OA18633A - Sulfonamide compounds as voltage-gated sodium channel modulators. - Google Patents

Sulfonamide compounds as voltage-gated sodium channel modulators. Download PDF

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Publication number
OA18633A
OA18633A OA1201800081 OA18633A OA 18633 A OA18633 A OA 18633A OA 1201800081 OA1201800081 OA 1201800081 OA 18633 A OA18633 A OA 18633A
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OAPI
Prior art keywords
phenyl
trifluoromethyl
sulfonamide
chroman
substituted
Prior art date
Application number
OA1201800081
Inventor
Rajender Kumar Kamboj
Venkata P. Palle
Ganesh Navinchandra Gote
Vidya Ramdas
Rajeshkumar Maganlal Loriya
Moloy Banerjee
Pradeep Rangrao Patil
Advait Arun Joshi
Laxmikant Shamlal Datrange
Deepak Sahebrao Walke
Talha Hussain Khan
Amit Kumar Das
Vaibhav Madhukar Kalhapure
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Lupin Limited, Kalpataru Inspire
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Publication of OA18633A publication Critical patent/OA18633A/en

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Abstract

The present invention relates to sulfonamide compounds Formula (I)

Description

SULFONAMIDE COMPOUNDS AS VOLTAGE-GATED SODIUM CHANNEL MODULATORS
Related applications
The présent application claims the benefit of priority to Indian Provisional Patent
Application No. 3420/MUM/2015 filed on Sep 04, 2015 and 201621011342 filed on Mar 31, 2016 and the entire provisional spécifications.
Field of the Invention
The invention relates to sulfonamide compounds their pharmaceutically 10 acceptable salts thereof and pharmaceutical compositions for the treatment, management, and/or lessening severity of diseases, disorders, syndromes or conditions which are associated with the voltage-gated sodium channels (VGSC). The invention also relates to processes for the préparation of compounds of the invention and methods of treating, managing and/or lessening the severity of the diseases disorders, syndromes or conditions 15 associated with voltage-gated sodium channels (VGSC).
Background of the Invention
Voltage-gated sodium channels play a crucial rôle in maintaining a spécifie membrane potential (intra- and extracellular ionic environments) across the mammalian cell membrane. The intracellular concentration of Na+ is kept low relative to the 20 extracellular by active sodium pumps that eject three Na+ ions for every two K+ ions taken in. This generates a négative membrane potential (since more positive charge is pumped out and less taken in) and maintains the Na+ concentration of 6 and 140 mM in the intra and extracellular milieu. On opening of the voltage-gated sodium channels (VGSC), Na+ rushes in and leads to depolarization of the membrane because of the 25 associated positive charge. The entry of Na+ via VGSC’s occurs in cells of the heart, central and peripheral nervous System and is essential to initiate the firing of an action potential.
VGSCs consist of a pore-forming»alpha subunit and a stabilizing beta subunit, 9 isoforms of the alpha subunit hâve been identified till date (Navl.l to Nayl.9). Ail nine 30 members of the family hâve >50% identity in the amino acid sequence in the extracellular and transmembrane domain. The channels hâve also been further classified based on their sensitivity to the puffer fish toxin (tetrodotoxin, TTX). Channels Nayl.8, Nayl.9 and Nayl.5 are TTX résistant (TTX-R) whereas the remaining channels are sensitive to TTX (TTX-S). (England and Rawson. Future Med. Chem. (2010), 2, 775-790). However, 5 Navl .7 gene is prominently responsible to cause to pain.
Loss of function mutations in the human Nayl.7 gene lead to congénital insensitivity to pain which was observed for the first time in certain Pakistani families. Affected individuals displayed painless bums, fractures, and injuries of the lips and tongue. The patients did not hâve any autonomie or motor abnormalities, and reportedly 10 had normal tear formation, sweating ability, reflexes, and intelligence. This genetic evidence clearly indicates that gain or loss of Nayl.7 function can lead to exacerbation or loss of pain sensation respectively. Thus, it may be possible to treat chronic pain by pharmacologically blocking Nayl.7. Moreover, Nayl.7 has also been implicated in epilepsy. Small molécule Nav1.7 blockers showed efficacy in in vivo epilepsy models. It 15 has therefore been proposed that sélective Nayl.7 blockers may lead to therapeutic benefit in epilepsy (Hoyt et al. Bioorganic & Médicinal Chemistry Letters (2008), 18, 1963-1966).
Genetic evidence stems from the human gain of function as well as loss of function mutations that lead to inherited pain disorders and insensitivity to pain 20 respectively. Non sélective VGSC blockers hâve been shown to alleviate pain in animal models as well as in humans (e.g., Carbamazepine). Ralfinamide, another non-selective sodium channel blocker, is also being developed for the treatment of neuropathie pain.
Voltage-gated sodium channels are implicated in various diseases and disease conditions, including but not limited to chronic pain, viscéral pain, arrhythmia, multiple 25 sclerosis, epilepsy and related disorders as well as cancer. Thus, small molécules targeting one or more of the relevant VGSCs is likely to alleviate the suffering from these conditions.
International publication numbers WO 2006/110917, WO 2007/109324, WO 2008/046049, WO 2008/046084, WO 2008/046087, WO 2008/060789, WO
2009/012242, WO 2010/035166, WO 2010/045197, WO 2010/045251, WO
2010/053998, WO 2010/078307, WO2010/151595, WO2010/151597, WO 2011/002708, WO 2011/026240, WO 2011/103196, WO 2011/056985, WO 2011/058766, WO 2011/088201, WO2011/140425, WO 2015/151001, WO 2013/122897 and Bioorganic & Médicinal Chemistry Letters (2011), 21, 3676-681 disclose compounds related to voltagegated sodium channel (VGSC) modulators for the treatment of various diseases mediated by VGSC modulation.
Summary of the Invention
In accordance with one aspect, the invention provides compounds having the structure of Formula (I), wherein,
Ai and A2 are independently hydrogen or substituted or unsubstituted (C|. Cô)alkyl; or
Ai and A2, together with the carbon atom to which they are attached, form a substituted or unsubstituted 3- to 6- membered cycloalkyl ring or 4- to 6- membered heterocyclic ring;
Ri is selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted (Ci.Côjalkyl and substituted or unsubstituted (Ci.Cô)alkoxy;
R2, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted (Cj.Côjalkyl, (Cj.Côjhaloalkyl, -(CH2)o-2-S(0)2-alkyl, -O-Ré, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted (Cj.Cgjcycloalkyl, substituted or unsubstituted (Cé.Cio)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl, -C(O)OH, -C(O)O-alkyl and C(O)NR4R5;
ring A is monocyclic six membered heteroaryl containing l- to 3- nitrogen atoms in the ring;
R3, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted (Ci.Côjalkyl and substituted or unsubstituted (Ci.Côjalkoxy;
R4 and R5 are independently selected from hydrogen or substituted or unsubstituted (Ci.Cô)alkyl; or R4 and R5 together with the nitrogen atom to which they are attached, form substituted or unsubstituted 5- to 6- membered heterocylic ring;
Rô is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci.Cô)alkyl, (Cj.Côjhaloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted (C3.Cg)cycloalkyl, substituted or unsubstituted (C6-Cio)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl;
‘m’is an integer ranging from 0 to 3, both inclusive;
‘n’ is an integer ranging from 0 to 3, both inclusive;
wherein the substituents for substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted alkoxyalkyl are one or more same or different and independently selected from the group consisting of hydroxy, halogen, carboxy, cyano, nitro, oxo (=O), (Ci.Cé)alkyl, (Ci.Côjhaloalkyl, hydroxy (Cj.CôJalkyl, alkoxyalkyl, (C2.C6)alkenyl, (C2-C6)alkynyl, (Cô-Cio)aryl, arylalkyl, (C3.Cg)cycloalkyl, cycloalkylalkyl, 5 to IO membered heteroaryl, 4 to IO membered heterocyclic ring, 3 to IO membered heterocyclylalkyl, heteroarylalkyl, -C(O)ORX, C(O)Ry, -C(S)Ry, -C(O)NRXRZ, -NRXC(O)NRXRZ, -N(Rx)S(O)2Ry, -NRXRZ, -NRxC(O)Ry, 18633
NRxC(S)Ry, -NRXC(S)NRXRZ, -S(O)2NRXRZ, -ORX, -OC(O)Ry, -C(RaRb),.3C(O)ORx, C(RaRb)i.3C(O)NRxRz, -OC(RaRb)2-3-ORx, -OC(RaRb)2.3-NRxRz, -OC(RaRb)2.3-S(O)0.2Ry, - C(RaRb),.3-NRxRz, -C(RaRb)I.3-S(O)0.2Ry, -OC(RaRb)i.3-C(O)NRxRz, -OC(RaRb)i.3C(O)ORX, and -S(0)o.2Ry;
each of Rx is selected from the group consisting hydrogen, (Cj.Côjalkyl, (Ci.
Cb)haloalkyl, (C2.C6)alkenyl, (C2.C6)alkynyl, (C6.Cio)aryl, arylalkyl, (C3.C8)cycloalkyl, (C3.C8)cycloalkenyl, 5 to 10 membered heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl;
each of Ry is selected from the group consisting (Ci.Côjalkyl, (C|.C6)haloalkyl, 10 (C2.Cô)alkenyl, (C2.C6)alkynyl, (C6-Cio)aryl, arylalkyl, (C3.C8)cycloalkyl, (C3. C8)cycloalkenyl, 5 to 10 membered heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl;
each of Rz is selected from the group consisting hydrogen, (Ci.Csjalkyl, (Ci. Cô)haloalkyl, (C2.Cb)alkenyl, (C2.C6)alkynyl, (C6-Cio)aryl, arylalkyl, (C3.C8)cycloalkyl, 15 (C3.C8)cycloalkenyl, 5 to 10 membered heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; or Rx and Rz together with the nitrogen atom to which they are attached form a substituted or unsubstituted, saturated or unsaturated 4- to 8- membered cyclic ring, wherein the unsaturated cyclic ring may hâve one or two double bonds; and each of Ra and Rb are independently selected from the group consisting of 20 hydrogen, halogen and substituted or unsubstituted (Ci.Côjalkyl;
or N-oxides thereof or a pharmaceutically acceptable sait thereof or stereoisomer thereof.
In accordance with one aspect, the invention provides compounds having the structure of Formula (I),
wherein,
Ai and A2 are independently hydrogen or substituted or unsubstituted alkyl; or
Ai and A2, together with the carbon atom to which they are attached, form a substituted or unsubstituted 3 to 6 membered cycloalkyl ring or 4-6 membered heterocyclyl ring;
Ri is selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl and substituted or unsubstituted alkoxy;
R2, which may be same or different at each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted alkyl, haloalkyl, -S(O)2-alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted monocyclic heterocyclyl, -C(O)OH, C(O)O-alkyl and -C(O)NR4R5;
ring A is monocyclic 6-membered heteroaryl containing 1- to 3- nitrogen atoms in the ring;
R3 is selected from halogen, cyano, substituted or unsubstituted alkyl and substituted or unsubstituted alkoxy;
R4 and R5 are independently selected from hydrogen or substituted or unsubstituted alkyl; or R4 and R5 together with the nitrogen atom to which they are attached, form substituted or unsubstituted 5 to 6 membered heterocylic ring;
‘m’ is an integer ranging from 0 to 3, both inclusive;
‘n’ is an integer ranging from O to 3, both inclusive;
wherein the substituents for substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, 5 substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted haloalkyl are one or more same or different and independently selected from the group consisting of hydroxy, halogen, carboxy, cyano, nitro, oxo (=0), alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroarylalkyl, -C(O)ORX, -C(O)Ry, -C(S)Ry, -C(O)NRXRZ, 10 NRXC(O)NRXRZ, -N(Rx)S(O)2Ry, -NRXRZ, -NRxC(0)Ry, -NRxC(S)Ry, -NRXC(S)NRXRZ, S(O)2NRXRZ, -0Rx, -OC(O)Ry, -C(RaRb)i-3C(O)ORx, -C(RaRb)1.3C(O)NRxRz, -OC(RaRb)2. 3-ORx, -OC(RaRb)2.3-NRxRz, -OC(RaRb)2.3-S(O)0.2Ry, - C(RaRb)!.3-NRxRz, -C(RaRb)1.3S(0)o.2Ry, -OC(RaRb)i.3-C(O)NRxRz, -OC(RaRb)i-3-C(O)ORx, and -S(O)0.2Ry;
Rx is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, 15 cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl;
Ry is selected from alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl;
Rz is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, 20 cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; or Rx and Rz together with the nitrogen atom to which they are attached form a substituted or unsubstituted, saturated or unsaturated 4 to 8 membered cyclic ring, wherein the unsaturated cyclic ring may hâve one or two double bonds; and each of Ra and Rb are independently selected from the group consisting of 25 hydrogen, halogen and substituted or unsubstituted alkyl;
or a pharmaceutically acceptable sait thereof.
In accordance with one aspect, the invention provides compounds having the structure of Formula (I),
wherein,
Ai and A2 are independently hydrogen or substituted or unsubstituted alkyl; or
Ai and A2, together with the carbon atom to which they are attached, form a substituted or unsubstituted 3- to 6- membered cycloalkyl ring or 4- to 6- membered heterocyclic ring;
Ri is selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted alkyl and substituted or unsubstituted alkoxy;
R2, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted alkyl, haloalkyl, -(CH2)o-2-S(0)2-alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl, -C(O)OH, -C(O)O-alkyl and C(O)NR4R5;
ring A is monocyclic six membered heteroaryl containing l- to 3- nitrogen atoms in the ring;
R3, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted alkyl and substituted or unsubstituted alkoxy;
R4 and R5 are independently selected individually from hydrogen or substituted or unsubstituted alkyl; or R4 and R5 together with the nitrogen atom to which they are attached, form substituted or unsubstituted 5- to 6- membered heterocylic ring;
‘m’is an integer ranging from 0 to 3, both inclusive;
‘n’ is an integer ranging from 0 to 3, both inclusive;
wherein the substituents for substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted alkoxyalkyl are one or more same or different and independently selected from the group consisting of hydroxy, halogen, carboxy, cyano, nitro, oxo (=0), alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroarylalkyl, -C(O)ORX, -C(O)Ry, -C(S)Ry, C(O)NRXRZ, -NRXC(O)NRXRZ, -N(Rx)S(O)2Ry, -NRXRZ, -NRxC(O)Ry, -NRxC(S)Ry, NRXC(S)NRXRZ, -S(O)2NRXRZ, -ORX, -OC(O)Ry, -C(RaRb)l.3C(O)ORx, -C(RaRb)!. 3C(O)NRXRZ, -OC(RaRb)2.3-ORx, -OC(RaRb)2.3-NRxRz, -OC(RaRb)2.3-S(O)0-2Ry, C(RaRb)i.3-NRxRz, -C(RaRb)|.3-S(O)0.2Ry, -OC(RaRb)l.3-C(O)NRxR2, -OC(RaRb)(.3C(O)ORX, and -S(0)o.2Ry;
Rx is selected from the group consisting hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl;
Ry is selected from the group consisting alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl;
Rz is selected from the group consisting hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; or Rx and Rz together with the nitrogen atom to which they are attached form a substituted or unsubstituted, saturated or unsaturated 4- to
8- membered cyclic ring, wherein the unsaturated cyclic ring may hâve one or two double bonds; and each of Ra and Rb are independently selected individually from the group consisting of hydrogen, halogen and substituted or unsubstituted alkyl;
or a pharmaceutically acceptable sait thereof.
The details of one or more embodiments of the invention set forth in the below are only illustrative in nature and not intended to limit the scope of the invention. Other features, objects and advantages of the inventions will be apparent from the description and claims.
According to one embodiment, the invention provides compounds having the structure of Formula (II) (R3)n
R2 or N-oxides thereof or a pharmaceutically acceptable sait thereof or stereoisomer thereof;
wherein, ring A is monocyclic six membered heteroaryl containing 1- to 2- nitrogen atoms in the ring;
A] and A2 are independently hydrogen or substituted or unsubstituted (Ci. C6)alkyl;
R2a is selected from halogen, cyano, substituted or unsubstituted (Ci.Cejalkyl, (C|.
Cô)haloalkyl, -(CH2)o.2-S(0)2-alkyl, -O-Rô, substituted or unsubstituted alkoxyalkyl, (C3.
Cg)cycloalkyl, substituted or unsubstituted (Cô.Ciojaryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl, -C(O)OH, -C(O)O-alkyl and -C(O)NR4R5 where R4 and R5 are hydrogen or (Ci-Cô)alkyl;
Rô is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci.Cô)alkyl, (Ci.Côjhaloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted (Cj.Cgjcycloalkyl, substituted or unsubstituted (C6.Cio)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl;
Ri, R2, R3 and ‘n’ are as defined herein above.
According to another embodiment, the invention provides compounds having the structure of Formula (III)
or N-oxides thereof or a pharmaceutically acceptable sait thereof or stereoisomer thereof;
wherein,
R2a is selected from halogen, cyano, substituted or unsubstituted (Ci.Cé)alkyl, (C]. Cô)haloalkyl, -(CH2)o.2-S(0)2-alkyl, -O-R6, substituted or unsubstituted alkoxyalkyl, (C3. Cg)cycloalkyl, substituted or unsubstituted (C6-Ci2)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl, -C(O)OH, -C(O)O-alkyl and -C(O)NR4Rs where R4 and R5 are hydrogen or (Ci-Cô)alkyl;
Rô is selected from the group consisting of hydrogen, substituted or unsubstituted (C|.C6)alkyl, (Ci.Côjhaloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted (C3.Cg)cycloalkyl, substituted or unsubstituted (C6-Ci2)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl;
Ri, R2, R3 and ‘n’ are as defined herein above.
In one embodiment there are provided compounds of Formula (III) wherein
Ri is hydrogen, halogen or (Ci-Cé)alkyl;
R2 is selected from halogen, cyano, (Ci.Cô)alkyl, (C|.C6)haloalkyl, -O-R6, alkoxyalkyl and (Cj.Cgjcycloalkyl; Rô is selected hydrogen, (C].Cô)alkyl, (Ci. Côjhaloalkyl and alkoxy alkyl;
R 3 is halogen, cyano, substituted or unsubstituted (C|-C6)alkyl and substituted or unsubstituted (Ci-Cô)alkoxy; ‘n’ is 0 or 1.
According to another embodiment, the invention provides compounds having the structure of Formula (IV)
R2 or N-oxides thereof or a pharmaceutically acceptable sait thereof or stereoisomer thereof;
wherein,
R2a is selected from halogen, cyano, substituted or unsubstituted (C|.C&)alkyl, (Cp Cô)haloalkyl, -(CH2)o-2-S(0)2-alkyl, -O-Rô, substituted or unsubstituted alkoxyalkyl, (C3. Cgjcycloalkyl, substituted or unsubstituted (C6-C|2)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl, -C(O)OH, -C(O)O-alkyl and -C(O)NR4R5 where R4 and R5 are hydrogen or (Ci-Cô)alkyl;
Rô is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C6)alkyl, (Ci.Cô)haloalkyl, substituted or unsubstituted alkoxyalkyl, (C3. Cg)cycloalkyl, substituted or unsubstituted (C6.Ci2)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl;
Ri, R2, R3 and ‘n’ are as defined herein above.
In one embodiment there are provided compounds of Formula (IV) wherein
Ri is hydrogen, halogen or (Ci-Côjalkyl;
R2 is selected from halogen, cyano, (Ci.Cô)alkyl, (Ci.C6)haloalkyl, -O-R6, alkoxyalkyl and (C3.Cg)cycloalkyl; Ré is selected hydrogen, (Cj.Côjalkyl, (Ci. Côjhaloalkyl and alkoxy alkyl;
R3 is halogen, cyano, substituted or unsubstituted (C|-C6)alkyl and substituted or unsubstituted (Ci-Côjalkoxy; ‘n’ is 0 or 1.
According to another embodiment, the invention provides compounds having the structure of Formula (V)
R2 or N-oxides thereof or a pharmaceutically acceptable sait thereof or stereoisomer thereof;
wherein,
R2a is selected from halogen, cyano, substituted or unsubstituted (Cj.Côjalkyl, (Ci. Côjhaloalkyl, -(CH2)o-2-S(0)2-alkyl, -O-Rô, substituted or unsubstituted alkoxyalkyl, (C3. Cg)cycloalkyl, substituted or unsubstituted (C6-Ci2)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl, -C(O)OH, -C(O)O-alkyl and -C(O)NR4R5 where R4 and R5 are hydrogen or (Ci-Côjalkyl;
R& is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci.Côjalkyl, (Cj.Côjhaloalkyl, substituted or unsubstituted alkoxyalkyl, (C3. Cg)cycloalkyl, substituted or unsubstituted (C6-Ci2)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl;
Ri, R2, R3 and ‘n’ are as defined herein above.
In one embodiment there are provided compounds of Formula (V), wherein
Ri is hydrogen, halogen or (Ci-Cô)alkyl;
R2 is selected from halogen, cyano, (Cj.Côjalkyl, (Ci.Côjhaloalkyl, -O-Rô, alkoxyalkyl and (C.Cg)cycloalkyl; R6 is selected hydrogen, (Cj.Côjalkyl, (Ci.Côjhaloalkyl and alkoxy alkyl;
R3 is halogen, cyano, substituted or unsubstituted (CpCôJalkyl and substituted or unsubstituted (Ci-Côjalkoxy; ‘n’ is 0 or 1.
According to another embodiment, the invention provides compounds having the structure of Formula (VI)
R2 or N-oxides thereof or a pharmaceutically acceptable sait thereof or stereoisomer thereof;
wherein,
R2a is selected from halogen, cyano, substituted or unsubstituted (Ci.Ce)alkyl, (Ci. CôJhaloalkyl, -(CH2)o-2-S(0)2-alkyl, -O-Rô, substituted or unsubstituted alkoxyalkyl, (C3. Cg)cycloalkyl, substituted or unsubstituted (C6.Ci2)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl, -C(O)OH, -C(O)O-alkyl and -C(O)NR4R5 where R4 and R5 are hydrogen or (Ci-Cejalkyl;
Rô is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-Céjalkyl, (Ci.Céjhaloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted (C3.Cg)cycloalkyl, substituted or unsubstituted (C6.Ci2)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl;
Ri, R2, R3 and ‘n’ are as defined herein above.
In one embodiment there are provided compounds of Formula (VI), wherein
Ri is hydrogen, halogen or (Ci-Cé)alkyl;
R2 is selected from halogen, cyano, (C].C6)alkyl, (Ci.Côjhaloalkyl, -O-Rô, alkoxyalkyl and (C3.Cg)cycloalkyl; R6 is selected hydrogen, (Cj.Côjalkyl, (Ci. Côjhaloalkyl and alkoxy alkyl;
R3 is halogen, cyano, substituted or unsubstituted (C]-C6)alkyl and substituted or unsubstituted (Ci-Cé)alkoxy; ‘n’ is 0 or 1.
According to another embodiment, the invention provides compounds having the structure of Formula (VII) and (VIII)
or a pharmaceutically acceptable sait thereof;
wherein, ring A, A|, A2, R|, R2, R3,‘m’and ‘n’ are as defïned herein above.
According to another embodiment, the invention provides compounds having the structure of Formula (lia) and (Ilb)
or a pharmaceutically acceptable sait thereof;
wherein, ring A, Ai, A2, R|, R2, R2a, R3 and ‘n’ are as defïned herein above.
According to certain embodiments ring A is selected
According to certain embodiments R3 is halogen, cyano, (Ci-C6)alkyl and (CiCéjalkoxy; and ‘n’ is 0 or 1.
According to certain embodiments Ai and A2 are independently hydrogen or (C|C6)alkyl.
According to certain embodiments A| and A2 together with the carbon atom to which they are attached, form a 3- to 6- membered cycloalkyl ring.
According to certain embodiments R| is hydrogen, halogen or (Ci-Cô)alkyl;
According to certain embodiments R2 is selected from halogen, cyano, substituted or unsubstituted (C|.C6)alkyl, (Ci.C6)haloalkyl, -(CH2)0.2-S(O)2-alkyl, -O-R6, substituted or unsubstituted alkoxyalkyl, (Cj.Côsjcycloalkyl, substituted or unsubstituted (C6-Ci2)aryl (e.g. phenyl), substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl (e.g pyridyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl), substituted or unsubstituted 4- to 6membered monocyclic heterocyclyl (e.g. pyrrolidinone, oxazolidinone, morpholine, morpholinone, thiomorpholine 1,1-dioxide, tetrahydropyran), -C(O)OH, -C(O)O-alkyl and -C(O)NR4R5 where R4 and R5 are hydrogen or (C|-C6)alkyl; Ré is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci.Côjalkyl, (Ci.Côjhaloalkyl, substituted or unsubstituted alkoxyalkyl, (Cs.Cgjcycloalkyl, substituted or unsubstituted (C6-C|2)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl; and ‘m’ is 0, 1 or 2.
In certain embodiments R2a is selected from halogen, substituted or unsubstituted (Ci.Côjalkyl, (Ci.Côjhaloalkyl, (CH2)o-2-S(0)2-alkyl, -O-Rô, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted (C6-C|2)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, or substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl; where R& is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci.Côjalkyl, (Cj.Côjhaloalkyl, substituted or unsubstituted alkoxyalkyl, (Cs.Cgjcycloalkyl, substituted or unsubstituted (C6-C|2)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl; preferably, R2a is pyridyl, pyrazolyl, phenyl, triazolyl, thiazolyl, oxazolyl, pyrolidinone, oxazolidinone, pyrolidinone, morpholine, morpholinone, thiomorpholine 1,1 -dioxide, tetrahydropyran or -(CH2)2SO2CH3 and R2 is halogen, -ORô or (Ci.Céjhaloalkyl, preferably -CFj.
Compounds of the invention include, for example, compounds of the Formula (1) or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of ring A, R2, R3, ‘m’, ‘n’, Ai and A2 has any of the meanings defined hereinbefore or independently in any of paragraphe (1) to (7):
wherein, ) ring A is selected from
2) R] is hydrogen, halogen or (Ci-Côjalkyl.
3) R2 is selected from halogen, cyano, substituted or unsubstituted (C|.C6)alkyl, (Ci.Côjhaloalkyl, -(CH2)o-2-S(0)2-alkyl, -O-R6, substituted or unsubstituted alkoxyalkyl, (C3.Cg)cycloalkyl, substituted or unsubstituted (C6-C|2)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl, C(O)OH, -C(O)O-alkyl and -C(O)NR4Rj where R4 and R5 are hydrogen or (C|-C6)alkyl; and Ré is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci.Cé)alkyl, (Ci.Céjhaloalkyl, substituted or unsubstituted alkoxyalkyl, (C3.Cg)cycloalkyl, substituted or unsubstituted (Cé. Ci2)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl.
4) R3 is halogen, cyano, substituted or unsubstituted (Ci-Céjalkyl and substituted or unsubstituted (CpCéjalkoxy.
5) ‘m’is an integer ranging from 0 to 3, both inclusive.
6) ‘n’ is an integer ranging from 0 to 2, both inclusive.
7) Ai and A2 are independently hydrogen or substituted or unsubstituted (Ci. Cé)alkyl; or Ai and A2, together with the carbon atom to which they are attached, form a 3- to 6- membered cycloalkyl.
According to another embodiment, there are provided compounds having the structure of Formula (II) (R3)n
R2 wherein Ai and A2 are hydrogen; Ri is hydrogen; ring A is monocyclic six membered heteroaryl containing 1- to 2- nitrogen atoms in the ring (e.g.
); R2 is halogen, (Ci.Côjhaloalkyl (e.g. CF3) or -O-R6; R2a is halogen, substituted or unsubstituted (Ci.C6)alkyl, -(CH2)o-2-S(0)2-alkyl, -O-R6, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted (C6-Cio)aryl (e.g.
o
V , V ), substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl (e.g.
unsubstituted (Cj.Céjalkyl, substituted or unsubstituted alkoxyalkyl and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl (e.g.
O); R3 is halogen, substituted or unsubstituted (Ci.Côjalkyl and substituted or unsubstituted (Cj.Cejalkoxy; and ‘n’ is 0 or l.
It should be understood that the Formula (I) to (VI) structurally encompasses ail tautomers, stereoisomers, enantiomers and diastereomers, including isotopes wherever applicable and pharmaceutically acceptable salts that may be contemplated from the Chemical structures generally described herein.
Below Examples l to 245 are représentative compounds, which are only illustrative in nature and are not intended to limit to the scope of the invention:
(S)-7V-(6-Fluoropyridin-2-yl)-4-(2-( l -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl) phenyl) chroman-7-sulfonamide;
(R)-7V-(6-Fluoropyridin-2-yl)-4-(2-( l -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl) phenyl) chroman-7-sulfonamide;
(S&R)-V-(4-Fluoropyridin-2-yl)-4-(2-(l-methyl-lH-pyrazol-5-yl)-4(trifluoromethyl)phenyl) chroman-7-sulfonamide;
(S&R)-V-(5-Fluoropyridin-2-yl )-4-(2-( l -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl)phenyl) chroman-7-sulfonamide;
(S&R)-jV-(5-Fluoropyrimidin-2-yl)-4-(2-(l -methyl-1 H-pyrazol-5-yl )-4(trifluoromethyl) phenyl) chroman-7-sulfonamide;
(S&R)-4-(2-( l -Methyl-1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-4-yl) chroman-7-sulfonamide;
(S&R)-4-(2-( l -Methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N(pyrazin-2-yl) chromane-7-sulfonamide;
(S&R)-4-(2-( l -Methyl-1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl) chromane-7-sulfonamide;
(S&R)-4-(2-(l-Methyl-l/f-pyrazol-5-yl )-4-(trifluoromethyl)phenyl)-jV(pyrimidin-2-yl) chromane-7-sulfonamide;
(S&R)-7V-(3-Fluoropyridin-2-yl)-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl)phenyl) chromane-7-sulfonamide;
(S&R)-4-(2-( 1 -Methyl-1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(6methylpyridin-2-yl)chroman-7-sulfonamide;
(S&R)-4-(2-( 1 -Methyl-1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(5methylpyridin-2-yl)chroman-7-sulfonamide;
(S&R)-4-(2-(l-Methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(4methylpyridin-2-yl)chroman-7-sulfonamide;
(S&R)-N-(6-Isopropoxypyridin-2-yl )-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
(S&R)-N-(2-Fluoropyridin-3-yl )-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
(S&R)-4-(2-( 1 -Methyl-1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(4methylpyrimidin-2-yl)chroman-7-sulfonamide;
(S&R)-4-(4-Chloro-2-( 1 -methyl-1 H-pyrazol-5-yl)phenyl)-N-(6-fluoropyridin2-yl)chroman-7-sulfonamide;
(S&R)-N-(6-Fluoropyridin-2-yl)-4-(4-isopropoxy-2-( 1 -methyl-1 H-pyrazol-5yl)phenyl)chroman-7-sulfonamide;
(S&R)-4-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-7V-(pyrimidin2-yl)chromane-7-sulfonamide;
(S&R)-4-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-7V-(5fluoropyrimidin-2-yl) chromane-7-sulfonamide;
(S&R)-4-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin4-yl)chromane-7-sulfonamide;
(S&R)-4-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin3-yl)chromane-7-sulfonamide;
(S&R)-4-(4'-Fluoro-5-(trifluoromethyl)-[l,r-biphenyl]-2-yl)-N-(pyrimidin-2yl)chromane-7-sulfonamide;
(S&R)-4-(4'-Fluoro-5-(trifluoromethyl)-[l,r-biphenyl]-2-yl)-N-(5fluoropyrimidin-2-yl) chrornane-7-sulfonamide;
(S&R)-4-(4'-Fluoro-5-(trifluoromethyl)-[ l, l '-biphenyl]-2-yl)-N-(pyrimidin-4yl)chromane-7-sulfonamide;
(S&R)-4-(4'-Fluoro-5-(trifluoromethyl)-[ l, l '-biphenyl]-2-yl)-N-(6fluoropyridin-2-yl) chromane-7-sulfonamide;
(S&R)-4-(2-(\H-1,2,3-Triazol-1 -yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin2-yl)chromane-7-sulfonamide;
(S&R)-4-(2-( l H-1,2,3-Triazol-1 -yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin3-yl)chromane-7-sulfonamide;
(S&R)-4-(2-( 1//-1,2,3-Triazol-l-yl)-4-(trifluoromethyl)phenyl)-jV-(5-fluoro pyrimidin-2-yl) chromane-7-sulfonamide;
(S&R)-4-(2-(lH-l,2,3-Triazol-l-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin
-4-yl )chromane-7-sul fonamide;
(S&R)-4-(2-(lH-l,2,3-Triazol-l-yl)-4-(trifluoromethyl)phenyl)-N-(6fluoropyridin-2-yl) chromane-7-sulfonamide;
(S&R)-V-(6-Fluoropyridin-2-yl)-4-(2-(2-methylthiazol-4-yl)-4-(trifluoro methyl)phenyl) chroman-7-sulfonamide;
(S&R)-4-(2-(2-Methylthiazol-4-yl)-4-(trifluoromethyl)phenyl)-jV-(pyrimidin2-y l )chroman-7-sulfonamide;
(S&R)-A^(5-Fluoropyrimidin-2-yl)-4-(2-(2-methylthiazol-4-yl)-4-(trifluoro methyl)phenyl) chroman-7-sulfonamide;
(S&R)-4-(2-(2-Methylthiazol-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin4-yl)chroman-7-sulfonamide;
(S&R)-4-(2-(2-Methylthiazol-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin3 -yl)chroman-7-sulfonamide;
(S&R)-/V-(5-Fluoropyrimidin-2-yl)-4-(2-(2-methyloxazol-4-yl)-4-(trifluoro methyl) phenyl) chroman-7-sulfonamide;
(S&R)-7V-(6-Fluoropyridin-2-yl)-4-(2-(2-methyloxazol-4-yl)-4-(trifluoro methyl)phenyl) chroman-7-sulfonamide;
(S&R)-4-(2-(2-Methyloxazol-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin2-yl)chroman-7-sulfonamide;
(S&R)-4-(2-(2-Methyloxazol-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin4-yl)chroman-7-sulfonamide;
(S&R)-4-(2-(2-Methyloxazol-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin3-yl)chroman-7-sulfonamide;
(S&R)-7V-(6-Fluoropyridin-2-yl)-4-(2-(2-(methylsulfonyl)ethyl)-4(trifluoromethyl)phenyl) chroman -7-sulfonamide;
(S&R)-4-(2-(2-(Methylsulfonyl)ethyl)-4-(trifluoromethyl)phenyl)-7V(pyrimidin-2-yl)chroman-7-sulfonamide;
(S&R)-jV-(5-Fluoropyrimidin-2-yl)-4-(2-(2-(methylsulfonyl)ethyl)-4(trifluoromethyl)phenyl) chroman-7-sulfonamide;
(S&R)-4-(2-(2-(Methylsulfbnyl)ethyl)-4-(trifIuoromethyl)phenyl)-N(pyrimidin-4-yl) chroman-7-sulfonamide;
(S&R)-4-(2-( l H-Pyrazol-1 -yl)-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin2-yl)chroman-7-sulfonamide;
(S&R)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(thiazol-2-yl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
(R/S)-N-(Pyrimidin-2-yl)-4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenyl) chroman-7-sulfonamide;
(R/S)-N-(Pyrimidin-4-yl)-4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenyl) chroman-7-sul fonamide;
(R/S)-N-(Pyridazin-3-yl)-4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenyl) chroman-7-sulfonamide;
(R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenyl) chroman-7-sulfonamide;
(S&R)-4-(2-(6-Isopropoxypyridin-3-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide;
(S&R)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(6-isopropoxypyridin-3-yl)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
(S&R)-4-(2-(6-Ethoxypyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide;
(R/S)-4-(2-(6-Ethoxypyridin-3-yl)-4-(trifluoiOmethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
(<S/7?)-4-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)chroman-7sulfonamide;
(S/R)-4-(2-Chloro-4-(trifluoromethyl) phenyl)-N-(5-fluoropyrimidin-2-yl) chroman-7-sulfonamide;
(S/Â)-4-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)chiOman-7sulfonamide;
(S'Z/î)-4-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(pyridazin-3-yl)chroman-7sulfonamide;
(S/R)-4-(2-ChloiO-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin-2yl)chroman-7-sulfonamide;
(S&R)-N-(Pyrimidin-2-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)-4(trifluoromethyl) phenyl)chroman-7-sulfonamide;
(S&R)-7R(6-Fluoropyridin-2-yl)-4-(2-(2-oxopynOlidin-l-yl)-4(trifluoromethyl)phenyl) chroman-7-sulfonamide;
(S&R)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(2-oxopyrrolidin-1 -yl)-4(trifluoromethyl) phenyl)chroman-7-sulfonamide;
(R/S)-4-(2-(2-OxopynOlidin-l-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
(R/S)-4-(2-(2-Oxopyrrolidin-l-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl )chroman-7-sul fonamide;
(R/S)-4-(2-(2-Oxopyrrolidin-l-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chromane-7-sulfonamide;
(S&R)-4-(2-Morpholino-4-(trifluoiOmethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
(S/R)-N-(5-Fluoropyrimidin-2-yl)-4-(2-morpholino-4-(trifluorornethyl)phenyl) chroman-7-sulfonamide;
(R/S)-4-(2-Morpholino-4-(trifluorornethyl)phenyl)-N-(pyrimidin-4-yl) chroman-7-sulfonamide;
(R/S)-4-(2-Morpholmo-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
(R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-morpholino-4-(trifluoromethyl)phenyl) chroman-7-sulfonamide;
(S&R)-4-(2-(2-Methoxyethoxy)-4-(trifluoiOmethyl)phenyl)-N-(pyrimidin-2yl)chroman-7 -sul fonamide;
(R/S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(2-methoxyethoxy)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
(R/S)-4-(2-(2-Methoxyethoxy)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
(R/S)-4-(2-(2-Methoxyethoxy)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl )chroman-7-sul fonamide;
(R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-(2-methoxyethoxy)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
(S&R)-4-(2-(3-Methoxypropoxy)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
(R/S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(3-methoxypropoxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
(R/S)-4-(2-(3-Methoxypropoxy)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
(R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-(3-methoxypropoxy)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
(R/S)-4-(2-(2-Methoxyethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
(R/S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(2-rnethoxyethyl)-4-(trifluorornethyl) phenyl)chroman-7-sulfonamide;
(R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-(2-methoxyethyl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
(R/S)-4-(2-(2-Methoxyethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl )chroman-7-sul fonamide;
(R/S)-4-(2-(2-Methoxyethyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
(S&R)-4-(2-(3-Methoxypropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
(R/S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(3-methoxypropyl)-4-(trifluoro methyl)phenyl)chroman-7-sulfonamide;
(R/S)-4-(2-(3-Methoxypropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
(R/S)-4-(2-(3-Methoxypropyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
(R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-(3-methoxypropyl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
(S&R)-4-(2-(4-Methoxybutyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl )chroman-7-sul fonamide;
(R/S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(4-methoxybutyl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
(R/S)-4-(2-(4-Methoxybutyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
(R/S)-4-(2-(4-Methoxybutyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
(S&R)-N-(6-Fluoropyridin-2-yl)-4-(2-(4-methoxybutyl)-4-(trifluoro methyl)phenyl)chroman-7-sulfonamide;
(R/S)-4-(2-(2-Fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
(R/S)-4-(2-(2-Fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(5-fluoro pyrimidin2-yl)chroman-7-sulfonamide;
(R/S)-4-(2-(2-Fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
(R/S)-4-(2-(2-Fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3-yl) chroman-7-sulfonamide;
(R/S)-4-(2-(2-Fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin-2yl)chroman-7-sulfonamide;
(R/S)-4-(2-(3-Fluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
(R/S)-4-(2-(3-Fluoropropyl)-4-(trifluoromethyl)phenyl)-N-(5-fluoropyrimidin2-yl)chroman-7-sulfonamide;
(R/S)-4-(2-(3-FluoiOpropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
(R/S)-4-(2-(3-Fluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
(R/S)-4-(2-(3-Fluoropropyl)-4-(trifluoromethyl)phenyl)-N-(6-fluoiOpyridin-2yl)chroman-7-sulfonamide;
(R/S)-4-(2-(4-Fluorobutyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
(R/S)-4-(2-(4-Fluorobutyl)-4-(trifluoromethyl)phenyl)-N-(5-fluoropyrimidin2-yl)chroman-7-sulfonamide;
(R/S)-4-(2-(4-Fluorobutyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
(R/S)-4-(2-(4-Fluorobutyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3-yl) chroman-7-sulfonamide;
(R/S)-4-(2-(4-Fluorobutyl)-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin-2yl)chroman-7-sulfonamide;
(R&S)-N-(Pyrimidin-2-yl)-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
(R&S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
(R&S)-N-(Pyrimidin-4-yl)-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
(R&S)-N-(Pyridazin-3-yl)-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
(R&S)-N-(6-Fluoropyridin-2-yl)-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
(R&S)-N-(Pyrimidin-2-yl)-4-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
(R&S)-N-(6-Fluoropyridin-2-yl)-4-(2-(((S)-tetrahydrofiiran-3-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
(S/R)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
(S/R)-N-(Pyrimidin-4-yl)-4-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4(trifluoromethyl )phenyl) chroman- 7-sulfonamide;
(S/R)-N-(Pyridazin-3-yl)-4-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
(S&R)-N-(Pyrimidin-2-yl)-4-(2-(((R)-tetrahydrofiiran-3-yl)oxy)-4-(trifluoro methyl)phenyl)chroman- 7-sul fonami de;
(S&R)-2'-(7-(N-(Pyrimidin-2-yl)sulfamoyl)chroman-4-yl)-5'(trifluoromethyl)-[ l, l '-biphenyl]-4-carboxylic acid;
(S&R)-2'-(7-(N-(5-Fluoropyrimidin-2-yl)sulfamoyl)chroman-4-yl)-5'(trifluoromethyl)-[l,l'-biphenyl]-4-carboxylic acid;
(R/S)-2'-(7-(N-(Pyridazin-3-yl)sulfamoyl)chroman-4-yl)-5'-(trifluoromethyl)[1,1 '-biphenyl]-4-carboxylic acid;
(R/S)-2'-(7-(N-(6-Fluoropyridin-2-yl)sulfamoyl)chroman-4-yl)-5'(trifluoromethyl)-[l,r-biphenyl]-4-carboxylic acid;
(S&R)-4-(2-(5-Fluoropyridin-2-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin2-yl)chroman-7-sulfonamide;
(S&R)-4-(2-(5-Fluoropyridin-2-yl)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide;
(S&R)-4-(2-(5-Fluoropyridin-2-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin4-yl)chroman-7-sulfonamide;
(S&R)-4-(2-(5-Fluoropyridin-2-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin3 -yl)chroman-7-sulfonamide;
(S)-4-(2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
(R)-4-(2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
(R/S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(6-methylpyridin-3-yl)-4-(trifluoro methyl)phenyl)chroman-7-sulfonamide;
(R/S)-4-(2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl )chroman- 7-sulfonamide ;
(R/S)-4-(2-(6-Methylpyridin-3-yl)-4-(trifluorornethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
(R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-(6-methylpyridin-3-yl)-4(tri fluoromethyl )phenyl) chroman-7-sul fonamide;
(R/S)-4-(2-(2-Oxooxazolidin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin2-yl)chroman-7-sulfonamide;
(R/S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(2-oxooxazolidin-3-yl)-4-(trifluoro methyl)phenyl)chroman-7-sulfonamide;
(R/S)-4-(2-(2-Oxooxazolidin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sul fonamide;
(R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-(2-oxooxazolidin-3-yl)-4(trifluoromethyl)phenyl)chromane-7-sulfonamide;
(R/S)-4-(2-(3,3-Difluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
(R/S)-4-(2-(3,3-Difluoropropyl)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide;
(R/S)-4-(2-(3,3-Difluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
(R/S)-4-(2-(3,3-Difluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sul fonamide;
(R/S)-4-(2-(3,3-Difluoropropyl)-4-(tri fluoromethyl )phenyl)-N-(6fluoropyridin-2-yl)chromane-7-sulfonamide;
(R&S)-4-(2-(Oxetan-3-yloxy)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
(S/R)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(oxetan-3-yloxy)-4-(tri fluoromethyl) phenyl)chroman-7-sulfonamide;
(S/R)-N-(6-Fluoropyridin-2-yl)-4-(2-(oxetan-3-yloxy)-4-(trifluoromethyl) phenyl)chromane-7-sulfonamide;
(S&R)-4-(2-(3-Fluoropropoxy)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sul fonamide;
(R/S)-4-(2-(5-Fluoro-6-methylpyridin-2-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide;
(R/S)-4-(2-(5-FluoiO-6-methylpyridin-2-yl)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide;
(R/S)-4-(2-(5-Fluoro-6-methylpyridin-2-yl)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl)chroman-7-sulfonamide;
(R/S)-4-(2-(5-Fluoro-6-methylpyridin-2-yl)-4-(trifluoromethyl)phenyl)-N-(6fluoropyridin-2-yl)chroman-7-sulfonamide;
(S&R)-4-(2-Methoxy-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)chroman7-sulfonamide;
(S&R)-N-(6-Fluoropyridin-2-yl)-4-(2-methoxy-4-(trifluoromethyl) phenyl) chroman-7-sul fonamide;
(S&R)-4-(2-(3-Oxomorpholino)-4-(trifluoromethyl)phenyl)-N-(pyrimidin -2yl)chroman-7-sulfonamide;
(S&R)-4-(2-( 1,1 -Dioxidothiornorpholino)-4-(trifluorornethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide;
(R/S)-4-(2-( 1,1 -Dioxidothiornorpholino)-4-(trifluorornethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide;
(R/S)-4-(2-( 1,1 -Dioxidothiomorpholino)-4-(trifluoromethyl)phenyl)-N-(6fluoropyridin-2-yl)chrornan-7-sulfonarnide;
(R/S)-4-(2-(l, 1 -Dioxidothiomorpholino)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl)chroman-7-sulfonamide;
(R/S)-4-(2-( 1,1 -Dioxidothiomorpholino)-4-(trifluoromethyl)phenyl)-N(pyrimidin-4-yl)chromane-7-sulfonamide;
(S&R)-4-(2-propyl-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)chroman-7sulfonamide;
(S&R)-N-(5-fluoropyrimidin-2-yl)-4-(2-propyl-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
(S&R)-4-(2-propyl-4-(trifluoromethyl)phenyl)-N-(pyridazin-3-yl)chroman-7sulfonamide; and (S&R)-N-(6-fluoropyridin-2-yl)-4-(2-propyl-4-(trifluoromethyl)phenyl) chroman-7-sulfonamide or racemate thereof, N-oxide thereof or a pharmaceutically acceptable sait thereof.
In another embodiment, the invention provides a compound of Formulae (I) to (VI) wherein the compound is in free base form.
In another embodiment, the invention provides a compound of Formulae (I) to (VI) wherein the compound is pharmaceutically acceptable sait.
In another embodiment, the invention provides compounds of Formulae (I) to (VI) structurally encompass stereoisomers including enantiomers or diastereomers.
In another embodiment, the invention provides a compound of Formulae (I) to (VI) wherein the compound is racemic mixture containing ‘R’ isomer and ‘S’isomer.
In another embodiment, the invention provides a compound of Formulae (I) to (VI) wherein the compound is ‘R’ isomer.
In another embodiment, the invention provides a compound of Formulae (I) to (VI) wherein the compound is ‘S’isomer.
In another aspect of the invention, there is provided a compound of Formulae (I) to (VI) or a pharmaceutically acceptable sait thereof for use as a médicament.
In another aspect of the invention, there is provided a compound of Formulae (I) to (VI), or a pharmaceutically acceptable sait thereof, for use in treating the diseases, disorders, syndromes or conditions associated with VGSC particularly Navl.7.
In another aspect, the invention provides a pharmaceutical composition comprising at least one compound of Formulae (I) to (VI), or a pharmaceutically acceptable sait thereof and at least one pharmaceutically acceptable excipient.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of Formulae (I) to (VI), or a pharmaceutically acceptable sait thereof, for use in treating, the diseases disorders, syndromes or conditions associated with VGSC particularly Navl.7 in a subject, in need thereof by administering to the subject, one or more compounds described herein in a therapeutically effective amount to cause modulation of such receptor.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of Formulae (I) to (VI), or a pharmaceutically acceptable sait thereof, N-oxide thereof, or a pharmaceutically acceptable stereoisomer thereof, together with a pharmaceutically acceptable excipient.
In another aspect of the invention, there is provided use of a compound of Formulae (I) to (VI), or a pharmaceutically acceptable sait thereof, for the manufacture of a médicament for treating, the diseases, disorders, syndromes or conditions associated with VGSC.
In another aspect, there are provided process for the préparation of compounds of Formula (la):
wherein ring A, R|, R?, R3, ‘m’ and ‘n’ are as defined herein above;
the process comprising the steps of:
a) reacting a compound of formula (2) with NCS followed by pentafluorophenol gives the pentafluoro ester of formula (7)
(i) NCS, (ii) Pentafluorophenol
b) reacting a compound of formula (7) with p-tosyl hydrazine to give the hydrazone compound of formula (8)
c) coupling of a compound of formula (8) with compound of formula (4) in presence of suitable Pd catalyst to give compound of formula (6) which can also be prepared from compound of formula (5) by reacting with sulfuryl chloride or NCS or dichlorohydantoin followed by pentafluorophenol
d) reducing a compound of formula (6) using Pd/C to give compound of formula (9)
e) coupling of compound of formula (9) with amine of formula ( 10) to give compound of formula (la)
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, 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.
Unless otherwise stated, in the présent application “oxo” means C(=O) group. Such an oxo group may be a part of either a cycle or a chain in the compounds of the présent invention.
The term alkyl refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molécule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1dimethylethyl (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.
The term alkenyl refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), wo-propenyl, 2-methyl-lpropenyl, 1-butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, ail alkenyl groups described or claimed herein may be straight chain or branched.
The terrn alkynyl refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon- carbon triple bond. Non- limiting examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, ail alkynyl groups described or claimed herein may be straight chain or branched.
The terrn alkoxy dénotés an alkyl group attached via an oxygen linkage to the rest of the molécule. Représentative examples of such groups are -OCH3 and -OC2H5. Unless set forth or recited to the contrary, ail alkoxy groups described or claimed herein may be straight chain or branched.
The terrn alkoxyalkyl refers to an alkoxy group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2-O-CH3, -CH2-O-CH2CH3, CH2CH2-O-CH3 and the like.
The terrn hydroxyalkyl refers to an alkyl group, as defmed above that is substituted by one or more hydroxy groups. Preferably, the hydroxyalkyl is monohydroxyalkyl or dihydroxyalkyl. Non-limiting examples of a hydroxyalkyl include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and the like.
The terrn haloalkyl refers to an alkyl group as defmed above that is substituted by one or more halogen atoms as defmed above. Preferably, the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can hâve one iodine, bromine, chlorine or fluorine atom. Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms. Preferably, a polyhaloalkyl is substituted with up to 12 halogen atoms. Non-limiting examples of a haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. A perhaloalkyl refers to an alkyl having ail hydrogen atoms replaced with halogen atoms. Unless set forth or recited to the contrary, ail haloalkyl groups described or claimed herein may be straight chain or branched.
The term cycloalkyl refers to a non-aromatic mono or multicyclic ring System having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbomyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl and the like.
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.
The term cycloalkylalkyl refers to a cycloalkyl group as defïned above, directly bonded to an alkyl group as defïned above, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, etc.
The term aryl refers to an aromatic radical having 6- to 14- carbon atoms, including monocyclic, bicyclic and tricyclic aromatic Systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl and the like.
The term arylalkyl refers to an aryl group as defïned above directly bonded to an alkyl group as defïned above, e.g., -CH2C6H5 and -C2H4C6H5.
A 4 to 8 membered cyclic ring as used herein refers to a monocyclic or bicyclic heteroaryl or heterocyclic ring Systems.
The term heterocyclic ring or heterocyclyl ring or heterocyclyl, unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15membered ring which consists of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S. The heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring Systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation States. In addition, the nitrogen atom may be optionally quatemized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefmic bond(s) and one or two carbon atoms(s) in the heterocyclic ring or heterocyclyl may be interrupted with -CF2-, -C(O)-, -S(O)-, S(O)2, -C(-N-alkyl)-, or -C(=Ncycloalkyl), etc. In addition heterocyclic ring may also be fused with aromatic ring. Nonlimiting examples of heterocyclic rings include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone indoline, benzodioxole, tetrahydroquinoline, tetrahydrobenzopyran and the like. The heterocyclic ring may be attached to the main structure at any heteroatom or carbon atom that results in the création of a stable structure.
The term heteroaryl unless otherwise specified, refers to a substituted or unsubstituted 5- to 14- membered aromatic heterocyclic ring with one or more heteroatom(s) independently selected from N, O or S. In addition the nitrogen atom in a heteroaryl ring is optionally quatemized to form corresponding N-oxide. The heteroaryl may be a mono-, bi- or tricyclic ring System. The heteroaryl ring may be attached to the main structure at any heteroatom or carbon atom that results in the création of a stable structure. Non-limiting examples of a heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like.
The term heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the création of a stable structure.
The term heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the création of a stable structure.
The compounds of the présent invention may hâve one or more chiral centers. The absolute stereochemistry at each chiral center may be ‘R’ or ‘S’. The compounds of the invention include ail diastereomers and enantiomers and mixtures thereof. Unless specifically mentioned otherwise, reference to one stereoisomer applies to any of the possible stereoisomers. Whenever the stereoisomeric composition is unspecified, it is to be understood that ail possible stereoisomers are included.
The term stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term enantiomer refers to two stereoisomers whose 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 enantiomers. The terms racemate or racemic mixture refer to a mixture of equal parts of enantiomers. ‘orl’ mentioned in the structures herein refers to single stereoisomer that is assigned to be either R isomer or S isomer.
The term treating or treatment of a State, disease, disorder, condition or syndrome includes: (a) preventing or delaying the appearance of clinical symptoms of the State, disease, disorder, condition or syndrome developing in a subject that may be afflicted with or predisposed to the state, disease, disorder, condition or syndrome but does not yet expérience or display clinical or subclinical symptoms of the state, disease, disorder, condition or syndrome; (b) inhibiting the state, disease, disorder, condition or syndrome, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; c) lessening the severity of a disease disorder or condition or at least one of its clinical or subclinical symptoms thereof; and/or (d) relieving the disease, i.e., causing régression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
The term modulate or “modulating” or “modulation” refers to a decrease or inhibition in the amount, quality, or effect of a particular activity, fonction or molécule; by way of illustration that antagonists of a voltage-gated sodium channels are modulators of VGSC. Any such modulation, whether it is partial or complété inhibition or prévention of ion flux, is sometimes referred to herein as blocking and corresponding compounds as blockers. For example, the compounds of invention are useful as modulators of the NaVl.7. In general, the compounds of the invention modulâtes the activity of a sodium channel downwards, inhibits the voltage-dependent activity of the sodium channel, and/or reduces or prevents sodium ion flux across a cell membrane by preventing sodium channel activity such as ion flux.
The term subject includes mammals, preferably humans and other animais, such as domestic animais; e.g., household pets including cats and dogs.
A therapeutically effective amount refers to the amount of a compound that, when administered to a subject in need thereof, is sufficient to cause a desired effect. The therapeutically effective amount will vary depending on the compound, the disease and its severity, âge, weight, physical condition and responsiveness of the subject to be treated.
Pharmaceutically Acceptable Salts:
The compounds of the invention may form salts with acid or base. The compounds of invention may be sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable 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 examples of pharmaceutically acceptable salts are inorganic, organic base addition salts formed by addition of bases. The compounds of the invention may also form salts with amino acids. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
With respect to the overall compounds described by the Formula (I), the invention extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or 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 stereospeciftc or asymmetric synthesis or chiral HPLC (high performance liquid chromatography. Tautomeric forms and mixtures of compounds described herein are also contemplâted.
Compound Screening:
The screening of compounds of the invention for VGSC modulatory activity can be achieved by using various in vitro and in vivo protocols. Some of the methods include measuring current (electrophysiology), estimating membrane potential (using membrane potential dyes or voltage spécifie dye pairs), measuring ion flux (e.g., Sodium or Guanidium), measuring second messenger and transcription factor levels, measuring sodium concentration or by Rubidium efflux assay. These assays can be performed in tissue slices or cell fines that endogenously express sodium channels (e.g. ND7/23, SHSY-5Y). Altematively, one can also use cell fines stably expressing the NaV of interest (e.g., stable cell fines generated in HEK293 cells or CHO cells).
Pharmaceutical Compositions:
The invention relates to pharmaceutical compositions containing the compound of Formula (I). In particular, the pharmaceutical compositions contain a therapeutically effective amount of at least one compound of Formula (I) and at least one pharmaceutically acceptable excipient (such as a carrier or diluent). Preferably, the pharmaceutical compositions include the compound(s) described herein in an amount sufficient to modulate the ion flux through a voltage-dependent sodium channel to treat sodium channel mediated diseases such as pain when administered to a subject.
The compound of the invention may be incorporated 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 a pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
Examples of suitable carriers 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, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifymg agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active 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 administered in conventional forms, for example, capsules, tablets, aérosols, solutions, suspensions or products for topical application.
The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, 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, capsules (soft or hard gelatin), 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, 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 Formulation.
Liquid Formulations include, but are not limited to, syrups, émulsions, suspensions, solutions, émulsions, 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 dissolved 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 quantities of the active component. The unit dosage form can be a packaged préparation, the package containing discrète quantities of préparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
For administration to human 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 O.l mg to 10000 mg, more typically l.O mg to 1000 mg, and most typically 10 mg to 500 mg, according to the potency of the active component or mode of administration.
Suitable doses of the compounds for use in treating the diseases disorders, syndromes and conditions described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to resuit in a desired therapeutic benefit without causing unwanted side effects for the patient. For example, the daily dosage of the Sodium channel modulator can range from about 0.1 to about 30.0 mg/kg. Mode of administration, dosage fonns, 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:
In one aspect, the invention are provided compounds and pharmaceutical compositions that are useful in the treatment of diseases, disorders, syndromes and/or conditions modulated by NaV channel. The invention further provides a method of treating a disease, condition and/or disorder modulated by NaV channel 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.
One aspect of the invention provides methods for decreasing ion flow through voltage-gated sodium channels in a cell, comprising contacting a cell containing the target ion channels with a compound, associated to voltage-dependent gated ion channel, described herein.
In another aspect of the invention, the methods are also useful for the diagnosis of conditions that can be treated by acting on ion flux through voltage-dependent gated ion channel, for determining if a patient will be responsible to therapeutic agents.
In still another aspect of the invention provides a method for the treatment of a disorder or condition through modulating a voltage-gated sodium channel. In this method, a subject in need of such treatment is administered an effective amount of a compound described herein and/or according to Formulae (I) to (VI) described herein.
The compound of Formulae (I) to (VI), being a voltage-dependent gated sodium channel modulator, is potentially useful in the treating, managing and/or lessening of diseases, disorders, syndromes or conditions including but not limited to pain, erythromyalgia, neurological disorders, cardiovascular conditions, neuromuscular conditions, multiple sclerosis, cancer, pruritus, benign prostatic hyperplasia (BPH) and the like.
Pain includes, but is not limited to, acute pain, musculoskeletal pain, postoperative pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain.
The compounds, compositions and methods of the invention are of particular use in treating, managing and/or lessening of pain including inflammatory, neuropathie, nociceptive and idiopathic pain.
The compounds, compositions and methods of the invention are of particular use in treating, managing and/or lessening of pain including but not limited to postoperative pain, arthritis pain, osteoarthritis pain, pain associated with cancer including chemotherapy pain, neuropathie pain secondary to metastatic inflammation, neuralgic, orofacial pain, bum pain, somatic pain, dental pain, sciatica pain, intestinal obstruction pain, viscéral pain, colicky pain, myofascial pain, trauma pain, labour pain, trigeminal neuralgia, glossopharyngeal neuralgia, adiposis dolorosa, acute herpetic and postherpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, goût, phantom limb pain, pain following stroke, thalamic lésions, radiculopathy, chronic headache, migraine pain, familial hémiplégie migraine, conditions associated with cephalic pain, sinus headache, tension headache, cardiac pain arising from an ischémie myocardium, pain following stroke, neuropathy secondary to metastatic inflammation, pain due to connective tissue damage, and other forms of neuralgic, neuropathie, and idiopathic pain syndromes.
Idiopathic pain is pain of unknown origin, for example, phantom limb pain. Neuropathie pain is generally caused by injury or infection of the peripheral sensory nerves generally it includes, but is not limited to, pain from peripheral nerve trauma, herpes virus infection, diabètes mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathie pain is also caused by nerve damage from chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiencies.
The compounds of the invention may be useful for treating certain types of inflammatory disease such as pancreatitis, which includes acute pancreatitis and chronic pancreatitis, is characterized by recurring or persistent abdominal pain with or without steatorrhea or diabètes mellitus, hereditary pancreatitis, pancreatic dysfunction. And it may also useful for treating the pain associated with pancreatitis and its related disorders.
The compounds of the invention may be useful for treating cardiovascular conditions such as arrhythmias, atrial fibrillation and ventricular fibrillation.
Navl .7 was first cloned from the pheochromocytoma PCI2 cell line (Toledo-Aral, J. J., et al. Proc. Natl. Acad. Sci. USA (1997), 94, 1527-1532). Its presence at high levels in the growth cônes of small-diameter neurons suggested that it could play a rôle in the transmission of nociceptive information. Although this has been challenged by experts in the field as Nav 1.7 is also expressed in neuroendocrine cells associated with the autonomie System (Klugbauer, N., et al. EMBO J. (1995), 14, 1084-90) and as such has been implicated in autonomie processes. The compounds of the invention may be useful for treating Crohns disease, multiple sclerosis (MS) and pain associated with multiple sclerosis (MS), amyotrophie latéral sclerosis (ALS), disseminated sclerosis, motor failure, ataxia, tremor, muscle weakness, and dystonia. Epilepsy and cardiac arrhythmias are often targets of sodium channel blockers. Recent evidence from animal models suggests that sodium channel blockers may also be useful for neuroprotection under ischémie conditions caused by stroke or neural trauma and in patients with multiple sclerosis (MS).
The compounds of the invention may be useful for treating certain type of cancers for example prostate cancer, breast cancer, ovarian cancer, testicular cancer, thyroid neoplasia. The VGSC’s are reported to hâve been expressed in prostate and breast cancer cells. Navl-5 has been identified in breast cancer cells and the enhanced expression of this isoform was associated with strong metastatic potential in vitro and breast cancer progression in vivo. (Fraser et al. Clin. Cancer Res. (2005), 11, 5381-5389). Expression of Navl.7 is upregulated ~20 fold in prostate cancer. Moreover, the expression correlates with high metastatic potential in vitro. (Current Pharmaceutical Design (2006), 12, 36813695; Prostate Cancer and Prostatic Diseases (2005), 8, 266-273).
The compounds of invention may be useful in the treatment of epilepsy, partial and general tonie seizures, arrhythmias, fibromyalgia, neuroprotection under ischaemic conditions caused by stroke, glaucoma or neural trauma, neuromuscular conditions such as restless leg syndrome and muscle paralysis or tetanus.
The compounds of invention may be useful in the treatment of pruritus and related diseases such as psoriatic pruritus, itch due to hemodialysis, aguagenic pruritus, itching caused by skin disorders, allergie itch, insect bite itch, itch caused by hypersensitivity such as dry skin, acné, eczema, psoriasis or injury, itch caused by vulvar vestibulitis and the similar itch.
The compounds of the invention may be useful in treating the symptoms associated with BPH (benign prostate hyperplasia) including but not limited to acute urinary rétention and urinary tract infection.
It is to be understood that the invention encompasses any of the compounds of Formulae (I) to (VI) or pharmaceutically acceptable salts thereof for use in the treatment of any of the conditions disclosed herein.
It is to be understood that the invention encompasses the use of any of the compounds of Formulae (I) to (VI), or pharmaceutically acceptable salts thereof for the manufacture of a médicament for the treatment of any of the conditions disclosed herein.
General Methods of Préparation
The compounds described herein may be prepared by techniques known in the art. In addition, the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme-1 to Scheme-3. Further, in the following schemes, where 5 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 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 10 invention. Ail the isomers of the compounds described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention. The absolute stereochemistry of the compounds is assigned using vibrational circular dichroism (VCD) spectra.
General scheme-1
Compound of formula (l) reacts with benzyl thiol in the presence of Pd catalyst to give the compound of formula (2). The keto compound of formula (2) reacts with the p-tosyl hydrazine in MeOH to give the hydrazone compound of formula (3) which reacts with halo dérivative of formula (4) in the presence of Pd catalyst and base to give compound of formula (5). The compound of formula (5) reacts with sulfuryl chloride or NCS (NChlorosuccinimide) or dichlorohydantoin using suitable solvent to give sulfonyl chloride which on treatment with pentafluorophenol in the presence of organic base like TEA gives the pentafluoro ester of formula (6).
Altematively, the compound of Formula (6) can also be prepared by reacting compound of formula (2) with NCS using suitable solvents to give sulfonyl chloride which on treatment with pentafluorophenol in the presence of organic base like TEA gives the pentafluoro ester of formula (7). The compound of formula (7) reacts with p-tosyl hydrazine in MeOH to give the hydrazone compound of formula (8) which further reacts with halo dérivative of formula (4) in the presence of Pd catalyst and base to give compound of formula (6).
Finally compound of formula (6) undergoes réduction reaction using H2, Pd/C to give the compound of formula (9). The réduction of olefin can also be achieved enantioselectively using chiral ligands/catalysts which are known in the literature to obtain stéréo sélective product. The compound of formula (9) then reacts with the amine of formula (10) in the presence of base like LiHMDS in suitable solvent to give compound of formula (la).
General scheme2
The hydroxy group in compound of formula (H) can be protected with suitable protecting group like TBDMS to give the compound of formula (l 2), which further reacts 5 with triflating agents like triflic anhydride or l,l,l-trifluoro-N-phenyl-N((trifluoromethyl)sulfonyl) methane sulfonamide in the presence of a base like pyridine to give compound of formula (13). The compound of formula (13) undergoes Suzuki coupling reaction in presence of boronic acid or boronic ester of formula (14) followed by réduction and deprotection of hydroxyl group to give the compound of formula (16). The 10 compound of formula (16) reacts with suitable triflating agents in the presence of base to give compound of formula (17) which further reacts with benzyl mercaptan in the presence of Pd catalyst and solvent like 1,4-dioxane to give the compound of formula (18). The compound of formula (18) reacts with sulfuryl chloride or dichlorohydantoin or NCS and water: acetic acid in suitable solvent to give sulfonyl chloride which on 15 treatment with pentafluorophenol in the presence of organic base like TEA to give the pentafluoro ester of formula (9). The compound of formula (9) reacts with compound of formula (10) in the presence of a suitable base such as LiHMDS in suitable solvent like THF to give the compound of formula (la).
General scheme-3
Substituted coumarin of formula (19) reacts with benzyl thiol in the presence of Pd catalyst gives the compound of formula (20). The hydroxyl compound of formula (20) reacts with triflic anhydride in the presence of suitable base like TEA to give the triflate compound of formula (21) which further reacts with boronic acid or boronic ester of formula (14) under Suzuki coupling condition gives the compound of formula (22). The compound of formula (22) can be converted to diol of formula (23) using reagents like NaBH4/ COCI2.6H2O which can further cyclize to give the compound of formula (18). The compound of formula (18) can be converted to compound of formula (la) as described in general scheme-2.
Experimental
The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. The examples set forth below demonstrate the synthetic procedures for the 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.
Unless 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, implies purification by silica gel chromatographie techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase.
Intermediate-1:
hydrazide
INTERMEDIATES
7V-(7-(Benzylthio)chroman-4-ylidene)-4-methylbenzenesulfono
BnS. -x .O
Step-1: 7-(Benzylthio)chroman-4-one
7-bromochroman-4-one (390g, 1.718mol) was dissolved in 1, 4-dioxane (4500 ml) and the solution was purged with nitrogen and then added Pd2(dba)3 (39.3g, 0.0429mol), Hunig's Base (600 ml, 3.435mol) and benzyl mercaptan (193 ml, 1.632mol). The reaction mixture was heated to 80 °C maintained for 1 h. After completion of reaction as indicated by TLC, the compound was extracted with ethyl acetate and washed with water. The ethyl acetate layer was then dried over Na2SÛ4 and evaporated under vacuum. The crude product was purified by column chromatography to obtain title compound as a pale yellow solid (279g, 60%). 'H NMR (400 MHz, Chloroform-J) δ 7.78 (d, J= 8.3 Hz, 1H), 7.49 - 7.23 (m, 5H), 6.90 (dd, J = 8.3, 1.8 Hz, 1H), 6.85 - 6.75 (m, 1H), 4.52 (m, 2H), 4.20 (s, 2H), 2.78 (m, 2H).
Step-2:7V-(7-(Benzylthio)chroman-4-ylidene)-4-methylbenzenesulfonohydrazide BnS ~
7-(Benzylthio)chroman-4-one (100g, 0.370mol) and 4-methylbenzenesulfonohydrazide (76g, 0.407mol) was added into MeOH (2.5 lit.) and the mixture was heated at 80 °C for overnight. The reaction mixture was then cooled in an ice sait bath for Ih and then the pale yellow solid was filtered and was washed with éthanol. The solid product was then triturated with hexane and dried under vacuum to obtain title compound (153g, 94%). LCMS(ESI): m/z 439.09(M+H)+; *H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 8.4 Hz, 1H), 7.38 - 7.29 (m, 7H), 6.86 (dd, J = 8.4, 1.9 Hz, 1H),
6.77 (d, J= 1.8 Hz, IH), 4.25 - 4.18 (m, 2H), 4.16 (s, 2H), 2.75 (t, J= 6.1 Hz, 2H), 2.44 (s,3H).
Intermediate-2: 5-(2-bromo-5-(trifluoromethyl)phenyl)-l-methyl-IH-pyrazole
CF3
Step-1 : N-(2-bromo-4-(trifluoromethyl)phenyl)acetamide
Acetyl chloride (32.6 ml, 458 mmol) was added to drop wise to a solution of 2-bromo-4(trifluoromethyl)aniline (50 g, 208 mmol) in ethyl acetate (250 ml). After the addition, the reaction mixture was heated at 60 °C for 45 min. The solution was cooled to room température and the reaction mixture was poured into ice cold NaHCO3 solution and the product was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to obtain the product as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.56 (d, J= 8.7 Hz, 1H), 7.82 (à,J= 2.1 Hz, 1H), 7.77 (s, 1H), 7.59 (dd, J= 8.7, 2.1 Hz, 1H), 2.30 (s, 3H).
Step-2: N-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)acetamide
A mixture of 1,4-dioxane (500 ml) and water (50 ml) was degassed and potassium phosphate (78g, 369 mmol), N-(2-bromo-4-(trifluoromethyl)phenyl)acetamide (52 g, 184 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (38.4 g, 184 mmol) and PdCl2(dppf)-CH2Cl2Adduct (15.06 g, 18.44 mmol) was added and the reaction mixture was refluxed for Ih. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with water, dried over Na2SO4 and evaporated under vacuum to obtain title compound (52g, 100 %). LCMS (ESI): m/z 283.40(M+H)+.
Step-3: 2-(l-methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)aniline
N-(2-(l-methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)acetamide (132g, 466 mmol) was dissolved in a mixture of MeOH (600 ml) / water (200 ml) and KOH (78 g, 1398 mmol) was added and the reaction mixture was heated at 70 °C for 6h. The reaction mixture was then acidified with conc HCl to pH 2 and the aq. layer was washed with ethyl acetate. The aqueous layer was then basified and the product was then extracted with ethyl acetate. The organic layer was dried over Na2SÛ4 and concentrated to obtain the title compound (l 12g, 100%). LCMS (ESI): m/z 241.95(M+H)+.
Step-4: 5-(2-bromo-5-(trifluoromethyl)phenyl)-1 -methyl-1 H-pyrazole
2-(l-methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)aniline (110 g, 456 mmol) was dissolved in acetonitrile (3 lit) and copper(II) bromide (50.9g, 228 mmol) was added to it. The reaction mixture was heated at 70 °C and tert-butyl nitrite (90 ml, 684 mmol) was added to it drop wise. After the addition, the reaction was continued for 3 h then poured into ice cold brine solution and extracted with ethyl acetate. The organic layer was dried over Na2SÛ4 and concentrated and the crude purified by column chromatography to obtain the product as a yellow solid (84g, 60 %). 1H NMR (400 MHz, Chloroform-d) δ 7.87 (d, 7=8.1 Hz, 1H), 7.70 - 7.53 (m, 3H),6.34 (d,7= 1.9 Hz, 1H), 3.76 (s, 3H).
Intermediate-3: Perfluorophenyl 4-(2-(1 -methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonate
O,,o
cf3
Step-1: 5-(2-(7-(Benzylthio)-2H-chromen-4-yl)-5-(trifluoromethyl)phenyl)-l -methyl- 1Hpyrazole
cf3
A mixture of 1,4-dioxane (2400 ml) and water (400 ml) was degassed for 30 min with N2 after which Intermediate-2 (84g, 0.275 mol), Intermediate-1 (121g, 0.275mol), sodium carbonate (73g, 0.688mol) and PdCl2(dppf)-DCM adduct (22.48 g, 0.0275 mol) were added and the reaction mixture was refluxed for 5h. The compound was extracted with ethyl acetate, dried over Na2SO4 and evaporated under vacuum. The crude was purified by column chromatography to obtain title compound as an off white solid (100g, 76%). LCMS(ESI): m/z 479.09(M+H)+; 'H NMR (400 MHz, Chloroform-d) δ 7.74 (d, 7= 8.0
Hz, l H), 7.67 (s, l H), 7.51 (d, J = 8.1 Hz, l H), 7.40 (d, J = 1.9 Hz, 1 H), 7.36 - 7.30 (m, 4H), 7.28 (s, IH), 6.79 (d,J=1.8 Hz, IH), 6.70 (dd, J= 8.1, 1.9 Hz, IH), 6.56 (d,J=8.1 Hz, IH), 6.16 (d, J= 1.9 Hz, IH), 5.50 (t, J= 3.9 Hz, IH), 4.71 (d, J= 3.9 Hz, 2H), 4.13 (s, 2H), 3.65 (s, 3H).
Step-2: Perfluorophenyl 4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-2Hchromene-7-sulfonate
F °w°
cf3
5-(2-(7-(benzylthio)-2H-chromen-4-yl)-5-(trifluoromethyl)phenyl)-1 -methyl-1 H-pyrazole (100g, 199 mmol) was dissolved in DCM (1500 ml) and acetic acid (45.5 ml) followed by water (14.31 ml) and the solution was cooled to -5 °C and sulfuryl chloride (48.4 ml, 0.596 mol) was added drop wise. After the addition, the reaction was stirred for Ih. TLC showed formation of sulfonyl chloride. The reaction mixture was washed with water and the DCM layer was dried over Na2SÛ4 and concentrated. The crude sulfonyl chloride product was diluted with 500 mL of DCM and added slowly to a stirred solution of 2, 3, 4, 5, 6-pentafluorophenol (54.8g, 0.298mol) and triethylamine (138 ml, 0.993mol) in DCM at -5 °C. The reaction mixture was stirred for Ih after which it was washed with water and the DCM layer was dried over Na2SC>4 and concentrated. The crude product was purified by column chromatography to obtain title compound as a pale yellow solid (85g, 71%). LCMS(ESI): m/z 603.03(M+H)+; 'H NMR (400 MHz, Chloroform-d) δ 7.82 (dd, 8.1, 1.9 Hz, IH), 7.72 (d, J= 1.9 Hz, IH), 7.56 (d, J= 8.0 Hz, IH), 7.44 - 7.31 (m, 3H), 6.83 (d, J= 8.1 Hz, IH), 6.13 (d, J= 1.9 Hz, IH), 5.84 (t, J= 3.8 Hz, IH), 4.92 (d,J=3.8 Hz, 2H), 3.70 (s, 3H).
Step-3: Perfluorophenyl 4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonate
Ethyl acetate (1000 ml) was degassed and perfluorophenyl 4-(2-(1 -methyl-1 H-pyrazol-5yl)-4-(trifluoromethyl)phenyl)-2H-chromene-7-sulfonate (85g, 0.141mol) was dissolved in it. The solution was put in a Pan shaker and 10% Pd-C (67.6g, 0.0635mol) was added and the mixture was hydrogenated at 50 psi for 4h. After completion of reaction, the reaction mixture was filtered through a pad of celite and the pad was washed with ethyl acetate. The filtrate was concentrated and the crude was purified by column chromatography to obtain the product as a pale yellow solid (80g, 94%). LCMS(ESI): m/z 604.08(M+H)+; 'H NMR (400 MHz, Chloroform-d) δ 7.69 (dd, J= 8.3, 2.0 Hz, IH), 7.63 (dd, J= 5.1, 1.9 Hz, 2H), 7.50 (d, J= 2.0 Hz, IH), 7.38 (dd, J= 8.2, 2.0 Hz, IH), 7.16 (d, J = 8.2 Hz, l H), 6.96 - 6.88 (m, l H), 6.36 (d, J = l .9 Hz, l H), 4.39 - 4.30 (m, l H), 4.27 (t, J=7.5 Hz, IH), 4.21 -4.l6(m, IH), 3.81 (s, 3H), 2.24 - 2.14 (m, IH), 2.07-1.98 (m, IH).
ïntermediate-4: Perfluorophenyl 4-(2-tosylhydrazono)chroman-7-sulfonate
F
Step-1: Perfluorophenyl 4-oxochroman-7-sulfonate
To a suspension of 7-(benzylthio) chroman-4-one (37g, 137 mmol) in acetic acid (200 ml) and water (50 ml) was added 7V-chlorosuccinimide (NCS) (54.8g, 411 mmol) in two portion. Stirred for 45 min. Reaction mixture was diluted with ether: water and extracted with ether. The combined organic layer was washed with water, brine, dried over Na2SÛ4 and evaporated to dryness under reduced pressure. This sulfonyl chloride intermediate taken in DCM (dicloromethane) and charged into the stirring solution of 2,3,4,5,6pentafluorophenol (35.3 g, 192 mmol) and triethanolamine (TEA) (114 ml, 821 mmol) in DCM (200 ml) at 0 °C. Stirred for 45 min then quenched with water and extracted with DCM. The combined organic layer was dried over Na2SO4 and evaporated under vacuum. The crude was purified by column chromatography (25 % ethyl acetate/ petroleum ether) to obtain off-white solid(35g, 65 %). 'H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J= 8.2 Hz, 1 H), 7.71 (d, J = 1.8 Hz, IH), 7.65 (dd,J=8.2, 1.9 Hz, IH), 4.70 (t,J=6.5 Hz, 2H), 2.95 (t, J=6A Hz, 2H).
Step-2: Perfluorophenyl 4-(2-tosylhydrazono)chroman-7-sulfonate
A mixture of perfluorophenyl 4-oxochroman-7-sulfonate (34g, 86 mmol) and 4methylbenzenesulfonohydrazide (16.06 g, 86 mmol) was heated in MeOH (200 ml) at 65 °C maintained for 16h. After completion of reaction as indicated by TLC, reaction mixture was evaporated to minimize the MeOH and then filtered the solid and washed with MeOH to obtain title compound as pale yellow solid (35g, 72 %). 'H NMR (400 MHz, DMSO-d6) δ ll.O8 (s, IH), 8.03 (d, J= 8.4 Hz, 1H), 7.85 (d, 2H), 7.55 (dd, J = 8.5, 2.0 Hz, l H), 7.49 (d, J = 2.0 Hz, l H), 7.43 (d, J = 8.1 Hz, 2H), 4.32 (t, J = 6.2 Hz, 2H), 2.82 (t, J= 6.2 Hz, 2H), 2.39 (s, 3H).
Intermediate-5: 5-(2-Bromo-5-(trifluoromethyl)phenyl)-2-fluoropyridine
cf3
Step 1: A mixture of toluene (780 ml), water (520 ml) and EtOH (260 ml) was degassed by bubbling a stream of nitrogen and 2-bromo-4-(trifluoromethyl)aniline (118g, 492 mmol), (6-fluoropyridin-3-yl)boronic acid (90g, 639 mmol), sodium carbonate (182g, 1721 mmol) and Pd(Ph3P)4 (56.8g, 49.2 mmol) was added to it and the mixture was refluxed for 8h. After completion of reaction as indicated by TLC, the reaction mixture was diluted with ethyl acetate. The ethyl acetate layer was washed with brine, dried, concentrated and the crude 2-(6-fluoropyridin-3-yl)-4-(trifluoromethyl) aniline was used for the further reaction. LCMS: m/z 257.09 (M+H)+.
Step-2: 2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl) aniline (126g, 492 mmol) was dissolved in acetonitrile (1500 ml)) and cupric bromide (65.9 g, 295 mmol) was added to it. The reaction mixture was heated at 65 °C and tert-butyl nitrite (97 ml, 738 mmol) was added to it drop wise. After the addition, the reaction was continued for Ih and then cooled. The reaction mixture was then passed through a celite bed and the filtrate was concentrated and the crude purified on column to obtain the product as a white solid (115g, 73%). 'H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J= 2.5 Hz, IH), 7.91 (dd, J= 8.1,2.6 Hz, 1 H), 7.89 - 7.84 (m, 1 H), 7.59 (d, J = 2.2 Hz, 1 H), 7.55 (dd, 7=8.3,2.3 Hz, 1 H), 7.07 (dd, J = 8.5, 2.9 Hz, 1 H).
Intermediate-6: Perfluorophenyl 4-(2-(6-fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl) chromane-7-sulfonate
Step-1 : Perfluorophenyl 4-(2-(6-fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-2Hchromene-7-sulfonate
A mixture of 1,4-dioxane (200 ml) and water (33 ml) was degassed by bubbling a stream of nitrogen and Intermediate-4 (22.85g, 40.6 mmol), Intermediate-5 (10g, 31.2 mmol), sodium carbonate (8.28g, 78 mmol) and PdChidppfj-CPhCh (2.55g, 3.12 mmol) was added and the mixture was heated to 100 °C maintained for 45 min. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with brine. The ethyl acetate layer was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography to obtain the title compound as a white solid (10g, 52%). LCMS: m/z 618.03 (M+H)+; 'H NMR (400 MHz, Chloroform-d) δ 8.22 (d, J= 2.5 Hz, IH), 7.80 (dd, J = 7.9, 1.8 Hz, IH), 7.76 - 7.66 (m, 2H), 7.55 (d, J= 7.9 Hz, IH), 7.32 (dd, J = 13.2, 1.9 Hz, 2H), 6.89 (dd, J=8.5, 2.9 Hz, IH), 6.75 (d,J=8.1 Hz, IH), 5.95 (t,J=3.7 Hz, IH), 4.98-4.92 (m, 2H).
Step-2: Perfluorophenyl 4-(2-(6-fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)chromane7-sulfonate
To a solution of perfluorophenyl 4-(2-(6-fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)2H-chromene-7-sulfonate (28g, 45.3 mmol) in degassed ethyl acetate(150 ml), 10% Pd-C (12.06g, 11.34 mmol) was added and the mixture was stirred under 50 psi hydrogen pressure in a Parr shaker at room température for 16h, then catalyst was filtered through a pad of celite and the filtrate was concentrated and the crude passed through a column to obtain the title compound as a white solid (26g, 90%). LCMS: m/z 620.10 (M+H)+; *H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J= 2.5 Hz, IH), 7.85 (td, J= 7.9, 2.5 Hz, IH), 7.66 (dd, J= 8.2, 2.0 Hz, IH), 7.58 (d, J= 2.0 Hz, IH), 7.50 (d, J= 2.0 Hz, IH), 7.38 (dd, J = 8.2, 2.0 Hz, IH), 7.18 - 7.09 (m, 2H), 6.94 (dd, J = 8.1, 1.0 Hz, IH), 4.42 - 4.28 (m, 2H), 4.20 - 4.10 (m, IH), 2.25 - 2.07 (m, 2H).
Intermediate-7: 5-(2-bromo-5-isopropoxyphenyl)-1 -methyl-1 H-pyrazole
Step-1: 1 -bromo-2-iodo-4-isopropoxybenzene
A mixture of 4-bromo-3-iodophenol (7.2g, 24.09 mmol) and CS2CO3 (9.81g, 30.1 mmol) in acetonitrile (25 ml) was stirred for 10 min, after which 2-bromopropane (6.78 ml, 72.3 mmol) and Kl (0.40g, 2.409 mmol) was added and heated at 50 °C for ovemight. The volatiles were concentrated and the residue was diluted with ethyl acetate and washed with water. The ethyl acetate layer was concentrated and the crude was purified by column chromatography to obtain the title compound as colorless oil (4g, 48 %). ‘H NMR (400 MHz, Chloroform-d) δ 7.47 (d, J= 8.8 Hz, IH), 7.40 (d, J= 2.8 Hz, IH), 6.76 (dd, J = 8.9, 2.8 Hz, 1 H), 4.50 (p, J = 6.1 Hz, 1 H), 1.34 (d, J = 6.0 Hz, 6H).
Step-2: 5-(2-bromo-5-isopropoxyphenyl)-1 -methyl-1 H-pyrazole
DMF (15 ml) was degassed and l-bromo-2-iodo-4-isopropoxybenzene (2g, 5.87 mmol), 1 -methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole ( 1,22g, 5.87 mmol), potassium phosphate (2.49g, 11.73 mmol) and PdC12(dppf)-DCM adduct (0.24g, 0.293 mmol) was added and the mixture was heated at 80 °C for 3h. The reaction mixture was cooled and quenched with water and extracted with ethyl acetate. The ethyl acetate layer was dried and conc. The crude was purified by column chromatography to obtain the product as a viscous oil (0.7g, 40 %). ’H NMR (400 MHz, Chloroform-tf) δ 7.60 7.52 (m, 2H), 6.91-6.83 (m, 2H), 6.28 (d, J= 1.8 Hz, IH), 4.54 (h, J = 6.1 Hz, IH), 3.75 (s, 3H), 1.37 (d, J = 6.1 Hz, 6H).
Intermediate-8: Perfluorophenyl 4-(4-isopropoxy-2-( 1 -methyl-1 H-pyrazol-5-yl)phenyl) chroman-7-sul fonate
The title compound was prepared by following similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-7. 'H NMR (400 MHz, Chloroform-J) δ 7.59 (d, J= 1.8 Hz, IH), 7.46 (d, J= 1.9 Hz, IH), 7.35 (dd, J= 8.2, 2.0 Hz, IH), 7.02 - 6.79 (m, 4H), 6.29 (d, J = 1.9 Hz, IH), 4.56 (h, J = 6.0 Hz, IH), 4.37 4.28 (m, IH), 4.21 - 4.06 (m, 2H), 3.81 (s, 3H),2.l7-l.97(m, 2H), 1.38 (d, J= 6.1 Hz, 6H).
Intermediate-9: 4'-Fluoro-2-iodo-5-(trifluoromethyl)-1, l ’-biphenyl
Step 1: 4'-Fluoro-5-(trifluoromethyl)-[l,r-biphenyl]-2-amine
The title compound was prepared by following the similar procedure as described in step1 of Intermediate-5 using 2-bromo-4-(trifluoromethyl)aniline and 4-fluorophenyl boronic acid.
LCMS: m/z 255.16 (M)+; 'H NMR (400 MHz, Chloroform-d) δ 7.47 - 7.39 (m, 3H), 7.36 (d, J = 2.2 Hz, 1 H), 7.22 -7.15 (m, 2H), 6.81 (d, J = 8.4 Hz, 1 H), 4.10 (brs, 2H).
Step 2: 4'-Fluoro-2-iodo-5-(trifluoromethyl)-l,r-biphenyl
4'-Fluoro-5-(trifluoromethyl)-[l,r-biphenyl]-2-amine (1.5g, 5.88 mmol) was dissolved in acetonitrile (20 ml) and 4-methylbenzenesulfonic acid (3.04g, 17.63 mmol) was added to get the précipitation. This was dissolved by the addition of 5 ml of water, and the solution cooled in an ice bath. A mixture of sodium nitrite (0.811 g, 11.75 mmol) and potassium iodide (2.44g, 14.69 mmol) was dissolved in 20 ml water and added drop wise to the solution of the amine. The color of the solution tumed brown and after 1 h, TLC showed completion of reaction. The reaction was quenched by the addition of dilute solution of sodium thiosulfate and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated to obtain the crude which was purified to obtain the title compound as oil (1.75 g, 81%). LCMS: m/z 365.98 (M)+; 'H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J = 8.3 Hz, IH), 7.54 (d, J= 2.2 Hz, IH), 7.37 - 7.29 (m, 3H), 7.17 (t, J = 8.7 Hz, 2H). Intermediate-10: Perfluorophenyl 4-(4'-fluoro-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-2-yl) chromane-7-sulfonate
The title compound was prepared by following the similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-9.
'H NMR (400 MHz, Chloroform-d) δ 7.61 - 7.55 (m, 2H), 7.49 (d, J= 2.0 Hz, IH), 7.39 - 7.34 (m, 3H), 7.21 (t, J = 8.4 Hz, 2H), 7.08 (d, J= 8.1 Hz, IH), 6.96 (d, J = 8.2 Hz, IH), 4.45-4.40 (m, IH), 4.39-4.31 (m, IH), 4.18-4.14 (m, IH), 2.20-2.07 (m, 2H). Intermediate-11: 1-(2-Iodo-5-(trifluoromethyl) phenyl)-lH-l, 2, 3-triazole Step-1: 2-Azido-1-iodo-4-(trifluoromethyl) benzene
2-Iodo-5-(trifluoromethyl) aniline (13g, 45.3mmol) was dissolved in a mixture of water (100 ml) and acetonitrile (50 ml) into which HCl (34.4 ml, 1132 mmol) was added. The solution was cooled to -5 °C and a solution of sodium nitrite (4.69g, 67.9 mmol) in water was added slowly. The solution was stirred at that température for 30 min after which a solution of sodium azide (4.42 g, 67.9 mmol) was added to this mixture. The solution was warmed to room température over another 30 min and the reaction mixture was extracted with ethyl acetate and the ethyl acetate layer dried and concentrated to obtain the product as viscous dark oil (14 g, 99%). 'H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 8.2 Hz, IH), 7.35 (s, IH), 7.14 (d, 7=8.2 Hz, IH).
Step-2: l-(2-Iodo-5-(trifluoromethyl)phenyl)-4-(trimethylsilyl)-lH-l,2,3-triazole
cf3
2-Azido-l-iodo-4-(trifluoromethyl)benzene (7.2g, 23.00 mmol), ethynyltrimethylsilane (2.26 g, 23.00 mmol), sodium 2-((S)-l,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5dihydroftiran-3-olate (l.82g, 9.20 mmol), potassium carbonate (6.36 g, 46.0 mmol) was dissolved in a mixture of i-butanol (50 ml) and water (50 ml) and copper(II) sulfate penthydrate (l.l5g, 4.60 mmol) was added to it. The ppt was observed and the reaction mixture was stirred for 16h after which it was dissolved in ethyl acetate and washed with water. The ethyl acetate layer was dried and concentrated and the crude purified on column to obtain the product as a pale brown solid (4 g, 42%). LCMS: m/z 412.16 (M+H)+; 'H NMR (400 MHz, Chloroform-d) δ 8.18 (d, J = 8.3 Hz, IH), 7.89 (s, 1H), 7.72 (d, J = 2.1 Hz, l H), 7.50 (dd, J = 8.3, 2.1 Hz, l H), 0.43 (s, 9H).
Step-3: l -(2-Iodo-5-(trifluoromethyl)phenyl)-1 H-1,2,3-triazole 1 YN\
CF3
-(2-Iodo-5-(trifluoromethyl)phenyl)-4-(trimethylsilyl)-1 H-1,2,3-triazole (8g, 19.45 mmol) was dissolved in ethyl acetate(80 ml), and a solution of 8% HCl (70 ml, 19.45 mmol) was added to it. The reaction mixture was heated to 50 °C maintained for 5h and then diluted with ethyl acetate. The organic phase was washed with water, brine, dried over Na3SO4 and concentrated. The crude was purified by column chromatography to obtain l-(2-iodo-5-(trifluoromethyl) phenyl)-lH-l,2,3-triazole (6g, 91%). LCMS: m/z 339.84 (M+H)+; ‘H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J= 8.3 Hz, 1H), 7.96 (dd, J = 13.5, 1.2 Hz, 2H), 7.74 (d, J = 2.1 Hz, 1 H), 7.53 (dd, J = 8.3, 2.1 Hz, 1 H).
Intermediate-12: Perfluorophenyl 4-(2-(1 H-l, 2,3-tri azol-l-yl)-4-( tri fluoromethyl) phenyl) chromane-7-sulfonate
The title compound was prepared by following the similar procedure as described in Intermediate-3 using Intermediate-1 and Intermediate-11. LCMS: m/z 592.20 (M+H)+; ’H NMR (400 MHz, Chloroform-d) δ 7.97 (d, 7= 15.9 Hz, 2H), 7.77 (d, 7= 8.3 Hz, IH), 7.68 (s, l H), 7.51 (d, 7 = 2.0 Hz, l H), 7.38 (dd, 7 = 8.2, 2.0 Hz, lH), 7.26 (d, 7 = 8.2 Hz, IH), 7.00 (d, 7= 8.2 Hz, IH), 4.40 - 4.25 (m, 2H), 4.25 - 4.17 (m, IH), 2.50 - 2.37 (m, IH), 2.23-2.09 (m, IH).
Intermediate-13: 4-(2-Bromo-5-(trifluoromethyl)phenyl)-2-methylthiazole
CF3
Step-1: 2-Bromo-l-(2-bromo-5-(trifluoromethyl)phenyl)ethanone
To a solution of l-(2-Bromo-5-(trifluoromethyl)phenyl)ethanone (5g, 18.72 mmol) in DCM (100 ml), pyridinium tribromide (7.32g, 20.60 mmol) was added and the mixture was stirred at room température for Ih. After completion of reaction, reaction mixture was poured into water and extracted with DCM. The combined organic layer was dried over Na2SO4 and concentrated. The crude was purified by column chromatography to obtain the product as off white solid. 'H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J = 8.4 Hz, IH), 7.73 (d, 7= 2.2 Hz, IH), 7.63 (dd, 7= 8.4, 2.2 Hz, IH), 4.52 (s, 2H).
Step-2: 4-(2-Bromo-5-(trifluoromethyl)phenyl)-2-methylthiazole
To a solution of 2-Bromo-l-(2-bromo-5-(trifluoromethyl)phenyl)ethanone (2g, 5.78 mmol) in EtOH (20 ml), thioacetamide (0.43g, 5.78 mmol) was added and the solution was heated in a sealed tube for 12h at 80 °C. The solution was cooled and concentrated under vacuum. The reaction mixture was extracted with ethyl acetate, washed with water, dried over Na2SÜ4 and concentrated under vacuum. The crude was purified by column chromatography to obtain the product as a red oil (l.8g, 99 %). *H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J = 2.3 Hz, l H), 7.82 (d, J = 8.4 Hz, l H), 7.70 (s, l H), 7.45 (dd, J= 8.4, 2.3 Hz, IH), 2.82 (s, 3H).
Intermediate-14: Perfluorophenyl 4-(2-(2-methylthiazol-4-yl)-4-(trifluoromethyl) phenyl) chroman-7-sulfonate
F
The title compound was prepared by following the similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-13. LCMS(ESI): m/z 622.00(M+H)+; 'H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J= 2.0 Hz, 1H), 7.57 (dd, 7=7.9,2.0 Hz, 1H), 7.50 (d,7=2.0 Hz, 1H), 7.36 (dd, 7= 8.2, 2.0 Hz, 1H), 7.28 (s, 1H), 7.07 (d, 7= 8.2 Hz, 2H), 4.92 (t, 7= 7.0 Hz, 1H), 4.39 - 4.29 (m, 1H), 4.27 - 4.19 (m, 1 H), 2.81 (s, 3H), 2.43 - 2.32 (m, 1 H), 2.20 - 2.11 (m, 1 H).
Intermediate-15: 4-(2-Bromo-5-(trifluoromethyl)phenyl)-2-methyloxazole
cf3
2-Bromo-l-(2-bromo-5-(trifluoromethyl)phenyl)ethanone (1g, 2.89 mmol) was dissolved in N,N-Dimethylformamide (6 ml) in a 20 ml microwave vial and acetamide (0.43g, 7.23 mmol) was added to the solution. It was heated at 150 °C under microwave irradiation for 1.5 h. The reaction mixture was diluted with ether and washed with water. The ether layer was dried over Na2SÛ4 and concentrated. The crude was purified by column chromatography to obtain title compound (0.67g, 76 %). 'H NMR (400 MHz,
Chloroform-d) δ 8.42 (s, IH), 8.35 (d, J= 2.3 Hz, IH), 7.78 (d, 7 = 8.4 Hz, IH), 7.41 (dd, J = 8.4, 2.2 Hz, IH), 2.57 (s, 3H).
Intermediate-16: Perfluorophenyl 4-(2-(2-methyloxazol-4-yl)-4-(trifluoromethyl) phenyl) chroman-7-sulfonate
F
The title compound was prepared by following the similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-15. LCMS (ESI): m/z 606.11(M+H)+.
Intermediate-17: l-Bromo-2-(2-(methylsulfonyl)ethyl)-4-(trifluoromethyl)benzene
Br O O
Step-1: 2-Bromo-5-(trifluoromethyl)phenethyl 4-methylbenzenesulfonate
To a solution of 2-(2-bromo-5-(trifluoromethyl) phenyl) éthanol (5g, 18.58 mmol) (Synthesise as described in JACS, 2011, vol. 133(20), 7916 - 7925) in DCM (50 ml) was added Ts-Cl (3.9g, 20.44 mmol), 4-dimethylaminopyridine (DMAP) (0.227 g, 1.858 mmol) and TEA (5.70 ml, 40.9 mmol) at room température and stirred for 2h. After completion of reaction as indicated by TLC, reaction mass was poured into water and extracted with DCM. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography to obtain 2-bromo-5-(trifluoromethyl) phenethyl-4-methylbenzenesulfonate (6g, 76 %). 'H NMR (400 MHz, Chloroform-7) δ 7.69 (d, J= 8.3 Hz, 2H), 7.61 (d, J= 8.3 Hz, IH), 7.41 (d, J = 2.3 Hz, IH), 7.35 (dd, J= 8.4, 2.2 Hz, IH), 7.28 (d, J= 8.2 Hz, 2H), 4.32 (t, 7 = 6.6 Hz, 2H), 3.17 (t, 7= 6.6 Hz, 2H), 2.45 (s, 3H).
Step-2: 1-Bromo-2-(2-(methylsulfonyl) ethyl)-4-(trifluoromethyl) benzene
To a solution of 2-Bromo-5-(trifluoromethyl)phenethyl 4-methylbenzenesulfonate (9g, 21.26 mmol), in éthanol (100 ml) was added sodium methanethiolate (l.78g, 25.5 mmol) at room température for 2h, after which oxone (65.4g, 106 mmol) followed by water (30 ml) was added to the reaction mixture. The reaction mixture was stirred for 12h at 25 °C, then poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography to obtain l-bromo2-(2-(methylsulfonyl)ethyl)-4-(trifluoromethyl)benzene as white solid(6g, 85 %) 'H NMR (400 MHz, Chloroform-J) δ 7.74 (d, J= 8.3 Hz, IH), 7.59 (d, J= 2.3 Hz, IH), 7.44 (dd, J = 8.4, 2.1 Hz, IH), 3.36 (s, 4H), 2.99 (s, 3H).
Intermediate-18: Perfluorophenyl 4-(2-(2-(methylsulfonyl)ethyl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonate
The title compound was prepared by following the similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-17. 'H NMR (400 MHz, Chloroform-t/) δ 7.57 - 7.47 (m, 3H), 7.39 (dd, J = 8.1, 1.9 Hz, IH), 7.02 - 6.91 (m, 2H), 4.68 - 4.61 (m, IH), 4.41 - 4.26 (m, 2H), 3.49 - 3.31 (m, 4H), 3.01 (s, 3H), 2.48 - 2.36 (m, IH), 2.17-2.08 (m, IH).
Intermediate-19: l-(2-Iodo-5-(trifluoromethyl)phenyl)-l/f-pyrazole
CF3
Step-1: 2-(l//-Pyrazol-l-yl)-4-(trifluoromethyl) aniline 2-Bromo-4-(trifluoromethyl)aniline (3.5g, 14.58 mmol), 1/Z-pyrazole (1.98g, 29.2 mmol), 7Vl,7V2-dimethylethane-l,2-diamine (0.78 ml, 7.29 mmol), césium carbonate (10.45g, 32.1 mmol) was added to degassed 1,4-dioxane (15 ml) in a sealed tube and copper(i) iodide (0.55g, 2.92 mmol) was added. The tube was sealed and heated at 120 °C for 72h. After the solution was cooled, the mixture was passed through a pad of celite and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4 and concentrated. The crude was purified by column chromatography to obtain the product as off white solid (2.7g, 83%). LCMS (ESI): m/z 228.39(M+H)+.
Step-2: 1 -(2-Iodo-5-(trifluoromethyl)phenyl)-l/f-pyrazole
2-(lH-Pyrazol-l-yl)-4-(trifluoromethyl)aniline (2.74g, 12.06 mmol) was dissolved into acetonitrile (30 ml) and water (15 ml) followed by the addition of 4methylbenzenesulfonic acid (8.31g, 48.2 mmol). Potassium iodide (5.01g, 30.2 mmol) and sodium nitrite (1.664g, 24.12 mmol) in water was added to the reaction mixture slowly at -5 °C. Reaction mixture was stirred for another 1.5h at -5 °C then quenched by addition of water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and conc. under reduced pressure. The crude product was purified by chromatography (3 % ethyl acetate/ petroleum ether) to obtain title compound (3.5g, 87 %). 'H NMR (400 MHz, Chloroform-d) δ 8.13 (d, J= 8.3 Hz, IH), 7.83 - 7.78 (m, 2H), 7.70 (d, J= 2.1 Hz, IH), 7.41 (dd, J= 8.3, 2.1 Hz, IH), 6.53 (t, .7=2.1 Hz, IH).
Intermediate-20: Péril uorophenyl 4-(2-( 1 H-pyrazol-1 -yl)-4-(trifluoromethyl)phenyl) chroman-7-sul fonate
F
Step-1 : N'-(7-(Benzyloxy) chroman-4-ylidene)-4-methylbenzenesulfonohydrazide
To a stirred solution of 7-(benzyloxy)chroman-4-one (1g, 3.93 mmol) in methanol (30 ml), 4-methylbenzenesulfonohydrazide (0.81g, 4.33 mmol), was added and reaction was stirred for I2h at 75 °C. After completion of reaction as indicated by TLC, reaction mixture was concentrated under vacuum and purified by column chromatography to obtain title compound as a pale yellow solid (l.3g, 78 %). LCMS (ESI): m/z 422.884(M+H)+.
Step-2: l -(2-(7-(Benzyloxy)-2H-chromen-4-yl)-5-(trifluoromethyl)phenyl)-1 H-pyrazole BnO.^.Ck
JL n çr N y.f F^F
A solution of Intermediate-19 (l.2g, 3.55 mmol), N'-(7-(benzyloxy)chroman-4-ylidene)4-methylbenzenesulfono hydrazide (Step-l) (l.5g, 3.55 mmol) in l,4-dioxane (50 ml): water (10 ml) was purged with nitrogen then Na2COî (0.941 g, 8.87 mmol) and PdCl2(dppf)-DCM adduct (0.290g, 0.355 mmol) was added and reaction was stined for I2h at HO °C. After completion of reaction, it was poured in to water and extracted with ethyl acetate. Organic layer was dried over Na2SÛ4 and concentrated under vacuum. The crude was purified by column chromatography to obtain title compound as pale yellow oil (0.4g, 25 %). LCMS (ESI): m/z 448.54(M+H)+.
Step-3: 4-(2-( l//-Pyrazol-l-yl)-4-(trifluoromethyl)phenyl)chroman-7-ol
To the stirred solution of l-(2-(7-(Benzyloxy)-2H-chromen-4-yl)-5(trifluoromethyl)phenyl)-lH-pyrazole (0.70g, l.56l mmol) in ethyl acetate (20 ml), 10 % Pd-C (0.17g, 0.156 mmol) was added and reaction mixture was stirred under hydrogen balloon at room température for I2h. After completion of reaction, it was filtered through celite bed, the filtrate was concentrated under vacuum and purified by column chromatography to obtain title compound (0.4g, 71 %). LCMS (ESI): m/z 36l.26(M+H)+. Step-4: 4-(2-( lH-Pyrazol-l-yl)-4-(trifluoromethyl) phenyl) chroman-7-yl trifluoro methane sulfonate
A solution of 4-(2-( lH-pyrazol-l-yl)-4-(trifluoromethyl) phenyl) chroman-7-ol (0.40g, l.l l mmol) and 2,6-lutidine (0.26 ml, 2.22 mmol) in DCM (15 ml) was cooled to -30°C. trifluoromethylsulfonic anhydride (0.28 ml, 1.67 mmol) was added drop wise to the reaction mixture and stirred allowing it to corne at room température for Ih. Reaction mixture was quenched with cold water and extracted with ethyl acetate. Combined organic layer was dried over Na2SO4 and concentrated under vacuum. The crude was purified by column chromatography to obtain title compound (0.32, 58 %). LCMS (ESI): m/z493.17(M+H)+.
Step-5: l-(2-(7-(Benzylthio) chroman-4-yl)-5-(trifluoromethyl)phenyl)-l/7-pyrazole
4-(2-( 1 H-pyrazol-1 -yl)-4-(trifluoromethyl)phenyl)chroman-7-yl trifluoromethanesulfonate (0.32g, 0.650 mmol) was dissolved in 1,4-dioxane (10 ml) and the solution was degassed by passing nitrogen. Xantphos (0.019g, 0.032 mmol), Pd2(dba)3 (0.015g, 0.016 mmol), Hunig's Base (0.227 ml, 1.300 mmol) and benzyl mercaptan (0.077 ml, 0.650 mmol) was added into the reaction mass and heated at 100 °C for 18h. After completion of reaction, reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated. The crude was purified by column chromatography to obtain title compound (0.30 g, 97 %). LCMS (ESI): m/z 467.09(M+H)+.
Step-6: Perfluorophenyl 4-(2-(1 H-pyrazol-l-yl)-4-(trifluoromethyl) phenyl) chroman-7sulfonate
To an ice-cold solution of l-(2-(7-(benzylthio)chroman-4-yl)-5-(trifluoromethyl)phenyl)IH-pyrazole (0.35g, 0.750 mmol) in DCM (10 ml) was added acetic acid (0.215 ml, 3.75 mmol), water (0.068 ml, 3.75 mmol) followed by sulfuryl chloride (0.183 ml, 2.251 mmol). The reaction mixture was stirred at same température for 15 min then diluted with DCM: water and extracted with DCM. The combined organic layer was dried over Na2SÛ4, and concentrated under vacuum. This crude product was taken in DCM and added drop wise to a solution of 2,3,4,5,6-pentafluorophenol (0.207g, 1.125 mmol) and TEA (0.837 ml, 6.00 mmol) in DCM (5 mL) at 0-5 °C. Stirred for 30 min at room température then the reaction mixture was diluted with DCM:water, extracted with DCM. The organic layer was dried over Na2SÜ4, and concentrated to dryness, the crude was purified by column chromatography to obtain title compound (0.27g, 61 %). LCMS (ESI): m/z 591.01(M+H)+.
Intermediate-21: 2-(2-bromo-5-(trifluoromethyl)phenyl)thiazole
Step-1: 2-(thiazol-2-yl)-4-(trifluoromethyl)aniline
A mixture of Water (Volume: 10 ml) and 1,4-Dioxane (30 ml) was degassed and 2(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (2.9g, 10.10 mmol), 2-bromothiazole (1.09 ml, 12.12 mmol), sodium carbonate (4.28g, 40.4 mmol) and PdCl2(dppf)-DCM adduct (0.825g, 1.010 mmol) was added and the mixture refluxed ovemight. The mixture was cooled and water was added followed by extraction with ethyl acetate. The EA layer was dried and concentrated and the product purified on column chromatography (1.9g, 77 %). LCMS (ESI): m/z 244.89(M+H)+.
Step-2: 2-(2-bromo-5-(trifluoromethyl)phenyl)thiazole
To a solution of 2-(thiazol-2-yl)-4-(trifluoromethyl)aniline (1.9 g, 7.78 mmol) and Cu(II)Br (0.956 g, 4.28 mmol) in acetonitrile (20 ml), tert-butylnitrite (1.110 ml, 9.34 mmol) was added drop wise at 60 °C and stirred for 30 min. After completion of reaction as indicated by TLC, Reaction mixture was poured into water and extract with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under vacuum. The crude product was purified by column chromatography to obtain title compound (1.4g, 58 %). 'H NMR (400 MHz, Chloroform-d) δ 8.43(d, J= 2.3 Hz, IH), 8.04 (d, J = 3.2 Hz, IH), 7.88 (d, J= 8.4 Hz, IH), 7.59 (d, J= 3.3 Hz, IH), 7.54 (dd, J= 8.4, 2.3 Hz, IH).
Intermediate-22a/22b: (R&S)-perfluorophenyl 4-(2-(thiazol-2-yl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonate
CF3 cf3
The title compound was prepared by following the similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-21. LCMS (ESI): m/z 607.96(M+H)+.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1 %DEA), B = (IPA), A:B = 80:20, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.86 min (Intermediate-22a) and rétention time 6.52 min (Intermediate-22b).
Intermediate-23: 5-(2-bromo-5-(trifluoromethyl)phenyl)-2-isopropoxypyridine
CF3
Step-1: 5- Bromo-2-isopropoxypyridine
In a 2-Propanol (100 ml) NaH (2.73g, 68.2 mmol) was added slowly then the mixture was heated at 80 °C for Ih. 5-bromo-2-fluoropyridine (5g, 28.4 mmol) was added and the résultant mixture was heated at 80 °C for further 15h. Reaction was monitored by TLC. The solvent was evaporated under vacuum, water was added in the residue and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over Na2SO4 and concentrated under vacuum to obtain title compound as an oil (5 g, 81 %). 'H NMR (400 MHz, Chloroform-t/) δ 8.20 (d, J = 3.2 Hz, IH), 7.64 (d, J= 8.7 Hz, IH), 6.62 (dd, J= 8.7, 2.6 Hz, 1 H), 5.26 (Quint, J =6.6 Hz, IH), 1.41 - 1.32 (d, 6H).
Step-2: 2-Isopropoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine
A stirred suspension of 5-bromo-2-isopropoxypyridine (5g, 23.14 mmol), potassium acetate (5.68 g, 57.9 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (8.81 g, 34.7 mmol) in 1,4-dioxane (50 ml) was degassed using nitrogen for 20 min. PdCl2(dppf)-DCM adduct (1.89g, 2.314 mmol) was added and reaction mixture was heated at 110 °C for Ih. Water was added to the reaction mixture and it was extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over Na2SÛ4 and concentrated under vacuum. The crude was purified by column chromatography title compound as oil (5 g, 82 % yield). ’H NMR (400 MHz,
Chloroform-7) δ 8.54 (s, IH), 7.92 (d, 7= 8.3 Hz, IH), 6.76 - 6.46 (m, IH), 5.45 - 5.25 (m, IH), l.37(d, 7=2.4 Hz, 6H), 1.28 (s, 12H).
Step-3: 2-(6-isopropoxypyridin-3 -yl )-4-(trifluoromethyl)ani l ine
A mixture of toluene (30 ml)/water (20 ml)/EtOH (10.00 ml) was degassed and 2-bromo4-(trifluoromethyl)aniline (4g, 16.67 mmol), 2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyridine (5.7g, 21.66 mmol) , sodium carbonate (6.18 g, 58.3 mmol) and Pd(Ph3P)4 (1.93g, 1.67 mmol) was added and the mixture was refluxed for 4h. TLC shown completion of reaction. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography to obtain title compound as an oil (3.30 g, 66.8 %). ‘H NMR (400 MHz, Chloroform-7) δ 8.27 (s, IH), 7.76 (d, 7= 8.5 Hz, IH), 7.43 (d, 7= 8.5 Hz, IH), 7.34 (s, IH), 6.91 - 6.81 (m, 2H), 5.41 (quint, 7= 6.4 Hz, IH), 1.44 (d, 6H).
Step-4: 5-(2-bromo-5-(trifluoromethyl)phenyl)-2-isopropoxypyridine
The title compound was prepared by following similar procedure as described in Intermediate-21 (Step-2) using step-3 intermediate. 'H NMR (400 MHz, Chloroform-7) δ 8.21 (s, 1 H), 7.83 (d, J = 8.3 Hz, 1 H), 7.68 (dd, 7 = 8.6, 2.4 Hz, 1 H), 7.58 (d, 7 = 2.3 Hz, 1 H), 7.49 (d, J = 8.3 Hz, 1 H), 6.79 (d, 7 = 8.6 Hz, 1 H), 5.39 (quint, J = 6.2 Hz, 1 H), 1.42 (d, 7=6.1 Hz, 6H).
Intermediate-24: Perfluorophenyl 4-(2-(6-isopropoxypyridin-3-yl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonate
The title compound was prepared by following the similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-23. LCMS (ESI): m/z 659.46(M+H)+.
Intermediate-25: 5-(2-bromo-5-(trifluoromethyl)phenyl)-2-ethoxypyridine
CF3
The title compound was prepared by following similar procedure as shown in Intermediate-23. *H NMR (400 MHz, Chloroform-7) δ 8.21 (s, IH), 7.83 (d, J= 8.4 Hz, IH), 7.68 (d, 7=8.5 Hz, IH), 7.58 (s, IH), 7.49 (d, 7=8.1 Hz, IH), 6.83 (d, 7=8.6 Hz, 5 IH), 4.44 (q, 2H), 1.46 (t, 7= 7.1, 2.5 Hz, 3H).
Intermediate-26: perfluorophenyl 4-(2-(6-ethoxypyridin-3-yl)-4-(trifluoromethyl) phenyl ) chroman- 7-sulfonate
The title compound was prepared by following the similar procedure as described in 10 Intermediate-6 using Intermediate-4 and Intermediate-25. LCMS (ESI): m/z 646.11(M+H)+.
Intermediate-27a/27b: (R&S)-Perfluorophenyl-4-(2-chloro-4-(trifluoromethyl)phenyl) chromane-7-sulfonate
A solution of Intermediate-4 (5g, 8.89 mmol) in 1,4-dioxane (30 ml) and water (6 ml) was purged with N2 and then added into l-bromo-2-chloro-4-(trifluoromethyl)benzene (2.77g, 10.67 mmol), PdCl2(dppf)-DCM adduct (0.73g, 0.889 mmol) and Na2CO3 (2.35g, 22.22 mmol). The reaction mixture was heated and maintained for 1.5 hr at 90 °C. After the completion of reaction as indicated by TLC, reaction mixture was cooled and diluted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness under reduced pressure. Flash column chromatography (15 % ethyl acetate/ petroleum ether) to obtain pale yellow oil, which further added into ethyl acetate (30 ml) and in 10 % Pd/C (0.946 g, 8.89 mmol) and stirred ovemight under H2 balloon pressure. After the completion of reaction as indicated by TLC, reaction mixture was filtered through celite and filtrate was evaporated to dryness to obtain title compound as off white solid (2.5g, 50 %). 'H NMR (400 MHz, Chloroform-d) δ 7.77 7.74 (m, 1H), 7.55 (d, J= 2.0 Hz, 1H), 7.48 (dt, J= 8.1, 1.2 Hz, 1H), 7.42 (dd, J= 8.2, 2.0 Hz, 1 H), 7.06 (dd, J = 8.1, 0.9 Hz, 1 H), 6.96 (d, J = 8.1 Hz, 1 H), 4.82 (t, J = 6.1 Hz, 1H), 4.37 - 4.20 (m, 2H), 2.49 - 2.38 (m, 1H), 2.25 - 2.14 (m, 1H).
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% DEA), B = IPA, A:B = 90:10 to afford isomer 1 and isomer 2. These isomers were obtained at rétention time: 5.59 min (Intermediate-27a) and rétention time: 6.20 min (Intermediate-27b).
Intermediate-28: 4-(2-bromo-5-(trifluoromethyl)phenyl)-3,6-dihydro-2H-pyran
Br Mo 0*^
CF3
Step-1: 4-(2-bromo-5-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-ol
To a solution of l-bromo-2-iodo-4-(trifluoromethyl)benzene (2g, 5.70 mmol) in 10 ml dry THF was slowly added isopropylmagnesium chloride (2.85 ml, 2M solution, 5.70 mmol) at -10 °C and reaction mixture was stirred for next 30 min. Then the solution of dihydro-2H-pyran-4(3H)-one (0.63 g, 6.27 mmol) in 10 ml THF was added to the reaction mixture and stirred further for 1,5h. After completion of reaction as indicated by TLC, reaction mixture was quenched by adding saturated NH4CI solution and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SÛ4 and concentrated under vacuum. The crude was purified by column chromatography to obtain title compound (0.55g, 29 %).
Step-2: 4-(2-bromo-5-(trifluoromethyl)phenyl)-3,6-dihydro-2H-pyran
To a solution of 4-(2-bromo-5-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-ol (Ig, 3.08 mmol) in toluene (50 ml) was added p-toluenesulfonic acid monohydrate (0.29g, 1.54 mmol) and reaction mixture was refluxed for 7h. The solvent was removed under vacuum and the crude residue was purified by column chromatography to obtain title compound (0.75, 79 %). *Η NMR (400 MHz, Chloroform-c/) δ 7.71 (d, J= 8.3 Hz, 1H), 7.48 - 7.37 (m, 2H), 5.78 (t, J= 2.3 Hz, 1H), 4.34 (q, J= 2.8 Hz, 2H), 3.96 (t, J= 5.3 Hz, 2H), 2.47 (tq, J= 5.0, 2.4 Hz, 2H).
Intermediate-29: Perfluorophenyl 4-(2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl) phenyl)chromane-7-sulfonate
F
CF3
The title compound was prepared by following the similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-28. LCMS (ESI): m/z 609.05(M+H)+.
Intermediate-30: l -(2-Bromo-5-(trifluoromethyl) phenyl) pyrrolidin-2-one Step-1: 7V-(2-Bromo-5-(trifluoromethyl) phenyl)-4-hydroxybutanamide 2-Bromo-5-(trifluoromethyl)aniline (2g, 8.33 mmol) was dissolved in DCM (25 ml) and trimethyl aluminum (5.83 ml, 11.67 mmol) was added slowly to it. After the addition the solution was stirred for 15 min after which dihydrofiiran-2(3H)-one (0.897 ml, 11.67 mmol) was added to it and the reaction mixture stirred at room température overnight. The reaction was quenched by the slow addition of IN HCl and extracted with ethyl acetate. The ethyl acetate layer was dried and conc. and the crude purified on column to obtain the product as a white solid (1.8g, 66 %) *H NMR (400 MHz, Chloroform-d) δ 8.74 (d, J= 2.3 Hz, 1H), 7.92 (s, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.25 (dd, J= 8.4, 2.2 Hz, 1H), 3.81 (q, J = 5.5 Hz, 2H), 2.66 (t, J = 7.0 Hz, 2H), 2.06 - 1.98 (m, 2H).
Step-2: 1 -(2-Bromo-5-(trifluoromethyl)phenyl)pyrrolidin-2-one
7V-(2-Bromo-5-(trifluoromethyl)phenyl)-4-hydroxybutanamide (l.36g, 4.17 mmol) was dissolved in DCM (60 ml) and triphenylphosphine (l.3lg, 5.00 mmol) was added to it. Diethyl azodicarboxylate (DEAD) (0.792 ml, 5.00 mmol) was added to this solution drop wise (color disappears) and the reaction mixture was allowed to stir at room température ovemight. The volatiles were then conc. and the crude purified by column chromatography to obtain the product as a white solid (Ig, 78 %). *H NMR (400 MHz, Chloroform-d) δ 7.82 (d, J= 8.4 Hz, IH), 7.57 (d, J= 2.2 Hz, IH), 7.48 (dd, J = 8.4, 2.1 Hz, IH), 3.83 (t, J= 7.0 Hz, 2H), 2.63 (t, J=8.l Hz, 2H), 2.37 - 2.23 (m, 2H).
Intermediate-31 a/31 b: (R&S)-Perfluorophenyl 4-(2-(2-oxopyrrolidin-1 -yl)-4(trifluoromethyl) phenyl)chroman-7-sulfonate
The title compound was prepared by following the similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-30. 'H NMR (400 MHz, Chloroform-7) δ 7.59 - 7.47 (m, 3H), 7.40 - 7.26 (m, 2H), 7.08 (d, J= 8.2 Hz, IH), 4.51 - 4.22 (m, 3H), 4.00 - 3.81 (m, 2H), 2.67 (t, J= 8.1 Hz, 2H), 2.42 - 2.28 (m, 2H), 2.22 1.85 (m, 2H).
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IC; Mobile phase: A = (Hexane + 0.1 %DEA), B = (IPA: DCM = 1:1), A:B = 70:30, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.89 min (Intermediate-31 a) and rétention time 6.71 min (Intermediate-31b).
Intermediate-32: 4-(2-bromo-5-(trifluoromethyl)phenyl)morpholine
Br Ç 0 ik A J
CF3
Step-1: 4-(2-nitro-5-(trifluoromethyl)phenyl)morpholine
To a solution of 2-fluoro-l-nitro-4-(trifluoromethyl)benzene (7g, 33.5 mmol) and morpholine (3.79g, 43.5 mmol) in DMF (70 ml) was added K2CO3 (11.57g, 84 mmol) and stirred for 4h at 120 °C. Reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was washed with brine, dried over Na2SO4 and concentrated to obtain title compound (8.9g, 96 %). 'H NMR (400 MHz, Chloroform-d) δ 7.86 (d, J= 8.4 Hz, IH), 7.40 - 7.26 (m, 2H), 3.87 (t, 4H), 3.13 (t, 4H).
Step-2: 2-morpholino-4-(trifluoromethyl)aniline
To a solution of 4-(2-nitro-5-(trifluoromethyl)phenyl)morpholine (7.5g, 27.2 mmol) in MeOH (100 ml) was added 10 % Pd-C (2.89g, 27.2 mmol) and reaction mixture was stirred for 3h under H2 atmosphère. Reaction was monitored by TLC. Reaction mixture was filtered through celite pad and filtrate was washed with ethyl acetate. The combined filtrate was concentrated under vacuum to obtain title compound (6.6g, 99 %). LCMS (ESI): tm/z 246.22(M+l)+.
Step-3: 4-(2-bromo-5-(trifluoromethyl)phenyl)morpholine
The title compound was prepared by following similar procedure as described for Intermediate-2l (Step-2), using 2-morpholino-4-(trifluoromethyl)aniline. LCMS (ESI): m/z 310.34 & 3l2.34(M+l)+.
Intermediate-33a/33b: (R&S)-Perfluorophenyl 4-(2-morpholino-4(trifluoromethyl)phenyl) chroman-7-sulfonate
CF3 cf3
The title compounds were prepared by following the similar procedure as described in Step-l and Step-2 of Intermediate-6 using Intermediate-4 and Intermediate-32. LCMS (ESI): w/z610.0(M+H)+.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IC; Mobile phase: A = (Hexane + O.l %DEA), B = (IPA: MeOH = l:l), A:B =
90:10, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time
7.85 min (lntermediate-33a) and rétention time 9.07 min (Intermediate-33b).
Intermediate-34: l-bromo-2-(2-methoxyethoxy)-4-(trifluoromethyl)benzene
CF3
A solution of 2-bromo-5-(trifluoromethyl)phenol (5g, 20.75 mmol), l-bromo-2methoxyethane (5.77g, 41.5 mmol) and Cs2CO3 (20.28g, 62.2 mmol) in acetonitrile (10 ml) was heated to 80 °C for 16h. The reaction was quenched by the addition of water and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and concentrated under vacuum. The crude was purified by column chromatography to obtain the product as white gummy liquid (6g, 97%).
Intermediate-35a/35b: (R&S)-perfluorophenyl 4-(2-(2-methoxyethoxy)-4(trifluoromethyl) phenyl)chroman-7-sulfonate
CF3
The title compounds were prepared by following the similar procedure as described Step1 and Step-2 of Intermediate-6 using Intermediate-4 and Intermediate-34. LCMS(ESI): w/z621.04(M+Na)+.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1 % DEA), B = (IPA:DCM = 1:1), A:B = 90:10, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.69 min (Intermediate-35a) and rétention time 6.34 min (Intermediate-35b).
Intermedaite-36: 2-bromo-1 -(3-methoxypropoxy)-4-(trifluoromethyl)benzene cf3
A mixture of 2-bromo-5-(trifluoromethyl)phenol (2g, 8.30 mmol), 3-bromopropan-l-ol (l.73g, 12.45 mmol) and CS2CO3 (l3.52g, 41.5 mmol) in acetonitrile (IO ml) was heated at 80 °C for I6h. The reaction mixture was quenched by the addition of water and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography to obtain 3-(2-bromo-4-(trifluoromethyl)phenoxy)propan-l-ol as white gummy liquid (2g, 81 %).
NaH (0.401 g, 10.03 mmol) was added in DMF (IO ml) at 0 °C and then added 3-(2bromo-4-(trifluoromethyl)phenoxy)propan-l-ol (Ig, 3.34 mmol) and stirred for IO min. Methyl iodide (0.475g, 3.34 mmol) was added to the reaction mixture and stirred further 16h. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure and the crude purified by column chromatography to obtain the product as white gummy liquid. ‘H NMR (400 MHz, Chloroform-J) δ 7.67 (d, J = 8.1 Hz, IH), 7.24 - 7.07 (m, 2H), 4.19 (t, J = 6.1 Hz, 2H), 3.64 (t, J = 6.0 Hz, 2H), 3.39 (s, 3H), 2.15 (quintet, J = 6.1 Hz, 2H).
Intermediate-37a/37b: (R&S)-Perfluorophenyl 4-(2-(3 -methoxypropoxy)-4(trifluoromethyl) phenyl) chroman-7-sulfonate
The title compounds were prepared by following the similar procedure as described in Step-l and Step-2 of Intermediate-6 using Intermediate-4 and Intermediate-36. LCMS(ESI): m/z 6l3.02(M+H)+.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + O.l % TFA), B = (IPA), A:B = 90:10, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.12 min (Intermediate-37a) and rétention time 6.92 min (Intermediate-37b).
Intermediate-38: l-bromo-2-(2-methoxyethyl)-4-(trifluoromethyl)benzene
Br
Step-1: 2-(2-bromo-5-(trifluoromethyl)phenyl)ethanol
To a suspension of (methoxymethyl)triphenylphosphonium chloride (13.55 g, 39.5 mmol) in THF (70 ml) was added potassium tert-butoxide (4.43 g, 39.5 mmol) under nitrogen and stirred for Ih at 0 °C, then 2-bromo-5-(trifluoromethyl)benzaldehyde (5 g, 19.76 mmol) in THF (10 ml) was added to the reaction mixture and allowed to stir at room température for 3h. Reaction mixture was quenched with water, extracted with ethyl acetate, dried over Na2SÛ4 and concentrated under vacuum. The crude was purified by column chromatography and then taken it in THF and heated with 5N HCl for 2.5h at 70 °C. It was then neutralized with bicarbonate solution and extracted with diethyl ether. The combined organic layer was dried over Na2SÛ4 and evaporated to give the crude compound and this was taken in MeOH (40 ml) and NaBH4 (0.673 g, 17.79 mmol) was added and maintained for Ih. The solvent was evaporated under reduced pressure and reaction mixture was quenched with water. The product was extracted with ethyl acetate and combined organic layers washed with water, brine, dried over Na2SÛ4 and concentrated under vacuum. The crude was purified to obtain title compound as oil. (3.5 g, 66 %). LCMS (ESI): m/z 268.06 & 270.08(M+H)+.
Step-2: 1 -bromo-2-(2-methoxyethyl)-4-(trifluoromethyl)benzene
To a suspension of NaH (0.580 g, 14.49 mmol) in THF(30 ml) at 0 °C, a solution of 2-(2bromo-5-(trifluoromethyl)phenyl)ethanol (3 g, 11.15 mmol) in THF was added drop wise and stirred for 10 min. lodomethane (1.394 ml, 22.30 mmol) was added to the reaction mixture and stirred further 45 min. After completion of reaction as indicated by TLC, The reaction mixture was quenched by addition of water and extracted with ethyl acetate.
Organic layer combined and washed with brine, dried over sodium sulfate and concentrated under vacuum.
The crude was purified by column chromatography to obtain title compound (1.8g, 57 %). 'H NMR (400 MHz, Chloroform-i/) δ 7.69 (d, J= 8.3 Hz, IH), 7.58 - 7.52 (m, IH), 7.36 (dd, J= 8.4, 2.2 Hz, IH), 3.66 (t, J= 6.8 Hz, 2H), 3.39 (s, 3H), 3.10 (t, J= 6.8 Hz, 2H).
Intermediate-39a/39b: (S&R)-perfluorophenyl 4-(2-(2-methoxyethyl)-4(trifluoromethyl) phenyl) chroman-7-sulfonate
The title compounds were prepared by following the similar procedure as described in Step-1 and Step-2 of Intermediate-6 using Intermediate-4 and Intermediate-38.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1 % DEA), B = (IPA), A:B = 90:10, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.56 min (Intermediate-39a) and rétention time 7.91 min (Intermediate-39b).
LCMS (ESI): m/z 605.05(M+Na)+. 'H NMR (400 MHz, Chloroform-J) δ 7.57 - 7.54 (m, IH), 7.52 (d, J= 2.0 Hz, IH), 7.42 (dd, J= 8.3, 2.0 Hz, IH), 7.36 (dd, J= 8.2, 2.0 Hz, IH), 6.98 (dd, J= 8.2, 0.9 Hz, IH), 6.91 (d, J= 8.2 Hz, IH), 4.73 (t, J= 6.9 Hz, IH), 4.39 - 4.27 (m, 2H), 3.78 - 3.64 (m, 2H), 3.37 (s, 3H), 3.22 - 3.11 (m, IH), 3.06 - 2.96 (m, IH), 2.41 -2.32 (m, IH), 2.15-2.05 (m, IH).
Intermediate-40: 1 -bromo-2-(3-methoxyprop-l -yn-1 -yl)-4-(trifluoromethyl)benzene
Step-1: 3-(2-bromo-5-(trifluoromethyl)phenyl)prop-2-yn-1 -ol
The title compound was prepared by following similar procedure as shown in Intermediate-48 (Step-1) using l-bromo-2-iodo-4-(trifluoromethyI)benzene and prop-2yn-l-ol. ‘H NMR (400 MHz, Chloroform-d) δ 7.78 - 7.71 (m, 2H), 7.44 (dd, J= 8.5, 2.2 Hz, 1 H), 4.59 (s, 2H).
Step-2: 1 -bromo-2-(3-methoxyprop-1 -yn-1 -yl)-4-(trifluoromethyl)benzene
To a solution of 3-(2-bromo-5-(trifluoromethyl)phenyl)prop-2-yn-l-ol (2.7g, 9.68 mmol) in dry THF (50 ml) was added NaH (0.43g, 10.64 mmol) at 0 °C and stirred for another 15 min then added Mel (0.907 ml, 14.51 mmol). Reaction mixture was stirred for additional 30 min at room température. After completion of reaction, reaction mixture was poured into aqueous NH4C1 solution and extracted with ethyl acetate. The organic phase was washed with IN HCl, brine, dried over Na2SO4 and concentrated to obtain title compound (2.5g, 88 %). 'H NMR (400 MHz, Chloroform-d) δ 7.79 - 7.70 (m, 2H), 7.48 - 7.39 (m, IH), 4.41 (s, 2H), 3.52 (s, 3H).
Intermediate-41a/41b: (S&R)Perfluorophenyl 4-(2-(3-methoxypropyl)-4(trifluoromethyl) phenyl) chroman-7-sulfonate
F F
CF3 cf3
The title compounds were prepared by following the similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-40. LCMS(ESI): m/z 597.03(M+H)+.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + O.l %DEA), B = (IPA), A:B = 95:5, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 7.09 min (Intermediate-4la) and rétention time 8.69 min (Intermediate-4lb).
Intermediate-42: l -bromo-2-(4-methoxybut-1 -yn-1 -yl)-4-(trifluoromethyl)benzene
The title compound was prepared by following similar procedure as described for Intermediate-40 using l-bromo-2-iodo-4-(trifIuoromethyl)benzene and but-3-yn-l-ol. LCMS (ESI): m/z 306.93 & 308.93(M+l)+.
Intermediate-43a/43b: (R&S)Perfluorophenyl 4-(2-(4-methoxybutyl)-4(trifluoromethyl) phenyl) chroman-7-sulfonate
The title compounds were prepared by following the similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-42. LCMS (ESI): m/z 611.13(M+H)+.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1 %DEA), B = (IPA), A:B = 90:10, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.63 min (Intermediate-43a) and rétention time 6.83 min (Intermediate-43b).
Intermediate-44: l-bromo-2-(2-fluoroethyl)-4-(trifluoromethyl)benzene
Br
CF3
Step-1: 2-(2-bromo-5-(trifluoromethyl)phenyl)ethanol
To a suspension of (methoxymethyl)triphenylphosphonium chloride (13.55 g, 39.5 mmol) in THF (70 ml) was added potassium tert-butoxide (4.43 g, 39.5 mmol) under nitrogen and stirred for Ih at 0 °C, then 2-bromo-5-(trifluoromethyl)benzaldehyde (5 g, 19.76 mmol) in THF(10 ml) was added to the reaction mixture and allowed to stir at room température for 3h. Reaction mixture was quenched with water, extracted with ethyl acetate, dried over Na2SÛ4 and concentrated under vacuum. The crude was purified by column chromatography and then taken it in THF and heated with 5N HCl for 2.5h at 70 °C. It was then neutralized with bicarbonate solution and extracted with diethyl ether. The combined organic layer was dried over Na2SO4 and evaporated to dryness to give the crude compound. Which was taken in MeOH (40 ml) and NaBH4 (0.673 g, 17.79 mmol) was added and the résultant mixture was stirred for Ih. The solvent was evaporated under reduced pressure and reaction mixture was quenched with water. The product was extracted with ethyl acetate and combined organic layers washed with water, brine, dried over Na2SO4 and concentrated under vacuum. The crude was purified to obtain title compound as oil. (3.5 g, 66 %). LCMS (ESI): m/z 268.06 & 270.08(M+H)+.
Step-2: 1 -bromo-2-(2-fluoroethyl)-4-(trifluoromethyl)benzene
To stirred solution of 2-(2-bromo-5-(trifluoromethyl)phenyl)ethanol (3.5g, 13.01 mmol) in DCM (50 ml) DAST (4.30 ml, 32.5 mmol) was added at 0°C, then reaction mixture was allowed to warm to room température & stirred at for 16h. After completion of reaction as indicated by TLC, reaction mixture was quenched with sat NaHCOj solution and then extracted with DCM. The organic layer was evaporated under vacuum and the crude was purified by column chromatography to obtain title compound as oil (2.10 g, 59). 'H NMR (400 MHz, Chloroform-i/) δ 7.72 (d, J= 8.4 Hz, IH), 7.58 (d, J= 2.2 Hz, 1 H), 7.40 (dd, J = 8.4, 2.2 Hz, 1 H), 4.77 (t, J = 6.2 Hz, 1 H), 4.66 (t, J = 6.2 Hz, 1 H), 3.28 (t, J=6.2 Hz, 1 H), 3.22 (t, 7=6.2 Hz, IH).
Intermediate-45a/45b: (S&R)-Perfluorophenyl 4-(2-(2-fluoroethyl)-4-(trifluoromethyl) phenyl) chroman-7-sulfonate
The title compounds were prepared by following similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-44.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA), A:B = 80:20, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.36 min (Intermediate-45a) and rétention time 7.47 min (Intermediate-45b).
'H NMR (400 MHz, Chloroform-i/) δ 7.61 - 7.42 (m, 3H), 7.36 (d, J= 8.1 Hz, 1H), 6.96 (dd, J = 8.3, 2.8 Hz, 2H), 4.90 - 4.57 (m, 3H), 4.40 - 4.25 (m, 2H), 3.37 - 3.08 (m, 2H), 2.47-2.30 (m, 1H),2.21 -2.08 (m, 1H).
Intermediate-46: l-bromo-2-(3-fluoropropyl)-4-(trifluoromethyl)benzene Br
CF3
Step-1: Ethyl 3-(2-bromo-5-(trifluoromethyl)phenyl)acrylate
Ethyl 2-(diethoxyphosphoryl)acetate (1.53g, 6.82 mmol) was added to a suspension of NaH (0.31g, 7.71 mmol) in THF (20 ml) at room température. After stirring for an hour, a solution of 2-bromo-5-(trifluoromethyl)benzaldehyde (1.5g, 5.93 mmol) in THF was added to the reaction mixture followed by stirring for another Ih. After completion of reaction as indicated by TLC, reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium chloride solution and dried over Na2SÛ4. The solvent was removed under vacuum and the residue was purified by column chromatography to obtain title compound (0.9g, 47 %). LCMS (ESI): m/z 323.01(M+)+·
Step-2: ethyl 3-(2-bromo-5-(trifluoromethyl)phenyl)propanoate
To a stirred solution of ethyl 3-(2-bromo-5-(trifluoromethyl)phenyl)acrylate (0.9g, 2.79 mmol) in THF (5 ml) and water (5 ml) was added 4-methylbenzenesulfonohydrazide (1.04 g, 5.57 mmol) and sodium acetate (0.69g, 8.36 mmol). The reaction mixture was refluxed for 16h. After completion of reaction; water was added to the reaction mixture and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. This was purified by column chromatography to obtain title compound as a colorless oil (0.8g, 88 %). LCMS (ESI): m/z 325.03(M+)+.
Step-3: 3-(2-bromo-5-(trifluoromethyl)phenyl)propan-l-ol
To a solution of ethyl 3-(2-bromo-5-(trifluoromethyl)phenyl)propanoate (0.8g, 2.461 mmol) in toluene (10 ml) was added DIBAL-H (7.38 ml, l molar, 7.38 mmol) at -78 °C drop wise. The reaction mixture was allowed to warm to room température over 30 min. then quenched with saturated solution of sodium sulfate and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SC>4 and concentrated under vacuum. The crude product was purified by column chromatography (0.65, 93 %). LCMS (ESI): m/z 284.06 (M+)+.
Step-4: l -bromo-2-(3-fluoropropyl)-4-(trifluoromethyl)benzene
To a solution of 3-(2-bromo-5-(trifluoromethyl)phenyl)propan-l-ol (0.65g, 2.296 mmol) in DCM (7 ml) was added DAST (0.455 ml, 3.44 mmol) drop wise. The reaction was allowed to stir at room température over 16h. The reaction mixture was quenched with saturated solution of sodium bicarbonate and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SÛ4 and concentrated under vacuum. The crude product was purified by column chromatography (0.6g, 92 %). 'H NMR (400 MHz, Chloroform-7) δ 7.70 (d, J= 8.3 Hz, IH), 7.51 (s, IH), 7.36 (d, J = 8.4 Hz, IH), 4.59 (t,J=5.8 Hz, 1H),4.47 (t, J= 5.8 Hz, IH), 3.01 -2.92 (m, 2H), 2.16 1.97 (m, 2H).
Intermediate-47a/47b: Perfluorophenyl (S&R)-4-(2-(3-fluoropropyl)-4-(trifluoromethyl) phenyl)chromane-7-sulfonate
The title compound was prepared by following similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-46.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = IPA, A:B = 80:20 to afford isomer l and isomer 2. These isomers were obtained at rétention time: 5.58 min (Intermediate-47a) and rétention time: 6.51 min (Intermediate-47b).
LCMS(ESI): m/z 607.06(M+Na)+; 'H NMR (400 MHz, DMSO-76) δ 7.67 (d, J= 2.0 Hz, 1H), 7.50 (dd, J = 8.2, 2.0 Hz, IH), 7.45 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.2, 2.1 Hz, IH), 7.00 (d, J= 8.2 Hz, 2H), 4.73 (t, J= 7.0 Hz, 1H), 4.60 (t, J= 5.9 Hz, IH), 4.49 (t, J = 5.9 Hz, IH), 4.41 - 4.26 (m, 2H), 3.01 - 2.82 (m, 2H), 2.37 - 2.27 (m, IH), 2.12 - 2.01 (m, 3H).
Intermediate-48: 1 -bromo-2-(4-fluorobut-1 -yn-1 -yl)-4-(trifluoromethyl)benzene Br
CF3
Step-1: 4-(2-bromo-5-(trifluoromethyl)phenyl)but-3-yn-l-ol
To the N2 purged solution of TEA (10 ml) and DMF (10 ml) was added but-3-yn-l-ol (0.75 g, 10.69 mmol), l-bromo-2-iodo-4-(trifluoromethyl)benzene (2.5g, 7.12 mmol), copper(I) iodide (0.27g, 1.425 mmol), bis(triphenylphosphine)palladium(II) chloride (0.50g, 0.712 mmol) at room température and stirred further for 15 min. After completion of reaction as indicated by TLC, reaction mass was poured in to water and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, conc under reduced pressure and purified by column chromatography to obtain title compound (1.4g, 67%). LCMS (ESI): m/z 292.96(M+H)+.
Step-2: l -bromo-2-(4-fluorobut-1 -yn-1 -yl)-4-(trifluoromethyl)benzene
To a solution of 4-(2-bromo-5-(trifluoromethyl)phenyl)but-3-yn-l-ol (l.4g, 4.78 mmol) in dichloromethane (10 ml) was added DAST (1.58 ml, 11.94 mmol) drop wise at 0 °C. The reaction was allowed to stir at room température over 16h. The reaction mixture was quenched with saturated solution of sodium bicarbonate and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography to obtain title compound (Ig, 70 %). 'H NMR (400 MHz, Chloroform-if) δ 7.76 - 7.69 (m, 2H), 7.44 - 7.37 (m, IH), 4.72 (t, J= 6.6 Hz, IH), 4.60 (t, J= 6.6 Hz, IH), 2.94 (dt, J= 19.9, 6.6 Hz, 2H).
Intermediate-49a/49b: (R&S)-Perfluorophenyl 4-(2-(4-fluorobutyl)-4-(trifluoromethyl) phenyl )chroman-7-sulfonate
The title compound was prepared by following similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-48.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = IP A, A:B = 80:20 to afford isomer 1 and isomer 2. These isomers were obtained at rétention time: 5.64 min (Intermediate-49a) and rétention time: 6.76 min (Intermediate-49b).
'H NMR (400 MHz, Chloroform-i/) δ 7.53 (s, 2H), 7.42 (d, J= 8.5 Hz, IH), 7.36 (d, J = 8.2 Hz, IH), 6.93 (d, J= 8.2 Hz, 2H), 4.63 - 4.53 (m, 2H), 4.52 - 4.47 (m, IH), 4.40 4.32 (m, 2H), 2.95 - 2.79 (m, 2H), 2.42 - 2.32 (m, 1 H), 2.18 - 2.09 (m, 1 H), 1.93 - 1.81 (m, 4H).
Intermediate-50: 4-(2-bromo-5-(trifluoromethyl)phenoxy)tetrahydro-2H-pyran cf3
To a solution of tetrahydro-2H-pyran-4-ol (2g, 19.58 mmol) and 2-bromo-5(trifluoromethyl)phenol (3.78g, 15.67 mmol) in THF (100 ml) was added triphenylphosphine (6.16 g, 23.50 mmol) followed by DIAD (4.57 ml, 23.50 mmol) at 0 °C then allowed to stir the reaction mixture at room température. After completion of reaction as indicated by TLC, reaction mixture was evaporated under vacuum and purified by column chromatography to obtain title compound (3.5g, 55%). *H NMR (400 MHz, Chloroformé) δ 7.70 (d, J = 8.3 Hz, IH), 7.21 - 7.11 (m, 2H), 4.72 - 4.62 (m, IH), 4.04 (ddd, J= 11.3, 7.5, 3.5 Hz, 2H), 3.72 - 3.62 (m, 2H), 2.13 - 2.01 (m, 2H), 1.96 1.83 (m, 2H).
Intermediate-51: Perfluorophenyl 4-(2-((tetrahydro-2H-pyran-4-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonate
F
The title compound was prepared by following similar procedure as described for Intermediate-6 using Intermediate-4 and Intermediate-50. *H NMR (400 MHz, Chloroformé) δ 7.52 (d, J= 2.0 Hz, IH), 7.39 (dd, J= 8.1, 2.0 Hz, IH), 7.18 (d, J = 8.0 Hz, IH), 7.12 (s, IH), 7.05 (d, J= 8.2 Hz, IH), 6.95 (d, J= 7.9 Hz, IH), 4.69 - 4.60 (m, 2H), 4.34 - 4.20 (m, 2H), 4.01 - 3.85 (m, 2H), 3.72 - 3.59 (m, 2H), 2.36 - 2.21 (m, 2H), 2.17-1.79 (m,4H).
Intermediate-52: (S)-3-(2-bromo-4-(trifluoromethyl)phenoxy)tetrahydrofuran
Br
CF3
The title compound was prepared similarly as shown in Intermediate-50 using 2-bromo-5(trifluoromethyl)phenol and (R)-tetrahydrofuran-3-ol. LCMS (ESI): m/z 310.00 & 3ll.88(M+H)+.
Intermediate-53a/53b: (R&S)-perfluorophenyl 4-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4 (trifluoro methyl)phenyl) chroman-7-sulfonate
CF3 cf3
The title compound was prepared by following similar procedure as described for
Intermediate-6 using Intermediate-4 and Intermediate-52. LCMS (ESI): m/z 633.07(M+Na)+;
Further the enantiomers were separated using chiral préparative HPLC (Column: 10 ChiralPak IA; Mobile phase: A = (Hexane + 0.1% DEA), B = IPA, A:B = 90:10, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 7.76 min (Intermediate-53a) and rétention time 9.38 min (Intermediate-53b).
Intermediate-54: (R)-3-(2-bromo-4-(trifluoromethyl)phenoxy)tetrahydrofuran
Br
CF3
The title compound was prepared similarly as shown in Intermediate-50 using 2-bromo-5(trifluoromethyl)phenol and (S)-tetrahydrofuran-3-ol. LCMS (ESI): m/z 309.93 & 312.01(M+H)+.
Intermediate-55: Perfluorophenyl 4-(2-(((R)-tetrahydrofuran-3-yl)oxy)-4(trifluoromethyl) phenyl)chroman-7-sulfonate
The title compound was prepared by following similar procedure as described for Intermediate-6 using Intermediate-4 and Intermediate-54. 'H NMR (400 MHz, Chloroform-c/) δ 7.52 (d, J= 2.1 Hz, IH), 7.43 - 7.35 (m, IH), 7.20 (d, J= 8.1 Hz, IH), 7.09-7.02 (m, 2H), 6.92 (dd,J = 22.4, 8.1 Hz, IH), 5.13 - 5.01 (m, IH), 4.69-4.56 (m,
H), 4.32 - 4.16 (m, 2H), 4.10 - 3.81 (m, 4H), 2.41 - 1.99 (m, 4H).
Intermediate-56: tert-butyl 2'-bromo-5'-(trifluoromethyl)-[ 1,1 '-biphenyl]-4-carboxylate
Step-1: tert-butyl 4-bromobenzoate
To a solution of 4-bromobenzoic acid (10g, 49.7 mmol) in Chloroform (150 ml), 2methylpropan-2-ol (18.44g, 249 mmol), EDC.HC1 (23.84g, 124 mmol), followed by DMAP (15.19g, 124 mmol) was added and stirred for 18h at room température. After completion of reaction as indicated by TLC, the mixture was poured into water and extracted with DCM. The organic layer was collected and dried over sodium sulphate, finally evaporated and purified by column chromatography (7g, 55 %). (H NMR (400 MHz, Chloroform-<7) δ 7.87 (d, 2H), 7.57 (d, 2H), 1.61 (s, 9H).
Step-2: tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate
The title compound was prepared by following similar procedure as described in Intermediate-23, Step-2 using tert-butyl 4-bromobenzoate and 4,4,4',4',5,5,5',5'octamethyl-2,2'-bi( 1,3,2-dioxa borolane) 'H NMR (400 MHz, Chloroformé) δ 7.98 (d, 2H), 7.86 (d, J= 8.0 Hz, 2H), 1.62 (s, 9H), 1.38 (s, 12H).
Step-3: tert-butyl 2'-amino-5'-(trifluoromethyl)-[l,r-biphenyl]-4-carboxylate
A solution of 2-bromo-4-(trifluoromethyl)aniline(5g, 20.83 mmol), tert-butyl 4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (6.34g, 20.83 mmol), and sodium carbonate (5.52g, 52.1 mmol) in toluene (30 ml) / water (20 ml)/ Ethanol (10 ml), N2 was purged for 10 min. then Tetrakistriphenyl phosphinePd (0) (2.407g, 2.083 mmol) was charged and stirred at 95 °C for 4h. After completion of reaction as indicated by TLC, the mixture was poured into water and extracted with ethyl acetate. The organic layer was collected and dried over sodium sulphate, finally evaporated and purified by column chromatography (4.5g, 64 %). LCMS (ESI): m/z 338.10(M+H)+.
Step-4: tert-butyl 2'-bromo-5'-(trifluoromethyl)-[ 1,1 ’-biphenyl]-4-carboxylate
To a solution of tert-butyl 2'-amino-5'-(trifluoromethyl)-[l,r-biphenyl]-4-carboxylate (4.5g, 13.34 mmol) in acetonitrile (60 ml), copper(II) bromide (1.64g, 7.34 mmol) was added followed by tert-butyl nitrite (2.4 ml, 20.01 mmol) was added dropwise and reaction was heated for 45 min at 65 °C. Reaction was monitored by TLC. After completion the mixture was added to water and extracted with ethyl acetate. The organic layer was collected and dried over sodium sulphate, finally evaporated to get crude which was purified by column.
’H NMR (400 MHz, Chloroformé) δ 8.13 - 8.07 (m, 2H), 7.84 (d, J= 8.3 Hz, IH), 7.58 (d,7=2.2 Hz, IH), 7.54-7.45 (m, 3H), 1.65 (s, 9H).
Intermediate-57a/57b: (R&S)-tert-butyl 2'-(7-((perfluorophenoxy)sulfonyl)chroman-4yl)-5'-(trifluoromethyl)-[ 1,1 '-biphenyl]-4-carboxylate
CF3 cf3
The title compound was prepared by following the similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-56. LCMS (ESI): m/z 723.08(M+H)+.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane), B = (IPA:DCM = 1:1), A:B = 75:25, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 3.99 min (Intermediate-57a) and rétention time 6.10 min (Intermediate-57b).
Intermediate-58: 2-(2-bromo-5-(trifluoromethyl)phenyl)-5-fIuoropyridine 1-oxide
Br
0'
F F F
Step-1; 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline
NH2 O 1 B
CF3
A stirred suspension of 2-bromo-4-(trifluoromethyl)aniline (50g, 208 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2’-bi(l,3,2-dioxaborolane) (79g, 312 mmol) and potassium acetate (53.2g, 542 mmol) in 1,4-dioxane (150 ml) was degassed for 20 min and then PdCl2(dppf)-DCM adduct (17.01g, 20.83 mmol) was added to the reaction mixture and heated for 5h at 95 °C. After completion of reaction as indicated by TLC, Reaction mixture was filtered through celite bed and residue was washed with ethyl acetate. The filtrate was evaporated and the crude was purified by column chromatography to obtain title compound as off white solid (35g, 58 %). 'H NMR (400 MHz, Chloro form-ίΖ) δ 7.91 -7.85 (m, IH), 7.44 (dd, J= 8.6, 2.3 Hz, IH), 6.64 (d,J=8.5Hz, IH), 1.37 (s, 12H).
Step-2: 2-(5-fluoropyridin-2-yl)-4-(trifluoromethyl)aniline
Nitrogen was purged containing 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4(trifluoromethyl)aniline (1.5g, 5.22 mmol), 2-bromo-5-fluoropyridine(1.01g, 5.75 mmol) in 1,4-dioxane (15 ml), water (3 ml) for 10 minutes. After which PdCl2(dppf)DCM complex (0.382 g, 0.522 mmol) and sodium carbonate (1.38g, 13.06 mmol) were added and heated at 90 °C for I8h. After completion of reaction as indicated by TLC, reaction mixture was cooled to room température and concentrated under vacuum. The crude brown solid was purified by column chromatography to obtain title compound (l.2g, 90 %). LCMS (ESI): m/z 256.lO(M+H)+.
Step-3: 2-(2-bromo-5-(trifluoromethyl)phenyl)-5-fluoropyridine
To a stirred solution of 2-(5-fluoropyridin-2-yl)-4-(trifluoromethyl)aniline(0.70g, 2.73 mmol) in acetonitrile (25 ml), copper(II) bromide (0.3g, 1.639 mmol) was added and heated reaction mixture at 60 °C. After 5 min tert-butylnitrite (0.31 ml, 4.10 mmol) was added drop wise and stirred further Ih. After completion of reaction as indicated by TLC, reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was collected and washed with water, dried over Na2SO4 and evaporated under vacuum. The crude was purified by column chromatography to obtain title compound (0.55g, 62 %). 'H NMR (400 MHz, Chloroform-d) δ 8.62 (d, 7= 2.9 Hz, IH), 7.87 - 7.79 (m, 2H), 7.69 (dd, 7= 8.7,4.3 Hz, IH), 7.55 (td, 7= 8.6, 2.7 Hz, 2H).
Step-4: 2-(2-bromo-5-(trifluoromethyl)phenyl)-5-fluoropyridine l -oxide
To a stirred solution of 2-(2-bromo-5-(trifluoromethyl)phenyl)-5-fluoropyridine (0.50g, 1.56 mmol) in CHCl3 (10 ml), m-CPBA (0.59 g, 3.44 mmol) was added and reaction mixture was heated at 45 °C for 4h. After completion of reaction, reaction mixture was conc. under vacuum. The crude was purified by column chromatography to obtain title compound (0.40 g, 76 %). LCMS (ESI): m/z 336.03 & 337.78 (M+H)+.
Intermediate-59: Perfluorophenyl 4-(2-(5-fluoropyridin-2-yl)-4-(trifluoromethyl)phenyl) chroman-7-sulfonate
The title compound was prepared by following the similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-58. LCMS (ESI): m/z 620.02(M+H)+.
Intermediate-60: (R&S)-perfluorophenyl 4-(2-bromo-4(trifluoromethyl)phenyl)chroman-7-sulfonate
A stirred suspension of l-bromo-2-nitro-4-(trifluoromethyl)benzene (10 g, 37.0 mmol), perfluorophenyl 4-(2-tosylhydrazono)chroman-7-sulfonate (22.92 g, 40.7 mmol) and Na2CÛ3 (11.78 g, 111 mmol) in 1,4-Dioxane (210 ml)/ Water (35 ml) was degassed using nitrogen for 20 min. then PdCl2(dppf)-CH2Cl2 adduct (3.02g, 3.70 mmol) was added and reaction was heated at 100 °C for Ih. After completion of reaction as indicated by TLC, reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with water, brine dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography to obtain title compound as yellow thick mass (14.0 g, 66 %). LCMS(ESI): m/z 590.00(M+H)+; 'H NMR (400 MHz, Chloroform-7) δ 8.42 - 8.38 (m, IH), 8.04 - 7.98 (m, IH), 7.62 (d, J = 7.9 Hz, IH), 7.49 (d, J= 1.9 Hz, IH), 7.38 (dd, J = 8.1, 2.0 Hz, IH), 6.72 (d, J= 8.1 Hz, IH), 5.99 (t, J= 3.7 Hz, IH), 5.15 - 5.02 (m, 2H).
Step-2: Perfluorophenyl 4-(2-amino-4-(trifluoromethyl)phenyl)chroman-7-sulfonate
A stirred suspension of perfluorophenyl 4-(2-nitro-4-(trifluoromethyl)phenyl)-2H5 chromene-7-sulfonate (I4g, 24.68 mmol) and 10 % Pd-C (13.13 g, 123 mmol) in ethyl acetate (150 ml) was kept under hydrogen ballon gas pressure for 48h. After completion of reaction as indicated by LCMS, reaction mixture was filtered through celite bed and concentrated under vacuum. The crude was purified by column chromatography to obtain title compound (l 1.50 g, 86 %). LCMS(ESI): m/z 540.0l(M+H)+; 'H NMR (400 MHz, 10 DMSO-î/6) δ 7.46 - 7.39 (m, 2H), 7.17 (d, J = 7.9 Hz, 1 H), 7.03 (d, J = 1.9 Hz, 1 H), 6.73 (dd, J=8.2, 1.9 Hz, 1H), 6.58 (d,J=8.0 Hz, 1H), 5.75 (brs, 2H), 4.54 (t,J=5.6 Hz, 1H), 4.33 - 4.23 (m, 1 H), 4.15 - 4.06 (m, 1 H), 2.24 - 2.17 (m, 1 H), 2.06- 1.97 (m, 1 H).
Step-3: (S/R)-perfluorophenyl 4-(2-bromo-4-(trifluoromethyl)phenyl)chroman-7sulfonate
To a stirred suspension of Cu(II)Br (1.86g, 8.34 mmol) and perfluorophenyl 4-(2-amino4-(trifluoromethyl)phenyl)chroman-7-sulfonate (9g, 16.69 mmol) in acetonitrile (90 ml) was added tert-butyl nitrite (3.76 ml, 25.03 mmol) at 70 °C. This was stirred for Ih at 70 °C. After completion of reaction as indicated by TLC, Saturated solution of ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SÛ4 and concentrated under vacuum. The crude was purified by column chromatography to obtain title compound as a mixture of isomers (3.2g, 32 %).
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + O.l % DEA), B = (IPA), A:B = 90:10, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.75 (Intermediate-60a) min and rétention time 7.81 (Intermediate-60b) min.
Intermediate-61 : (R/S)-perfluorophenyl 4-(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonate
A stirred suspension of Intermediate-60b (0.70g, 1.160 mmol), 2-methyl-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.64g, 2.90 mmol) and Na2CO3 (0.25g, 2.321 mmol) in 1,4-dioxane (10 ml)/ water (1.0 ml) was degassed for 15 min using nitrogen then PdC12(dppf)-CH2Cl2 adduct (0.095g, 0.116 mmol) was added and heated at 100 °C for 2h. After completion of reaction as indicated by TLC, reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with water, brine dried over Na2SÛ4 and concentrated under vacuum. The crude product was purified by column chromatography to obtain title compound (0.65g, 91 %).
LCMS (ESI): m/z 516.11(M+H)+;
Intermediate-62: 3-(2-iodo-5-(trifluoromethyl)phenyl)oxazolidin-2-one
Step-1: 3-(2-amino-5-(trifluoromethyl)phenyl)oxazolidin-2-one
NH, r—\
CF3
2-bromo-4-(trifluoromethyl)aniline (4g, 16.67 mmol), oxazolidin-2-one (3.63 g, 41.7 mmol), Nl,N2-dimethylethane-l,2-diamine (0.88g, 10.00 mmol), césium carbonate (13.57g, 41.7 mmol) and copper(I) iodide (1.27g, 6.67 mmol) was added to degassed 1,4dioxane (20 ml) and heated reaction mixture in seaied tube at 110 °C for 12h. After the solution was cooled, the mixture was passed through a pad of celite and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4 and conc. The crude was purified by column chromatography to obtain title compound (1.2g, 29 %). LCMS (ESI): m/z 246.99(M+H)+.
Step-2: 3 -(2-iodo-5 -(trifluoromethyl)phenyl)oxazolidin-2-one
CF3
3-(2-amino-5-(trifluoromethyl)phenyl)oxazolidin-2-one (1.2g, 4.87 mmol) was dissolved into acetonitrile (20 ml) & water (5 ml) followed by the addition of 4methylbenzenesulfonic acid (3.36g, 19.50 mmol) into it. Kl (2.02g, 12.19 mmol) and sodium nitrate (0.82g, 9.75 mmol) in water (5 ml) was added to the reaction mixture slowly at -5 to 0 °C. Reaction mixture was stirred at -5 to 0 °C for 1.5h then quenched by addition of water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude was purified by column chromatography to obtain title compound. *H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J = 8.2 Hz, IH), 7.64 (d,7=2.1 Hz, IH), 7.36 (dd, 7= 8.2, 2.1 Hz, IH), 4.62 (t,7 = 7.9 Hz, 2H), 4.07 (t, 7= 7.9 Hz, 2H).
Intermediate-63a/63b: (R&S)-Perfluorophenyl 4-(2-(2-oxooxazolidin-3-yl)-4(trifluoromethyl)phenyl)chroman-7-sulfonate
The title compound was prepared by following the similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-62. LCMS (ESI): m/z 6lO.lO(M+H)+.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + O.l % TFA), B = (IPA), A:B = 65:35, to afford isomer-l and isomer-2. These isomers were obtained at rétention time 5.59 min (Intermediate-63a) and rétention time 6.51 min Intermediate-63b).
Intermediate-64: l-bromo-2-(3,3-difluoropropyl)-4-(trifluoromethyl)benzene
Br F
CF3
Step-1: 3-(2-bromo-5-(trifluoromethyl)phenyl)propanal
To a solution of ethyl 3-(2-bromo-5-(trifluoromethyl)phenyl)propanoate (1g, 3.08 mmol) in toluene (10 ml), DIBAL-H (9.23 ml,lM solution, 9.23 mmol) was added at -78 °C and stirred for 30 min. Reaction was monitored by TLC. After completion, the mixture was added to 2(N) HCl and extracted with ethyl acetate. The organic layer was collected and dried over Na2SO4, finally evaporated to get crude which was purified by column chromatography to obtain title compound (0.7g, 81 %). ’H NMR (400 MHz, Chloroformd) δ 9.87 (s, IH), 7.69 (dd, J = 8.4, 4.6 Hz, IH), 7.56 - 7.49 (m, IH), 7.37 (dd, J = 8.3, 2.2 Hz, IH), 3.14 (t, J= 7.5 Hz, 2H), 2.87 (t, 2H).
Step-2: 1 -Bromo-2-(3,3-difluoropropyl)-4-(trifluoromethyl)benzene
To a solution of 3-(2-bromo-5-(trifluoromethyl)phenyl)propanal (0.7 g, 2.490 mmol) in DCM (10 ml) was added DAST (1.32 ml, 9.96 mmol) at 0 °C and reaction was allowed to warm to room température and stirred for 16h. Reaction mixture was quenched slowly with sat NaHCO3 and extracted with DCM. The combined organic layer was dried over Na2SO4 and concentrared. The crude was purified by column chromatography to obtain title compound (0.25g, 33 %). 'H NMR (400 MHz, Chloroform-J) δ 7.71 (d, J= 8.3 Hz, IH), 7.51 (d, J= 2.2 Hz, IH), 7.38 (dd, J = 8.3, 2.2 Hz, IH), 5.92 (tt, J= 56.3, 4.2 Hz, IH), 3.04 - 2.95 (m, 2H), 2.30 - 2.12 (m, 2H).
Intermediate-65a/65b: (R&S)-Perfluorophenyl 4-(2-(3,3-difluoropropyl)-4(trifluoromethyl) phenyl)chroman-7-sulfonate
100
F P
cf3 cf3
The title compound was prepared by following similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-64. LCMS (ESI): m/z 625.09(M+Na)+;
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = IP A, A:B = 80:20 to afford isomer 1 and isomer 2. These isomers were obtained at rétention time: 5.02 min (Intermediate-65a) and rétention time: 5.93 min (Intermediate-65b).
In ter media te-66: 3-(2-bromo-5-(trifluoromethyl)phenoxy)oxetane
Br
CF3
It was prepared similarly as shown in Intermediate-50 using 2-bromo-5(trifluoromethyl)phenol and oxetan-3-ol. 'H NMR (400 MHz, Chloroform-d) δ 7.72 (d, J = 8.2 Hz, IH), 7.17 (dd, J= 8.3, 1.9 Hz, IH), 6.64 (d, J = 1.9 Hz, IH), 5.32quintet, J = 5.6 Hz, IH), 5.09-5.01 (m, 2H), 4.91 -4.83 (m, 2H).
Intermediate-67a/67b: (R&S)-Perfluorophenyl 4-(2-(oxetan-3-yloxy)-4(trifluoromethyl) phenyl)chroman-7-sulfonate
101
The title compound was prepared by following similar procedure as described for Intermediate-6 using Intermediate-4 and Intermediate-66. LCMS (ESI): m/z 619.03(M+Na)+;
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IC; Mobile phase: A = (Hexane + 0.1% DEA), B = IPA, A:B = 60:40, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 7.51 min (Intermediate-67a) and rétention time 8.54 min (Intermediate-67b).
Intermediate-68: 2-bromo-l-(3-fluoropropoxy)-4-(trifluoromethyl)benzene Br
CF3
3-(2-bromo-4-(trifluoromethyl)phenoxy)propan-l-ol (1g, 3.34 mmol), was dissolved in DCM (10 ml) and DAST (0.701 g, 4.35 mmol) was added at 0 °C and stirred for Ih. The reaction mixture was quenched by the addition of water and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SÜ4 and concentrated under vacuum. The crude product was purified by column chromatography to obtain the product as white gummy liquid (0.65g, 64 %). LCMS (ESI): m/z 300.05 & 302. 05(M+H)+.
Intermediate-69: Perfluorophenyl 4-(2-(3-fluoropropoxy)-4-(trifluoromethyl)phenyl) chroman-7-sulfonate
The title compound was prepared by following similar procedure as described for Intermediate-6 using Intermediate-4 and Intermediate-68. *H NMR (400 MHz, Chloroform-rZ) δ 7.52 (d, J = 2.0 Hz, 1 H), 7.39 (dd, J = 8.2, 2.0 Hz, 1 H), 7.33 -7.11 (m, 2H), 7.06 (d, J= 8.1 Hz, IH), 6.92 (d, J= 7.9 Hz, IH), 4.76 - 4.47 (m, 3H), 4.33 - 4.14 (m, 4H), 2.49 - 2.02 (m, 4H).
102
Intermediate-70: 6-(2-bromo-5-(trifluoromethyl)phenyl)-3-fluoro-2-methylpyridine
The title compound was prepared by following similar procedure as described in Intermediate-58 (Step-1 to 3) using 2-bromo-4-(trifluoromethyl)aniline and 6-bromo-35 fluoro-2-methylpyridine. 'H NMR (400 MHz, Chloroformé) δ 7.88 - 7.76 (m, 2H),
7.58 - 7.35 (m, 3H), 2.64 (d, J= 3.0 Hz, 3H).
Intermediate-71a/71b: (R&S)-Perfluorophenyl 4-(2-(5-fluoro-6-methylpyridin-2-yl)-4(trifluoro methyl)phenyl)chroman-7-sulfonate
F F
The title compound was prepared by following similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-70.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = Hexane, B = IP A, A:B = 90:10, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.33 min (Intermediate-71a) and 15 rétention time 6.82 min (Intermediate-71b).
‘H NMR (400 MHz, Chloroformé) δ 7.68 (d, J = 2.0 Hz, IH), 7.61 (dd, J = 8.1, 2.0 Hz, IH), 7.53 - 7.46 (m, 2H), 7.41 - 7.32 (m, 2H), 7.16 - 7.03 (m, 2H), 4.70 (t, J= 8.2, 6.2 Hz, IH), 4.42-4.32 (m, IH), 4.25-4.15 (m, 1 H), 2.59 (d, J= 2.9 Hz, 3H), 2.44 - 2.32 (m, IH), 2.28-2.15 (m, IH).
Intermediate-72: Perfluorophenyl 4-(2-methoxy-4-(trifluoromethyl)phenyl)chroman-7sulfonate
103
F
CF3
The title compound was prepared by following similar procedure as described in Intermediate-6 using lntermediate-4 and l-bromo-2-methoxy-4-(trifluoromethyl)benzene. 'H NMR (400 MHz, Chloroformé) δ 7.51 (d, J= 2.0 Hz, IH), 7.38 (dd, J= 8.1, 2.0 Hz, 5 1 H), 7.22 - 7.12 (m, 2H), 7.05 (d, J = 8.1 Hz, 1 H), 6.87 (d, J = 7.8 Hz, 1 H), 4.68 (t, J =
6.0 Hz, IH), 4.34-4.18 (m, 2H), 3.94 (s, 3H), 2.41 -2.26 (m, 1 H), 2.27-2.13 (m, IH).
Intermediate-73: 4-(2-Bromo-5-(trifluoromethyl)phenyl)morpholin-3-one
Br
The title compound was prepared by following similar procedure as described for 10 Intermediate-32 using 2-fluoro-l-nitro-4-(trifluoromethyl)benzene and morpholin-3-one.
'H NMR (400 MHz, Chloroformé) δ 7.85 (d, J= 8.4 Hz, IH), 7.62 - 7.49 (m, 2H), 4.41 (s, 2H), 4.15 - 4.07 (m, 2H), 3.72 (t, J = 5.0 Hz, 2H).
Intermediate-74: Perfluorophenyl 4-(2-(3-oxomorpholino)-4-(trifluoromethyl)phenyl) chroman-7-sulfonate
F
cf3
The title compound was prepared by following similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-73. LCMS (ESI): m/z 624.06(M+H)+.
104
Intermediate-75: 4-(2-bromo-5-(trifluoromethyl)phenyl)thiomorpholine 1,1-dioxide
Br ( S=O N A
CF3
Step-1:4-(2-nitro-5-(trifluoromethyl)phenyl)thiomorpholine
The title compound was prepared by following similar procedure as described in Intermediate-32 (Step-1) using 2-fluoro-l-nitro-4-(trifluoromethyl)benzene and thiomorpholine. LCMS (ESI): m/z 292.88 (M+H)+.
Step-2: 4-(2-nitro-5-(trifluoromethyl)phenyl)thiomorpholine 1,1 -dioxide
CF3
To a solution of 4-(2-nitro-5-(trifluoromethyl)phenyl)thiomorpholine (6.3g, 21.55 mmol) in MeOH (50 ml) was added solution of OXONE (26.6g, 86 mmol) in water (50 ml) at room température and stirred for 12h. After completion of reaction, as indicated by TLC, solvent was removed and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SÛ4 and concentrated to obtain title compound (5.5g, 79 %). 'H NMR (400 MHz, Chloroform-7) δ 7.95 (d, J = 8.7 Hz, IH), 7.60 - 7.49 (m, 2H), 3.71 3.54 (m, 4H), 3.34 - 3.18 (m, 4H).
Step-3: 4-(2-bromo-5-(trifluoromethyl)phenyl)thiomorpholine 1,1 -dioxide
Br S=O
CF3
105
The title compound was prepared by following similar procedure as described in Intermediate-32 (Step-2&3).
'H NMR (400 MHz, Chloroform-7) δ 7.75 (d, J= 8.3 Hz, IH), 7.36 - 7.25 (m, 2H), 3.64
- 3.56 (m, 4H), 3.34 - 3.27 (m, 4H).
Intermediate-76a/76b: (R&S)-Perfluorophenyl 4-(2-( 1,1 -dioxidothiomorpholino)-4(trifluoromethyl)phenyl)chroman-7-sulfonate
cf3 cf3
The title compounds were prepared by following similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-75.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IC; Mobile phase: A = (Hexane + 0.1% DEA), B = (IPA.DCM = 1:1), A:B = 30:70, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.94 min (Intermediate-76a) and rétention time 7.17 min (Intermediate-76b).
'H NMR (400 MHz, Chloroform-7) δ 7.59 (s, IH), 7.55 (d, J = 1.9 Hz, IH), 7.50 - 7.44 (m, IH), 7.37 (dd, 7 =8.2, 1.9 Hz, IH), 7.08 (d,7=8.2 Hz, IH), 6.87 (d,7=8.2 Hz, IH), 4.77 (d, 7= 7.6 Hz, IH), 4.46 - 4.26 (m, 2H), 3.65 - 3.34 (m, 4H), 3.31 - 3.08 (m, 4H), 2.41 -2.12 (m, 2H).
Intermediate-77: (4-chloro-2-( 1 -methyl-1 H-pyrazol-5-yl)phenyl)boronic acid
Cl
Step-1: 4-chloro-2-( 1 -methyl-1 H-pyrazol-5-yl)aniline
A solution of N-(2-bromo-4-chlorophenyl)acetamide (6g, 24.14 mmol) and l-methyl-5(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol (7.54 g, 36.2 mmol) in 1,4dioxane (80 ml): water (15 ml ) was purged with nitrogen for 5 min. after which
106 potassium phosphate (12.81g, 60.4 mmol) and PdCl2(dppf).DCM adduct (1.76g, 2.414 mmol) was added and reaction was stirred for 4h at 100 °C. Reaction was monitored by TLC. After completion, the reaction mixture was poured in to water and extracted with ethyl acetate. The organic layer was collected and dried over Na2SÛ4, finally evaporated to get crude which was heated with 60 ml conc. HCl for hydrolysis. After completion as shown by TLC the mixture was evaporated to dryness. The crude material was dissolved in water and basified with saturated sodium carbonate. The layer was extracted with ethyl acetate. The organic layer was collected and washed with brine, dried over Na2SÛ4 and evaporated. The crude was purified by column chromatography to obtain title compound (2.5g, 50%). LCMS (ESI):w/z 249.91(M+H)+.
Step-2: 5-(2-bromo-5 -chlorophenyl)-1 -methyl-1 H-pyrazole
The title compound was prepared by following similar procedure as described for Intermediate-5 (Step-2) *H NMR (400 MHz, Chloroform-J) δ 7.64 (d, J= 8.5 Hz, IH), 7.57 (d, J= 2.0 Hz, IH), 7.42 - 7.28 (m, 2H), 6.30 (d, J= 1.9 Hz, IH), 3.75 (s, 3H).
Step-3: (4-chloro-2-( 1 -methyl-1 H-pyrazol-5-yl)phenyl)boronic acid 5-(2-bromo-5-chlorophenyl)-l-methyl-1 H-pyrazole (3g, 11.05 mmol) and triisopropyl borate (3.08 ml, 13.26 mmol) was dissolved in diethyl ether (25 ml) and the solution was cooled to -78 °C. n-BuLi (8.29 ml, 1.6 M, 13.26 mmol) was added to this mixture drop wise. Following the addition, the cooling bath was removed after 30 min, and the mixture was warmed to room température. An aq. 2N NaOH solution (20 ml, 40 mmol) was added, and the resulting mixture was stirred vigorously for Ih. The mixture was diluted with water and diethyl ether. The layers were separated, and the ethereal layer was extracted with water. The combined aqueous layer was acidified with 3N aq. HCl and was extracted with ethyl acetate. The combined organic extracts were dried over Na2SÛ4, and concentrated to obtain the product as a pale yellow fluffy solid (1.5g, 63 %). *H NMR (400 MHz, Chloroform-ύΟ δ 7.95 (d, J= 8.2 Hz, IH), 7.61 - 7.38 (m, 3H), 6.36 (d, J = 10.5 Hz, IH), 3.47 (s, 3H).
Intermediate-78: 2-allyl-1 -bromo-4-(trifluoromethyl)benzene
107
Br
CF3
It was prepared from 2-allyl-4-(trifluoromethyl)aniline (OrgLett, 2012, 14(12), 3048 3051) by following similar procedure as described in Intermediate-21(Step-2). *H NMR (400 MHz, Chloroform-r/) δ 7.81 - 7.66 (m, 1H), 7.50 (d, J= 2.3 Hz, 1H), 7.48 - 7.32 (m,
1H), 5.98 (ddt, J= 16.8, 10.1, 6.5 Hz, 1 H), 5.21 (dq,J= 10.1, 1.5 Hz, 1H), 5.14 (dq, J =
17.1, 1.7 Hz, 1 H), 3.69-3.49 (m, 2H).
Intermediate-79: Perfluorophenyl 4-(2-propyl-4-(trifluoromethyl)phenyl)chroman-7sulfonate
F
CF3
The title compound was prepared by following similar procedure as described in Intermediate-6 using Intermediate-4 and Intermediate-78. *H NMR (400 MHz, Chloroform-J) δ 7.55 - 7.50 (m, 2H), 7.44 - 7.32 (m, 2H), 6.98 - 6.88 (m, 2H), 4.57 (t, J = 6.9 Hz, 1H), 4.42 - 4.27 (m, 2H), 2.89 - 2.68 (m, 2H), 2.42 - 2.32 (m, 1H), 2.22 - 2.05 (m, 1 H), 1.83 - 1.67 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H).
EXAMPLES
Example-1 and 2: (S)-A-(6-Fluoropyridin-2-yl)-4-(2-(l -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl) phenyl) chroman-7-sulfonamide and (R)-jV-(6-Fluoropyridin-2-yl)-4(2-( 1 -methyl-1 H-pyrazol-5-yl)-4-(trifluoromethyl) phenyl) chroman-7-sulfonamide
108
cf3
6-Fluoropyridin-2-amine (0.11 g, 0.993 mmol) was dissolved in THF (10 ml) and lithium bis(trimethylsilyl)amide (LiHMDS) (0.943 ml, IM in THF, 0.943 mmol) was added to it. After 10 min a solution of Intermediate-3 (0.30g, 0.496 mmol) in THF was added and the dark red reaction mixture was allowed to stir at room température for 1.5h. After completion of the reaction, it was quenched with a saturated solution of NH4CI and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a IN HCl solution and then dried over Na2SÜ4 and concentrated. The crude was purified by column chromatography to obtain the product as a white solid (0.25g, 96 %). Further the enantiomers were separated using chiral préparative HPLC (Column: Chiral pak IE; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH’.MeOH = 1:1), A:B = 50:50, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time: 5.42 min (Example-1) and rétention time 6.25 min (Example-2) and the absolute stereochemistry was assigned to be S and R, respectively, using vibrational circular dichroism (VCD) spectra. The compound having alpha configuration provided better in vitro activity against Navl .7.
Example-2
LCMS(ESI): m/z 533.07(M+H)+; *H NMR (400 MHz, DMSO-d6) δ 11.39 (s, IH), 7.86
7.74 (m, 3H), 7.52 (d, 7 = 1.9 Hz, IH), 7.35 - 7.24 (m, 3H), 6.92 (dd, 7= 13.6, 8.1 Hz, 2H), 6.71 (d, 7= 8.0 Hz, IH), 6.42 (s, IH), 4.30-4.15 (m, IH), 4.19 - 4.08 (m, 2H), 3.69 (s, 3H), 2.18 - 2.08 (m, 1 H), 2.02 - 1.90 (m, 1 H).
109
Example-3/4: (S&R)-jV-(4-Fluoropyridin-2-yl)-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl)phenyl) chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-3 and 4-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = EtOH, A:B = 50:50, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time: 5.90 min (Example-3) and rétention time 7.61 min (Example-4).
LCMS(ESI): m/z 533.07(M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 8.13 (s, IH), 7.82 7.70 (m, 2H), 7.53 (d, J = 1.9 Hz, 1 H), 7.27 (d, J = 7.3 Hz, 3H), 6.96 - 6.80 (m, 3H), 6.44 (s, IH), 4.28 - 4.19 (m, IH), 4.20-4.10 (m, 2H), 3.69 (s, 3H), 2.19 - 2.07 (m, IH), 2.03 1.89 (m, IH).
Example-5/6: (S&R)-V-(5-Fluoropyridin-2-yl )-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl)phenyl) chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-3 and 5-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: DCM =1:1), A:B = 60:40, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.83 min (Example-5) and rétention time 7.07 min (Example-6).
110
LCMS(ESI): m/z 533.06(M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 11.13 (s, IH), 8.21 (d, J =3.0 Hz, IH), 7.81-7.73 (m, 2H), 7.68 (dt, J= 8.6, 5.1 Hz, IH), 7.53 (s, IH), 7.32 - 7.23 (m, 3H), 7.17 - 7.07 (m, IH), 6.88 (d, J = 8.1 Hz, IH), 6.42 (s, IH), 4.27 - 4.18 (m, IH), 4.18-4.10 (m, 2H), 3.69 (s, 3H), 2.17-2.07 (m, 1 H), 2.04 - 1.91 (m, IH).
Example-7/8: (S&R)-7V-(5-Fluoropyrimidin-2-yl)-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl) phenyl) chroman-7-sulfonamide
cf3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-3 and 5-Fluoropyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: DCM = 1:1), A:B = 60:40, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.69 min (Example-7) and rétention time 6.91 min (Example-8).
LCMS(ESI): m/z 534.07(M+H)+; ‘H NMR (400 MHz, DMSO-d6) δ 11.88 (s, IH), 8.65 (s, 2H), 7.83 - 7.70 (m, 2H), 7.53 (d, J = 1.8 Hz, 1 H), 7.36 (d, J = 7.1 Hz, 2H), 7.28 (d, J = 8.2 Hz, 1 H), 6.90 (d, J = 8.1 Hz, 1 H), 6.44 (s, 1 H), 4.29 - 4.19 (m, 1 H), 4.20 - 4.07 (m, 2H), 3.69 (s, 3H), 2.18- 2.08 (m, 1 H), 2.03 - 1.94 (m, 1 H).
Example-9/10: (S&R)-4-(2-(l -Methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-4-yl) chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-3 and pyrimidin-4-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: DCM = l:l), A:B = 60:40, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.40 min (Example-9) and rétention time 6.68 min (Example-l0).
LCMS(ESI): m/z 5l6.06(M+H)+; *H NMR (400 MHz, DMSO-d6) δ 8.65 (s, IH), 8.36 (d, J= 6.3 Hz, IH), 7.86 - 7.72 (m, 2H), 7.53 (s, IH), 7.36 - 7.24 (m, 3H), 7.05 (d, J= 6.2 Hz, IH), 6.88 (d, J= 8.5 Hz, IH), 6.44 (s, IH), 4.28 - 4.20 (m, IH), 4.20 - 4.06 (m, 2H), 3.69 (s, 3H), 2.21 -2.05 (m, IH), 2.05 - l.9l (m, IH).
Example-11/12: (S&R)-4-(2-(l-Methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N(pyrazin-2-yl) chromane-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-3 and pyrazin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (EtOH + 0.1% TFA), B = (MeOH + 0.1% TFA), A:B = 90:10, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 9.90 min (Example-11) and rétention time 11.37 min (Example-12).
LCMS: m/z 516.04 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 11.59 (s, IH), 8.33 (s, IH), 8.22 (d, J =4.5 Hz, 2H), 7.81 - 7.73 (m, 2H), 7.52 (d, J= 1.8 Hz, IH), 7.33 (d, J = 7.6 Hz, 2H), 7.27 (d, J= 8.2 Hz, IH), 6.89 (d, J= 8.0 Hz, IH), 6.43 (s, IH), 4.23 (dt, J = 9.6, 4.2 Hz, IH), 4.18 - 4.11 (m, 2H), 3.69 (s, 3H), 2.17 - 2.08 (m, IH), 2.00 - 1.92 (m, IH).
Example-13/14: (S&R)-4-(2-(l -Methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl) chromane-7-sulfonamide
112
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-3 and pyridazin-3-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (EtOH + 0.1% TFA), B = (MeOH + 0.1% TFA), A:B = 50:50, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 10.62 min (Example-13) and rétention time 12.34 min (Example-14).
LCMS: m/z 516.19 (M+H)+; *H NMR (400 MHz, DMSO-d6) δ 8.34 (s, IH), 7.83 - 7.71 (m, 3H), 7.66 - 7.59 (m, IH), 7.54 (d, J= 1.9 Hz, IH), 7.32 - 7.20 (m, 3H), 6.83 (d, J = 8.3 Hz, IH), 6.46 (s, IH), 4.26 - 4.18 (m, IH), 4.16 - 4.09 (m, 2H), 3.70 (s, 3H), 2.14 2.10 (m, 1 H), 1.98 - 1.90 (m, IH).
Example-15/16: (S&R)-4-(2-(l-Methyl-l//-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-A(pyrimidin-2-yl) chromane-7-sulfonamide
CF3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-3 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: MeOH = 1:1), A:B = 40:60, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.10 min (Example-15) and rétention time 6.78 min (Example-16).
LCMS: m/z 516.19 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 11.76 (s, IH), 8.53 (d, J = 4.9 Hz, 2H), 7.82 - 7.73 (m, 2H), 7.53 (d, J= 1.8 Hz, IH), 7.37 (d, J= 8.3 Hz, 2H), 7.28
113 (d, J= 8.2 Hz, IH), 7.08 (s, IH), 6.89 (d, J= 8.1 Hz, IH), 6.44 (s, IH), 4.28 -4.20 (m, IH), 4.20-4.08 (m, 2H), 3.70 (s, 3H), 2.19 -2.07 (m, IH), 2.02 - 1.91 (m, IH).
Example-17/18: (S&R)-A-(3-Fluoropyridm-2-yl)-4-(2-(l -methyi-1 H-pyrazol-5-yl)-4(trifluoromethyl)phenyl) chromane-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-3 and 3-Fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: MeOH = 1:1), A:B = 60:40 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 8.39 min (Example-17) and rétention time 9.66 min (Example-18).
LCMS: m/z 533.07 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 8.05 - 7.97 (m, IH), 7.83 - 7.76 (m, 2H), 7.75 - 7.66 (m, IH), 7.54 (d, J = 1.8 Hz, IH), 7.38 (s, 2H), 7.28 (d, J = 8.2 Hz, 1 H), 7.15 - 7.06 (m, IH), 6.90 (d, J = 8.1 Hz, IH), 6.46 (s, IH), 4.28 - 4.20 (m, 1 H), 4.19 - 4.09 (m, 2H), 3.70 (s, 3H), 2.20 - 2.09 (m, IH), 2.04 - 1.94 (m, IH).
Example-19/20: (S&R)-4-(2-(l-methyi-lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N(6-methylpyridin-2-yl)chroman-7-sulfonamide
CF3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-3 and 6-methylpyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: MeOH =1:1), A:B
114
- 70:30, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 8.10 min (Example-19) and rétention time 9.29 min (Example-20).
LCMS(ESI): m/z 529.21(M+H)+; 'H NMR (400 MHz, Chloroformé) δ 7.64 (d, J= 8.3 Hz, IH), 7.61 -7.53 (m, 3H), 7.46 (d, J= 1.8 Hz, IH), 7.38 (dd, J= 8.1, 1.9 Hz, IH), 7.18 (d, 7= 8.2 Hz, IH), 7.08 (d, 7= 8.7 Hz, IH), 6.78 (d,7= 8.1 Hz, IH), 6.65 (d,7 = 7.3 Hz, IH), 6.31 (d, 7= 1.9 Hz, IH), 4.28 - 4.13 (m, 2H), 4.20-4.10 (m, IH), 3.77 (s, 3H), 2.48 (s, 3H), 2.13-1.93 (m, 2H).
Example-21/22: (S&R)-4-(2-(l-methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N(5-methylpyridin-2-yl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-3 and 5-methylpyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: MeOH = 1:1), A:B = 40:60, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.16 min (Example-21) and rétention time 8.91 min (Example-22).
LCMS(ESI): m/z 529.07(M+H)+; lH NMR (400 MHz, DMSOé6) δ 7.91 - 7.72 (m, 3H), 7.60-7.51 (m, 2H), 7.30-7.21 (m, 3H), 7.10 (d, 7= 8.7 Hz, IH), 6.84 (d,7=8.1 Hz, IH), 6.44 (s, IH), 4.25 - 4.18 (m, 1 H), 4.15 - 4.07 (m, 2H), 3.69 (s, 3H), 2.14 (s, 3H), 2.13 - 2.08 (m, 1 H), 1.98 - 1.90 (m, 1 H).
Example-23/24: (S&R)-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N(4-methylpyridin-2-yl)chroman-7-sulfonamide
115
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-3 and 4-methylpyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: MeOH = l:l), A:B = 60:40, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time
7.26 min (Example-23) and rétention time 8.32 min (Example-24).
LCMS(ESI): m/z 529.07(M+H)+; 'H NMR (400 MHz, DMSO-76) δ 7.86 - 7.73 (m, 3H), 7.53 (d, J= 1.8 Hz, IH), 7.30-7.21 (m, 3H), 7.04 (s, IH), 6.83 (d, J= 8.0 Hz, IH), 6.69 (s, IH), 6.45 (s, IH), 4.25 - 4.17 (m, IH), 4.16 - 4.08 (m, 2H), 3.70 (s, 3H), 2.25 (s, 3H), 2.17-1.88 (m, 2H).
Example-25/26: (S&R)-N-(6-isopropoxypyridin-2-yl)-4-(2-(l-methyl-lH-pyrazol-5-yl)4-(trifluoromethyl)phenyl)chroman-7-sulfonamide
To a stirred solution N-(6-fluoropyridin-2-yl)-4-(2-(l -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide (racemic mixture of Example-1/2) (Ig, 1.878 mmol) in 2-Propanol (10 ml) was added KOH (0.74g, 13.15 mmol). This was heated at 80 °C for I2h. The solvent was evaporated from the reaction mixture and the residue was partitioned between ethyl acetate and water. The combined organic layer was wahed with brine, dried over Na2SÛ4 and concentrated under vacuum. The crude was further purified by column chromatography to obtain mixture of isomers ((0.15g, 15 %).
116
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH), A:B = 80:20, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 8.04 min (Example-25) and rétention time 8.97 min (Example-26).
LCMS(ESI): m/z 573.12(M+H)+; *H NMR (400 MHz, DMSO-76) δ 11.02 (s, IH), 7.78 (d, J = 10.2 Hz, 2H), 7.58 - 7.46 (m, 2H), 7.35 - 7.21 (m, 3H), 6.89 (d, J = 8.0 Hz, IH), 6.48 - 6.40 (m, 2H), 6.28 (d, J = 8.1 Hz, IH), 4.85-4.77 (m, IH), 4.32 - 4.20 (m, lH),3.69(s, 3H), 4.19-4.04 (m, 2H), 2.23 - 1.90 (m, 2H), 1.13 (d, 7= 6.2 Hz, 3H), 1.10 (d, 7=6.1 Hz, 3H).
Example-27/28: (S&R)-N-(2-fluoropyridin-3-yl)-4-(2-( 1 -methyl-lH-pyrazol-5-yl)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-3 and 2-fluoropyridin-3-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: MeOH = 1:1), A:B = 70:30, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.09 min (Example-27) and rétention time 7.06 min (Example-28).
LCMS(ESI): m/z 533.07(M+H)+; 'H NMR (400 MHz, DMSO-4) δ 10.53 (s, IH), 7.99 (d, 7 = 4.8 Hz, IH), 7.83 - 7.72 (m, 3H), 7.54 (d, 7= 1.8 Hz, IH), 7.36 - 7.21 (m, 2H), 7.18 - 7.11 (m, 2H), 6.91 (d,7= 7.9 Hz, IH), 6.43 (s, IH), 4.28-4.09 (m, 3H), 3.69 (s, 3H), 2.20- 1.92 (m, 2H).
Example-29/30: (S&R)-4-(2-(l-methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N(4-methylpyrimidin-2-yl)chroman-7-sulfonamide
117
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-3 and 4-methylpyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: MeOH = 1:1), A:B = 50:50, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 9.41 min (Example-29) and rétention time 11.60 min (Example-30).
LCMS(ESI): m/z 530.08(M+H)+; 'H NMR (400 MHz, DMSO-t/6) δ 8.28 (s, IH), 7.82 7.72 (m, 2H), 7.53 (s, IH), 7.40 - 7.20 (m, 3H), 6.93 - 6.78 (m, 2H), 6.45 (s, IH), 4.25 4.06 (m, 3H), 3.70 (s, 3H),2.28(s, 3H), 2.17-1.90 (m, 2H).
Example-31/32 : (S&R)-4-(4-chloro-2-( 1 -methyl-1 H-pyrazol-5-yl)phenyl)-N-(6fluoropyridin-2-yl)chroman-7-sulfonamide
OH
7-bromo-4-hydroxy-2H-chromen-2-one (100g, 415 mmol) was dissolved in 1,4-dioxane (1.2 lit) and the solution was degassed by passing nitrogen and then, Xanthphos (12g, 20.74 mmol), Pd2(dba)3 (9.5g, 10.37 mmol), Hunig's base (145 ml, 830 mmol) and benzyl mercaptan (47 ml, 394 mmol) was added in a reaction mass and heated at 80 °C for 2h. Solvent was removed under vacuum and crude reaction mixture was suspended in 50 ml
118 of DMF and added to an ice cold water with vigorous stirring, after 15 min aqueous layer was carefully acidified till pH= 5-4 and filtered off. The residue was washed with 500 ml of water and dried under vacuum. Dry residue was then suspended in 500 ml of acetone, filtered and dried under vacuum. LCMS (ESI): m/z 285.27(M+H)+.
Step-2: 7-(benzylthio)-2-oxo-2H-chromen-4-yl trifluoromethanesulfonate
OTf
To a solution of 7-(benzylthio)-4-hydroxy-2H-chromen-2-one (Step-1) (25g, 88 mmol) in DCM (250 ml) was added TEA (36.8 ml, 264 mmol) followed by triflic anhydride (36.9 ml, 220 mmol) dropwise at 0-5 °C and stirred under nitrogen at same température for Ih. Ice cold water was added to stirred reaction mixture and diluted with DCM; organic layer was separated and washed with 2N HCl solution. Combined organic layer was dried over Na2SO4 and concentrated under vacuum. The crude was triturated with 100 ml of MeOH and filtered to obtain title compound (29.5g, 81 %). LCMS (ESI): m/z 416.91(M+H)+.
Step-3: 7-(benzylthio)-4-(4-chloro-2-(l-methyl-lH-pyrazol-5-yl)phenyl)-2H-chromen-2one
Cl
A solution of 7-(benzylthio)-2-oxo-2H-chromen-4-yl trifluoromethanesulfonate (Step-2) (3.8g, 9.13 mmol) and (4-chloro-2-( 1 -methyl-1 H-pyrazol-5-yl)phenyl)boronic acid (2.16g, 9.13 mmol) in 1,4-dioxane (20 ml) was purged with nitrogen after which potassium phosphate (4.84g, 22.82 mmol) and PdCl2(dppf) (0.67g, 0.913 mmol) was added. The reaction mixture was stirred for Ih at 80 °C. After completion of reaction as indicated by TLC, the mixture was poured into water and extracted with ethyl acetate. The organic layer was collected and dried over Na2SO4, and evaporated. The crude was purified by column chromatography to obtain title compound (2.6g, 62 %). *H NMR (400 MHz, Chloroform-J) δ 7.59 (dd, J = 8.2, 2.2 Hz, IH), 7.49 (d, J = 2.1 Hz, IH), 7.41
119
7.31 (m, 7H), 7.18 (d, J= 1.8 Hz, 1H), 7.01 (dd,J=8.5, 1.9 Hz, 1H), 6.92 (d,J=8.4 Hz, 1H), 6.12 (s, 1H), 6.01 (d,J=2.0 Hz, 1H), 4.21 (d,J=7.2 Hz, 2H), 3.68 (s, 3H).
Step-4: 5-(benzylthio)-2-( 1 -(4-chloro-2-( 1 -methyl-1 H-pyrazol-5-yl)phenyl)-3 hydroxypropyl)phenol
Cl
A solution of 7-(benzylthio)-4-(4-chloro-2-(l -methyl-1 H-pyrazol-5-yl )phenyl)-2Hchromen-2-one (Step-3) (2.6g, 5.66 mmol), cobalt(II)chloride hexahydrate (0.14g, 0.566 mmol) in DMF (0.5 ml):EtOH (2 ml) stirred for 30 min at room température and then cooled to 0 °C. NaBH4 (0.86g, 22.66 mmol) was added at 0 °C and stined for 16h. Reaction mixture was quenched by adding water and partitioned between ethyl acetate and water. Organic phase was washed with brine, dried over Na2SÛ4 and concentrated. The crude was purified by flash chromatography to obtain title compound (1g, 38 %). LCMS (ESI): m/z 465.23(M+H)+.
Step-5: 5-(2-(7-(benzylthio)chroman-4-yl)-5-chlorophenyl)-l-methyl-lH-pyrazole
Cl
To a solution of 5-(benzylthio)-2-(l-(4-chloro-2-(l-methyl-lH-pyrazol-5-yl)phenyl)-3hydroxypropyl)phenol (0.65g, 1.398 mmol) in THF (15 ml), triphenylphosphine(0.55g, 2.097 mmol) was added and cooled to 0 °C followed by DEAD (0.33 ml, 2.097 mmol) was added dropwise and stirred for 1 h. After completion the mixture was added to water and extracted with ethyl acetate. The organic layer was collected and dried over Na2SO4 and evaporated under vacuum. The crude was purified by column chromatography to obtain title compound (0.43g, 68 %). LCMS (ESI): m/z 447.23(M+H)+.
120
Step-6: Perfluorophenyl 4-(4-chloro-2-( 1 -methyl-1 H-pyrazol-5-yl)phenyl)chroman-7 sulfonate
Cl
The title compound was prepared by following similar procedure as described for Intermediate-3 (Step-2), using step-5 intermediate. LCMS (ESI): m/z 571.01(M+H)+.
Step-7: (S&R)-4-(4-chloro-2-( 1 -methyl-1 H-pyrazol-5-yl)phenyl)-N-(6-fluoropyridin-2yl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1 and 2 using Step-6 intermediate and 6-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: MeOH = 1:1), A:B = 50:50, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.24 min (Example-31) and rétention time 6.96 min (Example-32).
LCMS(ESI): m/z 499.30(M+H)+; *H NMR (400 MHz, DMSO-76) δ 11.38 (s, IH), 7.91 7.83 (m, 1 H), 7.51 - 7.44 (m, 3H), 7.36 - 7.28 (m, 2H), 7.08 - 7.03 (m, 1 H), 6.97 (dd, J = 8.0, 2.1 Hz, IH), 6.90 (d, J= 8.5 Hz, IH), 6.77 (dd, 7= 8.0, 2.3 Hz, IH), 6.36 (s, IH), 4.27-4.00 (m, 3H), 3.69 (s, 3H), 2.14-1.87 (m, 2H).
Example-33/34: (S&R)-N-(6-fluoropyridin-2-yl)-4-(4-isopropoxy-2-(l -methyl- 1Hpyrazol-5-yl)phenyl)chroman-7-sulfonamide
Ύ° Ύ°
121
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-8 and 6-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: MeOH = 1:1), A:B = 50:50, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.43 min (Example-33) and rétention time 7.23 min (Example-34).
LCMS(ESI): m/z 523.19(M+H)+; 'H NMR (400 MHz, DMSO-t/6) δ 11.37 (s, IH), 7.93 7.81 (m, IH), 7.46 (d, J= 1.8 Hz, IH), 7.31 (d,J=7.0Hz, 2H), 7.04-6.82 (m, 5H), 6.76 (dd, J = 8.0, 2.4 Hz, 1 H), 6.30 (s, 1 H), 4.70 - 4.59 (m, 1 H), 4.27 - 4.17 (m, 1 H), 4.163.90 (m, 2H), 3.69 (s, 3H), 2.09-2.00 (m, IH), 1.95 - 1.86 (m, IH), 1.26 (d, J= 6.0 Hz, 6H).
Example-35/36: (S&R)-4-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-A(pyrimidin-2-yl)chromane-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-6 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: MeOH + 0.1% TFA, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 4.43 min (Example-35) and rétention time 5.09 min (Example-36).
LCMS: m/z 531.09 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 11.79 (s, IH), 8.52 (d, J = 4.9 Hz, 2H), 8.38 (d, J= 2.5 Hz, 1 H), 8.15 (td, J = 8.1, 2.5 Hz, IH), 7.73 (dd, J = 8.4, 2.0 Hz, IH), 7.70 - 7.65 (m, IH), 7.40 - 7.29 (m, 3H), 7.24 (d, J = 8.2 Hz, IH), 7.07 (t, J = 4.9 Hz, IH), 6.96 (d, J= 8.1 Hz, IH), 4.28 - 4.18 (m, 2H), 4.18 - 4.08 (m, IH), 2.18 2.08 (m, IH), 2.02- 1.96 (m, IH).
Example-37 /38: (S&R)-4-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-?/-(5fluoropyrimidin-2-yl) chromane-7-sulfonamide
122
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-6 and 5-Fluoropyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 50:50, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.73 min (Example-37) and rétention time 7.58 min (Example-38).
LCMS: m/z 549.08 (M+H)+; ‘H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 2H), 8.38 (d, J = 2.5 Hz, IH), 8.15 (td, J= 8.2, 2.5 Hz, IH), 7.73 (dd, J= 8.4, 2.0 Hz, IH), 7.67 (d, J= 2.0 Hz, IH), 7.34 - 7.26 (m, 3H), 7.24 (d, J= 8.2 Hz, IH), 6.89 (d, J= 8.0 Hz, IH), 4.27 4.17 (m, 2H), 4.14 - 4.07 (m, IH), 2.18 - 2.09 (m, IH), 2.01 - 1.97 (m, IH).
Example-39/40: (S&R)-4-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-4-yl)chromane-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-6 and Pyrimidin-4-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (MeOH: DCM = 1:1), A:B = 70:30, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.30 min (Example-39) and rétention time 7.72 min (Example-40).
LCMS: m/z 530.82 (M+H)+; ‘H NMR (400 MHz, DMSO-d6) δ 8.64 (s, IH), 8.43 - 8.31 (m, 2H), 8.15 (td, J = 8.2, 2.5 Hz, IH), 7.73 (dd, J= 8.3, 2.1 Hz, IH), 7.70-7.67 (m, IH),
123
7.36 - 7.27 (m, 3H), 7.25 (d, J= 8.2 Hz, IH), 7.04 (s, IH), 6.96 (d, J= 8.6 Hz, IH), 4.29 4.18 (m, 2H), 4.18 - 4.08 (m, IH), 2.18 - 2.10 (m, IH), 2.04 - 1.94 (m, IH).
Example-41/42: (S&R)-4-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl)chromane-7-sulfonamide
cf3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-6 and pyridazin-3-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 50:50, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.62 min (Example-41) and rétention time 7.76 min (Example-42).
LCMS: m/z 531.02 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J= 2.4 Hz, IH), 8.34 (s, IH), 8.15 (td, J =8.1, 2.5 Hz, IH), 7.81 -7.71 (m, 2H), 7.68 (d,J=2.0 Hz, IH), 7.62 (dd, J= 9.6, 4.1 Hz, IH), 7.32 (dd, J= 8.4, 2.7 Hz, IH), 7.28 - 7.19 (m, 3H), 6.90 (d, J= 8.5 Hz, IH), 4.26 - 4.17 (m, 2H), 4.16 - 4.08 (m, IH), 2.19 - 2.08 (m, IH), 2.03 - 1.94 (m, IH).
Example-43/44: (S&R)-4-(4'-Fluoro-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-2-yl)-N(pyrimidin-2-yl)chromane-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-10 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% TFA), B = (MeOH: DCM = 1:1), A:B
124 = 60:40, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.91 min (Example-43) and rétention time 7.81 min (Example-44).
LCMS: m/z 530.19 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 11.76 (s, IH), 8.53 (d, J = 4.9 Hz, 2H), 7.72 - 7.65 (m, IH), 7.61 - 7.49 (m, 3H), 7.43 - 7.27 (m, 4H), 7.21 (d, J= 8.2 Hz, 1 H), 7.13 - 7.04 (m, 1 H), 6.93 (d, J = 8.4 Hz, 1 H), 4.37 - 4.19 (m, 2H), 4.19 — 4.01 (m, IH), 2.16-2.07 (m, IH), 2.05 - 1.99 (m, IH).
Example-45/46: (S&R)-4-(4'-Fluoro-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-2-yl)-N-(5fluoropyrimidin-2-yl) chromane-7-sulfonamide
cf3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-10 and 5-fluoropyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% DEA), B = (MeOH: DCM = 1:1), A:B = 70:30, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.93 min (Example-45) and rétention time 8.01 min (Example-46).
LCMS: m/z 547.99 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 11.88 (s, IH), 8.65 (s, 2H), 7.69 (d, J = 8.2 Hz, IH), 7.62 - 7.47 (m, 3H), 7.44 - 7.28 (m, 4H), 7.21 (d, J = 8.3 Hz, IH), 6.93 (d, J= 8.4 Hz, IH), 4.35 - 4.18 (m, 2H), 4.18 - 4.01 (m, IH), 2.13 - 2.06 (m, IH), 2.04- 1.95 (m, IH).
Example-47/48: (S&R)-4-(4'-Fluoro-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-2-yl)-N(pyrimidin-4-yl)chromane-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-10 and pyrimidin-4-amine.
125
I
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% DEA), B = (MeOH: DCM = 1:1), A:B = 70:30, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 7.83 min (Example-47) and rétention time 8.97 min (Example-48).
LCMS: m/z 529.97 (M+H)+; *H NMR (400 MHz, DMSO-d6) δ 8.65 (s, IH), 8.37 (s, IH), 7.69 (d, J = 8.3 Hz, IH), 7.62 - 7.48 (m, 3H), 7.43 - 7.26 (m, 4H), 7.22 (d, J = 8.3 Hz, IH), 7.05 (s, IH), 6.92 (d, J= 8.3 Hz, IH), 4.35-4.17 (m, 2H), 4.14 - 4.10 (m, IH), 2.11 - 2.09 (m, IH), 2.08- 1.94 (m, IH).
Example-49/50: (S&R)-4-(4'-Fluoro-5-(trifluoromethyl)-[l,l'-biphenyl]-2-yl)-N-(6fluoropyridin-2-yl) chromane-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-10 and 6-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% DEA), B = (MeOH: DCM = 1:1), A:B = 85:15, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 9.22 min (Example-49) and rétention time 10.00 min (Example-50).
LCMS: m/z 547.00 (M+H)+; *H NMR (400 MHz, DMSO-d6) δ 11.38 (s, IH), 7.87 (dd, IH), 7.68 (d, J= 8.3 Hz, IH), 7.61 - 7.47 (m, 3H), 7.32 (d, J= 8.6 Hz, 4H), 7.20 (d, J = 8.2 Hz, IH), 7.05 - 6.87 (m, 2H), 6.80 - 6.67 (m, IH), 4.33 - 4.16 (m, 2H), 4.16 - 4.06 (m, 1 H), 2.13 - 2.04 (m, 1 H), 2.04 - 1.96 (m, 1 H).
Example-51/52: (S&R)-4-(2-(l/Z-l,2,3-Triazol-l-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chromane-7-sulfonamide
126
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-12 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 50:50 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.04 min (Example-51) and rétention time 8.32 min (Example-52).
LCMS: m/z 502.98 (M+H)+; *H NMR (400 MHz, DMSO-d6) δ 11.84 (s, IH), 8.67 (s, IH), 8.49 (d, J = 4.9 Hz, 2H), 8.02 - 7.96 (m, 2H), 7.93 - 7.88 (m, IH), 7.43 - 7.34 (m, 3H), 7.05 - 6.98 (m, 1 H), 6.92 (d, J = 8.6 Hz, 1 H), 4.26 - 4.19 (m, 1 H), 4.16- 4.07 (m, IH), 4.04-3.97 (m, IH), 2.22-2.12 (m, 1 H), 2.09 -2.01 (m, IH).
Example-53/54: (S&R)-4-(2-(l/f-l,2,3-Triazol-l-yl)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl)chromane-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in
Example-1/2 using Intermediate-12 and pyridazin-3-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 50:50 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time
6.00 min (Example-53) and rétention time 7.33 min (Example-54).
LCMS: m/z 502.96 (M+H)+; ‘H NMR (400 MHz, DMSO-d6) δ 14.54 (s, IH), 8.69 (s, IH), 8.31 (s, IH), 8.05 - 7.96 (m, 2H), 7.94-7.84 (m, 2H), 7.75 - 7.66 (m, IH), 7.40 (d,
127
J = 8.3 Hz, 1 H), 7.25 (d, J = 9.4 Hz, 2H), 6.90 (d, J = 7.9 Hz, 1 H), 4.27 - 4.19 (m, 1 H), 4.15-4.07 (m, IH), 4.03-3.97 (m, IH), 2.21 -2.12 (m, IH), 2.09-2.00 (m, IH).
Example-55/56: (S&R)-4-(2-( 1 H-1,2,3-Triazol-1 -yl)-4-(trifluoromethyl)phenyl)-7V-(5fluoro pyrimidin-2-yl) chromane-7-sulfonamide
cf3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-12 and 5-fluoropyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 50:50 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.53 min (Example-55) and rétention time 7.82 min (Example-56).
LCMS: m/z 520.98 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 11.89 (s, IH), 8.70 - 8.63 (m, 3H), 8.00 (d, J = 7.4 Hz, 2H), 7.91 (d, J = 8.3 Hz, 1 H), 7.44 - 7.34 (m, 3H), 6.96 (d, J = 8.5 Hz, 1 H), 4.30 - 4.20 (m, 1 H), 4.18 - 4.08 (m, 1 H), 4.02 (t, J = 7.2 Hz, 1 H), 2.20 2.15 (m, 1 H), 2.09- 1.99 (m, 1 H).
Example-57/58: (S&R)-4-(2-( 1//-1,2,3-Triazol-l-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin -4-yl)chromane-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-12 and pyrimidin-4-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B =
128
50:50 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.18 min (Example-57) and rétention time 7.17 min (Example-58).
LCMS: m/z 502.94 (M+H)+; ’H NMR (400 MHz, DMSO-d6) δ 8.66 - 8.58 (m, 2H), 8.30 (s, 1H), 7.97 (d,J= 11.7 Hz, 2H), 7.91 (dd, 7=8.3, 1.9 Hz, 1H), 7.40 (d, 7 = 8.3 Hz, 1H), 7.34 - 7.26 (m, 2H), 7.01 (s, 1H), 6.91 (d, J= 8.0 Hz, 1H), 4.27 - 4.19 (m, 1H), 4.10 (t, J = 9.9 Hz, 1 H), 3.99 (t,7=7.4 Hz, 1H), 2.18 - 2.14 (m, 1H), 2.10-1.96 (m, 1H).
Example-59/60: (S&R)-4-(2-( 17/-1,2,3-Triazol-l-yl)-4-(trifluoromethyl)phenyl)-N-(6fluoropyridin-2-yl) chromane-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-12 and 6-fluoropyridin-2-amine.
The enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: MeOH = 1:1), A:B = 60:40 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.40 min (Example-59) and rétention time 6.20 min (Example-60).
LCMS: m/z 520.02 (M+H)+; lH NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 8.66 (s, 1H), 7.99 (d, J= 4.2 Hz, 2H), 7.94 - 7.81 (m, 2H), 7.43 - 7.30 (m, 3H), 6.97 (d, J= 8.1 Hz, 2H), 6.77 (dd, J = 8.2, 2.3 Hz, 1 H), 4.29 - 4.19 (m, 1 H), 4.13 (t, J = 10.1 Hz, 1 H), 4.02 (t, J = 7.4 Hz, 1 H), 2.22 - 2.13 (m, 1 H), 2.11 - 1.97 (m, 1 H).
Example-61/62: (S&R)-A-(6-Fluoropyridin-2-yl)-4-(2-(2-methylthiazol-4-yl)-4-(trifluoro methyl)phenyl) chroman-7-sulfonamide
129
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-14 and 6-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: MeOH = 1:1), A:B = 70:30 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.99 min (Example-61) and rétention time 7.00 min (Example-62).
LCMS(ESI): m/z 549.95(M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 11.38 (s, IH), 7.87 (d, J= 8.2 Hz, IH), 7.85 - 7.78 (m, 2H), 7.67 (d, J= 8.3 Hz, IH), 7.36 (d, J= 1.9 Hz, IH), 7.35 -7.27 (m, IH), 7.19 (d, J= 8.2 Hz, IH), 7.01 -6.93 (m, IH), 6.89 (d, 7= 8.1 Hz, IH), 6.81 - 6.70 (m, IH), 4.86 (t, IH), 4.30-4.15(m, 2H), 2.69 (s, 3H), 2.31 - 2.16 (m, 1 H), 2.14-2.02 (m, IH).
Example-63/64: (S&R)-4-(2-(2-Methylthiazol-4-yl)-4-(trifluoromethyl)phenyl)-7V(pyrimidin-2-yl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-14 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (MeOH: DCM = 1:1), A:B = 70:30 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 7.36 min (Example-63) and rétention time 8.21 min (Example-64).
LCMS(ESI): m/z 533.07(M+H)+; ’H NMR (400 MHz, DMSO-d6) δ 11.74 (s, IH), 8.608.50 (m, 2H), 7.85-7.80 (m, 2H), 7.68 (d, 7= 8.6 Hz, IH), 7.45-7.35 (m, 2H), 7.20 (d, 7 = 8.3 Hz, IH), 7.09 (s, IH), 6.87 (d, 7= 8.2 Hz, IH), 4.87 (t,7=7.2 Hz, IH), 4.26-4.15 (m, 2H), 2.70 (s, 3H), 2.29 - 2.20 (m, IH), 2.09 - 2.04 (m, IH).
Example-65/66: (S&R)-/V-(5-Fluoropyrimidin-2-yl)-4-(2-(2-methylthiazol-4-yl)-4(trifluoro methyl)phenyl) chroman-7-sulfonamide
130
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-14 and 5-fluoropyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (MeOH: DCM = 1:1), A:B = 75:25 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 7.06 min (Example-65) and rétention time 8.00 min (Example-66).
LCMS(ESI): m/z 550.70 (M+H)+; *H NMR (400 MHz, DMSO-d6) δ 11.88 (s, IH), 8.65 (s, 2H), 7.89 - 7.77 (m, 2H), 7.68 (dd, J= 8.2, 2.1 Hz, IH), 7.44 - 7.31 (m, 2H), 7.20 (d, 7=8.2 Hz, IH), 6.87 (d,7=8.I Hz, 1H),4.91 -4.82 (m, 1 H), 4.29 - 4.14 (m, 2H), 2.70 (s, 3H), 2.31 - 1.99 (m, 2H).
Example-67/68: (S&R)-4-(2-(2-Methylthiazol-4-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-4-yl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-14 and pyrimidin-4-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (MeOH: DCM = 1:1), A:B = 75:25 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.82 min (Example-67) and rétention time 7.72 min (Example-68).
LCMS (ESI): m/z 533.06(M+H)+; lH NMR (400 MHz, DMSO-76) δ 8.66 (s, IH), 8.37 (s, IH), 7.85 - 7.79 (m, 2H), 7.72 - 7.64 (m, IH), 7.35 - 7.27 (m, 2H), 7.20 (d, 7= 8.3 Hz,
131
IH), 7.06 (s, IH), 6.86 (d, J= 8.0 Hz, IH), 4.86 (t, 7 = 7.3 Hz, IH), 4.27 - 4.15 (m, 2H), 2.70 (s, 3H), 2.27-2.18 (m, 1 H), 2.09 - 2.04 (m, IH).
Example-69/70: (S&R)-4-(2-(2-Methylthiazol-4-yl)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-14 and pyridazin-3-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (MeOH: DCM = 1:1), A:B = 75:25 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 9.94 min (Example-69) and rétention time 10.92 min (Example-70).
LCMS (ESI): m/z 533.08 (M+H)+; *H NMR (400 MHz, DMSO-d6) δ 8.33 (s, IH), 7.94 7.81 (m, 3H), 7.75 - 7.65 (m, 2H), 7.29 - 7.17 (m, 3H), 6.83 (d, J= 8.0 Hz, IH), 4.85 (t, J = 7.1 Hz, IH), 4.29-4.12 (m, 2H), 2.71 (s, 3H), 2.27 - 2.06 (m, 2H).
ExampIe-71/72: (S&R)-A-(5-Fluoropyrimidin-2-yl)-4-(2-(2-methyloxazol-4-yl)-4(trifluoro methyl) phenyl) chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-16 and 5-fluoropyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IF; Mobile phase: A = (Hexane + 0.1% TFA), B = (MeOH: DCM = 1:1), A:B = 70:30 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.59 min (Example-71) and rétention time 7.90 min (Example-72).
132
LCMS (ESI): m/z 534.82(M+H)+; 'H NMR (400 MHz, DMSOé6) δ 11.89 (s, IH), 8.66 (s, 2H), 8.43 (s, IH), 8.01 (s, 1 H), 7.64 (d, .7=8.2 Hz, IH), 7.45-7.32 (m, 2H), 7.14 (d, J = 8.2 Hz, IH), 6.90 (d, J = 8.1 Hz, IH), 4.91 (t, J = 6.7 Hz, IH), 4.30 - 4.15 (m, 2H),2.48(s,3H), 2.36-2.25 (m, 1 H), 2.06 - 1.95 (m, IH).
Example-73/74: (S&R)-/V-(6-Fluoropyridin-2-yl)-4-(2-(2-methyloxazol-4-yl)-4-(trifluoro methyl)phenyl) chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-16 and 6-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IF; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: MeOH = 1:1), A:B = 60:40 to afford rétention time 6.06 min (Example-73) and rétention time 7.73 min (Example-74).
LCMS (ESI): m/z 534.07 (M+H)+; ‘H NMR (400 MHz, Chloroformé) δ 7.83 - 7.69 (m, 3H), 7.52 (d, J = 8.3 Hz, IH), 7.44 (d, J = 2.0 Hz, IH), 7.34 - 7.23 (m, 2H), 7.05 (d, J = 8.2 Hz, IH), 6.89 (d, J=8.2 Hz, IH), 6.64 (dd, J =8.0, 2.3 Hz, IH), 4.89 (t, J =6.9 Hz, IH), 4.33 - 4.10 (m, 2H), 2.55 (s, 3H), 2.36 - 2.28 (m, IH), 2.12 - 2.05 (m, IH).
Example-75/76: (S&R)-4-(2-(2-methyloxazol-4-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide
CF3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-16 and pyrimidin-2-amine.
133
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (MeOH: DCM = 1:1), A:B = 70:30 to afford rétention time 7.82 min (Example-75) and rétention time 8.96 min (Example-76).
LCMS (ESI): m/z 517.04(M+H)+; 'H NMR (400 MHz, DMSO-J6) δ 11.76 (s, IH), 8.61 8.51 (m, 2H), 8.44 (s, IH), 8.01 (d, J= 1.9 Hz, IH), 7.64 (d, J = 7.9 Hz, IH), 7.46-7.34 (m, 2H), 7.18 - 7.06 (m, 2H), 6.89 (d, J = 8.2 Hz, IH), 4.91 (t, J = 6.7 Hz, IH), 4.28 4.16 (m, 2H),2.5(s, 3H), 2.37- 1.95 (m, 2H).
Example-77/78: (S&R)-4-(2-(2-methyloxazol-4-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-4-yl)chroman-7-sulfonamide
CF3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-16 and pyrimidin-4-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (MeOH: DCM = 1:1), A:B = 75:25 to afford rétention time 7.19 min (Example-77) and rétention time 8.12 min (Example-78).
LCMS (ESI): m/z 516.82(M+H)+; 'H NMR (400 MHz, DMSO-J6) δ 8.66 (s, IH), 8.44 (s, IH), 8.37 (s, IH), 8.00 (d, J= 2.0 Hz, IH), 7.64 (d, J= 8.3 Hz, IH), 7.39 - 7.29 (m, 2H), 7.17 - 7.02 (m, 2H), 6.88 (d, J = 8.1 Hz, IH), 4.90 (t, J = 6.8 Hz, IH), 4.23 (d, J = 10.7 Hz, 2H), 2.53 (s, 3H), 2.30-2.00 (m, 2H).
Example-79/80: (S&R)-4-(2-(2-methyloxazol-4-yl)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl)chroman-7-sulfonamide
134
cf3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-16 and pyridazin-3-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (MeOH: DCM = 1:1), A:B = 70:30 to afford rétention time 7.71 min (Example-79) and rétention time 8.58 min (Example-80).
LCMS (ESI): m/z 516.82(M+H)+; *H NMR (400 MHz, DMSO-d6) δ 14.53 (s, IH), 8.44 (s, IH), 8.31 (s, IH), 8.04-7.87 (m, 2H), 7.75 - 7.60 (m, 2H), 7.32-7.22 (m, 2H), 7.14 (d, J = 8.2 Hz, IH), 6.84 (d, J = 8.0 Hz, IH), 4.89 (t, J= 6.6 Hz, IH), 4.27 - 4.13 (m, 2H),2.55(s, 3H), 2.38 - 1.95 (m, 2H).
Example-81/82: (S&R)-A-(6-Fluoropyridin-2-yl)-4-(2-(2-(methylsulfonyl)ethyl)-4(trifluoromethyl)phenyl) chroman -7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using perfluorophenyl Intermediate-18 and 6-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: DCM =1:1), A:B = 60:40 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.62 min (Example-81) and rétention time 7.40 min (Example-82).
LCMS (ESI): m/z 559.22 (M+H)+; 'H NMR (400 MHz, DMSO-î/6) δ 11.38 (s, IH), 7.92 -7.81 (m, IH), 7.75 (s, IH), 7.52 (d,J=8.2 Hz, IH), 7.39 (d,J= 1.9 Hz, 1 H), 7.33 (dd,J
135 = 8.1, 1.9 Hz, IH), 7.03 -6.95 (m, 2H), 6.92 (d, J= 8.2 Hz, IH), 6.77 (dd, J= 8.1, 2.4 Hz, IH), 4.61 (t, 1 H),4.31 - 4.18 (m, 2H), 3.63 - 3.45 (m, 2H), 3.30 - 3.13 (m, 2H), 3.05 (s, 3H), 2.35-2.23 (m, IH), 2.09 - 1.91 (m, IH).
Example-83/84: (S&R)-4-(2-(2-(Methylsulfonyl)ethyl)-4-(trifluoromethyl)phenyl)-V(pyrimidin-2-yl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-18 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: DCM = 1:1), A:B = 50:50 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.49 min (Example-83) and rétention time 6.83 min (Example-84).
LCMS (ESI): m/z 542.06 (M+H)+; *H NMR (400 MHz, DMSOé6) δ 11.77 (s, IH), 8.54 (d, J = 4.9 Hz, 2H), 7.75 (d, J= 2.0 Hz, IH), 7.52 (dd, J = 8.3, 2.0 Hz, IH), 7.45 - 7.33 (m, 2H), 7.11 - 6.95 (m, 2H), 6.89 (d, J = 8.2 Hz, IH), 4.61 (t, J = 6.8 Hz, IH), 4.34 4.18 (m, 2H), 3.64 - 3.46 (m, 2H), 3.29 - 3.14 (m, 2H), 3.05 (s, 3H), 2.36 - 2.25 (m, IH), 2.07- 1.94 (m, IH).
Example-85/86: (S&R)-A/-(5-Fluoropyrimidin-2-yl)-4-(2-(2-(methylsulfonyl)ethyl)-4(trifluoromethyl)phenyl) chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-18 and 5-fluoropyrimidin-2-amine.
136
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: DCM = 1:1), A:B = 50:50 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time
4.96 min (Example-85) and rétention time 6.00 min (Example-86).
LCMS (ESI): m/z 560.01 (M+H)+; 'H NMR (400 MHz, DMSOé6) δ 8.62 (s, 2H), 7.73 (s, IH), 7.57 - 7.48 (m, IH), 7.46 - 7.30 (m, 2H), 7.00 (d, J = 8.2 Hz, IH), 6.88 (d, J = 8.2 Hz, IH), 4.59 (t, J= 6.9 Hz, IH), 4.32 - 4.19 (m, 2H),3.55-3.45(m, 2H) 3.32 - 3.12 (m, 2H), 3.03 (s, 3H), 2.37 - 2.23 (m, IH), 2.07 - 1.93 (m, IH).
Example-87/88: (S&R)-4-(2-(2-(Methylsulfonyl)ethyl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-4-yl) chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1 /2 using Intermediate-18 and pyrimidin-4-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: DCM = 1:1), A:B = 50:50 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time
4.53 min (Example-87) and rétention time 6.96 min (Example-88).
LCMS (ESI): m/z 542.06(M+H)+; *H NMR (400 MHz, DMSOé6) δ 8.65 (s, IH), 8.36 (s,
H), 7.75 (s, 1 H), 7.53 (d, J = 8.2 Hz, 1 H), 7.38 - 7.23 (m, 2H), 7.11 - 6.98 (m, 2H), 6.89 (d, J = 8.1 Hz, IH), 4.60 (t, J = 6.9 Hz, IH), 4.35 - 4.19 (m, 2H), 3.64 - 3.46 (m, 2H), 3.30 - 3.15 (m, 2H), 3.06 (s, 3H), 2.37 - 2.24 (m, IH), 2.10 - 1.95 (m, IH).
Example-89/90: (S&R)-4-(2-(lH-pyrazol-l-yl)-4-(trifluoromethyl)phenyl)-N-(6 fluoropyridin-2-yl)chroman-7-sulfonamide
137
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-20 and 6-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: MeOH = 1:1), A:B = 70:30, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.02 min (Example-89) and rétention time 6.82 min (Example-90).
LCMS(ESI): m/z 519.19(M+H)+; *H NMR (400 MHz, DMSO-J6) δ 11.39 (s, IH), 8.23 (d, J= 2.4 Hz, IH), 7.92 - 7.72 (m, 4H), 7.38 - 7.27 (m, 3H), 7.01 - 6.92 (m, 2H), 6.77 (dd, J= 8.0, 2.4 Hz, IH), 6.58-6.51 (m, IH), 4.39-4.08 (m, 3H),2.24- 1.97 (m, 2H).
Example-91/92: (S&R)-N-(5-fluoropyrimidin-2-yl)-4-(2-(thiazol-2-yl)-4(trifluoromethyl) phenyl)chroman-7-sulfonamide
CF3 CF3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-22 and 5-fluoropyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% TFA), B = (EtOH: MeOH = 1:1), A:B = 50:50, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.43 min (Example-91) and rétention time 7.23 min (Example-92).
LCMS(ESI): m/z 523.19(M+H)+; *H NMR (400 MHz, DMSO-J6) δ 11.89 (s, IH), 8.66 (s, 2H), 8.07 - 7.92 (m, 3H), 7.79 (dd, J = 8.5, 2.1 Hz, IH), 7.42 - 7.33 (m, 2H), 7.30 (d,
138
J = 8.4 Hz, 1 H), 6.92 (d, J = 8.1 Hz, 1 H), 5.07 (t, J = 7.2 Hz, 1 H), 4.31 - 4.13 (m, 2H), 2.28-2.03 (m, 2H).
Example-93: (R/S)-N-(pyrimidin-2-yl)-4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenyl) chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-22b and pyrimidin-2-amine.
LCMS(ESI): m/z 518.95(M+H)+; ‘H NMR (400 MHz, DMSO-76) δ 11.75 (s, IH), 8.54 (d, J = 4.9 Hz, 2H), 8.06 - 7.93 (m, 3H), 7.79 (d, J= 8.3 Hz, IH), 7.43 - 7.33 (m, 2H), 7.29 (d, 7=8.3 Hz, 1 H), 7.08 (t,7=4.9 Hz, 1 H), 6.91 (d,7=8.2 Hz, 1 H), 5.07 (t,7=7.2 Hz, IH), 4.30 - 4.09 (m, 2H), 2.32 - 2.05 (m, 2H).
Example-94: (R/S)-N-(pyrimidin-4-yl)-4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenyl) chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-22b and pyrimidin-4-amine.
LCMS(ESI): m/z 518.96(M+H)+; 'H NMR (400 MHz, DMSO-J6) δ 8.65 (s, IH), 8.36 (s, IH), 8.12 - 7.93 (m, 3H), 7.79 (d, J= 8.3 Hz, IH), 7.40 - 7.23 (m, 3H), 7.05 (s, IH), 6.90 (d, 7=8.1 Hz, 1H),5.O6 (t, 7 = 7.1 Hz, IH), 4.30-4.12 (m, 2H),2.31 -2.05 (m, 2H).
Example-95: (R/S)-N-(pyridazin-3-yl)-4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenyl) chroman-7-sul fonamide
139
cf3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-22b and pyridazin-3-amine.
LCMS(ESI): m/z 518.88(M+H)+; 'H NMR (400 MHz, DMSO-76) δ 14.52 (s, IH), 8.30 5 (s, 1 H), 8.10 - 7.87 (m, 4H), 7.79 (dd, 7= 8.2, 2.0 Hz, 1 H), 7.70 (dd,7= 9.5, 3.7 Hz, IH),
7.37 - 7.14 (m, 3H), 6.87 (d, J = 8.0 Hz, IH), 5.05 (t, 7 = 7.1 Hz, IH), 4.30 - 4.12 (m, 2H), 2.30-2.07 (m, 2H).
Example-96: (R/S)-N-(6-fluoropyridin-2-yl)-4-(2-(thiazol-2-yl)-4(trifluoromethyl)phenyl) chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-22b and 6-fluoropyridin-2-amine.
LCMS(ESI): m/z 535.94(M+H)+; 'H NMR (400 MHz, DMSO-76) δ 11.37 (s, IH), 8.05 7.93 (m, 3H), 7.87 (dd, 7= 8.2 Hz, IH), 7.78 (dd, 7= 8.3, 2.0 Hz, IH), 7.39 - 7.26 (m, 15 3H), 7.01 -6.89 (m, 2H), 6.77 (dd,7= 7.9, 2.4 Hz, 1 H), 5.07 (t,7= 8.2, 6.1 Hz, IH), 4.31
- 4.13 (m, 2H), 2.31 - 2.08 (m, 2H).
Example-97/98: (S&R)-4-(2-(6-isopropoxypyridin-3-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide
140
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-24 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: DCM = 1:1), A:B = 60:40, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 9.69 min (Example-97) and rétention time 10.74 min (Example-98).
LCMS(ESI): m/z 571.14(M+H)+; *H NMR (400 MHz, DMSO-J6) δ 11.74 (s, IH), 8.53 (d, 7=4.8 Hz, 2H), 8.26 (s, IH), 7.82 (d,7= 8.8 Hz, IH), 7.68 (d,7= 8.3 Hz, IH), 7.62 (s, IH), 7.36 (d, 7= 8.7 Hz, 2H), 7.22 (d,7= 8.3 Hz, IH), 7.08 (s, IH), 6.92 (d, 7= 8.1 Hz, IH), 6.84 (d, 7= 8.5 Hz, IH), 5.33 - 5.23 (m, IH), 4.34 - 4.10 (m, 3H), 2.17 - 1.96 (m, 2H), 1.32 (d, 3H), 1.24 (d, 3H).
Example-99/100: (S&R)-N-(5-fluoropyrimidin-2-yl)-4-(2-(6-isopropoxypyridin-3-yl)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-24 and 5-fluoropyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: (MeOH + 0.1% TFA) to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.67 min (Example-99) and rétention time 6.21 min (Example-100).
141
LCMS(ESI): m/z 588.83(M+H)+; *H NMR (400 MHz, DMSO-76) δ 11.88 (s, IH), 8.65 (s, 2H), 8.25 (s, IH), 7.89 - 7.52 (m, 3H), 7.42 - 7.28 (m, 2H), 7.22 (d, J = 8.2 Hz, IH), 6.89 (dd, J= 36.7, 8.3 Hz, 2H), 5.29 (quint, J= 6.3 Hz, IH), 4.37-4.04 (m, 3H), 2.22 1.93 (m, 2H), 1.32 (d, 6H).
Example-101/102: (S&R)-4-(2-(6-ethoxypyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-26 and 5-fluoropyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: (MeOH + 0.1% TFA) to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.25 min (Example-101) and rétention time 7.25 min (Example-102).
LCMS(ESI): m/z 575.26(M+H)+; *H NMR (400 MHz, DMSO-76) δ 11.87 (s, IH), 8.65 (s, 2H), 8.26 (d, J = 2.5 Hz, 1 H), 7.83 (dd, J = 8.6, 2.5 Hz, 1 H), 7.69 (dd, J = 8.4, 2.1 Hz, 1 H), 7.62 (d, J = 2.0 Hz, 1 H), 7.39 - 7.32 (m, 2H), 7.22 (d, J = 8.3 Hz, 1 H), 6.99 - 6.85 (m, 2H), 4.35 (q, 2H), 4.31 -4.20 (m, 2H), 4.17-4.08 (m, IH), 2.21 - 1.96 (m, 2H), 1.34 (t, 7=7.0 Hz, 3H).
Exaniple-103: (R/S)-4-(2-(6-ethoxypyridin-3-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide
142
To the stirred solution of (R/S)-4-(2-(6-fIuoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide (Example-36) (0.10g, 0.19 mmol) in EtOH (5 ml), K2CO3 (0.078 g, 0.57 mmol) was added at room température and reaction was stirred for 15h at 100 °C. After completion of reaction as indicated by TLC, reaction mixture was poured in to water and extract with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated under vacuum. The crude product was purified by column chromatography followed by chiral préparative HPLC to obtain title compound (0.020g, 19.06 %). LCMS(ESI): m/z 557.12(M+H)+; 'H NMR (400 MHz, DMSO-76) δ 11.75 (s, 1H), 8.53 (d, J = 4.9 Hz, 2H), 8.26 (d, J= 2.4 Hz, 1H), 7.83 (dd, J = 8.4, 2.5 Hz, 1H), 7.69 (d, 7 = 8.3 Hz, 1H), 7.62 (s, 1H), 7.36 (d,7= 8.1 Hz, 2H), 7.22 (d,7= 8.2 Hz, 1H), 7.07 (d, 7= 6.2 Hz, 1H), 6.95 - 6.85 (m, 2H), 4.34 (q, 7= 6.9 Hz, 2H), 4.32 - 4.08 (m, 3H), 2.18 - 1.97 (m, 2H), 1.34 (t, 7= 7.0 Hz, 3H).
Example-104: (S/Æ)-4-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide
cf3
To a stirred solution of pyrimidine-2-amine (0.027g, 0.286 mmol) in THF (5 ml) was added LiHMDS(0.272 ml, IM in THF, 0.272 mmol) at 0 °C and stirred for 10 min. Intermediate-27b (0.080g, 0.143 mmol) in THF (5 ml) was added to the above reaction mixture at 0 °C . After completion of reaction as indicated by TLC, reaction mixture was quenched with citric acid solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The crude was purified by column chromatography to obtain title compound as white solid (0.025g, 37 %). LCMS (ESI): m/z 470.05(M+H)+; *H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1 H), 8.54 (d, 7 = 4.8 Hz, 2H), 7.95 (s, 1 H), 7.66 (d, 7 = 8.2 Hz, 1 H), 7.46-7.37 (m, 2H), 7.16 (d, 7= 8.2 Hz, 1H), 7.09 (t,7=4.9 Hz, 1H), 6.96 (d, 7=8.1 Hz, 1H), 4.74 (t, 7=6.5 Hz, 1H), 4.34-4.22 (m, 1H), 4.20-4.08 (m, 1H), 2.32 - 2.23 (m, 1H),2.152.04 (m, 1H).
143
Example-105: (5/7?)-4-(2-Chloro-4-(trifluoromethyl) phenyl)-N-(5-fluoropyrimidin-2-yl) chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-104 using Intermediate-27b and 5-fluoropyrimidin-2-amine. LCMS(ESI): m/z 487.92(M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 11.91 (s, IH), 8.67 (s, 2H), 7.95 (d, J = 1.9 Hz, 1 H), 7.66 (dd, J = 8.2, 2.0 Hz, 1 H), 7.45 - 7.36 (m, 2H), 7.17 (d, J = 8.1 Hz, 1 H), 6.97 (d, J = 8.1 Hz, IH), 4.74 (t, J = 6.5 Hz, IH), 4.28 (ddd, J = 10.9, 7.4, 2.9 Hz, IH), 4.15 (ddd,J= 11.0, 7.3,3.1 Hz, IH), 2.29 (à,J= 12.9 Hz, IH), 2.10 (d, J= 15.1 Hz, IH). Example-106: (S/Æ)-4-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl )chroman-7-sul fonam ide
The title compound was prepared by following the similar procedure as described in Example-104 using Intermediate-27b and pyrimidin-4-amine. LCMS (ESI): m/z 469.98(M+H)+; *H NMR (400 MHz, DMSO-d6) δ 8.66 (s, IH), 8.39 (s, IH), 7.95 (d, J = 1.9 Hz, 1 H), 7.71-7.59 (m, 1 H), 7.40-7.30 (m, 2H), 7.22 - 7.02 (m, 2H), 6.95 (d, J = 8.1 Hz, IH), 4.80 - 4.66 (m, IH), 4.33 - 4.22 (m, IH), 4.20 - 4.08 (m, IH), 2.34 - 2.26 (m, IH), 2.14-2.04 (m, IH).
Example-107: (57Jî)-4-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(pyridazin-3-yl)chroman7-sulfonamide
144
cf3
The title compound was prepared by following the similar procedure as described in Example-104 using Intermediate-27b and pyridazin-3-amine. LCMS(ESI): m/z 470.03(M+H)+; *H NMR (400 MHz, DMSO-d6) δ 14.54 (s, IH), 8.31 (s, IH), 7.98 - 7.89 (m, 2H), 7.75 - 7.63 (m, 2H), 7.32 - 7.24 (m, 2H), 7.16 (d, J = 8.2 Hz, 1 H), 6.92 (d, J =
7.9 Hz, IH), 4.77 - 4.68 (m, IH), 4.31 - 4.22 (m, IH), 4.17 - 4.10 (m, IH), 2.32 - 2.24 (m, IH), 2.14-2.06 (m, IH).
Example-108 : (S/R)-4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin-2yl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-104 using Intermediate-27b and 6-fluoropyridin-2-amine. LCMS(ESI): m/z 486.97(M+H)+; lH NMR (400 MHz, DMSO-</6) δ 11.39 (s, IH), 7.97 - 7.82 (m, 2H), 7.65 (dd, 8.3, 1.9 Hz, IH), 7.43 - 7.32 (m, 2H), 7.17 (d, J = 8.2 Hz, IH), 7.02 - 6.94 (m, 2H), 6.77 (dd, J =8.0, 2.4 Hz, 1 H), 4.74 (t, J = 6.5 Hz, 1 H), 4.33 -4.23 (m, 1 H), 4.21
-4.10 (m, IH), 2.31 -2.05 (m, 2H).
Example-109/110: (S&R)-N-(pyrimidin-2-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)-4(trifluoromethyl) phenyl)chroman-7-sulfonamide
145
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-29 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: DCM = 1:1), A:B = 70:30, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 9.22 min (Example-109) and rétention time 10.20 min (Example-110).
LCMS(ESI): m/z 520.08(M+H)+; ’H NMR (400 MHz, DMSO-î/6) δ 11.71(s, IH), 8.59 8.49 (m, 2H), 7.62 (s, IH), 7.52 - 7.34 (m, 3H), 7.18 - 7.04 (m, 2H), 6.82 (d, J= 8.1 Hz, IH), 4.80 - 4.66 (m, IH), 4.37 - 4.22 (m, 2H), 3.92 (d, J = 11.4 Hz, lH),3.80-3.08(m, 4H), 2.30 - 2.18 (m, 1 H), 2.06 - 1.93 (m, 1 H), 1.84 - 1.51 (m, 4H).
Example-111/112: (S&R)-jV-(6-Fluoropyridin-2-yl)-4-(2-(2-oxopyrrolidin-l-yl)-4(trifluoromethyl)phenyl) chroman-7-sulfonamide
cf3 CF3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-31 and 6-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IC; Mobile phase: A = (Hexane + 0.1% DEA), B = (EtOH: DCM =1:1), A:B = 60:40 to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 7.85 min (Example-111) and rétention time 8.90 min (Example-112).
LCMS (ESI): m/z 535.99(M+H)+; ‘H NMR (400 MHz, Chloroform-d) d 7.75 (dd, J= 8.0 Hz, IH), 7.55 - 7.48 (m, 2H), 7.43 (d, J= 1.9 Hz, IH), 7.29 - 7.25 (m, 3H), 7.09 (d, J =
146
8.1 Hz, IH), 6.64 (dd, J = 8.0, 2.4 Hz, IH), 4.35 - 4.26 (m, 2H), 4.26 - 4.11 (m, IH), 3.94 - 3.70 (m, 2H), 2.64 (t, J = 8.1 Hz, 2H), 2.44 - 2.24 (m, 3H), 2.15-1.99 (m, IH).
Example-113/114: (S&R)-N-(5-fluoropyrimidin-2-yl)-4-(2-(2-oxopynOlidin-l-yl)-4(trifluoromethyl) phenyl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-31 a & 31b respectively and 5-fluoropyrimidin -2-amine. LCMS(ESI): m/z 536.94 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 11.88 (s, IH), 8.66 (s, 2H), 7.79 (s, IH), 7.63 (d, J = 8.3 Hz, IH), 7.39 (s, IH), 7.35 (d, J = 8.0 Hz, IH), 7.19 (d, J = 8.2 Hz, IH), 6.91 (d, J= 8.2 Hz, IH), 4.41 (t, J= 7.4 Hz, IH), 4.30 - 4.20 (m, 2H), 3.87 - 3.66 (m, 2H), 2.32 -2.19 (m, 3H), 2.18 - 2.08 (m, 2H), 2.04 - 1.95 (m, 1 H). Example-115: (R/S)-4-(2-(2-oxopyrrolidin-l-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-31b and pyrimidin-2-amine. LCMS(ESI): m/z 518.94 (M+H)+; *H NMR (400 MHz, DMSO-d6) δ 11.74 (s, IH), 8.54 (d, J= 4.9 Hz, 2H), 7.79 (s, IH), 7.63 (d, J = 8.3 Hz, IH), 7.40 (s, IH), 7.36 (d, J = 8.0 Hz, IH), 7.19 (d, J = 8.3 Hz, IH), 7.13-7.03 (m, IH), 6.90 (d,J=8.2 Hz, IH), 4.41 (t, J =1.3 Hz, IH), 4.304.19 (m, 2H), 3.84-3.67 (m, 2H), 2.47 -2.39 (m, 2H), 2.31 -2.18 (m, IH), 2.18-2.07 (m, 2H), 2.07- 1.94 (m, IH).
147
Example-116: (R/S)-4-(2-(2-oxopyrrolidin-l-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-4-yl)chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-31 b and pyrimidin-4-amine. LCMS(ESI): m/z 519.04 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 8.66 (s, IH), 8.38 (brs, IH), 7.79 (s, IH), 7.63 (d, J= 8.2 Hz, IH), 7.39 - 7.25 (m, 2H), 7.19 (d, J= 8.4 Hz, IH), 7.07 (s, IH), 6.90 (d, J = 8.0 Hz, IH), 4.41 (t, J = 7.4 Hz, IH), 4.34 - 4.22 (m, 2H), 3.87 - 3.67 (m, 2H), 2.49 - 2.40 (m, 2H), 2.29 - 2.07 (m, 3H), 2.07 - 1.94 (m, I H).
Example-117: (R/S)-4-(2-(2-oxopynOlidin-l-yl)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl)chromane-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-31 b and pyridazin-3-amine.
LCMS(ESI): m/z 518.94 (M+H)+; *H NMR (400 MHz, DMSO-d6) δ 8.35 (s, IH), 7.88 (d, J= 9.6 Hz, IH), 7.78 (s, IH), 7.70 (dd, J= 9.5, 4.2 Hz, IH), 7.63 (d, J= 7.3 Hz, IH), 7.28-7.21 (m, 2H), 7.18 (d, J= 8.2 Hz, IH), 6.86 (d, J= 8.1 Hz, IH), 4.39 (t, J =7.2 Hz, IH), 4.30 - 4.19 (m, 2H), 3.85 - 3.67 (m, 2H), 2.48 - 2.39 (m, 2H), 2.28 - 2.19 (m, IH), 2.18-2.08 (m, 2H), 2.03 - 1.95 (m, 1 H).
Example-118/119: (S&R)-4-(2-morpholino-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide
148
CF3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-33 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: DCM = 1:1), A:B = 70:30, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 8.18 min (Example-118) and rétention time 9.46 min (Example-119).
LCMS(ESI): m/z 521.09(M+H)+; 'H NMR (400 MHz, DMSOé6) δ 8.54 (d, 7= 4.9 Hz, 2H), 7.58 (d, 7= 1.9 Hz, IH), 7.47 - 7.31 (m, 3H), 7.19 - 7.02 (m, 2H), 6.80 (d, 7= 8.1 Hz, IH), 4.79 (t, IH), 4.33 - 4.23 (m, 2H), 3.74 - 3.58 (m, 4H), 3.03 - 2.74 (m, 4H), 2.26 - 2.05 (m, 2H).
Example-120: (S/R)-N-(5-fluoropyrimidin-2-yl)-4-(2-morpholino-4(trifluoromethyl)phenyl) chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-33b and 5-fluoropyrimidin-2-amine. LCMS(ESI): m/z 539.07(M+H)+; 'H NMR (400 MHz, DMSOé6) δ 11.86 (s, IH), 8.66 (s, 2H), 7.58 (s, IH), 7.47-7.31 (m, 3H), 7.12 (d, 7= 8.1 Hz, IH), 6.81 (d,7=8.1 Hz, IH), 4.79 (t, IH), 4.32 - 4.24 (m, 2H), 3.73 - 3.57 (m, 4H), 3.00 - 2.75 (m, 4H), 2.28 - 2.07 (m, 2H).
Example-121: (R/S)-4-(2-morpholino-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl) chroman-7-sulfonamide
149
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-33b and pyrimidin-4-amine. LCMS(ESI): m/z 521.06(M+H)+; 'H NMR (400 MHz, DMSO-76) δ 8.66 (s, IH), 8.37 (s, IH), 7.58 (d, J =
1.8 Hz, 1 H), 7.43 (d, J = 8.3 Hz, 1 H), 7.36 - 7.26 (m, 2H), 7.19- 6.99 (m, 2H), 6.79 (d, J = 8.1 Hz, IH), 4.79 (t, J= 7.5 Hz, IH), 4.33 - 4.22 (m, 2H), 3.75 - 3.56 (m, 4H), 3.02 2.76 (m, 4H), 2.27-2.05 (m, 2H).
Example-122: (R/S)-4-(2-morpholino-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-33b and pyridazin-3-amine. LCMS(ESI): m/z 521.05(M+H)+; *H NMR (400 MHz, DMSO-76) δ 8.34 (s, IH), 7.90 (s, IH), 7.73 - 7.41 (m, 3H), 7.30-7.06 (m, 3H), 6.75 (d, J= 8.2 Hz, IH), 4.81 - 4.76 (m, IH), 4.33 - 4.22 (m, 15 2H), 3.77 - 3.62 (m, 4H), 3.00 - 2.76 (m, 4H), 2.27 - 2.04 (m, 2H).
ExampIe-123: (R/S)-N-(6-fluoropyridin-2-yl)-4-(2-morpholino-4(trifluoromethyl)phenyl) chroman-7-sulfonamide
150
cf3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-33b and 6-fluoropyridin-2-amine. LCMS(ESI): m/z 538.06 (M+H)+; 'H NMR (400 MHz, DMSO-76) δ 11.36 (s, IH), 7.87 (dd, J= 8.2 Hz, 5 IH), 7.58 (s, 1 H), 7.43 (d, J =8.2 Hz, IH), 7.39 - 7.27 (m, 2H), 7.12 (d, J= 8.1 Hz, IH), 6.98 (dd, 7= 7.9, 2.1 Hz, IH), 6.85 - 6.73 (m, 2H), 4.78 (t, 7= 7.4 Hz, IH), 4.32-4.24 (m, 2H), 3.73 - 3.53 (m, 4H), 2.98 - 2.73 (m, 4H), 2.27 - 2.04 (m, 2H).
ExampIe-124/125: (S&R)-4-(2-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide
CF3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-35a & Intermediate-35b respectively and pyrimidin-2amine.
LCMS(ESI): m/z 510.05(M+H)+; 'H NMR (400 MHz, DMSO-76) δ 11.73 (s, IH), 8.54 15 (d, 7= 4.9 Hz, 2H), 7.45 - 7.31 (m, 3H), 7.25 (d, 7= 7.9 Hz, 1 H), 7.13 - 7.02 (m, 2H),
6.91 (d, 7= 8.1 Hz, IH), 4.55 (t, 7= 6.6 Hz, IH), 4.27-4.00(m, 4H), 3.56 - 3.46 (m, IH), 3.45-3.37 (m, IH), 3.21 (s, 3H), 2.20-2.10 (m, 2H).
Example-126: (R/S)-N-(5-fluoropyrimidin-2-yl)-4-(2-(2-methoxyethoxy)-4(trifluoromethyl) phenyl)chroman-7-sulfonamide
151
Z—N
F —Ç 'V NH II Y I \=N
Q--O cf3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-35b and 5-fluoropyrimidin-2-amine.
LCMS(ESI): m/z 528.03 (M+H)+; *H NMR (400 MHz, DMSO-J6) δ 11.86 (s, IH), 8.66 (s, 2H), 7.41 - 7.32 (m, 3H), 7.26 (d, J= 7.9 Hz, IH), 7.06 (d, J= 7.9 Hz, IH), 6.92 (d, J = 8.0 Hz, IH), 4.56 (t, J = 6.7 Hz, IH), 4.29 - 4.00 (m, 4H), 3.55 - 3.37 (m, 2H), 3.21 (s, 3H), 2.22-2.09 (m, 2H).
Example-127: (R/S)-4-(2-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)-N-(pyrimidin4-yl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-35b and pyrimidin-4-amine.
LCMS(ESI): m/z 510.04 (M+H)+; *H NMR (400 MHz, DMSO-76) δ 8.66 (s, IH), 8.39 (s, IH), 7.44-7.29 (m, 3H), 7.26 (d, J = 7.9 Hz, IH), 7.18-7.01 (m, 2H), 6.92 (d, J= 8.0 Hz, IH), 4.56 (t, J = 6.6 Hz, IH), 4.32 - 4.05 (m, 4H), 3.58 - 3.37 (m, 2H), 3.22 (s, 3H), 2.21-2.11 (m, 2H).
Example-128: (R/S)-4-(2-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide
152 o^P (7 V-NH || T | \—/
Çr-Y cf3
The title compound was prepared by following the similar procedure as described in Example-1/2 using lntermediate-35b and pyridazin-3-amine.
LCMS(ESI): m/z 510.04 (M+H)+; 'H NMR (400 MHz, DMSO-76) δ 14.52 (s, IH), 8.31 (s, IH), 7.92 (s, IH), 7.70 (dd, 7=9.5, 4.2 Hz, IH), 7.34 (d, 7= 1.8 Hz, IH), 7.31-7.18 (m, 3H), 7.02 (d, 7= 7.9 Hz, IH), 6.89 (d, 7= 8.4 Hz, IH), 4.56 (t, 7= 6.4 Hz, IH), 4.34 - 4.07 (m, 4H), 3.62 - 3.44 (m, 2H), 3.24 (s, 3H), 2.26 - 2.07 (m, 2H).
Example-129 : (R/S)-N-(6-fluoropyridin-2-yl)-4-(2-(2-methoxyethoxy)-4(trifluoromethyl) phenyl)chroman-7-sulfonamide F\ O.,0 Mn x s χ/υ,ο.
cf3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-35b and 6-fluoropyridin-2-amine. LCMS(ESI): m/z 527.04 (M+H)+; 'H NMR (400 MHz, DMSO-76) δ 11.36 (s, IH), 7.87 (dd, 7= 8.1 Hz, IH), 7.42 - 7.29 (m, 3H), 7.25 (d, 7= 7.9 Hz, IH), 7.06 (d, 7= 7.9 Hz, IH), 6.98 (dd, 7 = 8.0, 2.1 Hz, IH), 6.93 (d,7 = 8.1 Hz, IH), 6.77 (dd,7 = 8.0, 2.4 Hz, IH), 4.55 (t,7=6.8 Hz, IH), 4.29 - 3.99 (m, 4H), 3.55 - 3.35 (m, 2H), 3.20 (s, 3H), 2.24 - 2.08 (m, 2H).
Example-130/131 : (S&R)-4-(2-(3 -methoxypropoxy)-4-(tri fluoromethyl)phenyl)-N (pyrimidin-2-yl)chroman-7-sulfonamide
153
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-37and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH =1:1), A:B = 40:60, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.43 min (Example-130) and rétention time 7.76 min (Example-131).
LCMS(ESI): m/z 524.11(M+H)+; *H NMR (400 MHz, DMSOé6) δ 11.73 (s, IH), 8.53 (d, J= 4.9 Hz, 2H), 7.42 - 7.33 (m, 2H), 7.30 - 7.22 (m, 2H), 7.16 - 7.05 (m, 2H), 6.89 (d, J= 8.0 Hz, IH), 4.53 (t, IH), 4.28-4.17 (m, 2H), 4.15 - 3.91 (m, 2H), 3.33 - 3.19 (m, 2H), 3.16 (s, 3H), 2.22-2.11 (m, 2H), 1.78- 1.63 (m, 2H).
Example-132: (R/S)-N-(5-fluoropyrimidin-2-yl)-4-(2-(3-methoxypropoxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-37b and 5-fluoropyrimidin-2-amine. LCMS(ESI): m/z 542.01(M+H)+; 'H NMR (400 MHz, DMSOé6) δ 11.85 (s, IH), 8.66 (s, 2H), 7.40 - 7.33 (m, 2H), 7.31-7.24 (m, 2H), 7.13 (d, J=7.9 Hz, IH), 6.90 (d,J=8.0Hz, IH), 4.53 (t,J = 7.0 Hz, IH), 4.27 - 4.18 (m, 2H), 4.13 - 3.94 (m, 2H), 3.31 - 3.20 (m, 2H), 3.16 (s, 3H), 2.21 - 2.13 (m, 2H), 1.78 - 1.64 (m, 2H).
Example-133: (R/S)-4-(2-(3-methoxypropoxy)-4-(trifluoromethyl)phenyl)-N-(pyridazin3-yl)chroman-7-sulfonamide
154
cf3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-37b and pyridazin-3-amine. LCMS(ESI): m/z 523.94(M+H)+; 'H NMR (400 MHz, DMSO-t/6) δ 14.51 (s, 1H), 8.30 (s, 1H), 7.92 (s, 5 1H), 7.74 - 7.66 (m, 1H), 7.31 - 7.22 (m, 4H), 7.09 (d, J= 7.8 Hz, 1H), 6.86 (d, J= 8.4
Hz, 1H), 4.53 (t, J= 6.7 Hz, 1H), 4.22 - 3.99 (m, 4H), 3.33 - 3.24 (m, 2H), 3.18 (s, 3H), 2.18-2.12 (m, 2H), 1.84- 1.73 (m, 2H).
Example-134: (R/S)-N-(6-fluoropyridin-2-yl)-4-(2-(3-methoxypropoxy)-4(trifluoromethyl) phenyl)chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-37b and 6-fluoropyridin-2-amine. LCMS(ESI): m/z 541.07(M+H)+; ‘H NMR (400 MHz, DMSO-c/6) δ 11.36 (s, 1H), 7.87 (dd, J = 8.2 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.29-7.22 (m, 2H), 7.13 (d, J = 7.8 Hz, 1H), 6.98 (dd, J= 7.9, 15 2.1 Hz, 1 H), 6.91 (d, J = 8.1 Hz, 1 H), 6.76 (dd, J = 8.0, 2.4 Hz, 1 H), 4.53 (t, J = 7.0 Hz,
1H), 4.27 - 4.17 (m, 2H), 4.14 - 3.91 (m, 2H), 3.33 - 3.16 (m, 2H), 3.15 (s, 3H), 2.21 2.11 (m, 2H), 1.79 - 1.60 (m, 2H).
Example-135: (R/S)-4-(2-(2-methoxyethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide
155
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-39b and pyrimidin-2-amine.
LCMS(ESI): m/z 494.02(M+H)+; 'H NMR (400 MHz, DMSO-î/6) δ 11.73 (s, IH), 8.54 (d, J = 4.9 Hz, 2H), 7.65 (d, J = 2.0 Hz, IH), 7.47 (dd, J= 8.2, 2.0 Hz, IH), 7.41 (d, J = 1.9 Hz, IH), 7.37 (dd, J= 8.1, 1.9 Hz, IH), 7.08 (t, J =5.0 Hz, IH), 6.99 (d,J=8.2 Hz, IH), 6.81 (d, J =8.2 Hz, IH), 4.66 (t, J=1A Hz, IH), 4.28-4.22 (m, 2H), 3.60 (t,J = 6.5 Hz, 2H), 3.24 (s, 3H), 3.14 - 3.06 (m, IH), 3.05 - 2.96 (m, IH), 2.30-2.19 (m, IH), 2.03- 1.92 (m, IH).
Example-136: (R/S)-N-(5-fluoropyrimidin-2-yl)-4-(2-(2-methoxyethyl)-4(tri fluoromethy 1 ) phenyl)chroman-7-sul fonam ide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-39b and 5-fluoropyrimidin-2-amine. LCMS(ESI): m/z 512.00(M+H)+; ‘H NMR (400 MHz, DMSO-<4) δ 11.87 (s, 1 H), 8.66 (s, 2H), 7.65 (d,J = 2.1 Hz, 1 H), 7.47 (dd, J = 8.3, 2.0 Hz, 1 H), 7.40 (d, J = 1.9 Hz, 1 H), 7.36 (dd, J = 8.1, 2.0 Hz, IH), 6.99 (d,J=8.2 Hz, IH), 6.82 (d,J=8.1 Hz, IH), 4.66 (t,J=7.0 Hz, IH), 4.324.20 (m, 2H), 3.60 (t, J= 6.5 Hz, 2H), 3.24 (s, 3H), 3.15 - 3.06 (m, IH), 3.06 - 2.97 (m, IH), 2.32-2.21 (m, 1 H), 2.04- 1.94 (m, IH).
Example-137: (R/S)-N-(6-fluoropyridin-2-yl)-4-(2-(2-methoxyethyl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide
156
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-39b and 6-fluoropyridin-2-amine. LCMS(ESI): m/z 511.01(M+H)+; *H NMR (400 MHz, DMSO-J6) δ 11.37 (s, IH), 7.87 (dd, J = 8.2 Hz, IH), 7.65 (d, J = 2.0 Hz, IH), 7.46 (dd, J = 8.3, 2.0 Hz, IH), 7.37 (d, J= 1.9 Hz, IH), 7.33 (dd, J = 8.1, 2.0 Hz, IH), 6.98 (dd, J = 7.9, 1.9 Hz, 2H), 6.83 (d, J= 8.2 Hz, IH), 6.77 (dd, J=8.0, 2.4 Hz, IH), 4.66 (t, J=1A Hz, IH), 4.30-4.23 (m, 2H), 3.59 (t, J = 6.5 Hz, 2H), 3.23 (s, 3H), 3.15 - 3.05 (m, IH), 3.05 - 2.95 (m, IH), 2.29 - 2.19 (m, IH), 2.03 - 1.92 (m, IH).
Example-138: (R/S)-4-(2-(2-methoxyethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-39b and pyrimidin-4-amine.
LCMS(ESI): m/z 493.91(M+H)+; *H NMR (400 MHz, DMSO-é/6) δ 8.66 (s, IH), 7.65 (d, J = 2.0 Hz, IH), 8.42(s, IH), 7.47 (d, J= 8.3 Hz, IH), 7.39 - 7.27 (m, 2H), 7.18 - 6.96 (m, 2H), 6.81 (d,J=8.1 Hz, IH), 4.66 (t, .7=7.0 Hz, IH), 4.32-4.20 (m, 2H), 3.60 (t, J = 6.5 Hz, 2H), 3.24 (s, 3H), 3.17 - 2.94 (m, 2H), 2.30 - 2.16 (m, IH), 2.09 - 1.91 (m, IH).
Example-139: (R/S)-4-(2-(2-methoxyethyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide
157
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-39b and pyridazin-3-amine.
LCMS(ESI): m/z 493.91(M+H)+; 'H NMR (400 MHz, DMSOé6) δ 14.52 (s, IH), 8.30 (s, IH), 7.93 (s, IH), 7.74 - 7.61 (m, 2H), 7.51 - 7.44 (m, IH), 7.30 - 7.20 (m, 2H), 6.99 (d, J = 8.2 Hz, IH), 6.77 (d, J = 7.9 Hz, IH), 4.64 (t, J = 6.9 Hz, IH), 4.31-4.19 (m, 2H), 3.60 (t, J= 6.5 Hz, 2H), 3.24 (s, 3H), 3.15 - 2.95 (m, 2H), 2.30 - 2.20 (m, IH), 2.06 - 1.90 (m, IH).
Example-140/141: (S&R)-4-(2-(3-methoxypropyl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide
cf3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-4la and Intermediate-41 b respectively and pyrimidin-2amine.
LCMS(ESI): m/z 508.22(M+H)+; *H NMR (400 MHz, DMSOé6) δ 11.74 (s, IH), 8.54 (d, J = 4.9 Hz, 2H), 7.60 (s, IH), 7.51 - 7.34 (m, 3H), 7.14 - 6.96 (m, 2H), 6.80 (d, J = 8.2 Hz, IH), 4.59 (t, J = 7.1 Hz, IH), 4.35 - 4.23 (m, 2H), 3.38-3.30 (m, 2H), 3.23 (s, 3H), 2.93 - 2.74 (m, 2H), 2.31 - 2.17 (m, 1 H), 2.09 - 1.94 (m, 1 H), 1.89 - 1.73 (m, 2H). Example-142: (R/S)-N-(5-fluoropyrimidin-2-yl)-4-(2-(3-methoxypropyl)-4-(trifluoro methyl)phenyl)chroman-7-sulfonamide
158
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-41b and 5-fluoropyrimidin-2-amine. LCMS(ESI): m/z 526.24(M+H)+; 'H NMR (400 MHz, DMSO-cZ6) δ 11.87 (s, IH), 8.66 (s, 2H), 7.61 - 7.45 (m, 2H), 7.43 - 7.32 (m, 2H), 7.02 (d, J= 8.3 Hz, IH), 6.81 (d, J= 8.2 Hz, IH), 4.59 (t, J = 7.2 Hz, IH), 4.32 - 4.24 (m, 2H), 3.38 - 3.34 (m, 2H), 3.23 (s, 3H), 2.90 - 2.74 (m, 2H), 2.26 - 2.19 (m, 1 H), 2.04- 1.97 (m, 1 H), 1.90 - 1.74 (m, 2H).
ExampIe-143: (R/S)-4-(2-(3-methoxypropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin4-y 1 )chroman- 7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using lntermediate-41b and pyrimidin-4-amine.
LCMS(ESI): m/z 507.94(M+H)+; ‘H NMR (400 MHz, DMSO-76) δ 8.66 (s, IH), 8.42(s, IH), 7.60 (d, J= 2.0 Hz, IH), 7.47 (dd, J = 8.3, 2.0 Hz, IH), 7.37-7.26 (m, 2H), 7.15 15 6.99 (m, 2H), 6.79 (d, J = 8.1 Hz, 1 H), 4.59 (t, 1 H), 4.32 - 4.24 (m, 2H), 3.38-3.28 (m,
2H), 3.23 (s, 3H), 2.96 - 2.72 (m, 2H), 2.29 - 2.20 (m, IH), 2.04 - 1.97 (m, IH), 1.85 1.72 (m, 2H).
Example-144: (R/S)-4-(2-(3-methoxypropyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide
159
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-41b and pyridazin-3-amine.
LCMS(ESI): m/z 507.94(M+H)+; 'H NMR (400 MHz, DMSOé6) δ 14.52 (s, IH), 8.30 (s, IH), 7.92 (s, 1 H), 7.70 (dd,J=9.6, 4.1 Hz, 1 H), 7.59 (d,J=2.0 Hz, 1 H), 7.47 (dd,J = 8.4, 2.0 Hz, IH), 7.29-7.21 (m, 2H), 7.02 (d, J=8.2 Hz, IH), 6.76 (d, J=8.0 Hz, IH), 4.58 (t, J= 7.1 Hz, IH), 4.33 - 4.22 (m, 2H), 3.40 - 3.34 (m, 2H), 3.23 (s, 3H), 2.93 2.76 (m, 2H), 2.31 - 2.20 (m, 1 H), 2.05 - 1.97 (m, 1 H), 1.86 - 1.81 (m, 2H).
Example-145 : (R/S)-N-(6-fluoropyridin-2-yl)-4-(2-(3 -methoxypropyl)-4(trifluoromethyl) phenyl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-41b and 6-fluoropyridin-2-amine LCMS(ESI): m/z 524.94(M+H)+; *H NMR (400 MHz, DMSOé6) δ 11.37 (s, IH), 7.88 (dd, J = 8.2 Hz, IH), 7.59 (d, J= 2.1 Hz, IH), 7.46 (d, J= 8.1 Hz, IH), 7.41 - 7.29 (m, 2H), 7.04 - 6.94 (m, 2H), 6.85 - 6.73 (m, 2H), 4.59 (t, J= 7.2 Hz, IH), 4.34 - 4.24 (m, 2H), 3.39 - 3.34 (m, 2H), 3.22 (s, 3H), 2.89 - 2.75 (m, 2H), 2.30 - 2.19 (m, 1 H), 2.05 - 1.95 (m, 1 H), 1.88 -1.76 (m, 2H).
Example-146/ 147: (S&R)-4-(2-(4-methoxybutyl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide
160
cf3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-43 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: DCM = 1:1), A:B = 70:30, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.90 min (Example-146) and rétention time 7.69 min (Example-147).
LCMS(ESI): m/z 522.09(M+H)+; 'H NMR (400 MHz, DMSO-J6) δ 8.54 (d, J= 4.9 Hz, 2H), 7.59 (s, 1 H), 7.50-7.33 (m, 3H), 7.12 - 6.98 (m, 2H), 6.78 (d, J = 8.1 Hz, 1 H), 4.60 (t, J = 8.2, 6.3 Hz, IH), 4.32 - 4.24 (m, 2H), 3.35 - 3.29 (m, 2H), 3.19 (s, 3H), 2.86 2.69 (m, 2H), 2.29 - 2.01 (m, 2H), 1.70 - 1.49 (m, 4H).
Example-148: (R/S)-N-(5-fluoropyrimidin-2-yl)-4-(2-(4-methoxybutyl)-4(trifluoromethyl) phenyl)chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-43 and 5-fluoropyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: DCM =1:1), A:B = 80:20, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 7.52 min and rétention time 8.87 min (Example-148).
LCMS(ESI): m/z 540.07(M+H)+; 'H NMR (400 MHz, DMSO-î/6) δ 11.88 (s, IH), 8.66 (s, 2H), 7.60 (s, IH), 7.46 (dd, J = 8.3, 2.0 Hz, IH), 7.42 - 7.32 (m, 2H), 7.02 (d, J = 8.2
161
Hz, IH), 6.79 (d, J = 8.1 Hz, IH), 4.60 (t, J = 7.1 Hz, IH), 4.35-4.24 (m, 2H), 3.363.28(m, 2H) 3.20 (s, 3H), 2.90-2.70 (m, 2H), 2.27 - 1.94 (m, 2H), 1.67- 1.48 (m, 4H).
Example-149: (R/S)-4-(2-(4-methoxybutyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-43 and pyrimidin-4-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: DCM = 1:1), A:B = 70:30, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.81 min and rétention time 6.75 min (Example-149).
LCMS(ESI): m/z 522.07(M+H)+;'H NMR (400 MHz, DMSO-î/6) δ 8.67 (s, IH), 8.39 (s, IH), 7.60 (s, IH), 7.47 (d, J= 8.2 Hz, IH), 7.37-7.25 (m, 2H),7.18-6.97(m ,2H), 6.78 (d, J= 8.1 Hz, IH), 4.59 (t, J= 7.2 Hz, IH), 4.32 - 4.24 (m, 2H), 3.35 - 3.30 (m, 2H), 3.20 (s, 3H), 2.89 - 2.71 (m, 2H), 2.30 - 1.98 (m, 2H), 1.70 - 1.53 (m, 4H).
Example-150: (R/S)-4-(2-(4-methoxybutyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-su!fonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-43 and pyridazin-3-amine.
162
Further the enantiomers were separated using chiral préparative HP LC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: DCM = 1:1), A:B = 70:30, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.47 min and rétention time 6.57 min (Example-150).
LCMS(ESI): m/z 521.94(M+H)+; 'H NMR (400 MHz, DMSO-76) δ 8.34 (s, 1H), 7.90 (s, 1H), 7.70 (dd, J= 9.5, 4.2 Hz, 1H), 7.60 (s, 1H), 7.47 (d, J= 8.3 Hz, 1H), 7.32 - 7.22 (m, 2H), 7.02 (d, 7=8.3 Hz, 1H), 6.74 (d,7=8.0 Hz, 1H), 4.58 (t, 7=7.1 Hz, 1H), 4.364.16 (m, 2H), 3.36 - 3.31 (m, 2H), 3.20 (s, 3H), 2.87 - 2.70 (m, 2H), 2.29 - 2.14 (m, 1H), 2.02 - 1.96 (m, 1H), 1.72 - 1.46 (m, 4H).
Example-151/152 : (S &R)-N-(6-fluoropyridin-2-yl)-4-(2-(4-methoxybutyl)-4-(trifluoro methyl)phenyl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-43 and 6-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: DCM = 1:1), A:B = 75:25, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 7.65 min (Example-151) and rétention time 8.69 min (Example-152).
LCMS(ESI): m/z 539.08(M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 7.87 (dd, 7=8.2 Hz, 1H), 7.59 (s, 1H), 7.46 (d,7=8.3 Hz, 1H), 7.38 (d, 7= 1.9 Hz, 1H), 7.32 (dd, 7= 8.1, 2.0 Hz, 1H), 7.06 - 6.94 (m, 2H), 6.84 - 6.73 (m, 2H), 4.60 (t, 7= 7.3 Hz, 1H), 4.35-4.25 (m, 2H), 3.35-3.24 (m, 2H), 3.19 (s, 3H), 2.82-2.60 (m, 2H), 2.29 - 2.17 (m, 1H), 2.05-1.95 (m, 1H), 1.75-1.50 (m, 4H).
Example-153: (R/S)-4-(2-(2-fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide
163
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-45b and pyrimidin-2-amine. LCMS(ESI): m/z 482.80(M+H)+; 'H NMR (400 MHz, DMSOé6) δ 11.73 (s, IH), 8.54 (d, J= 4.9 Hz, 2H), 5 7.71 (d, J= 2.1 Hz, IH), 7.52 (d, J= 8.2 Hz, IH), 7.45 - 7.27 (m, 2H), 7.15 - 6.95 (m,
2H), 6.81 (d, ./=8.1 Hz, IH), 4.78 (t, 7=6.2 Hz, IH), 4.72 -4.56 (m, 2H), 4.36 - 4.20 (m, 2H), 3.29-3.06 (m, 2H), 2.31 - 2.21 (m, IH), 2.02 - 1.92 (m, IH).
Example-154: (R/S)-4-(2-(2-fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(5-fluoro pyrimidin-2-yl)chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-45b and 5-fluoropyrimidin-2-amine. LCMS(ESI): m/z 500.07(M+H)+ ; ’H NMR (400 MHz, DMSOé6) δ 11.89 (s, IH), 8.66 (s, 2H), 7.72 (s, IH), 7.52 (d, J= 8.2 Hz, IH), 7.43 -7.33 (m, 2H), 7.03 (d, J= 8.3 Hz, IH), 6.82 (d, J = 15 8.1 Hz, IH), 4.78 (t, J = 6.2 Hz, IH), 4.70 - 4.62 (m, 2H), 4.31 - 4.20 (m, 2H), 3.32 3.12 (m, 2H), 2.30-2.20 (m, IH), 2.07 - 1.95 (m, IH).
Example-155: (R/S)-4-(2-(2-fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide
164
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-45b and pyrimidin-4-amine. LCMS(ESI): m/z 482.27(M+H)+ ; 'H NMR (400 MHz, DMSO-76) δ 8.66 (s, IH), 8.36 (s, IH), 7.71 (s, IH),
7.57 - 7.47 (m, IH), 7.39 - 7.24 (m, 2H), 7.10 - 6.95 (m, 2H), 6.80 (d, J = 8.0 Hz, IH),
4.78 (t, 7=6.2 Hz, IH), 4.71 -4.60 (m, 2H), 4.31 -4.21 (m, 2H), 3.32 - 3.15 (m, 2H), 2.28 - 2.18 (m, 1 H), 2.03 - 1.93 (m, 1 H).
Example-156: (R/S)-4-(2-(2-fluoroethyI)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3-yI) chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-45b and pyridazin-3-amine. LCMS(ESI): m/z 482.03(M+H)+ ; ’H NMR (400 MHz, DMSO-76) δ 14.52 (s, IH), 8.31 (s, IH), 7.92 (s, 1 H), 7.77 - 7.65 (m, 2H), 7.52 (d, 7 = 8.3 Hz, 1 H), 7.32 - 7.19 (m, 2H), 7.03 (d, 7 = 8.2 15 Hz, IH), 6.77 (d, 7= 8.1 Hz, IH), 4.79 (t, 7= 6.2 Hz, IH), 4.72 - 4.56 (m, 2H), 4.32 4.19 (m, 2H), 3.31 -3.12 (m, 2H), 2.31 -2.18 (m, IH), 2.02- 1.92 (m, IH).
Example-157: (R/S)-4-(2-(2-fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin2-yl)chroman-7-sulfonamide
165
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-45b and 6-fluoropyridin-2-amine. LCMS(ESI): m/z 499.07(M+H)+ ; 'H NMR (400 MHz, DMSO-î/6) δ 11.39 (s, IH), 7.92 - 7.83 (m, IH), 7.71 (d, J=2.0Hz, IH), 7.51 (dd, J = 8.2, 2.0 Hz, IH), 7.38 (d, J = 2.0 Hz, IH), 7.32 (dd, J = 8.1, 2.0 Hz, 1 H), 7.06 - 6.95 (m, 2H), 6.83 (d, J = 8.1 Hz, 1 H), 6.77 (dd, J = 8.0, 2.5 Hz, 1 H), 4.77 (t, J = 6.2 Hz, 1 H), 4.70 - 4.59 (m, 2H), 4.35 - 4.19 (m, 2H), 3.31 - 3.08 (m, 2H), 2.31 -2.17 (m, IH), 2.04-1.91 (m, IH).
Example-158: (R/S)-4-(2-(3-fluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-47b and pyrimidin-2-amine LCMS(ESI): m/z 496.08(M+H)+; ’H NMR (400 MHz, DMSO-e/6) δ 11.75 (s, IH), 8.60-8.46 (m, 2H), 7.64 (s, IH), 7.49 (d, J = 8.3 Hz, IH), 7.45 - 7.33 (m, 2H), 7.15-6.99 (m, 2H), 6.81 (d, J = 8.2 Hz, IH), 4.64 - 4.52 (m, 2H), 4.48 - 4.40 (m, IH), 4.33 - 4.22 (m, 2H), 2.98 - 2.81 (m, 2H), 2.28-2.17 (m, IH), 2.07 - 1.91 (m, 3H).
Example-159:
(R/S)-4-(2-(3-fluoropropyl)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide
166
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-47b and 5-fluoropyrimidin-2-amine. LCMS(ESI): m/z 513.94(M+H)+; *H NMR (400 MHz, DMSO-A) δ 11.89 (s, IH), 8.66 (s, 2H), 7.64 (d, J = 1.9 Hz, 1 H), 7.48 (d, 1 H), 7.43 - 7.29 (m, 2H), 7.03 (d, J = 8.2 Hz, 1 H), 6.82 (d, J = 8.2
Hz, IH), 4.64 - 4.52 (m, 2H), 4.44 (t, J = 5.9 Hz, IH), 4.33 - 4.23 (m, 2H), 2.97 - 2.80 (m, 2H),2.30-2.21 (m, 1 H), 2.08 - 1.90 (m, 3H).
Example-160: (R/S)-4-(2-(3-fluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-47b and pyrimidin-4-amine. LCMS(ESI): m/z 496.10(M+H)+; 'H NMR (400 MHz, DMSO-ri6) δ 8.59 (s, IH), 8.29 (d, J= 6.3 Hz, IH), 7.62 (d, J= 2.0 Hz, IH), 7.54 - 7.44 (m, IH), 7.34 - 7.24 (m, 2H), 7.06 - 6.96 (m, 2H), 15 6.77 (d, J = 8.1 Hz, IH), 4.62 - 4.52 (m, 2H), 4.44 (t, J= 5.9 Hz, IH), 4.30 - 4.22 (m,
2H), 2.95 - 2.77 (m, 2H), 2.29 - 2.20 (m, 1 H), 2.07 - 1.87 (m, 3H).
Example-161: (R/S)-4-(2-(3-fluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide
167
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-47b and pyridazin-3-amine. LCMS(ESI): m/z 495.95(M+H)+; ‘H NMR (400 MHz, DMSOé6) δ 14.52 (s, IH), 8.34 - 8.29 (m, IH), 5 7.97 - 7.86 (m, 1 H), 7.70 (dd, J = 9.6, 4.2 Hz, 1 H), 7.63 (s, 1 H), 7.49 (d, J = 8.2 Hz, 1 H),
7.29 - 7.21 (m, 2H), 7.03 (d, J = 8.2 Hz, IH), 6.77 (d, J = 8.0 Hz, IH), 4.63 - 4.53 (m, 2H), 4.45 (t, J = 5.9 Hz, 1 H), 4.31 - 4.23 (m, 2H), 2.98 - 2.83 (m, 2H), 2.30 - 2.21 (m, IH), 2.07- 1.89 (m, 3H).
Example-162: (R/S)-4-(2-(3-fluoropropyl)-4-(trifluoromethyl)phenyl)-N-(610 fluoropyridin-2-yl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-47b and 6-fluoropyridin-2-amine. LCMS(ESI): m/z 513.08(M+H)+; 'H NMR (400 MHz, DMSOé6) δ 11.38 (s, IH), 7.93 - 7.82 (m, IH),
7.64 (s, IH), 7.48 (d, J = 8.2 Hz, IH), 7.41 - 7.29 (m, 2H), 7.06 - 6.94 (m, 2H), 6.87 6.73 (m, 2H), 4.65 - 4.52 (m, 2H), 4.44 (t, J = 6.0 Hz, IH), 4.36 - 4.19 (m, 2H), 2.95 2.81 (m, 2H), 2.30-2.19 (m, IH), 2.07 - 1.88 (m, 3H).
Example-163 : (R/S)-4-(2-(4-fluorobutyl)-4-(tri fluoromethyl )phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide
168
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-49b and pyrimidin-2-amine. LCMS(ESI): m/z 510.11(M+H)+; *H NMR (400 MHz, DMSO-J6) δ 11.74 (s, IH), 8.54 (d, J= 4.8 Hz, 2H), 7.62 (s, IH), 7.51 - 7.24 (m, 3H), 7.21 - 6.99 (m, 2H), 6.79 (d, J = 8.2 Hz, IH), 4.68 4.50 (m, 2H), 4.44 - 4.17 (m, 3H), 2.95 - 2.71 (m, 2H), 2.30 - 1.95 (m, 2H), 1.79 - 1.44 (m, 4H).
Example-164: (R/S)-4-(2-(4-fluorobutyl)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-49b and 5-fluoropyrimidin-2-amine. LCMS(ESI): m/z 528.12(M+H)+; ‘H NMR (400 MHz, DMSO-76) δ 11.88 (s, IH), 8.66 (s, 2H), 7.62 (s, IH), 7.47 (d, IH), 7.43 -7.34 (m, 2H), 7.02 (d,J=8.2 Hz, IH), 6.80 (d,J=8.1 Hz, IH), 4.65 - 4.50 (m, 2H), 4.45 - 4.25 (m, 3H), 2.95 - 2.73 (m, 2H), 2.30 - 2.18 (m, IH), 2.07 - 1.94 (m, 1 H), 1.81 - 1.53 (m, 4H).
Example-165: (R/S)-4-(2-(4-fluorobutyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide
169
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-49b and pyrimidin-4-amine. LCMS(ESI): m/z 510.05(M+H)+; *H NMR (400 MHz, DMSO-J6) δ 8.66 (s, IH), 8.40(s, IH), 7.62 (d, J = 2.0 Hz, 1 H), 7.49 - 7.45 (m, 1 H), 7.38 - 7.24 (m, 2H), 7.03 (d, J = 8.2 Hz, 2H), 6.78 (d, J = 8.2 Hz, IH), 4.60 (t, 7=7.2 Hz, IH), 4.53 (t,7=5.8 Hz, IH), 4.44-4.39 (m, 1 H), 4.35 - 4.22 (m, 2H), 2.91 - 2.74 (m, 2H), 2.29 - 2.20 (m, IH), 2.06 - 1.95 (m, IH), 1.84 1.59 (m, 4H).
Example-166: (R/S)-4-(2-(4-fluorobutyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3-yl) chroman-7-sul fonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-49b and pyridazin-3-amine. LCMS(ESI): m/z 510.07(M+H)+; 'H NMR (400 MHz, DMSO-76) δ 14.52 (s, IH), 8.32 (s, IH), 7.91 (s, IH), 7.70 (dd, 7 = 9.5, 4.1 Hz, IH), 7.62 (d, 7 = 2.0 Hz, IH), 7.47 (dd, J = 8.3, 2.0 Hz, IH), 7.32 - 7.20 (m, 2H), 7.09 - 6.99 (m, IH), 6.75 (d, 7= 8.0 Hz, IH), 4.63 - 4.49 (m, 2H), 4.47 - 4.39 (m, IH), 4.34-4.21 (m, 2H), 2.94 - 2.73 (m, 2H), 2.25 - 2.19 (m, IH), 2.07 - 1.97 (m, 1 H), 1.82 - 1.59 (m, 4H).
Example-167: (R/S)-4-(2-(4-fluorobutyl)-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin2-yl)chroman-7-sulfonamide
170
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-49b and 6-fluoropyridin-2-amine. LCMS(ESI): m/z 527.06(M+H)+; ‘H NMR (400 MHz, DMSO-î/6) δ 11.37 (s, IH), 7.87 (dd, J = 8.2 Hz, IH), 7.62 (d, J= 2.0 Hz, IH), 7.49 - 7.44 (m, IH), 7.38 (d, J= 1.9 Hz, IH), 7.32 (dd, J = 8.2, 1.9 Hz, IH), 7.05 - 6.94 (m, 2H), 6.84 - 6.74 (m, 2H), 4.61 (t, J = 7.2 Hz, IH), 4.53 (t, J= 5.8 Hz, IH), 4.44 - 4.37 (m, IH), 4.33 - 4.22 (m, 2H), 2.92 - 2.71 (m, 2H), 2.30 2.16 (m, IH), 2.06- 1.97 (m, IH), 1.85- 1.49 (m, 4H).
Example-168/169: (R&S)-N-(pyrimidin-2-yl)-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide
CF3 CF3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-51 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: (Acetonitrile + 0.1% TFA), to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 4.82 min (Example-168) and rétention time 5.99 min (Example-169).
LCMS(ESI): m/z 535.94(M+H)+; *H NMR (400 MHz, Chloroformé) δ 8.66 (d, J = 4.9 Hz, 2H), 7.68 (d,J=1.9 Hz, IH), 7.56 (dd,J=8.2, 1.9 Hz, IH), 7.14 (d, J = 7.9 Hz, IH), 7.09 - 6.89 (m, 4H), 4.65 - 4.53 (m, 2H), 4.30 - 4.19 (m, 2H), 3.90- 3.70 (m, 2H),3.653.53(m, 2H), 2.29 - 2.18 (m, 2H),2.10-2.01 (m, IH), 1.97 - 1.75 (m, 2H), 1.60-1.40(m ,1H).
171
Example-170/171: (R&S)-N-(5-fluoropyrimidin-2-yl)-4-(2-((tetrahydro-2H-pyran-4yl)oxy)-4-(trifluoromethyl)phenyl)chroman-7-sulfonamide
CF3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-51 and 5-fluoropyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 50:50, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.37 min (Example-170) and rétention time 7.90 min (Example-171).
LCMS(ESI): m/z 553.95(M+H)+; *H NMR (400 MHz, DMSOé6) δ 11.84 (s, IH), 8.65 (s, 2H), 7.39 (d, J= 2.0 Hz, IH), 7.35 (dd, J= 8.1, 1.9 Hz, IH), 7.32 (s, IH), 7.24 (d, J = 6.4 Hz, 2H), 6.88 (d, J= 8.1 Hz, IH), 4.75-4.65 (m, IH), 4.53 (t, J= 7.3 Hz, IH), 4.304.17 (m, 2H), 3.63 (d, J= 7.9 Hz, IH), 3.50 - 3.38 (m, 3H), 2.32 - 2.06 (m, 2H), 1.901.84 (m, IH), 1.68-1.41 (m, 2H), 1.24-1.06(m, IH).
Example-172/173: (R&S)-N-(pyrimidin-4-yl)-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide
CF3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-51 and pyrimidin-4-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B =
172
40:60, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 7.07 min (Example-172) and rétention time 8.09 min (Example-173).
LCMS(ESI): m/z 535.94(M+H)+; ‘H NMR (400 MHz, DMSO-t/6) δ 8.66 (s, IH), 8.38 (s, IH), 7.32 (d, 7= 2.8 Hz, 3H), 7.23 (q,7= 8.0 Hz, 2H), 7.07 (s, IH), 6.87 (d,7= 7.9 Hz, IH), 4.75-4.65 (m, IH), 4.53 (t,7= 7.3 Hz, IH), 4.28-4.10 (m, 2H), 3.71-3.19 (m, 4H), 2.30-2.05 (m, 2H), 1.95 - 1.85 (m, 1 H), 1.71 - 1.45 (m, 2H), 1.19 - 1.02 (m, 1 H). Example-174/175: (R&S)-N-(pyridazin-3-yl)-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-51 and pyridazin-3-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 40:60, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 8.71 min (Example-174) and rétention time 10.18 min (Example-175).
LCMS(ESI): m/z 535.94(M+H)+; 'H NMR (400 MHz, DMSO-76) δ 14.52 (s, IH), 8.31 (s, 1 H),7.89(s, 1 H), 7.69 (dd, J = 9.5, 4.2 Hz, 1 H), 7.32 (s, 1 H), 7.28 -7.12 (m, 4H), 6.84 (d, 7 = 8.1 Hz, 1 H), 4.75 - 4.70 (m, 1 H), 4.53 (t, J = 7.0 Hz, 1 H), 4.25 - 4.17 (m, 2H), 3.68-3.63 (m, IH), 3.52 - 3.42 (m, 3H), 2.25 -2.07 (m, 2H), 1.94- 1.88 (m, IH), 1.69 - 1.49 (m, 2H), 1.35-1.05(m , IH).
Example-176/177: (R&S)-N-(6-fluoropyridin-2-yl)-4-(2-((tetrahydro-2H-pyran-4yl)oxy)-4-(trifluoromethyl)phenyl)chroman-7-sulfonamide
173
cf3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-51 and 6-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 60:40, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.98 min (Example-176) and rétention time 8.06 min (Example-177).
LCMS(ESI): m/z 552.82(M+H)+; 'H NMR (400 MHz, DMSO-76) δ 11.35 (s, IH), 7.86 (dd, J= 8.2 Hz, IH), 7.38-7.17 (m, 5H), 6.97 (dd, J= 7.9, 2.1 Hz, IH), 6.89 (d, J= 8.1 Hz, 1 H), 6.76 (dd, 7= 8.0, 2.4 Hz, IH), 4.72-4.65 (m, IH), 4.53 (t,7=7.3 Hz, IH), 4.30 - 4.16 (m, 2H), 3.70 - 3.61 (m, IH), 3.52 - 3.42 (m, 2H), 3.32 - 3.23 (m, IH), 2.28 2.07 (m, 2H), 1.94 - 1.86 (m, 1 H), 1.62 - 1.48 (m, 2H), 1.13 - 0.99 (m, 1 H).
Example-178/179: (R&S)-N-(pyrimidin-2-yl)-4-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide
cf3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-53 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 30:70, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 7.21 min (Example-178) and rétention time 9.80 min (Example-179).
174
LCMS(ESI): m/z 522.04(M+H)+; 'H NMR (400 MHz, DMSOé6) δ 11.75 (s, IH), 8.53 (d, J= 5.0 Hz, 2H), 7.42 - 7.33 (m, 2H), 7.32 - 7.24 (m, 2H), 7.14 - 7.05 (m, 2H), 6.89 (d, J = 8.0 Hz, IH), 5.20 - 5.12 (m, IH), 4.52 (t, J = 6.8 Hz, IH), 4.27-4.12 (m, 2H), 3.79 - 3.55 (m, 4H), 2.24 - 1.95 (m, 4H).
Example-180/181: (R&S)-N-(6-fluoropyridin-2-yl)-4-(2-(((S)-tetrahydrofuran-3-yl)oxy)4-(trifluoromethyl)phenyl)chroman-7-sulfonamide
CF3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-53 and 6-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 65:35, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 7.07 min (Example-180) and rétention time 7.84 min (Example-181).
LCMS(ESI): m/z 539.10(M+H)+; *H NMR (400 MHz, DMSOé6) δ 11.36 (s, IH), 7.87 (dd, J = 8.1 Hz, 1 H), 7.36 (d, J = 1.9 Hz, 1 H), 7.33-7.18 (m, 4H), 6.98 (dd, J = 7.9, 2.1 Hz, IH), 6.89 (d, 7=8.1 Hz, IH), 6.76 (dd, 7= 8.1, 2.5 Hz, 1 H), 5.11 (d,7=5.7Hz, IH), 4.48 (t, J = 7.2 Hz, 1 H), 4.27 -4.15 (m, 2H), 3.85 (dd, 7 = 10.1,4.4 Hz, 1 H), 3.69 (d, J = 10.1 Hz, IH), 3.61 -3.41 (m, 2H), 2.20-2.05 (m, 2H), 1.91 - 1.80 (m, IH), 1.58-1.44(m, IH).
Example-182: (S/R)-N-(5-fluoropyrimidin-2-yl)-4-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide
CF3
175
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-53b and 5-fluoropyrimidin-2-amine.
LCMS(ESI): m/z 540.07 (M+H)+; 'H NMR (400 MHz, DMSO-î/6) δ 11.86 (s, IH), 8.65 (s, 2H), 7.38 (d, J = 1.9 Hz, IH), 7.34 (dd, J= 8.1, 2.0 Hz, IH), 7.30-7.24 (m, 2H), 7.19 (d, J =7.8 Hz, IH), 6.88 (d,J=8.1 Hz, IH), 5.14 (t, J =5.2 Hz, IH), 4.49 (t, J =7.2 Hz, IH), 4.26-4.14 (m, 2H), 3.87 (dd,J= 10.1,4.4 Hz, 1 H), 3.69 (d,J = 10.1 Hz, IH), 3.61 - 3.53 (m, IH), 3.48 - 3.39 (m, IH), 2.22 - 2.08 (m, 2H), 1.97 - 1.87 (m, IH), 1.51 1.39 (m, IH).
Example-183: (S/R)-N-(pyrimidin-4-yl)-4-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-53b and pyrimidin-4-amine. LCMS(ESI): m/z 540.07 (M+H)+; 'H NMR (400 MHz, DMSO-J6) δ 8.67 (s, IH), 8.38 (s, IH), 7.40 - 7.23 (m, 4H), 7.19 (d, J =8.0 Hz, IH), 7.07 (s, IH), 6.88 (d,J=8.0 Hz, IH), 5.20-5.06 (m, IH), 4.49 (t, J=7.3 Hz, IH), 4.25-4.14 (m, 2H), 3.87 (dd, J = 10.2, 4.6 Hz, IH), 3.78 - 3.54 (m, 3H), 2.22 - 2.07 (m, 2H), 1.98 - 1.84 (m, 1 H), 1.59- 1.35 (m, 1 H).
Example-184: (S/R)-N-(pyridazin-3-yl)-4-(2-(((S)-tetrahydrofiiran-3-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide
O,, \ O
CF3
The title compound was prepared by following the similar procedure as described in
Example-1/2 using Intermediate-53b and pyridazin-3-amine. LCMS(ESI): m/z 522.08
176 (M+H)+; 'H NMR (400 MHz, DMSO-îZ6) δ 8.31 (s, IH), 7.93 (s, IH), 7.71 (s, IH), 7.36 7.20 (m, 4H), 7.15 (d, J = 8.0 Hz, 1 H), 6.85 (d, J = 8.1 Hz, 1 H), 5.22 - 5.12 (m, 1 H), 4.55 -4.45 (m, IH), 4.26 -4.11 (m, 2H), 3.95-3.43 (m, 4H), 2.25-2.07 (m, 3H), 1.65 - 1.48 (m, IH).
Example-185/186: (S&R)-N-(pyrimidin-2-yl)-4-(2-(((R)-tetrahydrofuran-3-yl)oxy)-4(trifluoro methyl)phenyl)chroman-7-sulfonamide
CF3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-55 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 30:70, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 7.08 min (Example-185) and rétention time 9.87 min (Example-186).
LCMS(ESI): m/z 522.15(M+H)+; *H NMR (400 MHz, DMSO-76) δ 11.72 (s, IH), 8.53 (d, J = 4.9 Hz, 2H), 7.42 - 7.32 (m, 2H), 7.31 - 7.23 (m, 2H), 7.19 (d, J= 7.9 Hz, IH), 7.08 (t, J = 4.9 Hz, 1 H), 6.88 (d, J = 8.1 Hz, 1 H), 5.12 (s, 1 H), 4.49 (t, J = 7.1 Hz, 1 H), 4.20 (t, J= 5.0 Hz, 2H), 3.86 (dd, J= 10.2, 4.4 Hz, IH), 3.70 (d, J = 10.2 Hz, IH), 3.62 3.52 (m, IH), 3.51 -3.40 (m, IH), 2.17 - 2.07 (m, 2H), 1.94- 1.85 (m, IH), 1.49-1.41 (m, IH).
Example-187/188: (S&R)-2'-(7-(N-(pyrimidin-2-yl)sulfamoyl)chroman-4-yl)-5'(trifluoromethyl)-[ 1,1 '-biphenyl]-4-carboxylic acid
177
Step-1 : (S&R)-tert-butyl 2'-(7-(N-(pyrimidin-2-yl)sulfamoyl)chroman-4-yl)-5'(trifluoromethyl)-[ 1,1 '-biphenyl]-4-carboxylate
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-57 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (MeOH: DCM = 1:1), A:B = 80:20, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 8.96 min and rétention time 10.18 min respectively.
LCMS (ESI): m/z 612.14(M+H)+;
Step-2: (S&R)-2'-(7-(N-(pyrimidin-2-yl)sulfamoyl)chroman-4-yl)-5'-(trifluoromethyl)[1,1 ’-biphenyl]-4-carboxylic acid
To a stirred solution of (S/R)-tert-butyl 2'-(7-(N-(pyrimidin-2-yl)sulfamoyl)chroman-4yl)-5'-(trifluoromethyl)-[l,l'-biphenyl]-4-carboxylate (Isomer-1) (0.045g, 0.074 mmol) in DCM (10 ml), TFA (0.057 ml, 0.736 mmol) was added and stirred for 4h at room température. After completion of reaction as indicated by TLC, the reaction mixture was evaporated to dryness and washed with pentane to obtain white solid (0.035g, 86%) (Example-187).
Similarly Isomer-2 of stepl was treated with TFA and got the Example-188.
LCMS(ESI): m/z 555.82(M+H)+; *H NMR (400 MHz, DMSO-c/6) δ 8.52 (d, J= 4.9 Hz, 2H), 8.04 (d, J= 8.0 Hz, 2H), 7.71 (d, J= 8.3 Hz, 1H), 7.65 - 7.58 (m, 3H), 7.41 - 7.33 (m, 2H), 7.24 (d, J = 8.3 Hz, 1 H), 7.07 (t, J = 4.9 Hz, 1 H), 6.92 (d, J = 8.7 Hz, 1 H), 4.33 - 4.20 (m, 2H), 4.10 (t, J = 10.2 Hz, 1 H), 2.14 - 1.97 (m, 2H).
Example-189/190: (S&R)-2'-(7-(N-(5-fluoropyrimidin-2-yl)sulfamoyl)chroman-4-yl)5'-(trifluoromethyl)-[ 1,1 -biphenyl]-4-carboxylic acid
178
Step-1 : (S&R)-tert-butyl 2'-(7-(N-(5-fluoropyrimidin-2-yl)sulfamoyl)chroman-4-yl)-5'(trifluoromethyl)-[ 1,1 '-biphenyl]-4-carboxylate
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-57 and 5-fluoropyrimidin-2-amine).
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% TFA), B = (MeOH: DCM = 1:1), A:B = 80:20, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 8.02 min and rétention time 9.26 min respectively.
LCMS (ESI): m/z 652.12(M+Na)+;
Step-2: (S&R)-2'-(7-(N-(5-fluoropyrimidin-2-yl)sulfamoyl)chroman-4-yl)-5'(trifluoromethyl) -[l,T-biphenyl]-4-carboxylic acid
The title compound was prepared by following similar procedure as described in Example-187/188 (Step-2) using step-1 intermediates.
LCMS(ESI): m/z 573.82(M+H)+; 'H NMR (400 MHz, DMSOé6) δ 11.88 (s, IH), 8.64 (s, 2H), 8.04 (d, J = 7.9 Hz, 2H), 7.77 - 7.67 (m, IH), 7.65 - 7.60 (m, 3H), 7.40 - 7.33 (m, 2H), 7.24 (d, J = 8.3 Hz, 1 H), 6.93 (d, J = 8.5 Hz, 1 H), 4.34 - 4.20 (m, 2H), 4.10 (t, J = 10.2 Hz, 1 H), 2.13 - 1.98 (m, 2H).
179
ExampIe-191: (R/S)-2'-(7-(N-(pyridazin-3-yl)sulfamoyl)chroman-4-yl)-5'(trifluoromethyl)-[ 1,1 '-biphenyl]-4-carboxylic acid
CF3
Step-1: tert-butyl (R/S)-2'-(7-(N-(pyridazin-3-yl)sulfamoyl)chroman-4-yl)-5'5 (trifluoromethyl)-[ 1,1 '-biphenyl]-4-carboxylate
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-57b and pyridazin-3-amine.
LCMS (ESI): m/z 612.14(M+H)+;
Step-2: (R/S)-2'-(7-(N-(pyridazin-3-yl)sulfamoyl)chroman-4-yl)-5'-(trifluoromethyl)[1,1 ’-biphenyl]-4-carboxylic acid
The tert-butyl deprotection was carried out as described in Example-187/188 using TFA to obtain title compound. LCMS(ESI): m/z 555.82(M+H)+; 'H NMR (400 MHz, DMSOde) δ 8.34 (s, IH), 8.05 (d, J= 8.0 Hz, 2H), 7.87 (d, J= 9.6 Hz, IH), 7.76 - 7.66 (m, 2H), 15 7.65 - 7.57 (m, 3H), 7.28 - 7.20 (m, 3H), 6.87 (d, J= 8.0 Hz, IH), 4.27 - 4.02 (m, 3H),
2.15-1.98 (m, 2H).
Example-192: (R/S)-2'-(7-(N-(6-fluoropyridin-2-yl)sulfamoyl)chroman-4-yl)-5'(trifluoromethyl)-[ 1,1 '-biphenyl]-4-carboxylic acid
180
cf3
Step-1 : tert-Butyl (R/S)-2'-(7-(N-(6-fluoropyridin-2-yl)sulfamoyl)chroman-4-yl)-5'(trifluoromethyl)-[ 1,1 '-biphenyl]-4-carboxylate
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-57b and 6-fluoropyridin-2-amine. LCMS (ESI): m/z 628.71 (M+H)+;
Step-2: (R/S)-2'-(7-(N-(6-fluoropyridin-2-yl)sulfamoyl)chroman-4-yl)-5'(trifluoromethyl)-[ 1,1 '-biphenyl]-4-carboxylic acid
The tert-butyl deprotection was carried out as described in Example-187 using TFA to obtain title compound. ‘H NMR (400 MHz, DMSO-J6) δ 13.09 (s, IH), 11.37 (s, IH), 8.03 (d, J= 7.9 Hz, 2H), 7.86 (dd, J= 8.2 Hz, IH), 7.70 (d, IH), 7.65 - 7.57 (m, 3H), 7.37 - 7.28 (m, 2H), 7.22 (d, J = 8.3 Hz, IH), 7.00 - 6.92 (m, 2H), 6.75 (dd, J = 7.9, 2.4 Hz, IH), 4.35-4.18 (m, 2H), 4.10 (t, J = 10.2 Hz, IH), 2.18 - 1.97 (m, 2H).
Example-193/194: (S&R)-4-(2-(5-fluoropyridin-2-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide
cf3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-59 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = l:l), A:B = 30:70, to afford isomer-l and isomer-2. These isomers were obtained at rétention time 6.49 min (Example-193) and rétention time 7.80 min (Example-194).
LCMS(ESI): m/z 531.02 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ H.79 (s, IH), 8.69 (d, J= 2.9 Hz, IH), 8.53 (d, J=4.9 Hz, 2H), 7.89 (td, J= 8.7, 3.0 Hz, IH), 7.79 (dd, J = 8.7, 4.5 Hz, IH), 7.76 - 7.69 (m, 2H), 7.41 - 7.34 (m, 2H), 7.24 (d, J = 8.1 Hz, IH), 7.07 (t,J=4.9 Hz, IH), 6.91 (d, J=8.2 Hz, IH), 4.57 (t, J= 7.2 Hz, IH), 4.29-4.2l (m, IH), 4.16-4.09 (m, IH), 2.21 - 2.15 (m, IH), 2.11 - 2.03 (m, IH).
Example-195/196: (S&R)-4-(2-(5-fluoropyridin-2-yl)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-59 and 5-fluoropyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 30:70, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 4.97 min (Example-195) and rétention time 5.72 min (Example-196).
LCMS(ESI): m/z 548.70 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 11.88 (s, IH), 8.69 (d, J = 2.8 Hz, 1 H), 8.61 (s, 2H), 7.93 - 7.85 (m, 1 H), 7.79 (dd, J = 8.8, 4.4 Hz, 1 H), 7.76 - 7.70 (m, 2H), 7.39 - 7.30 (m, 2H), 7.24 (d, J = 8.3 Hz, IH), 6.90 (d, J = 8.3 Hz, IH), 4.56 (t, J = 7.6 Hz, IH), 4.30 - 4.19 (m, IH), 4.15-4.05 (m, IH), 2.22 - 2.11 (m, IH), 2.11-2.00 (m, IH).
182
Exemple-197/198: (S&R)-4-(2-(5-fluoropyridin-2-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-4-yl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-59 and pyrimidin-4-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: (MeOH + 0.1% TFA) to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.96 min (Example-197) and rétention time 7.61 min (Example-198).
LCMS(ESI): m/z = 531.22 (M+H)+; ‘H NMR (400 MHz, DMSO-d6) δ 14.52 (s, IH), 8.70 (d, J= 2.9 Hz, IH), 8.30 (s, IH), 7.90 (td, J= 8.9, 3.1 Hz, 2H), 7.79 (dd, J= 8.7, 4.5 Hz, IH), 7.76 - 7.67 (m, 3H), 7.28 - 7.19 (m, 3H), 6.87 (d, J = 7.9 Hz, IH), 4.59 - 4.50 (m, 1 H), 4.27 - 4.19 (m, 1 H), 4.14 - 4.07 (m, 1 H), 2.25 - 2.12 (m, 1 H), 2.10 - 1.99 (m, IH).
Example-199/200: (S&R)-4-(2-(5-fluoropyridin-2-yl)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-59 and pyridazin-3-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: DCM = 1:1), A:B =
183
60:40, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 7.20 min (Example-199) and rétention time 8.24 min ((Example-200).
LCMS(ESI): m/z 531.09 (M+H)+; ‘H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J= 2.9 Hz, IH), 8.65 (s, IH), 8.37 (s, IH), 7.89 (td, 7= 8.7, 3.0 Hz, IH), 7.79 (dd, 7= 8.7, 4.5 Hz, IH), 7.76-7.70 (m, 2H), 7.30 (s, 2H), 7.25 (d,7=8.3 Hz, IH), 7.06 (s, IH), 6.91 (d,7 = 7.6 Hz, IH), 4.56 (t, IH), 4.29 - 4.21 (m, IH), 4.12 (t, J = 9.6 Hz, IH), 2.23 - 2.11 (m, IH), 2.11-1.98 (m, IH).
Example-201: (S)-4-(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin2-yl)chromane-7-sulfonamide
Step-1:
( S/R)-perfl uorophenyl -4-(2-(6-methyl pyridi n-3 - yl )-4-(tri fl uoromethy 1 )phenyl )chromane7-sulfonate:
A solution of 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.16g, 0.716 mmol) and (R/S)-perfluorophenyl 4-(2-chloro-4-(trifluoromethyl)phenyl)chroman7-sulfonate (Intermediate-27a) (0.20 g, 0.358 mmol) in 1,4-dioxane (5 ml) was purged with N2 for 10 min and then added into potassium phosphate dibasic (0.19g, 1.074 mmol), tri tert butylphosphanium tetrafluoroborate(0.010g, 0.036 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.044g, 0.054 mmol). The reaction mixture was heated in sealed tube at 100 °C for Ih. After completion of reaction, as indicated by TLC, reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and evaporated under vacuum. The crude was purified by column chromatography to obtain title compound (0.11 g, 49 %).
'H NMR (400 MHz, Chloroform-7) δ 8.59 (d, 7= 2.3 Hz, IH), 7.70 - 7.61 (m, 2H), 7.58 (s, 1 H), 7.49 (d, 7 = 1.9 Hz, 1 H), 7.40 - 7.32 (m, 2H), 7.13 (d, 7 = 8.2 Hz, 1 H), 6.95 (d, 7
184 = 8.2 Hz, IH), 4.42 - 4.31 (m, 2H), 4.19 - 4.10 (m, IH), 2.70 (s, 3H), 2.30 - 1.85 (m, 2H).
Step-2: (S)-4-(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl) chromane-7-sulfonamide
The title compound was prepared by following similar procedure as described in Example-1/2 using the product from step-1 and pyrimidin-2-amine.
LCMS(ESI): m/z 527.03(M+H)+; ‘H NMR (400 MHz, DMSO-î/6) δ 8.57 (d, J= 2.3 Hz, IH), 8.53 (d, 7=4.9 Hz, 2H), 7.84 (d,7=7.9 Hz, IH), 7.71 (d,7=8.3 Hz, IH), 7.61 (d, 7 = 2.0 Hz, IH), 7.41 - 7.34 (m, 3H), 7.23 (d, 7= 8.2 Hz, IH), 7.07 (t,7= 4.9 Hz, IH), 6.93 (d, 7= 8.4 Hz, IH), 4.33 - 4.19 (m, 2H), 4.16 - 4.07 (m, IH), 2.53 (s, 3H), 2.17 - 2.10 (m, 1 H), 2.06-2.00 (m, IH).
The absolute stereochemistry of Example-201 was assigned to be S using vibrational circulât dichroism (VCD) spectra.
Example-202: (R)-4-(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin2-yl)chroman-7-sulfonamide ci
To a solution of pyrimidin-2-amine(0.021g, 0.219 mmol) in dry THF (2 ml) was added LiHMDS (0.190 ml, IM in THF, 0.190 mmol) at 0 °C, and stirred for 10 min, then Intermediate- 61 (0.09g, 0.146 mmol) in THF (3 ml) was added. The résultant mixture was stirred for Ih. After completion of reaction as indicated by TLC, reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with water, brine dried over Na2SÛ4 and concentrated under vacuum. The crude product was purified by column chromatography to obtain title compound as white solid (0.02g, 26 %). LCMS(ESI): m/z 527.11(M+H)+; ‘H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1 H), 8.56 (d, 7 = 2.3 Hz, 1 H), 8.53 (d, 7 = 4.9 Hz, 2H), 7.82 (dd, 7 = 7.9, 2.4 Hz, 1 H), 7.70 (dd, 7 = 8.3, 2.0 Hz, 1 H), 7.62 (d, 7 = 2.0 Hz, 1 H), 7.41 - 7.32 (m, 3H), 7.23 (d, 7 =
185
8.3 Hz, 1 H), 7.07 (t, J = 4.9 Hz, 1 H), 6.93 (d, J = 8.5 Hz, 1 H), 4.31 - 4.19 (m, 2H), 4.164.07 (m, 1 H), 2.53 (s, 3H), 2.19- 2.08 (m, 1 H), 2.07 - 2.00 (m, 1 H).
The absolute stereochemistry of Example-202 was assigned to be R using vibrational circular dichroism (VCD) spectra. The compound having alpha configuration provided better in vitro activity against Navl .7.
Example-203 : (R/S)-N-(5-fluoropyrimidin-2-yl)-4-(2-(6-methylpyridin-3 -yl)-4-(trifluoro methyl)phenyl)chroman-7-sulfonamide
The title compound was prepared by following similar procedure as described for Example-202 using Intermediate-61 and 5-fluoropyrimidin-2-amine. LCMS(ESI): m/z 545.09(M+H)+; ‘H NMR (400 MHz, DMSO-d6) δ 11.88 (s, IH), 8.65 (s, 2H), 8.58 (s, IH), 7.87 (d, 7=7.9 Hz, IH), 7.71 (d,7=8.3 Hz, IH), 7.63 (s, IH), 7.41 (d,7=8.0 Hz, IH), 7.38 - 7.32 (m, 2H), 7.24 (d, J = 8.2 Hz, IH), 6.94 (d, J = 8.5 Hz, IH), 4.30 - 4.19 (m, 2H), 4.12 (t, 7 = 10.2 Hz, 1 H), 2.55 (s, 3H), 2.19 - 2.08 (m, 1 H), 2.08 - 1.95 (m, 1 H). Example-204: (R/S)-4-(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-4-yl)chroman-7-sulfonamide
The title compound was prepared by following similar procedure as described for Example-202 using Intermediate-61 and pyrimidin-4-amine. LCMS(ESI): m/z 527.04(M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 8.65 (s, IH), 8.56 (s, IH), 8.40 (s, IH),
7.83 (d, 7= 8.0 Hz, IH), 7.71 (d,7= 8.5 Hz, IH), 7.62 (s, IH), 7.38 (d,7= 8.0 Hz, IH),
186
7.30 (s, 2H), 7.24 (d, J = 8.5 Hz, 1 H), 7.10 (s, 1 H), 6.97 - 6.86 (m, 1 H), 4.33 - 4.18 (m, 2H), 4.18 - 4.06 (m, 1 H), 2.54 (s, 3H), 2.22 - 2.08 (m, 1 H), 2.08- 1.95 (m, 1 H).
Example-205: (R/S)-4-(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl)chroman-7-sulfonamide
CF3
The title compound was prepared by following similar procedure as described for Example-202 using Intermediate-61 and pyridazin-3-amine. LCMS(ESI): m/z 527.06(M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 8.65 (s, IH), 8.56 (s, IH), 8.40 (s, IH), 7.83 (d, 7= 8.0 Hz, IH), 7.71 (d,7 = 8.5 Hz, IH), 7.62 (s, IH), 7.38 (d,7= 8.0 Hz, IH), 10 7.30 (s, 2H), 7.24 (d, J = 8.5 Hz, 1 H), 7.10 (s, 1 H), 6.97 - 6.86 (m, 1 H), 4.33 - 4.18 (m,
2H), 4.18-4.06 (m, IH), 2.54 (s, 3H), 2.22-2.08 (m, IH), 2.08 - 1.95 (m, IH).
Example-206: (R/S)-N-(6-fluoropyridin-2-yl)-4-(2-(6-methylpyridin-3-yl)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide
CF3
Step-1: Perfluorophenyl 4-(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)chroman7-sulfonate
187
A solution of 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (3g, 13.69 mmol) and Intermediate-27 (4.5g, 8.05 mmol) in 1,4-dioxane (100 ml) was purged with nitrogen for 10 min. After which potassium phosphate dibasic (4.21g, 24.16 mmol), tri-tert-butylphosphanium tetrafluoroborate (0.23g, 0.805 mmol) and PdCl2(dppf)-CH2C12 adduct (0.99g, 1.208 mmol) was added then heated in seaied tube at 114 °C for 2h. After completion of reaction as indicated by TLC, reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography to obtain title compound (1.9g, 38 %). *H NMR (400 MHz, Chloroform-7) δ 8.60 (s, IH), 7.72 (d, 7= 7.9 Hz, IH), 7.64 (d,7= 8.2 Hz, IH), 7.57 (s, IH), 7.51 - 7.47 (m, IH), 7.43 - 7.34 (m, 2H), 7.13 (d, 7= 8.2 Hz, IH), 6.95 (d, 7= 8.2 Hz, IH), 4.40 -4.31 (m, 2H), 4.20 - 4.12 (m, IH), 2.73 (s, 3H), 2.30-1.85(m, 2H).
Step-2: (R/S)-N-(6-fluoropyridin-2-yl)-4-(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide
The title compound was prepared by following similar procedure as described for Example-202 using Perfluorophenyl 4-(2-(6-methylpyridin-3-yl)-4(trifluoromethyl)phenyl)chroman-7-sulfonate (Step-1) and 6-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 60:40, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 8.27 min and rétention time 9.50 min (Example-206).
LCMS(ESI): m/z 544.03(M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 11.37 (s, IH), 8.55 (d, 7=2.3 Hz, IH), 7.90-7.78 (m, 2H), 7.70 (dd,7= 8.4, 1.9 Hz, 1 H), 7.62 (s, 1 H), 7.36 (d, 7 = 8.0 Hz, IH), 7.34 - 7.29 (m, 2H), 7.22 (d, 7= 8.2 Hz, IH), 6.95 (d, 7= 8.0 Hz,
188
2H), 6.73 (d, J= 8.0 Hz, IH), 4.31-4.19 (m, 2H), 4.12 (t, J = 10.2 Hz, IH), 2.53 (s, 3H), 2.16-2.08 (m, 1 H), 2.05- 1.95 (m, 1 H).
Example-207: (R/S)-4-(2-(2-oxooxazolidin-3-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-63b and pyrimidin-2-amine. LCMS(ESI): m/z 520.94 (M+H)+; ’H NMR (400 MHz, DMSO-d6) δ 11.74 (s, IH), 8.54 (d, J= 4.9 Hz, 2H), 7.99 (s, IH), 7.66 (d, J=8.2 Hz, IH), 7.41 (s, IH), 7.36 (dd, J= 8.1, 1.9 Hz, IH), 7.22 (d,J = 8.2 Hz, IH), 7.08 (t, J = 4.9 Hz, IH), 6.87 (d, J=8.1 Hz, IH), 4.61 (t, J=8.7, 6.1 Hz, IH), 4.54-4.41 (m, 2H), 4.33 -4.23 (m, 2H), 4.11-3.90 (m, 2H), 2.31 -2.19 (m, IH), 2.10-1.96 (m, IH).
Example-208: (R/S)-N-(5-fluoropyrimidin-2-yl)-4-(2-(2-oxooxazolidin-3-yl)-4-(trifluoro methyl)phenyl)chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-63b and 5-fluoropyrimidin-2-amine. LCMS(ESI): m/z 539.02 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ 11.88 (s, IH), 8.66 (s, 2H), 7.99 (s, IH), 7.66 (d, J= 8.2 Hz, IH), 7.44-7.30 (m, 2H), 7.21 (d, J= 8.2 Hz, IH), 6.88 (d, J = 8.2 Hz, IH), 4.61 (t, J = 7.6 Hz, IH), 4.56 - 4.41 (m, 2H), 4.34 - 4.22 (m, 2H), 4.12 4.01 (m, IH), 4.01 -3.90 (m, 1 H), 2.30 - 2.20 (m, IH), 2.08 - 1.97 (m, IH).
189
Example-209: (R/S)-4-(2-(2-oxooxazolidin-3-yl)-4-(trifluoromethyl)phenyl)-N(pyridazin-3 -yl)chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in 5 Example-1/2 using Intermediate-63b and pyridazin-3-amine.
LCMS(ESI): m/z 520.94 (M+H)+; ‘H NMR (400 MHz, DMSO-d6) δ 14.52 (s, IH), 8.33 (s, IH), 8.02 - 7.96 (m, IH), 7.89 (s, IH), 7.75 - 7.63 (m, 2H), 7.28 - 7.18 (m, 3H), 6.83 (d, 7=8.0 Hz, IH), 4.59 (t, 7= 7.3 Hz, IH), 4.54-4.46 (m, 2H), 4.30-4.21 (m, 2H), 4.12 - 3.94 (m, 2H), 2.32 - 2.20 (m, IH), 2.08 - 2.00 (m, IH).
Example-210: (R/S)-N-(6-fluoropyridin-2-yl)-4-(2-(2-oxooxazolidin-3-yl)-4(trifluoromethyl)phenyl)chromane-7-sulfonamide
F
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-63b and 6-fluoropyridin-2-amine. LCMS(ESI): m/z 15 537.95 (M+H)+; ‘H NMR (400 MHz, DMSOé6) δ 11.40 (s, IH), 7.99 (s, IH), 7.93 7.81 (m, IH), 7.66 (d,7=8.3 Hz, IH), 7.39-7.28 (m, 2H), 7.21 (d,7=8.3 Hz, 1H),6.96 (d, 7= 8.0 Hz, IH), 6.88 (d, 7= 8.2 Hz, IH), 6.75 (d, 7= 8.0 Hz, IH), 4.61 (t, 7= 7.5 Hz, IH), 4.54 - 4.40 (m, 2H), 4.35 - 4.24 (m, 2H), 4.12 - 3.88 (m, 2H), 2.30 - 2.19 (m, IH), 2.11-1.95 (m, IH).
190
Example-211: (R/S)-4-(2-(3,3-difluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin2-yl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-65b and pyrimidin-2-amine. LCMS(ESI): m/z 513.94(M+H)+; 'H NMR (400 MHz, DMSO-î/6) δ 11.75 (s, IH), 8.54 (d, J= 4.9 Hz, 2H), 7.68 (d, J = 2.0 Hz, IH), 7.57 - 7.31 (m, 3H), 7.14 - 6.93 (m, 2H), 6.83 (d, J = 8.1 Hz, 1 H), 6.23 (t, 1 H), 4.59 (t, J = 7.0 Hz, 1 H), 4.37 - 4.16 (m, 2H), 2.95 - 2.85(m, 2H), 2.32 - 1.94 (m, 4H).
Example-212: (R/S)-4-(2-(3,3-difluoropropyl)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-65b and 5-fluoropyrimidin-2-amine. LCMS(ESI): m/z 532.05(M+H)+; 'H NMR (400 MHz, DMSO-î/6) δ 11.88 (s, IH), 8.66 (s, 2H), 7.68 (d, J = 2.0 Hz, IH), 7.50 (dd, J= 8.2, 2.1 Hz, IH), 7.43 - 7.32 (m, 2H), 7.03 (d, J = 8.2 Hz, IH), 6.84 (d, J =8.1 Hz, IH), 6.09 (t, J =56.6 Hz, 1 H), 4.60 (t,J=7.0 Hz, IH), 4.35-4.21 (m, 2H), 2.99 - 2.86 (m, 2H), 2.30 - 1.94 (m, 4H).
Example-213: (R/S)-4-(2-(3,3-difluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin4-yl)chroman-7-sulfonamide
191
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-65b and pyrimidin-4-amine. LCMS(ESI): m/z 513.94(M+H)+; *H NMR (400 MHz, DMSO-76) δ 8.66 (s, 1H), 8.38 (s, 1H), 7.68 (d, J =
2.0 Hz, 1 H), 7.50 (dd, J = 8.2, 2.0 Hz, 1 H), 7.40 - 7.27 (m, 2H), 7.17 - 7.00 (m, 2H), 6.83 (d, J= 8.1 Hz, 1H), 6.16 (t, 1H), 4.59 (t, 1H), 4.34 - 4.21 (m, 2H), 3.05 - 2.83 (m, 2H), 2.30- 1.93 (m, 4H).
Example-214: (R/S)-4-(2-(3,3-difluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin3-yl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-65b and pyridazin-3-amine. LCMS(ESI): m/z 513.94(M+H)+; *H NMR (400 MHz, DMSO-76) δ 14.52 (s, 1H), 8.30 (s, 1H), 7.92 (d,7 = 9.3 Hz, 1H), 7.81 - 7.62 (m, 2H), 7.60 - 7.47 (m, 1H), 7.38 - 7.13 (m, 2H), 7.04 (d, J =
8.2 Hz, 1H), 6.79 (d, 7= 8.0 Hz, 1H), 6.17 (t, 1H), 4.57 (t, 1H), 4.44 - 4.12 (m, 2H), 3.10
-2.71 (m, 2H), 2.35- 1.94 (m, 4H).
Example-215: (R/S)-4-(2-(3,3-difluoropropyl)-4-(trifluoromethyl)phenyl)-N-(6fluoropyridin-2-yl)chromane-7-sulfonamide
192
cf3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-65b and 6-fluoropyridin-2-amine. LCMS(ESI): m/z 531.02(M+H)+; 'H NMR (400 MHz, DMSOé6) δ 11.37 (s, IH), 7.87 (q, J = 8.2 Hz, IH), 7.68 (d, J = 2.0 Hz, IH), 7.49 (d, J = 8.2 Hz, IH), 7.44 - 7.27 (m, 2H), 7.07 - 6.92 (m, 2H), 6.92 - 6.66 (m, 2H), 6.16 (t, J = 59.2, 54.7 Hz, IH), 4.59 (t, J = 7.1 Hz, IH), 4.35 - 4.18 (m, 2H), 3.00 - 2.80 (m, 2H), 2.27 - 2.01 (m, 4H).
Example-216/217: (R&S)-4-(2-(oxetan-3-yloxy)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide
CF3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-67 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: (IPA: MeOH = 1:1) to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.17 min (Example-216) and rétention time 6.74 min (Example-217).
LCMS(ESI): m/z 508.06 (M+H)+; *H NMR (400 MHz, DMSOé6) δ 8.53 (d, J= 4.9 Hz, 2H), 7.46 - 7.34 (m, 2H), 7.30 (d, J= 8.0 Hz, 1 H), 7.16 - 7.05 (m, 2H), 6.98 - 6.89 (m, 2H), 5.42 (t, IH), 4.88 (t, J = 6.6 Hz, IH), 4.77 (t, J= 6.6 Hz, IH), 4.64 (t, J = 6.7 Hz, IH), 4.45 (t, J= 6.1 Hz, IH), 4.31 (t, J = 6.0 Hz, IH), 4.21 (dd, J = 20.9, 6.5 Hz, 2H), 2.25-2.14 (m, 2H).
193
ExampIe-218:
(S/R)-N-(5-fluoropyrimidin-2-yl)-4-(2-(oxetan-3-yloxy)-4(trifluoromethyl) phenyl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-67b and 5-fluoropyrimidin-2-amine. LCMS(ESI): m/z 526.00 (M+H)+; 'H NMR (400 MHz, DMSOé6) δ 11.86 (s, IH), 8.65 (s, 2H), 7.43 7.33 (m, 2H), 7.30 (d, J= 8.0 Hz, IH), 7.14 (d, J = 7.9 Hz, IH), 6.98 - 6.89 (m, 2H), 5.42 (quintet, J= 5.4 Hz, IH), 4.86 (t, J= 6.7 Hz, IH), 4.76 (t, J= 6.6 Hz, IH), 4.64 (t, J= 6.8 Hz, IH), 4.41 (t, IH), 4.31 -4.16(m, 3H), 2.23-2.13 (m, 2H).
Example-219: (S/R)-N-(6-fluoropyridin-2-yl)-4-(2-(oxetan-3-yloxy)-4-(trifluoromethyl) phenyl)chromane-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-67b and 6-fluoropyridin-2-amine. LCMS(ESI): m/z 524.94 (M+H)+; 'H NMR (400 MHz, DMSOé6) δ 11.36 (s, IH), 7.87 (dd, J = 8.2 Hz, IH), 7.40-7.23 (m, 3H), 7.11 (d, J= 8.0 Hz, IH), 7.01-6.94 (m, 2H), 6.91 (s, IH), 6.76 (dd, J=8.0, 2.4 Hz, IH), 5.41 (quint, J =5.4 Hz, IH), 4.87 (t,J=6.6 Hz, IH), 4.76 (t, J = 6.7 Hz, IH), 4.64 (t, J = 6.8 Hz, IH), 4.44 (dd, J = 7.2, 4.9 Hz, IH), 4.36 - 4.12 (m, 3H), 2.24-2.13 (m, 2H).
Example-220/221: (S&R)-4-(2-(3-fluoropropoxy)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide
194
cf3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-69 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 30:70, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.72 min (Example-220) and rétention time 7.90 min (Example-221).
LCMS(ESI): m/z 512.03(M+H)+; *H NMR (400 MHz, DMSO-76) δ 8.54 (d, J= 4.9 Hz, 2H), 7.43 - 7.34 (m, 2H), 7.32 - 7.24 (m, 2H), 7.14 - 7.06 (m, 2H), 6.91 (d, J = 8.1 Hz, IH), 4.55 (t, J = 7.0 Hz, lH),4.50-4.30(m, 2H), 4.24 - 4.10 (m, 4H), 2.14 (d, J= 5.6 Hz, 2H), 1.93-1.76 (m, 2H).
Example-222: (R/S)-4-(2-(5-fluoro-6-methylpyridin-2-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-71b and pyrimidin-2-amine. LCMS(ESI): m/z 543.94(M+H)+; *H NMR (400 MHz, DMSO-76) δ 11.74 (s, IH), 8.53 (d, J= 4.9 Hz, 2H), 7.80 - 7.68 (m, 3H), 7.59 (dd, J= 8.5, 3.6 Hz, IH), 7.40 - 7.32 (m, 2H), 7.24 (d, J= 8.5 Hz, IH), 7.08 (t, J= 4.9 Hz, IH), 6.90 (d, 7=8.0 Hz, IH), 4.62 - 4.54 (m, IH), 4.31 4.23 (m, IH), 4.20 - 4.10 (m, IH), 2.46 (d, 7= 2.9 Hz, 3H), 2.28- 2.18 (m, IH), 2.16 2.04 (m, IH).
195
Example-223: (R/S)-4-(2-(5-fluoro-6-methylpyridin-2-yl)-4-(trifluoromethyl)phenyl)-N(5-fluoropyrimidin-2-yl)chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-71 b and 5-fiuoropyrimidin-2-amine. LCMS(ESI): m/z 563.07(M+H)+; lH NMR (400 MHz, DMSO-d6) δ 11.87 (s, IH), 8.65 (s, 2H), 7.83 - 7.68 (m, 3H), 7.59 (dd, J= 8.5, 3.6Hz, IH), 7.40-7.31 (m, 2H), 7.24 (d, J= 8.7 Hz, IH), 6.90 (d, J = 8.0 Hz, IH), 4.58 (dd, J= 8.6, 6.2 Ηζ,ΙΗ), 4.31 -4.24 (m, IH), 4.21-4.11 (m, 1 H), 2.46 (d, J = 2.9 Hz, 3H), 2.29 - 2.18 (m, 1 H), 2.18 - 2.07(m, 1 H).
Example-224: (R/S)-4-(2-(5-fluoro-6-methylpyridin-2-yl)-4-(trifluoromethyl)phenyl)-N(pyridazi n-3 -yl )chroman- 7-sul fonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-71 b and pyridazin-3-amine. LCMS(ESI): m/z 543.94(M+H)+; ‘H NMR (400 MHz, DMSO-76) δ 14.51 (s, IH), 8.30 (s, IH), 7.91 (s, IH), 7.81 - 7.66 (m, 4H), 7.60 (dd, J = 8.4, 3.6 Hz, IH), 7.23 (dd, J = 8.4, 5.3 Hz, 3H), 6.86 (d, J = 8.5 Hz, 1 H), 4.60 - 4.52 (m, 1 H), 4.31 - 4.20 (m, 1 H), 4.18 - 4.09 (m, 1 H), 2.47 (d, J =2.9 Hz, 3H), 2.28 - 2.19 (m, 1 H), 2.15 - 2.03 (m, 1 H).
Example-225: (R/S)-4-(2-(5-fluoro-6-methylpyridin-2-yl)-4-(trifluoromethyl)phenyl)-N(6-fluoropyridin-2-yl)chroman-7-sulfonamide
196
cf3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-71b and 6-fluoropyridin-2-amine. LCMS(ESI): m/z 561.95(M+H)+; *Η NMR (400 MHz, DMSO-76) δ 11.37 (s, IH), 7.92 - 7.83 (m, IH), 7.81 - 7.64 (m, 3H), 7.58 (dd, 7=8.6, 3.6 Hz, IH), 7.38 - 7.27 (m, 2H), 7.24 (d, 7= 8.3 Hz, IH), 6.96 (dd, 7= 7.9, 2.0 Hz, IH), 6.91 (d,7=8.1 Hz, IH), 6.76 (dd, 7= 8.2, 2.4 Hz, IH), 4.57 (t, 7= 7.5 Hz, IH), 4.32 - 4.22 (m, IH), 4.15 (t, 7= 10.0, Hz, IH), 2.45 (d,7 = 2.9 Hz, 3H), 2.27-2.18 (m, IH), 2.17-2.05 (m, IH).
Example-226/227: (S&R)-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide
cf3 cf3
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-72 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: DCM = 1:1), A:B = 70:30, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.74 min (Example-226) and rétention time 7.36 min (Example-227).
LCMS(ESI): m/z 465.99(M+H)+; 'H NMR (400 MHz, DMSO-J6) δ 11.73 (s, IH), 8.54 (d, 7= 4.9 Hz, 2H), 7.43 - 7.35 (m, 2H), 7.32 (d, 7= 1.7 Hz, IH), 7.24 (d, 7= 8.0 Hz, IH), 7.12 - 7.06 (m, IH), 6.98 - 6.90 (m, 2H), 4.59 (t, 7= 6.3 Hz, IH), 4.30 - 4.19 (m, IH), 4.15 - 4.04 (m, IH), 3.87 (s, 3H), 2.25 - 1.99 (m, 2H).
197
Example-228/229: (S&R)-N-(6-fluoropyridin-2-yl)-4-(2-methoxy-4-(trifluoromethyl) phenyl) chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-72 and 6-fluoropyridin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: DCM = 1:1), A:B = 60:40, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 8.31 min (Example-228) and rétention time 9.37 min (Example-229).
LCMS(ESI): m/z 482.99(M+H)+; 'H NMR (400 MHz, DMSOé6) δ 11.38 (s, IH), 7.87 (dd, J= 8.2 Hz, IH), 7.42 - 7.28 (m, 3H), 7.24 (d, J= 8.0 Hz, IH), 6.96 (ddd, J= 12.8, 8.1,2.5 Hz, 3H), 6.77 (dd, J = 8.0, 2.4 Hz, 1 H), 4.58 (t, J = 6.2 Hz, 1 H), 4.28 - 4.19 (m, IH), 4.14 - 4.04 (m, IH), 3.85 (s, 3H), 2.22 - 2.02 (m, 2H).
Example-230/231: (S&R)-4-(2-(3-oxomorpholino)-4-(trifluoromethyl)phenyl)-N(pyrimidin -2-yl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-74 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: DCM = 1:1), A:B = 60:40, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.65 min (Example-230) and rétention time 6.45 min (Example-231 ).
198
LCMS(ESI): m/z 535.0(M+H)+; *H NMR (400 MHz, DMSOé6) δ 11.75 (s, IH), 8.54 (d, 7= 4.9 Hz, 2H), 7.88 (s, IH), 7.70 - 7.62 (m, IH), 7.44 - 7.30 (m, 2H), 7.19 (d, 7= 8.3 Hz, IH), 7.12 - 7.05 (m, IH), 7.00 - 6.82 (m, IH), 4.50 - 4.16 (m, 5H), 4.08 - 3.98 (m, 2H), 3.95-3.85 (m, lH),3.65-3.49(m, IH), 2.29 - 2.15 (m, IH), 2.04 - 1.95 (m, IH). Example-232/233: (S&R)-4-(2-(l,l-dioxidothiomorpholino)-4-(trifluoromethyl)phenyl)N-(pyrimidin-2-yl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-76 and pyrimidin-2-amine.
Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: DCM = 1:1), A:B = 50:50, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 5.23 min (Example-232) and rétention time 5.99 min (Example-233).
LCMS(ESI): m/z 569.07(M+H)+; 'H NMR (400 MHz, DMSOé6) δ 11.74 (s, IH), 8.54 (d, 7= 4.8 Hz, 2H), 7.71 (d,7=1.8 Hz, IH), 7.46 (d, 7= 8.1 Hz, IH), 7.41 (d, 7= 1.9 Hz, IH), 7.35 (dd, 7= 8.1, 2.0 Hz, IH), 7.12 - 7.03 (m, 2H), 6.85 (d, 7= 8.1 Hz, IH), 4.85 (t, IH), 4.40-4.16 (m, 2H), 3.52 - 3.14 (m, 8H), 2.32 - 2.22 (m, IH), 2.12 - 1.96 (m, IH). Example-234: (R/S)-4-(2-(l,l-dioxidothiomorpholino)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-76b and 5-fluoropyrimidin-2-amine. LCMS(ESI): m/z
199
586.83(M+H)+; 'H NMR (400 MHz, DMSO-76) δ 11.86 (s, IH), 8.66 (s, 2H), 7.72 (s, IH), 7.46 (d, J = 8.2 Hz, IH), 7.42 - 7.30 (m, 2H), 7.13 - 7.06 (m, IH), 6.86 (d, J = 8.2 Hz, IH), 4.87 - 4.82 (m, IH), 4.39 - 4.19 (m, 2H), 3.51-3.18 (m, 8H), 2.33 - 2.23 (m, IH), 2.11 - 1.97 (m, IH).
ExampIe-235: (R/S)-4-(2-(l,l-dioxidothiomorpholino)-4-(trifluoromethyl)phenyl)-N-(6fluoropyridin-2-yl)chroman-7-sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-76b and 6-fluoropyridin-2-amine. LCMS(ESI): m/z 585.95(M+H)+; 'H NMR (400 MHz, DMSO-76) δ 11.37 (s, IH), 7.87 (dd, J = 8.2 Hz, IH), 7.71 (s, IH), 7.45 (d,7=8.0Hz, IH), 7.37 (d, J= 2.0 Hz, IH), 7.31 (dd,7=8.2,2.0 Hz, IH), 7.08 (s, IH), 6.98 (dd,7=8.0, 2.1 Hz, IH), 6.86 (d,7=8.1 Hz, IH), 6.77 (dd, 7 = 8.0, 2.4 Hz, IH), 4.90 - 4.79 (m, IH), 4.39 - 4.21 (m, 2H), 3.50 - 3.21 (m, 8H), 2.33 2.21 (m, IH), 2.11-2.00 (m, IH).
ExampIe-236: (R/S)-4-(2-( 1,1 -dioxidothiomorpholino)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl)chroman-7-sulfonamide
CF3
The title compound was prepared by following the similar procedure as described in Example-1/2 using Intermediate-76b and pyridazin-3-amine. LCMS(ESI): m/z 568.95(M+H)+; 'H NMR (400 MHz, DMSO-J6) δ 14.51 (s, IH), 8.30 (s, IH), 7.93 (s, IH), 7.71 (s, 2H), 7.46 (d, 7= 8.5 Hz, IH), 7.30 - 7.20 (m, 2H), 7.09 (d, 7= 8.2 Hz, IH),
200
6.80 (d, ./=8.1 Hz, IH), 4.88-4.79 (m, IH), 4.38-4.19 (m, 2H), 3.52 - 3.21 (m, 8H),
2.30 - 2.20 (m, 1 H), 2.08 - 1.95 (m, 1 H).
Example-237: (R/S)-4-(2-(l,l-dioxidothiomorpholino)-4-(trifluoiOmethyl)phenyl)-N(pyrimidin-4-yl)chromane-7-sulfonamide
The title compound was prepared by following the similar procedure as described in Example-1/2 using (R/S)-perfluorophenyl 4-(2-(l,l-dioxidothiomorpholino)-4-(trifluoro methyl)phenyl)chroman-7-sulfonate (Intermediate-76b) and pyrimidin-4-amine. LCMS(ESI): m/z 568.95(M+H)+; ‘H NMR (400 MHz, DMSO-î/6) δ 8.78 - 8.36 (m, 2H), 7.71 (d, J = 1.7 Hz, IH), 7.46 (d, J= 8.2 Hz, IH), 7.38 - 7.23 (m, 2H), 7.19 - 7.05 (m, 2H), 6.84 (d, J =8.1 Hz, IH), 4.91 -4.80 (m, IH), 4.40-4.18 (m, 2H), 3.52 - 3.19 (m, 8H), 2.30-2.19 (m, IH), 2.10-1.95 (m, IH).
Example-238/239: (S&R)-4-(2-propyl-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl )chroman-7 -sulfonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-79 and pyrimidin-2-amine. Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 30:70, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.79 min (Example-238) and rétention time 8.33 min (Example-239). LCMS(ESI): m/z 478.04(M+H)+; 'H NMR (400
201
MHz, DMSO-76) δ 11.73 (s, 1H), 8.54 (d, 7=4.9 Hz, 2H), 7.59 (d,7=2.1 Hz, 1H), 7.46 (d, 7= 8.2 Hz, 1H), 7.41 (d, 7= 1.9 Hz, 1H), 7.37 (dd, 7= 8.1, 2.0 Hz, 1H), 7.13 - 6.98 (m, 2H), 6.78 (d, 7= 8.2 Hz, 1H), 4.60 (t, 7= 7.2 Hz, 1H), 4.33 -4.22 (m, 2H), 2.76 (dd, 7= 33.8, 8.5 Hz, 2H), 2.29 - 2.17 (m, 1H), 2.09 - 1.94 (m, 1H), 1.67 - 1.55 (m, 2H), 0.93 (t, 7=7.2 Hz, 3H).
Example-240/241: (S&R)-N-(5-fluoropyrimidin-2-yl)-4-(2-propyl-4-(trifluoromethyl) phenyl)chroman-7-su!fonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-79 and 5-fluoropyrimidin-2-amine. Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 30:70, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 4.61 min (Example-240) and rétention time 5.49 min (Example-241). LCMS(ESI): m/z 496.01(M+H)+; 'H NMR (400 MHz, DMSO-76) δ 11.88 (s, 1H), 8.66 (s, 2H), 7.60 (s, 1H), 7.50 - 7.32 (m, 3H), 7.02 (d, 7= 8.2 Hz, 1H), 6.79 (d, 7= 8.1 Hz, 1H), 4.64 - 4.56 (m, 1H), 4.36 - 4.22 (m, 2H), 2.84 - 2.68 (m, 2H), 2.28 - 2.19 (m, 1H), 2.03 - 1.97 (m, 1H), 1.67 - 1.54 (m, 2H), 0.94 (t, 7= 7.3 Hz, 3H).
ExampIe-242/243: (S&R)-4-(2-propyl-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7 -sulfonami de
202
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-79 and pyridazin-3-amine. Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 30:70, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 6.57 min (Example-242) and rétention time 7.67 min (Example-243). LCMS(ESI): m/z 478.03(M+H)+; 'H NMR (400 MHz, DMSO-dé) δ 14.53 (s, IH), 8.31 (s, IH), 7.91 (s, IH), 7.70 (dd, J= 9.5, 4.1 Hz, 1 H), 7.59 (d, J = 2.0 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.34 - 7.18 (m, 2H), 7.02 (d, J = 8.2 Hz, 1 H), 6.74 (d, J = 8.0 Hz, 1 H), 4.58 (t, J = 7.1 Hz, 1 H), 4.34 - 4.20 (m, 2H), 2.88 2.70 (m, 2H), 2.30-2.19 (m, IH), 2.06- 1.93 (m, IH), 1.71 -1.52 (m, 2H), 0.95 (t,J = 7.3 Hz, 3H).
Example-244/245: (S&R)-N-(6-fluoropyridin-2-yl)-4-(2-propyl-4(trifluoromethyl )phenyl ) chroman-7-sul fonamide
The title compounds were prepared by following the similar procedure as described in Example-1/2 using Intermediate-79 and 6-fluoropyridin-2-amine. Further the enantiomers were separated using chiral préparative HPLC (Column: ChiralPak IE; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH = 1:1), A:B = 50:50, to afford isomer-1 and isomer-2. These isomers were obtained at rétention time 4.91 min (Example-244) and
203 rétention time 5.64 min (Example-245). LCMS(ESI): m/z 495.06(M+H)+; ’H NMR (400 MHz, DMSOé6) δ 11.38 (s, IH), 7.87 (dd, J= 8.2 Hz, IH), 7.59 (d, J= 2.0 Hz, IH), 7.49 - 7.42 (m, IH), 7.38 (d, J= 1.9 Hz, IH), 7.32 (dd, J= 8.2, 2.0 Hz, IH), 7.05 - 6.93 (m, 2H), 6.83 - 6.74 (m, 2H), 4.60 (t, J = 7.2 Hz, IH), 4.36 - 4.22 (m, 2H), 2.86 - 2.65 (m, 2H), 2.28 - 2.16 (m, IH), 2.07 - 1.94 (m, IH), 1.72 - 1.48 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).
Pharmacological activity
Certain illustrative compounds within the scope of the invention are screened for Nav activity according to the procedure given below. The screening of the compounds may be carried by other methods and procedures known to skilled in the art.
Analysis of inhibition of sodium channels by test compounds:
HEK.-293 cells overexpressing the channel of interest were seeded in a 96-well plate at a density of 30000 cells/well and incubated at 37°C / 5% CO2 for 48 hr. The assay was carried out using the Red Membrane Potential Dye (Molecular Devices) following the manufacturer’s instructions. Briefly, the cells were incubated with IX red membrane potential dye for 1.5 hour. The cells were then treated with various concentrations of the test compounds for 15-20 min followed by depolarization with 1030 μΜ Veratridine. The fluorescence was read following excitation at 510-545 nm and émission at 565-625 nm in FLIPR. The “max-min” fluorescence values were used to calculate the % inhibition. IC50 values were calculated by plotting % inhibition against concentration and curve fitting into a sigmoidal dose response.
Through the use of the above described assay procedure, compounds were found to exhibit functional activity against Nav 1.7 in vitro and particularly well suited for the treatment of diseases or disorders as described herein above. The IC50 (nM) values of the représentative compounds for Nav 1.7 and Nav1.5 in vitro are set forth in Table-1
Table-1: _____________________________________________________________
Ex. No Nav1.7 IC50 nM or inhibition @ 10 μΜ Nav1.5 IC50 nM or % inhibition @ 10 μΜ Ex. No Nav1.7 IC50 nM or inhibition @ 10 μΜ Nav1.5 IC50 nM or % inhibition @ 10 μΜ
204
l 48 > 10 μΜ 125 395 2636
2 0.3 62% 126 140 > 10 μΜ
3 1241 > 10 μΜ 127 4 37%
4 1 57% 128 145 55%
5 733 58% 129 16 62%
6 17 46% 130 1689 > 10 μΜ
7 4323 > 10 μΜ 131 53 66%
8 20 > 10 μΜ 132 163 > 10 μΜ
9 1358 > 10 μΜ 133 128 66%
10 3 > 10 μΜ 134 31 1345
11 96% > 10 μΜ 135 708 > 10 μΜ
12 86 > 10 μΜ 136 655 33 %
13 74% > 10 μΜ 137 12 3641
14 33 15% 138 588 > 10 μΜ
15 96% > 10 μΜ 139 33 > 10 μΜ
16 17 > 10 μΜ 140 1741 > 10 μΜ
17 96% > 10 μΜ 141 69 65%
18 759 > 10 μΜ 142 179 > 10 μΜ
19 1008 > 10 μΜ 143 16 534
20 245 — 144 86 2683
21 4274 57% 145 19 2407
22 2057 74% 146 790 > 10 μΜ
23 3691 59% 147 199 60%
24 816 3921 148 172 > 10 μΜ
25 221 > 10 μΜ 149 21 58 %
26 685 > 10 μΜ 150 31 1428
27 80% > 10 μΜ 151 390 57%
28 1574 > 10 μΜ 152 40 67%
29 91 % > 10 μΜ 153 39 35%
30 72% > 10 μΜ 154 83 > 10 μΜ
31 2054 > 10 μΜ 155 4 > 10 μΜ
32 151 > 10 μΜ 156 42 36%
33 514 > 10 μΜ 157 42 > 10 μΜ
34 57 > 10 μΜ 158 130 505
35 86% > 10 μΜ 159 10 943
36 12 74% 160 0.7 61 %
37 248 > 10 μΜ 161 12 1352
38 2 > 10 μΜ 162 0.7 2637
39 182 > 10 μΜ 163 42 307
40 0.04 > 10 μΜ 164 61 81 %
41 622 > 10 μΜ 165 5 303
42 0.2 644 166 50 134
43 1071 — 167 58 241
205
44 16 770 168 3903 > 10 μΜ
45 2294 > 10 μΜ 169 43 4887
46 162 > 10 μΜ 170 1092 > 10 μΜ
47 64% > 10 μΜ 171 125 53 %
48 802 > 10 μΜ 172 2740 > 10 μΜ
49 793 > 10 μΜ 173 12 63 %
50 77 38% 174 2456 > 10 μΜ
51 > 10 μΜ > 10 μΜ 175 248 1686
52 698 > 10 μΜ 176 1310 57%
53 70% 44% 177 11 232
54 706 > 10 μΜ 178 149 > 10 μΜ
55 4326 > 10 μΜ 179 38 64%
56 601 > 10 μΜ 180 831 > 10 μΜ
57 2673 > 10 μΜ 181 0.9 43 %
58 54 > 10 μΜ 182 55 30%
59 187 > 10 μΜ 183 11 > 10 μΜ
60 0.3 > 10 μΜ 184 170 67%
61 568 > 10 μΜ 185 1025 > 10 μΜ
62 5 42% 186 83 46%
63 526 > 10 μΜ 187 2599 —
64 3 > 10 μΜ 188 67 > 10 μΜ
65 16 > 10 μΜ 189 1811 > 10 μΜ
66 8 > 10 μΜ 190 257 > 10 μΜ
67 30 > 10 μΜ 191 671 > 10 μΜ
68 0.9 29% 192 8 > 10 μΜ
70 115 > 10 μΜ 193 80 > 10 μΜ
71 1512 > 10 μΜ 194 1 65%
72 15 > 10 μΜ 195 478 > 10 μΜ
73 842 44% 196 1 > 10 μΜ
74 0.2 44% 197 551 > 10 μΜ
75 86% > 10 μΜ 198 7 2516
76 46 > 10 μΜ 199 355 > 10 μΜ
77 858 > 10 μΜ 200 0.5 > 10 μΜ
78 1 1168 201 85 > 10 μΜ
79 2515 > 10 μΜ 202 0.5 > 10 μΜ
80 114 53 % 203 6 > 10 μΜ
81 993 34% 204 8 1103
82 20 > 10 μΜ 205 8 250
83 71 % > 10 μΜ 206 4 1312
84 2575 > 10 μΜ 207 49 > 10 μΜ
85 2723 > 10 μΜ 208 46 > 10 μΜ
86 2387 > 10 μΜ 209 47 28 %
87 58 % > 10 μΜ 210 48 > 10 μΜ
206
88 626 > 10 μΜ 211 7 777
89 108 > 10 μΜ 212 18 > 10 μΜ
90 15 > 10 μΜ 213 34 65%
91 1116 > 10 μΜ 214 2 635
92 11 > 10 μΜ 215 38 1354
93 4 56% 216 2728 > 10 μΜ
94 3 51 % 217 152 50%
95 11 74% 218 43 > 10 μΜ
96 8 70% 219 34 40%
97 170 71 % 220 > 10 μΜ > 10 μΜ
98 11 432 221 42 1466
99 1065 80% 222 63 73 %
100 75 > 10 μΜ 223 82 33%
101 2594 51 % 224 51 2124
102 39 > 10 μΜ 225 12 1496
103 10 932 226 2346 86%
104 184 > 10 μΜ 227 177 > 10 μΜ
105 1505 > 10 μΜ 228 55 % > 10 μΜ
106 147 > 10 μΜ 229 156 42%
107 229 > 10 μΜ 230 4421 > 10 μΜ
108 57 2184 231 559 > 10 μΜ
109 740 > 10 μΜ 232 36 % > 10 μΜ
110 156 1748 233 164 > 10 μΜ
111 814 67% 234 83 > 10 μΜ
112 801 65 % 235 173 > 10 μΜ
113 65% > 10 μΜ 236 113 > 10 μΜ
114 624 > 10 μΜ 237 19 > 10 μΜ
115 41 > 10 μΜ 238 1757 > 10 μΜ
116 1957 > 10 μΜ 239 124 62%
117 106 > 10 μΜ 240 2737 > 10 μΜ
118 727 > 10 μΜ 241 172 > 10 μΜ
119 5 30% 242 1055 3654
120 11 > 10 μΜ 243 92 2407
121 3 248 244 474 69%
122 38 54% 245 41 75%
123 1 103
124 2234 71 %
207

Claims (23)

  1. l. A compound having the Formula (I):
    wherein,
    Ai and A2 are independently hydrogen or substituted or unsubstituted (C|. Cô)alkyl; or
    Ai and A2, together with the carbon atom to which they are attached, form a substituted or unsubstituted 3- to 6- membered cycloalkyl ring or 4- to 6- membered heterocyclic ring;
    Ri is selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted (Ci.Côjalkyl and substituted or unsubstituted (Ci.Cèjalkoxy;
    R2, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted (Ci.Céjalkyl, (Ci.Côjhaloalkyl, -(CH2)o.2-S(0)2-alkyl, -O-R6, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted (Cs.Cgjcycloalkyl, substituted or unsubstituted (C6.Cio)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl, -C(O)OH, -C(O)O-alkyl and C(O)NR4R5;
    ring A is monocyclic six membered heteroaryl containing l- to 3- nitrogen atoms in the ring;
    208
    R3, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted (C|.C6)alkyl and substituted or unsubstituted (Ci.Cô)alkoxy;
    R4 and R5 are independently selected from hydrogen or substituted or unsubstituted (C|.Cô)alkyl; or R4 and R5 together with the nitrogen atom to which they are attached, form substituted or unsubstituted 5- to 6- membered heterocylic ring;
    Rô is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci.Cô)alkyl, (Ci.Côjhaloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted (C3_Cg)cycloalkyl, substituted or unsubstituted (Cô-Ciojaryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl;
    ‘m’ is an integer ranging from 0 to 3, both inclusive;
    ‘n’ is an integer ranging from 0 to 3, both inclusive;
    wherein the substituents for substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted alkoxyalkyl are one or more same or different and independently selected from the group consisting of hydroxy, halogen, carboxy, cyano, nitro, oxo (=O), (Ci.Cô)alkyl, (Ci.Côjhaloalkyl, hydroxy (Ci.Cô)alkyl, alkoxyalkyl, (C2.Cô)alkenyl, (C2.C6)alkynyl, (Cô-Cio)aryl, arylalkyl, (C3.Cg)cycloalkyl, cycloalkylalkyl, 5 to IO membered heteroaryl, 4 to IO membered heterocyclic ring, 3 to IO membered heterocyclylalkyl, heteroarylalkyl, -C(O)ORX, C(O)Ry, -C(S)Ry, -C(O)NRXRZ, -NRXC(O)NRXRZ, -N(Rx)S(O)2Ry, -NRXRZ, -NRxC(O)Ry, NRxC(S)Ry, -NRXC(S)NRXRZ, -S(O)2NRXRZ, -ORX, -OC(O)Ry, -C(RaRb)|.3C(O)ORx, C(RaRb)i.3C(O)NRxRz, -OC(RaRb)2.3-ORx, -OC(RaRb)2.3-NRxRz, -OC(RaRb)2.3-S(O)0.2Ry, - C(RaRb)l.3-NRxRz, -C(RaRb)i.3-S(O)0.2Ry, -OC(RaRb)!.3-C(O)NRxRz, -OC(RaRb)l.3C(O)ORX and -S(O)0.2Ry;
    209 each of Rx is selected from the group consisting hydrogen, (C|.C6)alkyl, (Cj. Côjhaloalkyl, (C2.C6)alkenyl, (Ci-Cejalkynyl, (C6.Ci0)aryl, arylalkyl, (C3.Cg)cycloalkyl, (Cî.Cgjcycloalkenyl, 5 to 10 membered heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl;
    each of Ry is selected from the group consisting (Ci.Côjalkyl, (Ci.Côjhaloalkyl, (C2.C6)alkenyl, (C2.C6)alkynyl, (C6-Cio)aryl, arylalkyl, (Cj.Cgjcycloalkyl, (C3. Cg)cycloalkenyl, 5 to IO membered heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl;
    each of Rz is selected from the group consisting hydrogen, (Cj.Côjalkyl, (C|. C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C&-Cio)aryl, arylalkyl, (Cj.Cgjcycloalkyl, (C3.Cg)cycloalkenyl, 5 to IO membered heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; or Rx and Rz together with the nitrogen atom to which they are attached form a substituted or unsubstituted, saturated or unsaturated 4- to 8- membered cyclic ring, wherein the unsaturated cyclic ring may hâve one or two double bonds; and each of Ra and Rb are independently selected from the group consisting of hydrogen, halogen and substituted or unsubstituted (Ci.Côjalkyl;
    or N-oxides thereof or a pharmaceutically acceptable sait thereof or stereoisomer thereof.
  2. 2. The compound of claim-l having the Formula (II):
    (R3)n
    R2
    210 or N-oxides thereof or a pharmaceutically acceptable sait thereof or stereoisomer thereof;
    wherein, ring A is monocyclic six membered heteroaryl containing 1- to 2- nitrogen atoms in the ring;
    Ai and A2 are independently hydrogen or substituted or unsubstituted (C|. C6)alkyl;
    R2a is selected from halogen, cyano, substituted or unsubstituted (Cj.Côjalkyl, (C|. Céjhaloalkyl, -(CH2)o.2-S(0)2-alkyl, -O-Rô, substituted or unsubstituted (C3.C8)cycloalkyl, substituted or unsubstituted (Cô-Ciojaryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl, -C(O)OH, -C(O)O-alkyl and -C(O)NR4R$ where R4 and R5 are hydrogen or (CrC6)alkyl;
    Rô is selected from the group consisting of hydrogen, substituted or unsubstituted (C|.Cé)alkyl, (Cj.Côjhaloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted (C3.C8)cycloalkyl, substituted or unsubstituted (Cô-Ciojaryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl;
    Ri, R2, R3 and ‘n’ are as defîned in claim-1.
  3. 3. The compound of claim-1 having the Formula (III)
    211 or N-oxides thereof or a pharmaceutically acceptable sait thereof or stereoisomer thereof;
    wherein,
    R2a is selected from halogen, cyano, substituted or unsubstituted (Cj.C6)alkyl, (Ci. Céjhaloalkyl, -(CH2)o.2-S(0)2-alkyl, -Ο-Ré, substituted or unsubstituted alkoxyalkyl, (C3. Cg)cycloalkyl, substituted or unsubstituted (C6.Cio)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl, -C(O)OH, -C(O)O-alkyl and -C(O)NR4RS where R4 and R5 are hydrogen or (Ci-Cé)alkyl;
    Ré is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci.Cé)alkyl, (Ci.Cé)haloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted (C3.Cg)cycloalkyl, substituted or unsubstituted (Cé-Cio)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl;
    Ri, R2, R3 and ‘n’ are as defmed in claim-1.
  4. 4. The compound of claim-1 having the Formula (IV)
    R2 or N-oxides thereof or a pharmaceutically acceptable sait thereof or stereoisomer thereof;
    wherein,
    R2a is selected from halogen, cyano, substituted or unsubstituted (Ci.Cé)alkyl, (Ci. Cé)haloalkyl, -(CH2)o.2-S(0)2-alkyl, -Ο-Ré, substituted or unsubstituted alkoxyalkyl, (C3.
    212
    Cgjcycloalkyl, substituted or unsubstituted (C6.Clo)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl, -C(O)OH, -C(O)O-alkyl and -C(O)NR4R5 where IG and R5 are hydrogen or (Ci-Côjalkyl;
    Re is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci.C6)alkyl, (C|.Cô)haloalkyl, substituted or unsubstituted alkoxyalkyl, (C3. Cgjcycloalkyl, substituted or unsubstituted (C6.Cio)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl;
    Ri, R2, R3 and ‘n’ are as defined in claim-1.
  5. 5. The compound of claim-1 having the Formula (V)
    R2 or N-oxides thereof or a pharmaceutically acceptable sait thereof or stereoisomer thereof;
    wherein,
    R2a is selected from halogen, cyano, substituted or unsubstituted (C|.C6)alkyl, (C|. Côjhaloalkyl, -(CH2)o.2-S(0)2-alkyl, -O-R6, substituted or unsubstituted alkoxyalkyl, (C3. Cg)cycloalkyl, substituted or unsubstituted (C6-Cio)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl, -C(O)OH, -C(O)O-alkyl and -C(O)NR4R5 where R4 and R5 are hydrogen or (Ci-C6)alkyl;
    Rô is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci.Cô)alkyl, (Ci.Côjhaloalkyl, substituted or unsubstituted alkoxyalkyl, (C3.
    213
    C8)cycloalkyl, substituted or unsubstituted (C6.Cio)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl;
    Ri, R2, R3 and ‘n’ are as defmed in claim-1.
  6. 6. The compound of claim-1 having the Formula (VI)
    R2 or N-oxides thereof or a pharmaceutically acceptable sait thereof or stereoisomer thereof;
    wherein,
    R2a is selected from halogen, cyano, substituted or unsubstituted (Ci.Cô)alkyl, (C|. Côjhaloalkyl, -(CH2)o.2-S(0)2-alkyl, -O-R6, substituted or unsubstituted alkoxyalkyl, (C3. C8)cycloalkyl, substituted or unsubstituted (C6-Cio)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl, -C(O)OH, -C(O)O-alkyl and -C(O)NR4R5 where R4 and R5 are hydrogen or (C|-C6)alkyl;
    Rô is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci.Cô)alkyl, (C|.C6)haloalkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted (C3.C8)cycloalkyl, substituted or unsubstituted (C6-Cio)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl;
    Ri, R2, R3 and ‘n’ are as defmed in claim-1.
  7. 7. The compound of claim-1 to 6 wherein R| is hydrogen, halogen or (Ci-Côjalkyl.
    214
  8. 8. The compound of claim-1 wherein ring A is selected from
  9. 9. The compound of claim-1 to 6 wherein R3 is halogen, cyano, substituted or unsubstituted (Ci-Cé)alkyl and substituted or unsubstituted (Ci-Cé)alkoxy; and ‘n’ is 0 or 1.
  10. 10. The compound of claim-1 wherein Ai and A2 are independently hydrogen or substituted or unsubstituted (C[-Cé) alkyl.
  11. 11. The compound of claim-1 wherein Ai and A2 together with the carbon atom to which they are attached, form a substituted or unsubstituted 3- to 6- membered cycloalkyl ring.
  12. 12. The compound of claim-1 to 6 wherein R2 is selected from halogen, cyano, substituted or unsubstituted (Ci-Cé)alkyl, (Ci.Cé)haloalkyl, -(CH2)o-2-S(0)2-alkyl, O-Rô, substituted or unsubstituted alkoxyalkyl, (C3.Cg)cycloalkyl, substituted or unsubstituted (C6-Cio)aryl (e.g. phenyl), substituted or unsubstituted 5- to 6membered monocyclic heteroaryl (e.g pyridyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl), substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl (e.g. pyrrolidinone, oxazolidinone, morpholine, morpholinone, thiomorpholinel,ldioxide, tetrahydropyran), -C(O)OH, -C(O)O-alkyl and -C(O)NR4R5 where R4 and R5 are hydrogen or (Ci-Cé)alkyl; Ré is selected from the group consisting of hydrogen, substituted or unsubstituted (Ci.Cé)alkyl, (Ci.Cé)haloalkyl, substituted or unsubstituted alkoxyalkyl, (C3.Cg)cycloalkyl, substituted or unsubstituted (C6. Cio)aryl, substituted or unsubstituted 5- to 6- membered monocyclic heteroaryl, and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl; and ‘m’ is 0, 1 or 2.
  13. 13. A compound of any of daims 2 to 6 wherein R2 is halogen, (Ci.Cé)haloalkyl or ORé where Ré is hydrogen or (Ci.Cé)alkyl.
  14. 14. The compound of claim-1 having the Formula (II):
    215 (R3)n
    R2 wherein Ai and A2 are hydrogen; R| is hydrogen; ring A is monocyclic six membered heteroaryl containing 1- to 2- nitrogen atoms in the ring (
    C R N or N ); r2 is halogen, (Ci.C6)haloalkyl or -O-R6; R2a is halogen, substituted or unsubstituted (Ci.C6)alkyl, (Ci.C6)haloalkyl, -(CH2)0.2-S(O)2-alkyl, -O-R6, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted (C6.C|0)aryl
    OH
    substituted or unsubstituted 5- to 6- membered
    substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl (
    where R6 is substituted or unsubstituted (Ci-Côjalkyl, substituted or unsubstituted alkoxyalkyl and substituted or unsubstituted 4- to 6- membered monocyclic heterocyclyl (
    / /
    216 <^A-O); r3 is halogen, substituted or unsubstituted (Ci.Cô)alkyl and substituted or unsubstituted (Ci.Côjalkoxy; and ‘n’ is 0 or 1;
    or a free base thereof, N-oxide thereof, or stereoisomers thereof or a pharmaceutically acceptable sait thereof.
  15. 15. A compound which is selected from:
    (S)-N-(6-Fluoropyridin-2-yl)-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl) phenyl) chroman-7-sulfonamide;
    (R)-N-(6-Fluoropyridin-2-yl)-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl) phenyl) chroman-7-sulfonamide;
    (S&R)-A-(4-Fluoropyridin-2-yl)-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl)phenyl) chroman-7-sulfonamide;
    (S&R)-JV-(5-Fluoropyridin-2-yl)-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl)phenyl) chroman-7-sulfonamide;
    (S&R)-A-(5-Fluoropyrimidin-2-yl)-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl) phenyl) chroman-7-sulfonamide;
    (S&R)-4-(2-(l-Methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-4-yl) chroman-7-sulfonamide;
    (S&R)-4-(2-(l-Methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N(pyrazin-2-yl) chromane-7-sulfonamide;
    (S&R)-4-(2-( 1 -Methyl-1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl) chromane-7-sulfonamide;
    (S&R)-4-(2-( 1 -Methyl-1 //-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-A(pyrimidin-2-yl) chromane-7-sulfonamide;
    (S&R)-V-(3-Fluoropyridin-2-yl)-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl)pheny 1) chromane-7-sulfonamide;
    217 (S&R)-4-(2-( 1 -Methyl-1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(6methylpyridin-2-yl)ehroman-7-sulfonamide;
    (S&R)-4-(2-( 1 -Methyl-1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(5methylpyridin-2-yl)chroman-7-sulfonamide;
    (S&R)-4-(2-(l-Methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(4methylpyridin-2-yl)chroman-7-sulfonamide;
    (S&R)-N-(6-Isopropoxypyridin-2-yl)-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
    (S&R)-N-(2-Fluoropyridin-3-yl)-4-(2-( 1 -methyl-1 H-pyrazol-5-yl)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
    (S&R)-4-(2-( 1 -Methyl-1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(4methylpyrimidin-2-yl)chroman-7-sulfonamide;
    (S&R)-4-(4-Chloro-2-( 1 -methyl-1 H-pyrazol-5-yl)phenyl)-N-(6-fluoropyridin2-yl)chroman-7-sulfonamide;
    (S&R)-N-(6-Fluoropyridin-2-yl)-4-(4-isopropoxy-2-( 1 -methyl-1 H-pyrazol-5yl)phenyl)chroman-7-sulfonamide;
    (S&R)-4-(2-(6-FluoiOpyridm-3-yl)-4-(trifluoromethyl)phenyl)-jV-(pyrimidin2-yl)chromane-7-sulfonamide;
    (S&R)-4-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-A-(5fluoropyrimidin-2-yl) chromane-7-sulfonamide;
    (S&R)-4-(2-(6-FluoiOpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin4-yl)chromane-7-sulfonamide;
    (S&R)-4-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazm3-yl)chromane-7-sulfonamide;
    (S&R)-4-(4'-Fluoro-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-2-yl)-N-(pyrimidin-2yl)chromane-7-sulfonamide;
    (S&R)-4-(4'-Fluoro-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-2-yl)-N-(5fluoropyrimidin-2-yl) chromane-7-sulfonamide;
    218 (S&R)-4-(4'-Fluoro-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-2-yl)-N-(pyrimidin-4yl)chromane-7-sulfonamide;
    (S&R)-4-(4'-Fluoro-5-(trifluoromethyl)-[ 1,1 '-biphenyl]-2-yl)-N-(6fluoropyridin-2-yl) chromane-7-sulfonamide;
    (S&R)-4-(2-(l//-l,2,3-Triazol-l-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin2-yl)chromane-7-sulfonamide;
    (S&R)-4-(2-( 1//-1,2,3-TriazoI-l-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin3-yl)chromane-7-sulfonamide;
    (S&R)-4-(2-( 1 H-1,2,3-Triazol-1 -yl)-4-(trifluoromethyl)phenyl)-7V-(5-fluoro pyriinidin-2-yl) chromane-7-sulfonamide;
    (S&R)-4-(2-( 1//-1,2,3-Triazol-1 -yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin
    -4-yl)chromane-7-sulfonamide;
    (S&R)-4-(2-( 1//-1,2,3-Triazol-l -yl)-4-(trifluoromethyl)phenyl)-N-(6fluoropyridin-2-yl) chromane-7-sulfonamide;
    (S&R)-7V-(6-Fluoropyridin-2-yl)-4-(2-(2-methylthiazol-4-yl)-4-(trifluoro methyl)phenyl) chroman-7-sulfonamide;
    (S&R)-4-(2-(2-Methylthiazol-4-yl)-4-(trifluoromethyl)phenyl)-./V-(pyrimidin2-yl)chroman-7-sulfonamide;
    (S&R)-7V-(5-Fluoropyrimidin-2-yl)-4-(2-(2-methylthiazol-4-yl)-4-(trifluoro methyl)phenyl) chroman-7-sulfonamide;
    (S&R)-4-(2-(2-Methylthiazol-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin4-yl)chroman-7-sul fonamide;
    (S&R)-4-(2-(2-Methylthiazol-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin3-yl)chroman-7-sulfonamide;
    (S&R)-/V-(5-Fluoropyrimidin-2-yl)-4-(2-(2-methyloxazol-4-yl)-4-(trifluoro methyl) phenyl) chroman-7-sulfonamide;
    (S&R)-7V-(6-Fluoropyridin-2-yl)-4-(2-(2-methyloxazol-4-yl)-4-(trifluoro methyl)phenyl) chroman-7-sulfonamide;
    219 (S&R)-4-(2-(2-Methyloxazol-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin2-yl)chroman-7-sulfonamide;
    (S&R)-4-(2-(2-Methyloxazol-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin4-yl)chroman-7-sulfonamide;
    (S&R)-4-(2-(2-Methyloxazol-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin3-yl)chroman-7-sulfonamide;
    (S&R)-7V-(6-Fluoropyridin-2-yl)-4-(2-(2-(methylsulfonyl)ethyl)-4(trifluoromethyl)phenyl) chroman -7-sul fonamide;
    (S&R)-4-(2-(2-(Methylsulfonyl)ethyl)-4-(trifluoromethyl)phenyl)-A(pyrimidin-2-yl)chroman-7-sulfonamide;
    (S&R)-7V-(5-Fluoropyrimidin-2-yl)-4-(2-(2-(methylsulfonyl)ethyl)-4(trifluoromethyl)phenyl) chroman-7-sulfonamide;
    (S&R)-4-(2-(2-(Methylsulfonyl)ethyl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-4-yl) chroman-7-sulfonamide;
    (S&R)-4-(2-(lH-Pyrazol-l-yl)-4-(trifluoromethyl)phenyl)-N-(6-fluoiOpyridin2-yl)chroman-7-sulfonamide;
    (S&R)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(thiazol-2-yl)-4-(tri fluoromethyl) phenyl)chroman-7-sulfonamide;
    (R/S)-N-(Pyrimidin-2-yl)-4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenyl) chroman-7-sulfonamide;
    (R/S)-N-(Pyrimidin-4-yl)-4-(2-(thiazol-2-yl)-4-(trifIuoromethyl)phenyl) chroman-7-sulfonamide;
    (R/S)-N-(Pyridazin-3-yl)-4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenyl) chroman-7-sulfonamide;
    (R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenyl) chroman-7-sulfonamide;
    (S&R)-4-(2-(6-Isopropoxypyridin-3-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonamide;
    220 (S&R)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(6-isopropoxypyridin-3-yl)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
    (S&R)-4-(2-(6-Ethoxypyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(6-Ethoxypyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
    (S/Æ)-4-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)chroman-7sulfonamide;
    (S/7?)-4-(2-Chloro-4-(trifluoromethyl) phenyl)-N-(5-fluoropyrimidin-2-yl) chroman-7-sulfonamide;
    (S/Â)-4-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yI)cluOman-7sulfonamide;
    (S/7?)-4-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(pyridazin-3-yl)chroman-7sulfonamide;
    (S/R)-4-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin-2yl)chroman-7-sulfonamide;
    (S&R)-N-(Pyrimidin-2-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)-4(trifluoromethyl) phenyl)chroman-7-sulfonamide;
    (S&R)-2V-(6-Fluoropyridin-2-yl)-4-(2-(2-oxopyrrolidin-1 -yl)-4(trifluoromethyl)phenyl) chroman-7-sulfonamide;
    (S&R)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(2-oxopyrrolidin-1 -yl)-4(trifluoromethyl) phenyl)chroman-7-sulfonamide;
    (R/S)-4-(2-(2-OxopynOlidin-l-yl)-4-(trifluoiOmethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(2-Oxopyrrolidin-l-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(2-Oxopyrrolidin-l-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chromane-7-sulfonamide;
    221 (S&R)-4-(2-Morpholino-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl )chroman-7-sul fonamide;
    (S/R)-N-(5-Fluoropyrimidin-2-yl)-4-(2-morpholino-4-(trifluoromethyl)phenyl) chroman-7-sul fonamide;
    (R/S)-4-(2-Morpholino-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl) chroman-7-sulfonamide;
    (R/S)-4-(2-Morpholino-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
    (R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-morpholino-4-(trifluoromethyl)phenyl) chroman-7-sul fonami de;
    (S&R)-4-(2-(2-Methoxyethoxy)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl )chroman-7-sul fonam i de;
    (R/S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(2-methoxyethoxy)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
    (R/S)-4-(2-(2-Methoxyethoxy)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(2-Methoxyethoxy)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
    (R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-(2-methoxyethoxy)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
    (S&R)-4-(2-(3-Methoxypropoxy)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
    (R/S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(3-methoxypropoxy)-4( tri fluoromethyl )phenyl )chroman-7-sul fonamide;
    (R/S)-4-(2-(3-Methoxypropoxy)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl )chroman- 7-sul fonamide;
    (R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-(3-methoxypropoxy)-4-( tri fluoromethyl) phenyl)chroman-7-sulfonamide;
    222 (R/S)-4-(2-(2-Methoxyethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
    (R/S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(2-methoxyethyl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
    (R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-(2-methoxyethyl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
    (R/S)-4-(2-(2-Methoxyethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(2-Methoxyethyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
    (S&R)-4-(2-(3-Methoxypropyl)-4-(trifIuoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
    (R/S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(3-methoxypropyl)-4-(trifluoro methyl)phenyl)chroman-7-sulfonamide;
    (R/S)-4-(2-(3-Methoxypropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(3-Methoxypropyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
    (R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-(3-methoxypropyl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
    (S&R)-4-(2-(4-Methoxybutyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
    (R/S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(4-methoxybutyl)-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
    (R/S)-4-(2-(4-Methoxybutyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(4-Methoxybutyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
    223 (S&R)-N-(6-Fluoropyridin-2-yl)-4-(2-(4-methoxybutyl)-4-(trifluoro methyl)phenyl)chroman-7-sulfonamide;
    (R/S)-4-(2-(2-Fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(2-Fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(5-fluoro pyrimidin2-yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(2-Fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
    . (R/S)-4-(2-(2-Fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3-yl) chroman-7-sulfonamide;
    (R/S)-4-(2-(2-Fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin-2yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(3-Fluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(3-Fluoropropyl)-4-(trifluoromethyl)phenyl)-N-(5-fluoropyrimidin2-yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(3-FluoropiOpyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4y l )chroman-7-sul fonami de;
    (R/S)-4-(2-(3-Fluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(3-Fluoropropyl)-4-(trifluoromethyl)phenyl)-N-(6-fluoiOpyridin-2yl)chroman-7-sul fonamide;
    (R/S)-4-(2-(4-Fluorobutyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(4-Fluorobutyl)-4-(trifluoromethyl)phenyl)-N-(5-fluoropyrimidin2-yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(4-Fluorobutyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
    224 (R/S)-4-(2-(4-Fluorobutyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3-yl) chroman-7-sul fonami de;
    (R/S)-4-(2-(4-Fluorobutyl)-4-(trifluoiOmethyl)phenyl)-N-(6-fluoropyridin-2yl)chroman-7-sulfonamide;
    (R&S)-N-(Pyrimidin-2-yl)-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
    (R&S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
    (R&S)-N-(Pyrimidin-4-yl)-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
    (R&S)-N-(Pyridazin-3-yl)-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
    (R&S)-N-(6-Fluoropyridin-2-yl)-4-(2-((tetrahydro-2H-pyran-4-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
    (R&S)-N-(Pyrimidin-2-yl)-4-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
    (R&S)-N-(6-Fluoropyridin-2-yl)-4-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
    (S/R)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
    (S/R)-N-(Pyrimidin-4-yl)-4-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
    (S/R)-N-(Pyridazin-3-yl)-4-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
    (S&R)-N-(Pyrimidin-2-yl)-4-(2-(((R)-tetrahydrofuran-3-yl)oxy)-4-(trifluoro methyl)phenyl)chroman-7-sulfonamide;
    (S&R)-2'-(7-(N-(Pyrimidin-2-yl)sulfamoyl)chroman-4-yl)-5'(trifluoromethyl)-[ l, l '-biphenyl]-4-carboxylic acid;
    225 (S&R)-2'-(7-(N-(5-Fluoropyrimidin-2-yl)sulfamoyl)chroman-4-yl)-5'(trifluoromethyl)-[ l, l '-biphenyl]-4-carboxylic acid;
    (R/S)-2'-(7-(N-(Pyridazin-3-yl)sulfamoyl)chroman-4-yl)-5'-(trifluoromethyl)[ l, l '-biphenyl]-4-carboxylic acid;
    (R/S)-2'-(7-(N-(6-Fluoropyridin-2-yl)sulfamoyl)chroman-4-yl)-5'(trifluoromethyl)-[l, l '-biphenyl]-4-carboxylic acid;
    (S&R)-4-(2-(5-Fluoropyiïdin-2-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin2-yl)chroman-7-sulfonamide;
    (S&R)-4-(2-(5-Fluoropyridin-2-yl)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide;
    (S&R)-4-(2-(5-Fluoropyridin-2-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin4-yl)chroman-7-sulfonamide;
    (S&R)-4-(2-(5-FluoiOpyridin-2-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin3-yl)chroman-7-sulfonamide;
    (S)-4-(2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
    (R)-4-(2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
    (R/S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(6-methylpyridin-3-yl)-4-(trifluoro methyl)phenyl)chroman-7-sulfonamide;
    (R/S)-4-(2-(6-Methylpyridin-3 -yl)-4-(tri fluoromethyl)phenyl )-N-(pyrimidin-4yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
    (R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-(6-methylpyridin-3-yl)-4(trifluoromethyl)phenyl)chroman-7-sulfonamide;
    (R/S)-4-(2-(2-Oxooxazolidin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin2-yl)chroman-7-sulfonamide;
    226 (R/S)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(2-oxooxazolidin-3-yl)-4-(trifluoro methyl)phenyl)chroman-7-sulfonamide;
    (R/S)-4-(2-(2-Oxooxazolidin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
    (R/S)-N-(6-Fluoropyridin-2-yl)-4-(2-(2-oxooxazolidin-3-yl)-4(trifluoromethyl)phenyl)chromane-7-sulfonamide;
    (R/S)-4-(2-(3,3-Difluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(3,3-Difluoropropyl)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(3,3-Difluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(3,3-Difluoropropyl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(3,3-Difluoropropyl)-4-(trifluoromethyl)phenyl)-N-(6fluoropyridin-2-yl)chromane-7-sulfonamide;
    (R&S)-4-(2-(Oxetan-3-yloxy)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
    (S/R)-N-(5-Fluoropyrimidin-2-yl)-4-(2-(oxetan-3-yloxy)-4-(trifIuoromethyl) phenyl)chroman-7-sulfonamide;
    (S/R)-N-(6-Fluoropyridin-2-yl)-4-(2-(oxetan-3-yloxy)-4-(trifluoromethyl) phenyl)chromane-7-sulfonamide;
    (S&R)-4-(2-(3-Fluoropropoxy)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(5-Fluoro-6-methylpyridin-2-yl)-4-(trifluoromethyl)phenyl)-N(pyrimidin-2-yl)chroman-7-sulfonainide;
    (R/S)-4-(2-(5-Fluoro-6-methylpyridin-2-yl)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide;
    227 (R/S)-4-(2-(5-Fluoro-6-methylpyridin-2-yl)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(5-Fluoro-6-methylpyridin-2-yl)-4-(trifluoromethyl)phenyl)-N-(6fluoropyridin-2-yl)chroman-7-sulfonamide;
    (S&R)-4-(2-Methoxy-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)chroman7-sulfonamide;
    (S&R)-N-(6-Fluoropyridin-2-yl)-4-(2-methoxy-4-(trifluoromethyl) phenyl) chroman-7-sulfonamide;
    (S&R)-4-(2-(3-Oxomorpholino)-4-(trifluoromethyl)phenyl)-N-(pyrimidin -2yl)chroman-7-sulfonamide;
    (S&R)-4-(2-( l, l -Dioxidothiomorpholino)-4-(trifluoromethyl)phenyl)-N (pyrimidin-2-yl)chroman-7-sulfonamide;
    (R/S)-4-(2-( l, l -Dioxidothiomorpholino)-4-(trifluoromethyl)phenyl)-N-(5fluoropyrimidin-2-yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(l,l-Dioxidothiomorpholino)-4-(trifluoromethyl)phenyl)-N-(6fluoropyridin-2-yl)chroman-7-sulfonamide;
    (R/S)-4-(2-(l,l-Dioxidothiomorpholino)-4-(trifluoromethyl)phenyl)-N(pyridazin-3-yl)chroman-7-sulfonamide;
    (R/S)-4-(2-( l, 1 -Dioxidothiomorpholino)-4-(trifluoromethyl)phenyl)-N(pyrimidin-4-yl)chromane-7-sulfonamide;
    (S&R)-4-(2-propyl-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)chroman-7sulfonamide;
    (S&R)-N-(5-fluoropyrimidin-2-yl)-4-(2-propyl-4-(trifluoromethyl) phenyl)chroman-7-sulfonamide;
    (S&R)-4-(2-propyl-4-(trifluoroinethyl)phenyl)-N-(pyridazin-3-yl)chroman-7sulfonamide; and (S&R)-N-(6-fluoropyridin-2-yl)-4-(2-propyl-4-(trifluoromethyl)phenyl) chroman-7-sulfonamide
    228 or racemate thereof, N-oxide thereof or a pharmaceutically acceptable sait thereof.
  16. 16. A pharmaceutical composition comprising one or more compounds according to any one of the preceding claims, and one or more pharmaceutically acceptable excipients.
  17. 17. Use of a compound for treating, managing and/or lessening diseases or disorders, syndromes or conditions associated with the modulation of Navl.7 fonction in a subject in need thereof wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to any one of the preceding claims, or a pharmaceutically acceptable sait thereof.
  18. 18. The use of claim 17, wherein the diseases, disorders, syndromes or conditions associated with the modulation of Nayl.7 fonctions are selected from the group consisting of pain and erythromelalgia.
  19. 19. The use of claim 17, wherein the diseases, disorders, syndromes or conditions associated with the modulation of Nayl.7 fonctions are selected from the group consisting of neurological disorders, cardiovascular conditions, neuromascular conditions, multiple sclerosis, cancer, pruritis, or benign prostatic hyperplasia (BPH).
  20. 20. The use of claim 18, wherein the pain is neuropathie pain.
  21. 21. The use of claim 18, wherein the pain is inflammatory pain.
  22. 22. The use of claim 17, wherein the diseases, disorders, syndromes or conditions associated with the modulation of Nayl.7 fonction are selected from the group consisting of postoperative pain, arthritis pain, osteoarthritis pain, pain associated with cancer including chemotherapy pain, neuropathie pain secondary to metastatic inflammation, neuralgic, orofacial pain, bum pain, somatic pain, dental pain, sciatica pain, intestinal obstruction pain, viscéral pain, colicky pain, myofascial pain, trauma pain, labour pain, trigeminal neuralgia, glossopharyngeal neuralgia, adiposis dolorosa, acute herpetic and postherpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflux sympathetic dystrophy, fibromyalgia, goût, phantom limb pain, pain following stroke, thalamic
    229 lésions, radiculopathy, chronic headache, migraine pain, familial hémiplégie migraine, conditions associated with cephalic pain, sinus headache, tension headache, cardiac pain arising from an ischémie myocardium, pain following stroke, neuropathy secondary to metastatic inflammation, pain due to connective tissue
    5 damage, and other forms of neuralgic, neuropathie, and idiopathic pain syndromes in a subject in need thereof comprising administering to the subject with a therapeutically effective amount.
  23. 23. A process for the préparation of compound of Formula (la):
    10 wherein ring A, R], R2, R3, ‘m’ and ‘n’ are as defined in claim-1 ;
    the process comprising the steps of:
    a) reacting a compound of formula (2) with NCS followed by pentafluorophenol gives the pentafluoro ester of formula (7)
    F
    15 b) reacting a compound of formula (7) with p-tosyl hydrazine to give the hydrazone compound of formula (8)
    c) coupling of a compound of formula (8) with compound of formula (4) in presence of suitable Pd catalyst to give compound of formula (6) which can also be
    230 prepared from compound of formula (5) by reacting with sulfuryl chloride or NCS or dichlorohydantoin followed by pentafluorophenol
    5 d) reducing a compound of formula (6) using Pd/C to give compound of formula (9)
    e) coupling of a compound of formula (9) with amine of formula (10) to give compound of formula ( l a)
    231
    ABSTRACT
    The présent invention relates to sulfonamide compounds Formula (I) wherein the substituents are as described herein, and their use in a medicine for the treatment of diseases, disorders associated with the inhibition of Voltage-gated sodium channels
    5 (VGSC) particularly Navl.7. It further relates to the compounds herein and their pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof useful in treating diseases, disorders, syndromes and/or conditions associated with the inhibition of Voltage-gated sodium channels (VGSC) particularly Navl -7. The invention also relates to process for the préparation of the compounds of the invention.
OA1201800081 2015-09-04 2016-09-03 Sulfonamide compounds as voltage-gated sodium channel modulators. OA18633A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3420/MUM/2015 2015-09-04
IN201621011342 2016-03-31

Publications (1)

Publication Number Publication Date
OA18633A true OA18633A (en) 2019-01-31

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