (m, 1H), 3.40-3.24 (m, 2H), 2.27-2.22 (m, 1H), 2.00-1.91 (m, 1H), 1.75 (d, J =6.8 Hz, 3H).
74	3	2-Methyl-3-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino)methyl)chroman-4-yl)benzoic acid hydrochloride	451.6
		HCl
		O
		’HNMR (400MHz, DMSO-d_a): δ 12.89 (bs, 1H), 9.87 (bs, 1H), 9.54 (bs, 1H), 8.30 (d, J=8.4Hz, 1H), 8.04-8.00 (m, 3H), 7.70-7.48 (m, 4H),7,18-7.12 (m, 2H), 7.00 (m, 1H), 6.90 (d, J=8.0Hz, 1H), 6.82 (t, J=7.2 Hz, 1H>, 6.53 (m, 1H), 5.46-5.44 (m, 1H), 4.69-4.66 (m, 2H), 3.40-3.37 (m, 1H), 3.29-3.22 (m, 1H), 2.56 (S, 3H), 2.26-2.19 (m, 1 H>, 1.95-1.93 (m, 1 H), 1.75 (d, J - 6.4 Hz, 3H).
75	4	3-Methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride	452.1

		g ..... OA
		’H NMR (400 MHz, DMSO-d_e): δ 12.91(bs, 1H), 9.96 (bs, 1H). 9.53 (bs, 1H), 8.30 (d. J=8.4 Hz,1H), 8.02 (t. J=7.2 Hz, 3H), 7.68-7.59 (m. 4H), 7.54 (s, 1H), 7.27 (s, 1H), 7.14 (t, J=7.6 Hz, 1H ), 6.88 (d. J=7.6 Hz, 1H ), 6.79 (t, J=7.6 Hz, 1H ), 6.57 (d, J=7.6 Hz, 1H), 5.505.45 (m, 1H), 4.68-4.63 (m, 1H), 4.33-4.28 (m. 1H), 3.40 (m,1H), 3.22-3.16 (m, 1H), 2.33 (s, 3H), 2.26-2.22 (m. 1 H),1.95-1.92 (m, 1H), 1.76 (d. J= 6.8 Hz. 3H).
76	5	4-Methyl-3-((2R_l4S)-2-((((R)-1 -(naphthalen-1 -yl)ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride	451.6
		OcY’Yj HCl o
		’HNMR(400MHz, DMSO-d_e): δ 12.80 (bs, 1H), 9.90 (bs, 1H). 9.48 (bs, 1H), 8.27 (d. J=8.4Hz. 1H), 8.04-8.01 (m, 3H). 7.72-7.59 (m, 4H), 7.49-7.39 (m. 2H), 7.15 (t, J 8.0 Hz. 1H). 6.91 (d, J - 8.4Hz, 1H), 6.80 (t. J = 8.0 Hz, 1H), 6.53 (d. J=7.2 Hz,1H), 5.48 -5.44 (m,1H), 4.68 (m, 1H), 4.58-4.54 (m, 1H), 3.40 (m. 1H), 3.21-3.17 (m, 1H), 2.50 (s. 3H). 2.26 (m,1H), 1.98-1.88 (m. 1H), 1.77 (d. J = 6.8 Hz, 3H).

77a,	6a	2-Ethyl-5-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl)benzolc acid hydrochloride ^Ï^OH ’H NMR (400 MHz, DMSO- d6): 0012.85 (bs, 1H), 9.47 (bs, 1H), 9.26 (bs, 1H), 8.23-8.21 (d, J= 8.4Hz, 1H), 7.99-7.90 (m, 2H), 7.88-7.86 (d, J=6.8Hz, 1H), 7.70-7.59 (m, 3H), 7.39-7.38 (d, J=2Hz, 1H), 7.27-7.20 (m, 2H), 7.12-7.10 (m, 1H ), 6.97-6.87 (m, 3H), 5.46-5.38 (m, 1 H),4.32-4.31 (m, 1H), 4.14-4.12 (m. 1H), 3.38-3.34 (m, 1H), 3.20-3.19 (m, 1 H), 2.87-2.64 ( q, 2H), 2.08-1.90 (m, 2H), 1.69-1.67 (d, J = 6.8Hz, 3H), 1.16-1.13 (t, 3H).	466.1
77b	6b	2-Ethyl-5-((2R,4S)-2-((((R)-1 -(naphthalen-1 -yl)ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride \ 0 ’HNMR (400 MHz. DMSO- d6): 0012.80 (bs, 1H). 9.64 (bs, 1H), 9.28 (bs, 1H), 8.29-8.27 (d, J = 8.4Hz, 1H), 8.05 -8.01 (t, J = 7.2Hz, 2H). 7.95 -7.93 (d , J = 7.2Hz, 1H), 7.70 -7.58 (m, 4H), 7.29 (s, 2H). 7.16-7.13 (t, J=7.6Hz, 1H), 6.89-6.87 (d. J = 7.6 Hz ,1H), 6.83-6.79 (t, J=7.6Hz, 1H), 6.59-6.57 (d. J = 7.6Hz , 1H), 5.48 5.47 (m, 1 H), 4.63-4.61 (m, 1 H). 4.32-4.28 (m, 1 H), 3.30-

		3.28 (m, 2H), 2.92-2.87 (q, 2H), 2.23-2.25 (m, 1H), 1.98- 1.90 (m. IH), 1.74-1.72 (d, J = 6.8Hz, 3H), 1.17-1.13 (t, 3H).
78	7	2-lsopropyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl)benzolc acid hydrochloride ⁰ ’HNMR (400MHz, DMSO-d_e):DDO 13.0 (bs, 1H), 9.76 (bs, 1H), 9.36 (bs, 1H), 8.24-8.22 (d. J- 8 Hz, 1H), 8.057.96 (m, 3H), 7.68 -7.61 (m, 3H),7.42-7.40 (d, J=7.6Hz, 2H), 7.36-7.29 (dd. J= 8Hz, 1H), 7.16-7.12 (t, J= 7.6Hz, 1H), 6.88-6.86 (d, J= 7.2Hz, 1H), 6.83-6.79 (t, J= 7.6Hz, 1H) 6.59-6.57 (d, J= 7.6 Hz, 1H), 5.48-5.46 (m, 1H), 4.63-4.55 (m, 1H), 4.31-4.27 (m, 1H), 3.78-3.66 (m, 1H), 3.39-3.34 (m, 1H), 3.25-3.23 (m, 1H), 2.23-2.19 (m, 1H) , 1.97-1.88 (m, 1H), 1.75-1.73 (d, J - 6.4 Hz, 3H),1,14-1.12 (m, 6 H).	480.1
79a,	8a	2-Cyclopropyl-5-((2R,4R)-2-((((R)-1 -(naphthalen-1 yl)ethyl) amîno)methyl)chroman-4-yl)benzoic acid hydrochloride OÇrcd? ’HNMR (400MHz, DMSO-d6): 00012.90 (bs, 1H), 9.60	478.1

		(bs, 1H), 9.30 (bs, 1H), 8.23-8.21 (d, J=8Hz, 1H), 8.027.97 (m, 2H), 7.86-7.84 (d, J=6.8Hz, 1 H), 7.65-7.57 (m, 3H), 7.31 -7.30 (d, J=2Hz, 1H), 7.24 -7.20 (t, J=8.4Hz, 1H), 7.06-7.04 (d, J=8.4Hz, 1H), 6.97-6.87 (m, 4H), 5.40-5.35 (m, 1 H), 4.35-4.15 (m, 2H), 3.25-3.10 (m, 2H), 2.65-2.55 (m, 1H), 2.10-1.95 (m, 2H), 1.69-1.67 (d, J= 6.4 Hz, 3H), 0.93-0.83 (m, 2H), 0.69-0.67 (m, 2H).
79b	8b	2-Cyclopropyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1yl)ethyl) amino)methyl)chroman-4-yl)benzoic acid hydrochloride	478.1
		ÇjXoH 1 o
		¹HNMR (400MHz, DMSO-d6):nnD12.90 (bs, 1H), 9.70 (bs, 1H), 9.20 (bs,1 H),8.29-8.27 (d, J=8.8 Hz, 1H), 8.058.02 ( t, J=7.6Hz, 2H) , 7.94-7.92 (d , J=6.8Hz, 1H), 7.69-7.64 (m, 3H) ,7.52-7.51 (d, J=2Hz, 1H), 7.25-7.22 (dd, J=8.4 & 2,1 H), 7.14-7.12 (t, J=7.6Hz , 1H), 6.966.94 (d, J=8.4Hz, 1H), 6.88-6.86 (d, J=7.2Hz, 1H), 6.82 -6.78 (t, 8.4Hz, 1H). 6.59-6.57 (d, J=7.6Hz, 1H), 5.50-5.40 (m, 1H), 4.65-4.55 (m, 1H). 4.32-4.20 (m, 1H), 3.40-3.20 (m, 2H), 2.70-2.60 (m, 1H), 2.25-2.10 (m, 1H), 2.00-1.90 (m, 1H), 1.76-1.73 (d, J= 6.4 Hz, 3H), 0.97-0.94 (m, 2H), 0.69-0.65 (m, 2H).
80	9	2,6-Difluoro-3-((2R_l4R)-2-((((R)-1-(naphthalen-1-yl)ethyl) amlno)methyl)chroman-4-yl)benzoic acid hydrochloride	474.1

		F 0 ’H NMR (400MHz, DMSO-d_fl): 0 13.98 (bs, 1H), 9.82 (bs, 1H), 9.48 (bs, 1H), 8.27 (d, 8.4 Hz, 1H), 8.05- 7.98 (m, 3H), 7.67-7.60 (m, 3H), 7.37 (s, 1H), 7.21-7.14 (m, 2H), 6.90-6.82 (d, 7.6Hz, 1H), 6.86 (t, J= 8 Hz,1H), 6.63( d, J=8 Hz, 1H ), 5.47 (m, 1H), 4.69-4.53 (m. 1 H), 4.57-4.55 (m, 1H), 3.40-3.22 (m, 2H). 2.33-2.22 (m, 1 H), 2.02-1.96 (m, 1 H), 1.76 (d, J = 6.4 Hz, 3H).
81a,	10a	4-Fluoro-2-methyl-3-((2R,4S)-2-((((R)-1-(naphthalen-1yl) ethyl) amino )methyl)chroman-4-yl)benzolc acid hydrochloride 0 ’HNMR (400MHz. DMSO-d6): δ 12.81 (bs, 1H), 9.52 (bs, 1H), 9.34 (bs, 1H), 8.24-8.22 (d, J=8Hz, 1H), 8.05-7.99 (m,2H), 7.90-7.88 (d, J=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,1H), 4.49-4.48 (m.1H), 4.22-4.10 (m,1H), 3.30-3.18(m, 2H), 2.49 (s, 3H), 2.15-1.90 (m, 2H),1.64-1.62 (d, J= 6.4 Hz, 3H).	470.42
81b	10b	4-Fluoro-2-methyl-3-((2R,4R)-2-((((R)-1-(naphthalen-1yl) ethyl) amino)methyl)chroman-4-yl)benzoic acid hydrochloride	470.42

		0
		¹HNMR (400MHz, DMSO-d6): δ 12.93 (bs, 1H), 9.68 (bs, 1 H), 9.29 (bs, 1H), 8.29-8.27 (d, J=8.4Hz, 1H), 8.05-8.01 (m, 2H), 7.95-7.93 (d, J=7.2Hz, 1H),7.69-7.60 (m, 4H), 7.22-7.14 (m, 2H), 6.90-6.88 (d, J=7.6Hz, 1H), 6.84-6.80 (t, J=7.6Hz, 1H), 6.62-6,18 (d, J=7.6Hz, 1H), 5.48-5.46 (m, 1H), 4.66-4.57 (m, 1 H), 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, 1 H), 1.75 -1.73 (d, J= 6.8Hz, 3H).
82	11	2,3-Dimethyt-5-((2R,4S)-2-((((R)-1 -(naphthalen-1 yljethyl) amino)methyl)chroman-4-yl)benzolc acid hydrochloride	466.1
		r^il

		' 0
		¹HNMR (400MHz, DMSO-d_e): δ 12.83 (bs, 1H), 9,81(bs, 1H), 9.41 (bs, 1H), 8.30 (d, J=8,4Hz, 1H), 8.05-7.98 (m, 3H), 7.68-7.60 (m, 3H). 7.36 (S, 1H), 7.15-7.11 (m, 2H), 6.87 (d, J=8Hz, 1H), 6.81 (t, J=7.6Hz, 1H), 6.59 (d, J=7.6 Hz, 1H), 5.48-5.47 (m, 1H), 4.65-4.61 (m, 1H), 4.25-4.20 (m, 1H), 3.40-3.24 (m, 2H), 2.35 (s, 3H), 2.24 (s, 3H), 2.22-2.17 (m, 1 H),1.96-1.93 (m, 1H), 1.75 (d, J=6.4Hz, 3H).
83	12	5-((2R,4S)-2-((((R)-1-(Naphthalen-1-yl)ethyl)amino) methyl) chroman-4-y!)-2-(trifluoromethyl)benzoic acid	505.5

		hydrochloride LJL,oh CFj 0 . ’H NMR(400MHz, DMSO-de): δ 12.9 (bs, 1H), 9.82 (bs, 1H), 9.43 (bs, 1H), 8.30 (d, J= 8 Hz, 1H), 8.04-7.98 (m. 3H), 7.82 (d, Z=8 Hz, 1H), 7.68-7.60 (m, 4H ), 7.55 (d, J=7.6 Hz, 1H), 7.19-7.12 (m, 1H) , 6.91 (d, J=8 Hz,1H), 6.84 (m, 1H), 6.57 (d, J=7.6 Hz, 1H), 5.47 (m, 1H), 4.63 (m, 1H), 4.50-4.45 (m, 1H), 3.24 (m, 2H), 2.28-2.25 (m, 1H), 1.98-1.95 (m, 1H), 1.75 (d, J=6.4Hz, 3H).
84a,	13a	2-Methy1-5-((2R,4R)-2-((((R)-1 -(naphthalen-1 -yl) ethyl) amino) methyl)chiOman-4-yl)benzoic acid hydrochloride oçqM? ’HNMR(400MHz, DMSO-de): δ 12.79 (bs, 1H), 9.49 (bs, 1H), 9.28 (bs, 1H), 8.24 (d, J= 8 Hz, 1H), 8.02 (t, J = 8.4Hz, 2H), 7.89 (d, J=7.2 Hz, 1H), 7.64-7.58 (m, 3H ), 7.44 (d, J=2 Hz, 1H), 7.24-7.20 (m. 2H), 7.11 (dd, J=8 Hz & 2Hz, 1H), 6.97-6.88 (m, 3H), 5.40-5.38 (m, 1H), 4.33 (m, 1H), 4.25-4.20 (m, 1H). 3.20 (m, 2H), 2.46 (s, 3H), 2.09-2.05 (m, 1H), 1.99-1.95 (m, IH), 1.69 (d, J=6.4Hz, 3H ).	451.92
84b	13b	2-Methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1yl)ethyl)amino) methy1)chroman-4-y1)benzoic acid	451.92

		hydrochloride kUL,oH I 0 ¹HNMR (400MHz, DMSO-d_e): δ 12.88 (bs, 1H), 10.37 (bs, 1H), 9.93 (bs, 1H), 8.30 (d, J=8.8Hz, 1H), 8.19 (t, J= 8.4Hz, 1H>. 8.02 (t, J=7.2Hz, 2H), 7.66-7.57 (m, 4H). 7.23 (s, 2H), 7.13 (t, J=7.6Hz, 1H), 6.86 (dd, J=8Hz & 0.8Hz, 1H), 6.77 (t, J=8Hz, 1H), 6.55 (d, J=7.6Hz, 1H), 5.51-5.49 (m, 1H). 4.76-4.74 (m, 1H),4.28-4.24 (m, 1H), 3.29-3.27 (m, 1 H), 3.19-3.17 (m, 1H), 2.48 (s, 3H), 2.272.23 (m, 1H), 1.93-1.87 (m, 1H), 1.78 (d, J=6.4 Hz, 3H).
85	14	2-F!uoro-3-((2R,4R)-2-((((R)-1-(naphthalen-1-yl) ethyljamino) methyl)chroman-4-yl)benzoic acid hydrochloride Y0.OH 0 ¹HNMR (400 MHz, DMSO-d_e): δ 13.24 (bs, 1H), 9.89 (bs, 1 H), 9.52 (bs, 1 H), 8.30 (d, J=8.0Hz, 1H), 8.04-8.00 (m, 3H), 7.79-7.75 (m, 1H). 7.67-7.59 (m, 3H), 7.42 (m, 1H), 7.26 (t, J=7.6Hz, 1H),7.15 (t, J=7.6Hz, 1H), 6.89 (d, J=8Hz, 1H), 6.82 (t, J=7.4Hz, 1H), 6.61 (d, J=7.6 Hz, 1H), 5.48-5.46 (m, 1H), 4.72-4.68 (m, 1H), 4.59-4.58 (m, 1H), 3.38-3.24 (m, 2H), 2.25-2.24 (m, 1H), 2.00 1.97 (m, 1H), 1.76 (d, J = 6.4Hz, 3H).	456.1

86	15	3-Fluoro-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyl)amlno) methyl) chroman-4-yl)benzolc acid hydrochloride	456.42

		VV _HC\| O

		0
		¹HNMR (400MHz, DMS0-d_e): δ 13.34 (bs, 1H), 10.07 (bs, 1H), 10.00 (bs, 1H), 8.30 (d, J=8.4Hz, 1H), 8.04 (m,3H), 7.67-7.54 (m, 5H), 7.37 (d, J=8.4 Hz, 1H ), 7.187.14 (t, J=7.6Hz, 1H), 6.89 (d, J=7.2Hz,1H), 6.83 (t. J=7.6Hz,1H ),6.59 (d, J=8Hz, 1H) , 5.49 (m, 1H), 4.674.63 (m,1H), 4.44-4.39 (m, 1H), 3.40-3.22 (m, 2H) , 2.29-2.24 (m, 1H), 2.01-1.92 (m, 1H), 1.76 (d, J = 6.8 Hz, 3H).
87	16	4-Fluoro-3-((2R,4R)-2-((((R)-1 -(naphthalen-1 -yl) ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride	456.1
		(Ύ’ΊΓίΐάτ
		hci
		0!0°η 0
		¹HNMR(400MHz,DMSO-de): δ 13.08 (bs, 1 H), 9.80 (bs, 1H), 9.4 (bs, 1 H), 8.29 (d, J=8.4Hz, 1H), 8.05-7.97 (m, 3H), 7.93-7.89 (m, 1H), 7.79-7.60 (m, 4H), 7.35 (t, J=8.0Hz, 1H), 7.17 (t, J=8.0Hz, 1H), 6.90 (d, J=8.0Hz, 1H), 6.84 (t, J=7Hz, 1H), 6.62 (d, J=7.6Hz, 1H), 5.475.46 (m, 1 H), 4.68-4.59 (m, 2H), 3.40-3.25 (m, 2H), 2.332.25 (m, 1H), 2.03-1.99 (m. 1H), 1.75(d, J=6.4Hz, 3H).
88	17	2-Methoxy-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyl)	466.86

		amino) methyl)chroman-4-yl)benzoic acid hydrochloride
		0
		’HNMR (400MHz, DMSO-d₆): δ 12.62 (bs,1H), 9.95 (bs, 1H), 9.54 (bs, 1H), 8.29 (d, J=8.4Hz, 1H), 8.04-8.00 (m, 3H), 7.67-7.61 (m,3H), 7.43 (d, J=2.4Hz, 1H), 7.32 (dd, J=8.8Hz & 2.4Hz, 1H), 7.13-7.08 (m, 2H), 6.85 (d, J=7.6Hz, 1H), 6.79 (t, J=7.2Hz, 1H), 6.57 (d, J=7.6Hz, 1H), 5.50-5.45 (m, 1H), 4.67-4.63 (m, 1H), 4.27-4.22 (m, 1H), 3.80 (s, 3H), 3.32-3.21 (m, 2H), 2.23-2.18 (m, 1H), 1.96-1.87 (m, 1H), 1.75 (d, J=6.4 Hz, 3H).
89a	18a	2-Methoxy-3-((2/?,4S)-2-((((/?)-1-(naphthalen-1-yl)ethyl) amino)methyl)chroman-4-yl)benzoic acid hydrochloride	468.48
		oonâ? ôç. 0
		¹HNMR (400MHz, DMSO-d_e): δ 13.01 (bs, 1H), 9.70 (bs, 1H), 9.42 (bs, 1H), 8.23 (d, J=8.4Hz, 1H), 8.04-7.94 (m, 3H), 7.64-7.54 (m, 4H), 7.20 (t, J=6.8Hz, 1H), 7.02 (t, J=7.6Hz, 1H), 6.95-6.88 (m, 3H), 6.69 (d, J=6.4Hz, 1H), 5.50-5.45 (m, 1H), 4.52-4.51 (m, 1H), 4.30-4.26 (m, 1H), 3.84 (s, 3H), 3.33-3.16 (m, 2H), 2.12-2.05 (m, 1H), 1.961.93 (m, 1H), 1.69 (d, J=6.4 Hz, 3H).

9»

89b	18b	2-Methoxy-3-((2R,4R)-2-((((R)-1 -(naphthalen-1 -yl)ethyl ) amino)methyl)chroman-4-yl)benzoic acid hydrochloride	468.48

		HCl xJLxh o
		’HNMR (400MHz, DMSO-d₆): δ 12.98 (bs, 1H), 9.95 (bs, 1H), 9.57 (bs, 1H), 8.29 (d, J=8.4Hz, 1H), 8.02 (t, J=7.6Hz, 3H), 7.67-7.59 (m, 4H), 7.13 (t, J=7.6Hz, 3H), 6.87 (d, J=8Hz, 1H), 6.80 (t, J=8Hz, 1H), 6.57 (d, J=7.6Hz, 1H), 5.49-5.48 (m, 1H>, 4.72 (m, 2H), 3.79 (s, 3H), 3.37 (m, 1H), 3.24 (m, 1H), 2.23 (m, 1H>, 1.93, (m, 1H), 1.77 (d, J=6.4 Hz, 3H).
90	19	4-Methoxy-3-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride	468
		XJXzOH 0
		’HNMR (400 MHz, DMSO-d_e): δ 12.62 (bs, 1H), 9.96 (bs, 1H), 9.54 (bs, 1H), 8.29 (d, J=8.4 Hz, 1H), 8.02 (t, J=7.6Hz, 3H), 7.67-7.61 (m, 3H). 7.43(d, J=2.4 Hz, 1H), 7.33 (dd, J=6Hz & 2.4Hz, 1H) , 7.14-7.08 (m, 2H), 6.85 (d. J=7.6Hz, 1H), 6.79 (t, J=7.2Hz, 1H), 6.57 (d, J=7.6 Hz, 1H). 5.50-5.45 (m, 1H), 4.67-4.63 (m, 1H), 4.274.22 (m,1H), 3.80 (s, 3H),3.27-3.22 (m, 2H), 2.23-2.18 (m, 1 H),1.96-1.87 (m, 1H),1.74(d, J=6.4Hz,3H).
91	20	2-(2-Methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino)methyl)chroman-4-yl)phenoxy)acetic acid	482.1

100

		hydrochloride
		¹ 0
		’HNMR (400MHz, DMSO-d_e): δ 12.93 (bs, 1H), 9.95 (bs, 1H), 9.56 (bs, 1H), 8.23 (m, 1H), 8.04-8.00 (m, 3H), 7.67-7.61 (m, 3H), 7.11-7.08 (m, 2H), 6.85 (d, J=7.6Hz, 1H), 6.77 (t, J=7.2Hz, 1H), 6.68 (t, J=7.6Hz, 2H), 6.61 (d, J=7.6Hz, 1H), 5.49-5.48 (m, 1H), 4.68 (m, 1H), 4.62 (s, 2H), 4.18-4.14 (m, 1H), 3.28 (m, 2H), 2.20 (m, 1H), 2.16 (s, 3H), 1.97-1.88 (m, 1H), 1.76 (d, J=6.8Hz, 3H)
92	21	2-(3-Methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl)phenoxy)acetic acid hydrochloride	481.55
		ΑΑ₀-γ^0Η 0
		’HNMR (400MHz, DMSO-d_e): δ 12.96 (bs, 1H), 10.09 (bs, 1H), 9.67 (bs, 1H), 8.29 (d, J=8.0Hz, 1H), 8.08-8.00 (m, 3H), 7.67-7.59 (m, 3H), 7.11 (t, J=7.6Hz, 1H), 6.84 (d. J=7.6Hz, 1H), 6.78 (t, J=7.6Hz, 1H), 6.62-6.57 (m, 4H), 5.49 (m, 1H), 4.67 (m. 1H), 4.60 (s, 2H). 4.15 (m, 1H), 3.28-3.21 (m, 2H), 2.22 (s, 3H), 2.18 (m, 1H), 1.92 (m, 1H), 1.77 (d, J=6.8 Hz, 3H).
93a,	22a	2-(2-Fluoro-5-((2R,4R)-2-((((R)-1 -(naphthalen-1 -yl)ethyl) amino)methyl)chroman-4-yl)phenoxy)acetic acid	486,0

101

		hydrochloride
		Ç^o^Y* ¹HNMR (400 MHz, DMSO-d_e): δ 13.02 (bs,1H), 9.67 (bs,1H), 9.46 (bs,1 H). 8.24 (d, J=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), 4.284.22 (m, 2H), 3.39-3.29 (m, 1H), 3.13 (m,1H), 2.07-1.97 (m, 2H),1.68(d, J=6.8 Hz, 3H).
93b	22b	2-(2-Fluoro-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino)methyl)chroman-4-yl) phenoxy) acetic acid hydrochloride OXfu ÇU-yin F O ’HNMR(400 MHz,DMSO-de): δ 12.92 (bs, 1H), 9.64 (bs, 1H), 9.43 (bs,1 H), 8.29 (d, J= 8.4Hz, 1H), 8,05-7.99 (m, 3H), 7.67-7.61 (m, 3H), 7.20-7.13 (m, 2H),6,94(dd, J=8.0 Hz & J= 1.6Hz, 1 H),6.85-6.72 (m, 3H), 6.58 (d, J=7.6 Hz, 1 H), 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, J=6.8 Hz, 3H).
94	23	2-(2-Fluoro-3-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino)methyl)chroman-4-yl)phenoxy)acetic acid	486,0

102

		hydrochloride ÔÇyOH 0 ’H NMR (400 MHz, DMSO-d_e): δ 13.07 (bs, 1H), 9.90 (bs, 1H), 9.52 (bs, 1H), 8.28 (d, J=8.0Hz, 1H), 8.04-8.00 (m, 3H), 7.67-7.59 (m, 3H), 7.14 (t, J=7.6Hz, 1H), 7.05 (t, J=8.0Hz, IH) , 6.96 (t, J=8.0Hz, 1H), 6.87 (d, J=8.0Hz, 1 H), 6.81 (t, J=7.2Hz, 1H), 6.72 (s, 1H). 6.61 (d, J=7.2Hz, 1H), 5.47 (m, 1H), 4.76 (s, 2H), 4.70 (m, 1H), 4.53 (m, 1H), 3.38-3.33 (m, 1H), 3.26 (m, 1H), 2.272.22 (m. 1H), 1.98 (m, 1H), 1.75 (d, J=6.4 Hz, 3H).
95a,	24a	2-(3-Fluoro-5-((2R,4R)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino)methyl)chroman-4-yl)phenoxy)aceticacid hydrochloride oçrn? _fXZ'L_o ^z'''y°^h0 ’H NMR (400 MHz, DMSO-de): δ 12.92 (bs, 1H), 9.64 (bs, 1H), 9.43 (bs, 1H), 8.24 (d , J=8.4 Hz, 1H), 8.04 7.93 (m, 3H), 7.65-7.57 (m, 3H),7.22 (t, J=15.2Hz, 1H) ,6.96-6.88 (m, 3H), 6.66 (d, J= 10.8 Hz, 1 H),6.41 (s, 2H), 5.41 (m, 1H), 4.64 (s, 2H), 4.32-4.26 (m, 2H), 3.39 -3.29 (m, 1H). 3.16 (m, 1H), 2.04 (m,2H), 1.70 (d, J=6.4 Hz , 3H).	486.0
95b	24b	2-(3-Fluoro-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyl)chroman-4-yl)phenoxy)acetic acid	486.0

103

		hydrochloride ίΑΓθΎ^ΗΧιι ΧχΜχ HCl XX _ρΧα_ο-ύ°^η0 ¹HNMR (400MHz, DMSO-d_fl): δ 13.05 (bs, 1H), 9.95 (bs, 1H), 9.55 (bs, 1H), 8.29 (d, J=8.0 Hz, 1H), 8.04-8.00 (m, 3H), 7.67-7.59 (m, 3H), 7.14 (t, J=7.2Hz, 1H), 6.86 (dd, J=8.0, 0.8Hz, 1H), 6.81 (dt, J=7.6, 0.8Hz, 1H), 6.71 (td, J=10.8, J=2.4Hz, 1H), 6.65-6.57 (m, 3H), 5.48 (m, 1H), 4.68 (s, 2H), 4.62 (m, 1H), 4.26 (m, 1H), 3.39-3.31 (m, 1H), 3.18 (m, 1H), 2.22 (m, 1H), 1.95 (m, 1H), 1.72 (d, J=6.4 Hz, 3H).
96	25	2-(4-Fluoro-3-((2/?,4/?)-2-((((/?)-1-(naphthalen-1-yl) ethyl) amino) methyl)chroman-4-yl) phenoxy)acetic acid hydrochloride Χίο^ζΟΠ 0 ¹HNMR (400MHz, DMSO-d_e): δ 12.97 (bs, 1 H), 9.87 (bs, 1H), 9.49 (bs, 1H), 8.29 (d, J=8.4 Hz, 1H), 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, 1H), 5.48 (m, 1H), 4.68 (m, 1H), 4.60 (s. 2H), 4.46 (m,1H), 3.38-3.24 (m, 2H), 2.18 (m, 1 H), 2.08 (m, 1 H), 1.73 (d, J=6.4 Hz, 3H).	486.1
97	26	2-Methyl-2-(3-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amlno)methyl)chroman-4-yl)phenoxy)propanoicacid	505.5

104

		hydrochloride
		o=< >····* I /⁼\
		’HNMR (400 MHz, DMSO-d_e): C 13.03 (bs, 1H), 9.36 (bs, 1H), 9.3 (bs, 1H), 8.28 (d, J=8.4Hz, 1H), 8.05 (t, J=7.4Hz, 1 H), 7.95 (d, J=4.4Hz, 1H), 7.68-7.59 (m, 3H), 7.28-7.20 (m, 2H), 7.15-7.12 (m, IH), 7.02 (s, 1H), 6.87 (d, J=8Hz, 1H), 6,83-6.79 (m, 1H), 6.69-6.60 (m, 3H), 5.48(m, 1H), 4.62 (m, 1H), 4.22-4.19 (m, 1H), 3.24-3.20 (m, 2H), 2.23-2.19 (m, 1 H). 1.91-1.85 (m, 1H), 1.75 (d, J = 6.4Hz, 3H), 1.38 (s, 3H),1.22 (s, 3H).
98a	27a	4-((2R,4R)-2-((((R)-1-{Naphthalen-1-yl)ethyl)amino) methyl) chroman-4-yl)benzoic acid hydrochloride	437.60
		occù?
		HO^O ¹H NMR (400MHz, DMSO-d_fl): 0012.89 (bs, 1H), 9.48 (bs, 1H), 9.21 (bs, 1H), 8.24-8.22 (d, J =8.4 Hz, 1H), 8.00-7.91 (m, 2H) ,7.85 -7.81 (m, 2H),7.64-7.58 (m, 3 H), 7.33-7.31 (d, J = 8.4Hz, 1H), 7.26 -7.21 (t, J8.8Hz, 1 H), 7.13-7.11 (d, 8 Hz. 2H), 6.97-6.81 (m, 3H), 5.39-5.38 (m, 1 H), 4.37 (m, 1H), 4.18-4.1 (m, 1H), 3.37-3.30 (m, 2H), 2.15-1.95 (m, 2 H), 1.67-1.66 (d, J = 6.4 Hz, 3H).
98b	27b	4-((2R,4S)-2-((((R)-1-(Naphthalen-1-yl)ethyl)amino) methyl) chroman-4-yl)benzoic acid hydrochloride	437.60

105

		QYÔl? HCI
		hcYo
		’H NMR (400 MHz, DMSO-d_e): 0012.90 (bs, 1 H), 9.82 (bs, 1H), 9.46 (bs, 1 H), 8.30-8.28 (d, J =8.4Hz, 1H), 8.05-7.98 (m. 3H), 7.92 -7.90 (d, J = 8.4 Hz, 2H),7.687.60 (m, 3 H), 7.31-7.29 (d. J - 8Hz, 2H). 7.17-7.13(t, J=7.6Hz, 1 H), 6.90-6.88 (d, J = 7.6 Hz, 1H). 6.82-6.78 (t, J =7.2 Hz, 1H). 6.56-6.55 (d, J = 7.6 Hz , 1H), 5.485.47(m, 1 H), 4.67-4.63 (m, 1 H). 4.39-4.34 (m, 1 H), 3.38 -3.24 (m, 2H), 2.27-2.23 (m, 1 H), 1.98-1.92 (m, 1H). 1.76-1.74 (d, J = 6.8Hz, 3H).
99a,	28a	2-Methyl-4-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride	452.1
		Λ
		V ηοΎ
		’HNMR (400MHz, DMSO-d6): δ 12.80 (bs, 1H). 9.60 (bs, 1H). 9.40 -9.30 (bs. 1H), 8.24-8.22 (d, J=8.4Hz, 1H), 8.02-7.97 (m. 2H), 7.88-7.86 (d , J= 6.8Hz, 1H), 7.727.70 (m, 2H ), 7.65-7.57 (m. 3H). 7.25-7.20 (m, 1H), 6.97-6.83 (m, 4H ). 5.39-5.38 (m, 1H), 4.31 (m, 1H), 4.25 (m, 1H), 3.28 (m, 1H), 3.20-3.10 (m, 1H), 2.41 (s, 3H), 2.20-1.90 (m, 2H), 1.69-1.67 (d, J= 6.8Hz, 3H).
99b	28b	2-Methyl-4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride	452.1

106

		ηοΎ
		’HNMR(400MHz, DMS0-d6): δ 12.77 (bs, 1H), 9.69 (bs, 1H), 9.34 (bs, 1H), 8.30-8.28 (d, J=8Hz, 1H), 8.06-8.02 (t, J=7.6Hz, 2H),7.93-7.92 (d, J=7.2Hz, 1H), 7.81 -7.79 (d, J= 7.6Hz, 1H), 7.69-7.61 (m, 3H), 7.17-7.08 (m ,3H), 6.90-6.88 (d, J=8.4Hz, 1H ), 6.82-6.79 (t, J=7.2Hz, 1H), 6.59-6.57 (d, J=7.6Hz, 1H), 5.49-5.48 (m, 1H), 4.654.61 (m, 1 H), 4.32-4.27 (m, 1H), 3.38-3.23 (m, 2H), 2.46 (s, 3H), 2.24-2.20 (m, 1H), 2.0-1.91 (m, 1 H), 1.75 (d, J=6.4 Hz, 3H).
100a,	29a	4-((2R,4R)-2-((((R)-1-(Naphthalen-1-yl)ethyl)amino) methyl) chroman-4-yl)-2-(trifluoromethy!)benzolc acid hydrochloride	505.5
		ocrÂ? ά. HoX
		¹HNMR (400MHz, DMSO-d_e): δ 13.56 (bs, 1H), 9.72 (bs, 1H), 9.47 (bs, 1H), 8.25 (d, J=8.8Hz, 1H). 8.01 (m, 3H), 7.76 (d, J=8Hz, 1H) , 7.64-7.56 (m, 3H), 7.55 (s, 1H), 7.29-7.21 (m, 2H). 7.09-6.82 (m, 3H), 5.40-5.39 (m, 1H), 4.48 (m, 1H), 4.26-4.21 (m, 1H), 3.35 (m, 1H), 3.18-3.16 (m, 1H), 2.14-2.04 (m, 2H), 1.71(d, J=6.4 Hz, 3H).

107

100b 29b

4-((2R,4S)-2-((((R)-1 -(Naphthalen-1 -yl)ethyl)amino) methyi) chroman-4-yl)-2-(trifluoromethyl)benzoîc acid hydrochloride

505.5

101 30

’HNMR (400MHz, DMSO-d_e): δ 13.57 (bs, 1H), 10.17 (bs, 1H), 9.76 (bs, 1H), 8.25 (d, J=8.8Hz, 1H), 8.10 (d, J=7.2Hz, 1H), 8.01 (t, J=8.8Hz, 2H), 7.80 (d, J=8Hz, 1H), 7.67-7.59 (m, 4H), 7.55(d, J=8.4 Hz, 1H), 7.17 (t, J=7.6Hz, 1H), 6.89 (d, J=7.6Hz, 1 H), 6.82 (t, J=7.6 Hz, 1H), 6.55 (d, J=7.6Hz, 1H), 5.49 (m, 1 H). 4.71-4.68 (m, 1H), 4.50-4.46 (m, 1H), 3.27 (m, 1H), 3.20-3.16 (m, 1 H), 2.31-2.26 (m, 1H), 1.99-1.90 (m, 1H), 1.76 (d, J=6.4 Hz, 3H).

2,6-Difluoro-4-((2R_l4S)-2-((((R)-1 -(naphthalen-1 -yl) ethyl) amino)methyl)chroman-4-yl)benzoic acid hydrochloride

473.3

’HNMR (400 MHz, DMSO-d6): 0013.80 (bs, 1H), 9.91 (bs, 1H), 9.54 (bs, 1H), 8.31-8.29 (d, J - 8.4Hz, 1H). 8.05-8.00 (m, 3H), 7.69 -7.60 (m, 3H), 7.19-7.15 (t, J 7.2Hz, 1H), 7.07-7.05 (m, 2H), 6.89-6.87 (d, J= 8Hz, 1H), 6.85-6.81 (t, J=7.6Hz, 1H), 6.63-6.61 (d, J =7.6 Hz,

L

108

		1H), 5.50 -5.48 (m, 1H), 4.65-4.63 (m, 1H), 4.40-4.35 (m, 1H). 3.35-3.23 (m, 2H). 2.32-2.22 (m, 1H), 2.01-1.96 (m. 1 H), 1.76-1.74 (d. J = 6.8 Hz, 3H).
102a,	31a	3-Methoxy-4-((2R,4R)-2-((((R)-1 -(naphthalen-1 -yl)ethyt) amino) methyt)chroman-4-yl)benzolc acid hydrochloride 00X0? -à oAoH ¹HNMR (400MHz, DMSO-d6): 0013.00 (bs, 1H), 9.609.50 (bs, 1H), 9.30-9.20 (bs, 1H), 8.23-8.21 (d, J=8Hz, 1H). 8.01-7.97 (m. 2H), 7.90-7.88 (d, J=6.8Hz, 1 H),7.637.58 (m, 3H), 7.51-7.50 (d, J=1.6Hz, 1H), 7.42-7.40 (d, J=7.6Hz, 1H), 7.23-7.21 (m, 1H), 6.97-6.95 (d, J=8Hz, 1H), 6.90-6.89 (m. 2H), 6.52-6.50 (d, J=8Hz, 1H), 5.405.30 (m, 1H), 4.52-4.51 (m, 1H), 4.18-4.15 (m, 1H), 3.91 (s, 3H), 3.40-3.16 (m, 2H), 2.07-1.93 (m, 2H), 1.69 (d, J=6.4Hz, 3H).	468.1
102b	31b	3-Methoxy-4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino)methyl)chroman-4-yl)benzoic acid hydrochloride O^OH ¹HNMR (400MHz, DMSO-d6) : DDDl3.10(bs, 1H), 9.809.70 (bs, 1H), 9.50-9.40 (bs, 1H), 8.29-8.27 (d, J= 8Hz, 1H), 8.05-8.01 (m, 2H), 7.94-7.92 (d, J= 6.8Hz, 1H), 7.70-7.60 (m, 3H), 7.55-7.50 (m, 2H),7.15 -7.07 (m,	468.1

109

		2H), 6.88-6.86 (d, J =7.6Hz, 1H), 6.81-6.77 (t, J=7.2Hz, 1H), 6.57-6.55 (d, J = 7.6Hz ,1H), 5.48-5.46 (m, 1H), 4.68-4.66 (m, 2H), 3.83 (s, 3H), 3.35-3.31 (m, 1H), 3.103.05 (m, 1H), 2.19-2.16 (m,1H), 2.10-1.95 (m, 1H), 1.74 (d, J=6.8 Hz, 3H).
103	32	3-Fluoro-4-((2R,4R)-2-((((R)-1-(naphthalen-1-y1) ethyl) amino) methyl)chroman-4-yl)benzolc acid hydrochloride HCl HO^O ’H NMR (400 MHz, DMSO-d_e): 0013.29 (bs, 1H), 9.63 (bs, 1H), 9.33 (bs, 1H), 8.29-8.27 (d, J = 8.4 Hz, 1H), 8.05-8.01 (m, 2H) , 7.94-7.92 (d, J = 6.8Hz, 1H), 7.777.74 (dd, J = 8Hz, 1 H),7.68-7.62 (m, 4H), 7.34-7.32 (m, 1H), 7.19-7.15 (t, J = 8Hz, 1H), 6.91-6.89 (d, J = 8Hz, 1H), 6.84-6.81 (t, J = 7.6Hz ,1 H). 6.62 -6.60 (d, J = 8Hz, 1H), 5.49-5.47 (m. 1H). 4.68-4.59 (m, 2H), 3.51-3.25 (m, 2H), 2.28-2.23(m,1 H), 2.01-1.98(m, 1H), 1.74-1.73 (d, J = 6.4 Hz, 3H).	454.3
104	33	2-Fluoro-4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride HCl ηοΎ ¹H NMR (400MHz, DMSO- d6): 00013.10 (bs, 1H),	456.0

110

		9.80 (bs, 1H), 9.40 (bs, 1H), 8.30-8.28 (d , J= 8.8 Hz, 1H), 8.05 -7.97 (m, 3H), 7.86-7.82 (t, J=8Hz, 1H), 7.687.61 (m, 3H), 7.16 -7.09 (m, 3H), 6.90-6.88 (d, J=8.4Hz, 1H). 6.82-6.80 (t, J=7.6Hz, 1H ), 6.60 -6.58 (d ,J =7.6Hz, 1H), 5.48-5.40 (m. 1H), 4.64-4.60 (m. 1H), 4.40-4.36 (m, 1H), 3.40-3.30 (m, 2H), 2.27-2.23 (m, 1 H),2.08-1.93(m, 1 H), 1.75-1.73 (m, 3H).
105a,	34a	2-(4-((2R,4R)-2-((((R)-1 -(Naphthalen-1 -yl)ethyl)amlno) methyl)chroman-4-yl)phenoxy)acetic acid hydrochloride 00Ύ Φ x° ΗθΎ) Ή NMR(400 MHz, DMSO-de): δ 12.99 (bs, 1H), 9.55 (bs, 1H), 9.35 (bs, 1H), 8.25 (d, J ~ 8.4 Hz, 1H), 8.027.90 (m, 3H), 7.65 -7.57 (m, 3H), 7.21-7.08 (m, 2H), 6.94-6.80 (m, 6H), 5.40(m, 1H) ,4.65 (S, 2H), 4.39-4.21 (m, 2H), 3.40-3.16 (m, 2H),2.05-2.02 (m,1H), 1.971.91 (m, 1 H), 1.69 (d, J = 6.8 Hz, 3H).	467,8
105b	34b	2-(4-i(2R,4S)-2-((((R)-1 -(Naphthalen-1 -yl)ethyl) amino)methyl) chroman-4-yl)phenoxy)acetic acid hydrochloride crpYj H et x° hoXd ’H NMR (400 MHz, DMSO-d_e): δ 12.84 (bs, 1H), 9.77 (bs, 1H), 9.41 (bs,1H). 8.30 (d, J=8.4 Hz, 1 H), 8.05 (t.	467.8

112

106b	35b	2-(2-Fluoro-4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino)methyl)chroman-4-y1)phenoxy)acetic acid hydrochloride	486.0
		OX u hci £° ^F
		HO^O
		¹HNMR (400 MHz, DMSO-d6): 0013.09 (bs, 1H), 9.67 (bs, 1H), 9.34 (bs, 1H) ,8.30-8.27 (d, J=8.4Hz 1H), 8.058.01 (t, J=8Hz, 2H), 7.95-7.93 (d, J=7.2Hz, 1H). 7.687.60 (m, 3H), 7.16-7.12 (t, J=8Hz, 1H), 7.04-7.01 (m, 2H), 6.95-6.93 (d, J=8.8Hz, 1 H), 6.87 -6.85 (d, J=8.4Hz, 1H), 6.83-5.72 (t, J=7.6Hz, 1H). 6.61-6.59 (d, J=7.6H , 1H), 5.47(m, 1H), 4.75 (s, 2H), 4.60-4.58 (m, 1H), 4.154.14 (m, 1H), 3.37-3.33(m, 2H), 2.21-2.16 (m, 1H) ,1.971.88(m, 1H), 1.74 (d, J=6.8Hz, 3H).
107a,	36a	244-((2R,4R)-2-((((R)-1-(Naphthalen-1-yl)ethyl)amino) methyi)chroman-4-yl)phenyl)acetic acid hydrochloride	451.6
		OCn v ; HCl .? 0
		¹H NMR (400MHz, DMSO-d_fl): 0000000(08, 1 H), 9.4 (bs, 1H), 9.1 (bs, 1 H), 8.24-8.22 (d, J =8.4 Hz, 1H), 8.02-7.98 (m, 2H), 7.86 -7.84 (d, J=7.2Hz, 1HJ.7.68-7.59 (m, 3H), 7.32-7.09(m, 3H), 6.96 -6.82 (m, 5H), 5.39

113

		(m,1H), 4.26 (m, 2H), 3.55 (s, 2H), 3.44 -3.29 (m, 2H), 2.17-2.07 (m, 1H), 1.98- 1.95 (m, 1 H), 1.69 (d, J =6.4 Hz, 3H).
107b	36b	2-(4-((2R,4S)-2-((((R)-1 -(Naphthalen-1 -yi)ethy1) amlno) methy1)chroman-4-yl)phenyl)acetic acid hydrochloride v I HCl HO.J 0 ¹H NMR (400 MHz, DMSO-d_e): 0012.32 (bs. 1H), 9.59 (bs. 1H) . 9.29 (bs, 1H), 8.29-8.27 (d, J = 8Hz, 1H), 8.05-8.01 (t. J - 7.2 Hz . 2H), 7.93-7.92 (d, J = 6.8 Hz, 1H) , 7.70-7.60 (m, 3H). 7.23-7.21 (d. J = 8Hz, 2H) . 7.15-7.11(m, 3H), 6.89-6.87 (d, J= 7.2Hz, IH), 6.816.78 (t, J- 7.6Hz, 1H), 6.60-6.58 (d. J= 7.6Hz. 1H), 5.485.45 (m. 1H), 4.64-4.59 (m. 1H), 4.26-4.22 (m, 1H) ,3.55 (s, 2H), 3.44-3.29 (m, 2H), 2.22-2.17 (m. 1H), 1.97-1.88 (m. 1H), 1.72 (d, J = 6.4 Hz, 3H).	451.6
108a	37a	2-Methyl-2-(4-((2R,4R)-2-((((R)-1 -(naphthalen-1 -y1)ethy1) amino)methyl)chroman-4-yl)phenyl)propanoic acid hydrochloride αΤί?? -S 0 ’H NMR (400 MHz, DMSO-d_e): 0 12.31 (bs, 1H), 9.49 (bs, 1H), 9.25 (bs, 1H), 8.24-8.22 (d, J = 8.4 Hz, 1H), 8.00-7.88 (m. 3H), 7.70 -7.50 (m, 3H), 7.28-7.12 (m,	479.4

114

		3H), 6.96-6.86 (m, 5H), 5.40-5.38 (m, 1H), 4.25 (m, 2H), 3.43-3.29 (m. 2H), 2.07-1.91 (m, 2H), 1.69 (d, J = 6.4 Hz, 3H), 1.46 (s, 6H).
108b	37b	2-Methyl-2-(4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethylj amlno)methyl)chroman-4-yl) phenyl) propanoic acid hydrochloride	479.4
		ho
		H0.J— 0
		¹HNMR(400MHz, DMSO-de):DC 12.31 (bs, 1H), 9.80 (bs, 1H), 9.45 (bs, 1H), 8.29-8.27 (d, J =8.4 Hz, 1H), 8.05-7.98 (m, 2 H), 7.86-7.85 (d, J=6.8Hz 1 H),7.66-7.61 (m, 3H), 7.30-7.28 (d. J= 8.4 Hz, 2H), 7.18-7.12 (m, 3 H), 6.88-6.86 (d, J =7.6Hz, 1H), 6.81-6.77 (t, J = 7.6Hz, 1H), 6.59-6.57 (d, J =7.6Hz, 1H), 5.48-5.47 (m, 1H), 4.63 (m, 1H), 4.26-4.22 (m, 1H), 3.37-3.31 (m, 1H), 3.24 - 3.14 (m, 1H), 2.18-2.14 (m, 1H), 1.93- 1.85 (m, 1H), 1.75 (d, J= 6.4 Hz, 3H) ,1.44 (s, 6H).
109	38	3-Methyl-4-((2R,4S)-2-((((R)-1 -(naphthalen-1 yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid hydrochloride	452.1
		HCl
		HCT^O
		¹HNMR(400MHz, DMSO-d6): □□ 12.92 (bs, 1H), 9.82 (bs, 1H) , 9.51 (bs, 1H), 8.30-8.28 (d, J=8.4Hz, 1H),

115

		8.03-7.98 (m, 3H) ,7.80 (s, 1H), 7.69-7.60 (m, 4H), 7.167.12 (t, J= 7.6Hz, 1H), 6.98(s, 1H) , 6.89-6.87 (d, J=8Hz, 1H), 6.81-6.77 (t, J=7.2Hz, 1H), 6.53-6.51 (d, J= 8.8Hz, 1 H), 5.42 (m, 1H), 4.58-4.54 (m, 2H), 3.29-3.23 (m, 1H), 3.15-3.13 (m,1H), 2.45 (s, 3H),2.25-2.24 (m, 1 H), 1.90-1.80(m, 1 H), 1.71 (d, J = 6.4 Hz, 3H).
110	39	2-Fluoro-5-((2S,4R)-2-((((R)-1 -(naphthalen-1 -ytjethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride cô'V? φγ^0ΗF 0 Ή NMR (400MHz, DMSO-d_e): δ 13.30 (bs, 1H), 10.04 (bs, 1H), 9.27 (bs, 1H), 8.28 (d, J=8.4Hz, 1H), 8.047.98 (m, 3H), 7.68-7.59 (m, 4H), 7.46-7.42 (m. 1H) , 7.29-7.24 (m, 1H), 7.17 (t, J = 7.6Hz, 1H),6.92 (d, J =8.4Hz, 1H), 6.82 (t, J=8.0Hz, 1H). 6.57 (d, J=7.8Hz, 1H), 5.46 (m, 1H), 4.61-4.56 (m, 1H), 4.39-4.34 (m, 1H), 3.11 (m, 2H), 2.21-2.16 (m, 1H), 1.98-1.88 (m. 1H), 1.76 (d, J = 6.8 Hz, 3H).	456.1
111	40	3-((2S,4R)-2-((((R)-1-(Naphthalen-1-yl)ethyl) amino) methyl) chroman-4-yl)benzoic acid hydrochloride Ο^γΟΗ 0 ’H NMR (400MHz, DMSO -d6): δ 13.05 (bs, 1 H), 10.08 (bs, 1H). 9.28 (bs, 1H). 8.28 (d, J =8.4 Hz, 1H), 8.04- 7.99 (m, 3H), 7.84-7.81 (m. 1H), 7.74-7.60 (m, 4H),7.46 -	437.73

116

		7.44 (m, 2H), 7.15 (t, J = 8.0 Hz, 1 H>, 6.93 (d, J - 8.0 Hz, 1H), 6.81 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 5.46 (m, 1 H), 4.63-4.58 (m, 1H), 4.39-4.34 (m, 1H), 3.38-3.34 (m, 1H>, 3.14-3.12 (m, 1H), 2.23-2.19 (m, 1 H), 1.99-1.90 (m, 1H>, 1.76 (d, J = 6.4Hz, 3H).
112a	41a	2-Methyl-5-((2S,4R)-2-((((R)-1-(naphthalen-1-y1) ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride	451.92
		nrYti'W HCl Yx

		’H NMR (400 MHz, DMSO-d6): δ 12.85(bs, 1H), 9.9 (bs, 1H), 9.3 (bs, 1H), 8.29 (d, J= 8.4 Hz, 1H), 8.05 (t, J=9.2 Hz & 8 Hz, 1H) ,7.98 (d, J=7.2 Hz, 2H),7.68-7.60 (m, 4H), 7.25 (s, 2H), 7.16 (t, J=7.6 Hz & 7.2 Hz, 1 H), 6.92 (dd, J=8.4 Hz & 1.2Hz, 1H), 6.81 (t, J=7.6 Hz & 1.2 Hz,1H) ,6.57 (d, J= 7.6 Hz, 1H), 5.47-5.46 (m, 1H), 4.60-4.58 (m, 1H), 4.32-4.27 (m, 1 H), 3.34 (m, 1H), 3.17-3.13 (m, 1H) ,2.49 (s, 3H),2.17 (m, 1 H),1.95 (m, 1 H), 1.76(d, J=6.8Hz, 3H).
112b	41b	2-Methyl-5-((2S,4S)-2-((((R)-1-(naphthalen-1-yl) ethyljamîno) methyl) chroman-4-yl)benzoic acid hydrochloride	451.92
		u hci ΥχΑ,ΟΗ 1 O
		’H NMR (400MHz, DMSO-d6): δ 12.8 (bs, 1H), 9.6 (bs, 1H), 9.2 (bs, 1H), 8.21(d, J=8.4 Hz, 1H), 8.03 (t, J=8.8

117

		Hz, 2H), 7.89 (d, J= 7.2 Hz, 1H). 7.66-7.58 (m, 3H), 7.45 (d, J=1.6Hz, 1H), 7.26-7.21 (m, 2H), 7.15 (dd, J=8 Hz, J=2 Hz, 1H), 6.98 ( t, J=7.6 Hz, 1H), 6.93 ( t, J=7.6 Hz, 2H), 5.39 (m, 1H), 4.32 (m, 1H), 4.27-4.22 (m, 1H), 3.34(m, 1H), 3.05-3.04 (m, 1 H), 2.49 (s, 3H), 2.11-2.06 (m, 1H), 2.05-1.98 (m, 1H), 1.67 (d, J=6.8 Hz, 3H).
113a,	42a	2-(4-((2S,4R)-2-((((R)-1 -(Naphthalen-1 -y1)ethy1)amino) methyl) chroman-4-y1)phenoxy)acetlc acid hydrochloride Orn? 7 ho 9 ? Hcrro ¹H NMR (400 MHz,DMSO-d6): 612.97 (bs, 1 H),10.04 (bs, 1H), 9.23 (bs, 1H), 8.28 (d, J = 8.4 Hz, 1 H), 8.047.97 (m, 3H), 7.68-7.59 (m, 3H), 7.14-7.07 (m, 3H), 6.89 -6.84 (m, 2H), 6.80 (t, J =7.6Hz, 2H), 6.58 (d, J =7.6 Hz, 1H), 5.45 (m, 1H), 4.64 (s, 2H), 4.60-4.56 (m, 1 H),4.204.16 (m, 1H), 3.16-3.09 (m, 2H), 2.16-2.08 (m, 1H), 1.941.85 (m, 1 H), 1.76 (d, J = 6.8 Hz, 3H).	466.8
113b	42b	2-(4-((2S,4S)-2-((((R)-1-(Naphthalen-1-y1)ethy1)amino) methyl) chroman-4-y1)phenoxy)acetic acid hydrochloride • Οΰ'Φ T HCl x° ηοΆ) ¹H NMR (400 MHz, DMSO-d6): δ 12.97 (bs, 1H), 9.77 (bs, 1H) , 9.25 (bs, 1H), 8.24 (d, J = 8.4Hz, 1H), 8.02-	466.8

118

		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, 1H) ,4.63 (s, 2H), 4.33-4.30 (m, 1 H), 4.21(m, 1 H), 3.40-3.04 (m, 2H), 2.06-1.96 (m, 2H), 1.68 (d, J =6.8 Hz, 3H).
114	45	4-((2R,4S)-2-((((R)-1-(4-Fluoro-3-methoxyphenyl) ethyl) amino) methyl)chroman-4-yl)-2-methylbenzoic acid hydrochloride oôYcC JL ^Ha Cr OH ¹HNMR(400MHz, DMSO-d_e): δ 12.25 (bs, 1H), 9.70 (bs. 2H), 7.81 (d, J=8 Hz, 1H), 7.61-7.60 (m, 1H), 7.30 (t, J=8.4 Hz, 1H ), 7.15-7.08 (m, 4H), 6.91 (d, J=8 Hz,1H)_t6.79 (t, J=7.6Hz, 1H), 6.58 (d, J=7.6 Hz, 1H), 4.53 (m, 2H), 4.27-4.25 (m, 1H), 3.87 (s, 3H), 3.09 (m, 1H), 2.95 (m, 1H), 2.46 (s, 3H), 2.23 (m, 1H), 1.94-1.85 (m,1H), 1.65 (d, J = 6.8 Hz, 3H).	450.1
115	46	3-((2R,4S)-2-((((R)-1 -(4-Fluoro-3-methoxyphenyl) ethyl) amlno)methyl)chroman-4-yl)-2-methylbenzoic acid hydrochloride arûc LJ0OH 0 ¹HNMR (400MHz, DMSO-d_e): δ 12.78 (bs, 1H), 9.739.63 (bs, 2H),7.59-7.50 (dd, J= 13.6Hz,7.2 Hz, 2H) . 7.31 (t, J= 8.4Hz, 1H), 7.21 (m, 3H), 7.02 (d, J= 8Hz, 1H), 6.93 (d, J= 8.4Hz, 1H), 6.80 (t, J=7.2 Hz ,1H), 6.53 (m, 1H), 4.55-4.47 (m, 3H), 3.83 (s, 3H), 2.95-2.93 (m,	450.1

119

		1 H). 2.56-2.51 (m, 1H>, 2.50 (s, 3H), 2.33-2.27 (m, 1H), 1.79-1.77 (m, 1 H), 1.65 (d, J=6.8 Hz, 3H)
116	47	5-((2R,4S)-2-((((R)-1 -(4-Fluoro-3-methoxypheny!) ethyl) amino) methy!)chroman-4-yl)-2-methy! benzoîc acid hydrochloride	450.1
		\| HCl ^{v F} LA,oh 1 0
		’HNMR(400MHz, DMSO-d_e): δ 12.84 (bs, 1H), 9.78 (bs, 1H), 9.70 (bs, 1H), 7.65 (d, J=8.4Hz, 2H), 7.30-7.26 (m, 3H), 7.15-7.08 (m, 2H), 6.91(d, J=8Hz, 1H), 6.80 (t, J=7.2Hz, 1H), 6.56 (d, J=7.6 Hz, 1H), 4.55-4.53 (m, 1H), 4.48 (m, 1H), 4.29-4.25 (m, 1H), 3.87 (s, 3H), 3.11-3.10 (m, 1H), 2.95 (m, 1H), 2.46 (s, 3H), 2.25-2.18 (m. 1H), 1.89-1.83 (m, 1H), 1.65 (d, J=6.4 Hz, 3H).
117	48	3-((2R,4S)-2-((((R)-1-(4-Fluoro-3-methoxypheny!) ethyl) amino)methyl)chroman-4-yl)-5-methy!benzoic acid hydrochloride	450.1
		αχόχ j HCl ^Fo
		¹HNMR(400MHz, DMSO-d_e): 512.91 (bs, 1H). 9.71-9.66 (bs, 2H), 7.66 (s, 1H), 7.63 (d, J=6.8 Hz, 1H), 7.54 (s, 1H), 7.31-7.27 (m, 2H), 7.16-7.09 (m, 2H), 6.92 (d, J=8 Hz, 1H), 6.81(t, J= 7.2 Hz ,1H), 6.58 (d, J=7.6Hz , 1H),4.55-4.48(m, 2H), 4.32-4.28 (m, 1H), 3.87(s, 3H), 3.11 (m, 1H), 2.97 (m, 1H). 2.33 (s, 3H), 2.23 (m, 1H), 1.94 (m, 1 H). 1.67 (d, J=6.4Hz, 3H).

120

118	49	3-((2R,4S)-2-((((R)-1 -(4-Fluoro-3-methoxyphenyl) ethyl ) amino)methyl)chroman-4-yt)-4-methytbenzolc acid hydrochloride	450.1
		Οφηγχ T HCl ^F pjYzOH 0
		’HNMR (400MHz, DMSO-d_e): δ 12.8 (bs,1H), 9.8 (bs, 1H), 9.68 (bs, 1H), 7.71 (dd, J=7.2Hz, 7.6Hz, 2H), 7.45 (m, 1H), 7.31-7.24 (m, 2H). 7.16-7.13 (m, 2H), 6.94 (d, J=8Hz, 1H), 6.80-6.76 (t, J=7.2 Hz, 1H), 6.54 (d, J=6.8Hz, 1H), 4.58-4.48 (m , 3H), 3.88 (s, 3H), 3.11-3.10 (m, 1H), 2.95 (m, 1 H). 2.46 (s, 3H), 2.32-2.27 (m, 1H), 1.79 (m, 1H), 1.62 (d, Λ6.4 Hz, 3H).
119a	43a	5-((2R,4R)-2-((((R)-1-(4-Fluoronaphthalen-1-yt) ethyl) amino) methyl)chroman-4-yt)-2-methyl benzolc acid hydrochloride	470.56
		cçrx£ ÇY
		’HNMR (400 MHz, DMSO-d_e): 0012.81 (bs, 1H), 9.45 (bs, 1 H), 9.23 (bs, 1H), 8.33-8.30 (m, 1H). 8.15-8.13 (d, J=8.4Hz, 1H), 7.90-7.88 (m, 1H), 7.80-7.73 (m, 2H), 7.55-7.43 (m, 2H). 7.23-7.21 (m, 2H), 7.11-7.09 (m, 1 H), 6.97-6.90 (m, 3H), 5.40-5.36 (m, 1H). 4.32 (m, 1H), 4.22-4.20 (m. 1 H). 3.37-3.10 (m, 2H), 2.48 (s, 3H), 2.081.94 (m, 2H), 1.72-1.68 (d, J= 7.6 Hz, 3H).
119b	43b	5-((2R,4 S)-2-((((R)-1-(4-Fluoronaphthalen-1-yl) ethyl) amino) methyt)chroman-4-yt)-2-methyt benzoic acid	470.56

121

		hydrochloride CjLx)^h ’ 0 Ή NMR (400 MHz, DMSO-de): 0012.85 (bs, 1H), 9.86 (bs, 1 H), 9.47 (bs. 1H), 8.30-8.28 (d, J= 8Hz, 1H), 8.188.16 (d, J=7.2Hz, 1H), 7.86-7.84 (m, 1H), 7.79-7.72 (m, 2H). 7.59 (s, 1H), 7.51-7.46 (m, 1H), 7.27 (s, 2H), 7.157.11 (t, J=8Hz, 1H), 6.88-6.86 (d, J=8 Hz, 1H), 6.816.76 (t, J = 7.6Hz, 1H), 6.55-6.53 (d, J =7.6Hz, 1H), 5.38-5.36 (m, 1H), 4.62-4.45 (m, 1H), 4.32-4.27 (m, 1H), 3.37-3.33 (m, 1 H). 3.24-3.14 (m, 1H), 2.48 (S,3H), 2.24-2.19 (m, 1H), 1.97-1.88 (m, 1H), 1.71-1.70 (d, J6.4Hz, 3H).
120a	44a	3-((2R,4S)-2-((((R)-1-(4-Fluoronaphthalen-1-yl)ethyl) amlno)methyl)chroman-4-yl)-2-methoxybenzoic acid hydrochloride	485.9
		cûxé?, ός~ 0
		¹H NMR (400 MHz, DMSO-d_e): 0013.1 (bs, 1H), 9.76 (bs, 1H), 9.5 (bs, 1H), 8.33-8.31 (d, J = 8.4 Hz, 1H), 8.14-8.12(d, J= 7.6 Hz, 1 H),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), 4.514.50 (m, 1 H),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, J= 6.4 Hz, 3H).

122

120b

44b

3-((2R,4R)-2-((((R)-1-(4-fluoronaphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl)-2-methoxybenzoic acid hydrochloride CO0X L0L.OH 0 ’H NMR (400 MHz, DMSO-d_e): 0012.95 (bs, 1H), 10.14 (bs, 1H), 9.76 (bs, 1H), 8.38-8.36 (d, J = 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, J=8.8 Hz, 1.2Hz, 1H), 7.14-7.10 (m, 3H), 6.87-6.85 (d, J= 8 Hz, 1 H), 6.80-6.77 (t, J= 7.6 Hz, 1H), 6.56-6.54 (d, J- 7.2 Hz, 1 H),5.50-5.40 (m, 1H), 4.804.70 (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, J= 6.4 Hz. 3H)

Example-121

2-Fluoro-5-((2S, 4R)-2-(2-(((R)-1-(naphthalen-1-yl) ethyi) amino) ethyi) chroman-4-yl) benzolc acid hydrochloride

To a solution of Example-50 (0.15 g, 0.31 mmol) 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 distitled off under vacuum then cooled to O’C and acidifled with dilute HCl solution [pH=3 to 4).

The résultant white solid was filtered, washed and dried under vacuum to give white solid (110 mg, 78%).

123

Further, HCl sait of these amino compounds were prepared by following the similar hydrochloride sait procedure as described in Example-72a, 72b.

m/z-470; ’HNMR (400MHz. DMSO-d_e): δ 13.25 (bs, 1H), 9.98 (bs, 1 H), 9.27 (bs, 1H), 8.28-8.26 (d, J=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. J=8.8 & 2 Hz, 1H), 7.09-7.05 (t. J=7.2Hz, 1H), 6.76-6.70 (m, 2H), 6.55-6.53 (d, J= 7.6Hz, 1H). 5.385.36 (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, J=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 10 Example-51 to58.

Table-8:

Ex. No.	Ester Ex. No.	Structure	Mass (m/z)
122	51	2-Fluoro-5-((2R,4S)-2-(2-(((R)-1-(naphthalen-1-yljethyl) amino) ethyl)chroman-4-yl)benzolc acid hydrochloride	470.42
		XXJ Ηα l
		QjXon F O
		’HNMR (400 MHz, DMSO- d6):O □ □ 13.3-12.9 (bs, 1 H), 9.409.30 (bs, 1H), 9.40 (bs, 1 H), 8.29-8.27 (d, J = 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, J= 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, 1 H), 1.70-1.68 (d, J= 6Hz, 3H).
123	52	2-Methyl-5-((2S,4R)-2-(2-(((R)-1-(naphthalen-1-yl)ethyl)	466.10

124

		amlno)ethyl)chroman-4-yl)benzoic acid hydrochloride 00« ’HNMR (400MHz, DMSO-d_fl): δ 12.65 (bs, 1 H), 9.95 (bs, 1H), 9.25 (bs, 1H), 8.25-8.23 (d, J=8.4Hz, 1H), 8.02-7.98 (t, J=7.6Hz, 2H), 7.83-7.81 (d, J=6.8Hz, 1H), 7.66-7.58 (m, 4H) , 7.27-7.22 (m, 2H), 7.08-7.04 (t, J=7.6Hz, 1H), 6.75-6.69 (m, 2H), 6.53-6.52 (d, J=7.6 Hz, 1H), 5.35-5.33 (m, 1H), 4.264.02 (m, 2H), 3.29-3.23 (m, 1H), 3.05-2.98 (m, 1H ), 2.45 (s, 3H), 2.16-2.11 (m, 1H), 2.08-2.02 (m, 2H), 1.82-1.73(m, 1H), 1.68-1.66 (d, J=6.4 Hz,3H)
124	53	2-Methyl-5-((2R,4S)-2-(2-(((R)-1-(naphthalen-1-yl)ethyl) amino)ethyl)chroman-4-yl)benzoic acid hydrochloride HCl 1 Cj0°^h 1 0 ¹HNMR (400MHz, DMSO-d_fl): δ 12.84 (bs, 1H), 9.68 (bs, 1H), 9.16 (bs,1H), 8.29-8.27 (d, J=8.4Hz, 1 H), 8.03-7.99 (m, 2H), 7.85-7.93 (d, J=7.2Hz, 1H), 7.67-7.59 (m, 4H), 7.277.26 (m, 2H), 7.09-7.05 (t, J=7.2Hz, 1H), 6.75-6.70 (m, 2H), 6.55-6.53 (d, J = 7.6Hz, 1H) , 5.38-5.37 (m, 1H), 4.28-4.22 (m, 2H), 3.29-3.26 (m, 1H), 3.24-3.14 (m, 1H), 2.46 (s, 3H), 2.16-2.07 (m, 3H), 1.84-1.75 (m, 1H) , 1.70-1.69 (d, J=6.4 Hz, 3H)	466.36

125

125	54	2-Methoxy-3-((2R,4R)-2-(2-(((R)-1-(naphthalen-1-yl)ethyl) amîno)ethyl)chroman-4-yl)benzoIc acid hydrochloride	482.1

		o
		’HNMR (400MHz, DMSO-d6):nnOD13.3 ( bs, 1H>, 9.80 (bs, 1H), 9.30 (bs, 1H>, 8.29-8.27 (d, J = 8.4Hz, 1H), 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, J =7.6Hz, 1H>, 5.45-5.40 (m, 1H), 4.62 (m, 1H), 4.40-4.32 (m, 1H>, 3.62 (s, 3H), 3.24-3.22 (m, 1H), 3.15-3.11 (m, 1H), 2.14-2.08 (m, 3H), 1.90-1.75 (m, 1H), 1.71-1.69 (d, J= 6.8Hz, 3H)
126	55	5-((2S,4R)-2-(2-(((R)-1 -(4-Fluoronaphthalen-1-yl)ethyl) amino) ethyi)chroman-4-yi)-2-methylbenzolc acid hydrochloride	484.1

		o x
		Ή NMR (400 MHz, DMSO- d6):nOD12.84 (bs, 1H), 9.81 (bs, 1H), 9.20 (bs, 1H), 8.37-8.35 (d, J=8.4Hz, 1H), 8.16-8.14 (m , 1H), 7.99-7.95 (m, 1H), 7.77-7.70 (m , 2H), 7.61 (s, 1H), 7.53-7.48 (m, 1H), 7.25 (s, 2H), 7.08-7.04 (m, 1H), 6.75-6.68 (m, 2H), 6.54-6.52 (d, J = 8.0Hz, 1H), 5.36-5.35 (m , 1H), 4.28-4.21 (m, 2H), 3.28-3.26 (m, 1H), 3.01-2.99 (m, 1H), 2.49 (s, 3H), 2.17-2.06 (m, 3H), 1.85-1.76 (m, 1 H). 1.70-1.68 (d, 6.8Hz, 3H)
127	56	5-((2R,4S)-2-(2-(((R)-1 -(4-Fluoronaphthalen-1-yl)ethyÎ) amino) ethyl)chroman-4-yl)-2-methylbenzoic acid hydrochloride	484.1

126

		I o ’H NMR (400 MHz, DMSO-d6):nnnnni2.8 ( bs, 1H). 9.8 (bs, 1H), 9.20 (bs, 1H), 8.37-8.35(d, J=8.4Hz, 1H), 8.168.14 (m , 1 H), 8.01-7.97 (m, 1H). 7.77-7.70 (m, 2H). 7.61 (s. 1H). 7.54 -7.49 (m, 1H), 7.25 (s, 2H), 7.08-7.04 (m. 1H), 6.75-6.70 (m, 2H), 6.55 -6.53 (d. J=8Hz, 1H). 5.35-5.32 (m, 1H), 4.29-4.21 (m, 2H), 3.23-3.21 (m, 1H). 3.13-3.11 (m. 1H), 2.49 (s, 3H), 2.15-2.07 (m, 3H), 1.90-1.75 (m, 1H) 1.70-1.68 (d, J= 6.8Hz. 3H)
128	57	5-((2S,4R>-2-(2-(((R)-1'(4-Fluoro-3-methoxy phenyl) ethyl) amino) ethyl) chroman-4-yl)-2-methylbenzoic acid hydrochloride θ' co-Ύ’ X⁰ ’H NMR (400 MHz, DMSO-d6): ΠΠ12.84 (bs, 1H), 9.50 (bs, 1H), 9.30 (bs. 1H), 7.62 (s, 1 H),7.57-7.54 (d, J=8.4, 1H), 7.32-7.26 (m, 3H), 7.15-7.05 (m , 2H), 6.76-6.72 (m, 2H), 6.54-6.52 (d, J= 7.6Hz, 1H), 4.41-4.39 (m, 1 H), 4.27-4.23 (m, 2H), 3.86 (s, 3H), 3.08-3.01 (m, 1H), 2.95-2.88 (m, 1H), 2.45 (s, 3H), 2.16-2.11 (m, 1H), 2.01-1.99 (m, 2H), 1.80-1.76 (m, 1H), 1.58-1.56 (d, J=6.4Hz, 3H)	463.9
129	58	5-(( 2 R,4S)-2-(2-(( (R}-1 -(4-Fluoro-3-methoxy phenyl)ethyl) amino)ethyl)chroman-4-yl)-2-methylbenzolc acid hydrochloride	463.9

127

’H NMR (400MHz, DMSO- d6):DDDD 12.84 ( bs, 1H), 9.7 (bs, 1H), 9.3 (bs, 1H), 7.63 (s, 1H), 7.60-7.58 (d, J= 8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.14-7.05 (m , 2H), 6.76-6.70 (m, 2H), 6.55-6.53 (d, J= 7.6Hz, 1H), 4.42-4.40 (m , 1H), 4.274.22 (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),1.59-1.57(d, J= 6.4Hz, 3H)

Example-130

2-Ffuoro-5-((2S, 4S)-2-(3-(((R)-1-(naphthalen-1-yl) ethyl) amino) propyl) chroman-4-yl) benzoic acid hydrochloride

fo

To a solution of Example-59 (0.120 g, 0.24 mmol) in methanol (6 mL), THF (6mL) and water (1mL), 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], 10 the résultant 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):0 013.3 (bs, 1 H), 9.71 (bs, 1H), 9.22 (bs, 1H), 8.268.24 (d J=8.4Hz, 1H), 8.02-7.98 (m, 3H), 7.83 (m, 1H), 7.65-7.57 (m, 4H), 7.44-7.41 (m, 1H), 7.30-7.25 (dd, J=8.8, 2Hz, 1H), 7.09-7.05 (t, J=7.6Hz, 1H), 6.69-6.67 (d. J=7.6 Hz, 1H). 6.5415 6.52 (d, J=7.6Hz, 1H), 5.34-5.32 (m, 1H), 4.30-4.27 (m, 1H), 4.12-4.11 (m, 1H), 3.09-3.00 (m,

1H), 2.89-2.86 (m, 1H), 2.13-2.09 (m, 1H), 1.88-1.66 (m, 8H).

128

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 sait of these amino compounds were prepared by following the similar 5 hydrochloride sait procedure as described In Example-72a, 72b.

129

Table-9:

Ex. No.	Ester Ex. No.	Structure	Mass (m/z)
131	60	2-Fluoro-5-((2R,4R)-2-(3-(((R)-1 -(naphthalen-1 -yl) ethyl) amino) propyl)chroman-4-y1)benzolc acid hydrochloride CÇ)'K“Y φγ^0Η F 0 ’HNMR (400MHz, DMSO-de): δ 13.6 (bs, 1 H), 9.75 (bs, 1H), 9.20 (bs, 1H), 8.29-8.27 (d. J=8.4Hz, 1H), 8.01-7.96 (m. 3H), 7.65-7.59 (m, 4H), 7.41-7.40 (m, 1H). 7.29-7.24 (dd. J=8.4 & 2Hz, 1H), 7.07-7.03 (t, J=7.2Hz, 1H), 6.756.71 (dd, J=8.4 & 1.2Hz, 1H), 6.56-6.51 (m, 2H), 5.34-5.32 (m, 1H), 4.32-4.27 (m, 1H), 4.13-4.08 (m, 1H), 3.05-3.03 (m, 1H), 2.89-2.86 (m, 1H), 2.13-2.08 (m, 1H), 1.95-1.82 (m, 2H), 1.77-1.65 (m , 6H).	484.36
132	61	2-Methy1-5-((2S,4S)-2-(3-(((R)-1-(naphthalen-1-y1) ethyl) amino) propy1)chroman-4-yl)benzolc acid hydrochloride 1 0 ’HNMR (400MHz, DMSO-de): δ 12.84 (bs, 1H), 9.95, (bs, 1H), 9.35 (bs, 1H), 8.28-8.26 (d, J=8Hz, 1H), 8.05-7.97 (m, 3H), 7.64-7.57 (m, 4H), 7.27-7.22 (m, 2H), 7.08-7.03 (t, J=7.6Hz, 1H), 6.74-6.67 (m, 2H), 6.53-6.51 (d, J=7.6Hz, 1H), 5.34-5.33 (m, 1H), 4.25-4.21 (m, 1H), 4.13-4.09 (m,	479.3

130

		1H). 3.10-2.95 (m, 1H), 2.90-2.75 (m. 1H), 2.45(s, 3H). 2.10-2.06 (m, 1 H) ,1.94-1.85 (m, 2H). 1.78-1.65 (m, 6H).
133	62	2-Methyt-5-« 2R,4R)-2-(3-(((R)-1 -(naphthalen-1 -yt) ethyl) amino) propyl)chroman-4-yt)benzolc acid hydrochloride	479.3
		CQ'X
		’HNMR (400MHz, DMSO-d_e): δ 12.82 (bs, 1H), 9.83 (bs, 1H), 9.24 (bs, 1H), 8.29-8.27 (d, J=8.4Hz, 1H), 8.04-7.98 (m, 3H), 7.65-7.58 (m, 4H), 7.27-7.21 (m, 2H), 7.06-7.02 (t, J=7.2Hz, 1H), 6.73-6.69 (t, J=8.4Hz, 1H), 6.55-6.51 (m, 2H). 5.34-5.33 (m, 1H), 4.25-4.20 (m, 1H), 4.14 -4.08 (m, 1H), 3.1-2.91 (m, 1H), 2.95-2.75 (m, 1H), 2.45 (s. 3H), 2.10-2.07 (m, 1 H), 1.91 -1.87 (m. 2H), 1.77-1.65 (m, 6H).
134	63	5-((2S,4S)-2-(3-(((/?)-1-(4-Fluoro-3-methoxyphenyl) ethyt) amlno)propyt)chroman-4-yl)-2-methytbenzoic acid hydrochloride	478.42
		cçxàx
		.A O X
		¹H NMR (400 MHz, DMSO-d_e): δ 12.84 (bs, 1H), 9.45 (bs, 1H), 9.25 (bs, 1H), 7.62 (s, 1H), 7.55 (dd, J=8.4 Hz & J=1.6 Hz, 1H), 7.30-7.25 (m. 3H), 7.13-7.05 (m, 2H). 6.75-6.71 (m, 2H), 6.54 (d, J=7.6Hz,1H), 4.38-4.36 (m, 1H), 4.28-4.23 (m, 1H), 4.17-4.12 (m, 1H ), 3.84(s, 3H). 2.86 (m. 1H), 2.67 (m, 1H), 2.5 (s, 3H), 2.14 -2.09 (m,

131

		1 H). 1.91-1.89 (m, 1H), 1.82-1.73 (m, 2H),1.70-1.67 (m, 2H),1.58(d, J=6.8 Hz, 3H).
135	64	4-((2S,4S)-2-(3-(((R)-1-(4-Fluoronaphthalen-1-yl)ethy!) amino) propyl)chroman-4-y!)-3-methylbenzoic acid hydrochloride ηοΎ ¹HNMR (400MHz, DMSO): 0012.81 (bs, 1H), 9.77 (bs, 1 H). 9.23 (bs, 1 H). 8.37-8.35 (d, J = 8.0Hz, 1H), 8.15-8.13 (d, J-7.6 Hz, 1 H), 8.01-7.98 (m, 1 H). 7.79-7.67 (m, 4H), 7.52-7.47 (dd, J = 8.4,2 Hz . 1H), 7.08-7.04 (t, J=7.6 Hz, 1 H), 6.94 (s, 1H), 6.74-6.70 (t, J= 7.6 Hz, 1 H), 6.686.66 (d, J= 8.4Hz, 1H), 6.48-6.47 (d, J= 7.2 Hz, 1H), 5.32-5.30 (m, 1H), 4.53-4.51 (m, 1H), 4.16 (m,1H), 3.113.00 (m,1H), 2.89-2.80 (m, 1H), 2.46(s, 3H). 2.11-2.0 (m, 1H), 1.99-1.65 (m, 3H), 1.70-1.68 (m, 5H).	498.5
136	65	4-((2S,4S)-2-(3-(((R)-1 -(4-Fiuoronaphthalen-1 -yQethyl) amino) propy!)chroman-4-y!)benzoic acid hydrochloride ΗοΎ) ¹HNMR (400MHz, DMSO-de): 0012.90 (bs, 1H), 9.66 (bs, 1H), 9.20 (bs, 1H), 8.37-8.35 (d. J=8.0 Hz, 1H), 8.15-8.14 (d, J=7.2Hz ,1H), 7.98-7.95 (m, 1 H), 7.91-7.89 (d, J=8Hz, 2H), 7.76-7.68 (m, 2H). 7.52-7.48 (dd, J=8.4,2 Hz, 1H),	484.0

132

		7.29-7.27 (d, J=8Hz, 2H) , 7.09-7.07 (t, J=7.2Hz, 1H), 6.74-6.71 (t, J=7.6Hz, 1H), 6.68-6.66 (d, J=8Hz, 1H), 6.526.50 (d, J=7.6Hz, 1H), 5.32-5.31 (m, 1 H), 4.33-4.29 (m, 1 H), 4.15-4.12 (m, IH), 3,15-3.00 (m, 1H), 2.90-2.80 (m. 1 H). 2.14-2.08 (m, IH), 1.90- 1.75 (m, 3H). 1.69-1.67 (m, 5H).
137	66	5-((2S,4S)-2-(3-(((R)-1 -(4-Fluoronaphthalen-1 -yljethyl) amino) propyl)chroman-4-y1)-2-methy1benzoic acid hydrochloride	498.5
		1 O
		¹H NMR (400 MHz,DMSO-d6): 0012.84 (bs, 1H), 9.74 (bs, 1H) , 9.24 (bs, 1 H), 8.37-8.35 (d. J =8.4 Hz, 1H), 8.15-8.13 (d, J- 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, J=8.4,2Hz, 1H), 7.27-7.22 (m, 2H), 7.07-7.04 (t, J=7.2 Hz, 1 H), 6.74-6.70 (t, J= 7.6Hz, 1H), 6.67-6.65 (d, J= 8.0 Hz, 1 H), 6.54-6.52 (d, J= 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), 1.681.63 (m, 5H).

Example-138

Methyl 2-(3-((2R, 4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyl) chroman-4-yl) benzamido) acetate

o

133

To a stirred solution of Example-73 (0.14g, 0.295mmoi) in THF (10mL), (3(ethylimlnomethyleneamlno)-N,N-dimethylpropan-1-amine) (EDC) (0.062g, 0.325 mmol), HOBT (0.05g,0.325mmol) and Ν,Ν-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 ovemtght. 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 Na₂SO₄ and concentrated under reduced pressure to give crude product (0.14g, 93% yield); m/z-509.1.

Example-139

Methyl 2-(2-methyl-5-((2R, 4S)-2-((((R)-1 -(naphthalen-1 -yl) ethyl) amino) methyl) chroman-4-yl) benzamido) acetate

The titie 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-((2/7,4S)-2-((( (/7)-1 -(Naphthalen-1 -yl) ethyl) amino) methyl) chroman-4-yl) benzamido) acetic acid hydrochloride

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 ovemight. The progress of reaction was monitored by TLC. Solvent was distilied off under vacuum then cooled to 0’C and acidîfied with dilute HCl solution [pH=3 to 4]. Extracted the product with ethyl acetate (10mLX2), washed with water (5 mL X2) followed by

134 brine solution (5 mL), dried over sodium sulfate and concentrated under vacuum to get solid. Ethereal HCl (2mL) was added and stirred for 10 min. The solvent was removed and the résultant solid washed with diethyl ether (2 mL) followed by n-pentane (2 mL), dried to get product as a hydrochloride sait. (0.1g, 64% yield):

m/z 495.1; ’HNMR (400 MHz, DMSO-de): δ 12.5 (bs. 1H), 9.8 (bs, 1H), 9.5 (bs, 1H), 8.54-8.51 (m, 1H), 8.30-8.28 (m, 1H), 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, 1H), 5.49 (d, J=6.4Hz, 1H), 4.67 (d, J=6.3Hz, 1H), 4.27-4.25 (m, 1H), 3.86 (d, J=6.2 Hz, 2H), 3.31 (m, 2H), 2.21-2.19 (m, 1H), 2.0.-1.99 (m,1H), 1.76 (d, J=6.4 Hz ,3H).

Example-141

2-(2-Methyt-5-((2R, 4S)-2-((((R)-1-(naphthalen-1-y1) ethyl) amino) methyl) chroman-4yl) benzamido) acetic acid hydrochloride

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_e): δ 9.8 (bs, 1H), 9.5(bs, 1 H), 8.54-8.51 (m, 1H), 8.30-8.28 (m, 1H), 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, 1H), 5.49 (d, J=6.4 Hz,1H), 4.67 (d, J=6.3 Hz. 1H), 4.27-4.25 (m. 1H), 3.86 (d, J=6.24 Hz, 2H), 3.37 (m, 2H), 2.45 (s, 3H), 2.21-2.19 (m, 1H), 2.0.-1.99 (m, 1H), 1.76 (d, J=6.4 Hz, 3H).

Example-142

N, 2-Dimethyl-5-((2R, 4S)-2-((((R)-1-(naphthalen-1-yt) ethyl) amino) methyl) chroman-4-yl) benzamide hydrochloride

135

To a solution of Example-84b (100mg, 0.205 mmol) in DMF (3 mL), 1.Tcarbonyldiimidazole (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. Réaction was quenched with ice water (3mL) the résultant solid was filtered and washed with water (5 mL X 2). Dry this solid at 45 °C. Further, HCl sait of these amino compound was prepared by following the similar hydrochloride sait procedure as described ln Example-72a, 72b (18.5mg, 38.9 %) m/z-464.5; ¹HNMR (400MHz, DMSO-d_e): 9.78 (bs, 1H), 9.43 (bs, 1H), 8.31 (d, J=8.4Hz, 1H), 8.13 (q, J=4.8Hz, 1H), 8.05 (t, J=7.6Hz, 2H). 7.99 (d, J=7.6Hz, 1H), 7.71-7.60 (m, 2H), 7.20 (t, J=8Hz, 1H), 7.16-7.11 (m, 3H), 6.88 (d, J=8Hz, 1H), 6.81 (t, J=6.8Hz & 8.4Hz, 1H), 6.62 (d, J=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, J=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 taklng appropriate acid compound of Example-84b and appropriate amine;

136

Table-10:

Ex. No.	Structure	Mass (m/z)
143	N,N,2-Trimethyl-5-((2R_l4S)-2-((((R)-1 -{naphthalen-1 yl)ethyl) amino)methyl)chroman-4-yl)benzamlde hydrochloride ΤΠ I 0 ’HNMR (400 MHz, DMSO-d_e): 9.71 (bs, 1 H), 9.34 (bs, 1H), 8.30 (d, </=8.4 Hz, 1H), 8.05 (t, J=7.6Hz & 8Hz, 2H), 7.96 (d, </=7.6 Hz, 1H), 7.68-7.60 (m, 3H), 7.28 (d, J=8Hz, 1H), 7.16-7.11 (m, 2H), 6.94 (s, 1H), 6.88 (d, J=8Hz, 1H), 6.81 (d, </=6.8 Hz, 1H), 6.59 (d, J =7.6Hz, 1H), 5.49-5.47 (m, 1H). 4.65-4.60 (m, 1H), 4.27- 4.23 (m, 1H), 3.37 (m, 2H), 2.96 (s, 3H), 2.71 (s, 3H), 2.16 (s, 3H), 2.23-2.16 (m, 1 H), 2.02-2.11 (m, 1H), 1.75 (d, J=6.8 Hz, 3H).	478.6
144	2-Methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl)benzamide hydrochloride OT u HCl f 0 ’HNMR (400MHz, DMSO-d_e): 9.80 (bs,1H), 9.44 (bs,1H), 8.28 (d, J=8.4 Hz, H), 8.05 (m, 3H), 7.68 (m, 3H), 7.61 (bs, 1H), 7.36 (bs, 1H), 7.19-7.09 (m. 4H), 6.88 (d, </=6.8 Hz &0.8 Hz, 1H), 6.81 (t, </=6.8 Hz & 0.8 Hz, 1H), 6.63 (d, </=7.6 Hz, 1H), 5.49-5.48 (m, 1H), 4.64 (m, 1H), 4.26-4.22	450.7

137

	(m, 1H), 3.32-3.31 (m, IH), 3.25-3.24 (m, 1H), 2.34 (s, 3H), 2.21-2.17 (m, 1H), 1.99-1.91 (m, 1H), 1.76 (d, J=6.8 Hz, 3H).
145	MEthyl-N,2-dimethyl-54(2R,4S)-2-((((R)-1-(naphthalen-1 yl) ethyl)amino)methyl)chroman-4-yl)benzamide hydrochloride Tï^ I 0 ’HNMR(400 MHz. DMSO-d_e): 9.71 (bs, 1H), 9.35 (bs. 1H), 8.30 (d, J=8.4 Hz. 1H), 8.05 (t, J=7.6Hz & 8Hz, 2H), 7.96 (d, J=7.6 Hz, 1H), 7.67-7.60 (m, 3H), 7.23-7.22 (m. 1H). 7.16-7.09 (m, 2H). 6.88 (d. J=8Hz, 2H). 6.81 (t, J =7.6 Hz & 7.2Hz, 1H) 6.59 (t, J =6.4 Hz & 7.2 Hz ,1H), 5.49-5.47 (m. 1H). 4.62 (m, 1H). 4.26-4.24 (m. 1H), 3.39-3.37 (m, 2H),2.92 (S, 2H), 2.55 (s, 3H), 2.33 (s, 3H). 2.16 (m. 1H), 1.98 (m. 1H). 1.75(d, J=6.8 Hz, 3H),1.12 (t, J=6 Hz, 3H).	493.49
146	N,N-Diethyl-2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1yl) ethyl) amino)methyl)chroman-4-yl)benzamide hydrochloride OXÂf? ^V Y HCl ÛLyfO I 0 ’HNMR (400 MHz, DMSO-d_e): 9.69 (bs, 1H), 9.35 (bs, 1 H). 8.3 0 (d, J=8.4 Hz, 1H), 8.06 (t, J= 8 Hz, 2H), 7.94 (d, J=7.2 Hz, 1H), 7.67-7.60 (m, 3H), 7.23 (d, J=8Hz, 1H), 7.21-7.12 (m, 2H) , 6.88 (d, J=7.2 Hz, 2H), 6.81 (t, J=7.6 Hz & 7.2 Hz, 1H). 6.58 (d, J=7.6 Hz, 1 H). 5.48 -5.47 (m. 1H) .4.62 (m, 1H), 4.28-4.24 (m, 1 H). 3.39 (m. 4H). 3.27	493.49

138

	(m, 1 H). 3.05 (m, 1H), 2.19 (m, 1H), 2.16 (s, 3H), 1.96-1.92 (m, 1H). 1.75 (d, J=6.8 Hz, 3H), 1.14 (m, 6H).
147	(2-Methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yt)ethy1) amino)methyl)chroman-4-yt)phenyt)(pyrrolidin-1-yl) methanone hydrochloride > 0 ’HNMR (400 MHz, DMSO-d_e): 9.99 (bs, 1H), 9.58 (bs, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.04-8.00 (m, 3H), 7.67-7.59 (m, 3H), 7.22 (d, J= 8 Hz, 1H), 7.15-7.09 (m, 2H), 6.98 (s, 1H), 6.87 (d, J=7.6 Hz,1H), 6.81 (d, J=1.2 Hz, 1H), 6.58 (d, J=7.6 Hz,1H), 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, J=6.8 Hz, 3H), 1.73 (m, 4H).	504.6

The below Examples 148 to 165 given Table-11 can be prepared by foliowing the similar procedures as described herein above by taking appropriately substituted intermediates. Table-11:

Ex.No.	Structure	Ex.No.	Structure
148		i	149		î
	-8	HO		TJ	HO LjJ
	ri			rïl
	LJ			M-
	r				0
	HO'XD
150			151		:
				_o. jf J
	UU	H l J HCl			HCl
	rîi			U-
		o—_f ^0HO			0

140

162	OYDX kJk,OH I 0	163	orrec
164	oçLcc F 0	165	ΟΥΜ Xy HCl

ln-vitro Pharmacoloqlcal 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.

ln-vitro assay method of Calcimlmetlcs through modulation of Calcium Sensing Receptor (CaSR):

The ability of the compounds to modulate Calcium sensing receptor Is determined by measurlng an Increase in Intraceilular calcium [Ca²*}. Stably transfected HEK293 cells expressing hCaSR_pTriEx-3 hygro vector are developed. Cells are grown ovemight on a 96-well plate to 80% confluency in Ham's F12 containing 20% FBS at 37°C, 5% CO₂. Subsequently, cells are washed extensively with 20mM HEPES buffer containing 126mM NaCI₂, 1mM MgCI₂ and 4mM KCI to remove sérum components that mlght interfère with the assay. Cells are loaded with calcium sensing Fluo4NW dye In HEPES base buffer containing 0.1% BSA and 1mg/mi glucose for 30 minutes to measure changes In intraceilular calcium. The activities of the compounds are measured In FLIPR using 0.3mM CaCI₂ In 20mM HEPES base buffer. The effectiveness of the compound to modulate receptor activity Is determined by calculatlng the ECm responses for that compound In an 8-point assay and plotted using GraphPad Prlsm 5.

The compounds prepared were tested using the above assay procedure and the results obtained are given below. The ECso(nM) values of few représentative compounds are set forth In Table-12.

The ln-vitro activity data has been given in Table-12 for représentative compounds.

Table-12:

Example number

ECso Range

141

67, 72b, 73, 75, 81b, 83,84b, 89b, 91, 93a, 93b, 99b, 102b, 104,105b, 119b, 124, 136, 140	Less than 20nM
88, 89a, 97, 101,107b, 111,146	Between 20.01-50.00 nM
81a, 98a, 98b, 108a, 108b, 114,116, 145	Between 50.01-200 nM

Thus, the above In-vitro assay method shows that the compounds of the Invention were found to exhibit agonlstic activity for CaSR, thereby showing utility for treating diseases, disorders associated with the modulation of CaSR.

In-vivo activity in CKD Wistar rats:

Animais 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, animais were randomized based on plasma PTH (intact PTH) levels before using them for the study. Ovemight fasted animais 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 animais were used in each group then compounds of the invention were administered at 1 mg/kg dose. Post 2 h oral dosing animais were fed with feed and water ad libitum. Post treatment blood samples were collected by retro-orbital bleeding under light ether anesthesla 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 J 00

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.

Ali patents, patent applications and other publications cited in this application are hereby incorporated by reference in their entirety for ali purposes to the same extent as if each Individual patent, patent application or publication were so individually denoted.

142

Although certain embodiments and examples hâve been described in detail above, those having ordinary skili In the art will clearly understand that many modifications are possible In the embodiments and examples without departing from the teachings thereof. Ail such modifications are intended to be encompassed within the below claims ofthe Invention.

Claims

CLAIMS:

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, haiogen, 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 haiogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted aikenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, ORe, nitro, cyano, -C(O)ORe, -(CH^rCfOJORe, -O-C(O)ORe, -O(CH₂)rC(O)ORe, -NR₇Ra, -(CH₂)_rNR₇R_e-, -C(O)Rg, -C(O)NR₇Re, -(CH₂)_r-C(O)NR₇R_e, -NR₇C(O)R_e, S(0)o-iRe, -S(O)2NR₇Re. and -NR₇S(O)₂R₉;

X is selected from a bond, -(CRcRdJr-, -O-, -NRr, -NRXCRcRJr. -O(CR_cR_d)_r-, C(O)NR_r, -C(O)NR₇(CRcRd)r, -(CRcRdîrNRXCRçRdJr, -(CRcRd)^ycioaikylene-, cycioalkylene, cycloalkylenefCRcRdîr and -O-cycloalkylene where cycioalkylene may be substituted or unsubstituted;

Rc and R<j, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted aikyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or Rc and R<j 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 -OReOr-NRi₀Rn;

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

144 or unsubstituted cycloalkyl, -ORe, -C(O)R₀₁ -NR₇Ra, -(CH^NR^-, -<CH₂)r-C(O)ORe, -OC(O)ORe, -O(CH₂)r-C(O)ORe, -C(O)NR₇Ra. -(CH₂)_rC(O)NR₇R_a, -NR₇C(O)R₉, -S(0)o.₂R₇, StOfeNRiRe and -NR₇S(O)2R₉:

R₂ Is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl;

R3 and R4 may be same or different and are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy and substituted or unsubstituted cycloalkyl;

Rs Is substituted or unsubstituted alkyl;

Re, 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 Ra, which may be same or different at each occurrence, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl; or R₇ and Ra, 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 hâve one or two double bonds;

at each occurrence, Rg Is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;

R₁₀ and Ru may be same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -(CRçRdJr-CÎOJORa, 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 Rio and Rn, 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 hâve one or two double bonds;

'n* is an integer ranging from 1 to 3, both inclusive;

145 ’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 T is an integer ranging from 1 to 3, both Inclusive;

or its pharmaceutically acceptable sait thereof.
2. The compound of claim 1. having the Formula (II):

or its pharmaceutically acceptable sait thereof;

wherein,

R₂ Is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;

R, R_1t X, Z, ’p’ and ’q’ are as defined ln claim 1.
3. The compound of claim 1, having the Formula (III):

or its pharmaceutically acceptable sait thereof; wherein,

R₂ is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;

R, Ri, X, Z, ’p' and ’q’ are as defined ln claim 1.
4. The compound of claim 1, having the Formula (IV):

146 (IV) or its pharmaceutically acceptable sait thereof;

wherein,

R₂ Is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
5 R, Ri, X, Z, 'p* and *q’ are as defined in claim 1.

(V) or Its pharmaceutically acceptable sait thereof;

10 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.

15
8. The compound of claim 1, wherein 'q' is 0,1 or 2.
9. The compound of claim 1 to claim 5, wherein R! is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, cyano, -ORe, -C(O)alkyl, wherein R« Is hydrogen, substituted or unsubstituted

147 alkyt, substituted or unsubstîtuted haloalkyl, or substituted or unsubstîtuted cycloalkyl; and 'q' ls 0,1,or2.
10. The compound of claim 1, whereln R₂ is substituted or unsubstîtuted aryl whereln the aryl Is substituted or unsubstîtuted phenyl or substituted or unsubstîtuted 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 unsubstîtuted alkyl, substituted or unsubstîtuted haloalkyl, and substituted or unsubstîtuted alkoxy.
12. The compound of claim 1 to claim 5, wherein X is selected from a bond, -(CRcRd)r, -O-, -NRr. -NRKCRcRi)r. -O(CRcRd)r, -C(O)NRr, -CtOJNRKCRcRdïr, (CRcRdJrNRrtCRcRdIr, -(CRcRdJrCycloaikylene-, cycloalkylene, -cycloalkylene(CRcRd)r and -O-cycioaikylene where cycloalkylene may be substituted or unsubstîtuted; R₇ is hydrogen or substituted or unsubstîtuted alkyl; Rc and Rj are hydrogen or alkyl and T’Is 1,2 or 3.
13. The compound of claim 1 to claim 5, wherein Z is -ORe whereln Re Is selected from hydrogen, substituted or unsubstîtuted alkyl, substituted or unsubstîtuted haloalkyl, substituted or unsubstîtuted aryl or substituted or unsubstîtuted arylalkyl.
14. The compound of claim 1 to claim 5, wherein Z Is NR_wRn whereln R_w and Rn may be same or different and are independently selected from hydrogen, substituted or unsubstîtuted alkyl, -(CRcRd)rC(O)OH, -(CRcRd)rC(O)O-alkyl, substituted or unsubstîtuted cycloalkyl, substituted or unsubstîtuted aryl or substituted or unsubstîtuted arylalkyl; or R₁₀ and Rn. 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 cyciic ring may hâve one or two double bonds; wherein Rc and Rj are hydrogen or substituted or unsubstîtuted alkyl and ’r* Is 1, 2 or 3.
15. The compound of claim 1, wherein R_a is hydrogen; R_b is hydrogen; R, is selected from halogen, substituted or unsubstîtuted alkyl, substituted or unsubstîtuted haloalkyl, substituted or unsubstîtuted cycloalkyl, cyano, -ORe, -C(O)alkyl whereln Re Is hydrogen, substituted or unsubstîtuted alkyl, substituted or unsubstîtuted haloalkyl, or substituted or unsubstîtuted cycloalkyl; *q' Is 0, 1, or 2; R₂ Is substituted or unsubstîtuted aryl; R3 Is hydrogen; R< is hydrogen; R₅ Is substituted or unsubstîtuted alkyl; X Is selected from a bond, -(CRcRd)r. -O-, -NRr, -NR₇(CRcRd)r, -O(CRcRd)r, -C(O)NRr, -C(O)NR₇(CRcRJ_rwherein R₇ is hydrogen or substituted or unsubstîtuted alkyl, Rc and Re are hydrogen or substituted or unsubstîtuted alkyl, ’r* is 1, 2, or 3; Z Is -ORe or NR₁₀Rn wherein Re is selected from hydrogen, substituted or unsubstîtuted alkyl, substituted or unsubstîtuted

148 haloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted aryialkyl; Rio and Ru may be same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl, -(CRcRd)r-C(O)OH, -(CRcRd)rC(O)O-alkyl, substituted or unsubstituted cycloalkyl or R₁₀ and Rn together may form a substituted or unsubstituted, saturated or unsaturated 3 to 12 membered cyciic ring, where the unsaturated cyciic ring may hâve one or two double bonds, *n’ is 1, 2 or 3; ’m' Is 0 or 1; and ‘p‘ is 0;

or Its pharmaceutically acceptable sait thereof.
16. The compound of claim 5, wherein Ri is selected from halogen, substituted or unsubstituted alky!, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, cyano, -ORe, -C(O)alkyl wherein Re 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, -(CRcRd)r. -O-, -NR_r. -NRXCRcRjr, -O(CR_eR_d)_r, -C(0)NRr. -CfOÏNRXCRcRdïr wherein R? Is hydrogen or substituted or unsubstituted alkyl, Rc and Rj are hydrogen or substituted or unsubstituted alkyl, Τ’ Is 1, 2, or 3; Z Is -ORe or NR10R11 wherein Re is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted aryialkyl; R_w and Ru may be same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl, -(CRcRdïrCtOÏOH, -ÎCRcRd)rC(O)O-alkyl. substituted or unsubstituted cycloalkyl or R₁₀ and Rn together may form a substituted or unsubstituted, saturated or unsaturated 3 to 12 membered cyciic ring, where the unsaturated cyciic ring may hâve one or two double bonds; and *n* is 1, 2 or 3;

or its pharmaceutically acceptable sait thereof.
17. The compound of claim 1, which Is selected from:

Methyl 2-fluoro-5-((2R,4R)-2-((((R)-1-(naphthalen-1 -yl)ethyl)amino)methyl) chroman-4y!)benzoate;

Methyl 2-fluoro-5-((2R_l4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yl)benzoate;

Methyl-3-((2R,4S)-2-((((R>1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl) benzoate;

Methyl 2-methyl-3-((2R,4S)-2-((((R)-1-(naphthalen-1-y!)ethyl)amino)methyl) chroman-4yl)benzoate;

Methyl 3-methy!-5-((2R,4S)-2-((((R)-1-(naphthalen-1-y!)ethyl)amino)methy!) chroman-4y!)benzoate;

149

Methyl 4-methyl-3-((2R,4S)-2-((((R)-1 -(naphthalen-1-yl)ethyl)amlno)methyl) chroman-4yl)benzoate;

Methyl 2-ethyl-5-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yl)benzoate;

Methyl 2-ethyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yl)benzoate;

Methyl 2-isopropyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yl)benzoate;

Methyl 2-cyclopropy1-5-((2R,4R)-2-((((R)-1-(naphthalen-1-y1)ethy1)amino) methyl) chroman4-yl)benzoate;

Methyl 2-cyclopropyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yljbenzoate;

Methyl 2,6-difluoro-3-((2R_l4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl)benzoate;

Methyl 4-fluoro-2-methyl-3-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amlno) methyl)chroman-4-yl)benzoate;

Methyl 4-fluoro-2-methyl-3-((2R_l4S)-2-((((R)-1-{naphthalen-1-yl)ethyl)amino) methyl)chroman-4-yl)benzoate;

Methyl 2,3-dimethyl-5-((2R_l4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl)benzoate;

Methyl 5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amlno)methy1)chroman-4-yl)-2(trifluoromethyl)benzoate;

Methyl 2-methyl-5-((2R,4R)-2-((((R)-1-(naphthalen-1 -yl)ethyl)amino)methyl) chroman-4yl)benzoate;

Methyl 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amlno)methyl)chroman-4yljbenzoate;

Methyl 2-fluoro-3-((2R,4R)-2-((((R)-1 -(naphthalen-1-yl)ethyl)amino)methyl)chroman -4yl)benzoate;

Methyl 3-fluoro-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yl)benzoate;

Methyl 4-fluoro-3-((2R,4R)-2-{({(R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yljbenzoate;

Methyl 2-methoxy-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl)benzoate;

150

Methyl 2-methoxy-3-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4y1)benzoate;

Methyl 2-methoxy-3-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl) benzoate;

Methyl 4-methoxy-3-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)aniino)methyl)chroman-4yljbenzoate;

Methyl 2-(2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl)phenoxy)acetate;

Methyl 2-(3-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4y1)phenoxy)acetate;

Methyl 2-(2-fluoro-5-((2R,4R)-2-((((R)-1-{naphthalen-1-yl}ethyl)amino)methyl) chroman-4yl)phenoxy)acetate;

Methyl 2-(2-fluoro-5-((2R_l4S)-2-((((R)-1-(naphthalen-1-^)ethyl)amino)meth^) chroman-4yl)phenoxy)acetate;

Methyl 2-(2-fluoro-3-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yl)phenoxy)acetate;

Methyl 2-(3-fluoro-5-((2R,4R)-2-((((R)-1 -(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl)phenoxy)acetate;

Methyl 2-(3-fluoro-5-((2R,4S)-2-((((R)-1 -(naphthalen-1 -yl)ethyl)amino)methyl) chroman-4yl)phenoxy)acetate;

Methyl 2-(4-fluoro-3-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl)phenoxy)acetate;

Methyl 2-methyl-2-(3-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yl)phenoxy)propanoate;

Methyl 4-((2R,4R)-2-((((R)-1-{naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate;

Methyl 4-((2R,4S)-2-{(((R)-1-(naphthalen-1-yl)ethyl)amlno)methyl)chroman-4-yl)benzoate;

Methyl 2-methyl-4-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl) chroman-4yljbenzoate;

Methyl 2-methyl-4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amlno)methyl) chroman-4y1)benzoate;

Methyl 4-((2R,4R)-2-((((R)-14naphthalen-1-yl}ethyl)amino)methyl)chroman-4-yl)-2(trifluoromethyl)benzoate;

Methyl 4-((2R,4S)-2-((((RH4naphthalen-1-y1)ethy1)amïno)methy1)chrornan-4-yl}-2(trifluoromethyl)benzoate;

151

Methyl 2,6-difluoro-4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethy1)amino)niethy1) chroman-4yljbenzoate;

Methyl 3-methoxy-4-((2R,4R)-2-((((R)-1 -(naphthalen-1 -yl)ethy1)amino)methy1) chroman-4yl)benzoate;m

Methyl 3-methoxy-4-((2R_l4S)-2-((((R)-1-(naphthalen-1-y1)ethy1)aniino)niethy1) chroman-4y1)benzoate;

Methyl 3-fluoro-4-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethy1)amino)methyl)chroman-4y1)benzoate;

Methyl 2-fluoro-4-((2R,4S)-2-((((R)-1 -(naphthalen-1 -y1)ethy1)amino)methy1)chroman -4y1)benzoate;

Methyl 2-(4-((2R,4R)-2-((((R)-1 -(naphthalen-1 -yl)ethy1)amino)methy1)chronian-4yl)phenoxy)acetate;

Methyl 2-(4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethy1)aniino)niethyl)chroman-4y1)phenoxy)acetate;

Methyl 2-(2-fluoro-4-((2R,4R)-2-((((R)-1-(naphthaien-1-yl)ethyl)amino)methyl) chroman-4yl)phenoxy)acetate;

Methyl 2-(2-fluoro-4-((2R,4S)-2-((((R)-1 -(naphthalen-1 -yl)ethy1)aniino)niethy1)chroman-4y1)phenoxy)acetate;

Methyl 2-(4-((2R,4R)-2-((((R)-1-(naphthalen-1-y!)ethy1)amino)methy1)chroman-4yl)phenyl)acetate;

Methyl 2-(4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methy1)chroman-4yl)pheny1)acetate;

Methyl 2-methy1-2-(4-((2R_>4R)-2-((((R)-1-(naphthalen-1-yl)ethy1)amino)methyl) chroman-4y!)phenyl)propanoate;

Methyl 2-methyi-2-(4-((2R_>4S)-2-((((R)-1 -(naphthalen-1 -yl)ethyl)amino)methyl) chroman-4y1)phenyl)propanoate;

Methyl 3-methy1-4-((2R_>4S)-2-((((R)-1-(naphthalen-1-y1)ethy1)aniino)methy1) chroman-4yljbenzoate;

Methyl 2-tluoro-5-((2S_l4R)-2-((((R)-1-(naphthaien-1-yl)ethyl)amino)methyl) chroman-4yl) benzoate;

Methyl 3-((2S,4R)-2-((((R)-1-(naphthalen-1-y1)ethy1)amino)methyl)chroman-4-y1)benzoate;

Methyl 2-methyl-5-((2S, 4R)-2-((((R)-1 -(naphthalen-1 -yl)ethyl)amino)methyl)chroman-4y1)benzoate;

Methyl 2-methyt-5-((2S,4S)-2-((((R)-1 -(naphthalen-1 -y1)ethy1)amlno)methy1) chroman-4yljbenzoate;

152

Methyl 2-(4-((2S,4R)-2-{(((R)-1 -(naphthalen-1 -yl)ethyl)amino)methyl)chroman-4yl)phenoxy)acetate;

Methyl 2-(4-((2S,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amlno)methyl)chroman-4yl)phenoxy)acetate;

Methyl 5-((2R,4R)-2-((((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2methylbenzoate;

Methyl 5-((2R,4S)-2-((((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2methylbenzoate;

Methyl 3-((2R,4R)-2-((((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2methoxybenzoate;

Methyl 3-((2R,4S)-2-((((R)-1 -(4-fluoronaphthalen-1 -yl)ethyl)amino)methyl)chroman-4-yl)-2methoxybenzoate;

Methyl 4-((2R)-2-((((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-4-yl)-2methylbenzoate;

Methyl 3-((2R)-2-((((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)arnino)methyl)chroman-4-yl)-2methylbenzoate;

Methyl 5-((2R)-2-((((R)-1 -(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-4-yl)-2methylbenzoate;

Methyl 3-((2R)-2-((((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)amlno)methyl)chroman-4-yl)-5methylbenzoate;

Methyl 3-((2R)-2-((((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)chroman-4-yl)-4methylbenzoate;

Methyl 2-fluoro-5-((2S,4R)-2-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)chroman-4yljbenzoate;

Methyl 2-fluoro-5-((2R,4S)-2-(2-(((R)-1-(naphthalen-1-yl)ethyl)amlno)ethyl) chroman-4yl)benzoate;

Methyl 2-methyl-5-((2S_l4R)-2-(2-(((R)-1 -(naphthaien-1 -yl)ethyl)amino)ethyl) chroman-4yl)benzoate;

Methyl 2-methyl-5-((2R_I4S)-2-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl) chroman-4yljbenzoate;

Methyl 2-methoxy-3-((2R_l4R)-2-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl) chroman-4yljbenzoate;

Methyl 5-((2S,4R)-2-(2-(((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)ethyl)chroman-4-yl)-2methylbenzoate;

153

Methyl 5-((2R,4S)-2-(2-(((R)-1-(4-fluoronaphthalen-1-yl)ethy1)amino)ethy1)chroman-4-y1)-2methylbenzoate;

Methyl 5-((2S,4R)-2-(2-(((R)-1-(4-fluoro-3-methoxyphenyl)ethy1)amino)ethy1) chroman-4-yl)-

2- methylbenzoate;

Methyl 5-((2R,4S)-2-(2-(((R)-1-(4-fluoro-3-methoxypheny1)ethy1)amino)ethy1) hroman-4-y1)-2methylbenzoate;

Methyl 2-fluoro-5-((2S,4S)-2-(3-(((R)-1-(naphthalen-1-y1)ethyl)amino)propyl)chroman-4yl)benzoate;

Methyl 2-fluoro-5-((2R,4R)-2-(3-(((R)-1-(naphthalen-1-y1)ethy1)amino)propyl)chroman-4y1)benzoate;

Methyl 2-methy1-5-((2S_>4S)-2-(3-(((R)-1-(naphthalen-1-y1)ethyl)amino)propyl) chroman-4yljbenzoate;

Methyl 2-methy1-5-((2R,4R)-2-{3-{((R)-1-{naphthalen-1-y1)ethy1)amino)propy1) chroman-4yljbenzoate;

Methyl 5-< (2 S,4S}-2-(3-<(( R)-1 -(4-fluoro-3-methoxyphenyl)ethyl)amino)propy1) chroman-4yl )-2-methylbenzoate;

Methyl 4-((2S,4S)-2-(3-(((R)-1-(4-fluoronaphthalen-1-yl)ethy1)amino)propyl)chroman-4-yl)-3methylbenzoate;

Methyl 4-((2S,4S)-2-(3-(((R)-1-(4-fluoronaphthalen-1-y1)ethyl)amino)propyl) chroman-4y1)benzoate;

Methyl 5-((2S,4S)-2-(3-(((R)-1-(4-fluoronaphthalen-1-y1)ethyl)amino)prapy1) chroman-4-y1)-2methylbenzoate;

2.6- Dimethyl-3-((2R, 4S)-2-<(({R)-1 -(naphthalen-1 -yl) ethyl) amino) methyl) chroman-4yl)benzoic acid hydrochloride;

2.6- Dimethyl-3-((2R,4S)-2-(2-(((R)-1-(naphthalen-1-yl)ethyl) amino) ethyl)chroman-4-y1) benzolc acid hydrochloride;

2.6- Dimethy1-3-((2R,4R)-2-(3-(((R)-1-(naphthalen-1-y1)ethy1) amino) propyl) chroman-4yljbenzoic acid hydrochloride;

2.6- Dimethyl-3-((2S,4S)-2-(3-(((R)-1-(naphthalen-1-yljethyl) amino) propyl) chroman-4yl)benzolc acid hydrochloride;

3- ({2S,4S)-2-(3-(((R)-1-(4-Fluoro-3-methoxyphenyl)ethy1)amino) propyl)chroman-4-yl)-2,6dimethylbenzolc acid hydrochloride;

2-Fluoro-5-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methy1)chroman-4-y1)benzoic acid hydrochloride;

154

2- Fluoro-5-((2R,4S)-2-((((R)-1-(naphtha!en-1-yl)ethyl)amtno)methyl)chroman-4-yl)benzoic acid hydrochloride;

3- ((2R,4S)-2-((((R)-1-(Naphthaten-1-yl)ethyl)amino) methyl) chroman-4-yl)benzoic acid hydrochloride;

2- Methyl-3-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride;

3- Methyl-5-((2R,4S)-2-((((R)-1-(naphtha!en-1-yl)ethyl)amino) methyl)chroman-4-yl)benzoic add hydrochloride;

4- Methyl-3-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino) methyl)chroman-4-yl)benzoic add hydrochloride;

2-Ethyl-5-((2R,4R)-2-((((R)-1 -(naphthalen-l-yl)ethyl) amino) methyl )chroman-4-yl)benzoic add hydrochloride;

2-Ethyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl) benzoic add hydrochloride;

2-lsopropyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl) chroman-4yljbenzoic add hydrochloride;

2-Cyclopropyl-5-((2R,4R)-2-((((R)-1-(naphthaten-1-yl)ethyl)amino)methyl) chroman-4yl)benzoic add hydrochloride;

2-Cyclopropyl-5-((2R,4S)-2-((((R)-1 -(naphthalen-1-yl)ethyl) aminojmethyl) chroman-4yl)benzoic add hydrochloride;

2,6-Difluoro-3-((2R,4R)-2-((((R)-1 -(naphthalen-1 -yl)ethyl) amino)methyl) chroman-4yl)benzoic add hydrochloride;

4-Fluoro-2-methyl-3-((2R,4S)-2-{(((K)-1-Înaphthalen-1-yl) ethyl) amino)methyl) chroman-4yl)benzoic add hydrochloride;

4- Fluoro-2-methyl-3-((2R,4R)-2-((((R)-1’(naphthalen-1-yl) ethyl) aminojmethyl) chroman-4yljbenzoic add hydrochloride;

2,3-Dimethyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4yl)benzoic add hydrochloride;

5- ((2R,4S)-2-((((R)-1-(Naphthaten-1-yl)ethyl)amino) methyl) chroman-4-yl)-2(trifluoromethyl)benzoic acid hydrochloride;

2-Methyl-5-((2R,4R)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyl)chroman-4-yl)benzolc add hydrochloride;

2-Methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid hydrochloride;

155

2- Fluoro-3-((2R,4R)-2-((((R)-1 -(naphthalen-1 -yt) ethy1)amlno) methyt)chroman-4-y1)benzoic add hydrochloride;

3- Fluoro-5-((2R,4S)-2-((((R)-1-(naphthalen-1-y1) ethyljamino) methyl) chroman-4-yl)benzolc acid hydrochloride;

4- Fluoro-3-Î(2R,4R)-2-((((R)-1-(naphthalen-1-y1) ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride;

2-Methoxy-5-((2R,4S)-2-((((R)-1-(naphthalen-1-y1) ethyl) amino) methy1)chroman-4y1)benzolc add hydrochloride;

2-Methoxy-3-((2R,4S)-2-((((R)-1 -(naphthalen-1 -y1)ethy1) amino)methyl)chroman-4-yl)benzoic add hydrochloride;

2-Methoxy-3-((2R,4R)-2-((((R)-1 -(naphthalen-1 -y1)ethy1) aminojmethyl) chroman-4yl)benzoic acid hydrochloride;

4-Methoxy-3-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl) chroman-4-yl) benzolc acid hydrochloride;

2-(2-Methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amlno)methyl)chroman-4yl)phenoxy)acetic add hydrochloride;

2-(3-Methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethy1) amino) methyl) chroman-4y1)phenoxy)acetic acid hydrochloride;

2-(2-Fluoro-5-((2R,4R)-2-((((R)-1-(naphthalen-1-y1)ethy1) aminojmethyl) chroman-4y1)phenoxy)acetic acid hydrochloride;

2-(2-Fluoro-5-((2R_l4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) aminojmethyl) chroman-4-yl) phenoxy) acetic add hydrochloride;

2-(2-Fluoro-3-((2R,4R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amlno)methyl)chroman-4y1)phenoxy)acetic acid hydrochloride;

2-(3-Fluoro-5-((2R_>4R)-2-((((R)-1-(naphthalen-1-y1) ethyl) amlno)methy1) chroman-4y1)phenoxy)acetic acid hydrochloride;

2-(3-Fluoro-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyl) chroman-4-yl) phenoxy)acetic acid hydrochloride;

2-(4-Fluoro-3-((2R,4R)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyl)chroman-4-yl) phenoxy)acetic add hydrochloride;

2-Methy1-2-(3-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4y1)phenoxy)propanolc acid hydrochloride;

4-((2R,4R)-2-((((R)-1-(Naphthalen-1-yl)ethyl)amino) methyl) chroman-4-yl)benzolc acid hydrochloride;

156

4-((2R,4S)-2-((((R)-1-(Naphthalen-1-y1)ethy1) amino) methyl) chroman-4-y!)benzoic acid hydrochloride;

2-Methyt-4-((2R,4R)-2-((((R)-1-(naphthalen-1 -y1)ethy1) amino) methyf)chroman-4-yl)benzoic acid hydrochloride;

2- Methyl-4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl)chroman-4-y!) benzoic acid hydrochloride;

4-((2R,4R)-2-{(((R)-HNaphthalen-1-yt)ethyl)amino) methyl) chroman-4-y1)-2(trifiuoromethyt)benzoic acid hydrochloride;

4-((2R,4S>2-((((R)-1-(Naphthalen-1-yl)ethyl)amino) methyl) chroman-4-yl)-2(trifiuoromethyl)benzoic acid hydrochloride;

2,6-Difluoro-4-((2R,4S)-2-((((R)-1-(naphthalen-1-y!) ethyl) amino)methyf) chroman-4yl)benzoic acid hydrochloride;

3- Methoxy-4-((2R,4R)-2-((((R)-1-(naphthalen-1-yt)ethyl) amino) methyl) chroman-4yl)benzoic acid hydrochloride;

3-Methoxy-4-((2R,4S>2-{(((R)-1-(naphthalen-1-yt) ethyl) aminojmethyl) chroman-4yl)benzoic acid hydrochloride;

3-Fluoro-4-((2R_l4R)-2-((((R)-1-(naphthalen-1-y!) ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride;

2-Fluoro-4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride;

2-(4-{(2R_l4R)-2-((((R)-1-{Naphthalen-1-yl)ethy!)amino) methyf)chroman-4-yl) phenoxy)acetic acid hydrochloride;

2-(4-((2R,4S)-2-((((R)-1 -(Naphthalen-l-yt)ethyl) amino)methyl) chroman-4-y1)phenoxy)acetic acid hydrochloride;

242-Fluoro-4-((2R,4R)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino)methyl)chroman-4yl)phenoxy)acetic acid hydrochloride;

2-i2-Fluoro-4-((2R,4S)-2-((((R)-1-{naphthalen-1-yf) ethyl) amino)methyl)chroman-4yl)phenoxy)acetic acid hydrochloride;

2-{4-((2R_l4R)-2-((((R)-1-(Naphthalen-1-yl)ethyt)amino) methyl)chroman-4-yl) phenyl)acetic acid hydrochloride;

2-(4-((2R,4S)-2-((((R)-1-(Naphthalen-1-yt)ethyl) amino) methyl)chroman-4-y1) phenyl)acetic acid hydrochloride;

2-Methy1-2-(4-((2R_l4R)-2-((((R)-1-(naphthalen-1-yl)ethyl) amino)methyl)chroman-4yl)phenyt)propanoic acid hydrochloride;

157

2- Methyl-2-(4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyi) amino)methyl)chroman-4-yl) phenyl) propanolc acid hydrochloride;

3- Methyl-4-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid hydrochloride;

2- Fluoro-5-((2S,4R)-2-((((R)-1-(naphthalen-1 -yl)ethyl) amino) methyl)chroman-4-yl)benzoic acid hydrochloride;

3- ((2S,4R)-2-((((R)-1 -(Naphthaien-1 -yl)ethyl) amino) methyl) chroman-4-yl)benzoic acid hydrochloride;

2-Methyl-5-((2S,4R)-2-((((R)-1-(naphthalen-1-y!) ethyi) amino) methyl)chroman-4-yl)benzoic acid hydrochloride;

2-Methyl-5-((2S,4S)-2-((((R)-1-(naphtha1en-1-yl) ethyl)amïno) methyl) chroman-4-yl)benzoic acid hydrochloride;

2-(4-((2S,4R)-2-((((R)-1-(Naphthalen-1-yl)ethyl)amino) methyl) chroman-4-yl)phenoxy)acetic acid hydrochloride;

2- (4-i(2S,4S)-2-((((R)-1-(Naphthalen-1-yl)ethyl)amlno)methyl)chroman-4-yl)phenoxy)acetÎc acid hydrochloride;

4- t(2R,4S)-2-((((R)-1-(4-Fluoro-3-methoxyphenyl) ethyi) amino) methyl)chroman-4-yl)-2methylbenzolc acid hydrochloride;

3- ((2R,4S)-2-((((R)-1-(4-Fluoro-3-methoxyphenyl) ethyi) amino)methyl)chroman-4-yl)-2methylbenzoic acid hydrochloride;

5- ((2R,4S)-2-((((R)-1-(4-Fluoro-3-methoxyphenyl) ethyi) amino) methyl)chroman-4-yl)-2methyl benzoic acid hydrochloride;

3-((2R,4S)-2-((((R)-1-(4-Fluoro-3-methoxyphenyl) ethyi) amino)methyl)chroman-4-yl)-5methylbenzoic acid hydrochloride;

3-((2R,4S)-2-((((R)-1-(4-Fluoro-3-methoxyphenyl) ethyi) amino)methyl)chroman-4-yl)-4methylbenzolc acid hydrochloride;

5-((2R,4R)-2-((((R)-1-(4-Fluoronaphthalen-1-yl) ethyi) amino) methyl)chroman-4-yl)-2-methyl benzoic acid hydrochloride;

5-((2R,4 S)-2-((((R)-1-(4-Fluoronaphthalen-1-yl) ethyi) amino) methyl)chroman-4-y!)-2methyl benzolc acid hydrochloride;

3-((2R,4S)-2-((((R)-1-(4-Fiuoronaphthalen-1-yl)ethyl)amino) methyl)chroman-4-yl)-2methoxybenzoic acid hydrochloride;

3-((2R,4R)-2-((((R)-1-(4-Fluoronaphthalen-1-yl)ethyl) amino) methyl)chroman-4-yl)-2methoxybenzoic acid hydrochloride;

158

2-Fluoro-5-((2S, 4R)-2-(2-(((R)-1 -(naphthalen-1 -yl) ethyl) amino) ethyl) chroman-4-yl) benzolc acid hydrochloride;

2-Fluoro-5-({2R,4S}’2-(2-({(R}'1 -(naphthalen-1 -yljethyl) amino) ethy1)chroman-4-y!)benzolc acid hydrochloride;

2-Methyl-5-((2S,4R}-2-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)chroman-4-yl)benzoic acid hydrochloride;

2-Methy1-5-((2R,4S)-2-(2-(((R)-1 -(naphthalen-1 -yljethyl) amlno)ethyl)chroman-4-yl)benzolc acid hydrochloride;

2-Methoxy-3-((2R,4R}-2-(2-(((R}-1-(naphthalen-1-yl)ethyl)amino)ethyl)chroman-4-yl)benzolc acid hydrochloride;

5-((2S,4R)-2-(2-(((R)-1-(4-Fluoronaphthalen-1-yl)ethyl) amino) ethyl)chroman-4-y1}-2methylbenzoic acid hydrochloride;

5-((2R,4S)-2-(2-(((R)-1 -(4-Fluoronaphthalen-1-yl)ethyl) amino) ethyl)chroman-4-yl}-2methylbenzoic acid hydrochloride;

5-((2S,4R}-2-(2-(((R}-1-(4-Fluoro-3-methoxy phenyl) ethyl) amino) ethyl) chroma n-4-yl)-2methylbenzolc acid hydrochloride;

5-((2^45)-2-(2-(((^1 -(4-Fluoro-3-methoxy phenyljethyl) amlno)ethyl)chroman-4-yl)-2methylbenzoic acid hydrochloride;

2-Fluoro-5-((2S₁ 4S>2-(3-(((R}-1-(naphthalen-1-yl) ethyl) amino) propyl) chroman-4-yl) benzolc acid hydrochloride;

2-Fluoro-5-((2R_l4R)-2-(3-(((R)-1 -(naphthalen-1 -yl) ethyl) amino) propyl)chroman-4yljbenzolc acid hydrochloride;

2-Methyl-5-((2S,4S>2-(3-(((R}-1-(naphthalen-1-yl) ethyl) amino) propyl)chroman-4y1)benzoic acid hydrochloride;

2-Methyl-5-((2R_l4R}-2-(3-(((R)-1-(naphthalen-1-yl) ethyl) amino) propyl)chroman-4yl)benzoic acid hydrochloride;

5-((2S,4S)-2-(3-(((R)-1 -(4-Fluoro-3-methoxyphenyl) ethyl) amino)propyl)chroman-4-yl)-2methylbenzoic acid hydrochloride;

4-((2S,4S)-2-(3-{((R}d-(4-Fluoronaphthalen-1-y1)ethyl) amino) propyl)chroman-4-yl)-3methylbenzolc acid hydrochloride;

4- ((2S,4S)-2-(3-(((R}-1-(4-Fluoronaphthalen-1-yl)ethyl) amino) propyl)chroman-4-yl)benzoic acid hydrochloride;

5- ((2S,4S}-2-(3-(((R)-1-(4-Fluoronaphthalen-1-yl)ethyl)amino)propyl)chroman-4-yl}-2methylbenzolc acid hydrochloride;

159

Methyl 2-(3-((2R, 4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyl) chroman-4-yl) benzamido) acetate;

Methyl 2-(2-methyl-5-((2R, 4S)-2-((((R)-1 -(naphthalen-1 -yl) ethyl) amino) methyl) chroman-

4-yl) benzamido) acetate;

2-(3-((2R, 4S)-2-((((R)-1-(Naphthalen-1-yl) ethyl) amino) methyl) chroman-4-yl) benzamido) acetic acid hydrochloride;

2-(2-Methyl-5-((2R,4S)-2-((((R)-1 -(naphthalen-1 -yl) ethyl) amino) methyl) chroman-4yl) benzamido) acetic add hydrochloride;

N, 2-Dimethyl-5-((2R, 4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyl) chroman-4-yl) benzamide hydrochloride;

N, N, 2-Trimethyl-5-((2R,4S)-2-((((R)-1 -(naphthalen-1 -yljethyl) amino)methyl)chroman-4yljbenzamide hydrochloride;

2-Methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-y1)ethyl)amino) methyl)chroman-4y1)benzamlde hydrochloride;

W-Ethyl-N,2-dimethy1-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methy1) chroman-

4-yl)benzamide hydrochloride;

/V,N-Diethyl-2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyljchroman-

4-yl)benzamide hydrochloride; and (2-Methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl) amlno)methyl)chroman-4yl)phenyl)(pyrrolidin-1-yl)methanone hydrochloride;

or Its pharmaceutically acceptable sait thereof.
18. A pharmaceutical composition comprising one or more compounds of Formula (I) according to claim 1, and one or more pharmaceutically acceptable exdpients.
19. lise of a compound for the manufacture of a médicament 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 sait thereof.
20. The use of claim 19, wherein the diseases, disorders, syndromes or conditions associated with the modulation of calcium sensing receptor (CaSR) are selected from hyperparathyroidism, chronic rénal failure (with or without dialysis), chronic kldney disease (with or without dialysis) and their complications.
21. The use of claim 20, wherein hyperparathyroidism is primary hyperparathyroidism, secondary hyperparathyroidism or tertlary hyperparathyroidism.

160
22. The use 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 hyperplasla, parathyroid carclnoma, va s eu la r & valvular calcification, abnormal calcium homeostasls, hypercalcémie, abnormal phosphorous homeostasls, hypophosphatemia, bone related diseases or complications arising due to hyperparathyroidism, chronlc kidney disease or parathyroid carclnoma, bone loss post rénal transplantation, osteltis fibrosa cystlca, adynamie bone disease, rénal bone diseases, cardiovascular complications arising due to hyperparathyroidism or chronic kidney disease, certain malignancies in which (Ca²*)_eions are abnormally high, cardiac, rénal or intestinal dysfonctions, podocyte-related diseases, abnormal intestinal motility, diarrhea, augmenting gastrin or gastric acid sécrétion to directly or indirectly benefit In atrophie gastritis or to improve absorption of pharmacological compounds, drugs or suppléments from gastro-intestinal tract by augmenting gastric acidity.