OA16539A

OA16539A - Heteroaryl derivatives as alpha7 nAChR modulators

Info

Publication number: OA16539A
Application number: OA1201300348
Authority: OA
Inventors: Neelima Sinha; Gourhar JANA; Sachchidanand Sachchidanand; Sanjay Pralhad Kurhade; Navnath Popat Karche; Anil Kashiram Hajare; Ajay Ramchandra Tilekar; Venkata P. Palle; Rajender Kumar Kamboj
Original assignee: Lupin Limited
Priority date: 2011-02-23
Filing date: 2012-02-22
Publication date: 2015-10-22

Abstract

Disclosed is a compound of formula (I) :

Description

Background of the invention:

Cholinergic neurotransmission, mediated primarily through the neurotransmitter acétylcholine (ACh), is a prédominant regulator of the physiological functions of the body via the central and autonomie nervous system. ACh acts on the synapses of the neurons présent in of ail the autonomie ganglia, neuromuscular junctions and the central nervous system. Two distinct classes of ACh target receptors viz. muscarinic (mAChRs) and the nicotinic (nAChRs) have been identifïed in brain, forming a significant component of receptors carrying its mnemonic and other vital physiological functions.

Neural nicotinic ACh receptors (NNRs) belong to the class of ligand-gated ion channels (LGIC) comprising of five subunits (α2-α10, β2-β4) arranged in heteropentameric (α4β2) or homopertameric (a7) configuration (Paterson D et al,, Prog. Neurobiol., 2000, 61, 75-111). α4β2 and a7 nAChR constitute the prédominant subtypes expressed in the mammalian brain. a.7 nAChR has attained prominence as a therapeutic target due to its abundant expression in the leaming and memory centers of brain, hippocampus and the cérébral cortex (Rubboli F et ai., Neurochem. Int., 1994, 25, 69-71). Particularly, a7 nAChR is characterized by a high Ca²⁺ion permeability, which is responsible for neurotransmitter release and conséquent modulation of excitatory and inhibitory neurotransmission (Alkondon M et al., Eur. J. Pharmacol., 2000, 393, 59-67; Dajas-Bailador F et al., Trends Pharmacol. Sci., 2004, 25, 317-324). Furthermore, high Ca²⁺ ion influx also has implications on the long-term potentiation of memory via alterations in gene expression (Bitner RS et al., J. Neurosci., 2007, 27, 10578-10587; McKay BE et al., Biochem. Pharmacol., 2007, 74, 1120-1133).

Several recent studies hâve confïrmed the rôle of a7 nAChR in neural processes like attention, memory and cognition (Mansvelder HD et al., Psychopharmacology (Berl), 2006, 184, 292-305; Chan WK et al.,

Neuropharmacology, 2007, 52, 1641-1649; Young JW et al., Eur.

Neuropsychopharmacol., 2007, 17, 145-155). Gene polymorphisme associated with the a7 nAChR protein CHRNA7 hâve been implicated in the genetic transmission of schizophrenia, related neurophysiological sensory gating déficits and résultant cognitive impairment (Freedman R et al., Biol. Psychiatry, 1995, 38, 22-33; Tsuang DW et al., Am. J. Med. Genet., 2001, 105, 662-668). Also, preclinical studies in a 7 nAChR knock-out and anti-sense oligonucleotide treated mice hâve demonstrated impaired attention and defective cognition underscoring the prominent rôle of a.7 nAChR in cognition (Curzon P et al., Neurosci. Lett., 2006, 410, 15-19; Young JW et al., Neuropsychopharmacology., 2004, 29, 891-900). Additionally, pharmacological blockade of a 7 nAChR impairs memory and its activation enhances same in preclinical rodent models implicating a7 nAChR as target for cognitive enhancement (Hashimoto K et al., Biol. Psychiatry, 2008, 63, 92-97).

Pathological brain function in sensory-deficit disorders has been associated with nicotinic cholinergic transmission particularly through a7 receptors (Freedman R et al., Biol. Psychiatry, 1995, 38, 22-33; Tsuang DW et al., Am. J. Med. Genet., 2001, 105, 662-668; Carson R et al., Neuromolecular, 2008, Med. 10, 377-384; Leonard S et al., Pharmacol. Biochem. Behav., 2001, 70, 561-570; Freedman R et al., Curr. Psychiatry Rep., 2003, 5, 155-161; Cannon TD et al., Curr. Opin. Psychiatry, 2005, 18, 135-140). A defective pre-attention processing of sensory information is understood to be the basis of cognitive fragmentation in schizophrenia and related neuropsychiatrie disorders (Leiser SC et al., Pharmacol. Ther., 2009, 122, 302-311). Genetic linkage studies have traced sharing of the 0.7 gene locus for several affective, attention, anxiety and psychotic disorders (Leonard S et al., Pharmacol. Biochem. Behav., 2001, 70, 561570; Suemaru K et al., Nippon Yakurigaku Zasshi, 2002, 119, 295-300).

Perturbations in the cholinergic and glutamatergic homeostasis, has long been implicated as causative factors for host of neurological disease, including dementia(s) (Nizri E et al., Drug News Perspect., 2007, 20, 421429). Dementia is a severe, progressive, multi-factorial cognitive disorder affecting memory, attention, language and problem solving. Nicotinic ACh receptor, particularly the interaction of a7 receptor to αβι-42 is implicated as an up-stream pathogenic event in Alzheimer’s disease, a major 1^ causative factor for dementia (Wang HY et al., J. Neurosci., 2009, 29,

10961-10973). Moreover, gene polymorphisme in CHRNA7 hâve been implicated in dementia with lewy bodies (DLB) and Pick’s disease (Feher A et al., Dement. Geriatr. Cogn. Disord., 2009, 28, 56-62).

Disease modification potential of nAChRs particularly the a7 receptor has application for disease-modification of Alzheimer ’s disease (AD) and Parkinson’s disease (PD) by enhancing neuron survival and preventîng neurodegeneration (Wang et al. 2009; Nagele RG et al., Neuroscience, 2002, 110, 199-211; Jeyarasasingam G et al., Neuroscience, 2002, 109, 275-285). Additionally, a7 nAChR induced activation of anti-apoptotic (BCL-2) and an ti-inflammatory pathways in brain could hâve neuroprotective effects in neurodegenerative diseases (Marrero MB et al., Brain. Res., 2009, 1256, 1-7). Dopamine containing neurons of ventral tegmental area (VTA) and laterodorsal tegmental nucléus (LDT) are known to express nicotinic ACh receptors, particularly α4, α.3, β2, β3, β4 subunits (Kuzmin A et al., Psychopharmacology (Berl), 2009, 203, 99108). Nicotinic ACh receptors, α4β2 and α3β4 hâve been identified with candidate-gene approach to hâve strong mechanistic link for nicotine addiction (Weiss RB et al., PLoS Genet., 2008, 4, e 1000125). a7 nAChR has particularly been studied for a putative rôle in cannabis addiction (Solinas M et al., J. Neurosci., 2007, 27, 5615-5620). Varenicline, a partial agonist at α4β2, has demonstrated better efficacy in reducing the smoking addiction and relapse prévention in comparison to buproprion (Ebbert JO et al., Patient. Prefer. Adhérence, 2010, 4, 355-362).

Presence of a high-affînity nicotine binding site at α4β2 nAChR, in the descending inhibitory pathways from brainstem has sparked interest in the antinociceptive properties of nicotinic ACh receptor agonists like epibatidine (Decker MW et al., Expert. Opin. Investig. Drugs, 2001, 10,

1819-1830). Several new developments hâve opened the area for use of nicotinic modulators for therapy of pain (Rowbotham MC et al., Pain,

2009, 146, 245-252). Appropriate modulation of the nicotinic ACh receptors could provide for remédiai approach to pain related states.

Another key rôle of the a7 nAChR is the ability to modulate the production of pro-inflammatory cytokines, like interleukins (IL), tumor necrosis factor alpha (TNF-α), and high mobility group box (HMGB-1) in the central nervous system. Consequently, an anti-inflammatory and antinociceptive effect in pain disorders hâve been demonstrated (Damaj MI et al., Neuropharmacology, 2000, 39, 2785-2791). Additionally, ‘cholinergic antiinflammatory pathway’ is proposed to be a regulatory of local and systemic inflammation and neuro-immune interactions through neural and humoral pathways (Gallowitsch-Puerta M et al., Life Sci., 2007, 80, 23252329; Gallowitsch-Puerta and Pavlov 2007; Rosas-Ballina M et al., Mol. Med., 2009, 15, 195-202; Rosas-Ballina M et al., J. Intem. Med., 2009, 265, 663-679). Sélective modulators of nicotinic ACh receptors, particularly a7 type, like GTS-21, attenuate cytokine production and IL-Ιβ after endotoxin exposure. Furthermore, a7 nAChR are understood to hâve a central rôle in arthritis pathogenesis and potential therapeutic strategy for treatment of joint inflammation (Westman M et al., Scand. J. Immunol., 2009, 70, 136-140). A putative rôle for a7 nAChR has also been implicated in severe sepsis, endotoxemic shock and systemic inflammation (Jin Y et al. (2010) Int. J. Immunogenet., Liu C et al., Crit. Care. Med., 2009, 37, 634-641).

Angiogenesis, is a critical physiological process for the cell survival and pathologically important for cancer prolifération; several non-neural nicotinic ACh receptors, particularly α7, α5, α3, β2, β4, are involved (Arias HR et al., Int. J. Biochem. Cell. Biol., 2009, 41, 1441-1451; Heeschen C et al., J. Clin. Invest., 2002, 110, 527-536). A rôle of nicotinic ACh receptors in the development of cervical cancer, lung carcinogène sis and paediatric lung disorders in smoking-exposed population has also been studied (Calleja-Macias IE et al., Int. J. Cancer., 2009, 124, 1090-1096; Schuller HM et al., Eur. J. Pharmacol., 2000, 393, 265-277). Several a7 nAChR agonists, partial agonists, hâve been characterized for their efficacy in clinical and preclinical studîes. EVP-6124, an agonist at a7 nAChR, has demonstrated significant improvement in sensory processing and cognition biomarkers in Phase Ib study with patients suffering from schizophrenia (EnVivo Pharmaceuticals press release 2009, Jan 12). GTS21 (DMXB-Anabaseine), an a7 nAChR agonist, in the P II clinical trials, has shown efficacy in improving cognitive déficits in schizophrenia and inhibition of endotoxin-induced TNF-α release (Olincy A et al., Biol. Psychiatry, 2005, 57(8, Suppl.), Abst 44; Olincy A et al., Arch. Gen, Psychiatry, 2006, 63, 630-638; Goldstein R et al., Acad. Emerg. Med., 2007, 14 (15, Suppl. 1), Abst 474). CP-810123, a a7 nAChR agonist, exhibits protection against the scopolamine-induced dementia and inhibition of amphetamine-induced auditory evoked potentials in preclinical studîes (O'Donnell CJ et al., J. Med. Chem., 2010, 53, 12221237). SSR-180711 A, also an a7 nAChR agonist, enhances learning and memory, and protects against MK-801/Scopolamine-induced memory loss and prepulse inhibition in preclinical studîes (Redrobe JP et al., Eur. J. Pharmacol., 2009, 602, 58-65; Dunlop J et al., J. Pharmacol. Exp. Ther., 2009, 328, 766-776; Pichat P et al., Neuropsychopharmacology, 2007, 32, 17-34). SEN-12333, protected against scopolamine-induced amnesia in passive avoidance test in preclinical studîes (Roncarati R et al., J. Pharmacol. Exp. Ther., 2009, 329, 459-468). AR-R-17779, an agonist at a.7 nAChR, exhibits improvement in the social récognition task performed in rats (Van KM et al., Psychopharmacology (Berl), 2004, 172, 375-383),

ABBF, an agonist at a7 nAChR, improves social récognition memory and working memory in Morris maze task in rats (Boess FG et al., J. Pharmacol. Exp. Ther., 2007, 321, 716-725). TC-5619, a sélective a7 nAChR agonist has demonstrated efficacy in animal models of positive and négative symptoms and cognitive dysfunction in schizophrenia (Hauser TA et al., Biochem. Pharmacol., 2009, 78, 803-812).

An alternative strategy to reinforce or potentiate the endogenous cholinergic neurotransmission of ACh without directly stimulating the target receptor is the positive allosteric modulation (PAM) of a7 nAChR (Albuquerque EX et al., Alzheimer Dis. Assoc. Disord., 2001, 15 Suppl 1, S19-S25). Several PAMs hâve been characterized, albeit in the preclinical stages of discovery. A-86774, a7 nAChR PAM, improves sensory gating in DBA/2 mice by significantly reducing the T:C ratio in a preclinical model of schizophrenia (Faghih R et al., J. Med. Chem., 2009, 52, 3377-3384). XY-4083, an a7 nAChR PAM, normalizes the sensorimotor gating déficits in the DBA/2 mice and memory acquisition in 8-arm radial maze without altering the receptor desensitization kinetics (Ng HJ et al., Proc. Natl. Acad. Sci., U. S. A., 2007, 104, 8059-8064). Yet another PAM, PNU120596, profoundly alters a7 nAChR desensitization kinetics and simultaneously protecting against the disruption of prepulse inhibition by MK-801. NS-1738, another PAM, has exhibited efficacy in-vivo in the animal models of social récognition and spatial memory acquisition in the Morris maze task (Timmermann DB et al., J. Pharmacol. Exp. Ther., 2007, 323, 294-307). In addition, several patents/applications published are listed below - US20060142349, US20070142450, US20090253691, W02007031440, W02009115547, WO2009135944, WO2009127678,

W02009127679, W02009043780, W02009043784, US7683084, US7741364, WO2009145996, US20100240707, WO2011064288,

US20100222398, US20100227869, EP1866314, W02010130768,

WO2011036167, US20100190819 disclose efficacy of allosteric modulators of nicotinic ACh receptors and underscoring their therapeutic potential.

Summary of the Invention

Acccording to one aspect of the présent invention there is provided compounds represented by the general formula I, its tautomeric forms, its stereoisomers, its analogues, its prodrugs, its isotopically substituted analogues, its métabolites, its pharmaceutically acceptable salts, its polymorphe, its solvatés, its optical isomers, its clathrates, its co-crystals, their combinations with suitable médicament and pharmaceutical compositions containing them.

Thus the présent invention further provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined herein, its tautomeric forms, its stereoisomers, its analogues, its prodrugs, its isotopically substituted analogues, its métabolites, its pharmaceutically acceptable salts, its polymorphe, its solvatés, its optical isomers, its clathrates and its co-crystals in combination with the usual pharmaceutically employed carriers, diluents and the like are useful for the treatment and/or prophylaxis of diseases or disorder or condition such as Alzheimer’s disease (AD), mild cognitive impairment (MCI), senile dementia, vascular dementia, dementia of Parkinson’s disease, attention déficit disorder, attention déficit hyperactivity disorder (ADHD), dementia associated with Lewy bodies, AIDS dementia complex (ADC), Pick's disease, dementia associated with Down's syndrome, Huntington's disease, cognitive déficits associated with traumatic brain injury (TBI), cognitive décliné associated with stroke, poststroke neuroprotection, cognitive and sensorimotor gating déficits associated with schizophrenia, cognitive déficits associated with bipolar disorder, cognitive impaîrments associated with dépréssion, acute pain, post-surgical or post-operative pain, chronic pain, inflammation, inflammatory pain, neuropathie pain, smoking cessation, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation, arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, pouchitis, inflammatory bowel disease, celiac disease, perîodontitis, sarcoidosis, pancreatitis, organ transplant rejection, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, septic shock, toxic shock syndrome, sepsîs syndrome, dépréssion, and rheumatoid spondylitis.

The présent invention also provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined herein, its tautomeric forms, its stereoisomers, its analogues, its prodrugs, its isotopically substituted analogues, its métabolites, its pharmaceutically acceptable salts, its polymorphs, its solvatés, its optical isomers, its clathrates and its co-crystals in combination with the usual pharmaceutically employed carriers, diluents and the like are useful for the treatment and/or prophylaxie of diseases or disorder or condition classified or diagnosed as major or minor neurocognitive disorders, or disorders arising due to neurodegeneration.

The présent invention also provides method of administering a compound of formula I, as defined herein in combination with or as adjunct to médications used in the treatment of attention déficit hyperactivity disorders, schizophrenia, and other cognitive disorders such as Alzheimer's disease, Parkinson’s dementia, vascular dementia or dementia associated with Lewy bodies, traumatic brain injury. —

The présent invention also provides method of administering a compound of formula I, as defined herein in combination with or as an adjunct to acetylcholinesterase inhibitors, disease modifying drugs or biologics for neurodegenerative disorders, dopaminergic drugs, antidepressants, typical or an atypical antipsychotic.

The présent invention also provides use of a compound of formula I as definded herein in the préparation of a médicament for treating a disease or disorder or condition selected from the group classified or diagnosed as major or minor neurocognitive disorders, or disorders arising due to neurodegeneration.

The présent invention also provides use of a compound of formula I as definded herein in the préparation of a médicament for treating a disease or disorder or condition selected from the group consisting of attention déficit hyperactivity disorders, schizophrenia, cognitive disorders, Alzheimer's disease, Parkinson’s dementia, vascular dementia or dementia associated with Lewy bodies, and traumatic brain injury.

The présent invention also provides use of compound of formula I as defined herein in combination with or as an adjunct to acetylcholinesterase inhibitors, disease modifying drugs or biologics for neurodegenerative disorders, dopaminergic drugs, antidepressants, or a typical or atypical antipsychotic.

Detailed Description of the invention:

The présent invention relates to novel compounds of the general formula I, its tautomeric forms, its stereoisomers, its analogues, its prodrugs, its isotopically substituted analogues, its métabolites, its sulfoxides, its Noxides, its pharmaceutically acceptable salts, its polymorphs, its solvatés, its optical isomers, its clathrates, its co-crystals, their combinations with suitable médicament and pharmaceutical compositions containing them.

wherein, in the compound of formula I,

Z is selected from the group consisting of-S-, -O- and -N(R^a)-;

R^a is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl;

R¹ is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl;

R² is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halogen, perhaloalkyl, optionally substituted cycloalkyl, cyano, nitro, (R⁷)(R⁸)N-, R^7aC(=O)N(R⁷)-, (R⁷)(R⁸)NC(=A¹)N(R⁹)-, R^7aOC(=O)NR⁹-, R^7aSO₂N(R⁸)-, R⁷A*-, and

R^7aC(=O)-;

R³ is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, wherein each of the said optionally substituted cycloalkyl and optionally substituted heterocyclyl is optionally annulated or optionally bridged, (R⁷)(R⁸)N-, (R⁷)N(OR⁸)-, and RM¹-;

[R⁴]m is ‘m’times répétition of ‘R⁴’ groups, each R⁴ is independently selected from the group consisting of halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, R^7aC(=O), R^7aSO₂-, RM¹-, (R^7a)C{=O)N(R⁹)-, (R⁷)(R⁸)N-, (R⁷)(R⁸)NC(=A!)N(R⁹)-; wherein m = 0 to 3; or two R⁴ groups and the carbon atoms to which they are attached together form an optionally substituted 5- to 6membered cyclic System which optionally contains 1 to 4 hetero atoms/groups selected from the group consisting of -N-, -S-, -O-, C(=O)-, and -C(=S)-;

R⁵ and R⁶ are independently selected from the group consisting of hydrogen, R^7aC(=O)-, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or R⁵ and R⁶ together with the nitrogen atom to which they are attached form a 3- to 10- membered optionally substituted saturated/unsaturated heterocyclic ring system containing one to three hetero atoms/groups selected from the group consisting of -S, -N-, -O-, -C(=O)-_} and -C(=S)-;

wherein R⁷, R⁸, and R⁹ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;

A¹ is selected from the group consisting of O and S;

R^7a is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;

wherein, the term optionally substituted alkyl, means a alkyl group unsubstituted or substituted with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R^10aSO2-, R’^A¹-, R^10aOC(=O)-, Ri0aC(=O)O-, (R¹⁰)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, R^10aC(=O)N(H)-, (R¹⁰)(H)N-, (R¹⁰)(alkyl)N-, (Ri<’)(H)NC(=A¹)N(H)-_} and (Ri°)(alkyl)NC(=Ai)N(H)-;

the term optionally substituted alkenyl, means a alkenyl group unsubstituted or substituted with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R^10aSO2-, R^A¹-, R^10aOC(=O)-, <xz·

Ri0a_C(=O)O-, (R¹⁰)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, R^10aC(=O)N(H)-, (R¹⁰){H)N-, (Rio) (alkyl) N-, (Ri°)(H)NC(=Ai)N(H)-, and (R¹⁰)(alkyl)NC(=A¹)N(H)-;

the term optionally substituted alkynyl, means a alkynyl group unsubstituted or substituted with 1 to 6 substituents selected îndependently from the group consisting of oxo, halogen, nitro, cyano, aiyl, hereroaryl, cycloalkyl, R^10aSO2-, R^'A¹-, R^10aOC(=O)-, _Rioa_C(=0)0-, (R¹⁰)(H)NC(=O)-, (Ri°)(alkyl)NC(=O)-, Ri°«C(=O)N(H)-, (RW)(H)N-, (Rioj(alkyl)N-, (Ri°)(H)NC(=Ai)N(H)-, and (Ri°)(alkyI)NC(=Ai)N(H)-;

the term “optionally substituted heteroalkyl” means a heteroalkyl group unsubstituted or substituted with 1 to 6 substituents selected îndependently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, and cycloalkyl;

the term “optionally substituted cycloalkyl means a cycloalkyl group unsubstituted or substituted with 1 to 6 substituents selected îndependently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R^10aC(=O)-, R^10aSO₂-, R^l0A'-, R^10aOC(=O)-, R^10aC(=O)O-, (R¹⁰)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, Ri°^aC(=O)N(H)-, (Ri°)(H)N-, (Ri»)(alkyl)N-, (R¹⁰)(H)NC(=A¹)N(H)-, and (Ri°)(alkyl)NC(=Ai)N(H)-;

the term optionally substituted aryl means (i) an aryl group unsubstituted or substituted with 1 to 3 substituents selected îndependently from the group consisting of halogen, nitro, cyano, hydroxy, Ci to Ce alkyl, C₂ to Ce alkenyl, C₂ to Cf, alkynyl, C3 to Cg cycloalkyl, Ci to Cg perhaloalkyl, alkyl-O-, alkenyl-O-, alkynyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H₂N-, alkyl-SO₂-, perhaloalkyl-SO2-, alkyl-C(=O)N(alkyl)-, alkyl-C(=O)N(H)-, alkylN(alkyl)C(=O)-, alkyl-N(H)C(=O)-, H₂NC(=O)-> alkyl-N(alkyl)SO₂-, alkyl-N(H)SO₂-, H₂NSO₂-, 3- to 6- membered heterocycle containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, wherein the said 3- to 6- membered heterocycle is optionally substituted with alkyl, alkenyl, alkynyl, or alkyl-C(=O)- or (ii) the said substituted or unsubstituted aryl ring optionally fused with cycloalkane ring or heterocycle ring containing 1 to 3 heteroatoms selected from S, O, N, across a bond, wherein the said cycloalkane ring or heterocycle ring is optionally substituted with oxo, alkyl, alkenyl, alkynyl or alkyl-C(=O)~;

the term “optionally substituted heterocyclyl means a (i) heterocyclyl group unsubstituted or substituted on ring carbons with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R^A¹-, Ri0aoC(=O)-, R^10aC(=O)O-, (R¹⁰)(H)NC(=O)-, (R¹⁰) (alkyl) NC (O)-, R^10aC(=O)N(H)-, (R¹⁰)(H)N-, (R!0)(alkyl)N-, (Ri°)(H)NC(=A’)N(H)-, and (Ri°)(alkyl)NC(=Ai)N(H)-; (ii) heterocyclyl group optionally substituted on ring nitrogen(s) with one or more substituents selected from the group consisting of hereroaryl, alkyl, alkenyl, alkynyl, R^10aC(=O)-, R^10aSO₂-, R^10aOC(=O)-, (R¹⁰)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, and aryl unsubstituted or substituted with 1 to 3 substituents selected independently from halogen, alkyl, alkenyl, alkynyl, cyano or nitro;

the term optionally substituted heteroaryl means a heteroaryl group unsubstituted or substituted with 1 to 3 substituents selected independently from the group consisting of halogen, nitro, cyano, hydroxy, Ci to Ce alkyl, C2 to Ce alkenyl, C₂ to Ce alkynyl, C3 to Ce cycloalkyl, Ci to Ce perhaloalkyl, alkyl-O-, alkenyl-O-, alkynylO-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-, alkyl-SO2-, perhaloalkyl-SO2-, alkyl-C(=O)N(alkyl)-_} alkyl-C(=O)N(H)-, alkylN(alkyl)C(=O)-, alkyl-N(H)C(=O)-> H₂NC(=O)-, alkyl-N(alkyl)SO₂-, alkyl-N(H)SO₂-, H₂NSO₂-, and 3- to 6- membered heterocycle containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, wherein the heterocycle is optionally substituted with one to four substituents selected from the group consisting of alkyl alkenyl, alkynyl, or alkyl-C(=O)-;

the term “optionally substituted 5- to 6- membered cyclic system” means the 5- to 6- membered cyclic system unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R¹⁰»C(=O)-, R^10aSO₂-, R'W-, Rio*OC(=0)-,

Ri0a_C(=O)O-, (R¹⁰)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, Ri°^aC(=O)N(H)-, (R¹⁰)(H)N-, (R¹⁰) (alkyl) N-, (Ri°)(H)NC(=Ai)N(H)-, and (R¹⁰)(alkyl)NC(=A¹)N(H)-;

the term “3- to 10- membered optionally substituted saturated/unsaturated heterocyclic ring system” the 3- to 10membered saturated/unsaturated heterocyclic ring system unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, Ri0^aC(=O)-, Rio^aS02-, R¹⁰Ai-, RioaOC(=0)-, RioaC(₌₀)0-, (R¹⁰)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, Ri0a_C(=O)N(H)-, (R¹⁰)(H)N-, (Ri») (alkyl) N-, (RiO)(H)NC(=Ai)N(H)-, and (R¹⁰)(alkyl)NC(=A^I)N(H)-;

wherein R¹⁰ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; — and R^10a is selected from the group consisting of alkyl, alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.

Whenever a range of the number of atoms in a structure is indicated (e.g., a Ci-i2, Ci-β, Ci-6, or Ci-4 alkyl, alkylamino, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1-8 carbon atoms (e.g., Ci-Cs), 1-6 carbon atoms (e.g., Ci-C&), 1-4 carbon atoms (e.g., C1-C4), 1-3 carbon atoms (e.g., C1-C3), or 2-8 carbon atoms (e.g., C2-C8) as used with respect to any chemical group (e.g., alkyl, alkylamino, etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and/or 12 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon atoms, 1-12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms, 210 carbon atoms, 2-11 carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-11 carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-11 carbon atoms, and/or 4-12 carbon atoms, etc., as appropriate).

One of the embodiment of the présent invention is compound of formula la; d-'^-’

IS

wherein R¹, R², R³, R⁴, R⁵, R⁶ and m are as defined above.

Another embodiment of the présent invention is compound of formula Ib;

wherein R¹, R², R³, R⁴, R⁵, R⁶, R^a and m are as defined above.

Yet another embodiment of the présent invention is compound of formula le;

wherein R¹, R², R³, R⁴, R⁵, R⁶ and m are as defined above.

In any of the embodiments of the invention described above, R¹ is particularly selected from the group consisting of pyridyl, furanyl, indolyl,

N-methylisoindolyl, benzofuranyl, piperazinyl, 4-(4fluorophenyljpiperazinyl, morpholinyl, indolinyl, 2-oxoindolinyl, 2,316539 dihydrobenzo[b][l,4)dioxinyl, benzopyranyl, or phenyl optionally substituted with 1 to 2 substituents selected from group comprising of halo, cyclopropyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, dimethylamino, monomethylamino, tert-butyl and 4methy lpip erazinyl.

In any of the embodiments described above, R² is particularly selected from the group consisting of hydrogen, methyl, dimethylamino and dimethylaminomethyl.

In any of the embodiments described above, R³ is particularly selected from the group consisting of methyl, ethyl, n-propyl, methoxy, ethoxy, dimethylamino, N-methoxy-N-methyl amino, N-(2-hydroxy ethyl)-N-propyl amino, acetylaminomethyl and piperidinyl.

In any of the embodiments described above, R⁵ and R⁶ are particularly selected independently from the group consisting of hydrogen and methyl, or R⁴ and R⁵ together with the nitrogen atom to which they are attached form a piperidine ring.

In any of the embodiments described above, m is particularly selected from 0, 1 or 2, and R⁴ is selected from methyl or two R⁴s together with the carbon atoms to which they are attached forming a six membered carbo cycle.

In any of the embodiments described above, R^a is particularly selected from the group consisting of hydrogen, methyl, ethyl and cyclopropylmethyl.

In any of the embodiments of the présent invention of the compound of formula I, R¹ is selected from the group consisting of pyridyl, furanyl, indolyl, N-methylisoindolyl, benzofuranyl, piperazinyl, 4-(416539 fluorophenyl)piperazinyl, morpholinyl, indolinyl, 2-oxoindolinyl, 2,3dihydrobenzo[b][l,4]dioxinyl, benzopyranyl, and phenyl optionally substituted with 1 to 2 substituents selected from group consisting of halo, cyclopropyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, dimethylamino, monomethylamino and tert-butyl, 4methylpiperazinyl; R² is selected from the group consisting of hydrogen, methyl, dimethylamino and dimethylaminomethyl; R³ is selected from the group consisting of methyl, ethyl, n-propyl, methoxy, ethoxy, dimethylamino, N-methoxy-N-methyl amino, N-(2-hydroxy ethyl)-N-propyl amino, acetylaminomethyl, piperidinyl; R⁵ and R⁶ are selected independently from hydrogen and methyl, or R⁵ and R⁶ together with the nitrogen atom to which they are attached form a piperidine ring; m is selected from 0, 1 or 2, and R⁴ is selected from methyl or two R⁴s together with the carbon atoms to which they are attached form a six membered carbocycle; and R^a is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropylmethyl.

In any of the embodiments described above, R¹ is particularly selected from the group consisting of 4-chlorophenyl, 2-chlorophenyl, 3chlorophenyl, 4-fluorophenyl, 4-cyclopropylphenyl, 4trifluoromethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-ethoxyphenyl, 4-tolyl, 4-tert-butyl phenyl, 4-dimethylaminophenyl, 3-fluorophenyl, phenyl, 4-ethylphenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,4difluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methoxyphenyl, piperazin-l-yl, 4-(fluorophenyl)piperazinyl, morpholino, pyridin-4-yl, pyridin-3-yl, furan-3-yl, lH-indol-5-yl, 1-methyl-lH-indol-5-yl, benzofuran-5-yl, indolin-5-yl, 4-(4-methylpiperaziny-l-yl)phenyl, and 2,3dihydrobenzo[b] [ 1,4]dioxin-6-yl).

In any of the embodiments described above, Z is particularly selected as S.

General terms used in formula can be defined as follows; however, the meaning stated should not be interpreted as limiting the scope of the term per se.

The term alkyl, as used herein, means a straight chain or branched hydrocarbon containing from 1 to 20 carbon atoms. Preferably the alkyl chain may contain 1 to 10 carbon atoms. More preferably alkyl chain may contain up to 6 carbon atoms. Représentative examples of alkyl include, but are not limited to, methyl, ethyl. n-propyl. iso-propyl. n-butyl, secbutyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl.

The term “alkenyl” as used herein, means an ‘alkyl’ group as defined hereinabove containing 2 to 20 carbon atoms and containing at least one double bond.

The term “alkynyl” as used herein, means an ‘alkyl’ group as defined hereinabove containing 2 to 20 carbon atoms and containing at least one triple bond.

‘Alkyl’, ‘alkenyl’ or ‘alkynyl’ as defined hereinabove may be optionally substituted with one or more substituents selected independently from the group comprising of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, Ri0asO2-, R¹⁰A!-, R^10aOC(=O)-, R^10aC(=O)O-, (R¹⁰)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, Ri°^aC(=O)N(H)-, (Ri°)(H)N-, (R¹⁽))(alkyl)N-, (R¹⁰)(H)NC(=A¹)N(H)-, (R^MalkylJNC^AiJNfH)-; wherein R¹⁰ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and A¹ is selected from S and O; and R^10a is selected from alkyl, alkenyl, alkynyl perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.

The term “perhaloalkyl” used herein means an alkyl group as defined hereinabove wherein ail the hydrogen atoms of the said alkyl group are substituted with halogen, The perhaloalkyl group is exemplified by trifluoromethyl, pentafluoroethyl and the like.

The term “heteroalkyl” as used herein means hetero modified ‘alkyl’ group, where a CH₂ group is modified (or replaced) by -O-, -S-, -S(O₂)-, S(O)-, -N(R^m)-, Si(R^m)Rⁿ- wherein, R^m and Rⁿ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl. The group there by includes the linkages like CH3-S-, CH3CH2-O-, CH3-O-CH2-, CH3-S-CH2-, CH3-N(R^m)-CH2-, CH3-Si(R^m)Rⁿ-CH₂and the like.

The term “cycloalkyl as used herein, means a monocyclic, bicyclic, or tricyclic non-aromatic ring system containing from 3 to 14 carbon atoms, preferably monocyclic cycloalkyl ring containing 3 to 6 carbon atoms. Examples of monocyclic ring Systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic ring Systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge. Représentative examples of bicyclic ring Systems include, but are not limited to, bicycio[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2. l]nonane, bicyclo[3.3.2]decane, bicy cio [3.1.0] hexane, bicyclo[410]heptane, bicyclo[3.2.0]heptanes, octahydro-lH-indene. Tricyclic ring Systems are also exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge. Représentative examples of tricyclîc-ring Systems include, but are not limited to, tricyclo[3.3.1.0³-⁷]nonane and tricyclo[3.3.1.1³-⁷]decane (adamantane). The term cycloalkyl also include spiro Systems wherein one of the ring is annulated on a single carbon atom such ring Systems are exemplified by spiro[2.5]octane, w- spiro[4.5]decane, spiro[bicyclo[4.1.0]heptane-2, Γ-cyclopentane], hexahydro-2'H-spiro[cyclopropane-1,1 ’-pentalene].

cycloalkyl as defined hereinabove may be optionally substituted with one or more substituents selected independently from the group comprising of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, Ri0aC(=O)-, RioaSOa-, R^A¹-, R^10aOC(=O)-, R^10aC(=O)O-, (Ri«)(H)NC(=O)-, (R^l0)(alkyl)NC(=O)-, R^!0aC(=O)N(H)-, (Ri°)(H)N-, (Ri°)(alkyl)N-, (R¹⁰)(H)NC(=A¹)N(H)-, (R¹⁰)(alkyl)NC(=A¹)N(H)-; wherein R¹⁰ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and A¹ is selected from S and O; and R^10a is selected from alkyl, alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl

The term aryl refers to a monovalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. Aryl group also include partially saturated bicyclic and tricyclic aromatic hydrocarbons such as tetrahydro-naphthalene. The said aryl group also includes aryl rings fused with heteroaryl or heterocyclic rings such as 2,3dihydro-benzo[ 1,4]dioxin-6-yl; 2,3-dihydro-benzo[ 1,4]dioxin-5-yl; 2,3dihydro-benzofuran-5-yl; 2,3-dihydro-benzofuran-4-yl; 2,3-dihydrobenzofuran-6-yl; 2,3-dihydro-benzofuran-6-yl; 2,3-dihydro- lH-indol-5-yl; 2,3-dihydro-1 H-indol-4-yl; 2,3-dihydro-1 H-indol-6-yl; 2,3-dihydro-1Hindol-7-yl; benzo[l,3]dioxol-4-yl; benzo[l,3|dioxol-5-yl; 1,2,3,4tetrahydroquinolinyl; 1,2,3,4-tetrahydroisoquinolinyl; 2,3dihydrobenzothien-4-yl, 2-oxoindolin-5-yL

Aryl as defined hereinabove may be optionally substituted with one or more substituents selected independently from the group comprising of halogen, nitro, cyano, hydroxy, Ci to Cg alkyl, C2 to Cô alkenyl, C2 to Ce alkynyl, C3 to Cg cycloalkyl, Ci to Cg perhaloalkyl, alkyl-O-, alkenyl-O-, alkynyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H2N-, alkyl-SO2-, perhaloalkyl-SO₂-, alkyl-C(=O)N(alkyl)-, alkyl-C(=O)N(H)-, alkylN (alkyl) C(=O)-, alkyl-N(H)C(=O)-, H₂NC(=O)-, alkyl-N(alkyl)SO₂-, alkylN(H)SO₂-, H₂NSO₂-, 3 to 6 membered heterocycle containing 1 to 2 heteroatoms selected from N, O and S optionally substituted with alkyl, alkenyl, alkynyl, or alkyl-C(=O)-.

The term heteroaryl refers to a 5-14 membered monocyclic, bicyclic, or tricyclic ring system having 1-4 ring heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated), wherein at least one ring in the ring system is aromatic. Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent. Examples of heteroaiyl groups include pyridyl, 1-oxo-pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, îsoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl. triazolyl, thiadiazolyl, isoquinolinyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, and benzo(b)thienyl, 2,3-thiadiazolyl, lH-pyrazolo[5, l-c]-l,2,4-triazolyl, pyrrolo[3,4-d]-l,2,3-triazolyl, cyclopentatriazolyl, 3H-pyrrolo[3,4-c] îsoxazolyl and the like.

heteroaryl as defined hereinabove may be optionally substituted with one or more substituents selected independently from the group comprising of halogen, nitro, cyano, hydroxy, Ci to Ce alkyl, C₂ to Ce alkenyl, C₂ to Cg alkynyl, C3 to Cg cycloalkyl, Ci to Cg perhaloalkyl, alkyl-O-, alkenyl-O-, alkynyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, HaN-, alkyl-SO₂-, perhaloalkyl-SCh-, alkyl-C(=O)N(alkyl)-, alkyl-C(=O)N(H)-, alkylN(alkyl)C(=O)-, alkyl-N(H)C(=O)-, H₂NC(=O)-, alkyl-N(alkyl)SO₂-, alkylN(H)SO₂-, H₂NSO₂-, 3 to 6 membered heterocycle containing 1 to 2 heteroatoms selected from N, O and S optionally substituted with alkyl, alkenyl, alkynyl or alkyl-C(=O)-.

The term heterocycle or heterocyclic as used herein, means a ‘cycloalkyl’ group wherein one or more of the carbon atoms replaced by O-, -S-, -S(O₂)-, -S(O)-, -N(R^m)-, -Si(R^m)Rⁿ-, wherein, R^m and Rⁿ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl. The heterocycle may be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle. Représentative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl. oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl. pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thîadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1.1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. Représentative examples of bicyclic heterocycle include, but are not limited to 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3dihydro-1,4-benzodioxinyl, 2,3-dihydro- 1-benzofuranyl, 2,3-dihydro-1 benzothienyl, 2,3-dihydro-1 H-indolyl and 1,2,3,4-tetrahydroquinolinyl. The term heterocycle also include bridged heterocyclic Systems such as azabicyclo{3.2.1]octane, azabicyclo[3.3.1]nonane and the like.

Heterocyclyl group may optionally be substituted on ring carbons with one or more substituents selected independently from the group comprising of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R¹⁰A¹-,

Ri0aoC(=O)-, Ri0aC(=O)O-, (R¹0)(H)NC(=O)-, (Ræ)(alkyl)NC(O)-,

Ri°^aC(=O)N(H)-, (R¹⁰) (H) N-, (R^ialkylJN-, (Rîo)(H)NC(=A¹)N(H)-, (R¹⁰)(alkyl)NC(=A¹)N(H)-; wherein R¹⁰ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and A¹ is selected from S and O; and R^10a is selected from alkyl, alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.

Heterocyclyl group may further optionally be substituted on ring nitrogen(s) with substituents selected from the group comprising of aryl, hereroaryl, alkyl, alkenyl, alkynyl, R^10aC(=O)~, R^10aSO2-, R^10aOC(=O)-, (R¹⁰)(H)NC(=O)-, (R¹⁰)(alkyl}NC(=O)-; wherein R¹⁰is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and R^10ais selected from alkyl, alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.

The term ‘oxo’ means a divalent oxygen (=0) attached to the parent group. For example oxo attached to carbon forms a carbonyl, oxo substituted on cyclohexane forms a cyclohexanone, and the like.

The term ‘annulated* means the ring system under considération is annulated with another ring either at a carbon atom of the cyclic system or across a bond of the cyclic system as in the case of fused or spiro ring Systems.

The term ‘bridged’ means the ring System under considération contain an alkylene bridge having 1 to 4 methylene units joining two non adjuscent ring atoms.

A compound its stereoisomers, racemates, pharmaceutically acceptable sait thereof as described hereinabove wherein the compound of general formula I is selected from:

1. 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide.

2. 4-(5-(2-chlorophenyl)-4-methyl-2-propionylthiophen-3yljbenzene sulfonamide.

3. 4-(5-(3-chlorophenyl)-4-methyl-2-propionylthiophen-3yljbenzene sulfonamide.

4. 4-(5-(4-fluorophenyl)-4-methyl-2-propionylthiophen-3- yl) benzene sulfonamide.

5. 4-(5-(4-cyclopropylphenyl)-4-methyl-2-propionylthiophen-3- yl) benzene sulfonamide.

6. 4- (4 -methyl- 2 -pr op ionyl- 5 - (4 - (trifluoromethyl) phenyl) thi op hen 3-yl)benzene sulfonamide.

7. 4-(5-(4-methoxyphenyl)-4-methyl-2-propionylthiophen-3yljbenzene sulfonamide.

8. 4-(5-(4-ethoxyphenyl)-4-methyl-2-propionylthiophen-3yljbenzene sulfonamide.

9. 4-(4-methyl-2-propionyl-5-(4-(trifluoromethoxy)phenyl)thiophen3-yl) benzenesulfonamide.

10. 4-(4-methyl-2-propionyl-5-(4-tolyl)thiophen-3- yl) benzenesulfonamide.

11. 4-(5-(4-(tert-butyl)phenyl)-4-methyl-2-propionylthiophen-3- yl)benzene sulfonamide.

12. 4-((5-(4-dimethylamino)phenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide.

13. 4-(5-(3-fluorophenyl)-4-methyl-2-propionylthiophen-3- yl)benzene sulfonamide. '

14. 4-(4-methyl-5-phenyl-2-propionylthiophen-3yljbenzenesulfonamide.

15. 4-(5-(3-ethoxyphenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide.

16. 4-(5-(4-ethylphenyl)-4-methyl-2-propionylthiophen-3-yl)benzene sulfonamide.

17. 4-(5-(3,4-dichlorophenyl)-4-methyl-2-propionylthiophen-3yljbenzene sulfonamide.

18. 4-(5-(2,4-dichlorophenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide.

19. 4-(5-(2,4-difluorophenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide.

20. 4-(5-(3-chloro-4-fluorophenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide.

21. 4-(5-(3-chloro-4-methoxyphenyl)-4-methyl-2-propionylthiophen3-yl) benzenesulfonamide.

22. 4-(4-methyl-5-(piperazin-l-yl)-2-propionylthiophen-3-yl)benzene sulfonamide.

23. 4-(5-(4-(4-fluorophenyl)piperazin-l-yl)-4-methyl-2propionylthiophen-3-yl)benzenesulfonamide.

24. 4-(4-methyl-5-morpholino-2-propionylthiophen-3- yl) benzene sulfonamide.

25. 4 - (4-methyl-2 -propionyl- 5 - (pyridin-4-yl) thiophen- 3 yljbenzenesulfonamide.

26. 4-(4-methyl-2-propionyl-5-(pyridin-3-yl)thiophen-3- yl) benzen e su Ifon amide.

27. 4-(5-(furan-3-yl)-4-methyl-2-propionylthiophen-3- yljbenzenesulfonamide. os

28. 4-(5-( lH-indol-5-yl)-4-methyl-2-propîonylthiophen-3-yl) benzene sulfonamide.

29. 4-(4-methyl-5-(1-methyl-lH-indol-5-yl)-2-propionylthiophen-3yljbenzene sulfonamide.

30. 4-(5-(benzofuran-5-yl)-4-methyl-2-propionylthiophen-3yljbenzene sulfonamide.

31. 4-{5-(indolin-5-yl)-4-methyl-2-propionylthiophen-3- yl)b enzene su lfonamide.

32. 4-(4-methyl-5-(4-(4-methylpiperazin- l-yl)phenyl)-2propionylthiophen-3-yl)benzenesulfonamide.

33. 4-(5-(4-chlorophenyl)-2-propionylthiophen-3yl)benzenesulfonamide.

34. 4-(5-(4-chlorophenyl)-4-(dimethylamino)-2-propionylthiophen-3yl)benzene sulfonamide.

35. 4-(5-(4-chlorophenyl)-4-((dimethylamino)methyl)-2propionylthiophen-3-yl) benzenesulfonamide.

36. 5-(4-chlorophenyl)-/V_J7V,4-trimethyl-3-(4sulphamoylphenyl)thiophene-2-carboxamide.

37. 5-(4-chlorophenyl)-lV-methoxj/-lV_t4-dimethyl-3-(4sulphamoylphenyl) thiophene-2-carboxamide.

38. 5-(4-chlorophenyl)-7V-(2-hydroxyethi/Z/4-methyl-N-propyl-3-(4sulphamoyl phenyl)thiophene-2-carboxamide.

39. 4-(5-(4-chlorophenyl)-4-methyl-2-(piperidine-lcarbonyl)thiophen-3-yl) benzenesulfonamide.

40. 4-(2-acetyl-5-(4-chlorophenyl)-4-methylthiophen-3yl)benzenesulfonamide.

41. 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-2methylbenzene sulfonamide. w/

42. methyl 4-methyl-5-(2-oxoindolin-5-yl)-3-(4- sulfamoylphenyl)thiophen-2 -carboxylate.

43. ethyl 4-methyl-5-(2-oxoindolin-5-yl)-3-(4- sulfamoylphenyl)thiophen-2-carboxylate.

44. 4-(4-methyl-5-(4-mehylaminophenyl)-2-propionylthiophen-3yl)benzene sulfonamide.

45. 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-N,Ndimethylbenzenesulfonamide.

46. 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-Nmethylbenzenesulfonamide.

47. 4-(5-(3,4-difluorophenyl)-4-methyl-2-propionylthiophen-3yljbenzene sulfonamide.

48. 1 -(5-(4-chlorophenyl)-4-methyl-3-(4-(piperidin-1 ylsulfonyl)phenyl) thiophen-2-yl)propan- 1-one

49. 4-(5-(4-chlorophenyl)-1,4-dimethyl-2-propionyl-1 H-pyrrol-3-yl) benzene sulfonamide.

50. 5-(4-chlorophenyl)-lV,iV, l,4-tetramethyl-3-(4-sulfamoylphenyl)-

H-pyrrol-2-carboxamide.

51. 4-(5-(4-chlorophenyl)-1 -ethyl-4-methyl-2-propionyl-1 H-pyrrol-3yl)benzene sulfonamide.

52. 4-(5-(4-chlorophenyl)-l-(cyclopropylmethyl)-4-methyl-2propionyl-177-pyrrol- 3-yl) benzene sulfonamide.

53. 4-(5-(4-chlorophenyl)-4-methyl-2-propionyl- lH-pyrrol-3-yl) benzene sulfonamide.

54. 4-(5-(4-fluorophenyl)-1,4-dimethyl-2-propionyl-1 H-pyrrol-3-yl) benzene sulfonamide.

55. 4-(5-(4-methoxyphenyl)-1,4-dimethyl-2-propionyl-1 H-pyrrol-3yl) benzene sulfonamide.

56. 4-(2-butyryl -5- (4- chlorophenyl) -1,4-dimethyl -IH- pyrrol -3yl) benzene sulfonamide.

57. 4-(5-(2,4-dichlorophenyl)-l,4-dimethyl-2-propionyl-lH-pyrrol-3yl) benzene sulfonamide.

58. 4-(5-(2,3-dihydrobenzo[b][l,4]dioxin- 6 -yl) -1,4- dimethyl -2propionyl-lH-pyrrol-3-yl) benzene sulfonamide.

59. ethyl 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoyl-5,6,7,8- tetrahydro naphthalen- l-yl)thiophene-2-carboxylate.

60. ethyl 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)furan-2- carboxylate

According to another aspect of the présent invention, the compounds of general formula I where ail the symbols are as defined earlier were prepared by methods described below. However, the invention is not limited to these methods; the compounds may also be prepared by using procedures described for structurally related compounds in the literature.

Scheme 1 shows a method of préparation of a compound in accordance with an embodiment of the formula la. Compound of formula la can be prepared from compound of formula VI, where R¹, R², R⁴, R⁵, R⁶ and m are same as described under generic formula la. vv—

Compound of formula VI can be converted to its corresponding acid chloride using standard procedures known in synthetic organic chemistry or preferabiy by reaction with oxalyl chloride in dichloromethane along 5 with DMF followed by reaction with N, O-dimethyl hydroxy lamine hydrochloride in presence of triethylamine in dichloromethane to provide compound of formula VII.

Compound of the formula VII is reacted with a Grignard reagent R³MgX^Jwherein R³ is selected from optionally substituted alkyl, optionally 10 substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted hererocyclyl which may be optionally annulated or optionally bridged, and X¹ is a halogen, to obtain compound of formula la, where R³ is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally 15 substituted cycloalkyl, optionally substituted hererocyclyl which may be optionally annulated or optionally bridged, and R⁵ and R⁶ are same as described under general formula I or la. The reaction of compound of formula VII with R³MgX¹ may be carried out according to the procedure given in literature such as J. Med. Chem., 2009, 52, 3377.

Compound of formula VI, where R⁵ = R⁶ = hydrogen, can be converted to acid chloride using oxalyl chloride in dichloromethane along with DMF followed by reaction with Y, O-dimethy lhydroxy lamine hydrochloride in presence of triethylamine in dichloromethane to provide compound of formula VIIa, which can then be further converted to compound of formula la by reacting with R³MgX¹ as described herein above.

Compound of formula VI is alternatively reacted with (R⁷)(R⁸)NH, (R⁷)(OR⁸)NH, or R⁷OH, where R⁷ and R⁸ are as defined under définition of R³ in general formula la or I, to obtain compound of formula la, where R⁵and R⁶ are same as described under compound of formula I or la and R³ is selected from the group consisting of (R⁷)(R⁸)N-, (R⁷)(OR⁸)N-, and R⁷O-, wherein R⁷ and R⁸ are as defined under définition of R³ in general formula la or I. The reaction was carried out according to the conditions known in converting carboxylic acids to amides and esters as known to one skilled in the art. The reaction may be carried out in the presence of solvents, for example, DMF, THF, a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as xylene, benzene, toluene, or mixtures thereof or the like, in the presence of suitable base such as triethylamine, diisopropylethylamine, pyridine or the like at a température between 0-50°C using reagents such as l-(3dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDCI), 1,3dicyclohexylcarbodiimide (DCC), and auxiliary reagents such as 1hydroxy-7-azabenzotriazole (HOAT), hydroxybenzotriazole hydrate (HOBT) or the like.

Compound of formula la where R¹, R², and R³ are the same as described under compound of formula I or la, and R⁵ and R⁶ are as described under formula I or la excluding hydrogen were prepared by further reaction of compounds of formula la where R⁵ and R⁶ are hydrogen, with the reagents 5 selected from R5L¹ and R⁶L¹, where L¹ is halogen or -B(OH)2 in presence of a base or using appropriate conditions given in literature such as Tetrahedron letters 2005, 46(43), 7295-7298, Tetrahedron letters 2003, 44(16), 3385-3386, US2003236413, Synthetic Communications 2009, 39(12), 2082-2092, Tetrahedron letters 2010, 51(15), 2048-2051,

Tetrahedron letters 2008, 49(18), 2882-2885, and J. Amer. Chem. Soc.

2005, 127(36), 12640-12646.

Scheme 2 shows a method of préparation of compound of formula VI from compound of formula II and an alternative method for compound VI from 15 compound of formula VIII.

Compound of formula VI, where R¹ is as described under compound of generic formula la and R² is selected from optionally substituted alkyl, yv~ optionally substituted alkenyl, optionally substituted alkynyl, perhaloalkyl, optionally substituted cycloalkyl, R7A¹- and R^7aC(=O)-, can be prepared from compound represented by general formula II, where Ak is alkyl group, R¹ is optionally substituted, optionally fused aiyl; optionally substituted, optionally fused heteroaryl; wherein, aryl and hereroaryl include the fused ring Systems wherein the aiyl or heteroaryl ring is fused with saturated cyclic system; and R² is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, perhaloalkyl, optionally substituted cycloalkyl, R⁷A¹and R^7aC(=O)-. Compound of formula II was in turn prepared by the procedures described in the literature such as US5608082 and W02007092751. Groups covered under R² can be transformed from one to other în any of the succeeding steps of Scheme 1 or 2 by general group transformation method.

Compound of formula II on halogénation gave compound of formula III, where L is a halogen and other symbols are the same as defined earlier for compound of formula II, Halogénation can be carried out under a condition generally used in the synthetic organic chemistry using halogenating agents such as bromine, phosphorous tribromide, bromine chloride, aluminium tribromide, hydrogen iodide/iodine, iodine chloride, N-iodosuccinimide, iodine /sulfuric acid and N-chlorosuccinimide, The inventors hâve carried out bromination using bromine in the presence of zinc chloride.

Compound of formula III as obtained in the previous step was subjected to Suzuki coupling with compound of formula IV, where R⁴, R⁵, R⁶ and m are same as defined earlier in compound of formula la or I, to obtain compound of formula V where the symbols R¹ and R² are same as defined for compound of formula II and R⁴, R⁵, R⁶ and m are same as defined in general formula la or I. Suzuki coupling can be carried out under different coupling conditions with boronic acids and boronic esters well known in the art. Preferably, the Suzuki coupling is carried out in a mixture of water, éthanol, methanol and toluene, in presence of base such as potassium phosphate or potassium carbonate or the like, palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) at 50°C or higher température. Boronic acid used in this reaction can be prepared by the methods well known in the art by hydrolysing the correspondîng boronate. Boronates are generally commercially available. Besides, such boronates can also be prepared by reacting an appropriate iodo- or bromo compound with an alkyl lithium such as butyl lithium and then reacting with a borate ester or by methods well known in the art (EP 1012142; Review article by N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2547).

Ester hydrolysis of compound of formula V gave compound of formula VI, where R¹, R², R⁴ R⁵, R⁶ and m are the same as defined hereinabove for compound of formula V. Ester hydrolysis may be carried out using standard procedure generally used in synthetic organic chemistry or well known in the art with reagents such as sodium hydroxide, potassium hydroxide, lithium hydroxide or the like in solvents such as water, alcohol, THF or the like or mixtures thereof. Preferably aqueous solution of sodium hydroxide and éthanol were used for the reaction.

Alternatîvely, compound of formula VI can be prepared starting from compound of formula VIII, where R² is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, perhaloalkyl, optionally substituted cycloalkyl, R⁷A¹and R^7aC(=O)-; Ak is alkyl group; and Z¹ is bromo or amino, as follows.

Compound of formula VIII with Z¹ as bromo, was obtained by converting the amino group (the said amino compound is commercially available) to the corresponding bromo group under a condition usually applied in Sandmayer’s reaction. This involves diazotization by reacting the corresponding amino compound with a nitrite eg. tert-butyl nitrite or the like, followed by halogen exchange, which may be conveniently accomplished by reaction with a copper halide, preferabiy copper(II)bromide.

Compound of the formula VIII with Z¹ as bromo was subjected to Suzuki coupiing with the compound of formula IV, to obtain compound IX where the symbol R² is the same as defined for compound of formula VIII above, and R⁴, R⁵, R⁶ and m are same as defined in general formula la.

Compound of the formula IX on bromination gave compound of formula X. Bromination can be carried out under a condition generally used in the synthetic organic chemistry using brominating agents. The inventers hâve carried out bromination using bromine.

Compound of the formula X was subjected to Suzuki Coupiing with R^xB(OH)2, wherein R¹ is as defined in the generic formula la having point of attachment on carbon atom, to give compound of formula V where ail the symbols R², R⁴, R⁵, R⁶ and m are the same as defined in compound of formula IX and R¹ is as defined in the generic formula la having point of attachment on carbon atom. Ester hydrolysis of compound of formula V to compound of formula VI is carried out by foilowing the same procedure and réaction conditions as described earlier. Compound of formula VI so obtained was then converted to compound of formula la using the process described hereînabove in Scheme 1. The groups covered under R² can be introduced or transformed from one to another to arrive at the required groups as covered in compound of formula la at the stage of compound of formula V or in the succeeding steps also. —

Scheme 3 shows a method of préparation of a compound of formula VI, where, R² is selected from the group consisting of (R⁷)(R⁸)N-,

R^7aC(=O)N(R⁷)-, (R⁷)(R⁸)NC(=A¹)N(R⁹)-, R^7aOC(=O)N(R⁹)-, R^7aSO₂N(R⁷)-, cyano, nitro and halogen from dibromo compound of formula XI, where Ak is alkyl group.

Compound of the formula VI, where, R² is selected from (R⁷)(R⁸)N-, 10 R^7aC(=O)N(R⁷)-, (R⁷)(R⁸)NC(=O)N(R⁹)-, R^7aOC(=O)N(R⁹)-, R^7aSO₂N(R⁷)-, cyano, nitro and halogen can be prepared starting from the dibromo compound of formula XI as follows. Compound XI can be prepared by following the process provided in J. Chem. Soc. Perkin Trans.: Organic and Bioorganic chemistry (1972-1999), 1973, pages 1766 - 1770. w—

Compound of the formula XI on nitration gave compound XII, which upon réduction of the nitro group to an amino group gave compound of formula XIII. Nitration and its further réduction can be carried out under the conditions according to procedures generally known or used in synthetic organic chemistry. The inventers hâve carried out nitration using nitric acid, and réduction by the use of iron powder and acetic acid.

Compound of the formula XIII was further reacted with the reagents selected from R⁷L, R⁸L, R⁹L, where R⁷, R^7a, R⁸ and R⁹ are as defined earlier except being hydrogen, and L is halogen, and/or reacted with the reagents selected from the group consisting of R^7aC(=O)L, R^7aN=C=O, R^7aN=C=S and (R⁷)(R⁸)NC(=O)L, R^7aA¹C(=O)L, and R^7aSO2L, wherein R⁷, R^7aand R⁸are as defined earlier under general formula I or la, and L is halogen, to obtain compound of formula XIV with R² as (R⁷)(R⁸)N-, R^7aC(=O)N(R⁷)-, (R⁷)(R⁸)NC(=A¹)N(R⁹)-, R^7aOC(=O)NR⁹-, R^7aSO2N(R⁷)-, R⁷A^!~, or R^7aC(=O)-. R² in compound of formula XIV where R² is R^7aOC(=O)NR⁹was conveniently converted to (R⁷)(R⁸)NC(=O)N(R⁹)- by reaction with the amine of formula (R⁷)(R⁸)NH in the presence of a suitable base such as alkalimetal alkoxides or triethylamine or by using an aluminum amide [Tetrahedron 60 (2004) 3439-43] in non-polar organic solvent such as toluene or a polar solvent such as tetrahydrofuran.

Compound of formula XIV or compound of formula XII were subjected to Suzuki coupling with boronic acid of the formula ‘R^OH^’, where R¹ is the same as defined in general formula la, under standard Suzuki coupling conditions in presence of a base selected from potassium phosphate, potassium carbonate and the like, and a palladium catalyst tetrakis(triphenyIphosphine)palladium(0) in a solvent selected from water, éthanol, methanol, toluene and mixtures thereof in any suitable proportion, to obtain compound of formula XV, where the définition of R¹ is the same as defined in general formula la and R² is (R⁷)(R⁸)N-,

R^7aC(=O)N(R⁷)-, (R⁷)(R⁸)NC(=A¹)N(R⁹)-, R^7aOC(=O)NR⁹-, R^7aSO₂N(R⁷)-, RW-,

R^7aC(=O)- or nitro.

Compound of the formula XV was then subjected to Suzuki coupiing with 5 compound of formula IV to obtain compound of formula V where R¹, R⁴,

R⁵, R⁶ and m are the same as defined in general formula la, and R² is (R⁷)(R⁸)N-, R^7aC(=O)N(R⁷)-, (R⁷)(R⁸)NC(=A¹)N(R⁹)-, R^7aOC(=O)NR⁹-,

R^7aSO2N(R⁷)-, R⁷A¹-, R^7aC(=O)- or nitro. Suzuki coupiing has been carried out by foilowing the same procedure as described earlier. The compound 10 of formula V was further converted to the compound of formula VI by the application of procedures described hereinabove. Compound of formula V, where R² is nitro, the nitro group of the said compound can be further converted to cyano or halogen by known functional group conversion methods.

Scheme 4 shows method of préparation of a compound of formula VI, where, R² is hydrogen, from dibromo compound of formula XI, where Ak is alkyl group.

Compound of formula XI was first coupled with boronic acid of formula where R¹ is the same as defined in general formula la having point of attachment as carbon atom by Suzuki coupling to obtain compound of formula XVI, which was then subjected to Suzuki coupling with compound of formula IV to give the compound of formula V, where R²is hydrogen. Compound of formula V was converted to compound of formula VI, where R¹, R⁴, R⁵, R⁶ and m are same as defined in general formula la and R² is hydrogen using the procedure described earlier.

In another embodiment of compound of formula V, where the symbols R¹, R⁵, R⁶ and m are the same as defined in general formula la; R⁴ is selected from the group consisting of halogen, cyano, R^7aSO2-, R⁷A^l-, (R^7a)C(=O)N(R⁹)-, (R⁷)(R⁸)N- and (R⁷)(R⁸)NC(=A!)N(R⁹)-; Ak is the same as defined for compound of formula II; and R² is methyl, on bromination gave compound of formula XVII (Scheme 5). The compound of formula XVII, where the symbols R¹, R⁵, R⁶ and m are the same as defined in general formula la; and R⁴ is selected from the group consisting of halogen, cyano, R^7aSO₂-, R⁷Ai-, (R^7a)C(=O)N(R⁹)-, (R⁷)(R⁸)N- and (R⁷)(R⁸)NC(=Ai)N(R9)-; Ak is as defined for compound of formula II and L is bromo on reaction with (R¹⁰)NH₂, (R¹⁰)(alkyl)NH or RM¹!-!, where R¹⁰is the same as defined under compound of formula I and/or la, and further ester hydrolysis provide a compound of formula VI, where R² is alkyl (e.g., methyl) substituted with (R¹⁰)(H)N-, (R¹⁰)(alkyl)N- or R’M¹-. Synthesis of compound of formula la from compound of formula VI was carried out by foliowing the same procedure and reaction conditions as described earlier. If the compound of formula V has R⁵ = R⁶ = hydrogen, then the sulfonamide group needs to be protected using an appropriate protecting group such as N,Ndimethylformamide dimethyl acetal to obtain compound of formula XVIII, which can then be reacted with (R¹⁰)(H)N-, (R¹⁰)(alkyl)N- or R¹⁰A!H, where R¹⁰ is the same as defined under compound of formula I and/or la.

Alternatively, the compounds of the formula la where ail the substituents are the same as described under generic formula except R² being selected from hydrogen or optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, perhaloalkyl, optionally substituted cycloalkyl, cyano, nitro, (R⁷) (R⁸) N-, R^7aC(=O)N(R⁷)-, (R^fR^NC^A^NfR⁹)-, R^7aOC(=O)NR⁹-, R^7aSO₂N(R⁸)-, RM¹- or R^7aC(=O)can be prepared starting from compounds represented by general formula (a) as per the route provided in Scheme 6 as follows 16539

(where R^S“ R‘=Hydrogen)

where. R^s

Hydrogen

(la)

Wherein,

R'-H is

wherein, ’A' is a 3 to I0 membered optionally substituted salurated/unsaturatcd monocyclic/bicyclic or optionally bridged heterocyclic ring system containing one to three hetero atoms/groups such as S, N, O, C(=O), C(=S); wherein, the heterocyclic ring may optionally bc further annulated with cycloalkyl, heterocyclyl, aryl or heteroaryl ring Systems.

SCHEME 6

Compounds of formula (a) and (f) were prepared by adoptîng the procedure described in the literature such as Bioorganic chemistry, 22, 387-394 (1994). Compound of the formula (a) where the symbol R² is selected from hydrogen or optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, perhaloalkyl, optionally substituted cycloalkyl, cyano or nitro was protected using N,N-dimethylformamide acetal to give compound of formula (b). Protection may be carried out using a procedure given in literature such as EP 1790640. The înventers have done protection using 7V,7V-dimethylformamide diméthyl acetal in the presence of DMF.

Compound of the formula (b) was reacted with carbondi sulfide and dibromoethane in the presence of a base such as potassium carbonate, potassium tert. butoxide or the like in a solvent such as acetone or the like, to form dithietane ring as represented by formula (c).

Compound of the formula (c) was further reacted with R¹-!!, where R¹ is a heterocycle ‘A’ with a point of attachment on nitrogen atom;

Oviz. ^x, wherein A is a 3 to 10 membered optionally substituted heterocyclic ring system containing one to three hetero atoms/groups such as S, N, O, C(=O) or C(=S); wherein, the heterocyclic ring may optionally be further annulated with cycloalkyl, heterocyclyl, aryl or heteroaryl ring Systems; to give compound of formula (d).

Compound of formula (d) was further cyclized to obtain compound of formula (e). The inventers have carried out cyclization by reacting compound (d) with ethyl iodoacetate in the presence of a base such as potassium carbonate or the like.

Hydrolysis of compounds of the formula (e) gave compound of formula VI with R¹ selected as heterocycle attached through nitrogen atom, R², R⁴and m are as defined earlier under generic formula la or I, and Ak is alkyl group. The hydrolysis may be carried out by standard procedure generally used in synthetic organic chemistry or well known in the art with reagents such as sodium hydroxide, potassium hydroxide and lithium hydroxide in solvents such as alcohol or THF or the like. Preferably, the hydrolysis is carried out using aqueous solution of sodium hydroxide and éthanol. Compounds of formula VI, so obtained, was further converted to compound of formula la, where R¹ is a heterocycle connected through nitrogen atom, using the process described hereinbefore.

Compound of formula la, where R² is nitro, the nitro group of the said compound can be further converted to (R⁷)(R⁸)N-, R^7aC(=O)N(R⁷)-, (R⁷)(R⁸)NC(=A¹)N(R⁹)-, R^7aOC(=O)NR⁹-, R^7aSO₂N(R⁸)- using the known functional group transformation methods.

Compound of formula (f), where the nitrogen of the sulfonamido function has nonhydrogen substituents thereon, can be analogously converted to compound of formula VI following the chemistry described for conversion of compound of formula (a) to compound of formula VI, however such conversion does not require protection of the sulfonamido function as shown in Scheme 6.

According to another feature of the présent invention, the compounds of general formula lb where ail the symbols are as defined earlier, were prepared by method described below in Scheme 7. w—

whan R“ Is alkyl, compound (v) - compound 11» R“ = O-alkyl or alkyl

SCHEME 7

Compound of the formula Ib can be prepared starting from compound represented by general formula (ii) wherein R¹, R², and R^a are the same as defined under general formula I or Ib and R^b is alkyl or -O-alkyl; which in tum can be prepared by adopting the procedures described in literature such as Tetrahedron Letters 2005, 46, 4539-4542, W02005105789, Tetrahedron Letters 2010, 51, 1693-1695; J. Org. Chem. 2009, 74(2), 903-905; Organic Letters 2007, 9(25), 5191-5194; Tetrahedron 2006, 62, 8243-8255 or methods well known in the art. Groups covered under R² can be introduced or transformed into a suitable group of choice in any of^/—16539 the succeeding steps of Scheme 7 by general functional group transformation methods known to a person skilled in the relevant art.

Compound of the formula (ii) when R^b=O-alkyl or alkyl and other symbols are same as defined in general formula lb or I, on bromination can provide compound of formula (iii). Bromination can be carried out under a condition according to a procedure generally known in the literature using brominating agents such as bromine, N-bromo succinimide, phosphorous tribromide or the like (Synlett 2002, 7, 1152-1154).

Compound of the formula (iii) where ail the symbols are the same as defined earlier in general formula lb or I is subjected to Suzuki coupling with compound of formula IV, where R⁴, R⁵, R⁶ and m are the same as defined under general formula lb or I, to obtain compound of formula (v). Compound of formula (v), wherein Rb is alkyl, is nothing but a compound of formula lb where R³ is selected as alkyl group. Suzuki coupling can be carried out under suitable coupling conditions with boronic acids and boronic esters as well known in the art. Preferably, the coupling reaction is carried out in a mixture of water, éthanol, methanol and toluene, the in presence of a base such as potassium phosphate, potassium carbonate, or the like, and a palladium catalyst such as tetrakis(triphenylphosphine) palladium(O) at a température of about 50°C or higher. Boronic acid used in this reaction can be prepared by methods well known in the art, for example, by hydrolyzing the corresponding boronate. Boronates are generally commercially available. Besides, such boronates can also be prepared by reacting an appropriate iodo- or bromo compound with an alkyl lithium compound such as butyl lithium and then by reacting with a borate ester or by methods well known in the art (W0200530715; EP1012142; Review article by N.Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2547). sX

Ester hydrolysis of compound of formula (v), when R^b = O-alkyl, gave compound of formula (vi) where R¹, R², R⁴, R⁵, R⁶ and m are the same as defined hereinbefore for compounds of formula (iii) and (iv). Ester hydrolysis may be carrîed out using standard procedures generally used in synthetic organic chemistry or well known in the art with reagents such as sodium hydroxide, potassium hydroxide, lithium hydroxide or the like in solvents such as alcohol, THF, or the like. Preferably, aqueous solution of sodium hydroxide and éthanol are used for this reaction.

Compound of formula (vi) where ail the symbols are the same as defined earlier is converted to its corresponding amide of formula (vii) according to the conditions known to convert carboxylic acids to amides. The reaction can be carried out preferably with Α,Ο-dimethylhydroxylamine hydrochlorîde and triethylamine in DMF using reagents such as l-(3dimethylaminopropyl)-3-ethylcarbodimide hydrochlorîde (EDCI), benzotrîazole hydrate (HOBT) or the like.

In the case of compound of formula (vii) where R⁴ = R⁵ = hydrogen, the sulfonamido group should be protected before proceeding ahead with other subséquent reaction steps to préparé the compound of formula Ib. The protection of thesulfonamido group can be carried out under a condition known to a person skilled in the art or by utilizing the teaching provided in Organic Préparations and Procedures International 2002, 37(5), 545-549. The inventers have done protection using N,IVdimethylformamide dimethyl acetal in the presence of DMF to obtain compound of formula (viii).

Compound of the formula (viii) or a compound of formula (vii), which did not need protection of the sulfonamide group is reacted with a Grignard reagent R³MgX^x where R³ is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally.

substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted hererocyclyl, wherein each of the said optionally substituted cycloalkyl and optionally substituted heterocyclyl is optionally annulated or optionally bridged, and X¹ is a halogen, to obtain a compound of formula Ib. The reaction may be carried out under a suitable condition known to a person skilled in the art or by utilizing the teaching provided in J. Med. Chem., 2009, 52, 3377.

Compound of formula (vi) is aiternatively reacted with (R⁷)(R⁸)NH, (R⁷JN(OR⁸)H, or R⁷A^]H, where R⁷ and R⁸ are as defined under définition of R³ in general formula Ib or I, to obtain the compound of formula Ib, where R^s and R⁶ are same as defined earlier in general formula I or Ib and R³ is selected from the group consisting of (R⁷)(R⁸)N-, (R⁷)N(OR⁸)-, and R⁷A^I-, where R⁷ and R⁸ are as defined under définition of R³ in general formula Ib or I. The reaction can be carried out according to the conditions known in converting carboxylic acids to amides and esters as known to one skilled in the art. The reaction may be carried out in the presence of suitable solvents, for example, DMF, THF, a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as xylene, benzene, toluene, or mixtures thereof, or the like, in the presence of suitable base such as triethylamine, diisopropylethylamine, pyridine, or the like at a température between 0-50°C using reagents such as l-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1,3dicyclohexylcarbodiimide (DCC), and auxillary reagents such as 1hydroxy-7-azabenzotriazole (HOAT), hydroxybenzotriazole hydrate (HOBT), or the like.

Compound of the formula Ib where R⁵ and/or R⁶ are hydrogen, can be converted to compound of formula Ib where R⁵ and/or R⁶ are same as defined in general formula Ib excluding hydrogen by reaction with corresponding alkyl halides, alkenyl halides, alkynyl halides, alkanoyl halides or anhydride, aryl halides or boronic acids in presence of a base or by using appropriate conditions given in technical literature literature.

Compound of formula le may also be prepared by using a suitable starting material by adopting the chemistry provided for compounds of formula la and lb hereinabove.

The term ‘room température’ dénotés any température ranging between about 20°C to about 40°C, except and otherwise it is specifically mentioned in the spécification.

The intermediates and the compounds of the présent invention may obtained in pure form in a manner known per se, for example, by distilling off the solvent in vacuum and re-crystallizing the residue obtained from a suitable solvent, such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone or their combinations or subjecting it to one of the purification methods, such as column chromatography (e.g., flash chromatography) on a suitable support material such as alumina or silica gel using eluent such as dichloromethane, ethyl acetate, hexane, methanol, acetone and their combinations. Préparative LC-MS method is also used for the purification of molécules described herein.

Salts of compound of formula I can be obtained by dissolving the compound in a suitable solvent, for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, éthanol or isopropanol, which was then treated with the desired acid or base as described in Berge S.M. et al. “Pharmaceutical Salts, a review article in Journal of Pharmaceutical sciences volume 66, page 1-19 (1977)” and in handbook of pharmaceutical salts properties, sélection, and use by P.H.Einrich Stahland Camille G.wermuth, Wiley VCH (2002). Lists of suitable salts can also be found in Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977). For example, they can be a sait of an alkali métal (e.g., sodium or potassium), alkaline earth métal (e.g., calcium), or ammonium of sait.

The compound of the invention or a composition thereof can potentially be administered as a pharmaceutically acceptable acid-addition, base neutralized or addition sait, formed by reaction with înorganic acids, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an înorganic base, such as sodium hydroxide, potassium hydroxide. The conversion to a sait is accomplished by treatment of the base compound with at least a stoichiometric amount of an appropriate acid. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, éthanol, methanol, and the like, and the acid is added in a similar solvent. The mixture is maintained at a suitable température (e.g., between 0 °C and 50 °C). The resulting sait précipitâtes spontaneously or can be brought out of solution with a less polar solvent.

The stereoisomers of the compounds of formula I of the présent invention may be prepared by stereospecific synthèses or resolution of the achiral compound using an optically active amine, acid or complex forming agent, and separating the diastereomeric salt/complex by fractional crystallization or by column chromatography.

The term prodrug dénotés a dérivative of a compound, which dérivative, when administered to warm-blooded animais, e.g. humans, is converted into the compound (drug). The enzymatic and/or chemical hydrolytic cleavage of the compounds of the présent invention occurs in such a manner that the proven drug form (parent carboxylic acid drug) is released, and the moiety or moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced. For example, a carboxylic acid group can be esterifîed, e.g., with a methyl group or ethyl group to yield an ester. When an ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductîvely, oxidatively, or hydrolytically, to reveal the anionic group. An anionic group can be esterifîed with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently décomposés to yield the active compound.

The prodrugs can be prepared in situ during the isolation and purification of the compounds, or by separately reacting the purified compound with a suitable derivatizing agent. For example, hydroxy groups can be converted into esters via treatment with a carboxylic acid in the presence of a catalyst. Examples of cleavable alcohol prodrug moieties include substituted or unsubstituted, branched or unbranched lower alkyl ester moieties, e.g., ethyl esters, lower alkenyl esters, di-lower alkylamino loweralkyl esters, e.g., dimethylaminoethyl ester, acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aiyl esters, e.g., phenyl ester, aryl-lower alkyl esters, e.g., benzyl ester, optionally substituted, e.g., with methyl, halo, or methoxy substituents aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lwer alkyl amîdes, and hydroxy amides.

Modulation of the nicotinic cholinergic receptors, particularly a7 may provide for efïicacy in a range of cognitive states, right from pre-attention to attention and subsequently working, reference and récognition memory. Accordingly, this invention may find application in the treatment and prophylaxie of multitude of disease conditions including, either one or combinations of, schizophrenia, schizophreniform disorder, cognitive déficits in schizophrenia, brief psychotic disorder, delusional disorder, schizoaffective disorder, shared psychotic disorder, paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, attention déficit disorder, attention déficit hyperactivity disorder, dépréssion, maniac dépréssion, major dépressive disorder, posttraumatic stress disorder, generalized anxiety disorder, tourette’s syndrome, cyclothymie disorder, dysthymie disorder, agoraphobia, panic disorder (with or without agoraphobia), phobias (including social phobia) and bipolar disorders (Thomsen MS et al., Curr. Pharm. Des., 2010, 16, 323343; Peng ZZ et al., Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2008, 25, 154-158; Young JW et al., Eur. Neuropsychopharmacol., 2007, 17, 145155; Martin LF et al., Am. J. Med. Genet., B Neuropsychiatr. Genet., 2007, 144B, 611-614; Martin LF et al., Psychopharmacology (Berl), 2004, 174, 54-64; Feher A et al., Dement. Geriatr. Cogn. Disord., 2009, 28, 56-62; Wilens TE et al., Biochem. Pharmacol., 2007, 74, 1212-1223; Verbois SL et al., Neuropharmacology, 2003, 44, 224-233; Sanberg PR et al., Pharmacol. Ther., 1997, 74, 21-25). Cholinergic system, particularly through a7 nAChR seems to hâve implications in traumatic brain injuryinduced psychosis. Chronic nicotine treatment has shown to attenuate same. Thus, this invention may also find application in the treatment of — déficits in cholinergic a7 nAChR following traumatic brain injury (Bennouna M et al., Encéphale, 2007, 33, 616-620; Verbois SL et al.,

Neuropharmacology, 2003, 44, 224-233).

Modulation of nicotinic ACh receptors, particularly the a7 subtype could also help supplément the down-regulated cholinergic receptor expression and transmission as in dementia(s), and also slowing disease progression by réduction of α7-αβι-42 complexation and internalization in AD and Down’s syndrome (Nordberg A et al., Neurotox. Res., 2000, 2, 157-165; Haydar SN et al., Bioorg. Med. Chem., 2009, 17, 5247-5258; Deutsch SI et al., Clin. Neuropharmacol., 2003, 26, 277-283). Appropriately, this invention may find application in the treatment and prophylaxie of multitude of disease conditions including, either one or combinations of, dementia(s) due to Alzheimer’s disease, dementia with Lewy bodies, Down’s syndrome, head trauma, Stroke, hypoperfusion, Parkinson’s disease, Huntington’s disease, Prion diseases, progressive supranuclear palsy, radiation therapy, brain tumors, normal-pressure hydrocephalus, subdural hematoma, human immunodeficiency virus (HIV) infection, vitamin deflciency, hypothyroidism, drugs, alcohol, lead, mercury, aluminium, heavy metals, syphilis, Lyme disease, viral encephalitis, fungal infection and cryptococcosis (Zhao X et al., Ann. N. Y. Acad. Sci., 2001, 939, 179-186; Perry E et al., Eur. J. Pharmacol., 2000, 393, 215222; Harrington CR et al., Dementia, 1994, 5, 215-228; Wang J et al., J. Neurosci. Res., 2010, 88, 807-815; Duris K et al., Stroke 2011, 42(12), 3530-6). Thus, this invention may also find application in the prophylaxie and préventive measures immediately after early-stage identification of neurodegenerative disease like Alzheimer’s disease and Parkinson’s disease.

Modulation of nicotinic ACh receptors particularly α4β2, α3β4 and α7 may hâve implications in the development of thérapies for nicotine, cannabis addiction and relapse prévention. Accordingly, this invention may fïnd application in the prophylaxie or therapy of nicotine addiction, cannabis addiction, and relapse prévention of nicotine or cannabis addiction. Additionally, this invention may also provide for an alternative therapy for non-responding addiction patients, patients having intolérable side-effects with de-addiction thérapies or those requiring long-term maintenance thérapies. (Kuzmin A et al., Psychopharmacology (Berl), 2009, 203, 99108; Weiss RB et al., PLoS Genet., 2008, 4, e 1000125; Solinas M et al., J. Neurosci., 2007, 27, 5615-5620; Ebbert JO et al., Patient. Prefer. Adhérence, 2010, 4, 355-362)

This invention may also fïnd application in the treatment and prophylaxie of multitude of pain conditions încluding, either one or combinations of, pain arising from, peripheral nervous system (PNS), post-diabetic neuralgia (PDN), post-herpetic neuralgia (PHN), multiple sclerosis, Parkinson’s disease, low-back pain, fibromyalgia, post-operative pain, acute pain, chronic pain, mononeuropathy, primary latéral sclerosis, pseudobulbar palsy, progressive muscular palsy, progressive bulbar palsy, postpolio syndrome, diabètes induced polyneuropathy, acute demyelinating polyneuropathy (Gu îllain-Barre syndrome), acute spinal muscular atrophy (Werdnig-Hoffman disease) and secondaiy neurodegeneration (Donnelly-Roberts DL et al., J. Pharmacol. Exp. Ther., 1998, 285, 777-786; Rowley TJ et al., Br. J. Anaesth., 2010, 105, 201207; Bruchfeld A et al., J. Intern. Med., 2010, 268, 94-101). —

This invention may fînd application in the treatment and prophylaxie of plethora of inflammation and pain related states involving TNF-α and thus providing symptomatic relief in either any one or combination of, rheumatoid arthritis, bone résorption diseases, atherosclerosis, inflammatory bowel disease, Crohn’s disease, inflammation, cancer pain, muscle degeneration, osteoarthritis, osteoporosis, ulcerative colitis, rhinitis, pancreatitis, spondylitis, acute respiratory distress syndrome (ARDS), joint inflammation, anaphylaxie, ischemia reperfusion injury, multiple sclerosis, cérébral malaria, septic shock, tissue rejection of graft, brain trauma, toxic shock syndrome, herpes virus infection (HSV-1 & HSV-2), herpes zoster infection, sepsis, fever, myalgias, asthma, uveititis, contact dermatitis, obesity-related disease and endotoxemia (Giebelen IA T et al., Shock, 2007, 27, 443-447; Pena G et al., Eur. J. Immunol., 2010, 40, 2580-2589).

Thus the présent invention further provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, its tautomeric forms, its stereoisomers, its analogues, its prodrugs, its isotopically substituted analogues, its métabolites, its pharmaceutically acceptable salts, its polymorphs, its solvatés, its optical isomers, its clathrates and its co-crystals in combination with the usual pharmaceutically acceptable carriers, diluents and the like.

The pharmaceutically acceptable carrier (or excipient) is preferably one that is chemically inert to the compound of the invention and one that has no detrimental side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers preferably include saline (e.g., 0.9% saline), Cremophor EL (which is a dérivative of castor oil and ethylene oxide available from Sigma Chemical Co., St. Louis, MO) (e.g., 5%

Cremophor EL/5% ethanol/90% saline, 10% Cremophor EL/90% saline, or 50% Cremophor EL/50% éthanol), propylene glycol (e.g., 40% propylene glycol/10% ethanol/50% water), polyethylene glycol (e.g., 40% PEG 400/60% saline), and alcohol (e.g., 40% ethanol/60% water). A preferred pharmaceutical carrier is polyethylene glycol, such as PEG 400, and particularly a composition comprising 40% PEG 400 and 60% water or saline. The choice of carrier will be determined in part by the particular compound chosen, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the présent invention.

The following formulations for oral, aérosol, parentéral, subcutaneous, intravenous, intraarterial, intramuscular, interperitoneal, rectal, and vaginal administration are merely exemplary and are in no way limiting.

The pharmaceutical compositions can be administered parenterally, e.g., intravenously, intraarterially, subcutaneously, intradermally, intrathecally, or intramuscularly. Thus, the invention provides compositions for parentéral administration that comprise a solution of the compound of the invention dissolved or suspended in an acceptable carrier suitable for parentéral administration, including aqueous and nonaqueous, isotonie stérile injection solutions.

Overall, the requïrements for effective pharmaceutical carriers for parentéral compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986). Such compositions include solutions containing anti-oxidants, buffers, bacteriostats, and solutés that render the formulation isotonie with the blood of the intended récipient, and aqueous and non-aqueous stérile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound can be S administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a stérile liquid or mixture of liquide, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as éthanol, isopropanol (for example in topical applications), or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, 10 dimethylsulfoxide, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, 15 methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifyîng agents and other pharmaceutical adjuvants.

Oils useful in parentéral formulations include petroleum, animal, vegetable, and synthetic oils. Spécifie examples of oils useful in such 20 formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and minerai oil. Suitable fatty acids for use in parentéral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.

Suitable soaps for use in parentéral formulations include fatty alkali métal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefïn sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic détergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric détergents such as, for example, alkyl-p-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.

The parentéral formulations typically will contain from about 0.5% or less to about 25% or more by weight of a compound of the invention in solution. Preservatives and buffers can be used. In order to minimize or eliminate irritation at the site of injection, such compositions can contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobie base, formed by the condensation of propylene oxide with propylene glycol. The parentéral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the stérile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from stérile powders, granules, and tablets.

Topical formulations, including those that are useful for transdermal drug release, are well known to those of skill in the art and are suitable in the context of the present invention for application to skin. —

Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of a compound of the invention dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a pre-determined amount of the compound of the invention, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable émulsions. Liquid formulations can include diluents, such as water and alcohols, for example, éthanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fïllers, such as lactose, sucrose, calcium phosphate, and cornstarch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloïdal silicon dioxide, croscarmellose sodium, talc, magnésium stéarate, calcium stéarate, zinc stéarate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatîves, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the compound ingrédient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising a compound of the invention in an inert base, such as gelatin and glycerin, or sucrose and acacia, émulsions, gels, and the like containing, in addition to the compound of the invention, such excipients as are known in the art.

An compound of the présent invention, alone or in combination with other suitable components, can be made into aérosol formulations to be adminîstered via inhalation. A compound or epimer of the invention is preferably supplied in finely divided form along with a surfactant and propellant. Typical percentages of the compounds of the invention can be about 0.01% to about 20% by weight, preferably about 1% to about 10% by weight. The surfactant must, of course, be nontoxic, and preferably soluble in the propellant. Représentative of such surfactants are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride. Mixed esters, such as mixed or natural glycerides can be employed. The surfactant can constitute from about 0.1% to about 20% by weight of the composition, preferably from about 0.25% to about 5%. The balance of the composition is ordinarily propellant. A carrier can also be included as desired, e.g., lecithin, for intranasal delivery. These aérosol formulations can be placed into acceptable pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured préparations, such as in a nebulizer or an atomizer. Such spray formulations can be used to spray mucosa.

Additionally, the compound of the invention can be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the compound ingrédient, such carriers as are known in the art to be appropriate.

The concentration of the compound in the pharmaceutical formulations can vary, e.g., from less than about 1% to about 10%, to as mu ch as 20% to 50% or more by weight, and can be selected primarily by fluid volumes, and viscosities, in accordance with the particular mode of administration selected.

For example, a typical pharmaceutical composition for intravenous infusion could be made up to contain 250 ml of stérile Ringer’s solution, and 100 mg of at least one compound of the invention. Actual methods for preparing parenterally administrable compounds of the invention will be known or apparent to those skilled in the art and are described in more detail in, for example, Remington’s Pharmaceutical Science ( 17^th ed., Mack Publishing Company, Easton, PA, 1985).

It will be appreciated by one of ordinary skill in the art that, in addition to the aforedescribed pharmaceutical compositions, the compound of the invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes. Liposomes can serve to target a compound of the invention to a particular tissue, such as lymphoid tissue or cancerous hepatic cells. Liposomes can also be used to increase the half-life of a compound of the invention. Many methods are available for preparing liposomes, as described in, for example, Szoka et al., Ann. Rev. Biophys. Bioeng., 9, 467 (1980) and U.S. Patents 4,235,871, 4,501,728, 4,837,028, and 5,019,369.

The compounds or pharmaceutical compositions are useful, in an embodiment, for the treatment and/or prophylaxie of diseases or disorder or condition such as Alzheimer's disease (AD), mild cognitive impairment (MCI), senile dementia, vascular dementia, dementia of Parkinson’s disease, attention déficit disorder, attention déficit hyperactivity disorder (ADHD), dementia associated with Lewy bodies, AIDS dementia complex (ADC), Pick's disease, dementia associated with Down's syndrome,

Huntington's disease, cognitive déficits associated with traumatic brain injury (TBI), cognitive décliné associated with stroke, poststroke neuroprotection, cognitive and sensorimotor gating déficits associated with schizophrenia, cognitive déficits associated with bipolar disorder, 5 cognitive impairments associated with dépréssion, acute pain, postsurgical or post-operative pain, chronic pain, inflammation, inflammatory pain, neuropathie pain, smoking cessation, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation, 10 arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, pouchitis, inflammatory bowel disease, celiac disease, periodontitis, sarcoidosis, pancreatitis, organ transplant rejection, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, septic shock, toxic shock 15 syndrome, sepsis syndrome, dépréssion, and rheumatoid spondylitis.

In another embodiment, the pharmaceutical compositions are useful for the treatment and/or prophylaxie of diseases or disorder or condition classified or diagnosed as major or minor neurocognitive disorders, or 20 disorders arising due to neurodegeneration.

The présent invention also provide method of administering a compound of formula I, as defined hereinabove in combination with or as adjunct to médications used in the treatment of attention déficit hyperactivity 25 disorders, schizophrenia, and other cognitive disorders such as Alzheimer’s disease, Parkinson’s dementia, vascular dementia or dementia associated with Lewy bodies, traumatic brain injury,

The présent invention also provide method of administering a compound of formula I, as defined hereinabove in combination with or as an adjunct to acetylcholinesterase inhibitors, disease modifying drugs or biologics for neurodegenerative disorders, dopaminergic drugs, antidepressants, typical or an atypical antipsychotic.

Accordingly, compound of formula I is useful for preventing or treating a disorder mediated by nicotinic acétylcholine receptors. Such compounds can be administered to a subject having such a disorder or susceptible to such disorders in a therapeutically effective amount. The compounds are particularly useful for a method of treating a mammal having a condition where modulation of nicotinic acétylcholine receptor activity is of therapeutic beneflt, wherein the method is accomplished by administering a therapeutically effective amount of a compound of formula I to a subject having, or susceptible to, such a disorder.

The présent invention also provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, its tautomeric forms, its stereoisomers, its analogs, its prodrugs, its isotopes, its métabolites, its pharmaceutically acceptable salts, its polymorphe, its solvatés, its optical isomers, its clathrates and its co-crystals in combination with the usual pharmaceutically employed carriers, diluents and the like, and for use in any of the methods described herein.

The compounds of the invention can be administered in a dose sufficient to treat the disease, condition or disorder. Such doses are known in the art (see, for example, the Physicians’ Desk Reference (2004)). The compounds can be administered using techniques such as those described in, for example, Wasserman et al., Cancer, 36, pp. 1258-1268 (1975) and Physicians’ Desk Reference, 58th ed., Thomson PDR (2004). hx/

Suitable doses and dosage regimens can be determined by conventional range-fmding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound of the présent invention. Thereafter, the dosage is increased by small incréments until the optimum effect under the circumstances is reached. The présent method can involve the administration of about 0.1 pg to about 50 mg of at least one compound of the invention per kg body weight of the indivîdual. For a 70 kg patient, dosages of from about 10 pg to about 200 mg of the compound of the invention would be more commonly used, depending on a patient’s physiological response.

By way of example and not intending to limit the invention, the dose of the pharmaceutically active agent(s) described herein for methods of treating or preventing a disease or condition as described above can be about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg, 0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg/kg body weight per day. The dose of the pharmaceutically active agent(s) described herein for the described methods can be about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg/kg body weight per day.

In accordance with embodiments, the présent invention provides methods of treating, preventing, ameliorating, and/or inhibiting a condition py~ modulated by the nicotinic acetylchoine receptor comprising administering a compound of formula (I) or a sait thereof.

The terms “treat, “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complété treatment, prévention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prévention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefît or therapeutic effect. In this respect, the inventive methods can provide any amount of any level of treatment, prévention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. Furthermore, the treatment, prévention, amelioration, or inhibition provided by the inventive method can include treatment, prévention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer. Also, for purposes herein, “treatment,” “prévention, “amelioration,” or “inhibition” can encompass delaying the onset of the disorder, or a symptom or condition thereof.

In accordance with the invention, the term subject includes an “animal” which in turn includes a mammal such as, without limitation, the order Rodentia, such as mice, and the order Lagomorpha, such as rabbits. It is preferred that the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals are from the order Artiodactyla, including Bovines (cows) and Swine (pigs) or of the order Perssodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes). An especially preferred mammal is the human.

Following are the abbreviations used and meaning thereof in the spécification:

ACh: Acétylcholine.

AD: Alzheimer ’s disease.

ADC: AIDS dementia complex.

ADHD: attention déficit hyperactivity disorder.

AIDS: Acquired immunodefïciency syndrome.

ARDS: acute respiratory distress syndrome.

DCC: 1,3-dicyclohexylcarbodiimide.

DCE: dichloroethane.

DCM: dichloromethane.

DIPEA: diisopropyl ethyl amine

DLB: dementia with Lewy bodies.

DMF: N_tN-dimethylformamide.

EDCI: l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride.

FLIPR: Fluorometric Imaging Plate Reader.

HATU: 2-(lH-7-Azabenzotriazol-l-yl)-l,l,3_J3-tetramethyl uronium hexafluoropho sphate.

HBSS: Hank's balanced sait solution.

HEPES: 4-(2-hydroxyethyl)piperazine-l-ethanesulfonic acid.

HMGB: high mobility group box.

HOAT: l-hydroxy-7-azabenzotriazole.

HOBT: hydroxybenzotriazole hydrate.

HPLC: High Performance liquid chromatography.

IL: interleukins.

LDT: laterodorsal tegmental nucléus.

LGIC: ligand-gated ion channels.

MCI: mild cognitive impairment.

NBS: N-bromosuccinimide.

NC S: N-chlorosuccinimide.

NIS: N-iodosuccinamide

NNRs: Neural nicotinic ACh receptors.

PAM: positive allosteric modulation.

PD: Parkinson’s disease.

PDN: post-diabetic neuralgia.

PHN: post-herpetic neuralgia.

PMBO: p-methoxy benzyloxy.

PNS: peripheral nervous system.

TBI: traumatic brain injuiy.

THF: Tetrahydrofuran.

TLC: Thin layer chromatography.

TMS: tetramethylsilane.

TNF-α: tumor necrosis factor alpha.

VTA: ventral tegmental area.

a7 nAChR: nicotinic acétylcholine receptor a7 subunit.

The following examples are provided to further illustrate the présent invention and therefore should not be construed in any way to limit the scope of the présent invention. Ail ^XHNMR spectra were determined in the solvents indicated and chemical shifts are reported in Ô units downfïeld from the internai standard tetramethylsilane (TMS) and interproton coupling constants are reported in Hertz (Hz), w-''

Example 1: Préparation of 4-(5-(4-chlorophenyl)-4-methyl-2 propionylthiophen-3-yl)benzenesulfonamide (Compound 1)

Step 1: Methyl-3-bromo-5-(4-chlorophenyl)-4-methylthiophene-2carboxylate (la)

To a stirred solution of methyl-5-(4-chlorophenyl)-4-methylthiophene-2carboxylate (prepared according to the procedure reported in WO 2007092751, 4.0g, 15.0 mmol) in chloroform (50 ml) at 25°C was added zinc chloride (2.06g, 15.0 mmol) followed by the addition of bromine 15 (2.64g, 0.85 ml, 16.5 mmol) in a dropwise manner under a nitrogen atmosphère. The resulting mixture was stirred at 60-65°C for 1.5 hr. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 0°C and quenched with water (30 ml). The resulting organic layer was washed with 10% aqueous sodium bicarbonate solution (2x50 ml) and dried over anhydrous Na₂SO4. The solvent in the organic layer was evaporated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 3% ethyl acetate in hexanes as an eluent to obtain the title compound (2.2 g, 42.53%);

MS: m/z 345 (M+1),

1HNMR (CDCI3, 400 MHz): δ 7.43 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 3.9 (s, 3H), 2.28 (s, 3H).

The compounds given below were prepared by procedure similar to those described above for compound ‘la’ with appropriate variations of reactants, reaction conditions and quantifies of reagents

2a. Methyl—3-bromo-5-(2-chlorophenyl)-4-methylthiophene-2-carboxylate

MS: m/z 345 (M+1)

4a. Methyl-3-bromo- 5-(4-fluorophenyl)-4-methylthiophene-2-carboxylate

MS: m/z 330 (M+1) la. Methyl-3-bromo- 5-(4-(teri-butyl)phenyl)-4-methylthiophene-2carboxylate

MS: m/z 368 (M+1)

17a. Methyl-3-bromo- 5-(3,4-dichlorophenyl)-4-methylthiophene-2carboxylate

MS: m/z 381 (M+1)

18a. Methyl-3-bromo- 5-(2,4-dichlorophenyl)-4-methylthiophene-2carboxylate rfS

MS: m/z 381 (M+l)

19a. Methyl-3-bromo-5-(2,4-difluorophenyl)-4-methylthiophene-2carboxylate

MS: m/z 370 (M+23)

20a. Methyl -3 bromo- 5-(3-chloro-4-fluorophenyl)-4-methylthiophene-2carboxylate

MS: m/z 365 (M+l) la. Methyl-3-bromo- 5-(3-chloro-4-methoxyphenyl)-4-methylthiophene2-carboxyate

MS: m/z 377 (M+l)

47a. Ethyl-3-bromo- 5-(3,4-difluorophenyl)-4-methylthiophene-2carboxylate

MS: m/z 384 (M+23)

Step 2: Ethyl-5-(4-chlorophenyl)-4-methyl~3-(4sulfamoylphenyl)thiophene-2-carboxylate (lb)

To a solution of methyl-3-bromo-5-(4-chlorophenyl)-4-methylthiophene-2carboxylate (compound la, 2.2g, 6.3 mmol) in a mixture of toluene: w éthanol (10:30 ml) were added 4-aminosulfonylbenzene boronic acid (prepared according to the procedure given in EP 1012142, 1.28g, 6.3 mmol) and potassium carbonate (1.76g, 12.7 mmol) at 25°C in a sealed tube and nitrogen gas was bubbled through the reaction mixture for 15 minutes. To this was added tetrakis(triphenylphosphine)palladium(0) (0.370g, 0.318 mmol) under nitrogen and the reaction mixture was heated at about 95- about 100°C for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 25°C and filtered through celite. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (1.3g, 48%).

MS: m/z 436 (M+l), iHNMR (CDCI3, 400 MHz): Ô 8.01 (d, J=8.4 Hz, 2H), 7.46-7.41 (m, 6H). 4.89 (bs, 2H), 4.17(q, J=7.2 Hz, 2H), 1.99 (s, 3H), 1.9 (t, J=7.2 Hz, 3H).

The compounds given below were prepared by procedure similar to the one described above for compound ‘lb’ with appropriate variations of reactants, reaction conditions and quantities of reagents.

2b. Ethyl-5-(2-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylate

MS: m/z 436 (M+l),

4b. Ethyl 5-(4-fluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylate

MS: m/z420 (M+l) llb. Ethyl 5-(4-(tert-butyl)phenyl)-4-methyl-3-(4sulfamoylphenyl)thiophene-2-carboxylate

MS: m/z 458 (M+1)

17b. Ethyl 5-(3,4-dichlorophenyl)-4-methyl-3-(4sulfamoylphenyl)thiophene-2-carboxylate

MS: m/z 470 (M+1)

18b. Ethyl 5-(2,4-dichlorophenyl)-4-methyl-3-(4sulfamoylphenyl)thiophene-2-carboxylate

MS: m/z 470 (M+1)

19b. Ethyl 5-(2,4-difluorophenyl)-4-methyl-3-(4sulfamoylphenyl)thiophene-2-carboxylate

MS: m/z 438 (M+1)

20b. Ethyl 5-(3-chloro-4-fluorophenyl)-4-methyl-3-(4sulfamoylphenyl)thiophene-2-carboxylate

MS: m/z 454 (M+1)

21b. Ethyl 5-(3-chloro-4-methoxyphenyl)-4-methyl-3-(4sulfamoylphenyl)thiophene-2-carboxyate

MS: m/z 466 (M+1)

47b. Ethyl 5-(3,4-difluorophenyl)-4-inethyl-3-(4sulfamoylphenyl)thiophene-2-carboxylate

MS: m/z 438 (M+1) vZ

Step 3: 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid (le)

Ethyl-5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylate (compound lb, 1.9 g, 4.36 mmol) was suspended in éthanol (40 ml) and treated with IN solution of NaOH (0.9 ml) at 25°C. The reaction mixture was heated at 50-55°C under stirring for 30-40 minutes. The progress of reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue obtained was diluted with a mixture of ethylacetate:water (100:50 ml) To the resulting diluted mixture was added aqueous 10% HCl to bring the pH of the mixture to between 5 andô. The aqueous layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layer was dried over anhydrous Na2SC>4. The solvent in the organic layer was evaporated under reduced pressure to obtain the title compound. (1.72g, 97%).

MS: m/z 408 (M+1), !HNMR (DMSO, 400 MHz): δ 12.87 (bs, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.56 (bs, 4H). 7.5 (d, J=8.4 Hz, 2H), 7.45 (s, 2H), 1.95 (s, 3H).

The compounds given below were prepared by procedure similar to the one described above for compound ‘le’ with appropriate variations of reactants, reaction conditions and quantifies of reagents.

2c. 5-(2-chlorophenyl)-4-methyl-3-(4-sulfarrioylphenyl)thiophene-2carboxylic acid.

MS: m/z 408 (M+1).

4c. 5-(4-fluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z 392 (M+1).

le. 5-(4-(tert-butyl)phenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z 430 (M+1).

17c. 5-(3,4-dichlorophenyl)~4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z442 (M+1).

18c. 5-(2,4-dichlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z 442 (M+1).

19c. 5-(2,4-difluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z410(M+l).

20c. 5-(3-chloro-4-fluorophenyl)-4-methyl-3-(4sulfamoylphenyl)thiophene-2-carboxylic acid.

MS: m/z426 (M+1).

21c. 5-(3-chlorO“4-methoxyphenyl)-4-methyl-3-(4suIfamoylphenyl)thiophene-2-carboxylic acid, vv-—

MS: m/z438 (M+l).

47c. 5-(3,4-difluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylîc acid.

MS: m/z 410 (M+l).

Step 4: 5-(4-chlorophenyl)-3-(4-(lV((dimethylamino) methylene) su lfamoyl) phenyl) - IV- meth oxy- N, 4 dimethylthiophene-2 -carboxamide ( 1 d)

CH₃

H₃C'^N^|

Oxalyl chloride (2.1 g, 1.4 ml, 16.2 mmol) was added dropwise at 0°C to a solution of 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid (compound le, 2.2g, 5.4 mmol) in a mixture of dichloromethane (40 ml) and DMF (0.8 g, 0.8 ml, 10.8 m mol). The resulting mixture was allowed to warm to room température and stirred for 1.5 hr, under a nitrogen atmosphère. The progress of reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure and used directly for further reaction. The residue so obtained was dissolved in diy dichloromethane (40 ml) and to this was added triethylamine (2.8g, 3.9 ml, 27.0 mmol) followed by the addition of N,Odimethylhydroxylamine hydrochloride (1.06g, 10.8 mmol) under stirring. The reaction mixture was stirred at room température for 2 hr. The progress of reaction was monitored by TLC. The reaction mixure was washed with water (2 x 20 ml) and the organic layer obtained was dried m/· over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product was further purified by column chromatography over silica gel (100-200 mesh) using

80% ethylacetate in hexane as an eluent to obtain the title compound (2.36g, 86%).

MS: m/z 506 (M+l), ^rHNMR (CDCla, 400 MHz): δ 8.14 (s, IH), 7.95 (d, >8.4 Hz, 2H), 7.42 (bs,4H). 7.37 (d, >8.4 Hz, 2H), 3.68 (s, 3H), 3.17 (s, 3H), 3.13 (s, 3H), 3.05 (s, 3H), 1.98 (s, 3H).

The compounds given below were prepared by procedure similar to the one described above for compound ‘ld’ with appropriate variations of reactants, reaction conditions and quantities of reagents

2d. 5-(2-chlorophenyl)-3-(4-(lV-((dimethylamino) methylene) sulfamoyl) phenyl)-7V-methoxy-W,4-dimethylthiophene-2-carboxamide

MS: m/z 506 (M+l)

4d. 3-(4-(JV-((dimethylamino) methylene) sulfamoyl) phenyl)-5-(4-Fluoro phenyl)-7V-methoxy-iV,4-dimethylthiophene-2-carboxamide.

MS: m/z 490 (M+l).

lld. 5-(4-(tert-butyl)phenyl)-3-(4-(/V-((dimethylamino) methylene) sulfamoyl) phenyl)-/V-methoxy-iV,4-dimethylthiophene-2-carboxamide.

MS: m/z 528 (M+l).

17d. 5-(3,4-dichlorophenyl)-3-(4-(7V-((dimethylamino) methylene) sulfamoyl) phenyl)-iV-methoxy-W,4-dimethylthiophene-2-carboxamide.

MS: m/z 540 (M+l).

18d. 5-(2,4-dichlorophenyl)-3-(4-(7V-((dimethylamino) methylene) sulfamoyl) phenyl)-JV-methoxy-JV,4-dimethylthiophene-2-carboxamide.

MS: m/z 540 (M+1).

19d. 5-(2,4-Difluoro phenyl)-3-(4-(7V-((dimethylamino) methylene) sulfamoyl) phenyl)- -7V-methoxy-lV,4-dimethylthiophene-2-carboxamide.

MS: m/z 508 (M+1).

20d. 5-(3-Chloro-4-fluoro phenyl)-3-(4-(lV-((dimethylamino) methylene) sulfamoyl) phenyl)- -!V-methoxy-lV,4-dimethylthiophene-2-carboxamide.

MS: m/z 524 (M+1).

21d. 5-(3-Chloro-4-methoxyphenyl)-3-(4-(lV-((dimethylamino) methylene) sulfamoyl) phenyl)- -JV-methoxy-lV,4-dimethylthiophene-2-carboxamide.

MS: m/z 536 (M+1).

47d. 5-(3,4-Difluoro phenyl)-3-(4-(lV-((dimethylamino) methylene) sulfamoyl) phenyl)- lV-methoxy-7V,4-dîmethylthiophene-2-carboxamide.

MS: m/z 508 (M+1).

Step 5: Préparation of 4-(5-(4-chlorophenyl)-4-methyl-2propionylthiophen-3-yl)benzenesulfonamide (Compound 1).

To a stirred solution of 5-(4-chlorophenyl)-3-(4-(lV( (dimethyl amino) methylene) sul famoy l) phenyl) - Æ-me th oxy- N,4dimethylthiophene-2-carboxamide (compound ld, 2.3g, 4.55 mmol) in anhydrous THF (40 ml) at 25°C, Grignard reagent (ethyl magnésium bromide, 3.04g, 22.8ml, 22.77 mmol) was added dropwise and the reaction mixture was heated at 70-75°C for 1 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0°C, the reaction mixture was quenched by adding a solution of saturated ammonium chloride (40 ml) and the resulting mixture was extracted with ethyl acetate (3x50 ml). The combined organic layer was dried over anhydrous NaaSCU. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product; which was purified by column chromatography over silica gel (100-200 mesh) using 30-35% ethyl acetate in hexane as an eluent to obtain the title compound which was further purified by précipitation by dissolving 1.1 g of the compound in dichloromethane (10 ml) and precipitating it by slow addition of diisopropyl ether. (0.89g, 47 %)

MS: m/z420(M+l),

1HNMR (DMSO, 400 MHz): δ 7.95 (d, J=8.4 Hz, 2H), 7.59 (bs, 4H). 7.56 (d, J=8.4 Hz, 2H), 7.45 (s, 2H), 2.37 (q, J=6.8 Hz, 2H), 1.92 (s, 3H), 0.88 (t, J=6.8 Hz, 3H),

The following compounds were prepared according to the procedure described above but with appropriate changes to the reactants.

4-(5-(2-Chlorophenyl)-4-methyl-2-propionylthiophen-3yljbenzenesulfonamide (Compound 2).

MS: m/z 420 (M+1), k/ iHNMR (DMSO, 400 MHz): Ô 7.88(d, J=8.4 Hz, 2H), 7.56-7.58 (m, IH),

7.43-7-47(m, 7H), 2.34 (q, J=7.2 Hz, 2H), 1.70 (s, 3H), 0.89 (t, J=7.2 Hz,

3H).

4-(5-(4-Fluorophenyl)-4-methyl-2-propionylthîophen-3yl)benzenesulfonamide. (Compound 4).

MS: m/z 404 (M+1), iHNMR (DMSO, 400 MHz): δ 7.94 (d, J=8.4 Hz, 2H), 7.56-7-64 (m, 4H), 7.49 (bs-exchanges with D2O, 2H), 7.36-7-40 (m, 2H), 2.38 (q, J=7.2 Hz, 2H), 1.92 (s, 3H), 0.89 (t, J=7.2 Hz, 3H).

4-(5-((4-tert butyl)phenyl)-4-methyl-2-propionylthiophen-3-yl)benzene sulfonamide (Compound 11)

MS: m/z442 (M+1), iHNMR (CDC1_3j 400 MHz): δ 8.02 (d, J=8.4 Hz, 2H), 7.42-7.49 (m, 6H), 4.92 (bs-exchanges with D2O, 2H), 2.56 (q, J=7.2 Hz, 2H), 1.97 (s, 3H), 1.36 (s, 9H), 1.06 (t, J=7.2 Hz, 3H).

4-(5-(3,4-Dichlorophenyl)-4-methyl-2-propionylthiophen-3yljbenzenesulfonamide (Compound 17)

MS: MS: m/z 454 (M+1), iHNMR (CDCh, 400 MHz): δ 8.03 (d, J=8.4 Hz, 2H), 7.59 (d, J=2.0 Hz, IH), 7.54 (d, J=8.4 Hz, IH), 7.42 (d, J=8.4 Hz, 2H), 7.32 (dd, J=8.4, 2.0 Hz, IH), 4.91 (bs-exchanges with D2O, 2H), 2.52 (q, J=7.2 Hz, 2H), 1.95 (s, 3H), 1.04 (t, J=7.2 Hz, 3H).

4-(5-(2_J4-Dichlorophenyl)-4-methyl-2-propionylthiophen-3yl)benzenesulfonamide (Compound 18)

MS: MS: m/z 454 (M+1), !HNMR (CDCh, 400 MHz): Ô 8.04 (d, J=8.4 Hz, 2H), 7.53-7.54 (m, 1H),

7.44 (d, <7=8.4 Hz, 2H), 7.32-7.42 (m, 2H), 4.89 (bs-exchanges with D2O,

2H), 2.55 (q, J=7.2 Hz, 2H), 1.76 (s, 3H), 1.04 (t, J=7.2 Hz, 3H).

4-(5-(2,4-Difluorophenyl)-4-methyl-2-propionylthiophen-3yljbenzenesulfonamide (Compound 19)

MS: m/z 422(M+1),

1HNMR (CDCh, 400 MHz): Ô 8.04 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4Hz, 2H), 7.38-7.44 (m, 1H) 6.98-7.04 (m, 2H), 5.01 (bs-exchanges with D2O, 2H), 2.54 (q, J=7.2 Hz, 2H), 1.83 (s, 3H), 1.05 (t, J=7.2 Hz, 3H).

4-(5-(3-Chloro-4-fluorophenyl)-4-methyl-2-propionylthiophen-3yljbenzenesulfonamide (Compound 20)

MS: m/z 438 (M+1), iHNMR (CDCls, 400 MHz): δ 8.04 (d, J=8.4 Hz, 2H), 7.54 (dd, J=6.8, 2.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.35-7.38 (m, 1H), 7.25 (t, J=8.4 Hz, 1H), 4.92 (bs-exchanges with D2O, 2H), 2.54 (q, J=7.2 Hz, 2H), 1.94 (s, 3H), 1.04 (t, J=7.2 Hz, 3H).

4-(5-(3-Chloro-4-methoxyphenyl)-4-methyl-2-propionylthiophen-3yljbenzene sulfonamide (Compound 21)

MS: m/z 450 (M+1), !HNMR (DMSO, 400 MHz): δ 7.93 (d, J=8.4 Hz, 2H), 7.61 (d, J=2.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.50 (d, J=2.4 Hz, 1H), 7,49 (bs-exchanges with D₂O, 2H), 7.29 (d, J=8.8 Hz, 1H), 3.92 (s, 3H), 2.35 (q, J=7.2 Hz, 2H), 1.91 (s, 3H), 0.87 (t, J=7.2 Hz, 3H).

4-(2-Acetyl-5-(4-chlorophenyl)-4-methylthiophen-3-yl)benzenesulfonamide (Compound 40)

MS: m/z 406 (M+1), ά/ 'HNMR (DMSO, 400 MHz): δ 7.95 (d, J=8.4 Hz, 2H), 7.57-7.59 (m, 6H),

7.50 (bs-exchanges with D₂O, 2H), 1.99 (s, 3H), 1.93 (s, 3H).

4-(5-(3,4-Difluorophenyl)-4-methyl-2-propionylthiophen-3yl)benzenesulfonamide (Compound 47)

MS: m/z422 (M+l), 'HNMR (CDCh, 400 MHz): δ 8.03 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.25-7.33 (m, 3H), 4.98 (bs-exchanges with D₂O, 2H), 2.52 (q, J=7.2 Hz, 2H), 1.94 (s, 3H), 1.04 (t, J=7.2 Hz, 3H).

Example 2: Préparation of 4-(4-methyl-5-morpholino-2propionylthiophen-3-yl) benzenesulfonamide (Compound 24)

Step 1: Préparation of iV,JV-dimethyl-N’-((4-propionylphenyl)sulfonyl) formimidamide (24a)

To a stirred solution of 4-propionylbenzenesulfonamide (prepared according to the procedure reported in Bioorganic Chemistry 1994, 22, 387-394), 2.2g (10.3 mmol) in ethylacetate (20 ml) was added DMF (2.0 \

ml) followed by the addition of 7V,7V-dimethylformamidedimethyl acetal (1.36g, 1.51 ml, 11.36 mmol) in a dropwise manner at room température. The resulting mixture was stirred at room température for 4 hr. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain a solid product, which was washed with diisopropylether to obtain the title compound (2.6 g, 94%).

MS: m/z 269 (M+1),

1HNMR (DMSO, 400 MHz): δ 8.25 (s, 1H), 8.08 (d, J=8.8 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H), 3.15 (s, 3H), 3.09 (q, J=7.2 Hz, 2H), 2.91 (s, 3H), 1.08 (t, J=7.2 Hz, 3H).

Step 2: Préparation of N’-((4-(2-(l,3-dithiatan-2ylidene) propanoy 1) phenyl) sulfonyl) - N, N- dimethy lfor mimidamide (24 b)

To a stirred solution of !V,lV-dimethyl-N^,-((4-propionylphenyl)sulfonyl) formimidamide (compound 24a, 1.0g, 3.73 mmol) in dry THF (30 ml) was added potassium tert.butoxide (0.837g, 7.46 mmol) at 0°C under a nitrogen atmosphère. The resulting mixture was stirred at room température for 1 hr. The reaction mixture was cooled to 0°C and to the cooled reaction mixture was added carbon disulfide (0.425g, 0.34 ml, 5.59 mmol) in a dropwise manner at 0°C. The resulting reaction mixture was stirred at room température for 30 minutes. The resulting reaction mixture was cooled to 0°C and to the cooled reaction mixture was added dibromomethane (1.3g, 0.85 ml, 7.46 mmol) in a dropwise manner at 0°C.

The resulting reaction mixture was stirred at room température for 20 hr.

The progress of the reaction was monitored by TLC. The reaction mixture was poured into cold water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layer was dried over anhydrous Na₂SC>4. The solvent was evaporated under reduced pressure from the dried organic layer to obtain a crude product, which was further purified by column 10 chromatography over silica gel (100-200 mesh) using 2% methanol in dichloromethane as an eluent to obtain the title compound (0,65 g, 49%).

MS: m/z 357 (M+l), ïHNMR (CDCla, 400 MHz): δ 8.13 (s, IH), 7.93 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 4.16 (s, 2H), 3.15 (s, 3H), 3.04 (s, 3H), 1.83 (s, 3H).

Step 3: Préparation of N,N-dimethyl-N’-((4-(2-methyl-3-morpholino-3thioxopropanoyl)phenyl)sulfonyl)formimidamide (24c)

To a stirred solution of N -((4-(2-( l,3-dithiatan-2ylidene)propanoyl)phenyl)sulfonyl)-lV,lV-dimethylformimidamide (compound 24b, 0.53g, 1.48 mmol) in toluene (20 ml) was added morpholine (0.39g, 4.4 mmol) at room température. The reaction mixture was stirred at 115-120°C for 3 hr. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 2% methanol in dichloromethane as an eluent to obtain the title compound (0.191 g, 32.3%)

MS: m/z 398 (M+1), !HNMR (DMSO, 400 MHz): δ 8.23 (s, 1H), 7.85 (brs, 4H), 5.19 (q, J=6.4 Hz, 1H), 3.5-4.0 (m, 8H), 3.14 (s, 3H), 2.91 (s, 3H), 1.33 (d, J=6.4 Hz, 3H).

The compounds given below were prepared by procedure similar to the one described above for compound ‘24c’ with appropriate variations of reactants, reaction conditions and quantifies of reagents.

22c. tert-butyl 4-(3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-2methyl- 3 -oxopropan ethioy 1) piperazine-1 - car b oxylate

MS: m/z519(M+23)

23c. N’-((4-(3-(4-(4-fluorophenyl)piperazin- l-yl)-2-methyl-3thioxopropanoyl)phenyl)sulfonyl)-N,N-dimethylformimidamide

MS: m/z491(M+l),

Step 4: Préparation of ethyl-3-(4-(lV-((dimethylamino) methylene) sulfamoyl)phenyl)-4-methyl-5-morpholinothiophene-2-carboxylate (24d)

To a stirred solution of !V,iV-dimethyl-lV^,-((4-(2-methyl-3-morpholino-3thioxopropanoyl)phenyl)sulfonyl)formimidamide (compound 24c, 0.180g, 0.45 mmol) in diy acetone (15 ml) was added potassium carbonate (0.45g,

3.17 mmol) at room température. The resulting mixture was stirred at 5560°C for 2 hr. The reaction mixture was cooled to 0°C and to this was added ethyl iodoacetate (0.097g, 0.053 ml, 0.45 mmol) in a dropwise manner. The reaction mixture was stirred at reflux température for 4 hr. The progress of the reaction was monitored by TLC. The reaction mixture was allowed to warm to room température and filtered through a celite pad. The celite pad was washed with acetone (2x10 ml). The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 50-55% ethyl acetate in hexanes as an eluent to obtain the title compound (0.091 g, 43%)

MS: m/z 466 (M+1), ^:HNMR (CDCI3, 400 MHz): Ô 8.19 (s, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.3l(d, J=8.4 Hz, 2H), 4.10 (q, J=7.2 Hz, 2H), 3.87-3.84(m, 4H), 3.16 (s, 3H), 3.07 (s, 3H), 3.07-3.04 (m, 4H), 1.88 (s, 3H), 1.15 (t, J=7.2 Hz, 3H). aax'

The compounds given below were prepared by procedure similar to the one described above for compound ‘24d’ with appropriate variations of reactants, reaction conditions and quantifies of reagents

22d. tert-butyl 4- (4- (4- (N- ( (dimethylamino)methylene)sulfamoyl)phenyl)-5(ethoxycarbonyl)-3-methylthiophen-2-yl)piperazine-1 -carboxylate

MS: m/z565(M+l)

23d. Ethyl-3-(4-(]V-((dimethylamino) methylene) sulfamoyl)phenyl)-5-(4-(4fluorophenyl)piperazin-1 -yl)4-methyl-thiophene-2-carboxylate

MS: m/z559(M+l)

Step 5: Préparation of 4-methyl-5-morpholino-3-(4sulfamoylphenyl)thiophene-2-carboxylic acid (24e)

Ethyl-3-(4-(lV-((dimethylamino) methylene) sulfamoyl)phenyl)-4-methyl-5morpholinothiophene-2-carboxylate (compound 24d, 0.36g, 0.77 mmol) was suspended in éthanol (20 ml) and combined with 2N solution of NaOH (1.55 ml) at 25°C. The reaction mixture was heated at 95-100°C under stirring for lhr. The progress of the reaction was monitored by TLC. The resulting reaction mixture was concentrated at a reduced pressure. The residue obtained was diluted with mixture of ethylacetate:water (30:15 ml). To this was added aqueous 10 % HCl to bring the pH to between 5 and 6. The aqueous layer was extracted with ethyl acetate (2 x ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure from the dried organic layer to obtain the title compound (0.196g, 66%).

MS: m/z383(M+l),

JHNMR (DMSO, 400 MHz): δ 12.44 (bs, IH), 7.83 (d, J=8.4Hz, 2H), 7.42 (s, 2H), 7.41 (d, J=8.4Hz, 2H), 3.75 (t, J=4.8Hz, 4H), 2.98 (t, J=4.4Hz, 4H), 1.79 (s, 3H).

The compounds given below were prepared by procedure similar to the one described above for compound ‘24e’ with appropriate variations of reactants, reaction conditions and quantifies of reagents

22e. 5-(4-(tert-butoxycarbonyl)piperazin- l-yl)-4-methyl-3-(4sulfamoylphenyl) thiophene-2-carboxylic acid

MS: m/z 482(M+1)

23e. 5-(4-(4-fluorophenyl)piperazin-l-yl)4-methyl--3-(4sulfamoylphenyl)thiophene-2-carboxylic acid

MS: m/z476(M+l)

Step 6: Préparation of 3-(4-(7V-((dimethylamino) methylene) sulfamoyl)phenyl)-lV-methoxy-lV,4-dimethyl-5-morpholinothiophene-2carboxamide (24f)

Oxalyl chloride (0.19g, 0.13 ml, 1.49 mmol) was added dropwise at 0°C to a solution of 4-methyl-5-morpholino-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid (compound 24e, 0.19g, 0.497 mmol) in a mixture of dichloromethane (15 ml) and DMF (0.073g, 0.08 ml, 0.99 m mol). The resulting mixture was allowed to warm to room température and stirred for 1.5 hr, under a nitrogen atmosphère. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure and used directly for further reaction. The residue so obtained was dissolved in dry dichloromethane (15 ml) and to this was added triethylamine (0.251g, 0.35 ml, 2.48 mmol) followed by the addition of TV, O-dimethylhydroxylamine hydrochloride (0.098g, 0.99 mmol) under stirring at 0°C. The reaction mixture was stirred at room température for 2 hr. The progress of reaction was monitored by TLC. The reaction mixure was washed with water (2x 10 ml) and the resulting organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude product. The crude product was further purified by column chromatography over silica gel (100-200 mesh) using 1% methanol in dichloromethane as an eluent to obtain the title compound (0.127g, 53%).

MS: m/z 481 (M+1), !HNMR (CDCh, 400 MHz): δ 8.13 (s, 1H), 7.89 (d, J=8.4Hz, 2H), 7.29 (d,

J=8.4Hz, 2H), 3.86 (brs, 4H), 3.65 (s, 3H), 3.14 (s, 3H), 3.13 (s, 3H), 3.033.05 (m, 7H), 1.85 (s, 3H).

The compounds given below were prepared by procedure similar to the one described above for compound ‘24Γ with appropriate variations of reactants, reaction conditions and quantifies of reagents.

22f. tert-butyl 4-(4-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-5(methoxy(methyl)carbamoyl)-3-methylthiophen-2-yl)piperazine-1 carboxylate.

MS: m/z580(M+l).

23f. 3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-5-(4-(4fluorophenyl)piperazin-l-yl)-N-methoxy-N,4-dimethylthiophene-2carboxamide.

MS: m/z574(M+l).

Step 7: Préparation of 4-(4-methyl-5-morpholino-2-propionylthiophene-3yljbenzenesulfonamide (compound 24)

To a stirred solution of 3-(4-(lV-((dimethylamino) methylene) sulfamoyl)phenyl)-lV-methoxy-lV,4-dimethyl-5-morpholinothiophene-2carboxamide (compound 24f, 0.120g, 0.25 mmol) in anhydrous THF (10 ml) at 25°C, Grignard reagent (ethyl magnésium bromide, 0.17g, 1.25ml, 1.25 mmol) was added dropwise and the reaction mixture was heated to 70-75’0 for 1 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0°C, reaction mixture was quenched by adding a saturated ammonium chloride solution (10 ml) and the resulting mixture was extracted with ethyl acetate (2x20 ml). The combined organic layer was dried over anhydrous Na₂SO4. The solvent in the dried organic layer was evaporated under a reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 40-45% ethyl acetate in hexane as an eluent to obtain the title compound which was further purified by précipitation by dissolving 0.056 g of this compound in ethyl acetate (1.0 ml) and precipitating it by the slow addition of diisopropyl ether. The precipitate was filtered to obtain the title compoud. (0.047g, 48 %).

MS: m/z 395 (M+l), ^JHNMR (DMSO, 400 MHz): Ô 7.88 (d, J=8.4 Hz, 2H), 7.46-7.48 (m, 4H), 3.74-3.76 (m, 4H), 3.00-3.03 (m, 4H), 2.24 (q, J=7.2 Hz, 2H), 1.75 (s, 3H), 0.83 (t, J=7.2 Hz, 3H).

4-(4-methyl-5-(piperazin-1 -yl)-2-propionylthiophen-3yl)benzenesulfonamide (Compound 22).

MS: MS: m/z 394 (M+l), *HNMR (CDC1₃, 400 MHz): δ 7.84 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 6.31 (bs-exchanges with D₂O, 2H), 2.84-2.89 (m, 8H), 2.36 (bsexchanges with D₂O, IH), 2,16 (q, J=7.2 Hz, 2H), 1.63 (s, 3H), 0.80 (t, J=7.2 Hz, 3H).

4-(5-(4-(4-Fluorophenyl)piperazin-l-yl)-4-methyl-2-propionylthiophen-3-yl) benzene sulfonamide (Compound 23).

MS: m/z 488 (M+l),

1HNMR (DMSO, 400 MHz): Ô 7.88 (d, J=8.4 Hz, 2H), 7.47-7.49 (m, 4H), 7.00-7.10 (m, 4H), 3.34-3.36 (m, 4H), 3.24-3.26 (m, 2H), 3.16-3.19 (m, 2H), 2.24 (q, J=7.2 Hz, 2H), 1.78 (s, 3H), 0.83 (t, J=7.2 Hz, 3H).

Example 3: Préparation of 4-(5-(4-methoxyphenyl)-4-methyl-2propionylthiophen-3-yl)benzenesulfonamide (Compound 7)

Step lî Methyl 3-bromo-4-methylthiophene-2-carboxylate (7a)

To a stirred suspension of copper (II) bromide (14.3 g, 64.0 mmol) in acetonitrile (70 ml), t-butyl nitrite (7.83 g, 9.21 ml, 76.0 mmol) was added under a nitrogen atmosphère at room température (25°C). To this suspension solution of methyl 3-amino-4-methylthiophene-2-carboxylate (10.0 g, 58.0 mmol) in acetonitrile (30 ml) was added at 20°C in drop wise manner over a period of 2 hr. The reaction mixture was stirred at 25°C for hr. The progress of the reaction was monitored by TLC. The reaction mixture was then slowly added to 150 ml 2N HCl and extracted with ethyl acetate (2 x 150 ml). The resulting organic layer was washed with water (1 x 50 ml), brine (1 x 50 ml) and dried over sodium sulfate and concentrated under reduced pressure to obtain crude product as semi-solid (10. 5 g), which was then purified by column chromatography over silica gel (100200 mesh) using 7% ethyl acetate in hexanes as an eluent to obtain the title compound (9.0 g, 65.55%).

MS: m/z 236 (M+l), iHNMR (CDCI3, 400 MHz): δ 7.19 (s, 1H), 3.87 (s, 3H), 2.24 (s, 3H).

Step 2: Methyl 4-methyl-3-(4-sulfamoylphenyl) thiophene-2-carboxylate. (7b)

To a stirred suspension of methyl 3-bromo-4-methylthiophene-2carboxylate (compound 7a, 9.0 g, 38.0 mmol) in éthanol: toluene (100:30 ml) in sealed tube, (4-sulfamoylphenyl) boronic acid (8.46 g, 42.0 mmol) and potassium carbonate (10.57 g, 76.0 mmol) were added under a nitrogen atmosphère at room température (about 25°C). Nitrogen gas was purged to this suspension for further 15 minute at room température (about 25°C) and tetrakis(triphenyl phosphine)palladium(O) (2.21 g, 1.9 mmol) was added at 25°C and sealed tube was closed. The reaction mixture was stirred at 105°C for 15 hr and the progress of the reaction was monitored by TLC. Reaction mixture was filtered and washed with ethyl acetate (2 X 100 ml). Organic layer was concentrated under reduced pressure to obtain crude product as semi-solid (11.2 g); which was purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (20% ethyl ester as trans esterified product was observed) (8.8 g, 70.70%). MS: m/z 312 (M+1), iHNMR (CDCh, 400 MHz): Ô 7.97 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.23 (s, 1H), 4.91(bs-exchanges with D₂O, 2H) 3.71 (s, 3H), 2.20 (s, 3H).

Step 3: Methyl 5-bromo-4-methyl-3-(4-sulfamoylphenyl) thiophene~2carboxylate. (7c)

To a stirred suspension of methyl 4-methyl-3-(4-sulfamoylphenyl) thiophene-2-carboxylate (compound 7b, 8.80 g, 27.0 mmol) in DCM (150 ml), bromine (5.19 g, 1.67 ml, 32.0 mmol) was added at 0°C in a drop wise manner. The reaction mixture was stirred at 25°C for 2 hr and the progress of the reaction was monitored by TLC. The reaction mixture was then concentrated completely and again dissolved in DCM (250 ml). The organic layer so obtained was washed with water (2 x 50 ml), brine (1 x 50 ml) and dried over sodium sulfate and concentrated under reduced pressure to obtain crude product as semi-solid (10. 2 g), which was then purified by column chromatography over silica gel (100-200 mesh) using

50% ethyl acetate in hexanes as an eluent to obtain the title compound (20% ethyl ester as trans esterified product was observed) (9.0 g, 82.34%).

MS: m/z 391 (M+l), 'HNMR (CDCh, 400 MHz): δ 8.01 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 4.93(bs-exchanges with D2O, 2H), 3.72 (s, 3H), 1.95 (s, 3H).

Step 4: Methyl 5-(4-methoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl) thiophene-2-carboxylate. (7d)

To the solution of methyl 5-bromo-4-methyl-3-(4sulfamoylphenyl)thiophene-2-carboxylate (compound 7c, 3.0g, 7.69 mmol) in a mixture of toluene: éthanol (25:75 ml) was added (4methoxyphenyl)boronic acid (1.28g, 8.46 mmol) and potassium carbonate (3.18g, 23.07 mmol) at 25°C.Nitrogen gas was bubbled through reaction mixture for 15 minutes. To this was added tetrakis(triphenylphosphine)palladium(0) (0.487g, 0.422 mmol) under nitrogen and reaction mixture was heated at 95-100°C for lhr under stirring. The progress of reaction was monîtored by TLC. The reaction mixture was cooled to 25°C and filtered through celite, and then washed with ethyl acetate (50ml). The filtrate was concentrated under reduced pressure to obtain a crude product, that was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (20% ethyl ester as trans esterified product was observed) (2.69 g, 84%).

MS: m/z418 (M+1), iHNMR (CDCla, 400 MHz): δ 8.01 (d, J=8.4 Hz, 2H), 7.41-7.46 (m, 4H), 7.00(d, J=8.4 Hz, 2H). 4.96 (bs-exchanges with D₂O, 2H), 3.87(s, 3H), 3.73(s, 3H), 1.99 (s, 3H).

The compounds given below were prepared by procedure similar to the one described above for compound ‘7d’ with appropriate variations of reactants, reaction conditions and quantifies of reagents.

3d. Ethyl 5-(3-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylate.

MS: m/z 436 (M+1).

5d. Ethyl 5-(4-Cyclopropylphenyl)-4-methyl-3-(4sulfamoylphenyl)thiophene-2-carboxylate.

MS: m/z 442 (M+1).

6d. Ethyl 4-Methyl-3-(4-sulfamoylphenyl)-5-(4trifluoro methyl) phenyl) thiophene-2- carb oxylate.

MS: m/z 468 (M-l).

8d. Ethyl 5-(4-ethoxypheny 1)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2 carb oxylate.

MS: m/z 446 (M+1).

9d. Ethyl 4-Methyl-3-(4-sulfamoylphenyl)-5-(4trifluoromethoxy)phenyl)thiophene-2-carboxylate.

MS: m/z 486 (M+1).

lOd. Ethyl 4-Methyl-3-(4-sulfamoylphenyl)-5-(p-tolyl)thiophene-2carboxylate.

MS: m/z 416 (M+1).

12d. Ethyl 5-(4-(dimethylamino)phenyl)-4-methyl-3-(4sulfamoylphenyl) thiophene- 2 -carboxylate.

MS: m/z445 (M+1).

13d. Ethyl 5-(3-Fluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene2-carboxylate.

MS: m/z 420 (M+1).

14d. Ethyl 4-methyl-5-phenyl- 3-(4-sulfamoylphenyl)thiophene-2carboxylate.

MS: m/z 402 (M+1).

15d. Ethyl 5-(3-Ethoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene2-carboxylate.

MS: m/z446 (M+1).

16d. Ethyl 5-(4-Ethylphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylate.

MS: m/z 430 (M+1).

25d. Ethyl 4-methyl-5-(pyridin-4-yl)-3-(4-sulfamoylphenyl)thiophene-2carboxylate.

MS: m/z 403 (M+1). VvW

26d. Ethyl 4-methyl-5-(pyridin-3-yl)-3-(4-sulfamoylphenyl)thiophene-2carboxylate.

MS: m/z 403 (M+1).

27d. Ethyl 5-(Furan-3-yl)- 4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylate.

MS: m/z 392 (M+1).

28d. Ethyl 5-(lH-indol-5-yl)- 4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylate.

MS: m/z 441 (M+1).

29d. Ethyl 4-methyl -5-(l-methyl-lH-indol-5-yl)-3-(4sulfamoylphenyl)thiophene-2-carboxylate.

MS: m/z 455 (M+1).

30d. Ethyl 5-(benzofuran-5-yl)-4-methyl -3-(4-sulfamoylphenyl)thiophene2-carboxylate.

MS: m/z 442 (M+1).

31d. Ethyl 5-(l-acetylindolin-5-yl)-4-methyl -3-(4sulfamoy lphenyl) thiophene-2 -carboxylate.

MS: m/z 485 (M+1).

44d. Ethyl-5-(4-((tert-butoxycarbonyl)methyl)amino)phenyl)-4-methyl-3-(4sulfamoylphenyl)thiophene-2-carboxylate.

MS: m/z 531 (M+1).

Step 5: 5-(4-Methoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid. (7e)

H₂NO₂S

Methyl 5-(4-methoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylate (compound 7d, 3.02g, 7.24 mmol) was suspended in éthanol (50ml) and NaOH (1.44g, 36.2 mmol) in water 10 ml was added at 25°C. The reaction mixture was heated at 50-55°C under stirring for 2 hr. The progress of reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. Water, 50 ml was added to the residue so obtained and the mixture was cooled using icebath. Aqueous hydrochloric acid (10%) was then added to the mixture to bring the pH to between 5 and 6. The mixture was then extracted with ethyl acetate (2 x 75 ml). The combined organic layer was dried over anhydrous Na2SÛ4. The solvent was evaporated under reduced pressure to obtain a product (2.83g, 97%).

MS: m/z 404 (M+1),

1HNMR (DMSO, 400 MHz): δ 12.85 (bs-exchanges with D₂O, IH), 7.86 (d, J=8.4 Hz, 2H), 7.45-7.50 (m, 4H). 7.45 (bs-exchanges with D₂O, 2H), 7.07 (d, J=8.4 Hz, 2H), 3.81 (s, 3H), 1.90(s, 3H).

The compounds given below were prepared by procedure similar to the one described above for compound ‘7e’ with appropriate variations of reactants, reaction conditions and quantifies of reagents. y/S'

100

3e. 5-(3-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z 408 (M+1).

5e. 5-(4-Cyclopropylphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z 414 (M+1).

6e. 4-Methyl-3-(4-sulfamoylphenyl)-5-(4-trifluoromethyl)phenyl)thiophene2-carboxylic acid.

MS: m/z 442 (M+1).

8e. 5-(4-Ethoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z418 (M+1).

9e. 4-Methyl-3-(4-sulfamoylphenyl)-5-(4trifluoromethoxy) phenyl) thiophene-2 -carboxylic acid.

MS: m/z 458 (M+1).

10e. 4-Methyl-3-(4-sulfamoylphenyl)-5-(p-tolyl)thiophene-2-carboxylic acid.

MS: m/z 388 (M+1).

12e. 5-(4-(dimethylamino)phenyl)-4-methyl-3-(4sulfamoylphenyl)thiophene-2-carboxylic acid.

MS: m/z 417 (M+1).

13e. 5-(3-Fluorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid. Nf''

101

MS: m/z392 (M+1).

14e. 4-methyl-5-phenyl- 3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid.

MS: m/z 374(M+1).

15e. 5-(3-Ethoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z 418 (M+1).

16e. 5-(4-Ethylphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z 402 (M+1).

25e. 4-methyl-5-(pyridin-4-yl)-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z375(M+l).

26e. 4-methyl-5-(pyridin-3-yl)-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z 375 (M+1).

27e. 5-(Furan-3-yl)- 4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z 364 (M+1).

28e. 5-( lH-indol-5-yl)- 4-methyl-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z 413 (M+1).

102

29e. 4-methyl -5-(1 -methyl- lH-indol-5-yl)-3-(4sulfamoylphenyl)thiophene-2-carboxylic acid.

MS: m/z 427 (M+1).

30e. 5-(benzofuran-5-yl)-4-methyl -3-(4-sulfamoylphenyl)thiophene-25 carboxylic acid.

MS: m/z 414 (M+1).

31e. 5-(l-acetylindolin-5-yl)-4-methyl -3-(4-sulfamoylphenyl)thiophene-2carboxylic acid.

MS: m/z 457 (M+1).

44e. 5-(4-((tert-butoxycarbonyl)methyl)amino)phenyl)-4-methyl-3-(4sulfamoylphenyl) thiophene-2-carboxylic acid.

MS: m/z503(M+l).

Step 6: 3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-N-methoxy5- (4-methoxyphenyl) -N, 4-dimethylthiophene-2 -carboxamide. (71)

Oxalyl chloride (1.77 g, 1.2 ml, 13.9 mmol) was added drop wise at 0°C to a solution of 5-(4-methoxyphenyl)-4-methyl-3-(4sulfamoylphenyl)thiophene-2-carboxylic acid (compound 7e, 2.8g, 6.94

103 mmol) in a mixture of dichloromethane (75 ml) and DMF (1.01g, 1.1 ml,

13.89 mmol). The so obtained mixture was allowed to corne at room température and stirred for 1.5 hr under a nitrogen atmosphère. The progress of the reaction was monitored by TLC. The reaction mixture was 5 then concentrated under reduced pressure. The residue so obtained was dissolved in diy dichloromethane (75 ml) and to this was added triethylamine (2.8g, 3.9 ml, 27.76 mmol) followed by the addition of N_tOdimethylhydroxylamine hydrochloride (1.35g, 13.89 mmol) under stirring.

The réaction mixture was then stirred at room température for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then washed with water (2 x 25ml) and the organic layer so obtained was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude product. The crude product was further purified by column chromatography over silica gel (100-200 mesh) using 80% ethyl acetate in hexane as an eluent to obtain the title compound (2.73g, 78%).

MS: m/z 502 (M+l), iHNMR (CDC1₃, 400 MHz): δ 8.16 (s, IH), 7.95 (d, J=8.4 Hz, 2H), 7.45(d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.00(d, J=8.4 Hz, 2H), 3.88 (s, 3H), 3.70(s, 3H), 3.19 (s, 3H), 3.17 (s, 3H), 3.07 (s, 3H), 2.00 (s, 3H).

The compounds given below were prepared by procedure similar to the one described above for compound ‘7P with appropriate variations of reactants, reaction conditions and quantifies of reagents

3f. 5-(3-chlorophenyl)-3-(4-(lV-((dimethylamino) methylene) sulfamoyl) phenyl)-7V-methoxy-lV,4-dimethylthiophene-2-carboxamide.

MS: m/z 506 (M+l).

104

5f. 5 - (4- (Cyclopropylphenyl) - 3 - (4- ( N- ( (dimethylamino) methylene ) sulfamoyl) phenyl)-TV-methoxy-N,4-dimethylthiophene-2-carboxamide.

MS: m/z 512 (M+l).

6f. 3-(4-(7V-((dimethylamino) methylene) sulfamoyl) phenyl)- IV-methoxyN,4-dimethyl-5-(4-(trifluorornethyl) phenyl) thiophene-2-carboxamide.

MS: m/z 540 (M+l).

8f. 3-(4-(lV-((dimethylamino) methylene) sulfamoyl) phenyl)- 5-(4ethoxyphenyl) -7V-methoxy-JV,4-dimethyl thiophene-2-carboxamide.

MS: m/z 516 (M+l).

9f. 3-(4-(JV-((dimethylamino) methylene) sulfamoyl) phenyl)- JV-methoxylV,4-dimethyl-phenyl) -5-(4-(trifluromethoxy)phenyl)thiophene-2carboxamide.

MS: m/z 556 (M+l).

lOf. 3-(4-(lV-((dimethylamino) methylene) sulfamoyl) phenyl)- IV-methoxy7V,4-dimethyl-phenyl) -5-(4-(p-tolyl)thiophene-2-carboxamide.

MS: m/z 486 (M+l).

12f. 3-(4-(lV-((dimethylamino) methylene) sulfamoyl) phenyl)-5-(4(dimethylamino)phenyl)- 7V-methoxy-/V,4-dimethylthiophene-2carboxamide.

MS: m/z 515 (M+l).

13f. 3-(4-(JV-((dimethylamino) methylene) sulfamoyl) phenyl)-5-(3-Fluoro phenyl)-lV-methoxy-lV,4-dimethylthiophene-2-carboxamide.

MS: m/z490 (M+l).

105

14f. 3-(4-(7V-((dimethylamino) methylene) sulfamoyl) phenyl)- JV-methoxyJV,4-dimethyl-5-phenylthiophene-2-carboxamide.

MS: m/z 472 (M+l).

15f. 3-(4-(7V-((dimethylamino) methylene) sulfamoyl) phenyl)- 5-(3ethoxyphenyl) - JV-methoxy-/V,4-dimethylthiophene-2-carboxamide.

MS: m/z 516 (M+l).

16f. 3-(4-(JV-((dimethylamino) methylene) sulfamoyl) phenyl)- 5-(4ethylphenyl) - 7V-methoxy-JV,4-dimethylthiophene-2-carboxamide.

MS: m/z 500 (M+l).

25f. 3-(4-(/V-((dimethylamino) methylene) sulfamoyl) phenyl)-iV-methoxyIV,4-dimethyl-5-(pyridin-4-yl)thiophene-2-carboxamide.

MS: m/z 473 (M+l).

26f. 3-(4-(2V-((dimethylamino) methylene) sulfamoyl) phenyl)-7V-methoxyiV,4-dimethyl-5-(pyridin-3-yl)thiophene-2-carboxamide.

MS: m/z 473 (M+l).

27f. 3 -(4-(/V-({dimethylamino) methylene) sulfamoyl) phenyl)-5-(furan-3yl)-JV-methoxy-/V,4-dimethyl thiophene-2-carboxamide.

MS: m/z 462 (M+l).

28f. 3 -(4-(JV-((dimethylamino) methylene) sulfamoyl) phenyl)-5-(lH-indol5-yl) - iV-methoxy- N, 4 -dimethyl thiophene-2 -carboxamide.

MS: m/z 511 (M+l).

29f. 3 -(4-(iV-((dimethylamino) methylene) sulfamoyl) phenyl)-JV-methoxyiV_}4-dimethyl-5-( 1-methyl-1 H-indol-5-yl) thiophene-2-carboxamide.

106

MS: m/z 525 (M+l).

30f. 5-(Benzofuran-5-yl)-3 -(4-(7V-((dimethylamino) methylene) sulfamoyl) phenyl) - TV-methoxy- TV, 4-dimethylthiophene-2 -carboxamide.

MS: m/z 512 (M+l).

f. 5-( 1 -acetylindolin-5-yl)-3-(4-(N( (dimethylamino) methylene) su lfamoyl) ph enyl) - N- meth oxy- N, 4 demethylthiophene-2-carboxamide.

MS: m/z 555 (M+l).

44f. tert-butyl (4-(4-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-5(meth oxy (methyl) car b amoyl) - 3 - methy lth iophen-2y 1) phenyl) ( methyl) car bamate.

MS: m/z 601 (M+l).

Step 7: 4-(5-(4-methoxyphenyl)-4-methyl-2-propionylthiophen-3-yl) benzene sulfonamide (compound 7)

Grignard reagent (ethyl magnésium bromide, 3.59 g, 26.8 ml, 26.94 mmol) was added drop wise to a stirred solution of 3-(4-(N( (dimethylamino) methylene) sulfamoyl) phenyl) - N -methoxy- 5- (4methoxyphenyl)-N,4-dimethylthiophene-2-carboxamide (compound 7f, 2.7 g, 5.8 mmol) in anhydrous THF (100 ml) at 25°C, and the reaction

107 mixture was heated at about 70 to about 75°C for 1 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0°C, the reaction mixture was quenched by adding a solution of saturated ammonium chloride (50 ml) and the resulting mixture was extracted with ethyl acetate (2 x 100 ml). The combined organic layer was dried over anhydrous Na2SC>4· The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product; which was purified by Préparative HPLC to obtain the title compound (0.84 g, 37%).

MS: m/z 416 (M+1), ^JHNMR (CDC1₃, 400 MHz): δ 8.00 (d, J=8.4 Hz, 2H), 7.40-7.43 (m, 4H). 6.97 (d, J=8.4 Hz, 2H), 4.87 (bs-exchanges with D2O, 2H), 3.85 (s, 3H), 2.53 (q, J=7.2 Hz, 2H), 1.93 (s, 3H), 1.03 (t, J=7.2 Hz, 3H).

4-(5-(3-Chlorophenyl)-4-methyl-2-propionylthiophen-3yl)benzenesulfonamide (Compound 3)

MS: m/z 420 (M+1), iHNMR (DMSO, 400 MHz): δ 7.93 (d, J=8.4 Hz, 2H), 7.62 (t, J= 2.4 Hz, IH), 7.53-7-56 (m, 5H), 7.49 (bs-exchanges with D2O, 2H), 2.38 (q, J=7.2 Hz, 2H), 1.93 (s, 3H), 0.88 (t, J=7.2 Hz, 3H).

4-(5-(4-cyclopropylphenyl)-4-methyl-2-propionylthiophen-3yljbenzenesulfonamide (Compound 5)

MS: m/z 426 (M+1), !HNMR (CDCI3, 400 MHz): δ 8.01 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz,

2H), 7.38 (d, J=8.0 Hz, 2H). 7.15 (d, J=8.0 Hz, 2H), 4.87 (bs-exchanges

108 with D₂O, 2H), 2.55 (q, J=7.2 Hz, 2H), 1.91-1.97 (m, 4H), 1.01-1.06 (m,

5H), 0.75-0.78 (m, 2H).

4-(4-methyl-2-propionyl-5-(4-(trifluoromethyl)phenyl)thiophen-3yl)benzenesulfonamide (Compound 6)

MS: m/z 454 (M+1), ’HNMR (CDCh, 400 MHz): δ 8.03(d, J=8.4 Hz, 2H), 7.72 (d, J=8.0 Hz, 2H), 7.6 l(d, J=8.4 Hz, 2H). 7.43 (d, J=8.0 Hz, 2H), 5.02 (bs-exchanges with D₂O, 2H), 2.54 (q, J=7.2 Hz, 2H), 1.97 (s, 3H), 1.04 (t, J=7.2 Hz, 3H).

4-(5-(4-Ethoxyphenyl)-4-methyl-2-propionylthiophen-3yl)benzenesulfonamide (Compound 8)

MS: m/z 430 (M+1), ^JHNMR (CDCh, 400 MHz): δ 8.01 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4,88 (bs-exchanges with D₂O, 2H), 4.08 (q, J=6.8 Hz, 2H), 2.54 (q, J=7.2 Hz, 2H), 1.93 (s, 3H), 1.44 (t, J=6.8 Hz, 3H), 1.03 (t, J=7.2 Hz, 3H).

4-(4-methyl-2-propionyl-5-(4-(trifluoromethoxy)phenyl)thiophen-3yl)benzenesulfonamide(Compound 9)

MS: m/z 470 (M+1), !HNMR (CDCh, 400 MHz): δ 8.04(d, J=8.4 Hz, 2H), 7.52 (d, J=8.0Hz, 2H), 7.44(d, J=8.4Hz, 2H). 7.31 (d, J=8.0Hz, 2H), 4.98 (bs-exchanges with D₂O, 2H), 2.55 (q, J=7.2 Hz, 2H), 1.95 (s, 3H), 1.05 (t, J=7.2 Hz, 3H).

4-(4-methyl-2-propionyl-5-(4-tolyl)thiophen-3-yl)benzenesulfonamide (Compound 10)

MS: m/z 400 (M+1),

109 iHNMR (DMSO, 400 MHz): δ 7.92 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz,

2H), 7.49 (bs-exchanges with D₂O, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.33 (d,

J=8.4 Hz, 2H), 2.33-2.36 (m, 5H), 1.92 (s, 3H), 0.87 (t, J=7.2 Hz, 3H).

4-(5-((4-tert butyl)phenyl)-4-methyl-2-propionylthiophen-3yljbenzenesulfonamide (Compound 11)

MS: m/z 442 (M+l),

1HNMR (CDCI3, 400 MHz): δ 8.02 (d, J=8.4 Hz, 2H), 7.42-7.49 (m, 6H), 4.92 (bs-exchanges with D2O, 2H), 2.56 (q, J=7.2 Hz, 2H), 1.97 (s, 3H), 1.36 (s, 9H), 1.06 (t, J=7.2 Hz, 3H).

4-((5-(4-Dimethylamino)phenyl)-4-methyl-2-propionylthiophen-3yl)benzenesulfonamide (Compound 12)

MS: m/z 429 (M+l), ^XHNMR (CDCI3, 400 MHz): δ 8.0l(d, J=8.4 Hz, 2H), 7.44 (d, J=8.4Hz, 2H), 7.40(d, J=8.8Hz, 2H). 6.77 (d, J=8.8Hz, 2H), 4.83 (bs-exchanges with D₂O, 2H), 3.03 (s, 6H), 2.55 (q, J=7.2 Hz, 2H), 1.97 (s, 3H), 1.05 (t, J=7.2 Hz, 3H).

4-(5-(3-Fluorophenyl)-4-methyl-2-propionylthiophen-3yl)benzenesulfonamide (Compound 13)

MS: m/z404 (M+l),

JHNMR (CDCI3, 400 MHz): δ 8.02 (d, J=8.4 Hz, 2H), 7.40-7.46 (m, 3H), 7.26-7.29 (m, IH), 7.18-7.21 (m, IH), 7.09-7.14 (m, IH), 5.09 (bsexchanges with D2O, 2H), 2.55 (q, J=7.2 Hz, 2H), 1.96 (s, 3H), 1.03 (t, J=7.2 Hz, 3H).

4-(4-methyl-5-phenyl-2-propionylthiophen-3-yl)benzenesulfonamide (Compound 14)

MS: m/z 386 (M+l), vV''

110 ’HNMR (DMSO, 400 MHz): δ 7.93 (d, J=8A Hz, 2H), 7.45-7.57 (m, 9H),

2.36 (q, J=7.2 Hz, 2H), 1.93 (s, 3H), 0.88 (t, J=7.2 Hz, 3H).

4-(5-(3-Ethoxyphenyl)-4-methyl-2-propionylthiophen-3yl)benzenesulfonamide (Compound 15)

MS: m/z 430 (M+1), ’HNMR (CDCh, 400 MHz): δ 8.01 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.34 (t, J=8.0 Hz, 1H), 7.05 (dd, J=8.0, 2.0 Hz, 1H), 6.99 (t, J=2.0 Hz, 1H), 6.92 (dd, J=8.0, 2.0 Hz, 1H), 5.07 (bs-exchanges with D₂O, 2H), 4.06 (q, J=7.2 Hz, 2H), 2.53 (q, J=7.2 Hz, 2H), 1.95 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.02 (t, J=7.2 Hz, 3H).

4-(5-(4-Ethylphenyl)-4-methyl-2-propîonylthiophen-3yl)benzenesulfonamide (Compound 16)

MS: m/z414 (M+1), ’HNMR (CDCla, 400 MHz): δ 8.02 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.42 (t, J=8.0 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 5.00 (bs-exchanges with D₂O, 2H), 2.72 (q, J=7.6 Hz, 2H), 2.54 (q, J=7.2 Hz, 2H), 1.96 (s, 3H), 1.28 (t, J=7.6 Hz, 3H), 1.04 (t, J=7.2 Hz, 3H).

4-(4-methyl-2-propionyl-5-(pyridin-4-yl)thiophen-3-yl)benzenesulfbnamide (Compound 25)

MS: m/z 387 (M+1), ’HNMR (DMSO, 400 MHz): δ 8.71 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 7.57-7.59 (m, 4H), 7.50 (bs-exchanges with D₂O, 2H), 2.39 (q, J=7.2 Hz, 2H), 1.98 (s, 3H), 0.88 (t, J=7.2 Hz, 3H).

4-(4-methyl-2-propionyl-5-(pyridin-3-yl)thiophen-3-yl)benzenesulfonamide (Compound 26) w

111

MS: m/z 387 (M+l),

1HNMR (DMSO, 400 MHz): δ 8.77-8.78 (m, 1H), 8.66 (dd, >8.8, 1.6 Hz,

1H), 7.99-8.02 (m, 1H), 7.94 (d, >8.8 Hz, 2H), 7.54-7.58 (m, 3H),J, 7.50 (bs-exchanges with D₂O, 2H), 2.38 (q, >7.2 Hz, 2H), 1.94 (s, 3H), 0.88 (t, >7.2 Hz, 3H).

4-(5-(Furan-3-yl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide (Compound 27)

MS: m/z 376 (M+l), *HNMR (CDCI3, 400 MHz): δ 8.01 (d, >8.8 Hz, 2H), 7.68-7.69(m, 1H), 7.51 (t, >1.6 Hz, 1H), 7.38 (d, >8.4 Hz, 2H), 6.64-6.65 (m, 1H), 4.88 (bsexchanges with D₂O, 2H), 2.49 (q, >7.2 Hz, 2H), 1.96 (s, 3H), 1.02 (t, >7.2 Hz, 3H).

4-(5-(1 H-indol-5-yl)-4-methyl-2-propionylthiophen-3yl)benzenesulfonamide (Compound 28)

MS: m/z425 (M+l), ^NMR (DMSO, 400 MHz): δ 11.3 (bs-exchanges with D₂O, 1H), 7.92 (d, >8.4 Hz, 2H), 7.74-7.75 (m, 1H), 7.58 (d, >8.4 Hz, 2H), 7.52 (d, >8.4 Hz, 1H), 7.49 (bs-exchanges with D₂O, 2H), 7.45 (t, >2.8 Hz, 1H), 7.27 (dd, >8.4, 1.6 Hz, 1H), 6.52-6.53 (m, 1H), 2.36 (q, J=7.2 Hz, 2H), 1.96 (s, 3H), 0.85 (t, >7.2 Hz, 3H).

4-(4-methyl-5-( 1 -methyl-1 H-indol-5-yl)-2-propionylthiophen-3yl)benzenesulfonamide (Compound 29)

MS: m/z 439 (M+l), !HNMR (DMSO, 400 MHz): δ 7.92 (d, >8.4 Hz, 2H), 7.75 (s, 1H), 7.567.58(m, 3H), 7.49 (bs-exchanges with D₂O, 2H), 7.43 (d, >2.8 Hz, 1H),

112

7.34 (d, <7=8.4 Hz, IH), 6.52 (d, 7=2.8 Hz, IH), 3.83 (s, 3H), 2.37 (q, J=7.2

Hz, 2H), 1.96 (s, 3H), 0.88 (t, 7=7.2 Hz, 3H).

4-(5-(Benzofuran-5-yl)-4-methyl-2-propionylthiophen-3yl)benzenesulfonamide (Compound 30)

MS: m/z426 (M+l), 'HNMR (DMSO, 400 MHz): Ô 8.10 (s, IH), 7.93 (d, 7=8.0 Hz, 2H), 7.86 (s, IH), 7.75 (d, 7=8.4 Hz, IH), 7.58 (d, 7=8.0 Hz, 2H), 7.48 (m, 3H), 7.05 (s, IH), 2.37 (q, 7=7.2 Hz, 2H), 1.95 (s, 3H), 0.89 (t, 7=7.2 Hz, 3H).

4-(5-(Indolin-5-yl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide (Compound 31)

MS: m/z 427 (M+l), 'HNMR (CDCh, 400 MHz): δ 7.99 (d, 7=8.4 Hz, 2H), 7.40 (d, 7=8.4 Hz, 2H), 7.23 (s, IH), 7.14-7.16 (m, IH), 6.66 (d, 7=8.0 Hz, IH), 5.72 (bsexchanges with D₂O, 2H), 3.63 (t, 7=8.4 Hz, 2H), 3.08 (t, 7=8.4 Hz, 2H), 2.46 (q, 7=7.2 Hz, 2H), 2.01 (bs-exchanges with D₂O, IH), 1.93 (s, 3H), 1.01 (t, 7=7.2 Hz, 3H).

4-(4-methyl-5-(4-(4-methylpiperazin-l-yl)phenyl)-2-propionylthiophen-3yljbenzenesulfonamide (Compound 32)

MS: m/z 484 (M+l), 'HNMR (DMSO, 400 MHz): δ 7.90 (d, 7=8.4 Hz, 2H), 7.49 (d, 7=8.4 Hz, 2H), 7.41 (d, 7=8.4 Hz, 2H), 7.04 (d, 7=8.4 Hz, 2H), 5.04 (bs-exchanges with D₂O, 2H), 3.28-3.29 (m, 4H), 2.74-2.75 (m, 4H), 2.41 (s, 3H), 2.33 (q, 7=7.2 Hz, 2H), 1.88 (s, 3H), 0.85 (t, 7=7.2 Hz, 3H).

4-(4-Methyl-5-(4-methylaminophenyI)-2-propionylthiophen-3yl)benzenesulfonamide (Compound 44) W

113

MS: m/z 415 (M+1) ^rHNMR (DMSO, 400 MHz): δ 7.90 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4Hz, 2H),

7.47 (bs-exchanges with D₂O, 2H) 7.3l(d, J=8.4Hz, 2H). 6.63 (d, J=8.4Hz, 2H), 6.11 (q, J=4.8 Hz -exchanges with D₂O, 1H), 2.72 (d, J=4.8 Hz, 3H), 2.34(q, J=7.2 Hz, 2H), 1.90 (s, 3H), 0.87 (t, J=7.2 Hz, 3H).

Example 4: Préparation of Methyl 4-methyl-5-(2-oxoindolin-5-yl)-3-(4sulfamoyl phenyl)thiophen-2-carboxylate (Compound 42) and Ethyl 4methyl-5-(2-oxoindolin-5-yl)-3-(4-sulfamoylphenyl)thiophen-2carboxylate (Compound 43):

Following a procedure analogous to the one provided for compound of formula 7d (Step 4 of example 3) and replacing 4-methoxyphenyl boronic acid with an appropriate boronic acid or a similar reagent compounds of formula 42 and 43 were prepared.

Methyl 4-methyl-5-(2-oxoindolin-5-yl)-3-(4-sulfamoylphenyl)thiophen-2carboxylate (Compound 42)

MS: m/z 443 (M+1),

JHNMR (DMSO, 400 MHz): δ 10.60 (bs-exchanges with D₂O, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.40 (bs-exchanges with D₂O, 2H), 7.37-7.39 (m, 2H), 6.94 (d, J=8.0 Hz, 1H), 3.64 (s, 3H), 3.56 (s, 2H), 1.96 (s, 3H).

Ethyl 4-methyl-5-(2-oxoindolin-5-yl)-3-(4-sulfamoylphenyl)thiophen-2carboxylate (Compound 43)

MS: m/z 457 (M+1),

114 ^XHNMR (DMSO, 400 MHz): δ 10.59 (bs-exchanges with D₂O, IH), 7.86 (d,

J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.41 (bs-exchanges with D₂O, 2H),

7.37-7.39 (m, 2H), 6.94 (d, J=8.0 Hz, IH), 4.08 (q, J=7.2 Hz, 2H), 3.56 (s,

2H), 1.96 (s, 3H), 1.07 (t, J=7.2 Hz, 3H).

Example 5: Préparation of 4-(5-(4-chlorophenyl)-4-methyl-2propionylthiophen-3-yl)-N,N-dimethylbenzenesulfonamide (Compound 45)

4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-Nmethylbenzenesulfonamide (Compound 46)

To a solution of 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3yl)benzenesulfonamide (Compound 1, 0.50 g, 1.19 mmol) in acetonitrile (15 ml) was added K₂CO3 (0.25 g, 1.84 mmol) at room température and stirred for 15 minutes. To this was added methyl iodide (0.20 g, 0.08 ml, 1.42 mmol). The so obtained mixture was stirred at room température for 15 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The concentrated mass was diluted with water (20 ml). The mixture so obtained was —16539 lis extracted with ethyl acetate (3 x 30 ml). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude product. The crude product so obtained was purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain first title compound (0.05 g, 9.38%) and second title compound (0.045 g, 8.7%).

First title compound: 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen3-yl)-N,N-dimethylbenzenesulfonamide (Compound 45)

MS: m/z448 (M+1) iHNMR (DMSO, 400 MHz): δ 7.86 (d, J=8.4 Hz, 2H), 7.60-7.65 (m, 6H), 2.65 (s, 6H), 2.32 (q, J=7.2 Hz, 2H), 1.94 (s, 3H), 0.86 (t, J=7.2 Hz, 3H).

Second title compound: 4-(5-(4-chlorophenyl)-4-methyl-2propionylthiophen-3-yl)-N-methylbenzenesulfonamide (Compound 46)

MS: m/z 434 (M+1) !HNMR (DMSO, 400 MHz): δ 7.87 (d, J=8.4 Hz, 2H), 7.55-7.65 (m, 7H),

2.46 (d, J=4.8 Hz, 3H), 2.34 (q, J=7.2 Hz, 2H), 1.93 (s, 3H), 0.86 (t, J=7.2

Hz, 3H). •V''

Example 6: Préparation of 4-(5-(4-chlorophenyl)-4-((dimethylamino) methyl)-2-propionylthiophen-3-yl)benzenesulfonamide (Compound 35)

116

Step 1: Ethyl 4-(bromomethyl)-5-(4-chlorophenyl)-3-(4-sulfamoylphenyl) thiophene-2-carboxylate. (35a)

To a stirred solution of Ethyl 5-(4-chlorophenyl)-4-methyl-3-(4sulfamoylphenyl)thiophene-2-carboxylate (Compound lb, 4.0 g, 9.17 mmol) in chlorobenzene (50 ml) were added NBS (1.77 g, 10.09 mmol) and AIBN (1.65 g, 10.09 mmol) at 25°C. The reaction mixture was then stirred 15 at 85°C for 4 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to room température and was quenched in aqueous sodium chloride solution (50 ml). The mixture so obtained was then extracted with Ethyl acetate (2 x 50 ml). The organic layer was washed with brine (1 x 50 ml) and dried over sodium sulfate and concentrated under reduced pressure to obtain crude product (4.0 g). The crude product was then purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (2.8 g, 59.32 %).

MS: m/z 516 (M+1), iHNMR (DMSO, 400 MHz): Ô 7.90 (d, J=8.4 Hz, 2H), 7.59- 7.71 (m, 4H), 7.58(d, J=8.4 Hz, 2H), 7.51(bs-exchanges with D₂O, 2H) 4.29 (s, 2H), 4.10 (q, J=6.8 Hz, 2H), 1.06 (t, J=6.8 Hz, 3H).

Step 2: Ethyl 4-(bromomethyl)-5-(4-chlorophenyl)-3-(4-(lV

117 ((dimethylamino) methylene)sulfamoyl)phenyl) thiophene-2-carboxylate. (35b)

To a stirred suspension of Ethyl 4-(bromomethyl)-5-(4-chlorophenyl)-3-(4sulfamoylphenyl)thiophene-2-carboxylate (compound 35a, 2.7 g, 5.24 mmol) in ethyl acetate (30 ml) were added DMF (1.91 g, 2.01 ml, 26.2 mmol) and N, /V-Dimethylformamide dimethyl acetal (DMF-acetal) (0.69 g, 0.76 ml, 5.76 mmol) under a nitrogen atmosphère at room température —

118 (about 25°C). The reaction mixture was then stirred at room température (about 25°C) for 4 hr. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain 2.9 g of crude product. The crude product so obtained was then purified by column chromatography over silica gel (100-200 mesh) using 1.5% methanol in DCM as an eluent to obtain the title compound (2.2 g, 73.82 %).

MS: m/z 571 (M+1), ^rHNMR (DMSO, 400 MHz): δ 8.23 (s, IH) 7.85 (d, J=8.4 Hz, 2H), 7.62-7.75 (m,4H), 7.52 (d, J=8.4 Hz, 2H), 4.29 (s, 2H), 4.07 (q, J=7.2 Hz, 2H), 3.15 (s, 3H) 2.94 (s, 3H), 1.01 (t, J=7.2 Hz, 3H).

Step 3: Ethyl 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4-(JV( (dimethylamino) methylene) sulfamoyl) phenyl) thiophene-2 -carboxylate. (35c)

To a stirred suspension of Ethyl 4-(bromomethyl)-5-(4-chlorophenyl)-3-(4(7V-((dimethylamino)methylene)sulfamoyl)phenyl)thiophene-2-carboxylate (compound 35b, 2.20 g, 3.86 mmol) in benzene (30 ml), dimethyl amine (0.69 g, 7.6 ml 2M solution in THF, 15.4 mmol) was added at 0°C in a drop wise manner. The reaction mixture was then stirred at room température (about 25°C) for 16 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated to obtain the crude product as semi-solid (2.38 g). The crude product so obtained was purified by column chromatography over silica gel (100-200 mesh} using 1.2 % methanol in DCM as an eluent to obtain the title compound (1.1 g, 53.39 %).

MS: m/z534 (M+l), iHNMR (CDC1_3> 400 MHz): δ 8.16 (s, IH), 7.93 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H),7.39-7.42 (m, 4H), 4.14 (q, J=7.2 Hz, 2H), 3.15 (s, 3H), 3.07 (s, 2H), 3.04 (s, 3H),1.85 (s, 6H), 1.13 (t, J=7.2 Hz, 3H).

119

Step 4: 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3(4sulfamoylphenyl) thiophene-2-carboxylic acid (35d).

Ethyl 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4-(7V((dimethylamino) methylene) sulfamoyl)phenyl) thiophene-2-carboxylate (compound 35c, 1.0 g, 1.87 mmol) was suspended in éthanol (20ml) and a solution of NaOH (0.37 g, 9.36 mmol) in water (2 ml) was added to it at 25°C. The reaction mixture was heated at 75°C under stirring for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue so obtained was then

120 diluted with water (5 ml) and cooled using ice bath. To the cooled mixture was then added aqueous 10 % HCl to bring pH of the mixture to between and 6. The resulting solid was filtered and dried under reduced pressure to obtain the title compound {0.8 g, 94.78%).

MS: m/z 451 (M+1),

JHNMR (DMSO, 400 MHz): Ô 12.85 (bs-exchanges with D₂O, IH), 7.86 (d, J=8.0 Hz, 2H), 7.70 (d, J=8.0 Hz, 2H) 7.52-7.60 (m, 4H), 7.49 (bsexchanges with D₂O, 2H), 3.61 (s, 2H), 1.97 (s, 6H).

Step S: 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4-(lV( (dimethy lamino) methylene) sulfamoyl) phenyl) - IV-methoxy- Nmethylthiophene-2-carboxamide. (35e)

Oxalyl chloride (0.39 g, 0.26 ml, 3.1 mmol) was added drop wise at 0°C to a solution of 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3(4sulfamoylphenyl) thiophene-2-carboxylic acid (compound 35d, 0.7 g,

121

1.55 mmol) in a mixture of dichloromethane (25 ml) and DMF (0.27 g, 0.24 ml, 3.10 mmol). The mixture so obtained was allowed to corne at room température and stirred for 1.5 hr under a nitrogen atmosphère. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was dissolved in dry dichloromethane (25 ml), cooled to 0°C and to this was added triethylamine (0.94 g, 1.3 ml, 9.31 mmol) followed by the addition of JV, O- dimethylhydroxy lamine hydrochloride (0.3 g, 3.1 mmol) under stirring. The reaction mixture was then stirred at room température for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then diluted with DCM (25 ml) and washed with water (2 x 25ml), the organic layer so obtained was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product so obtained was purified by column chromatography over silica gel (100-200 mesh) using 6% methanol in DCM as an eluent to obtain the title compound (0.45 g, 52.81%).

MS: m/z 549 (M+1), iHNMR (DMSO, 400 MHz): δ 8.28 (s, IH), 7.78 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 3.63 (s, 3H), 3.47(s, 3H), 3.38 (s, 2H), 3.17 (s, 3H), 3.09 (s, 3H), 2.94 (s, 6H).

Step 6: 4-(5-(4-chlorophenyl)-4-((dimethylamino) methyl)-2propionylthiophen-3-yl)benzenesulfonamide (Compound 35) vc-—

122

Grignard reagent (ethyl magnésium bromide, 0.48 g, 3.6 ml IM solution in THF, 3.64 mmol) was added drop wise to a stirred solution of 5-(4chlorophenyl) -4-((dimethylamino) methyl) -3 - (4- ( IV( (dimethy lamino) methy lene) sulfamoy 1) phenyl) - IV-methoxy- Nmethylthiophene-2-carboxamide (compound 35e, 0.4 g, 0.72 mmol) in anhydrous THF (20 ml) at 25°C. The reaction mixture was then heated at about 70 to about 75°C for 2 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0°C, the reaction mixture was quenched by addition of a saturated solution of ammonium chloride (15 ml). The mixture so formed was then extracted with ethyl acetate (2 x 30 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent from the dried organic layer was evaporated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 60 % ethyl acetate in hexanes as an eluent to obtain the title compound (0.065 g, 19.28 %)

MS: m/z 463 (M+1), iHNMR (CDC13, 400 MHz): δ 7.99 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H),4.95 (bs-exchanges with D₂O, 2H), 3.05 (s, 2H), 2.51(q, J=7.2 Hz, 2H) 1.85 (s, 6H), 1.05 (t, J=7.2 Hz, 3H)

Example 7: Préparation of 4-(5-(4-chlorophenyl)-2-propionylthiophen3-yl)benzenesulfonamide (Compound 33)

123

Step 1: Ethyl 3-bromo-5-(4-chlorophenyl) thiophene-2-carboxylate. (33a)

To a solution of ethyl 3,5-dibromothiophene-2-carboxylate (Prepared according to procedure reported in J. Chem. Soc. Perkin Trans-l:Organic and Bioorganic Chemistry (1972-1999), 1973, p 1766-1770), 2.0 g (6.36 mmol) in a mixture of toluene: water (35:2 ml) was added (4chlorophenyljboronic acid [0.99 g, 6.36 mmol] and potassium carbonate (1.76 g, 12.73 mmol) at 25°C. Nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.31 mmol) under nitrogen atmosphère and the reaction mixture was heated at about 95 to about 100°C for 3 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25°C and filtered through celite and the celite cake was washed with ethyl acetate (50ml). The filtrate so obtained was concentrated under reduced pressure

124 to obtain a crude product, which was then purified by flash column chromatography using and 6% ethyl acetate in hexanes as an eluent to obtain the title compound (1.5 g, 68.18%).

MS: m/z 347 (M+l), !HNMR (CDCh, 400 MHz): δ 7.52 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.26 (s, IH), 4.38 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).

Step 2: Ethyl 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl) thiophene-2carboxylate. (33b)

H₂NO₂S

ci

To the solution of Ethyl 3-bromo-5-(4-chlorophenyl) thiophene-2carboxylate (compound 33a, 1.45 g, 4.19 mmol) in a mixture of toluene: éthanol (10:40 ml) was added (4-sulfamoylphenyl)boronic acid (0.84 g, 4.19 mmol) and potassium carbonate (1.16 g, 8.39 mmol) at 25°C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladïum(0) (0.24 g, 0.20 mmol) under nitrogen atmosphère and the reaction mixture was heated at about 95 to about 100°C for 16 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25°C and filtered through celite, the celite cake was washed with Ethanol (2x25 ml). «v—

125

The filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 50 % ethyl acetate in hexanes as an eluent to obtain the title compound (1.35 g, 76.27%).

MS: m/z 422 (M+1), ^lHNMR (DMSO, 400 MHz): δ 7.83-7.87 (m, 4H), 7.68-7.70 (m, 3H), 7.54 (d, J=8.4 Hz, 2H). 7.54 (bs-exchanges with D₂O, 2H), 4.19 (q, J=7.2Hz, 2H), 1.17 (t, J=7.2Hz, 3H).

Step 3: 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid. (33c)

Ethyl 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl) thiophene-2-carboxylate (compound 33b, 1.3 g, 3.08 mmol) was suspended in éthanol (30ml) and solution of NaOH (0.61 g, 15.4 mmol) in water (3 ml) was added to it at 25°C. The reaction mixture was then heated at about 75°C under stirring for 3 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so

126 obtained was diluted with water (5 ml) and cooled using ice bath. To the cooled mixture was then added aqueous 10 % HCl to bring pH to between 5 and 6. The mixture so obtained was extracted with ethyl acetate (3 x 25 ml). The combined organic layer was dried over anhydrous Na₂SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound (1.10 g, 90.9%).

MS: m/z 394M+1), 'HNMR (DMSO, 400 MHz): δ 12.85 (bs-exchanges with D₂O, 1H), 7.817.86 (m, 4H), 7.70-7.72 (m, 3H), 7.53 (d, J=8.4 Hz, 2H), 7.44 (bsexchanges with D₂O, 2H).

Step 4: 5-(4-chlorophenyl)-3-(4-(N( (dimethylamino) methylene) sulfamoyl) phenyl) - N -methoxy-Nmethylthiophene-2-carboxamide. (33d) /

—N

Oxalyl chloride (0.70 g, 0.48 ml, 5.58 mmol) was added drop wise at 0°C to a solution of 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)thiophene-2carboxylic acid (compound 33c, 1.10 g, 2.79 mmol) in a mixture of dichloromethane (30 ml) and DMF (0.40 g, 0.43 ml, 5.58 mmol). The mixture was then allowed to warm to room température and stirred for 1.5

127 hr under a nitrogen atmosphère. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was dissolved in dry dichloromethane (30 ml) and the mixture was then cooled to 0°C. To the 5 cooled mixture was added triethylamine (1.69 g, 2.32 ml, 16.75 mmol) followed by the addition of Λ) O-di methyl hydroxy lamine hydrochlorîde (0.54 g, 5.58 mmol) under stirring. The reaction mixture was then stirred at room température for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then diluted with DCM (25 ml) and 10 washed with water (2x 25ml) and organic layer so obtained was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by flash column chromatography using 0.8% methanol in DCM as an eluent to obtain the title compound (0.9 g, 65.69%).

MS: m/z 492 (M+1), !HNMR (CDCI3, 400 MHz): δ 8.14 (s, IH), 7.91 (d, J=8.4 Hz, 2H), 7.51-7.58 (m, 4H), 7.38 (d, J=8.4 Hz, 2H), 7.26 (s, IH), 3.65 (s, 3H), 3.22 (s, 3H), 3.13 (s, 3H), 3.02 (s, 3H).

128

Grignard reagent (ethyl magnésium bromide, 0.67 g, 5.0 ml IM solution in THF, 5.08 mmol) was added drop wise to a stirred solution of 5-(4chlorophenyl)-3-(4-(N-((dimethylamino)methylene) sulfamoyl)phenyl)-Nmethoxy-N-methylthiophene-2-carboxamide (compound 33d, 0.5 g, 1.01 mmol) in anhydrous THF (15 ml) at 25°C. The reaction mixture was then heated to about 70 to about 75°C for 2 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0°C, the reaction mixture was quenched by addition of a saturated solution of ammonium chloride (10 ml). The mixture so obtained was extracted with ethyl acetate (2x 30 ml), the combined organic layer was dried over anhydrous NaîSCU. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.06 g, 14.6%).

MS: m/z 406 (M+1), iHNMR (DMSO, 400 MHz): Ô 7.88 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H). 7.69-7.7 l(m, 3H) 7.55(d, J=8.4 Hz, 2H), 7.48 (bs-exchanges with D₂O, 2H), 2.58 (q, J=7.2 Hz, 2H), 0.95 (t, J=7.2 Hz, 3H).

Example 8: Préparation of 4-(5-(4-chlorophenyl)-4-(dimethylamino)-2propionyl thiophen-3-yl)benzenesulfonamide (Compound 34)

Step 1: Ethyl 3,5-dibromo-4-nitrothiophene-2-carboxylate. (34a)

129

Sulfuric acid (27.6 g, 15.0 ml, 281.0 mmol) was added in a dropwise manner to ethyl 3,5-dibromothiophene-2-carboxylate (Prepared according to procedure reported in JCS Perkin Trans-1:Organic and Bioorganic Chemistry (1972-1999), 1973, p 1766-1770), 5.0 g (15.92 mmol), at room température (about 25°C). The reaction mixture was then cooled to -5°C and to the cooled mixture was added nitric acid (2.0 g, 2.04 ml, 31.84 mmol) slowly, The reaction mixture was then stirred at 0°C for 1 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then poured onto ice-water (150 ml). The mixture so obtained was extracted with ethyl acetate (2 x 100 ml). The combined organic layer was dried over sodium sulphate and was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate in hexanes as an eluent to obtain the title compound (3.40 g, 59.54%).

MS: m/z 359 (M+l), 'HNMR (CDCh, 400 MHz): 6 4.40(q, 7=7.2 Hz, 2H), 1.40(t, 7=7.2 Hz, 3H).

Step 2: Ethyl 4-amino-3,5-dibromothiophene-2-carboxylate. (34b)

130

To the solution of Ethyl 3,5-dibromo-4-nitrothiophene-2-carboxylate (compound 34a, 10.0 g, 27.85 mmol) in acetic acid (100 ml) was added iron powder (7.77 g, 139.27 mmol). The reaction mixture was then heated at 60°C for 35 min under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25°C. Acetic acid from the reaction mixture was then evaporated under reduced pressure. The pH of the resulting reaction mass was brought to between 8 and 9 by adding to it saturated sodium bicarbonate solution. To the mixture so obtained was added ethyl acetate (150 ml), the resulting émulsion was filtered and then the organic layer was separated. The aqueous layer remaining behind was re-extracted with ethyl acetate (2x 100 ml). The combined organic layers were dried over sodium sulphate and the dried organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over siiica gel (100-200 mesh) using 2% ethyl acetate in hexanes as an eluent to obtain the title compound (6.00 g, 65.50%).

MS: m/z 330 (M+1), iHNMR (CDCh, 400 MHz): δ 4.34 (q, J=7.2 Hz, 2H), 4.03(bs-exchanges with D₂O, 2H), 1.36 (t, J=7.2 Hz, 3H).

Step 3: Ethyl 3,5-dibromo-4-(dimethylamino)thiophene-2-carboxylate (34c)

131

To a solution of Ethyl 4-amino-3,5-dibromothiophene-2-carboxylate (compound 34b, 5.0 g, 15.19 mmol) in DMF (25 ml) was added NaH (60% suspension in minerai oil) (1.82 g, 45.49 mmol) in portion wise manner at a température of about -5°C. The reaction mixture was then stirred at 5°C for 20 min. To the reaction mixture was then added iodomethane (6.47 g, 2.83 ml, 45.59 mmol) and stirring was continued for 40 min at 5°C. The progress of the reaction was monitored by TLC. The reaction mixture was then quenched by addition of cold water (50 ml), the mixture so obtained was then extracted with ethyl acetate (3x 100 ml). The combined organic layer was then dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 2.5% ethyl acetate in hexanes as an eluent to obtain the title compound (3.2 g, 58.97%).

MS: m/z 358 (M+1),

JHNMR (CDC1₃, 400 MHz): δ 4.33 (q, J=7.2 Hz, 2H), 2.89 (s, 6H), 1.35 (t, J=7.2 Hz, 3H).

Step 4: Ethyl 3-bromo-5-(4-chlorophenyl)-4-(dimethylamino)thiophene-2carboxylate. (34d)

132

To a solution of Ethyl 3,5-dibromo-4-(dimethylamino)thiophene-2carboxylate (compound 34c, 3.0 g, 8.40 mmol) in a mixture of tolueneæthanol (5ml:30ml) was added (4-chlorophenyl)boronic acid [1.44 g, 9.24 mmol] and potassium carbonate (2.32 g, 16.80 mmol) at 25°C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.42 mmol) under nitrogen atmosphère and the reaction mixture was heated at about 95 to 100°C for 3 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25°C and filtered through celite, the celite cake was then washed with ethyl acetate (50ml). The filtrate so obtained was then concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 12% ethyl acetate in hexanes as an eluent to obtain the title compound (2.5 g, 76.56%).

MS: m/z 389 (M+1), ’HNMR (CDC1₃, 400 MHz): δ 7.47 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.8 Hz, 2H) 4.38 (q, J=7.2 Hz, 2H), 2.78 (s, 6H), 1.40 (t, J=7.2 Hz, 3H).

Step 5: Ethyl 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4sulfamoylphenyl)thiophene-2-carboxylate. (34e)

133

To a solution of Ethyl 3-bromo-5-(4-chlorophenyl)-4(dimethylamino)thiophene-2-carboxylate (compound 34d, 2.20 g, 5.65 mmol) in a mixture of toluene:éthanol (10ml:30ml) was added (4sulfamoylphenyl)boronic acid (1.25 g, 6.22 mmol) and potassium carbonate (1.56 g, 11.30 mmol) at 25°C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.32 g, 0.28 mmol) under nitrogen and the reaction mixture was heated at about 95 to about 100°C for 16 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25°C and filtered through celite. The celite cake was then washed with éthanol (2x25 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 55% ethyl acetate in hexanes as an eluent to obtain the title compound (2.0 g, 76.05%).

MS: m/z 465 (M+1), iHNMR (DMSO, 400 MHz): Ô 7.85 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.52-7.55 (m, 4H). 7.44 (bs-exchanges with D₂O, 2H), 4.07(q, J=7.2 Hz, 2H) 2.33(s, 6H), 1.07 (t, J-7.24 Hz, 3H)

Step 6: 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4sulfamoylphenyl)thiophene-2-carboxylic acid. (34 f)

134

Ethyl 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4sulfamoylphenyl)thiophene-2-carboxylate (compound 34e, 2.00 g, 4.30 mmol) was suspended in éthanol (30ml) and solution of NaOH (0.86 g, 21.5 mmol) în water (4 ml) was added to it at 25°C. The reaction mixture was then heated at 75°C under stirring for 2 hr. The progress of the reaction was monïtored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was diluted with water (10 ml) and cooled using ice bath. To the cooled mixture was added aqueous 10 % HCl to brîng the pH od the solution to about 6. The mixture so obtained was extracted with ethyl acetate (3x 30 ml). The combined organic layer was then dried over anhydrous Na₂SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound (1.60 g, 85.1%)

MS: m/z 437 (M+1), iHNMR (DMSO, 400 MHz): δ 12.97(bs-exchanges with D₂O, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.58(d, J=8.4 Hz, 2H), 7.52-7.54 (m, 4H), 7.44 (bsexchanges with D₂O, 2H), 2.32 (s, 6H)

Step 7: 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4-(N( (dimethylamino) methylene) sulfamoyl) phenyl) - N-methoxy- N methylthiophene-2-carboxamide. (34g)

135 / —N

Oxalyl chloride (0.58 g, 0.39 ml, 4.57 mmol) was added drop wise to a solution of 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4sulfamoylphenyl)thiophene-2-carboxylic acid (compound 34f, 1.00 g, 2.28 mmol) in a mixture of dichloromethane (30 ml) and DMF (0.33 g, 0.35 ml, 4.57 mmol) at 0°C. The reaction mixture was then allowed to warm to room température and stirred for 1.5 hr under a nitrogen atmosphère. The progress of the reaction was monitored by TLC. The mixture was then concentrated under reduced pressure. The residue so obtained was dissolved in dry dichloromethane (30 ml) and cooled to 0°C. To the cooled reaction mixture was then added triethylamine (1.38 g, 1.90 ml, 13.68 mmol) followed by the addition of JV,O-dimethylhydroxylamine hydrochloride (0.40 g, 4.57 mmol) under stirring. The reaction mixture was then stirred at room température for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then diluted with DCM (25 ml) and washed with water (2x 25ml). The combined organic layer was then dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 1.6% methanol in DCM as an eluent to obtain the title compound (0.8 g, 65.35%).

MS: m/z 535 (M+1), ^!HNMR (DMSO 400 MHz): δ 8.27 (s, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.54(m,

4H) 7.44(d, J=8.4 Hz, 2H), 3.62 (s, 3H), 3.17 (s, 3H), 3.08 (s, 3H), 2.94 (s,

3H), 2.34 (s, 6H).

136

Step 8: 4-(5-(4-chlorophenyl)-4-(dimethylamino)-2-propionylthiophen-3-yl) benzene sulfonamide. (Compound 34)

Grignard reagent (ethyl magnésium bromide, 0.62 g, 4.66 ml IM solution in THF, 4.67 mmol) was added drop wise to a stirred solution of 5-(4chlorophenyl)-4-(dimethylamino)-3-(4-(N-((dimethylamino) methylene) sulfamoyl) phenyl) -N- methoxy -N- methylthiophene -2-carboxamide (compound 34g, 0.5 g, 0.93 mmol) in anhydrous THF (30 ml) at 25°C. The reaction mixture was then heated at about 70 to 75°C for 2 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0°C, the reaction mixture was quenched by addition of saturated solution of ammonium chloride (10 ml). The mixture so obtained was then extracted with ethyl acetate (2 x 30 ml). The combined organic layer was dried over anhydrous Na₂SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100200 mesh) using 40 % ethyl acetate in hexanes as an eluent to obtain the title compound (0.27 g, 64.43 %). The title compound was then purified by préparative HPLC (0.135 g, 32.2%). —

MS: m/z 449 (M+l), ‘HNMR (DMSO, 400 MHz): ô 7.90 (d, J=8.4 Hz, 2H), 7.60-7.62 (m, 4H).

7.54 (d, J=8.4 Hz, 2H), 7.48 (bs-exchanges with D₂O, 2H), 2.32-2.36 (s,

8H), 0.86 (t, J=7.2 Hz, 3H).

Example 9: 5-(4-Chlorophenyl)-IV,JV,4-trimethyl-3-(4sulphamoylphenyl) thiophene-2-carboxamide. (Compound 36)

137

Dimethyl amine (0.055 g, 0.61 ml 2M solution in THF, 1.22 mmol) was added drop wise to a solution of 5-(4-chlorophenyl)-4-methyl-3-(4sulfamoylphenyl)thiophene-2-carboxylic acid (compound le, 0.25 g, 0.61 mmol) in dry THF (15 ml) under a nitrogen atmosphère at 0°C. To the reaction mixture HATU (0.26 g, 0.67 mmol) and DIPEA (0.16 g, 0.21 ml, 1.24 mmol) were added at 0°C with stirring. The mixture was then allowed to warm to 10°C and stirred for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The concentrated mass so obtained was diluted with ethyl acetate (30 ml) and washed with saturated sodium bicarbonate solution (2 x 15 ml) and brine (1 x 15ml). The organic layer obtained was then dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 25 % ethyl acetate in hexanes as an eluent to obtain the title compound (0.06 g, 22.50 %).

MS: m/z435 (M+l),

138 ¹HNMR (DMSO, 400 MHz): Ô 7.89 (d, J=8.4 Hz, 2H), 7.57 (s, 4H), 7.49 (d,

J=8.4 Hz, 2H), 7.46 (bs-exchanges with D₂O, 2H), 3.61 (m, 3H), 3.13 (m,

3H), 2.11 (s, 3H).

5-(4-Chlorophenyl)-7V-methoxy-iV,4-dimethyl-3-(4sulphamoylphenyl)thiophene-2-carboxamide (Compound 37) MS: m/z 451 (M+1),

WR (DMSO, 400 MHz): δ 7.85 (d, J=8.4 Hz, 2H), 7.58 (s, 4H), 7.44 (d, J=8.4 Hz, 2H), 7.43 (bs-exchanges with D₂O, 2H), 3.64 (s, 3H), 3.09 (s, 3H), 2.01 (s, 3H).

5-(4-Chlorophenyl)-lV-(2-hydroxyethj/Z/-4-methyl-N-propyl-3-(4sulphamoylphenyl) thiophene-2-carboxamide(Compound 38) MS: m/z 493 (M+1), !HNMR (DMSO, 400 MHz): δ 7.87 (d, J=8.4 Hz, 2H), 7.55-7.57 (m, 4H), 7.52 (d, J=8.4 Hz, 2H), 7.45 (bs-exchanges with D₂O, 2H), 4.71 (bsexchanges with D₂O, IH), 3.25-3.30 (m, 4H), 3.16-3.21 (m, 2H), 2.11 (s, 3H), 1.27-1.29 (m, 2H), 1.02 (d, J= 6.0 Hz, 3H).

4-(5-(4-Chlorophenyl)-4-methyl-2-(piperidine-l-carbonyl)thiophen-3-yl) benzene sulfonamide (Compound 39)

MS: m/z 475 (M+1), ¹HNMR (DMSO, 400 MHz): δ 7.89 (d, J=8.4 Hz, 2H), 7.56-7.60 (m, 4H),

7.54 (d, J=8.4 Hz, 2H), 7.46 (bs-exchanges with D₂O, 2H), 3.59-3.64 (m,

2H), 3.12-3.16 (m, 2H), 2.12 (s, 3H), 1.22-1.27 (m, 6H).

Example 10: Préparation of 4-(5-(4-chlorophenyl)-l,4-dimethyl-2propionyl-lff-pyrrol-3-yl)benzenesulfonamide (Compound 49)

139

Step 1 : Methyl-5-(4-chlorophenyl)-1,4-dimethyl-1 H-pyrrole-2-carboxylate.

(49a)

To a stirred solution of sodium hydrîde (60% suspension in minerai oil) (0.529g, 13.22 mmol) in DMF (5 ml) at 0°C was added a solution of methyl-5-(4-chlorophenyl)-4-methyl-lH-pyrrole-2-carboxylate (prepared according to the procedure reported in J. org. Chem., 2009, 74(2), 90315 905, Org. Lett. 2007, 9(25), 5191-5194, 2.20g, 8.81 mmol) in DMF (10 ml), which was then followed by the addition of methyl iodide (1.88 g, 0.83 ml, 13.22 mmol). The resulting reaction mixture was stirred at room température for 45 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was then quenched with water (10 ml). The vu—.

140 mixture so obtained was then extracted with ethyl acetate (2 x 50 ml). The combined organic Iayer was dried over anhydrous Na₂SO4. The solvent was evaporated from the dried organic Iayer under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 15-20 % ethyl acetate in hexanes as an eluent to obtain the title compound (1.9 g, 81.9 %)

MS: m/z 264 (M+l) ^rHNMR (DMSO, 400 MHz): δ 7.55 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 6.48 (s, IH), 3.74 (s, 3H), 3.67 (s, 3H), 1.94 (s, 3H).

Step 2: Methyl-3-bromo-5-(4-chlorophenyl)-1,4-dimethyl- lH-pyrrole-2carboxylate. (49 β)

Bromine (1.69 g, 0.54 ml, 10.54 mmol) was added dropwise to a stirred solution of methyl-5-(4-chlorophenyl)-1,4-dimethyl-1 H-pyrrole-2carboxylate (compound 49a, 1.85 g, 7.03 mmol) in acetic acid (20 ml) at 10°C. The resulting reaction mixture was stirred at room température for 15 hr. The progress of the reaction was monitored by TLC. Acetic acid was removed from the reaction mixture under reduced pressure and residue ογ''

141 obtained was dissolved in ethyl acetate (150 ml). The mixture so obtained was washed with saturated sodium bicarbonate solution (50 ml) followed by washing with brine (50 ml). The combined organic layer was dried over anhydrous Na₂SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was washed with a mixture of ethyl acetate in hexanes (10:90) to obtain the title compound (2.1 g, 87.5%) !HNMR (CDCla, 400 MHz): δ 7.43 (d, J =8.4 Hz, 2H), 7.20 (d, J =8.4 Hz, 2H), 3.88 (s, 3H), 3.67 (s, 3H), 1.94 (s, 3H).

Step 3: Methyl-5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)lH-pyrrole-2-carboxylate. (49y)

To the solution of methyl-3-bromo-5-(4-chlorophenyl)-l,4-dimethyl-lHpyrrole-2-carboxylate (compound 49β, 2.0 g, 5.84 mmol) in a mixture of toluene: éthanol (15:40 ml) was added 4-aminosulfonylbenzene boronic acid (1.41 g, 7.01 mmol) and potassium carbonate (2.42 g, 17.52 mmol) at 25°C in a sealed tube and a nitrogen gass was bubbled through the resulting mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.349 g, 0.29 mmol) under

142 nitrogen and reaction mixture was heated at about 95 to about 100°C for 15 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25°C and filtered through celite. The celite cake was washed with éthanol (100 ml) and ethyl acetate (50 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 40 % ethyl acetate in hexanes as an eluent to obtain the title compound (1.7 g, 69.6 %).

MS: m/z 419 (M+1),

HNMR (CDCh, 400 MHz): Ô 7.92 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.8 Hz, 2H), 4.86 (bs, exchange with

D₂O,2H), 3.74 (s, 3H), 3.58 (s, 3H), 1.79 (s, 3H).

Step 4: 5-(4-chlorophenyl)-l,4-dimethyl-3-(4-sulfamoylphenyl)-lHpyrrole-2-carboxylic acid. (49ε)

Methyl 5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)-1 H-pyrrole2-carboxylate (compound 49y, 1.6 g, 3.82 mmol) was suspended in éthanol (100 ml) and treated with solution of NaOH (0.76 g 19.13 mmol) in water (20 ml) at 0°C. The reaction mixture was then heated at 80°C under

143 stirring for 15 h. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The reaction mixture was then treated with dilute HCl to bring pH of the mixture to between 6 and 7. The obtained mixture was then extracted with ethyl acetate (2 x 100 ml). The combined organic layer was then dried over anhydrous Na₂SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound (1.3 g, 84.4 %).

MS: m/z 405 (M+1), ’HNMR (DMSO, 400 MHz): δ 11.89 (bs, exchanges with D₂O, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.31 (bs, exchanges with D₂O, 2H), 3.67(s, 3H), 1.77 (s, 3H).

Step 5: 5-(4-chlorophenyl)-ïV-methoxy-lV, l,4-trimethyl-3-(4sulfamoylphenyl)-1 H-pyrrole-2-carboxamide. (49φ)

To a stirred solution of 5-(4-chlorophenyl)-l,4-dimethyl-3-(4sulfamoylphenyl)-lH-pyrrole-2-carboxylic acid (compound 49ε, 0.800 g, 1.98 mmol) in DMF (15 ml,) was added HOBT (0.333 g, 2.17 mmol) at room température followed by the addition of lV,O-dimethylhydroxylamine

144 hydrochlorîde (0.386g, 3.96 mmol). The reaction mixture was then cooled to 0°C, and to the cooled reaction mixture was added EDC (0.570g, 2.97 mmol) and triethylamine (0.80g, 1.10 ml, 7.92 mmol). The reaction mixture was then stirred at room température for 15 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was taken in ethyl acetate (100 ml) and washed with saturated sodium bicarbonate solution (20 ml) followed by washing with brine (20 ml). The organic layer obtained was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (0.680 g, 76.8 %).

MS: m/z 448 (M+1), !HNMR (DMSO, 400 MHz): S 7.83 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.8 Hz, 2H), 7.35 (bs, exchanges with D₂O, 2H), 3.43(s, 6H), 2.99(s, 3H), 1.96 (s, 3H).

Step 6: 5-(4-chlorophenyl)-3-(4-(N-((dîmethylamino)methylene)sulfamoyl) phenyl)-ÏV-methoxy-N, 1,4-trimethyl-1 H-pyrrole-2-carboxamide. (49ω)

145

To a stirred solution of 5-(4-chlorophenyl)-7V-methoxy-7V,l,4-trimethyl-3(4-sulfamoylphenyl)-lH-pyrrole-2-carboxamide (compound 49φ, 0.650 g, 1.45 mmol) in ethyl acetate (12 ml,) was added DMF (0.65 ml) and DMF 5 acetal (0.207 g, 0.233 ml, 1.74 mmol) sequentially at room température.

The reaction mixture was then stirred at room température for 15 hr under a nitrogen atmosphère. The progress of the reaction was monitored by TLC. The precipitated out product was filtered and washed with ether (10 ml) to obtain the title compound (0.600 g, 82.19 %).

MS: m/z 503 (M+1), iHNMR (DMSO, 400 MHz): δ 8.24 (s, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 3.43(s, 6H), 3.15 (s, 3H), 3.00 (s, 3H), 2.92 (s, 3H), 1.95 (s, 3H).

Step 7: 4-(5-(4-chlorophenyl)-l,4-dimethyl-2-propionyl-lH-pyrrol-3-yl) benzene sulfonamide (Compound 49)

146

Grignard reagent (ethyl magnésium bromide, 0.531 g, 3.98 ml, IM soin. In THF, 3.98 mmol) was added dropwise under a nitrogen atmosphère to a stirred solution of 5-(4-chlorophenyl)-3-(4-(N-((dimethylamino)methylene) sulfamoyl) phenyl)-IV-methoxy-N, 1,4-trimethyl-1 H-pyrroIe-2-carboxamide (compound 49ω, 0.400 g, 0.79 mmol) in anhydrous THF (15 ml) at 25°C, and the reaction mixture was then heated to about 70 to about 75°C for 1 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0°C, the cooled reaction mixture was quenched by addition of saturated solution of ammonium chloride (10 ml). The mixture so formed was extracted with ethyl acetate (2 x 50 ml). The combined organic layer was dried over anhydrous Na2SC>4. The solvent from the dried organic soultuon was evaporated under reduced pressure to obtain a crude product, which was then purified by préparative HPLC to obtain the title compound (0.070 g, 21.08 %)

MS: m/z417(M+l),

1HNMR (CDCla, 400 MHz): Ô 8.01 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 4.93 (bs, exchanges with D₂O, 2H), 3.69 (s, 3H), 2.16 (q, J=7.2 Hz, 2H), 1.76 (s, 3H), 0.93 (t, J=7.2 Hz, 3H).

Example 11: Préparation of 4-(5-(4-chlorophenyl)-l,4-dimethyl-2propionyl-lH-pyrrol-3-yl)benzenesulfonamide (Compound 49) (Alternative method)

147

Step 1: 1 -(5-(4-chlorophenyl)-1,4-dimethyl-1 H-pyrrol-2-yl) propan-1 -one (49a)

Ν,Ν-dimethyl propionamide (3.24 g, 3.52 ml, 32.08 mmol) was cooled at 05°C and and to this was added POCh (4.9 g, 2.9ml, 32.08 mmol) slowly in a dropwise manner. The resulting mixture was then stirred at room température (about 25°C) for 20 minutes. The reaction mixture was then diluted with 1,2-dichloroethane (60 ml) and cooled to 0°C. To the cooled reaction mixture was then added a solution of 2-(4-chlorophenyl)-l,3dimethyl-lH-pyrrole (prepared according to the procedure given in

Tetrahedron Letters 46 (2005) 4539-4542, 6.0 g, 29.17 mmol) in 1,2dichloroethane (60 ml) dropwise. The reaction mixture was then heated to <v^~~

148 reflux for 30 minutes. The progress of the reaction was monitored by TLC. The mixture so obtained was allowed to cool to room température and was diluted with aqueous solution of sodium acetate trihydrate (21.8 g, 160.4 mmol in 45 ml water). The mixture so obtained was further heated to reflux for 30 minutes, two layers were separated. The aqueous layer was extracted with dichloromethane (3*100 ml). The combined organic layer was washed with water (1*100 ml) and dried over anhydrous Na2SO4. The solvent from the reaction mixture was evaporated under reduced pressure to obtain a crude product. This crude product was purified by column chromatography over silica gel (100-200 mesh) using 4-6% ethyl acetate in hexanes as an eluent to obtain the title compound (6.55 g, 85.8%)

MS: m/z 262 (M+l), ’HNMR (CDCla, 400 MHz): δ 7.45 (d, >8.8 Hz, 2H), 7.24 (d, >8.8 Hz, 2H), 6.89 (s, IH), 3.76 (s, 3H), 2.83(q, >7.6 Hz, 2H), 2.02 (s, 3H),1.21 (t, >7.6 Hz, 3H).

The compounds given below were prepared by procedure similar to the one described above for compound ‘49a’ with appropriate variations of reactants, reaction conditions and quantities of reagents.

54a. 1 -(5-(4-Fluorophenyl)-1,4-dimethyl-1 H-pyrrol-2-yl)propan-1 -one

MS: m/z 246(M+1),

55a. 1 -(5-(4-Methoxyphenyl) -1,4-dimethyl-1 H-pvrrol-2-yl)propan- 1-one

MS: m/z 258 (M+l), n/v—

149

56a. 1 -(5-(4-chlorophenyl)-1,4-dimethyl-1 H-pyrrol-2-yl)butan-1 -one

MS: m/z 276 (M+l),

57a. 1-(5-(2,4-dichlorophenyl)- 1,4-dimethyl- lH-pyrrol-2-yl)propan-1-one

MS: m/z 297 (M+l),

58a. 1-(5-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)- 1,4-dimethyl- lH-pyrrol-2yl)propan-l- one. MS: m/z 286 (M+l),

Step 2: l-(3-Bromo-5-(4-chlorophenyl)-l,4-dimethyl-lH-pyrrol-2yl)propan-l-one. (49b)

CH

O.

Cl

A solution of N-bromosuccinimide (4.42 g, 24.83 mmol) in THF (62.5 ml) was added dropwise to a stirred solution of l-(5-(4-chlorophenyl)-1,4dimethyl-lH-pyrrol-2-yl)propan-l-one (compound 49a, 6.5 g, 24.83 mmol) in THF (100 ml) at -78°C.. The resulting reaction mixture was then stirred at a température of -78°C for 5 hr. The reaction mixture was allowed to warm to 25°C slowly during further 3 to 4 hr. The progress of the reaction was monitored by TLC. The solventfrom the reaction mixture was evaporated under reduced pressure and residue so obtained was mixed in M’

150 ethyl acetate (200 ml). The resulting mixture was washed with saturated sodium bicarbonate solution (l><100 ml) which was followed by washing with water (1x100 ml). The combined organic layer was dried over anhydrous Na₂SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 10% ethyl acetate in hexanes to obtain the title compound (7.58 g, 90%).

MS: m/z 342 (M+1), iHNMR (CDCh, 400 MHz): δ 7.45 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 3.67 (s, 3H), 3.12(q, J=7.2 Hz, 2H), 1.96 (s, 3H),1.21 (t, J=7.2 Hz, 3H).

The compounds given below were prepared by procedure similar to the one described above for compound ‘49b’ with appropriate variations of reactants, reaction conditions and quantifies of reagents.

54b. 1 -(3-Bromo-5-(4-Fluorophenyl)-1,4-dimethyl-1 H-pyrrol-2-yl)propan1-one

MS: m/z 325 (M+1).

55b. 1 -(3-Bromo-5-(4-Methoxyphenyl)-1,4-dimethyl-1 H-pyrrol-2yl)propan-l-one

MS: m/z 336 (M+1),

56b. 1 -(3-Bromo-5-(4-chlorophenyl)-1,4-dimethyl- l/i-pyrrol-2-yl)butan-1 151 one

MS: m/z 356 (M+1),

57b. l-(3-Bromo-5-(2,4-dichlorophenyl)-l,4-dimethyl-lH-pyrrol-2yl)propan-l-one

MS: m/z 376 (M+1),

58b. l-(3-Bromo-5-(2,3-dihydrobenzo[b] [ 1,4]dioxin-6-yl)-1,4-dimethyl-1Hpyrrol-2-yl) propan-1-one

MS: m/z 365 (M+1),

Step 3: 4-(5-(4-chlorophenyl)-1,4-dîmethyl-2-propionyl-1 H-pyrrol-3-yl) benzene sulfonamide. (Compound 49)

To a solution of l-(3-bromo-5-(4-chlorophenyl)-l,4-dimethyl-lH-pyrrol-2yl)propan-l-one (compound 49b, 3.0 g, 8.81 mmol) in a mixture of toluene:éthanol (15 ml:45 ml) were added 4-aminosulfonylbenzene boronic acid (1.947 g, 9.69 mmol) and potassium carbonate (2.43 g, 17.61 mmol) at 25°C in a sealed tube and a nitrogen gas was bubbled through it w/—

152 for 15 minutes. To the reaction mixture was the added tetrakis(triphenylphosphine)palladium(0) (0.51 g, 0.44 mmol) under nitrogen atmosphère and reaction mixture was heated at about 90 to about 95°C for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25°C and filtered through celite. The celite cake was washed with 10% methanol in dichloromethane. The combined filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (1.22 g, 33.2%).

MS: m/z 417 (M+1), 'HNMR (CDCh, 400 MHz): δ 8.02 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.30 (d, <7=8.4 Hz, 2H), 5.11 (bs, exchanges with D₂O, 2H), 3.71 (s, 3H), 2.17 (q, 7=7.2 Hz, 2H), 1.75 (s, 3H), 0.94(t, J=7.2 Hz, 3H).

4-(5-(4-Fluorophenyl)-1,4-dimethyl-2-propionyl-1 H-pyrrol-3-yl) benzene sulfonamide (Compound 54)

MS: m/z401(M+l), 'HNMR (CDCh, 400 MHz): ô 8.01 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.31-7.35 (m, 2H), 7.21 (t, J=8.4 Hz, 2H), 4.98 (bs-exchanges with D₂O, 2H), 3.70 (s, 3H), 2.18 (q, J=7.2 Hz, 2H), 1.74 (s, 3H), 0.94 (t, J=7.2 Hz, 3H).

153

4-(5-(4-Methoxyphenyl)-1,4-dimethyl-2-propionyl-1 H-pyrrol-3-yl) benzene sulfonamide (Compound 55)

MS: m/z413(M+l), *HNMR (CDC1₃, 400 MHz): Ô 8.01 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.03 (d, J=8.4 Hz, 2H), 4.89 (bs-exchanges with D₂O, 2H), 3.88 (s, 3H), 3.71 (s, 3H), 2.18 (q, J=7.2 Hz, 2H), 1.76 (s, 3H), 0.92 (t, J=7.2 Hz, 3H).

4-(2-butyryl-5-(4-chlorophenyl)-1,4-dimethyl-1 H-pyrrol-3-yl) benzene sulfonamide (Compound 56)

MS: m/z431(M+l),

1HNMR (CDCI3, 400 MHz): δ 8.01 (d, J=8.4 Hz, 2H), 7.46-7.49 (m, 4H), 7.31 (d, J=8.4 Hz, 2H), 4.96 (bs-exchanges with D₂O, 2H), 3.71 (s, 3H), 2.13 (t, J=7.2 Hz, 2H), 1.76 (s, 3H), 1.45-1.52 (m, 2H), 0.71 (t, J=7.2 Hz, 3H).

4-(5-(2,4-Dichlorophenyl)-l,4-dimethyl-2-propionyl-lH-pyrrol-3-yl) benzene sulfonamide (Compound 57)

MS: m/z452(M+l), iHNMR (CDCh, 400 MHz): δ 8.01 (d, J=8.4 Hz, 2H), 7.58 (d, J=2.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.39 (dd, J=8.4, 2.0 Hz, 1H), 7.26-7.28 (m, 1H), 4.93 (bs-exchanges with D₂O, 2H), 3.64 (s, 3H), 2.19 (q, J=7.2 Hz, 2H), 1.66 (s, 3H), 0.95 (t, J=7.2 Hz, 3H).

4-(5-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)-1,4-dimethyl-2-propionyl- 1Hpyrrol-3-yl) benzene sulfonamide (Compound 58)

MS: m/z 441 (M+1), !HNMR (DMSO, 400 MHz): Ô 7.89 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz,

2H), 7.44 (bs-exchanges with D₂O, 2H), 6.99 (d, J=8.4 Hz, IH), 6.86-6.91 (m, 2H), 4.30 (s, 4H), 3.61 (s, 3H), 2.12 (q, J=7.2 Hz, 2H), 1.71 (s, 3H),

0.83 (t, J=7.2 Hz, 3H).

Exemple 12: Préparation of 4-(5-(4-chlorophenyl)-4-methyl-2propionyl-lH-pyrrol-3-yl)benzenesulfonamide (Compound 53)

154

Step 1 : l-(5-(4-chlorophenyl)-4-methyl-lH-pyrrol-2-yl)propan-l-one.

(53a)

phosphorus oxychloride (1.496 g, 0.896 ml, 9.76 mmol) was added dropwise to previously cooled (0 to 5°C) Ν,Ν-dimethyl propionamide (0.987 g, 1.073 ml, 9.76 mmol) maintaining the température between about 0°C to about 5°C. The resulting reaction mixture was then allowed to warm to w''

155 room température (about 25°C), which was then stirred at room température (about 25°C) for 15 minutes. The reaction mixture was then diluted with 1,2-dichloroethane (17 ml), the resulting mixture was cooled to 0°C, to it was then added 2-(4-chlorophenyl)-3-methyl-lH-pyrrole (prepared according to the procedure given in Tetrahedron Letters 46 (2005) 4539-4542, 1.7 g, 8.87 mmol) in 1,2-dichloroethane (17 ml) dropwise. The reaction mixture so formed was heated to reflux for 30 minutes. The progress of the reaction was monïtored by TLC. The reaction mixture was then allowed to cool to room température, and to it was then added a solution of sodium acetate trihydrate (6.64 g, 48.8 mmol) in 14 ml water. The reaction mixture so obtained was heated to reflux for 30 minutes. Two phases formed in the reaction mixture were then separated. The aqueous layer was extracted with dichloromethane (3*50 ml). The combined organic layer was washed with saturated sodium bicarbonate solution (1x50 ml) followed by washing with water (1x50 ml), and then the organic layer was dried over anhydrous Na₂SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product. The crude product was then purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (1.82 g, 83%)

MS: m/z 247 (M+1), !HNMR (CDC1₃, 400 MHz): δ 9.75 (bs, exchanges with D₂O, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 6.81(d, J=2.4 Hz, 1H), 2.79 (q, J=7.2 Hz, 2H), 2.26 (s, 3H),1.21 (t, J=7.2 Hz, 3H).

Step 2: l-(3-Bromo-5-(4-chlorophenyl)-4-methyl-lH-pyrrol-2-yl)propan-lone. (53b)

156

A solution of N-bromosuccinimide (1.25 g, 7.06 mmol) in THF (20 ml) was added dropwise to a stirred solution of l-(5-(4-chlorophenyl)-4-methyl-lHpyrrol-2-yl)propan-l-one (compound 53a, 1.75 g, 7.06 mmol) in THF (40 ml) at about -78°C. The resulting reaction mixture was stirred at about 78°C for 5 hr. The reaction mixture was then allowed to warm to 25°C slowly during further 3 to 4 hr. The progress of the reaction was monitored by TLC. The solvent was evaporated from the reaction mixture under reduced pressure and to the residue so obtained was added ethyl acetate (200 ml). The mixture so obtained was washed with saturated sodium bicarbonate solution (1x50 ml) followed by washing with water (1x50 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 10 % ethyl acetate in hexanes to obtain the title compound (1.77 g, 77%)

MS: m/z 327 (M+1), !HNMR (CDCh, 400 MHz): Ô 9.67 (bs, exchangeable with D2O, 1H) 7.43 (m,4H), 3.05 (q, J=7.2 Hz, 2H), 2.21 (s, 3H),1.20 (t, J=7.2 Hz, 3H).

Step 3: 4-(5-(4-chlorophenyl)-4-methyl-2-propionyl- l/7-pyrrol-3-yl) benzene sulfonamide. (Compound 53) m/^-

157

To the solution of l-(3-bromo-5-(4-chlorophenyl)-4-methyl-lH-pyrrol-2yl)propan-l-one (compound 53b, 1.0 g, 3.06 mmol) in a mixture of toluene: éthanol (5:15 ml) was added 4-aminosulfonylbenzene boronic acid (0.67 g, 3.37 mmol) and potassium carbonate (1,26 g, 9.19 mmol) at a température of about 25°C in a sealed tube and a nitrogen gas was bubbled through the resulting reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.153 mmol) under nitrogen atmosphère and the reaction mixture was heated at about 90°C to 95°C for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25°C and filtered through celite. The celite cake was washed with 10% methanol in dichloromethane (3x25ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.082 g, 6.65%).

MS: m/z403 (M+l), iHNMR (DMSO, 400 MHz): δ 11.83 (bs, exchanges with D₂O, IH) 7.87 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.42 (bs, exchanges with D₂O, 2H), 2.40 (q, J=7.2 Hz, 2H), 1.91 (s, 3H), 0.91(t, J=7.2 Hz, 3H).

Example 13: 4-(5-(4-chlorophenyl)-l-ethyl-4-methyl-2-propionyl-lHpyrrol-3-yl)benzenesulfonamide (Compound 51)

158

Step 1: 2-(4-chlorophenyl)-l-ethyl-3-methyl-lH-pyrrole. (Sla)

A solution of 2-(4-chlorophenyl)-3-methyl-lH-pyrrole (prepared according to the procedure given in Tetrahedron Letters 46 (2005) 4539-4542, 1.0 g, 5.22 mmol) in DMF (10 ml) was added dropwise to a stirred suspension of Sodium hydride (0.23 g, 5.74 mmol, 60% dispersion in minerai oil) in 20 ml DMF at 0°C under a nitrogen atmosphère. The reaction mixture was then stirred at about 0°C for 30 min. Ethyl iodide (0.89 g, 0.47 ml, 5.74 mmol) was then added to the reaction mixture maintaining the température at 0°C. The reaction mixture was then stirred at 25°C for 3 hrs. The progress of the reaction was monitored by TLC. The reaction mixture was slowly quenched with cold water (30 ml) and the resulting mixture was then extracted with ethyl acetate (2x 30 ml). The combined organic layer was then washed with brine (lx 30 ml) and dried over sodium sulfate. The dried organic layer was then concentrated under reduced pressure to obtain crude product as semi-solid mass (0. 8 g), which was then purified by flash column chromatography using 5% ethyl

159 acetate in hexanes as an eluent to obtain the title compound (0.6 g,

52.3%).

MS: m/z 220 (M+1), iHNMR (CDCh, 400 MHz): ô 7.42 (d, J= 8.4 Hz, 2H), 7.24 (d, J= 8.4 Hz, 2H), 6.71 (d, J= 2.8 Hz, IH), 6.10 (d, J= 2.8 Hz, IH), 3.83 (q, J= 7.2 Hz, 2H), 2.05 (s, 3H), 1.24 (t, J= 7.2 Hz, 3H).

Step 2: l-(5-(4-chlorophenyl)-1 -ethyl-4-methyl-1 H-pyrrol-2-yl)propan-1one. (51b)

CH

Cl

Phosphorus oxychloride (0.47 g, 0.28 ml, 3.00 mmol) was added dropwise to previously cooled (0 to 5°C) Ν,Ν-dimethyl propionamide (0.30 g, 0.27 ml, 3.00 mmol) maintaining the température between about 0°C to about 5°C. The resulting reaction mixture was then allowed to warm to room température (about 25°C), which was then stirred at room température (about 25°C) for 20 minutes. The reaction mixture was then diluted with 1,2-dichloroethane (15 ml), the resulting mixture was cooled to 0°C, to it was then added 2-(4-chlorophenyl)-l-ethyl-3-methyl-lH-pyrrole (compound 51a, 0.6 g, 2.73 mmol) in 1,2-dichloroethane (15 ml) dropwise. The reaction mixture so formed was heated to reflux for 30 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was then allowed to cool to room température, and to it was then added a solution of sodium acetate trihydrate (1.23 g, 15.0 mmol) in 14 ml water. The reaction mixture so obtained was heated to reflux for 30 minutes. Two vZ

160 phases formed in the reaction mixture were then separated. The aqueous layer was extracted with dichloromethane (3x30 ml). The combined organic layer was washed with water (1*30 ml) and dried over anhydrous Na2SC>4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 10 % ethyl acetate in hexanes as an eluent to obtain the title compound (0.5 g, 66.4%).

MS: m/z276 (M+1), iHNMR (CDC1₃, 400 MHz): δ 7.46 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 6.90 (s, IH), 4.23 (q, J=7.2 Hz, 2H), 2.85 (q, J=7.2 Hz, 2H), 1.95 (s, 3H), 1.22 (t, J=7.2 Hz, 3H), 1.16 (t, J=7.2 Hz, 3H).

Step 3: 1 -(3-bromo-5-(4-chlorophenyl)-1 -ethyl-4-methyl-1 H-pyrrol-2yl)propan-1-one. (51c).

CH

O.

Cl

A solution of N-bromosuccinimide (0.35 g, 1.99 mmol) in THF (10 ml) was added dropwise to a stirred solution of l-(5-(4-chlorophenyl)-l-ethyl-4methyl-lH-pyrrol-2-yl)propan-l-one (compound 51b, 0.5 g, 1.81 mmol) in THF (25 ml) at about -78°C. . The resulting reaction mixture was stirred at about -78°C for 5 hr. The reaction mixture was then allowed to warm to 25°C slowly during further 3 to 4 hr. The progress of the reaction was monitored by TLC. The solvent was evaporated from the reaction mixture under reduced pressure and to the residue so obtained was added ethyl acetate (50 ml). The mixture so obtained was washed with saturated (/y

161 sodium bicarbonate solution (l><30 ml) followed by washing with water (1x30 ml). The combined organic layer was then dried over anhydrous Na₂SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.5 g, 78.0%).

^JHNMR (CDCla, 400 MHz): δ 7.45 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 4.20 (q, J=6.8 Hz, 2H), 3.14 (q, J=7.2 Hz, 2H), 1.91 (s, 3H), 1.22 (t, J=7.2 Hz, 3H), 1.12 (t, J=6.8 Hz, 3H).

Step 4: 4-(5-(4-chlorophenyl)-1 -ethyl-4-methyl-2-propionyl-1 H-pyrrol-3yljbenzene sulfonamide. (Compound 51)

H₂NO₂S

To the solution of l-(3-bromo-5-(4-chlorophenyl)-l-ethyl-4-methyl-lHpyrrol-2-yl)propan-l-one (compound 51c, 0.5 g, 1.41 mmol) in a mixture of toluene: éthanol (3:12 ml) was added 4-aminosulfonylbenzene boronic acid (0.34 g, 1.69 mmol) and potassium carbonate (0.48 g, 3.52 mmol) at a température of about 25°C in a sealed tube and a nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) under nitrogen atmosphère and the reaction mixture was heated at about 90°C to 95°C for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25°C and filtered through celite. The celite cake was washed with 10% —

162 methanol in dichloromethane (2x 20 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silicagel (100-200 mesh) using 30-35% ethyl acetate in hexanes as an eluent to obtain the title compound (0.2 g, 32.9%).

MS: m/z431 (M+l), !HNMR (CDCI3, 400 MHz): δ 8.02 (d, >8.4 Hz, 2H), 7.47-7.49 (m, 4H),

7.29 (d, >8.4 Hz, 2H), 4.94 (bs-exchanges with D2O, 2H), 4.21 (q, >6.8 Hz, 2H), 2.18 (q, >7.2 Hz, 2H), 1.69 (s, 3H), 1.16 (t, >6.8 Hz, 3H), 0.95 (t, >7.2 Hz, 3H).

Analogously, by practicing the above procedure with appropriate change in the reactants, following compound was prepared

4-(5-(4-Chlorophenyl)-1 -(cyclopropylmethyl)-4-methyl-2-propionyl-1Hpyrrol-3-yl) benzene sulfonamide (Compound 52)

MS: m/z457(M+1),

1HNMR (CDCI3, 400 MHz): δ 8.01 (d, >8.4 Hz, 2H), 7.46-7.50 (m, 4H),

7.30 (d, >8.4 Hz, 2H), 4.97 (bs-exchanges with D2O, 2H), 4.14 (q, >6.8 Hz, 2H), 2.20 (q, >7.2 Hz, 2H), 1.72 (s, 3H), 0.96 (t, >7.2 Hz, 3H), 0.860.87 (m, IH), 0.31-0.34 (m, 2H), -0.08- -0.04 (m, 2H).

Example 14: Préparation of 4-(5-(4-chlorophenyl)-4-methyl-2propionylthiophen-3-yl)-2-methylbenzenesulfonamide. (compound 41) Vu·'

163

HjNOjS

Step 1: Methyl 3-(4-(N-(tert-butyl)sulfamoyl)-3-methylphenyl)-4methylthiophene-2-carboxylate (41 a)

4-bromo-N-(tert-butyl)-2-methylbenzenesulfonamide (Prepared according to the procedure reported in the literature, Tetrahedron, 2006, 62, 79027910, 1.43 g, 4.68 mmol) and Potassium phosphate (2.25 g, 10.63 mmol) were added to a stirred suspension of methyl 4-methyl-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (Prepared according to the procedure reported in the literature, J. Org. Chem., 2010, 75, 3855-3858, 1.2 g, 4.25 mmol) in a mixture of 20 ml of THF and 4 ml of water in a tube under a nitrogen atmosphère at room température (25°C). Nitrogen was purging was continued to this suspension for 15 minute at room température (25°C). Triphenyl phospine (0.056 g, 0.21 mmol) and palladium (II) acetate (0.02 g, 0.08 mmol) were then added to it at 25°C and the tube was sealed. Reaction mixture was stirred at 70°C for 20 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then filtered and washed with ethyl acetate (2X30 ml). The organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using vu—

164

40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.7 g, 43.10%).

MS: m/z 382 (M+1) !HNMR (CDCls, 400 MHz): δ 8.09 (d, J=8.0 Hz, 1H), 7.16-7.23 (m, 3H), 4.52 (bs-exchanges with D₂O, 1H), 3.69 (s, 3H), 2.70 (s, 3H), 2.00 (s, 3H), 1.27 (s, 9H).

Step 2: Methyl 5-bromo-4-methyl-3-(3-methyl-4sulfamoylphenyl)thiophene-2-carboxylate (41b) h₂no₂s /

Br

Bromine (0.35 g, 0.11 ml, 2.2 mmol) was added drop wise to a stirred suspension of methyl 3-(4-(N-(tert-butyl)sulfamoyl)-3-methylphenyl)-4methylthiophene-2-carboxylate (41a, 0.70 g, 1.83 mmol) in DCM (15 ml) at 0°C. The reaction mixture was then stirred at 25°C for 3 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated. DCM (50 ml) was added to the residue. The mixture so obtained was washed with water (2x 20 ml), brine (lx 20 ml) and dried over sodium sulfate. The dried organic layer was then concentrated under reduced pressure to obtain a crude product as semi-solid (0.7 g), which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.63 g, 85.13%).

MS: m/z 405 (Μ+1]ύ^ ^lHNMR (CDCI3, 400 MHz): Ô 8.09 (d, J=8.0 Hz, 1H), 7.17-7.23 (m, 2H),

4.91 (bs-exchanges with D₂O, 2H), 3.73 (s, 3H), 2.72 (s, 3H), 1.95 (s, 3H).

Step 3: Ethyl 5-(4-chlorophenyl)-4-methyl-3-(3-methyl-4sulfamoylphenyl)thiophene-2-carboxylate. (41c)

165

(4-chlorophenyl)boronic acid [0.29 g, 1.85 mmol] and potassium carbonate (0.43 g, 3.09 mmol) were added to a solution of methyl 5-bromo-4-methyl3-(3-methyl-4-sulfamoylphenyl)thiophene-2-carboxylate (41b, 0.62 g,

1.54 mmol) in a mixture of 5 ml of toluene and 20 ml éthanol at 25°C. A nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladrum(0) (0.09 g, 0.08 mmol) under nitrogen atmosphère and the reaction mixture was heated at a température between about 95°C to 100°C for 3 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25°C and filtered through celite. The celite cake was washed with ethyl acetate (20ml). The combined filtrate was then concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the title compound (0.53 g, 76.8%).

MS: m/z 450 (M+l) *HNMR (CDCI3, 400 MHz): δ 8.09 (d, J=8.4 Hz, 1H), 7.41-7.46 (m, 4H), 7.21-7.24 (m, 2H), 4.88 (bs-exchanges with D2O, 2H), 4.17 (q, J=6.8 Hz, 2H), 2.73(s, 3H), 1.99 (s, 3H), 1.19 (t, J=6.8 Hz, 3H).

166

H₂NO₂S

Ethyl

5-(4-chlorophenyl)-4-methyl-3-(3-methyl-4 sulfamoylphenyl)thiophene-2-carboxylate (41c, 0.6 g, 1.33 mmol) was suspended in éthanol (20ml) and a solution of sodiumhydroxide (0.1 g, 2.66 mmol) in water (2 ml] was added to it at 25°C. The reaction mixture was then heated at 75°C under stirring for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue so obtained was then diluted with water (5 ml) and the mixture was cooled using ice bath. To the cooled mixture was added 10 % aqueous HCl to bring the pH of the mixture between about 5 and 6. The mixture was then extracted with ethyl acetate (2 x 35 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound (0.53 g, 94%).

MS: m/z 422 (M+1) ^XHNMR (DMSO, 400 MHz): δ 12.52 (bs-exchanges with D2O, IH), 7.89 (d, J=8.4 Hz, IH), 7.54-7.58 (m, 4H), 7.46 (bs-exchanges with D₂O, 2H), 7.277.32 (m, 2H), 2.62 (s, 3H), 1.98 (s, 3H).

Step S: 5-(4-chlorophenyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)3-methylphenyl)-N-methoxy-N,4-dimethylthiophene-2-carboxamide (41e)

167

Oxalyl chloride (0.47 g, 0.32 ml, 3.7 mmol) was added drop wise to a solution of 5-(4-chlorophenyl)-4-methyl-3-(3-methyl-4sulfamoylphenyl)thiophene-2-carboxylic acid (41d, 0.52 g, 1.23 mmol) in a mixture of dichloromethane (20 ml) and DMF (0.18 g, 0.19 ml, 2.46 mmol) at 0°C. The mixture was then allowed to warm to room température and stirred for 1.5 hr under a nitrogen atmosphère. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was then dissolved in dry dichloromethane (20 ml) and cooled to 0°C. To the cooled solution so obtained was then added triethylamine (0.74 g, 1.03 ml, 7.39 mmol), which was then followed by addition of N,Odimethylhydroxylamine hydrochloride (0.24 g, 2.46 mmol) under stirring. The reaction mixture was then stirred at room température for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then diluted with DCM (20 ml) and the mixture so obtained was washed with water (2 x 10 ml). The organic layer obtained was then dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by column chromatography over silica gel (100-200 mesh) using 0.8% methanol in DCM as an eluent to obtain the title compound (0.34 g, 53%)._A

168

MS: m/z 520 (M+1) iHNMR (CDCh, 400 MHz): δ 8.15 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.437.44 (m, 4H), 7.15-7.19 (m, 2H), 3.70 (s, 3H), 3.20 (s, 3H), 3.16 (s, 3H), 3.06 (s, 3H), 2.70(s, 3H), 1.98 (s, 3H).

Step 6: 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-2methylbenzene sulfonamide. (Compound 41)

Grignard reagent (Ethyl magnésium bromide, 0.42 g, 3.17 ml IM solution in THF, 3.17 mmol) was added drop wise to a stirred solution of (5-(4chlorophenyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)-3methylphenyl)-N-methoxy-N,4-dimethylthiophene-2-carboxamide (41e, 0.33 g, 0.63 mmol) in anhydrous THF (20 ml) at 25°C. The reaction mixture was then heated to about 70°C to 75°C for 1 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 0°C. The cooled reaction mixture was quenched by adding saturated solution of ammonium chloride (10 ml) and the mixture was then extracted with ethyl acetate (2x30 ml). The combined organic layer was dried over anhydrous Na₂SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by préparative HPLC to obtain the title compound (0.05 g, 18.1%)

MS: m/z 434 (M+1) nv—

ΉΝΜΚ (DMSO, 400 MHz): δ 7.93 (d, J=8.0 Hz, 1H), 7.56-7.59 (m, 4H),

7.51 (bs-exchanges with D₂O, 2H), 7.35-7.38 (m, 2H), 2.64 (s, 3H), 2.32 (q,

7=7.2 Hz, 2H), 1.92 (s, 3H), 0.87 (t, 7=7.2 Hz, 3H).

169

Example 15: Préparation of l-(5-(4-chlorophenyl)-4-methyl-3-(4(piperidin-l-ylsulfonyl)phenyl)thiophen-2-yl)propan-l-one (Compound 48).

Step 1: Ethyl 4-methyl-3-(4-(piperidin-l-ylsulfonyl)phenyl)thiophene-2carboxylate (48a)

(4-(piperidin-l-ylsulfonyl)phenyl) boronic acid (Prepared according to the procedure reported in US20060258670, 4.41 g, 16.38 mmol) and

Potassium carbonate (5.15 g, 37.2 mmol) were added to a stirred suspension of methyl 3-bromo-4-methylthiophene-2-carboxylate (7a, 3.5 g, 14.89 mmol) in a mixture of 100 ml of éthanol and 30 ml toluene in a tube under a nitrogen atmosphère at room température (25°C). Nitrogen was purged to this suspension for 15 minute at room température (25°C). tv-—

170

The the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.86 g, 0.74 mmol) at a température of about 25°C and the tube was sealed. The reaction mixture was then stirred at 105°C for 15 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then filtered and washed with ethyl acetate (2X50 ml). The combined organic layer was then concentrated under reduced pressure to obtain crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 45% ethyl acetate in hexanes as an eluent to obtain the title compound (3.5 g, 62.0%).

MS: m/z 394 (M+l) ‘HNMR (DMSO, 400 MHz): Ô 7.76 (d, J=8.4 Hz, 2H), 7.68 (s, IH), 7.50 (d, J=8.4 Hz, 2H), 4.06 (q, J=6.8 Hz, 2H), 2.93 (t, J=4.2 Hz, 4H), 1.98 (s, 3H), 1.54-1.59 (m, 4H), 1.36-1.39(m, 2H), 1.01 (t, J=6.8 Hz, 3H).

Step 2: ethyl 5-bromo-4-methyl-3-(4-(piperidin-lylsulfonyl)phenyl)thiophene-2-carboxylate (48b)

Prepared by following process provided in example 3 step 3 using 48a as a starting material.

MS: m/z 473 (M+l)

Step 3: Ethyl 5-(4-chlorophenyl)-4-methyl-3-(4-(piperidin-lylsulfonyljphenyl) thiophene-2-carboxylate. (48c)

171

Prepared by following process provided in example 3 step 4, using 48b and (4-chlorophenyl)boronic acid as reactants.

MS: m/z 504 (M+1).

Step 4: 5-(4-chlorophenyl)-4-methyl-3-(4-(piperidin-lylsulfonyl)phenyl)thiophene-2-carboxylic acid (48d)

Prepared by following process provided in example 3 step 5 using 48c as a starting material.

MS: m/z 476 (M+1).

Step-3: 5-(4-chlorophenyl)-N-methoxy-N,4-dimethyl-3-(4-(piperidin-lylsulfonyl) phenyl)thiophene-2-carboxamide (48e).

Prepared by following the process provided in example 3 step 6 using 48d as a starting material.

MS: m/z 519 (M+1)

172

Step-4: l-(5-(4-chlorophenyl)-4-methyl-3-(4-(piperidin-lylsulfonyl)phenyl)thiophen-2-yl)propan-l-one (compound 48)

Prepared by following process provided in example 3 step 7 using 48e as a 5 starting material.

MS: m/z488 (M+l) iHNMR (DMSO, 400 MHz): δ 7.84 (d, J=8.0 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.46 (m, 4H), 2.94 (t, J=5.2 Hz, 4H), 2.30 (q, J=7.2 Hz, 2H), 1.94 (s, 3H), 1.52-1.55 (m, 4H), 1.36-1.38 (m, 2H), 0.86 (t, J=7.2 Hz, 3H).

Example 16: Préparation of 5-(4-chlorophenyl)-N,N,l,4-tetramethyl-3(4-sulfamoylphenyl)-lH-pyrrole-2-carboxamide. (Compound 50)

To a stirred solution of 5-(4-chlorophenyl)-l,4-dimethyl-3-(415 sulfamoylphenyl)-7H-pyrrole-2-carboxylic acid (49ε, 1.00 g, 2.47 mmol) in

DMF (15 ml) was added HOBT (0.41 g, 2.72 mmol) at room température, which was then followed by the addition of dimethylamine hydrochloride

173 (0.40 g, 4.94 mmol). the reaction mixture was cooled to 0°C and to the cooled reaction mixture was then added EDC (0.71 g, 3.70 mmol) and triethylamine (1.00 g, 1.37 ml, 9.88 mmol). The reaction mixture was then stirred at room température for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. Ethyl acetate (100 ml) was added to the residue so obtained. The mixture so obtained was then washed with saturated sodium bicarbonate solution (20 ml) followed by washing with brine (20 ml). The organic layer obtained was dried over anhydrous sodium sulphate. The dried organic layer was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography over silica gel (100-200 mesh) using 90% ethyl acetate in hexanes as an eluent to obtain the title compound (0.94 g, 88.1%).

MS: m/z 432 (M+1) iHNMR (DMSO, 400 MHz): δ 7.82 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.36 (bs-exchanges with D₂O, 2H), 3.40 (s, 3H), 2.87 (s, 3H), 2.56 (s, 3H), 1.98 (s, 3H).

Example 17: Préparation of ethyl 5-(4-chlorophenyl)-4-methyl-3-(4sulfamoyl-5,6,7,8-tetrahydronaphthalen-l-yl)thiophene-2-carboxylate (Compound 59)

174

Step 1: 4-bromo-5,6,7,8-tetrahydronaphthalene-l-sulfonyl chloride (59a)

Br

Chlorosulfonic acid (13.80 g, 7.93 ml, 118.00 mmol was added dropwise to a stirred solution of 5-bromo-l,2,3,4-tetrahydronaphthalene (Prepared according to the procedure reported in the literature, W02004/792, 10.0 g, 47.4 mmol) in 50 ml chloroform at 0°C. The reaction mixture was then allowed to warm to about 25°C and was stirred at the same température for 45 min. The progress of the reaction was monitored by TLC. The reaction mixture was then poured in ice-water (50 ml) and the mixture so obtained was extracted with chloroform (2 X 150 ml). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to obtain the title compound (12.0 g, 81.6%), which was taken ahead as such without further purification for the next step.

MS: m/z 310(M+l) iHNMR (CDC1₃, 400 MHz): δ 7.81 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 2.72-7.81 (m, 4H), 1.83-1.89 (m, 4H).

Step 2: 4-bromo-N-(tert-butyl)-5,6,7,8-tetrahydronaphthalene-lsulfonamide (59b)

175

V

Br tert-butyl amine [8.5 g, 12.32 ml, 116.0 mmol) was added dropwise to a stirred suspension of 4-bromo-5,6,7,8-tetrahydronaphthalene-l-sulfonyl chloride (59a, 12.0 g, 38.8 mmol) in 150 ml tetrahydrofuran at 0°C. The reaction mixture was then stirred at a température of about 25°C for 2 hours. The progress of the reaction was monitored by TLC. Water (100 ml) was added to the reaction mixture, and the mixture so obtained was extracted with ethyl acetate (2 X 150 ml). The combined organic layer was then dried over sodium sulphate, and the dried organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 15% ethyl acetate in hexanes as an eluent to obtain the title compound (2.34 g, 17.4%).

MS: m/z 347 (M+1)

1HNMR (CDCh, 400 MHz): δ 7.79 (d, J=8.8 Hz, IH), 7.52 (d, J=8.8 Hz, IH), 4.53 (bs-exchanges with D₂O, IH), 2.76-7.83 (m, 4H), 1.80-1.85 (m, 4H), 1.22 (s, 9H).

Step 3: Methyl 3-(4-(N-(tert-butyl)sulfamoyl)-5,6,7,8tetrahydronaphthalen-1 -yl)-4-methylthiophene-2-carboxylate (59c)

V hno₂s f

M o

Q

176

-bromo-N -(tert-butyl) -5,6,7,8 -tetrahy dr onaphthalene-1 - su lfon amide (59b, 1.35 g, 3.90 mmol) and Potassium phosphate (0.75 g, 3.54 mmol) were added to a stirred suspension of methyl 4-methyl-3-(4,4,5,5tetram ethyl-1,3,2 -dioxaborolan-2 -y 1) thiophene-2 -carboxylate (Prepared according to the procedure reported in the literature, J. Org. Chem., 2010, 75, 3855-3858, 1.0 g, 3.54 mmol) in a mixture of 20 ml THF and 4 ml water in a tube under a nitrogen atmosphère at room température (about 25°C). A nitrogen gas was purged to this suspension for 15 minute at room température (about 25°C). To the reaction mixture was then added triphenyl phospine (0.028 g, 0.10 mmol) and) Palladium (II) acetate (0.016 g, 0.07 mmol) at 25°C and the tube was sealed. The reaction mixture was then stirred at about 75°C for 20 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then filtered and the cake obtained was washed with ethyl acetate (2X30 ml). The combined filtrate was then concentrated under reduced pressure to obtain crude product, which was then purified by flash column chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the title compound (0.11 g, 7.7%)

MS: m/z 422 (M+l] ^lHNMR (CDCh, 400 MHz): δ 7.99 (d, J=8.0 Hz, IH), 7.26 (s, IH), 6.98 (d, J=8.0 Hz, IH), 4.43 (bs-exchanges with D2O, IH), 3.66 (s, 3H), 3.23 (t, J=6.4 Hz, 2H), 2.21-2.43 (m, 2H), 1.87 (s, 3H), 1.69-1.81 (m, 4H), 1.27 (s, 9H).

Step 4: Methyl 5-bromo-4-methyl-3-(4-sulfamoyl-5,6,7,8tetrahydronaphthalen-l-yl)thiophene-2-carboxylate (59d)

177

Bromine (0.045 g, 0.015 ml, 0.28 mmol) was added dropwise to a stirred suspension of methyl 3-(4-(N-(tert-butyl)sulfamoyl)-5,6,7,8tetrahydronaphthalen-l-yl)-4-methylthiophene-2-carboxylate (59c, 0.10 g, 0.24 mmol) in 15 ml dichloromethane at a température of about 0°C. The reaction mixture was then stirred at about 25°C for 2 hours. the progress of the reaction was monitored by TLC. The reaction mixture was then concentrated. 20 ml of dichloromethane was added to the residue so obtained. The mixture so formed was washed with water (2x 10 ml), brine (lx 10 ml) and the organic layer so obtained was dried over sodium sulfate. The dried organic layer was then concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 20% ethyl acetate in hexanes as an eluent to obtain the title compound (0.08 g, 67.4%).

MS: m/z 445 (M+l) iHNMR (CDCh, 400 MHz): δ 7.97 (d, >8.4 Hz, IH), 6.97 (d, >8.4 Hz, IH), 4.43 (bs-exchanges with D2O, 2H), 3.73 (s, 3H), 3.22-3.28 (m, 2H), 2.24-2.46 (m, 2H), 1.69-1.82 (m, 7H).

Step 5: Ethyl 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoyl-5,6,7,8tetrahydronaphthalen-l-yl)thiophene-2-carboxylate (Compound 59) —

178

(4-chlorophenyl)boronic acid[ 0.027 g, 0.17 mmoljand potassium carbonate (0.043 g, 0.31 mmol) were added to a solution of methyl 5bromo-4-methyl-3-(4-sulfamoyl-5,6,7,8-tetrahydronaphthalen-lyl)thiophene-2-carboxylate (59d, 0.07 g, 0.16 mmol) in a mixture of 1 ml toluene and 4 ml éthanol at 25°C. A nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis (triphenylphosphine)palladium(O) (0.009 g, 0.008 mmol) under nitrogen atmosphère and the reaction mixture was heated at a température of about 95°C to about 100°C for 3 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25°C and filtered through celite, the celite cake washed with 10 ml ethyl acetate. The combined filtrate so obtained was then concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the title compound (0.027 g, 35.0%).

MS: m/z 490 (M+l) 'HNMR (CDCh, 400 MHz): δ 7.97 (d, J=8.0 Hz, IH), 7.45 (s, 4H), 7.05 (d, 7=8.0 Hz, IH), 5.31 (bs-exchanges with D₂O, 2H), 4.10-4.20 (m, 2H), 3.253.28 (m, 2H), 2.51-2.57 (m, IH), 2.31-2.37 (m, IH), 1.78-1.90 (m, 7H), 1.13 (t, 7=7.2 Hz, 3H). w'

Example 18: Préparation of ethyl 5-(4-chlorophenyl)-3-(4sulfamoylphenyl)furan-2-carboxylate (Compound 60)

179

Step 1: ethyl 3-(4-sulfamoylphenyl)furan-2-carboxylate (60a)

(4-sulfamoylphenyl) boronic acid (1.76. gm, 8.77 mmol) and Potassium carbonate (2.52 gm, 18.26 mmol) were added to a stirred suspension of ethyl 3-bromofuran-2-carboxylate (Prepared according to the procedure reported in the literature EP1489077A1, 2004, 1.6 gm, 7.30 mmol) in a mixture of 80 ml of éthanol and 20 ml of toluene (80 ml:20 ml) under nitrogen atmosphère at room température (25°C) in a tube. A nitrogen gas was purged to the suspension for 15 minute at room température (about 25°C). To the reaction mixture was then added Tetrakis(triphenyl phosphine) Palladium(O) (0.422 gm, 0.365 mmol) at 25°C and tube was —

180 sealed. The reaction mixture was then stirred at 100°C for 18 hours, The progress of the reaction was monitored by TLC. The reaction mixture was then filtered and washed with ethyl acetate (2X100 ml). The combined organic layer was then concentrated under reduced pressure to obtain a crude product as semi-solid (11.2 gm), which was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (1.2 g, 55.60%) MS: m/z 296 (M+1) ^lHNMR (CDC1₃, 400 MHz): δ 7.99 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.23 (d, J=2.0 Hz IH), 6.65 (d, J=2.0 Hz, IH), 4.85(bs-exchanges with D2O, 2H), 4.35 (q, J=7.2 Hz 2H), 1.33 (t, J=7.2 Hz, 3H).

Step 2: ethyl 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)furan-2-carboxylate (compound 60)

H₂NO₂S

l-bromo-4-chlorobenzene (0..214 g, 1.11 mmol) and potassium acetate (0.199 g, 2.03 mmol) were added to a solution of ethyl 3-(4sulfamoylphenyl)furan-2-carboxylate (60a, 0.3 g, 1.01 mmol) in dimethyl acetamide (5 ml) at 25°C in a tube. A nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added palladium (II) acetate (0.023 gm, 0.102 mmol) under nitrogen^/

181 atmosphère and the tube was sealed. The reaction mixture was then heated at 150°C for 20 hr with stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25°C and concentrated under reduced pressure. The residue so obtained was dissolved in ethyl acetate (30 ml). The solution so obtained was then washed with water (2X 10 ml), dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (0.040 gm, 9.70%).

MS: m/z 406 (M+1) !HNMR (CDC13, 400 MHz): δ 8.00 (d, J=8.8 Hz, 2H), 7.75-7.77 (m, 4H), 7.43 (d, J=8.8 Hz, 2H), 6.85 (s, 1H), 5.2 (bs-exchanges with D2O, 2H), 4.35 (q, J=7.2 Hz 2H), 1.34 (t, J=7.2 Hz, 3H).

Example 19: Pharmacological screening

Compounds were tested in a cell-based real-time kinetic assay in human IMR-32 cells with native expression of a7nAChR. The increase in intracellular Ca²⁺ levels was measured in a Fluorometric Imaging Plate Reader (FLIPR). Test compound and agonist solutions were made in assay buffer (HBSS, pH 7.4, 20 mM HEPES, and 10 mM CaCl₂). Briefly, cells were plated into Poly-D-Lysine coated back-walled clear-bottom 96-well microplates at a density of 80,000 to 100,000 cells/well and incubated at 37°C/5% CO₂ for 40-48 h prior to the experiment. For évaluation of compound mediated potentîation of agonist response, growth media was removed from the wells and 200 μΐ of FLIPR calcium 4 dye (Molecular Devices), reconstituted in assay buffer, and was added to the wells. Afterv\/^

182 dye loading, microplates were incubated for 30 min at 37°C and 30 min at room température and then directly transferred to the FLIPR. Baseline fluorescence was monitored for the first 10 to 30 s followed by the addition of 25 μΐ of test compound solution and subséquent monitoring of fluorescence changes for up to 10 min. This was followed by addition of 25 μΐ of agonist solution (PNU-282987, 10 μΜ) and measurement of fluorescence for 4 min. (Faghih R. et al. 2009, J. Med. Chem., 52, 3377 84.)

The compound induced fold increase in agonist response (fold PAM activity) was computed by dividing the maximum effect (Max-Min fluorescence) obtained with test compound in presence of agonist with the agonist-alone effect. ECso of the compound was calculated using GraphPad Prism software version 5.0, by plotting compound concentrations against fold PAM activity.

Fold activity at ΙμΜ concentration: compounds with activity below 5 folds are grouped as A, the compounds with activity between 5.1 folds and 15 folds are grouped as B and the compounds with activity above 15 folds are grouped as C.

Following table 1 provides fold activity of the compounds of the présent invention

Table 1

Sr.No.	Fold activation at ΙμΜ conc. (Group)	Compound No.
1	A	2, 3, 11, 13, 14, 15, 17, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 31, 32, 33, 34, 35, 36,

183

		37, 38, 39, 42, 43, 48, 50, 52, 53, 54, 57, 58
2	B	4, 5, 8, 9, 18, 19, 30, 40, 51, 55, 56,
3	C	1, 6, 7, 10, 12, 16, 44, 49,

AT

Claims

184

1. A compound of formula I, its tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts, wherein, in the compound of formula I,

Z is selected from the group consisting of-S-, -O- and -N(R^a)-;

R² is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halogen, perhaloalkyl, optionally substituted cycloalkyl, cyano, nitro, (R⁷)(R⁸)N-, R^7aC(=O)N(R⁷)-,

185 (R⁷)(R⁸)NC(=A¹)N(R⁹)-, R^7aOC(=O)NR⁹-, R^7aSO₂N(R⁸)-, R⁷A’-, and

R^7aC(=O)-;

R³ is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, wherein each of the said optionally substituted cycloalkyl and optionally substituted heterocyclyl is optionally annulated or optionally bridged, (R⁷)(R⁸)N-, (R⁷)N(OR⁸)-, and R⁷A’-;

is ‘m’times répétition of ‘R⁴’ groups, each R⁴ is independently selected from the group consisting of halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, R^7aC(=O), R^7aSO₂-, R⁷Ai-, (R^7a)C(=O)N(R⁹)-, (R⁷)(R⁸)N-, (R⁷)(R⁸)NC(=A¹)N(R⁹)-; wherein m = 0 to 3; or two R⁴ groups and the carbon atoms to which they are attached together form an optionally substituted 5- to 6membered cyclic system which optionally contains 1 to 4 hetero atoms/groups selected from the group consisting of-N-, -S-, -O-, C(=O)-, and -C(=S)-;

R⁵ and R⁶ are independently selected from the group consisting of hydrogen, R^7aC(=O)-, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or R⁵ and R⁶ together with the nitrogen atom to which they are attached form a 3- to 10- membered optionally substituted

186 saturated/unsaturated heterocyclic ring system containing one to three hetero atoms/groups selected from the group consisting of-S, -N-, -O-, -C(=O)-, and -C(=S)-;

A¹ is selected from the group consisting of O and S;

wherein, the term optionally substituted alkyl, means a alkyl group unsubstituted or substituted with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R^10aSO2-, R^A¹-, R^10aOC(=O)-, Ri0a_C(=O)O-, (R¹⁰)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, Ri°^aC(=O)N(H)-, (R^J0)(H)N-, (R¹⁰) (alkyl) N-, (R¹⁰)(H)NC(=A¹)N(H)-, and (R¹⁰)(alkyl)NC(=A¹)N(H)-;

the term optionally substituted alkenyl, means a alkenyl group unsubstituted or substituted with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, —

187 cyano, aryl, hereroaryl, cycloalkyl, R^10aSO2-, R^A¹-, R^10aOC(=O)-,

Rio_aC(=0)0-, (R¹⁰)(H)NC(=O)-, (Ri0)(alkyl)NC(=O)-, R^10aC(=O)N(H)-, (R¹⁰)(H)N-, (R¹⁰)(alkyl)N-, (Rio)(H)NC(=A¹)N(H)-, and (R¹⁰)(alkyl)NC(=A^l)N(H)-;

the term optionally substituted alkynyl, means a alkynyl group unsubstituted or substituted with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaiyl, cycloalkyl, R^10aSO2-, R¹⁰A^]-, R^10aOC(=O)-, Ri0aC(=O)O-, (R^w)(H)NC(=O)-> (Ri<>)(alkyl)NC{=0)-, R^10aC(=O)N(H)-, (R¹⁰)(H)N-, (R¹⁰)(alkyl)N-, (Ri°)(H)NC(=Ai)N(H)-, and (RiO)(alkyl)NC{=Ai)N(H)-;

the term “optionally substituted heteroalkyl means a heteroalkyl group unsubstituted or substituted with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, and cycloalkyl;

the term “optionally substituted cycloalkyl means a cycloalkyl group unsubstituted or substituted with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R^10aC(=O)-, R^10aSO₂-, R¹⁰Ai-, R^10aOC(=O}-, Ri°^aC(=O)O-, (Ri°)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, Ri°^aC(=O)N(H)-, (R¹⁰)(H)N-, (R¹⁰) (alkyl) N-, (RiûJiHJNC^A^NÎH)-, and (Ri°)(alkyl)NC(=Ai)N(H)-;

the term optionally substituted aryl means (i) an aryl group unsubstituted or substituted with 1 to 3 substituents selected independently from the group consisting of halogen, nitro, cyano, hydroxy, Ci to Ce alkyl, C₂ to Ce alkenyl, C₂ to Ct> alkynyl, C3 to Cô cycloalkyl, Ci to Cû perhaloalkyl, alkyl-O-, alkenyl-O-, alkynyl-O-,

188 perhaloalkyl-O-, alkyl-N (alkyl)-, alkyl-N(H)-, H₂N-, alkyl-SCh-, perhaloalkyl-SO₂-, alkyl-C(=O)N(alkyl)-, alkyl-C(=O)N(H)-, alkylN(alkyl)C(=O)-, alkyl-N(H)C(=O)-, H₂NC(=O)-, alkyl-N(alkyl)SO₂-, alkyl-N(H)SO₂-, H2NSO2-, 3- to 6- membered heterocycle containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, wherein the said 3- to 6- membered heterocycle is optionally substituted with alkyl, alkenyl, alkynyl, or alkyl-C(=O)- or (ii) the said substituted or unsubstituted aryl ring optionally fused with cycloalkane ring or heterocycle ring containing 1 to 3 heteroatoms selected from S, O, N, across a bond, wherein the said cycloalkane ring or heterocycle ring is optionally substituted with oxo, alkyl, alkenyl, alkynyl or alkyl-C(=O)-;

the term “optionally substituted heterocyclyl means a (i) heterocyclyl group unsubstituted or substituted on ring carbons with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R^li)A¹-, R^19aOC(=O)-, R^10aC(=O)O-, (R¹⁹)(H)NC(=O)-, (R¹⁰)(alkyl)NC(O)-, Ri°*C(=O)N(H)-, (R¹⁰)(H)N-, (R¹⁰) (alkyl) N-, (R¹⁰)(H)NC(=A¹)N(H)-, and (R¹⁰)(alkyl)NC(=A¹)N(H)-; (ii) heterocyclyl group optionally substituted on ring nitrogen(s) with one or more substituents selected from the group consisting of hereroaryl, alkyl, alkenyl, alkynyl, Ri°^aC(=O)-, Ri°^aSO₂-, R¹⁹«OC(=O)-, (Ri°)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, and aryl unsubstituted or substituted with 1 to 3 substituents selected independently from halogen, alkyl, alkenyl, alkynyl, cyano or nitro;

the term optionally substituted heteroaryl means a heteroaryl group unsubstituted or substituted with 1 to 3 substituents selected independently from the group consisting of halogen, nitro,

189 cyano, hydroxy, Ci to Ce alkyl, C₂ to C& alkenyl, C₂ to C& alkynyl, C3 to Ce cycloalkyl, Ci to Ce perhaloalkyl, alkyl-O-, alkenyl-O-, alkynylO-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H₂N-, alkyl-SO₂-, perhaloalkyl-SO₂-> alkyl-C(=O)N(alkyl)-, alkyl-C(=O)N(H)-, alkylN(alkyl)C(=O)-, alkyl-N(H)C(=O)-, H₂NC(=O)-, alkyl-N(alkyl)SO₂-, alkyl-N(H)SO₂-, H₂NSO₂-, and 3- to 6- membered heterocycle containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, wherein the heterocycle is optionally substituted with one to four substituents selected from the group consisting of alkyl alkenyl, alkynyl, or alkyl-C(=O)-;

the term “optionally substituted 5- to 6- membered cyclic system” means the 5- to 6- membered cyclic system unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, Ri°^aC(=O)-, Ri°^aSO₂-, RioA¹-, R¹⁰«OC(=O)-, Rioac(=0)0-, (R¹⁰)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, Ri°«C(=O)N(H)-, (R¹⁰)(H)N-, (R¹⁰)(alkyl)N-, (R¹⁰)(H)NC(=A¹)N(H)-, and (Rio)(alkyl)NC(=Ai)N(H)-;

the term “3- to 10- membered optionally substituted saturated/unsaturated heterocyclic ring system” the 3- to 10membered saturated/unsaturated heterocyclic ring system unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, Ri°^aC(=O)-, R^10aSO₂-, R^A¹-, R^10aOC(=OJ-, Rioac(=0)0-, (R¹⁰)(H)NC(=O)-, (Rio)(alkyl)NC(=OJ-, R^10aC(=O)N(H)-, (R¹⁰)(H)N-, (R¹⁰)(alkyl)N-, (Rio)(H)NC(=Ai)N(H)-, and (Ri°}(alkyl)NC(=Ai)N(H)-;

190 wherein R¹⁰ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;

and R^10a is selected from the group consisting of alkyl, alkenyl, alkynyl, perhaloalkyl, aiyl, heteroaryl, cycloalkyl or heterocyclyl.

2. The compound of formula I, its tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts, as claimed in claim 1, wherein R² is selected from the group consisting of hydrogen, optionally substituted alkyl, and (R^{5 * 7})(R⁸)N-.

3. The compound of formula I, its tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts, as claimed in claim 1 or 2, wherein R² is selected from the group consisting of hydrogen, methyl, dimethylamino and dimethylaminomethyl.

4. The compound of formula I, its tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts, as claimed in any one of claims 1-3, wherein R³ is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, R⁷A¹-, (R⁷)(R⁸)N- and (R⁷)N(OR⁸)-.

5. The compound of formula I, its tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts, as claimed in any one of claims 1-4, wherein R³ is selected from the group consisting of methyl, ethyl, n-propyl, methoxy, ethoxy, dimethylamino, Nmethoxy-N-methyl amino, N-{2-hydroxy ethyl)-N-propyl amino, acetylaminomethyl and piperidinyl.

191

6. The compound of formula I, its tautomeric forms, its stereoîsomers, and its pharmaceutically acceptable salts, as claimed in any one of daims 1-5, wherein R⁵ and R⁶ are selected independently from the group consisting of hydrogen, optionally substituted alkyl, or both R⁵ and R⁶ together with the nitrogen atom to which they are attached form a 3- to 10- membered optionally substituted saturated/unsaturated heterocyclic ring system containing one to three hetero atoms/groups selected from the group consisting of -S, -N-, -O-, -C(=O)-, and -C(=S)-.

7. The compound of formula I, its tautomeric forms, its stereoîsomers, and its pharmaceutically acceptable salts, as claimed in any one of daims 1-6, wherein R⁵ and R⁶ are selected independently from the group consisting of hydrogen, methyl, or both R⁵ and R⁶ together with the nitrogen atom to which they are attached form a piperidine ring.

8. The compound of formula I, its tautomeric forms, its stereoîsomers, and its pharmaceutically acceptable salts, as claimed in any one of daims 1-7, wherein m is 0, 1 or 2, and R⁴ is or are selected from optionally substituted alkyl group or groups or two R⁴s together with the carbon atoms to which they are attached form an optionally substituted 5- to 6- membered cyclic system which optionally contains 1 to 4 hetero atoms/groups selected from the group consisting of-N-, -S-, -O-, -C(=O)-, and -C(=S)-.

9. The compound of formula I, its tautomeric forms, its stereoîsomers, and its pharmaceutically acceptable salts, as claimed in any one of άΓ'

192 claims 1-8, wherein m is 0, 1 or 2, and R⁴ is or are selected from methyl group or groups or two R⁴s together with the carbon atoms to which they are attached form a six membered carbocycle.

10. The compound of formula I, its tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts, as claimed in any one of claims 1-9, wherein R^a is selected from hydrogen and optionally substituted alkyl.

11. The compound of formula I, its tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts, as claimed in any one of claims 1-10, wherein R^a is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropylmethyl.

12. The compound of formula I, its tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts, as claimed in any one of claims 1-11, wherein R² is selected from the group consisting of hydrogen, optionally substituted alkyl, and (R⁷)(R⁸)N-; R³ is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, R⁷A*-, (R⁷)(R⁸)N- and (R⁷)N(OR⁸)-; R⁵ and R⁶ are selected independently from the group consisting of hydrogen, optionally substituted alkyl, or both R⁵ and R⁶ together with the nitrogen atom to which they are attached form a 3- to 10membered optionally substituted saturated/unsaturated heterocyclic ring system containing one to three hetero atoms/groups selected from the group consisting of -S-, -N-, -O-, C(=O)-, and -C(=S)-; m is 0, 1 or 2, and R⁴ is or are selected from optionally substituted alkyl group or groups or two R⁴s together with the carbon atoms to which they are attached form an optionally

193 substituted 5- to 6- membered cyclic system which optionally contains 1 to 4 hetero atoms/groups selected from the group consisting of -N-, -S-, -O-, -C(=O)-, and -C(=S)-; and R^a is selected from the group consisting of hydrogen and optionally substituted alkyl.

13. The compound of formula I, its tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts, as claimed in any one of claims 1-12, wherein R¹ is selected from the group consisting of pyridyl, furanyl, indolyl, N-methylisoindolyl, benzofuranyl, piperazinyl, 4-(4-fluorophenyl)piperazinyl, morpholinyl, indolinyl, 2oxoindolinyl, 2,3-dihydrobenzo[b][l,4]dioxinyl, benzopyranyl, and phenyl optionally substituted with 1 to 2 substituents selected from group consisting of halo, cyclopropyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, dimethylamino, monomethylamino, tert-butyl and 4-methylpiperazinyl; R² is selected from the group consisting of hydrogen, methyl, dimethylamino and dimethylaminomethyl; R³ is selected from the group consisting of methyl, ethyl, n-propyl, methoxy, ethoxy, dimethylamino, N-methoxy-N-methyl amino, N-(2-hydroxy ethyl)-Npropyl amino, acetylaminomethyl and piperidinyl; R⁵ and R⁶ are selected independently from the group consisting of hydrogen, methyl, or R⁵ and R⁶ together with nitrogen atom to which they are attached form a piperidine ring; m is 0, 1 or 2, and R⁴ is selected from methyl groups or two R⁴s together with the carbon atoms to which they are attached forming a six membered carbocycle; and R^ais selected from the group consisting of hydrogen, methyl, ethyl and cyclopropylmethyl.

194

14. The compound of formula I its tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts, as claimed in any one of claims 1-13, wherein R¹ is selected from the group consisting of 4chlorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4cyclopropylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4ethoxyphenyl, 3-ethoxyphenyl, 4-tolyl, 4-tert-butyl phenyl, 4dimethylaminophenyl, 3-fluorophenyl, phenyl, 4-ethylphenyl, 3,4dichlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 3-chloro-4fluorophenyl, 3-chloro-4-methoxyphenyl, piperazin-l-yl, 4(fluorophenyl)piperazinyl, morpholino, pyridin-4-yl, pyridin-3-yl, furan-3-yl, lH-indol-5-yl, 1-methyl-lH-indol-5-yl, benzofuran-5-yl, indolin-5-yl, 4-(4-methylpiperaziny-l-yl)phenyl, and 2,3dihydrobenzo[b] [ 1,4]dioxin-6-yl).

15. The compound of formula I its tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts, as claimed in any one of claims 1-14, wherein Z is S.

16. The compound of formula I, its tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts, as claimed in any one of claims 1-15, wherein the compound is selected from the group consisting of:

4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide;

4-{5-(2-chlorophenyl)-4-methyl-2-propionylthiophen-3yljbenzene sulfonamide;

4-(5-(3-chlorophenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide; y/

195

4-(5-(4-fluorophenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide;

4-(5-(4-cyclopropylphenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide;

4-(4-methyl-2-propionyl-5-(4-(trifluoromethyl)phenyl)thiophen-

3- yl)benzene sulfonamide;

4- (5-(4-methoxyphenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide;

4-(5-(4-ethoxyphenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide;

4-(4-methyl-2-propionyl-5-(4(trifluoromethoxy)phenyl)thiophen-3-yl) benzenesulfonamide; 4-(4-methyl-2-propionyl-5-(4-tolyl)thiophen-3yl)benzenesulfonamide;

4-(5-(4-(tert-butyl)phenyl)-4-methyl-2-propionylthiophen-3yljbenzene sulfonamide;

4-((5-(4-dimethylamino)phenyl)-4-methyl-2-propionylthiophen-

3- yl)benzene sulfonamide;

4- (5-(3-fluorophenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide;

4-(4-methyl-5-phenyl-2-propionylthiophen-3yljbenzenesulfonamide;

4- ( 5- (3 -ethoxyphenyl) -4-methyl-2 -propiony lthiophen-3yl)benzene sulfonamide;

4-(5-(4-ethylphenyl)-4-methyl-2-propionylthiophen-3yljbenzene sulfonamide;

4-(5-(3,4-dichlorophenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide;

196

4-(5-(2,4-dichlorophenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide;

4-(5-(2,4-difluorophenyl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide;

4-(5-(3-chloro-4-fluorophenyl)-4-methyl-2-propionylthiophen-

3- yl)benzene sulfonamide;

4- (5-(3-chloro-4-methoxyphenyl)-4-methyl-2propionylthiophen-3-yl) benzenesulfonamide;

4-(4-methyl-5-(piperazin-l-yl)-2-propionylthiophen-3yl)benzene sulfonamide;

4-(5-(4-(4-fluorophenyl)piperazin-l-yl)-4-methyl-2propionylthiophen-3-yl) benzenesulfonamide;

4-(4-methyl-5-morpholino-2-propionylthiophen-3yl)benzenesulfonamide;

4-( 4-methyl-2-pr opionyl-5 - (py ri din-4-y 1) thiophen-3yljbenzenesulfonamide;

4-(4-methyl-2-propionyl-5-(pyridin-3-yl)thiophen-3yl) benzenesulfonamide;

4-(5-(furan-3-yl)-4-methyl-2-propionylthiophen-3yl)benzenesulfonamide;

4-(5-(1 H-indol-5-yl)-4-methyl-2-propionylthiophen-3yljbenzene sulfonamide;

4-(4-methyl-5-( 1-methyl- lH-indol-5-yl)-2-propionylthiophen-3yl)benzene sulfonamide;

4-(5-(benzofuran-5-yl)-4-methyl-2-propionylthiophen-3yl)benzene sulfonamide;

4-(5-(indolin-5-yl)-4-methyl-2-propionylthiophen-3yl)benzenesulfonamide; vy^-

197

4-(4-methyl-5-(4-(4-methylpiperazin-l-yl)phenyl)-2propionylthiophen-3-yl)benzenesulfonamide;

4-(5-{4-chlorophenyl)-2-propionylthiophen-3yl) benzen e su lfonamide ;

4-(5-(4-chlorophenyl)-4-(dimethylamino)-2-propionylthiophen-

3- yl)benzene sulfonamide;

4- (5 - (4- chloropheny 1 ) -4- ( (dimethy lamino) methyl) - 2 propionylthiophen-3-yl) benzenesulfonamide;

5- (4-chloroph enyl) - N, N, 4- trimethy 1-3 - (4 suiphamoylphenyl)thiophene-2-carboxamide;

5-(4-chlorophenyl)-7V-methoxï/-7V,4-dimethyl-3-(4sulphamoylphenyl) thiophene-2-carboxamide;

5-(4-chlorophenyl)-iV-(2-hydroxyetht/ZM-methyl-N-propyl-3-(4sulphamoyl phenyl)thiophene-2-carboxamide;

4-(5-(4-chlorophenyl)-4-methyl-2-(piperidine-1 carbonyl)thiophen-3-yl) benzenesulfonamide;

4-(2-acetyl-5-(4-chlorophenyl)-4-methylthiophen-3yl) benzenesu lfonamide;

4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-2methylbenzene sulfonamide;

Methyl 4-methyl-5-(2-oxoindolin-5-yl)-3-(4sulfamoy lphenyl)thiophen-2 -carboxy late ;

Ethyl 4-methyl-5-(2-oxoindolin-5-yl)-3-(4su lfamoylphe nyl) thiop hen - 2 -carboxy late ;

4-(4-methyl-5-(4-mehylaminophenyl)-2-propionylthiophen-3yl)benzene sulfonamide;

4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-N,Ndimethylbenzenesulfonamide;

198

4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)-Nmethylbenzenesulfonamide;

4-(5-(3,4-difluorophenyl) -4-methyl-2 -propi onylthioph en -3 yljbenzene sulfonamide;

1 -(5-(4-chlorophenyl)-4-methyl-3-(4-(piperidin-1 ylsulfonyljphenyl) thiophen-2-yl)propan-1 -one

4- (5-(4 -chlorophenyl) -1,4 -dimethyl-2 -propionyl-1 H-pyrrol-3-y I) benzene sulfonamide;

5- (4-chlorophenyl)-lV,lV,l,4-tetramethyl-3-(4-sulfamoylphenyl)-

1H -pyrr ol-2 - carb oxamide ;

4-(5-(4-chlorophenyl)- l-ethyl-4-methyl-2-propionyl- lH-pyrrol-

3- yl)benzene sulfonamide;

4- (5-(4-chlorophenyl)-l-(cyclopropylmethyl)-4-methyl-2propionyl-lH-pyrrol- 3-yl) benzene sulfonamide;

4-(5-(4-chlorophenyl)-4-methyl-2-propionyl-lH-pyrrol-3-yl) benzene sulfonamide;

4-(5-(4-fluorophenyl)-1,4-dimethyl-2-propionyl-1 H-pyrrol-3-yl) benzene sulfonamide;

4-(5-(4-methoxyphenyl)-1,4-dimethyl-2-propionyl- lH-pyrrol-3yl) benzene sulfonamide;

4-(2-butyryl -5- (4- chlorophenyl) -1,4-dimethyl - IH- pyrrol -3yl) benzene sulfonamide;

4-(5-(2,4-dichlorophenyl)-l,4-dimethyl-2-propionyl-lH-pyrrol-

3- yl) benzene sulfonamide;

4- (5-(2,3-dihydrobenzo[b][l,4]dioxin- 6 -yl) -1,4- dimethyl -2propionyl-lH-pyrrol-3-yl) benzene sulfonamide;

Ethyl 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoyl-5,6,7,8tetrahydro naphthalen-l-yl)thiophene-2-carboxylate; and V'

199 ethyl 5-(4- chlorophenyl) - 3 - (4- su lfamoylphe nyl) furan - 2 carboxylate.

17. A pharmaceutical composition comprising a compound of any one claims 1-16 and a pharmaceutically acceptable carrier.

18. Use of a compound of any one of claims 1-16 in the manufacture of a médicament for preventing or treating a disease or its symptoms or a disorder mediated partially or completely by nicotinic acétylcholine receptors.

19. Use of a compound of formula I, its tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts, wherein, in the compound of formula I,

Z is selected from the group consisting of-S-, -O- and -N(R^a)-;

R^a is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl; W'

200

R² is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halogen, perhaloalkyl, optionally substituted cycloalkyl, cyano, nitro, (R⁷)(R⁸)N-, R^7aC(=O)N(R⁷)-, (R⁷)(R⁸)NC(=A¹)N(R⁹)-, R^7aOC(=O)NR⁹-, R^7aSO₂N(R⁸)-, RW-, and R7aC(=O)-;

R³ is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, wherein each of the said optionally substituted cycloalkyl and optionally substituted heterocyclyl is optionally annulated or optionally bridged, (R⁷)(R⁸)N-, (R⁷)N(OR⁸)-, and R⁷A^X-;

(R⁴]m is ‘m’times répétition of ‘R⁴’ groups, each R⁴ is independently selected from the group consisting of halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, R^7aC(=O), R^7aSO2-, R⁷A^X-, (R^7a)C(=O)N(R⁹)-, (R⁷)(R⁸)N-, (R⁷)(R⁸)NC(=A^X)N(R⁹)-; wherein m = 0 to 3; or two R⁴ groups and the carbon atoms to which they are attached together form an optionally substituted 5- to 6membered cyclic System which optionally contains 1 to 4 hetero uv—

201 atoms/groups selected from the group consisting of-N-, -S-, -O-, C(=O)-, and -C(=S)-;

R⁵ and R⁶ are independently selected from the group consisting of hydrogen, R^7aC(=O)-, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or R⁵ and R⁶ together with the nitrogen atom to which they are attached form a 3- to 10- membered optionally substituted saturated/unsaturated heterocyclic ring system containing one to three hetero atoms/groups selected from the group consisting of-S, -N-, -O-, -C(=O)-, and -C(=S)-;

A¹ is selected from the group consisting of O and S;

wherein, V

202 the term optionally substituted alkyl, means a alkyl group unsubstituted or substituted with 1 to 6 substituents selected îndependently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R^10aSO2-, R^A¹-, R^10aOC(=O)-, Rioac(=0)0-, (Ri<>)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, Ri°^aC(=O)N(H)-, (R¹⁰)(H)N-, (R¹⁰)(alkyl)N-, (Ri°)(H)NC(=Ai)N(H)-, and (R¹⁰)(alkyl)NC(=A¹)N(H)-;

the term optionally substituted alkenyl, means a alkenyl group unsubstituted or substituted with 1 to 6 substituents selected îndependently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R^10aSO₂-, R^A¹-, R^10aOC(=O)-, Ri0ac(=O)O-, (Rio)(H)NC(=0)-, (R¹⁰)(alkyl)NC(=O)-, R“>^aC(=O)N(H)-, (R¹⁰)(H)N-, (R¹⁰) (alkyl) N-, (R¹⁰)(H)NC(=Ai)N(H)-, and (R¹⁰)(alkyl)NC(=A¹)N(H)-;

the term optionally substituted alkynyl, means a alkynyl group unsubstituted or substituted with 1 to 6 substituents selected îndependently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, cycloalkyl, R^l0aSC>2-, R^A¹-, R^10aOC(=O)-, Ri0a_C(=O)O-, (R¹⁰)(H)NC(=O)-, (R^l0)(alkyl)NC(=O)-, R^]üaC(=O)N(H)-, (R¹⁰)(H)N-, (R¹⁰)(alkyl)N-, (RW)(H)NC(=Ai)N(H)-, and (R¹⁰)(alkyl)NC(=A¹)N(H)-;

the term “optionally substituted heteroalkyl” means a heteroalkyl group unsubstituted or substituted with 1 to 6 substituents selected îndependently from the group consisting of oxo, halogen, nitro, cyano, aiyl, hereroaryl, and cycloalkyl;

the term “optionally substituted cycloalkyl means a cycloalkyl group unsubstituted or substituted with 1 to 6 substituents

203 selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl,

Rioac(=0)-, R^l0aSO₂-, R^A¹-, R^10aOC(=O)-, R^10aC(=O)O-, (R¹⁰)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, R^10aC(=O)N(H)-, (R¹⁰)(H)N-, (R¹⁰)(alkyl)N-, (Ri°)(H)NC(=Ai)N(H)-, and (R^flalkyljNC^A^NÎH)-;

the term optionally substituted aryl means (i) an aryl group unsubstituted or substituted with 1 to 3 substituents selected independently from the group consisting of halogen, nitro, cyano, hydroxy, Ci to Cô alkyl, C2 to C& alkenyl, C2 to Cô alkynyl, C3 to Ce cycloalkyl, Ci to Ce perhaloalkyl, alkyl-O-, alkenyl-O-, alkynyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkyl-N(H)-, H₂N-, alkyl-SO₂-, perhaloalkyl-S0₂-, alkyl-C(=O)N(alkyl)-, alkylC(=O)N(H)-, alkyl-N(alkyl)C(=O)-, alkyl-N(H)C(=O)-, H₂NC(=O)~, alkyl-N(alkyl)SO₂-, alkyl-N(H)SO₂-, H₂NSO₂-, 3- to 6- membered heterocycle containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, wherein the said 3- to 6membered heterocycle is optionally substituted with alkyl, alkenyl, alkynyl, or alkyl-C(=O)- or (ii) the said substituted or unsubstituted aryl ring optionally fused with cycloalkane ring or heterocycle ring containing 1 to 3 heteroatoms selected from S, O, N, across a bond, wherein the said cycloalkane ring or heterocycle ring is optionally substituted with oxo, alkyl, alkenyl, alkynyl or alkyl-C(=O)-;

the term “optionally substituted heterocyclyl means a (i) heterocyclyl group unsubstituted or substituted on ring carbons with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R^A¹-, R^10aOC(=O)-, R^10aC(=O)O-,

204 (R¹⁰)(H)NC(=O)-, (R¹⁰)(alkyl)NC(O)-, R^10aC(=O)N(H)-, (Rio)(H)N-, (R¹⁰)(alkyl)N-, (R¹o)(H)NC(=A¹)N(H)-, and (Rio)(alkyl)NC(=Ai)N(H)-; (ii) heterocyclyl group optionally substituted on ring nitrogen(s) with one or more substituents selected from the group consisting of hereroaryl, alkyl, alkenyl, alkynyl, R^10aC(=O)-, R^10aSO2-, _RioaoC(=0)-, (R¹⁰)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, and aiyl unsubstituted or substituted with 1 to 3 substituents selected independently from halogen, alkyl, alkenyl, alkynyl, cyano or nitro;

the term optionally substituted heteroaryl means a heteroaryl group unsubstituted or substituted with 1 to 3 substituents selected independently from the group consisting of halogen, nitro, cyano, hydroxy, Ci to Cr, alkyl, C2 to Cô alkenyl, C2 to Ce alkynyl, C3 to C& cycloalkyl, Ci to Ce perhaloalkyl, alkyl-O-, alkenyl-O-, alkynyl-O-, perhaloalkyl-O-, alkyl-N(alkyl)-, alkylN(H)-, H2N-, alkyl-SO2-, perhaloalkyl-SO2-, alkyl-C(=O)N(alkyl)-, alkyl-C(=O)N(H)-, alkyl-N(alkyl)C(=O)-, alkyl-N(H)C(=O)-,

H₂NC(=O)-, alkyl-N(alkyl)SO₂-, alkyl-N(H)SO₂-, H2NSO2-, and 3to 6- membered heterocycle containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, wherein the heterocycle is optionally substituted with one to four substituents selected from the group consisting of alkyl alkenyl, alkynyl, or alkyl-C(=O)-;

the term “optionally substituted 5- to 6- membered cyclic systern” means the 5- to 6- membered cyclic systern unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R^10aC(=O)-, R^10aSO2-, R^A¹-,

205

Ri0aoC(=O)-, R^10aC(=O)O-, (R¹⁰)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-,

RioaC(=0)N(H)-, (R¹⁰)(H)N-, (R¹⁰)(alkyl)N-, {RiQ)(H)NC(=A¹)N(H)-, and (R¹⁰)(alkyl)NC(=A¹)N(H)-;

the term “3- to 10- membered optionally substituted saturated/unsaturated heterocyclic ring system the 3- to 10membered saturated/unsaturated heterocyclic ring system unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, hereroaryl, alkyl, alkenyl, alkynyl, R^10aC(=O)-, R^10aSO2-, R¹⁰A'-, Ri0aOC(=O)-, R^10aC(=O)O-, (R^l0)(H)NC(=O)-, (R¹⁰)(alkyl)NC(=O)-, Ri0aC(=O)N(H)-, (R¹⁰)(H)N-, (R¹⁰)(alkyl)N-, (R¹0)(H)NC{=A¹)N(H)-, and (R¹⁰)(alkyl)NC(=A^])N(H)-;

wherein R¹⁰ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;

and R^10a is selected from the group consisting of alkyl, alkenyl, alkynyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; in the manufacture of a médicament for treating a disease or disorder or condition mediated partially or completely by nicotinic acétylcholine receptors.

20. The use as claimed in claim 19, wherein the disorder or condition or disease is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, senile dementia, vascular dementia, dementia of Parkinson’s disease, attention déficit disorder, attention déficit hyperactivity disorder, dementia associated with Lewy bodies, AIDS dementia complex, Pick's disease, dementia associated with Down's syndrome, Huntington’s disease, cognitive déficits associated with traumatic brain injuiy, cognitive décliné associated with stroke, y/

206 poststroke neuroprotection, cognitive and sensorimotor gating déficits associated with schizophrenia, cognitive déficits associated with bipolar disorder, cognitive impairments associated with dépréssion, acute pain, post-surgical or post-operative pain, chronic pain, inflammation, inflammatory pain, neuropathie pain, smoking cessation, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation, arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, pouchitis, inflammatory bowel disease, celiac disease, periodontitis, sarcoidosis, pancreatitis, organ transplant rejection, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, septic shock, toxic shock syndrome, sepsis syndrome, dépréssion, and rheumatoid spondylitis.

21. The use as claimed in claim 19, wherein the disease or disorder or condition is selected from the group classified or diagnosed as major or minor neurocognitive disorders, or disorders arising due to neu rode génération.

22. The use as claimed in claim 19, wherein the compound of formula I is for administration in combination with or as adjunct to médications utilized in the treatment of attention déficit hyperactivity disorders, schizophrenia, cognitive disorders such as Alzheimer¹ s disease, Parkinson’s dementia, vascular dementia or dementia associated with Lewy bodies, or traumatic brain injury. y/~

207

23. The use as claimed in claim 19, wherein the compound of formula I is for administration in combination with or as an adjunct to acetylcholinesterase inhibitors, disease modifying drugs or biologics for neurodegenerative disorders, dopaminergic drugs, antidepressants, or a typical or an atypical antipsychotic.

24. Use of a compound of claim 1 in préparation of a médicament for preventing or treating a disease or its symptoms or a disorder mediated partially or completely by nicotinic acétylcholine receptors, wherein, the disease or the disorder is selected from Alzheimer's disease, mild cognitive impairment, senile dementia, vascular dementia, dementia of Parkinson’s disease, attention déficit disorder, attention déficit hyperactivity disorder, dementia associated with Lewy bodies, AIDS dementia complex, Pick's disease, dementia associated with Down's syndrome, Huntington's disease, cognitive déficits associated with traumatic brain injury, cognitive décliné associated with stroke, poststroke neuroprotection, cognitive and sensorimotor gating déficits associated with schizophrenia, cognitive déficits associated with bipolar disorder, cognitive impairments associated with dépréssion, acute pain, postsurgical or post-operative pain, chronic pain, inflammation, inflammatory pain, neuropathie pain, smoking cessation, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation, arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, pouchitis, inflammatory bowel disease, celiac disease, periodontitis, sarcoidosis, pancreatitis, organ transplant rejection, acute immune disease associated with organ transplantation, chronic immune

208 disease associated with organ transplantation, septic shock, toxic shock syndrome, sepsis syndrome, dépréssion, and rheumatoid spondylitis.