BR112018073849B1 - BENZENOSULFONAMIDE COMPOUND, PHARMACEUTICAL COMPOSITIONS COMPRISING SAID COMPOUND AND USES THEREOF FOR THE TREATMENT OF EPILEPSY AND/OR EPILEPTIC CONVULSIVE DISORDER - Google Patents

Abstract

This invention relates to benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy.

Description

FIELD OF INVENTION

[001] The present invention relates to benzenesulfonamide compounds and pharmaceutical compositions comprising the compounds and methods of using the compounds and pharmaceutical compositions to treat sodium channel-mediated diseases or conditions, such as epilepsy and/or epileptic seizure disorder, as well as as well as other diseases and conditions associated with the mediation of sodium channels.

BACKGROUND OF THE INVENTION

[002] Voltage-dependent sodium channels (NaV's) are critical determinants of cellular excitability in muscle and nerve (Hille, B, Ion Channels of Excitable Membranes (2001), Sunderland, MA, Sinauer Associates, Inc.). Four isoforms, in particular, NaV1.1, NaV1.2, NaV1.3, and NaV1.6, represent the majority of sodium current in neurons of the central nervous system. NaV1,3 is expressed mainly in embryonic form. Beyond the neonatal stage, NaV1.1, NaV1.2, and NaV1.6 are the critical isoforms that regulate neuronal signaling in the brain (Catterall, W.A., Annual Review of Pharmacology and Toxicology (2014), Vol. 54, pp. 317 a 338).

[003]NaV1.5 is expressed mainly in cardiac myocytes (Raymond, C.K. et al., J. Biol. Chem. (2004), Vol. 279, No. 44, pp. 46234 to 41), including atria, ventricles, sinoatrial node, atrioventricular node and cardiac Purkinje fibers. Mutations in human NaV1.5 result in multiple arrhythmic syndromes, including, for example, long QT3 (LQT3), Brugada syndrome (BS), an inherited cardiac conduction defect, sudden unexpected nocturnal death syndrome (SUNDS), and sudden infant death (SIDS) (Liu, H., et al., Am. J. Pharmacogenomics (2003), Vol. 3, No. 3, pp. 173 to 9). Sodium channel blocker therapy has been widely used in the treatment of cardiac arrhythmias.

[004] Epilepsy is a condition characterized by excessive synchronous excitability in the brain that arises when the delicate balance of excitatory and inhibitory signals in the brain becomes out of balance. This can happen due to an excess of excitement or a deficiency of inhibition. Mutations in genes encoding NaV channels have been associated with both types of imbalance.

[005]NaV1.1 was identified as the primary isoform of NaV of inhibitory interneurons (Yu, F.H. et al., Nat. Neurosci. (2006), Vol. 9, pp. 1142 to 1149). These interneurons synapse on many other neurons, including excitatory glutamatergic neurons. Action potentials in interneurons induce the release of the neurotransmitter GABA in other neurons, hyperpolarizing them and thus attenuating excitation. This results in a negative feedback that allows controlled signaling and prevents local signals from expanding to form waves of excitation that spread across large regions of the brain. Because of this key role in inhibitory interneurons, mutations that impair NaV1,1 channel function can lead to a failure of those neurons to activate and release GABA (Ogiwara, I. et al., J. Neurosci. (2007), Vol. 27, pp. 5903 to 5914; ), Vol. 7, pp. 468 to 472; and Dutton, S.B., et al., (2013), Vol. 49, pp. 211 to 220). The result is a loss in the brain's inhibitory tone and a failure to contain the excitability of glutamatergic neurons. This failure of inhibitory interneurons can result in large-scale abnormal synchronous firing of neurons across regions of the brain (epilepsy).

[006] Mutations in the gene encoding NaV1.1 (SCN1A) are divided into two broad classes, those that cause generalized epilepsy with positive febrile seizures (GEFS+) and those that cause severe myoclonic epilepsy of childhood (SMEI), also known as Dravet syndrome or early infantile epileptic encephalopathy 6 (EIEE6) (McKusik, V.K. et al., A Epileptic Encephalopathy, Early Infantile 6, EIEE6 (2012), Online Mendelian Inheritance in Man: John Hopkins University). SMEI mutations are heterozygous autosomal dominant mutations and are often caused by a gene deletion or truncation that leads to a channel with little or no function. The mutations arise de novo, or in some cases have been shown to arise in asymptomatic mosaic parents (Tuncer, F.N. et al., Epilepsy Research (2015), Vol. 113, pp. 5-10). Patients are born phenotypically normal and meet developmental milestones until the onset of seizures, typically between 6 months and 1 year of age. This onset time is believed to be a consequence of the normal reduction in expression of the embryonic NaV1.3 isoform and the coincident increase in NaV1.1. When NaV1,1 channels fail to reach normal levels, the phenotype is revealed (Cheah, C.S. et al., Channels (Austin) (2013), Vol. 7, pp. 468 to 472). The initial seizure is often triggered by a febrile episode and may manifest as status epilepticus. Seizures continue and increase in frequency and severity in the first years of life and can reach frequencies of more than 100 episodes per day. Seizures may be triggered by fever or may appear spontaneously with no apparent cause. After the onset of seizures, patients begin to miss developmental milestones and accumulate significant cognitive and behavioral deficits (Dravet, C. and Oguni, H., Handbook of Clinical Neurology (2013), Vol. 111, pp. 627 to 633 ). It is believed that 80 to 85% of patients with phenotypically diagnosed Dravet syndrome have a responsible mutation in SCN1A, while the other 15 to 20% of patients have other mutations or are of unknown etiology. There is a high rate of sudden unexplained death in epilepsy (SUDEP) in patients with SMEI, with an estimated 37% of patients dying from SUDEP, but the mechanism for this catastrophic outcome remains unclear (Massey, C.A., et al., Nature Reviews Neurology (2014), Vol. 10, pp. 271 to 282). Clinically useful antiepileptic drugs that non-selectively target voltage-gated sodium channels, such as carbamazepine and phenytoin, are contraindicated for patients with SMEI as they may exacerbate seizures in these patients (Wilmshurst, J.M. et al., Epilepsia (2015), Vol . 56, pp. 1185 to 1197). This is presumed to be due to the fact that patients cannot tolerate further reductions in NaV1,1 function.

[007]GEFS+ is generally caused by SCN1A missense mutations that induce relatively moderate channel dysfunction, consistent with the relatively milder seizure phenotype. A large and increasing number of mutations have been identified, and both the severity and pervasiveness of the phenotype vary considerably. Many GEFS+ patients outgrow the seizure phenotype, but not all do, and GEFS+ patients with childhood epilepsy are considerably more likely to have epilepsy as adults than the general population. Mutations that cause deficits in other genes involved in GABA-ergic signaling, such as SCN1B which encodes the sodium channel auxiliary subunit and GABRG2 which encodes a GABAA receptor subunit can also give rise to GEFS+ (Helbig, I., Seminars in Neurology (2015) Vol. 35, pp. 288 to 292).

[008] Transgenic mice were developed that contain the same mutations identified in patients with SMEI and GEFS+. In both cases, mice replicate the human phenotype well, although the penetrance of the phenotype can be significantly impacted by genetic background. Some strains of mice tolerate the mutations relatively well, while in other strains the same mutations can cause drastic seizure phenotypes. These differences are presumed to be due to different expression levels of other genes that modulate the arousal phenotype (Miller, A.R. et al., Genes, Brain, and Behavior (2014), Vol. 13, pp. 163 to 172; Mistry, A. M. et al., Neurobiology of Disease (2014), Vol. 65, pp. 1 to 11; and Hawkins, N. A. et al., Epilepsy Research (2016), Vol. 119, pp. 20 to 23).

[009] In the brain, NaV1.2 and NaV1.6 are mainly expressed in excitatory glutamatergic neurons. Both channels are especially dense in the action initial segment (AIS), a region of the neuron adjacent to the neuronal soma that acts to integrate inputs and initiate action potential propagation to the soma and distal dendrites (Royeck, M. et al ., J. Neurophysiol. (2008), Vol. 100, pp. 69 to 73; et al., Nat. Neurosci. (2009), Vol. 12, pp. 996 to 1002). NaV1.6 tends to be especially densely located in the early AIS (distal from the soma) where it is believed to act to activate action potential initiation. NaV1,2 is most highly localized in the segment of the AIS most proximal to the soma. Mutations in both SCN2A (NaV1.2) and SCN8A (NaV1.6) have been associated with epilespy and cognitive delay. The effects of mutations are diverse, both in terms of impact on channel function and on the patient's phenotype. Both NaV1.2 and NaV1.6 are also expressed in peripheral neurons. NaV1.6 is especially dense in the nodes of Ranvier of myelinated neurons, where it is critical for maintaining saltatory conduction and high-speed neuronal signaling.

[010] Only one group of NaV1,2 mutations has been described, but they are mainly associated with pathologies of the central nervous system, especially epilepsy (Kearney, J.A. et al., Neuroscience (2001), Vol. 102, pp. 307 a 317; Zerem, A. et al., European Journal of Pediatric Neurology: EJPN: Official Journal of the European Pediatric Neurology Society (2014), Vol. 18, pp. 567-571; & Development (2015), Vol. 37, pp. 631 to 634; ), Vol. 117, pp. 1 to 6; Samanta, D. et al., Acta Neurologica Belgica (2015), Vol. 115, pp. 773 to 776; Vol. 26, pp. 60 to 65; and Schwarz, N. et al., Journal of Neurology (2016), Vol. 263, pp. 334 to 343). Epilepsy mutations are presumed to be primarily gain of function mutations, meaning that they lead to an increase in the amount of sodium current and therefore increase excitability. Establishing the impact on channel function in vivo beyond a reasonable doubt is challenging, and some of these mutations can lead to loss-of-function phenotypes.

[011]Mutations in SCN8A have also been reported to show a range of gain and loss of function effects on the NaV1.6 channel, for NaV1.6, the majority of mutations examined have been associated with gain of function phenotypes. Mutations in NaV1.6 have been associated with epilepsy and autism spectrum disorders (Trudeau, M.M. et al., Journal of Medical Genetics (2006), Vol. 43, pp. 527 to 530; Veeramah, K.R. et al., Am . J. Hum. Genet. (2012), Vol. 90, pp. 502 to 510; ; Estacion, M. et al., Neurobiology of Disease (2014), Vol. 69, pp. 117 to 123; , J.L. et al., Human Molecular Genetics (2014); Kong, W. et al., Epilepsia (2015), Vol. 56, pp. 431 to 438; Vol. 84, pp. 480 to 489). The best described SCN8A mutant patients have a syndrome known as early infantile epileptic encephalopathy, 13 (EIEE13). More than 100 EIEE13 patients have been identified. Patients typically present with intractable seizures between birth and 18 months of age. Patients have developmental and cognitive delays, and motor impairment is often associated with chronic muscular hypotonia. The most severely impacted patients never gain enough motor control to walk. Many are non-verbal. Less severe phenotypes learn to walk and talk, but are motor impaired and lose cognitive and social references. The majority of identified mutations consist of missense mutations, and the specific functional impact of the mutation is presumed to contribute to the variability of the phenotype, although genetic background is also likely involved (Larsen, J. et al., Neurology (2015), Vol. 84, pp. 480 to 489). Unlike patients with SMEI, anecdotal evidence suggests that antiepileptic drugs that target voltage-gated sodium channels non-selectively may improve symptoms in patients with SME13, although no controlled clinical trials have been completed (Boerma, R.S. et al., Neurotherapeutics : The Journal of the American Society for Experimental NeuroTherapeutics (2016), Vol. 13, pp. 192 to 197). Although phenytoin appears to provide efficacy for patients with EIEE13, it comes at a cost. Efficacy is only achieved at very high doses, where significant adverse effects are tolerated only because patients are in dire need. Adverse effects commonly associated with phenytoin therapy include hepatic necrosis, hypertrichosis, nervousness, hand tremor, numbness, dizziness, drowsiness, tremor, depression, confusion, fatigue, constipation, vertigo, ataxia, mental status changes, myasthenia, changes in mood, restlessness, irritability and excitement. It seems likely that a drug that selectively targets NaV1.6 will maintain efficacy while reducing its adverse event burden.

[012] Loss-of-function mutations in SCN8A in mice lead to a phenotype known as terminal motor disease (med) and multiple mutations and phenotypes have been linked to the med gene region prior to the identification of the SCN8A gene (Burgess, D.L. et al., Nat. Genet. (1995), Vol. 10, pp. 461 to 465). Mice with SCN8Amed mutations have varying degrees of muscle hypotonia, consistent with the degree of dysfunction of NaV1,6 function. SCN8Amed/jo mice have NaV1.6 channels that have a loss-of-function, but not null, phenotype. SCN8Amed and SCN8Amed/jo mice are resistant to seizures induced by chemical insult (flurotyl, kainic acid, and picrotoxin) (Martin, M.S. et al., Human Molecular Genetics (2007), Vol. 16, pp. 2892 to 2899; Hawkins, N.A. et al., Neurobiology of Disease (2011), Vol. 41, pp. 655 to 660; and Makinson, C.D. et al., Neurobiology of Disease (2014), Vol. 68, pp. 16 to 25). Interestingly, when SCN8Amed/jo mice are crossed with SCN1Anull mutant mice to produce a mouse that is heterozygous for both the SCN1Anull allele and the SCN8Amed/jo allele, the double mutant mice have a much better cognitive and seizure phenotype than those with only one SCN1Anull mutation (Martin, M.S. et al., Human Molecular Genetics (2007), Vol. 16, pp. 2892 to 2899). Such mice have a spontaneous seizure and mortality rate similar to wild-type mice and their seizure threshold following chemical insult is also increased. A similar result occurs when crossing mice with SCN1A missense mutations (a model of GEFS+) and mice with SCN8A loss-of-function mutations. Having a single allele of SCN8Amed/jo protected GEFS+ model mice against seizures and premature death (Hawkins, N.A. et al., Neurobiology of Disease (2011), Vol. 41, pp. 655 to 660). The ability of SCN8A to silence seizure resistance is not limited to knockouts in which the gene is globally absent during animal development. Silencing SCN8A in adult mice both globally and specifically in the hippocampus via a CRE-LOX inducible knockout approach also improved resistance to electrically and chemically induced seizures Makinson, C.D. et al., Neurobiology of Disease (2014), Vol. 68, pp. 16 to 25). These data suggest that the suppression of inhibitory signaling caused by reduced NaV1.1 current can be displaced, at least in part, by suppressing excitatory signaling through a reduction in NaV1.6 current.

[013] Voltage-dependent sodium channel antagonism is the most common mechanism of widely prescribed antiepileptic drugs (AED's) (Ochoa, J.R. et al., Sodium Channel Blockers. In: Antiepileptic Drugs (2016), Vol. (Benbadis, S., ed) Medscape News & Perspectives). It is believed that Carbamazepine, Eslicarbazepine, Oxcarbazepine, Lacosamide, Lamotrigine, Phenytoin, Rufinamide and Zonisamide act mainly by blocking this function of NaV channels. Despite the presumed mechanism of action, these drugs are relatively common. They block all NaV channel isoforms indiscriminately, thus, blockade of NaV1.1 could be expected to be pro-convulsant. Blockade of NaV1.6, and perhaps NaV1.2, could be anti-convulsant. In addition to sodium channels, these compounds also block other targets, including voltage-gated calcium channels. Selective NaV antagonists that spare NaV1,1 and other off-target receptors are expected to have both improved efficacy and therapeutic index over currently available NaV-blocking drugs.

[014] Therefore, there is an unmet medical need to treat epilepsy and other associated physiological states of NaV1.6 effectively and without adverse side effects due to blockade of other sodium channels such as NaV1.1 and/or NaV1.5. The present invention provides methods for satisfying these essential needs.

SUMMARY OF THE INVENTION

[015] The present invention relates to benzenesulfonamide compounds and pharmaceutical compositions comprising the compounds and methods of using the compounds and pharmaceutical compositions of the invention for the treatment of diseases or conditions associated with the activity of voltage-gated sodium channels, particularly , NaV1.6 activity, such as epilepsy and/or epileptic seizure disorder.

[016] Consequently, in one aspect, this invention relates to benzenesulfonamide compounds of formula (I):

[017] where:

[018]n is 1, 2, 3;

[019]m is 1, 2, 3 or 4;

[020]X is a direct bond or C(R9)R10;

[021] Y is a direct bond or C(R11)R12;

[022] R1 is hydrogen, alkyl, -R17-OR14, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted N-heterocyclyl, an optionally substituted N-heteroaryl, an optionally substituted O-heteroaryl or an optionally substituted S-heteroaryl;

[023] R2 is an optionally substituted 5-membered N-heteroaryl or an optionally substituted 6-membered N-heteroaryl;

[024]R3 is O or N(R13);

[025] R4 and R5 are each independently hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;

[026] or R4 and R1, together with the carbon to which they are attached, form an optionally substituted cycloalkyl, an optionally substituted heterocyclyl or an optionally substituted aryl, and R5, if present, is hydrogen, alkyl, haloalkyl, cycloalkyl optionally substituted, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;

[027] each R6 is independently hydrogen, alkyl, alkenyl, halo, haloalkyl, cyano, OR14 or optionally substituted cycloalkyl;

[028] R7 is alkyl, halo, haloalkyl, cyano or OR14;

[029] each R8 is independently hydrogen, alkyl, halo, haloalkyl or OR14;

[030] or two R8's, together with the carbon to which they are both attached, can form an optionally substituted cycloalkyl;

[031] R9, R10, R11 and R12 are each independently hydrogen, alkyl, haloalkyl or OR14;

[032]or R9 and R11 form an optionally substituted alkylene chain and R10 and R12 are as defined above; It is

[033] R13 is hydrogen, alkyl or haloalkyl;

[034] each R14 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl; It is

[035] R17 is a direct bond or an optionally substituted alkylene chain;

[036] as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;

[037] or a pharmaceutically acceptable salt, solvate or prodrug thereof;

[038] provided that when R3 is -O-, R2 is not optionally substituted thiadiazolyl.

[039] The compounds of the invention, which are the compounds of formula (I), as described above, as individual stereoisomers, enantiomers or tautomers thereof or mixtures thereof; or as pharmaceutically acceptable salts, solvates or prodrugs thereof, are useful in the treatment of diseases or conditions associated with voltage-gated sodium channels, preferably NaV1,6. Preferably, the compounds of the invention are inhibitors of NaV1,6. More preferably, the compounds of the invention show selectivity of inhibiting NaV1.6 compared to inhibiting NaV1.5 and/or NaV1.1. Without being bound by theory, it is believed that such selectivity advantageously reduces any side effects that may be associated with the inhibition of NaV1.5 and/or NaV1.1.

[040] In another aspect, the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound of formula (I), as described above, as a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[041] In another aspect, the invention provides methods for treating epilepsy and/or epileptic seizure disorder in a mammal, preferably a human being, wherein the methods comprise administering to the mammal in need thereof a therapeutically effective amount of a compound of the invention, as set forth above, as a stereoisomer, enantiomer or tautomer or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, as set forth above, as a stereoisomer, enantiomer or tautomer or mixtures thereof, or a salt, solvate or pharmaceutically acceptable prodrug and a pharmaceutically acceptable excipient.

[042] In another aspect, the present invention provides a method for treating or reducing the severity of a disease, condition or disorder in a mammal in which activation or hyperactivity of NaV1,6 is implicated in the disease, condition or disorder, in which the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of the invention, as set forth above, as a stereoisomer, enantiomer or tautomer or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, as set forth above, as a stereoisomer, enantiomer or tautomer or mixtures thereof, or a salt, solvate or pharmaceutically acceptable prodrug and a pharmaceutically acceptable excipient.

[043] In another aspect, the invention provides methods for treating or ameliorating, but not preventing, epilepsy and/or epileptic seizure disorder in a mammal, wherein the methods comprise administering to the mammal in need thereof a therapeutically effective amount of a compound of the invention, as set forth above, as a stereoisomer, enantiomer or tautomer or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, as set forth above, as a stereoisomer, enantiomer or tautomer or mixtures thereof, or a salt, solvate or pharmaceutically acceptable prodrug and a pharmaceutically acceptable excipient.

[044] In another aspect, the invention provides pharmaceutical therapy in combination with one more compounds of the invention or one or more accepted therapies or as any combination thereof to increase the potency of an existing or future drug therapy or to reduce associated adverse effects. to accepted therapy. In one embodiment, the present invention relates to a pharmaceutical composition that combines compounds of the present invention with established or future therapies for the indications mentioned herein.

[045] In another aspect, this invention provides methods for inhibiting a first voltage-gated sodium channel in a mammal through a second voltage-gated sodium channel, wherein the method comprises administering to the mammal an inhibitory amount of a compound of the invention, as set forth above, as a stereoisomer, enantiomer or tautomer or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, as set forth above, as a stereoisomer, enantiomer or tautomer or mixtures thereof, or a salt, solvate or pharmaceutically acceptable prodrug and a pharmaceutically acceptable excipient.

[046] In another aspect, this invention relates to the use of the compounds of the invention, as presented above, as a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof. , or the use of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the invention, as set forth above, as a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for the treatment of a disease or condition associated with the activity of a voltage-gated sodium channel, preferably NaV1.6, in a mammal and preferably wherein the disease or condition is epilepsy and/or disorder epileptic convulsive.

DETAILED DESCRIPTION OF THE INVENTION Definitions

[047] Certain chemical groups named in this document may be preceded by an abbreviated notation that indicates the total number of carbon atoms that should be found in the indicated chemical group. For example; C7-C12alkyl describes an alkyl group, as defined below, that has a total of 7 to 12 carbon atoms, and C4-C12cycloalkylalkyl describes a cycloalkylalkyl group, as defined below, that has a total of 4 to 12 carbon atoms. The total number of carbons in the abbreviated notation does not include carbons that may exist in substituents of the described group.

[048] In addition to the previous description, as used in the specification and attached claims, except where otherwise specified, the following terms have the meaning indicated:

[049] "Alkyl" refers to a branched hydrocarbon chain radical consisting exclusively of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms, more preferably, one to six carbon atoms, and which is linked to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n- pentyl, 1,1-dimethylethyl (t-butyl), 3-methylexyl, 2-methylexyl, and the like. When specifically indicated in the specification, an alkyl group may be optionally substituted by one of the following groups: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR20, -OC(O)-R20, - N(R20)2, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O)OR22, - N(R20)C(O )R22, -N(R20)S(O)pR22 (where p is 1 to 2), -S(O)pOR22 (where p is 1 to 2), - S(O)tR22 (where t is 0 to 2), and -S(O)pN(R20)2 (where p is 1 to 2) wherein each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[050] "Alkenyl" refers to a linear or branched hydrocarbon chain radical group consisting exclusively of carbon and hydrogen atoms, containing at least one double bond, which has from two to twelve carbon atoms, preferably, two to eight carbon atoms and which is linked to the rest of the molecule by a single bond, for example, ethenyl, propenyl, but1enyl, pent1enyl, penta1,4dienyl, and the like. When specifically indicated in the specification, an alkenyl group may be optionally substituted by one of the following groups: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR20, -OC(O)-R20, - N(R20)2, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O)OR22, - N(R20)C(O )R22, -N(R20)S(O)pR22 (where p is 1 to 2), -S(O)pOR22 (where p is 1 to 2), - S(O)tR22 (where t is 0 to 2), and -S(O)pN(R20)2 (where p is 1 to 2) wherein each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[051] "Alkylene" or "alkylene chain" refers to a linear or branched bivalent hydrocarbon chain that links the remainder of the molecule to a radical group or links two parts of the molecule, which consists exclusively of carbon and hydrogen, not containing unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain may optionally contain one or more heteroatoms in which a carbon in the alkylene chain is replaced by a heteroatom selected from oxygen, nitrogen or sulfur. The alkylene chain is linked to the rest of the molecule through a single bond and to the radical group through a single bond or is linked to two parts of the molecule through a single bond at each connection point. When specifically indicated in the specification, an alkylene chain may be optionally substituted by one of the following groups: alkyl, halo alkenyl, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR20, -OC( O)-R20, -N(R20)2, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)C(O)OR22, -N (R20)C(O)R22, -N(R20)S(O)pR22 (where p is 1 to 2), -S(O)pOR22 (where p is 1 to 2), -S(O) tR22 (where t is 0 to 2), and -S(O)pN(R20)2 (where p is 1 to 2) wherein each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl , heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[052] “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For the purposes of this invention, the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceantrylene, cenaphthylene, acephenantrilene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene , pyrene and triphenylene. When specifically indicated in the specification, an aryl group may be optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R21-OR20, -R21-OC(O)-R20, -R21- N(R20)2, -R21-C(O)R20, -R21-C(O)OR20, -R21 -C(O)N(R20)2, -R21-N(R20)C(O)OR22, -R21- N(R20)C(O)R22, -R21-N(R20)S(O)pR22 ( where p is 1 to 2), -R21-N=C(OR20)R20, -R21- S(O)pOR22 (where p is 1 to 2), -R21-S(O)tR22 (where t is 0 to 2), and -R21-S(O)pN(R20)2 (where p is 1 to 2) wherein each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R21 is independently a direct bond or a straight or branched alkylene chain; and each R22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl. Preferably, the optional substituents on an optionally substituted aryl group for R1 herein are selected from alkyl, optionally substituted cycloalkyl, halo, haloalkyl, optionally substituted aryl, -R21-OR20, -R21- C(O)OR20 and -R21-N(R20)2 (where R20 and R21 are as defined above). Preferably, the optional substitutions on an optionally substituted aryl group for R5 herein are halo.

[053] “Aralkyl” refers to a radical of the formula RbRc in which Rb is an alkylene chain as defined above and Rc is one or more aryl radicals as defined above, for example, benzyl, diphenyl methyl and the like. The alkylene chain portion of the arylalkyl radical may be optionally replaced as described above with an alkylene chain. The aryl part of the arylalkyl radical may be optionally substituted as described above by an aryl group.

[054] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, of preference. Having three to ten carbon atoms and which is saturated or unsaturated and linked to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, and the like. When specifically indicated in the specification, a cycloalkyl group may be optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R21-OR20, -R21-OC(O)-R20, -R21-N(R20)2, -R21-C(O)R20, - R21-C(O)OR20, -R21-C(O)N(R20)2, -R21-N(R20)C(O)OR22, -R21-N(R20)C(O)R22, -R21- N(R20)S(O) pR22 (where p is 1 to 2), -R21-N=C(OR20)R20, -R21-S(O)pOR22 (where p is 1 to 2), -R21-S(O)tR22 (in where t is 0 to 2), and -R21-S(O)pN(R20)2 (where p is 1 to 2) wherein each R20 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R21 is independently a direct bond or a straight or branched alkylene chain; and each R22 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl. Preferably, the optional substituents on the optionally substituted cycloalkyl group when R4 and R1, together with the carbon to which they are attached, form an optionally substituted cycloalkyl herein are aryl.

[055] “Cycloalkylalkyl” refers to a radical of the formula -Rb-Rg where Rb is an alkylene chain as defined above and Rg is a cycloalkyl radical as defined above. When specifically indicated in the specification, the alkylene chain and/or the cycloalkyl radical may be optionally substituted as defined above by an optionally substituted alkylene chain and optionally substituted cycloalkyl.

[056] “Halo” refers to bromine, chlorine, fluoro or iodine.

[057] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 -trifluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. The alkyl part of the haloalkyl radical may be optionally substituted as described above by an alkyl group.

[058] “Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical consisting of two to twelve carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Except where otherwise specifically indicated in the specification, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, bridged and spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, dioxynyl, thienyl[1,3]dithyanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, ila , oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, 1,2,4-thiadiazol-5(4H)-ylidene, tetrahydrofuryl, trioxanyl, tritianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1- oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. When specifically indicated in the specification, a heterocyclyl group may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl , heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R21-OR20, -R21-OC(O)-R20, -R21-N(R20)2, -R21-C(O)R20, -R21- C(O)OR20 , -R21-C(O)N(R20)2, -R21-N(R20)C(O)OR22, -R21-N(R20)C(O)R22, -R21- N(R20)S(O )pR22 (where p is 1 to 2), -R21-N=C(OR20)R20, -R21-S(O)pOR22 (where p is 1 to 2), -R21-S(O)tR22 ( where t is 0 to 2), and -R21-S(O)pN(R20)2 (where p is 1 to 2) wherein each R20 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl , aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R21 is independently a direct bond or a straight or branched alkylene chain; and each R22 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[059] "N-heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen. The point of attachment of the N-heterocyclyl to the rest of the molecule can be through a nitrogen atom or a carbon atom in the N-heterocyclyl. When specifically indicated in the specification, an N-heterocyclyl radical may be optionally substituted as described above by an optionally substituted heterocyclyl radical.

[060] “Heterocyclylalkyl” refers to a radical of the formula -RbRh wherein Rb is an alkylene chain as defined above and Rh is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl can be linked to the alkyl radical on the nitrogen atom. When specifically indicated in the specification, the alkylene chain of the heterocyclylalkyl radical may be optionally substituted as defined above by an optionally substituted alkylene chain. When specifically indicated in the specification, the heterocyclyl moiety of the heterocyclylalkyl radical may be optionally substituted as defined above by an optionally substituted heterocyclyl group.

[061] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and at least minus one aromatic ring. For the purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom may optionally be quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2- a]pyridinyl, benzoxazolinonyl, benzimidazolthionyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, iso thiazolyl , imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, inila, 1 -phenyl-1H- pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pyrimidinonyl, pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinyl, quinazolinyl , quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl, tetrazolyl, triazinyl and thiophenyl (i.e., thienyl). When specifically indicated in the specification, a heteroaryl group may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, thioxo, aryl, aralkyl, cycloalkyl , cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R21- OR20, -R21-OC(O)-R20, -R21-N(R20)2, -R21-C(O)R20, -R21-C(O )OR20, -R21-C(O)N(R20)2, - R21-N(R20)C(O)OR22, -R21-N(R20)C(O)R22, -R21-N(R20)S (O)pR22 (where p is 1 to 2), - R21-N=C(OR20)R20, -R21-S(O)pOR22 (where p is 1 to 2), -R21-S(O) tR22 (where t is 0 to 2), and -R21-S(O)pN(R20)2 (where p is 1 to 2) wherein each R20 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl , aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R21 is independently a direct bond or a straight or branched alkylene chain; and each R22 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[062] “N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen. The point of attachment of the N-heteroaryl to the rest of the molecule can be through a nitrogen atom or a carbon atom in the N-heteroaryl. When specifically indicated in the specification, an N-heteroaryl radical may be optionally substituted as described above by an optionally substituted heteroaryl radical herein. alkyl, optionally substituted cycloalkyl, halo, haloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and -R21-OR20 (wherein R20 and R21 are as defined above for heteroaryl groups. Preferably, the optional substitutions on an optionally N-heteroaryl group). substituted for R2 in this document are halo.

[063] "O-heteroaryl" refers to a heteroaryl radical as defined above in which the only heteroatoms present are oxygen. The point of attachment of the O-heteroaryl to the rest of the molecule is through a carbon atom in the O-heteroaryl radical. When specifically indicated in the specification, an O-heteroaryl radical may be optionally substituted as described above by an optionally substituted heteroaryl radical. Preferably, the optional substitutions on an optionally substituted O-heteroaryl group for R1 herein are alkyl and haloalkyl.

[064] “S-heteroaryl" refers to a heteroaryl radical as defined above in which the only heteroatoms present are sulfur. The point of attachment of the S-heteroaryl to the rest of the molecule is through a carbon atom in the S- radical heteroaryl. When specifically indicated in the specification, an S-heteroaryl radical may be optionally substituted as described above by an optionally substituted heteroaryl radical in this document.

[065] “Heteroarylalkyl” refers to a radical of the formula -Rb-Ri in which Rb is an alkylene chain as defined above and Ri is a heteroaryl radical as defined above. When specifically indicated in the specification, the heteroaryl part of the heteroaryl alkyl radical may be optionally substituted as defined above by an optionally substituted heteroaryl group. When specifically indicated in the specification, the alkylene chain portion of the heteroarylalkyl radical may be optionally substituted as defined above by an optionally substituted alkylene chain.

[066] “Prodrug” is intended to indicate a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound of the invention. Thus, the term "prodrug" refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. A prodrug may be inactive when administered to an individual in need of it, but is converted in vivo into an active compound of the invention. Prodrugs are typically rapidly transformed in vivo to produce the parent compound of the invention, for example, by hydrolysis in the blood. The prodrug compound generally offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7 to 9, 21 to 24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are fully incorporated by reference herein.

[067] The term "prodrug" is also intended to include any covalently linked carriers, which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the invention can be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. Prodrugs include compounds of the invention in which a hydroxy, amino or mercapto group is attached to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, is cleaved to form a free hydroxy, amino group. livre or mercapto livre, respectively. Examples of prodrugs include, but are not limited to, alcohol acetate, formate and benzoate derivatives or amide derivatives of amino-functional groups in the compounds of the invention and the like.

[068] The invention disclosed in this document also intends to cover all pharmaceutically acceptable compounds of formula (I) that are isotopically labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. Such radiolabeled compounds could be useful in helping to determine or measure the effectiveness of compounds by characterizing, for example, the site or mode of action on sodium channels, or the binding affinity to the pharmacologically important site of action on sodium channels. Certain isotopically labeled compounds of formula (I), for example, those that incorporate a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes of tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and available means of detection.

[069] Replacement with heavier isotopes such as deuterium, i.e., 2H, may provide certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. In one embodiment of the invention, the compounds of formula (I) are enriched with deuterium. Such deuterated compounds can be obtained by methods known to those skilled in the art, such as by exchanging protons with deuterium or by synthesizing the molecule with enriched starting materials.

[070] Replacement with positron-emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples and Preparations as set forth below using a suitable isotopically labeled reagent from the unlabeled reagent previously employed.

[071] The invention disclosed in this document is also intended to cover the in vivo metabolic products of the disclosed compounds. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, mainly due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising placing a compound of this invention in contact with a mammal for a period of time sufficient to produce a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey or human, allowing sufficient time for metabolism to occur and isolating their products from conversion from urine, blood or other biological samples.

[072] "Stable compound" and "stable structure" mean a compound that is robust enough to survive isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

[073] “Mammal” includes humans and domestic animals such as laboratory animals and pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wild animals and the like .

[074] “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances in which said event or circumstance occurs and instances in which it does not. For example, “optionally substituted arila " means that the aryl radical may or may not be substituted and that the description includes substituted aryl radicals and aryl radicals that have no substitution ("unsubstituted"). When a functional group is described as "optionally substituted," and in turn , substituents on the functional group also "optionally substituted" and so on, for the purposes of this invention, such iterations are limited to five, preferably, such iterations are limited to two.

[075] “Pharmaceutically acceptable carrier, diluent or excipient” includes, without limitation, any adjuvant, carrier, excipient, gliding agent, sweetening agent, diluent, preservative, dye/pigment, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[076] “Pharmaceutically acceptable salt” includes both acidic and basic addition salts.

[077] “Pharmaceutically acceptable acid addition salt” refers to those salts that maintain the biological efficacy and properties of free bases, that are not biologically or otherwise undesirable, and that are formed with inorganic acids such as, but without limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid , benzoic acid, 4-acetamidobenzoic acid, camphoric acid camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid , ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid , hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid , succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[078] “Pharmaceutically acceptable basic addition salt” refers to those salts that maintain the biological efficacy and properties of free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as ammonium resins, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromamamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[079] Generally, crystallizations produce a solvate of the compound of the invention. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of a compound of the invention with one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the compounds of the present invention can exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compound of the invention may be true solvates, while in other cases, the compound of the invention may maintain merely adventitious water or be a mixture of water plus some adventitious solvent.

[080] A "pharmaceutical composition" refers to a formulation of a compound of the invention and a means generally accepted in the art for delivering the biologically active compound to mammals, e.g., humans. Such medium includes all pharmaceutically acceptable carriers, diluents or excipients.

[081] "Therapeutically effective amount" refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human being, is sufficient to effect the treatment, as defined below, of a mediated disease or condition. through sodium channels in the mammal, preferably a human. The amount of a compound of the invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the form of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. taking into account your own knowledge and this revelation.

[082] "Treating" or "treatment" as used herein encompasses treating the disease or condition of interest in a mammal, preferably a human being, who has the disease or condition of interest, and includes:

[083] (a) prevent the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it;

[084](b) inhibit the disease or condition, that is, stop its development;

[085](c) mitigate (or improve) the disease or condition, that is, cause regression of the disease or condition; or

[086](D) attenuate (or improve) symptoms resulting from the disease or condition, for example, alleviating epilepsy without addressing the underlying disease or condition.

[087] As used herein, the terms "disease" and "condition" may be used interchangeably or may differ in that the specific illness or condition may not have a known causative agent (such that the etiology has not yet been worked out) and, therefore, is not yet recognized as a disease, but only as an undesirable condition or syndrome, in which a more or less specific set of symptoms has been identified by clinicians.

[088] The compounds of the invention, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and, therefore, may give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) - or (S)- or, like (D)- or (L)- for amino acids. The present invention is intended to include all of these possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, e.g. chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis of a suitable optically pure precursor or resolution of the racemate (or the racemate from a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). . When the compounds disclosed herein contain olefinic double bonds or other centers of geometric asymmetry, and except where otherwise specified, the compounds are intended to include E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included.

[089] A "stereoisomer" refers to a compound consisting of the same atoms linked by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other. See, for example, Smith, M. B., and J. March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th edition (Wiley, 2007), for a detailed description of the structure and properties of enantiomers and stereoisomers.

[090] A “tautomer” refers to a displacement of protons from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any of said compounds.

[091] The use of parentheses and brackets in substituent groups is done in this document to save space. Consequently, the use of parentheses around a substituent group indicates that the group within the parentheses is directly bonded to the atom preceding the parentheses. The use of parentheses around a substituent group indicates that the group enclosed within the parentheses is also directly bonded to the atom preceding the parentheses.

[092] The chemical nomenclature protocol and structure diagrams used in this document are a modified form of the I.U.P.A.C. nomenclature system, using the software program ChemBioDraw Ultra Version 14.0, in which the compounds of the invention are referred to in this document as derived from a central core structure, for example, the benzenesulfonamide structure. For complex chemical names used in this document, a substituent group is named before the group to which it is attached. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. In chemical structure diagrams, all bonds are identified except for a few carbon atoms, which are considered to be bonded to enough hydrogen atoms to complete the valence.

[093] "Enantiomers" refer to asymmetric molecules that can present themselves in two different isomeric forms that have different configurations in space. Other terms used to designate or refer to enantiomers include "stereoisomers" (due to the different arrangement or stereochemistry around the chiral center; although all enantiomers are stereoisomers, not all stereoisomers are enantiomers) or "optical isomers" (due to optical activity of pure enantiomers, which is the ability of different pure enantiomers to rotate plane-polarized light in different directions).

[094] The designations, "R" and "S", for the absolute configuration of an enantiomer of the invention may appear as a prefix or as a suffix in the name of the compound; they may or may not be separated from the name of the enantiomer by a hyphen; they may or may not be hyphenated; and they may or may not be in parentheses.

[095] Following standard chemical literature description practice and as used in this specification, a continuous bond, as illustrated above in Structure (A) and a dashed bond, as illustrated by exemplary structure (A) below, means that the substituents are in a trans configuration with respect to the plane of the ring:

[096] Likewise, the bonds in the following exemplary structures (Aa) and (Ab) are in a cis configuration relative to the plane of the ring:

[097] Following standard chemical literature description practice and as used in this specification, a total bond, as illustrated below in structure (B), means that the substituent attached to the ring by that bond, in this case, the substituent R30, is above the plane of the ring as illustrated on the page in a two-dimensional representation, and a dashed bond, as illustrated below in Structure (B), means that the substituent attached to the ring by that bond, in this case the substituent R31, is below the plane of the ring as shown on the page in a two-dimensional representation;

[098] Following standard chemical literature description practice and as used in this specification, a wavy bond, as illustrated below in structure (C), indicates that the substituent, in this case, the substituent R30, is below the plane of the ring or above the plane of the ring:

[099] In the formulas disclosed in this document, a bond to a substituent and/or a bond that connects a molecular fragment to the remainder of a compound can be shown as an intersection of one or more bonds in a ring structure. This indicates that the bond can be made to any of the atoms constituting the ring structure, as long as a hydrogen atom may otherwise be present on that atom. When no specific substituent is identified for a specific position in a structure, then hydrogen(s) is/are present at that position. For example, in the following structure (D), the bond connecting the substituent R30 can be on any of the carbons, including the carbon to which R31 is bonded, as long as the valence allows such a bond:

[0100] “Resolution” or “resolve” when used in reference to a racemic compound or a racemic mixture of a compound of the invention refers to the separation of the racemic compound or a racemic mixture into its two enantiomeric forms (i.e., (+ ) and (-); forms (R) and (S)).

[0101] “Enantiomeric excess" or "ee" as used herein, refers to a product in which one enantiomer is present in excess of the other, and is defined as the absolute difference in the mole fraction of each enantiomer. Enantiomer is typically expressed as a percentage of one enantiomer present in a mixture relative to the other enantiomer. For the purposes of this invention, the (S)-enantiomer of a compound prepared by the methods disclosed herein is considered to be "substantially free" of the enantiomer. (R)-enantiomer corresponding when the (S)-enantiomer is present in enantiomeric excess greater than 80%, preferably greater than 90%, more preferably greater than 95% and most preferably greater than 99%.

[0102] The chemical nomenclature protocol and structure diagrams used in the present document are a modified form of the I.U.P.A.C. nomenclature system, using the software program ChemBioDraw Ultra Version 14.0, in which the compounds of the invention are referred to in the present document as derived from a central core structure, for example, the benzenesulfonamide structure. For complex chemical names used in this document, a substituent group is named before the group to which it is attached. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. In chemical structure diagrams, all bonds are identified except for a few carbon atoms, which are considered to be bonded to enough hydrogen atoms to complete the valence.

[0103] Consequently, the enantiomer (R) of a compound of formula (I) as described above in the Summary of the Invention wherein n is 1, m is 1, X is a direct bond, Y is -C(R11)R12- , R1 is phenyl, R2 is thiazol-2-yl, R3 is -N(R13)-, R4 and R5 are each hydrogen, R6 is hydrogen, R7 is chlorine, R11 is hydrogen, R12 is hydrogen, and R13 is hydrogen, that is, the compound of the following formula:

[0104] is referred to herein as (R)-4-(1-benzylpyrrolidin-3-ylamino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide;

EMBODIMENTS OF THE INVENTION

[0105] One aspect of the invention are compounds of formula (I) as presented above in the Summary of the Invention, as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0106] In one embodiment, a compound of formula (I) is a compound of formula (I) in which R3 is O, in which the compound has the following formula (Ia):

[0107] where m, n, X, Y, R1, R2, R4, R5, R6, R7 and R8 are each defined above in the Summary of the Invention of the compounds of formula (I);

[0108] as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;

[0109] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0110] In another embodiment, a compound of formula (I) is a compound of formula (Ia) as defined above in which:

[0111]n is 1 or 2;

[0112]m is 1 or 2;

[0113]X is a direct bond or C(R9)R10;

[0114]Y is a direct bond or C(R11)R12;

[0115] R1 is hydrogen, alkyl, -R17-OR14, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted N-heterocyclyl, an optionally substituted N-heteroaryl, an optionally substituted O-heteroaryl or an optionally substituted S-heteroaryl;

[0116] R2 is an optionally substituted 5-membered N-heteroaryl or an optionally substituted 6-membered N-heteroaryl;

[0117] R4 and R5 are each independently hydrogen, alkyl or haloalkyl;

[0118] or R4 and R1, together with the carbon to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted aryl, and R5, if present, is hydrogen, alkyl, haloalkyl or optionally substituted aryl;

[0119] each R6 is independently hydrogen, alkyl, alkenyl, halo, haloalkyl, cyano, OR14 or optionally substituted cycloalkyl;

[0120] R7 is alkyl, halo, haloalkyl, cyano or OR14;

[0121] each R8 is independently hydrogen, alkyl, halo, haloalkyl or OR14;

[0122] or two R8's, together with the carbon to which they are both attached, can form an optionally substituted cycloalkyl;

[0123] R9, R10, R11 and R12 are each independently hydrogen, alkyl, haloalkyl, alkyl or OR14;

[0124]or R9 and R11 form an optionally substituted alkylene chain and R10 and R12 are as defined above; It is

[0125] R13 is hydrogen, alkyl or haloalkyl;

[0126] each R14 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl; It is

[0127] R17 is a direct bond or an optionally substituted alkylene chain;

[0128] as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;

[0129] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0130] In another embodiment, a compound of formula (I) is a compound of formula (Ia) in which X and Y are both a direct bond, that is, a compound of formula (Ia1):

[0131] where:

[0132]n is 1 or 2;

[0133]m is 1 or 2;

[0134] R1 is hydrogen, alkyl, -R17-OR14, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted N-heterocyclyl, an optionally substituted N-heteroaryl, an optionally substituted O-heteroaryl or an optionally substituted S-heteroaryl;

[0135] R2 is an optionally substituted 5-membered N-heteroaryl or an optionally substituted 6-membered N-heteroaryl;

[0136] R4 and R5 are each independently hydrogen, alkyl or haloalkyl;

[0137] or R4 and R1, together with the carbon to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted aryl, and R5, if present, is hydrogen, alkyl, haloalkyl or optionally substituted aryl;

[0138] each R6 is independently hydrogen, alkyl, alkenyl, halo, haloalkyl, cyano, OR14 or optionally substituted cycloalkyl;

[0139] R7 is alkyl, halo, haloalkyl, cyano or OR14;

[0140] each R8 is independently hydrogen, alkyl, halo, haloalkyl or OR14;

[0141] or two R8's, together with the carbon to which they are both attached, can form an optionally substituted cycloalkyl;

[0142] each R14 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl; It is

[0143] R17 is a direct bond or an optionally substituted alkylene chain;

[0144] as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;

[0145] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0146] One embodiment of the compounds of formula (Ia1) are compounds of formula (1a1) in which R2 is an optionally substituted 5-membered N-heteroaryl.

[0147] Of this embodiment, a preferred embodiment consists of compounds of formula (Ia1) in which R2 is optionally substituted isoxazolyl, optionally substituted thiazolyl or optionally substituted thiadiazolyl.

[0148] Of this embodiment, a preferred compound is 4-((1-benzylazetidin-3-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide.

[0149] Another preferred embodiment of compounds of formula (Ia1) consists of compounds of formula (Ia1) in which R2 is an optionally substituted 6-membered N-heteroaryl.

[0150] Of this embodiment, a preferred embodiment consists of compounds of formula (Ia1) in which R2 is optionally substituted pyridinyl.

[0151] In another embodiment, a compound of formula (I) is a compound of formula (Ia) in which X is C(R9)R10 and Y is a direct bond, that is, a compound of formula (Ia2):

[0152] where:

[0153]n is 1 or 2;

[0154]m is 1 or 2;

[0155] R1 is hydrogen, alkyl, -R17-OR14, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted N-heterocyclyl, an optionally substituted N-heteroaryl, an optionally substituted O-heteroaryl or an optionally substituted S-heteroaryl;

[0156] R2 is an optionally substituted 5-membered N-heteroaryl or an optionally substituted 6-membered N-heteroaryl;

[0157] R4 and R5 are each independently hydrogen, alkyl or haloalkyl;

[0158] or R4 and R1, together with the carbon to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted aryl, and R5, if present, is hydrogen, alkyl, haloalkyl or optionally substituted aryl;

[0159] each R6 is independently hydrogen, alkyl, alkenyl, halo, haloalkyl, cyano, OR14 or optionally substituted cycloalkyl;

[0160] R7 is alkyl, halo, haloalkyl, cyano or OR14;

[0161] each R8 is independently hydrogen, alkyl, halo, haloalkyl or OR14;

[0162] or two R8's, together with the carbon to which they are both attached, can form an optionally substituted cycloalkyl;

[0163] R9 and R10 are each independently hydrogen, alkyl, haloalkyl, alkyl or OR14;

[0164] each R14 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl; It is

[0165] R17 is a direct bond or an optionally substituted alkylene chain;

[0166] as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;

[0167] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0168] One embodiment of the compounds of formula (Ia2) are compounds of formula (1a2) in which R2 is an optionally substituted 5-membered N-heteroaryl.

[0169] Of this embodiment, a preferred embodiment consists of compounds of formula (Ia2) in which R2 is optionally substituted isoxazolyl, optionally substituted thiazolyl or optionally substituted thiadiazolyl.

[0170] Within the compounds of formula (Ia2), preferred compounds are selected from:

[0171](S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0172](S)-4-((1-benzylpyrrolidin-3-yl)oxy)-3-ethyl-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0173](S)-4-((1-benzylpyrrolidin-3-yl)oxy)-3-bromo-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0174](S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-2-yl)benzenesulfonamide;

[0175](S)-4-((1-benzylpyrrolidin-3-yl)oxy)-2,6-difluoro-N-(thiazol-4-yl)-3-vinylbenzenesulfonamide;

[0176]rac-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0177](S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0178](R)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0179](S)-4-((1-benzylpyrrolidin-3-yl)oxy)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0180](S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0181](S)-4-((1-benzylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide; It is

[0182](S)-4-((1-benzylpyrrolidin-3-yl)oxy)-3-chloro-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide.

[0183] Another preferred embodiment of compounds of formula (Ia2) consists of compounds of formula (Ia2) in which R2 is an optionally substituted 6-membered N-heteroaryl.

[0184] Of this embodiment, a preferred embodiment consists of compounds of formula (Ia2) in which R2 is optionally substituted pyridinyl.

[0185] In another embodiment, a compound of formula (I) is a compound of formula (Ia) in which X is C(R9)R10 and Y is C(R11)R12, that is, a compound of formula (Ia3) :

[0186]n is 1 or 2;

[0187]m is 1 or 2;

[0188]X is a direct bond or C(R9)R10;

[0189]Y is a direct bond or C(R11)R12;

[0190] R1 is hydrogen, alkyl, -R17-OR14, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted N-heterocyclyl, an optionally substituted N-heteroaryl, an optionally substituted O-heteroaryl or an optionally substituted S-heteroaryl;

[0191] R2 is an optionally substituted 5-membered N-heteroaryl or an optionally substituted 6-membered N-heteroaryl;

[0192] R4 and R5 are each independently hydrogen, alkyl or haloalkyl;

[0193] or R4 and R1, together with the carbon to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted aryl, and R5, if present, is hydrogen, alkyl, haloalkyl or optionally substituted aryl;

[0194] each R6 is independently hydrogen, alkyl, alkenyl, halo, haloalkyl, cyano, OR14 or optionally substituted cycloalkyl;

[0195] R7 is alkyl, halo, haloalkyl, cyano or OR14;

[0196] each R8 is independently hydrogen, alkyl, halo, haloalkyl or OR14;

[0197] or two R8's, together with the carbon to which they are both attached, can form an optionally substituted cycloalkyl;

[0198] R9, R10, R11 and R12 are each independently hydrogen, alkyl, haloalkyl, alkyl or OR14;

[0199]or R9 and R11 form an optionally substituted alkylene chain and R10 and R12 are as defined above; It is

[0200] each R14 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl; It is

[0201] R17 is a direct bond or an optionally substituted alkylene chain;

[0202] as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;

[0203] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0204] Of this embodiment, a preferred embodiment consists of compounds of formula (Ia3) in which R2 is an optionally substituted 5-membered N-heteroaryl.

[0205] Of this embodiment, a more preferred embodiment consists of compounds of formula (Ia3) in which R2 is optionally substituted isoxazolyl, optionally substituted thiazolyl or optionally substituted thiadiazolyl.

[0206] Of this preferred embodiment, a preferred embodiment consists of compounds of formula (Ia3) in which R1 is optionally substituted aryl or optionally substituted aralkyl; and R9, R10, R11 and R12 are each independently hydrogen or alkyl.

[0207] Within the compounds of formula (Ia3), preferred compounds are selected from:

[0208]5-chloro-2-fluoro-4-(1-(1-phenylethyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0209]3-chloro-4-(1-(1-phenylethyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0210]3-chloro-4-(1-(3-fluorobenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0211]3-chloro-4-(1-(3-(difluoromethyl)benzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0212]3-chloro-4-(1-(3-(difluoromethoxy)benzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0213]3-chloro-4-(1-((6-methylpyridin-2-yl)methyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0214]3-chloro-4-(1-(3-methoxybenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0215]3-chloro-4-(1-(3-chlorobenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0216]3-chloro-4-(1-(2-fluorobenzyl)-3-methylpiperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0217]3-chloro-4-(3-methyl-1-(3-methylbenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0218]4-(1-benzyl-3-methylpiperidin-4-yloxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide;

[0219]3-chloro-4-(1-(2-fluorobenzyl)-3-methylpiperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0220]3-chloro-4-(3-methyl-1-(3-methylbenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0221]4-(1-benzyl-3-methylpiperidin-4-yloxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide;

[0222]3-chloro-4-(1-(naphthalen-2-ylmethyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0223]3-chloro-4-(1-(2-fluorobenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0224]3-chloro-4-(1-(2-methylbenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0225]3-chloro-4-(1-(3-methylbenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0226]3-chloro-4-(1-(pyridin-2-ylmethyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0227]3-chloro-4-(1-(pyridin-3-ylmethyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0228]3-chloro-4-(1-(pyridin-4-ylmethyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0229]3-chloro-4-(1-(4-methoxybenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0230]3-chloro-4-(1-(3,4-dimethylbenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0231]3-chloro-4-(1-(3,5-dimethylbenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0232]3-chloro-4-(1-(4-methylbenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0233]4-(1-benzylpiperidin-4-yloxy)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide;

[0234]3-chloro-N-(thiazol-2-yl)-4-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yloxy)benzenesulfonamide;

[0235]3-chloro-4-(1-(4-fluorobenzyl)piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0236]4-(1-benzylpiperidin-4-yloxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide;

[0237]3-chloro-4-((1-(cyclohexylmethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0238]3-chloro-4-((1-cyclohexylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0239]3-chloro-N-(thiazol-2-yl)-4-((1-(2-(trifluoromethyl)benzyl)piperidin-4-yl)oxy)benzenesulfonamide;

[0240]3-chloro-4-((1-(2-chlorobenzyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0241]3-chloro-4-((1-((4-methylpyridin-2-yl)methyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0242]4-((1-benzyl-4-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide;

[0243]3-chloro-4-((1-(3-chlorobenzyl)-4-methylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0244]3-chloro-4-((1-(3-(difluoromethyl)benzyl)-4-methylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0245]3-chloro-4-((1-(2,3-dihydro-1H-inden-1-yl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0246](R)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0247](R)-5-chloro-2-fluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0248](R)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide;

[0249](S)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0250]3-chloro-4-((1-(2-phenylpropan-2-yl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0251]5-chloro-2-fluoro-4-((1-(2-phenylpropan-2-yl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0252](R)-2,3-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide;

[0253](R)-3-chloro-2-fluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide;

[0254]4-((1-benzylpiperidin-4-yl)oxy)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0255]4-((1-benzylpiperidin-4-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0256]3-chloro-4-((1-(1-phenylcyclopropyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide;

[0257]5-chloro-4-(((3R,4S)-1-(3-(difluoromethyl)benzyl)-3-fluoropiperidin-4-yl)oxy)- 2-fluoro-N-(thiazol-4- il)benzenesulfonamide;

[0258](R)-5-chloro-2-fluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide;

[0259](R)-3-chloro-4-((1-(1-(5-chloro-2-fluorophenyl)ethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide ;

[0260](R)-2,6-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide;

[0261](R)-3-chloro-N-(isoxazol-3-yl)-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)benzenesulfonamide;

[0262]3-chloro-4-((1-phenethylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0263](R)-3-chloro-4-((1-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)piperidin-4-yl)oxy)- N-(thiazol-4- il)benzenesulfonamide;

[0264]4-((1-benzylpiperidin-4-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-2-yl)benzenesulfonamide;

[0265]4-((1-benzylpiperidin-4-yl)oxy)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0266]4-((cis-1-benzyl-2-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; It is

[0267]4-((trans-1-benzyl-2-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide.

[0268](R)-3-chloro-4-((1-(1-(5-cyclopropyl-2-fluorophenyl)ethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide ;

[0269](R)-3-chloro-4-((1-(1-(5-(difluoromethyl)-2-fluorophenyl)ethyl)piperidin-4-yl)oxy)- N-(thiazol-4-yl )benzenesulfonamide;

[0270](R)-3-chloro-2,6-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide;

[0271]3-chloro-4-((1-(3-(difluoromethyl)benzyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide;

[0272](R)-5-chloro-2-fluoro-4-((1-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)piperidin-4-yl)oxy)-N-( thiazol-4-yl)benzenesulfonamide;

[0273]4-((1-benzylpiperidin-4-yl)oxy)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0274](R)-2,6-difluoro-3-methyl-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide;

[0275]4-((1-benzylpiperidin-4-yl)oxy)-3-chloro-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide; It is

[0276]4-((1-benzylpiperidin-4-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide.

[0277] Another preferred embodiment of the compounds of formula (Ia3) are the compounds of formula (Ia3) in which:

[0278] R1 is optionally substituted aryl or optionally substituted aralkyl;

[0279] R9 and R11 form an optionally substituted alkylene chain; It is

[0280] R11 and R12 are each independently hydrogen or alkyl.

[0281] In this embodiment, the preferred compounds of formula (Ia3) are selected from:

[0282]4-((1R,3s,5S)-8-benzyl-8-azabicyclo[3,2,1]octan-3-yloxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide;

[0283]4-((1R,3r,5S)-8-benzyl-8-azabicyclo[3,2,1]octan-3-yloxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide;

[0284]4-(((1R,3s,5S)-8-benzyl-8-azabicyclo[3,2,1]octan-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazole -2-yl)benzenesulfonamide;

[0285]5-chloro-4-(((1R,3s,5S)-8-(3-chlorobenzyl)-8-azabicyclo[3,2,1]octan-3-yl)oxy)-2-fluoro- N-(thiazol-2-yl)benzenesulfonamide;

[0286]3-chloro-4-(((1R,3s,5S)-8-(5-chloro-2-fluorobenzyl)-8-azabicyclo[3,2,1]octan-3-yl)oxy)- N-(thiazol-4-yl)benzenesulfonamide;

[0287]4-(((1R,3s,5S)-8-benzyl-8-azabicyclo[3,2,1]octan-3-yl)oxy)-3-chloro-N- (thiazol-4-yl )benzenesulfonamide;

[0288]3-chloro-4-(((1R,3s,5S)-8-(3-chloro-4-fluorobenzyl)-8-azabicyclo[3,2,1]octan-3-yl)oxy)- N-(thiazol-4-yl)benzenesulfonamide; It is

[0289]3-chloro-4-(((1R,3s,5S)-8-(3-(difluoromethyl)benzyl)-8-azabicyclo[3,2,1]octan-3-yl)oxy)-N -(thiazol-4-yl)benzenesulfonamide.

[0290] Another preferred embodiment of compounds of formula (Ia3) consists of compounds of formula (Ia3) in which R2 is an optionally substituted 6-membered N-heteroaryl.

[0291] Of this embodiment, a preferred embodiment consists of compounds of formula (Ia3) in which R2 is optionally substituted pyridinyl or optionally substituted pyrimidinyl.

[0292] In this embodiment, the preferred compounds of formula (Ia3) are selected from:

[0293](R)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(pyrimidin-4-yl)benzenesulfonamide;

[0294](R)-3-chloro-N-(5-fluoropyrimidin-2-yl)-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)benzenesulfonamide;

[0295](S)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(pyrimidin-4-yl)benzenesulfonamide;

[0296]4-((1-benzylpiperidin-4-yl)oxy)-3-chloro-N-(6-fluoropyridin-2-yl)benzenesulfonamide; It is

[0297]4-((1-benzylpiperidin-4-yl)oxy)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide.

[0298] In another embodiment, a compound of formula (I) is a compound of formula (I) wherein R3 is N(R13), wherein the compound has the following formula (Ib):

[0299] wherein m, n, X, Y, R1, R2, R4, R5, R6, R7, R8 and R13 are each as defined above in the Summary of the Invention of the compounds of formula (I);

[0300] as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;

[0301] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0302] In another embodiment, the compound of formula (I) is a compound of formula (Ib) as defined above in which:

[0303]n is 1 or 2;

[0304]m is 1 or 2;

[0305]X is a direct bond or C(R9)R10;

[0306]Y is a direct bond or C(R11)R12;

[0307] R1 is hydrogen, alkyl, -R17-OR14, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted N-heterocyclyl, an optionally substituted N-heteroaryl, an optionally substituted O-heteroaryl or an optionally substituted S-heteroaryl;

[0308] R2 is an optionally substituted 5-membered N-heteroaryl or an optionally substituted 6-membered N-heteroaryl;

[0309] R4 and R5 are each independently hydrogen, alkyl or haloalkyl;

[0310] or R4 and R1, together with the carbon to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted aryl, and R5, if present, is hydrogen, alkyl, haloalkyl or optionally substituted aryl;

[0311] each R6 is independently hydrogen, alkyl, alkenyl, halo, haloalkyl, cyano, OR14 or optionally substituted cycloalkyl;

[0312] R7 is alkyl, halo, haloalkyl, cyano or OR14;

[0313] each R8 is independently hydrogen, alkyl, halo, haloalkyl or OR14;

[0314] or two R8's, together with the carbon to which they are both attached, can form an optionally substituted cycloalkyl;

[0315] R9, R10, R11 and R12 are each independently hydrogen, alkyl, haloalkyl, alkyl or OR14;

[0316] or R9 and R11 form an optionally substituted alkylene chain and R10 and R12 are as defined above; It is

[0317] R13 is hydrogen, alkyl or haloalkyl;

[0318] each R14 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl; It is

[0319] R17 is a direct bond or an optionally substituted alkylene chain;

[0320] as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;

[0321] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0322] In another embodiment, the compound of formula (I) is a compound of formula (Ib) in which X and Y are both a direct bond, that is, a compound of formula (Ib1):

[0323]n is 1 or 2;

[0324]m is 1 or 2;

[0325] R1 is hydrogen, alkyl, -R17-OR14, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted N-heterocyclyl, an optionally substituted N-heteroaryl, an optionally substituted O-heteroaryl or an optionally substituted S-heteroaryl;

[0326] R2 is an optionally substituted 5-membered N-heteroaryl or an optionally substituted 6-membered N-heteroaryl;

[0327] R4 and R5 are each independently hydrogen, alkyl or haloalkyl;

[0328] or R4 and R1, together with the carbon to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted aryl, and R5, if present, is hydrogen, alkyl, haloalkyl or optionally substituted aryl;

[0329] each R6 is independently hydrogen, alkyl, alkenyl, halo, haloalkyl, cyano, OR14 or optionally substituted cycloalkyl;

[0330] R7 is alkyl, halo, haloalkyl, cyano or OR14;

[0331] each R8 is independently hydrogen, alkyl, halo, haloalkyl or OR14;

[0332] or two R8's, together with the carbon to which they are both attached, can form an optionally substituted cycloalkyl;

[0333] R13 is hydrogen, alkyl or haloalkyl;

[0334] each R14 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl; It is

[0335] R17 is a direct bond or an optionally substituted alkylene chain;

[0336] as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;

[0337] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0338] One embodiment of the compounds of formula (Ib1) are compounds of formula (1b1) in which R2 is an optionally substituted 5-membered N-heteroaryl.

[0339] Of this embodiment, a preferred embodiment consists of compounds of formula (Ib1) in which R2 is optionally substituted isoxazolyl, optionally substituted thiazolyl or optionally substituted thiadiazolyl.

[0340] In this embodiment, the preferred compounds of formula (Ib1) are selected from:

[0341]4-((1-benzyl-3-methylazetidin-3-yl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate;

[0342]4-((1-benzyl-3-methylazetidin-3-yl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0343]4-((1-benzyl-3-methylazetidin-3-yl)amino)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide;

[0344]4-((1-benzyl-3-methylazetidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; It is

[0345]4-((1-benzylazetidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide.

[0346] Another preferred embodiment of compounds of formula (Ib1) consists of compounds of formula (Ib1) in which R2 is an optionally substituted 6-membered N-heteroaryl.

[0347] Of this embodiment, a preferred embodiment consists of compounds of formula (Ib1) in which R2 is optionally substituted pyridinyl.

[0348] In another embodiment, a compound of formula (I) is a compound of formula (Ib) in which X is C(R9)R10 and Y is a direct bond, that is, a compound of formula (Ib2):

[0349]n is 1 or 2;

[0350]m is 1 or 2;

[0351] R1 is hydrogen, alkyl, -R17-OR14, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted N-heterocyclyl, an optionally substituted N-heteroaryl, an optionally substituted O-heteroaryl or an optionally substituted S-heteroaryl;

[0352] R2 is an optionally substituted 5-membered N-heteroaryl or an optionally substituted 6-membered N-heteroaryl;

[0353] R4 and R5 are each independently hydrogen, alkyl or haloalkyl;

[0354] or R4 and R1, together with the carbon to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted aryl, and R5, if present, is hydrogen, alkyl, haloalkyl or optionally substituted aryl;

[0355] each R6 is independently hydrogen, alkyl, alkenyl, halo, haloalkyl, cyano, OR14 or optionally substituted cycloalkyl;

[0356] R7 is alkyl, halo, haloalkyl, cyano or OR14;

[0357] each R8 is independently hydrogen, alkyl, halo, haloalkyl or OR14;

[0358] or two R8's, together with the carbon to which they are both attached, can form an optionally substituted cycloalkyl;

[0359] R9 and R10 are each independently hydrogen, alkyl, haloalkyl, alkyl or OR14;

[0360] R13 is hydrogen, alkyl or haloalkyl;

[0361] each R14 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl; It is

[0362] R17 is a direct bond or an optionally substituted alkylene chain;

[0363] as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;

[0364] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0365] One embodiment of the compounds of formula (Ia2) are compounds of formula (1b2) in which R2 is an optionally substituted 5-membered N-heteroaryl.

[0366] Of this embodiment, a preferred embodiment consists of compounds of formula (Ia2) in which R2 is optionally substituted isoxazolyl, optionally substituted thiazolyl or optionally substituted thiadiazolyl.

[0367] Of this embodiment, a preferred embodiment consists of compounds of formula (Ia2) in which R2 is optionally substituted thiadiazolyl.

[0368] In this embodiment, the preferred compounds of formula (Ib2) are selected from:

[0369](S)-3-chloro-4-((1-(3,5-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl )benzenesulfonamide;

[0370](S)-3-chloro-4-((1-(2,5-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl )benzenesulfonamide;

[0371](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(1,2,4-thiadiazol-5-yl) benzenesulfonamide;

[0372](S)-3-chloro-4-((1-(2,6-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl )benzenesulfonamide;

[0373](S)-3-chloro-4-((1-(2-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide ;

[0374](S)-2,6-difluoro-3-methyl-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(1, 2,4-thiadiazol-5-yl)benzenesulfonamide;

[0375](S)-3-chloro-2,6-difluoro-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(1, 2,4-thiadiazol-5-yl)benzenesulfonamide;

[0376](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(1,2,4-thiadiazol-5-yl) benzenesulfonamide;

[0377](S)-3-chloro-4-(ethyl(1-(3-methylbenzyl)pyrrolidin-3-yl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

[0378](S)-4-((1-benzylpyrrolidin-3-yl)(ethyl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

[0379](S)-3-chloro-4-(methyl(1-(3-methylbenzyl)pyrrolidin-3-yl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

[0380](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

[0381](R)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

[0382](S)-4-(1-benzylpyrrolidin-3-ylamino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

[0383](R)-4-(1-benzylpyrrolidin-3-ylamino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

[0384]4-(1-benzylpyrrolidin-3-ylamino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;

[0385](S)-3-chloro-4-((1-(3-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide ;

[0386](S)-3-chloro-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-N- (1,2,4-thiadiazol-5- il)benzenesulfonamide;

[0387](S)-3-chloro-4-((1-(3-chloro-2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5 -yl)benzenesulfonamide;

[0388](S)-3-chloro-4-((1-(5-chloro-2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5 -yl)benzenesulfonamide;

[0389](S)-3-chloro-4-((1-(2-fluoro-3-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5 -yl)benzenesulfonamide; It is

[0390](S)-3-chloro-4-((1-(2-fluoro-5-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazol-5 -yl)benzenesulfonamide.

[0391] Of the preferred embodiment of compounds of formula (Ib2) in which R2 is optionally substituted isoxazolyl, optionally substituted thiazolyl or optionally substituted thiadiazolyl, a preferred embodiment consists of compounds of formula (Ib2) in which R1 is optionally substituted aryl or optionally aralkyl replaced; It is

[0392] R2 is optionally substituted thiazolyl or isoxazolyl.

[0393] Of this preferred embodiment, the preferred compounds of formula (Ib2) are selected from:

[0394](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-bromo-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0395](S)-4-((1-benzylpyrrolidin-3-yl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0396](S)-5-chloro-2-fluoro-4-((1-(3-(2-hydroxypropan-2-yl)benzyl)pyrrolidin-3-yl)(methyl)amino)-N-( thiazol-4-yl)benzenesulfonamide;

[0397](S)-5-chloro-4-((1-(5-chloro-2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl )benzenesulfonamide;

[0398](S)-5-chloro-2-fluoro-4-((1-(2-fluoro-4-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl )benzenesulfonamide;

[0399](S)-5-chloro-2-fluoro-4-(methyl(1-(3-phenylpropyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0400](S)-4-((1-(2-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl) benzenesulfonamide;

[0401](S)-2-fluoro-4-((1-(2-hydroxybenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0402](S)-2-fluoro-4-((1-(3-hydroxybenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0403](R)-4-((1-benzylpyrrolidin-3-yl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0404](S)-5-chloro-4-((1-(3-(difluoromethoxy)benzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl) benzenesulfonamide;

[0405](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-cyclopropyl-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0406](S)-5-chloro-4-((1-(2,5-dichlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro- N-(thiazol-4-yl)benzenesulfonamide ;

[0407]5-chloro-2-fluoro-4-(methyl((S)-1-((R)-1-phenylpropyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide ;

[0408](S)-5-chloro-2-fluoro-4-(methyl(1-(4-propylbenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0409](S)-5-chloro-2-fluoro-4-((1-(2-fluoro-5-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl )benzenesulfonamide;

[0410](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0411](R)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0412](S)-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0413](S)-5-chloro-2-fluoro-4-(methyl(1-(2-phenylpropan-2-yl)pyrrolidin-3-yl)amino)- N-(thiazol-4-yl)benzenesulfonamide ;

[0414]3-chloro-4-(methyl((S)-1-((R)-1-phenylethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0415](S)-2-fluoro-5-methyl-4-(methyl(1-phenethylpyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0416](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isothiazol-3-yl)-5-methylbenzenesulfonamide;

[0417](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(isothiazol-3-yl)-3-methylbenzenesulfonamide;

[0418](S)-2-fluoro-4-((1-(2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0419](S)-4-((1-benzylpyrrolidin-3-yl)(ethyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0420](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0421]methyl (S)-3-((3-((2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenyl)(methyl)amino)pyrrolidin-1-yl )methyl)benzoate;

[0422](S)-5-chloro-4-((1-(2-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0423](S)-5-chloro-4-((1-(4-(dimethylamino)benzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl) benzenesulfonamide;

[0424](S)-4-((1-benzylpyrrolidin-3-yl)(ethyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0425](S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide;

[0426](S)-3-chloro-4-((1-(5-chloro-2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0427](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-bromo-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0428](S)-2-fluoro-4-((1-(3-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0429](S)-4-((1-(2,5-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl )benzenesulfonamide;

[0430](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-ethyl-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0431](S)-5-chloro-2-fluoro-4-((1-(3-isopropoxybenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0432](S)-5-chloro-2-fluoro-4-(methyl(1-(4-methylbenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0433](S)-5-chloro-4-((1-(2,6-dimethylbenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro- N-(thiazol-4-yl)benzenesulfonamide ;

[0434](S)-5-chloro-2-fluoro-4-((1-(3-fluoro-2-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl )benzenesulfonamide;

[0435](S)-5-chloro-2-fluoro-4-(methyl(1-phenethylpyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0436](S)-5-chloro-4-((1-(3-chloro-2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl )benzenesulfonamide;

[0437](S)-5-chloro-2-fluoro-4-((1-(2-methoxybenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0438](S)-5-chloro-2-fluoro-4-((1-(4-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0439]4-(((2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro- N-(thiazol-4-yl)benzenesulfonamide;

[0440](S)-4-((1-benzylpyrrolidin-3-yl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0441]3-chloro-4-(methyl((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0442](S)-4-((1-(2,3-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl- N-(thiazol-4-yl)benzenesulfonamide ;

[0443](S)-4-((1-(2,3-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl )benzenesulfonamide;

[0444](S)-2,6-difluoro-4-((1-(2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-3-methyl- N-(thiazol-4-yl)benzenesulfonamide ;

[0445](S)-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl) benzenesulfonamide;

[0446](S)-4-((1-(2,5-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-3-methyl- N-(thiazol-4-yl)benzenesulfonamide ;

[0447](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0448](S)-5-chloro-4-((1-(2,5-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro- N-(thiazol-4-yl)benzenesulfonamide ;

[0449](S)-5-chloro-4-((1-(3-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0450](S)-3-chloro-4-((1-(2-fluoro-5-methylbenzyl)-3-methylpyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0451](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,5-difluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0452](S)-2-fluoro-4-((1-(2-methoxybenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0453]4-(((3S,5S)-1-benzyl-5-methylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro- N-(thiazol-4-yl)benzenesulfonamide;

[0454]5-chloro-4-(((S)-1-((S)-1-(2-chlorophenyl)propyl)pyrrolidin-3-yl)(methyl)amino)- 2-fluoro-N-( thiazol-4-yl)benzenesulfonamide;

[0455](S)-5-chloro-4-((1-(2-(difluoromethoxy)benzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl) benzenesulfonamide;

[0456](S)-5-chloro-2-fluoro-4-((1-(4-fluoro-3-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl )benzenesulfonamide;

[0457]5-chloro-2-fluoro-4-(methyl((S)-1-((S)-1-phenylpropyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide ;

[0458]4-((1-benzyl-3-methylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide;

[0459](S)-5-chloro-4-((1-(4-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0460](R)-4-((1-benzylpyrrolidin-3-yl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0461](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isothiazol-4-yl)-5-methylbenzenesulfonamide;

[0462](S)-2,6-difluoro-4-((1-(3-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-3-methyl- N-(thiazol-4-yl)benzenesulfonamide ;

[0463](R)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0464](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-(difluoromethyl)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0465](S)-5-chloro-2-fluoro-4-(methyl(1-(2-methylbenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0466](S)-5-chloro-2-fluoro-4-((1-(2-hydroxybenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0467](S)-5-chloro-2-fluoro-4-((1-(3-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0468](S)-5-chloro-4-((1-(2,3-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro- N-(thiazol-4-yl)benzenesulfonamide ;

[0469](S)-5-chloro-2-fluoro-4-(methyl(1-(3-(trifluoromethyl)benzyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0470](S)-5-chloro-2-fluoro-4-((1-(2-fluoro-3-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl )benzenesulfonamide;

[0471](S)-5-chloro-2-fluoro-4-((1-(2-fluoro-5-methoxybenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl )benzenesulfonamide;

[0472](S)-5-chloro-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl) benzenesulfonamide;

[0473](R)-4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide;

[0474](S)-2-fluoro-5-methyl-4-(methyl(1-(2-methylbenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0475](S)-2-fluoro-4-((1-(4-hydroxybenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0476](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)-3-(trifluoromethyl)benzenesulfonamide;

[0477](S)-2-fluoro-4-((1-(2-fluoro-3-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl )benzenesulfonamide;

[0478](S)-4-((1-(2,5-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-3-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0479](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0480](S)-4-((1-(4-bromobenzyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0481](S)-5-chloro-2-fluoro-4-((1-(2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0482](S)-5-chloro-2-fluoro-4-((1-(3-methoxybenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0483](S)-5-chloro-4-((1-(2-chloro-6-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl )benzenesulfonamide;

[0484](S)-3-chloro-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0485](S)-4-((5-benzyl-5-azaspiro[2.4]heptan-7-yl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0486](S)-4-((5-benzyl-5-azaspiro[2.4]heptan-7-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl) benzenesulfonamide;

[0487](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0488](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0489](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0490](R)-4-(1-benzylpyrrolidin-3-ylamino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide;

[0491](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide;

[0492](S)-5-chloro-2-fluoro-4-(1-(3-methylbenzyl)pyrrolidin-3-ylamino)-N-(thiazol-2-yl)benzenesulfonamide;

[0493](S)-4-(1-benzylpyrrolidin-3-ylamino)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide;

[0494](R)-5-chloro-2-fluoro-4-(1-(3-methylbenzyl)pyrrolidin-3-ylamino)-N-(thiazol-2-yl)benzenesulfonamide;

[0495](R)-4-(1-benzylpyrrolidin-3-ylamino)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide;

[0496](S)-3-chloro-4-((1-(3-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;

[0497](S)-3-chloro-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;

[0498](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0499] (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide bis(trifluoroacetic acid) salt ;

[0500](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide;

[0501]3-chloro-4-(methyl((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl)benzenesulfonamide;

[0502]3-chloro-4-(methyl((S)-1-((R)-1-phenylethyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl)benzenesulfonamide;

[0503]4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide;

[0504](S)-3-chloro-4-(methyl(1-(2-phenylpropan-2-yl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0505](R)-3-chloro-4-((1-(3-chlorobenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl) benzenesulfonamide;

[0506](R)-3-chloro-4-((1-(3-methylbenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl) benzenesulfonamide;

[0507](R)-3-chloro-4-((1-(2-fluorobenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl) benzenesulfonamide;

[0508]4-((trans-1-benzyl-4-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide;

[0509]4-((cis-1-benzyl-4-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide; It is

[0510](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isoxazol-3-yl)-5-methylbenzenesulfonamide.

[0511] Of the preferred embodiment of compounds of formula (Ib2) in which R2 is optionally substituted isoxazolyl, optionally substituted thiazolyl or optionally substituted thiadiazolyl, another preferred embodiment consists of compounds of formula (Ib2) in which:

[0512] R1 is an optionally substituted N-heterocyclyl, an optionally substituted N-heteroaryl, an optionally substituted O-heteroaryl or an optionally substituted S-heteroaryl; It is

[0513] R2 is optionally substituted thiazolyl.

[0514] Of this preferred embodiment, the preferred compounds of formula (Ib2) are selected from:

[0515](S)-4-((1-((1,4-dimethyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)- 2-fluoro-5-methyl -N-(thiazol-4-yl)benzenesulfonamide;

[0516](S)-2-fluoro-5-methyl-4-(methyl(1-((4-methylthiazol-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4- il)benzenesulfonamide;

[0517](S)-2-fluoro-5-methyl-4-(methyl(1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0518](S)-2-fluoro-5-methyl-4-(methyl(1-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methyl)pyrrolidin-3- yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0519](S)-2-fluoro-5-methyl-4-(methyl(1-((2-methylthiazol-4-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4- il)benzenesulfonamide;

[0520](S)-2-fluoro-5-methyl-4-(methyl(1-((1-methyl-1H-pyrazol-3-yl)methyl)pyrrolidin-3-yl)amino)-N-( thiazol-4-yl)benzenesulfonamide;

[0521](S)-2-fluoro-4-((1-((3-fluoro-6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N -(thiazol-4-yl)benzenesulfonamide;

[0522](S)-4-((1-((1-benzyl-1H-pyrazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N -(thiazol-4-yl)benzenesulfonamide;

[0523](S)-5-chloro-2-fluoro-4-(methyl(1-((5-(trifluoromethyl)furan-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazole -4-yl)benzenesulfonamide;

[0524](S)-2-fluoro-5-methyl-4-(methyl(1-((2-methyloxazol-4-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4- il)benzenesulfonamide;

[0525](S)-2-fluoro-5-methyl-4-(methyl(1-((5-methylfuran-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4- il)benzenesulfonamide;

[0526](S)-2-fluoro-4-((1-((2-isopropyloxazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol- 4-yl)benzenesulfonamide;

[0527](S)-5-chloro-2-fluoro-4-((1-((6-methoxypyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol- 4-yl)benzenesulfonamide;

[0528](S)-5-chloro-2-fluoro-4-((1-((3-fluoro-6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-N -(thiazol-4-yl)benzenesulfonamide;

[0529](S)-5-chloro-2-fluoro-4-(methyl(1-(quinolin-8-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0530](S)-4-((1-((4-cyclopropylthiazol-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol- 4-yl)benzenesulfonamide;

[0531](S)-4-((1-((6-(azetidin-1-yl)pyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2- fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0532](S)-2-fluoro-5-methyl-4-(methyl(1-((2-phenylthiazol-4-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4- il)benzenesulfonamide;

[0533](S)-2-fluoro-5-methyl-4-(methyl(1-(thiazol-2-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0534](S)-2-fluoro-5-methyl-4-(methyl(1-((2-(trifluoromethyl)thiazol-4-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazole -4-yl)benzenesulfonamide;

[0535](S)-4-((1-((2-cyclopropylthiazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol- 4-yl)benzenesulfonamide;

[0536](S)-2-fluoro-5-methyl-4-(methyl(1-((4-methyloxazol-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4- il)benzenesulfonamide;

[0537](S)-2-fluoro-4-((1-((3-isopropoxypyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol- 4-yl)benzenesulfonamide;

[0538](S)-2-fluoro-4-((1-((3-fluoro-6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-3-methyl-N -(thiazol-4-yl)benzenesulfonamide;

[0539](S)-5-chloro-2-fluoro-4-((1-((3-methoxypyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol- 4-yl)benzenesulfonamide;

[0540](S)-4-((1-((6-bromopyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol- 4-yl)benzenesulfonamide;

[0541](S)-4-((1-((1H-pyrrol-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol- 4-yl)benzenesulfonamide;

[0542](S)-5-chloro-2-fluoro-4-(methyl(1-((5-methylfuran-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4- il)benzenesulfonamide;

[0543](S)-2-fluoro-5-methyl-4-(methyl(1-(thiazol-4-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0544](S)-4-((1-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)pyrrolidin-3-yl)(methyl)amino)- 2-fluoro-5-methyl -N-(thiazol-4-yl)benzenesulfonamide;

[0545](S)-3-chloro-2,6-difluoro-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol- 4-yl)benzenesulfonamide;

[0546](S)-5-chloro-2-fluoro-4-(methyl(1-((1-methyl-1H-pyrrol-2-yl)methyl)pyrrolidin-3-yl)amino)-N-( thiazol-4-yl)benzenesulfonamide;

[0547](S)-4-((1-((1H-indol-3-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol- 4-yl)benzenesulfonamide;

[0548](S)-2-fluoro-5-methyl-4-(methyl(1-((5-(trifluoromethyl)furan-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazole -4-yl)benzenesulfonamide;

[0549](S)-2-fluoro-5-methyl-4-(methyl(1-(oxazol-4-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0550](S)-2-fluoro-5-methyl-4-(methyl(1-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)methyl)pyrrolidin-3- yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0551](S)-2-fluoro-4-((1-((3-methoxypyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)- 5-methyl-N-(thiazol- 4-yl)benzenesulfonamide;

[0552](S)-5-chloro-2-fluoro-4-(methyl(1-((1-methyl-1H-pyrazol-3-yl)methyl)pyrrolidin-3-yl)amino)-N-( thiazol-4-yl)benzenesulfonamide;

[0553](S)-5-chloro-2-fluoro-4-((1-(imidazo[1,5-a]pyridin-3-ylmethyl)pyrrolidin-3-yl)(methyl)amino)-N- (thiazol-4-yl)benzenesulfonamide;

[0554](S)-5-chloro-2-fluoro-4-(methyl(1-((2-(trifluoromethyl)pyridin-4-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazole -4-yl)benzenesulfonamide;

[0555](S)-5-chloro-4-((1-((6-(difluoromethyl)pyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N- (thiazol-4-yl)benzenesulfonamide;

[0556](S)-5-chloro-2-fluoro-4-((1-(isoquinolin-8-ylmethyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide ;

[0557](S)-5-chloro-2-fluoro-4-(methyl(1-((6-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazole -4-yl)benzenesulfonamide;

[0558](S)-2-fluoro-4-((1-((2-isopropylthiazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol- 4-yl)benzenesulfonamide;

[0559](S)-4-((1-(benzo[d]thiazol-2-ylmethyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4 -yl)benzenesulfonamide;

[0560](S)-2-fluoro-5-methyl-4-(methyl(1-((5-methylisothiazol-3-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4- il)benzenesulfonamide;

[0561](S)-2-fluoro-5-methyl-4-(methyl(1-(pyrazolo[1,5-a]pyridin-2-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazole -4-yl)benzenesulfonamide;

[0562](S)-4-((1-((1H-indol-5-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol- 4-yl)benzenesulfonamide;

[0563](S)-5-chloro-2-fluoro-4-(methyl(1-(thiophen-2-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0564](S)-5-chloro-2-fluoro-4-(methyl(1-((4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4- il)benzenesulfonamide;

[0565](S)-5-chloro-2-fluoro-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4- il)benzenesulfonamide;

[0566](S)-2-fluoro-4-((1-((4-isopropylthiazol-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol- 4-yl)benzenesulfonamide;

[0567](S)-4-((1-((5-chlorothiazol-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol- 4-yl)benzenesulfonamide;

[0568](S)-4-((1-((1-(difluoromethyl)-1H-pyrazol-3-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl -N-(thiazol-4-yl)benzenesulfonamide;

[0569](S)-2,6-difluoro-3-methyl-4-(methyl(1-((6-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N- (thiazol-4-yl)benzenesulfonamide;

[0570](S)-5-chloro-4-((1-((6-(difluoromethyl)-3-fluoropyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro -N-(thiazol-4-yl)benzenesulfonamide;

[0571](S)-5-chloro-2-fluoro-4-(methyl(1-((5-methylthiophen-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4- il)benzenesulfonamide;

[0572](S)-4-((1-((1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro -5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0573](S)-2-fluoro-5-methyl-4-(methyl(1-((2-methyl-5-(trifluoromethyl)oxazol-4-yl)methyl)pyrrolidin-3-yl)amino)- N-(thiazol-4-yl)benzenesulfonamide;

[0574](S)-4-((1-((2,5-dimethyloxazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-( thiazol-4-yl)benzenesulfonamide;

[0575](S)-2-fluoro-5-methyl-4-(methyl(1-((4,5,6,7-tetrahydropyrazol[1,5-a]pyridin-2-yl)methyl)pyrrolidin- 3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0576](S)-2-fluoro-5-methyl-4-(methyl(1-((4-(trifluoromethyl)thiazol-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazole -4-yl)benzenesulfonamide; It is

[0577](S)-2,6-difluoro-3-methyl-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-(thiazol- 4-yl)benzenesulfonamide.

[0578] Of the preferred embodiment of compounds of formula (Ib2) in which R2 is optionally substituted isoxazolyl, optionally substituted thiazolyl or optionally substituted thiadiazolyl, another preferred embodiment consists of compounds of formula (Ib2) in which:

[0579] R1 is hydrogen, alkyl, -R17-OR14 or an optionally substituted cycloalkyl; It is

[0580] R4 and R5 are each independently hydrogen, alkyl or haloalkyl;

[0581] or R4 and R1, together with the carbon to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted aryl, and R5, if present, is hydrogen, alkyl, haloalkyl or optionally substituted aryl.

[0582] Of this preferred embodiment, the preferred compounds of formula (Ib2) are selected from:

[0583]2-fluoro-5-methyl-4-(methyl((S)-1-((1s,3R)-3-phenylcyclobutyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl )benzenesulfonamide;

[0584](S)-5-chloro-4-((1-(2,3-dihydro-1H-inden-2-yl)pyrrolidin-3-yl)(methyl)amino)- 2-fluoro- N-(thiazol-4-yl)benzenesulfonamide;

[0585](S)-5-chloro-2-fluoro-4-(methyl(1-(1-phenylcyclopropyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0586](S)-4-((1-(2,3-dihydro-1H-inden-2-yl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl- N-(thiazol-4-yl)benzenesulfonamide;

[0587](S)-5-chloro-4-((1-(3,3-dimethylbutyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide ;

[0588]4-(((S)-1-((S)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro- 5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0589](S)-5-chloro-2-fluoro-4-((1-(1-(2-fluorophenyl)cyclobutyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4- il)benzenesulfonamide;

[0590](S)-4-((1-(2-(benzyloxy)ethyl)pyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro- N-(thiazol-4-yl) benzenesulfonamide;

[0591]5-chloro-4-(((S)-1-((R)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)(methyl)amino)- 2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0592]2-fluoro-5-methyl-4-(methyl((S)-1-((1r,3S)-3-phenylcyclobutyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl )benzenesulfonamide;

[0593](S)-4-((1-(cyclohexylmethyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide;

[0594]3-chloro-4-(((S)-1-((S)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)(methyl)amino)- 2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0595]5-chloro-4-(((S)-1-((S)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)(methyl)amino)- 2-fluoro-N-(thiazol-4-yl)benzenesulfonamide;

[0596](S)-2-fluoro-5-methyl-4-(methyl(1-neopentylpyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide; It is

[0597](S)-4-((1-(3,3-dimethylbutyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide .

[0598] Another preferred embodiment of compounds of formula (Ib2) consists of compounds of formula (Ib2) in which R2 is an optionally substituted 6-membered N-heteroaryl.

[0599] Of this embodiment, a preferred embodiment consists of compounds of formula (Ib2) in which R2 is optionally substituted pyridinyl.

[0600] Of this preferred embodiment, the preferred compounds of formula (Ib2) are selected from:

[0601](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(5-fluoropyridin-2-yl)-3-methylbenzenesulfonamide;

[0602](S)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(methyl(1-(2-phenylpropan-2-yl)pyrrolidin-3-yl)amino )benzenesulfonamide;

[0603](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-3-methylbenzenesulfonamide;

[0604](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(5-fluoropyridin-2-yl)-5-methylbenzenesulfonamide;

[0605](S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(6-fluoropyridin-2-yl)-5-methylbenzenesulfonamide;

[0606] (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide bis(acid) salt trifluoroacetic);

[0607]3-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl)amino) benzenesulfonamide; It is

[0608]5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(methyl((S)-1-((R)-1-phenylethyl)pyrrolidin-3-yl)amino )benzenesulfonamide.

[0609] In another embodiment, a compound of formula (I) is a compound of formula (Ib) in which X is C(R9)R10 and Y is C(R11)R12, that is, a compound of formula (Ib3) :

[0610]n is 1 or 2;

[0611]m is 1 or 2;

[0612]X is a direct bond or C(R9)R10;

[0613]Y is a direct bond or C(R11)R12;

[0614] R1 is hydrogen, alkyl, -R17-OR14, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted N-heterocyclyl, an optionally substituted N-heteroaryl, an optionally substituted O-heteroaryl or an optionally substituted S-heteroaryl;

[0615] R2 is an optionally substituted 5-membered N-heteroaryl or an optionally substituted 6-membered N-heteroaryl;

[0616] R4 and R5 are each independently hydrogen, alkyl or haloalkyl;

[0617] or R4 and R1, together with the carbon to which they are attached, form an optionally substituted cycloalkyl or an optionally substituted aryl, and R5, if present, is hydrogen, alkyl, haloalkyl or optionally substituted aryl;

[0618] each R6 is independently hydrogen, alkyl, alkenyl, halo, haloalkyl, cyano, OR14 or optionally substituted cycloalkyl;

[0619] R7 is alkyl, halo, haloalkyl, cyano or OR14;

[0620] each R8 is independently hydrogen, alkyl, halo, haloalkyl or OR14;

[0621] or two R8's, together with the carbon to which they are both attached, can form an optionally substituted cycloalkyl;

[0622] R9, R10, R11 and R12 are each independently hydrogen, alkyl, haloalkyl, alkyl or OR14;

[0623]or R9 and R11 form an optionally substituted alkylene chain and R10 and R12 are as defined above; It is

[0624] R13 is hydrogen, alkyl or haloalkyl;

[0625] each R14 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl; It is

[0626] R17 is a direct bond or an optionally substituted alkylene chain;

[0627] as an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;

[0628] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0629] Of this embodiment, a preferred embodiment consists of compounds of formula (Ib3) in which R2 is an optionally substituted 5-membered N-heteroaryl.

[0630] Of this embodiment, a more preferred embodiment consists of compounds of formula (Ib3) in which R2 is optionally substituted isoxazolyl, optionally substituted thiazolyl or optionally substituted thiadiazolyl.

[0631] Of this preferred embodiment, the preferred compounds of formula (Ib3) are selected from:

[0632](R)-5-chloro-2-fluoro-4-(methyl(1-(1-phenylethyl)piperidin-4-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0633](R)-2-fluoro-5-methyl-4-(methyl(1-(1-phenylethyl)piperidin-4-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide;

[0634]4-((1-benzylpiperidin-4-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide; It is

[0635]4-(1-benzylpiperidin-4-ylamino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide.

[0636] Another preferred embodiment of compounds of formula (Ia3) consists of compounds of formula (Ib3) in which R2 is an optionally substituted 6-membered N-heteroaryl.

[0637] Of this embodiment, a preferred embodiment consists of compounds of formula (Ib3) in which R2 is optionally substituted pyridinyl.

[0638] Another embodiment of the invention consists of compounds of formula (I) in which R7 is in the ortho position with respect to R3.

[0639] Another embodiment of the invention consists of compounds of formula (I) in which R7 is in the ortho position with respect to R3 and is halo.

[0640] Another embodiment of the invention is in which R7 is chlorine or fluoro.

[0641] Another embodiment of the invention consists of compounds of formula (I) in which R2 is an optionally substituted monocyclic N-heteroaryl. Another embodiment of the invention consists of compounds of formula (I) in which R2 is an optionally substituted 5-membered N-heteroaryl. Another embodiment of the invention consists of compounds of formula (I) in which R2 is an optionally substituted 5-membered N-heteroaryl selected from isoxazolyl, thiazolyl or thiadiazolyl. Another embodiment of the invention consists of compounds of formula (I) in which R2 is an optionally substituted 6-membered N-heteroaryl. Another embodiment of the invention consists of compounds of formula (I) in which R2 is an optionally substituted 6-membered N-heteroaryl selected from pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl. Another embodiment of the invention consists of compounds of formula (I) in which R2 is an optionally substituted pyridinyl.

[0642] Another embodiment of the invention is a method of using compounds of formula (I) as standards or controls in in vitro or in vivo assays to determine the effectiveness of test compounds in modulating voltage-gated sodium channels.

[0643] It is understood that any embodiment of the compounds of the invention, as presented above, and any substituent presented herein for a group n, m, X, ,Y, R1, R2, R3, R4, R5, R6, R7 , R8, R9, R10, R11, R12, R13, R14 and R17 specific in the compounds of the invention, as set forth above, may be independently combined with other embodiments and/or substituents of compounds of the invention to form embodiments of the inventions not specifically set forth in this document. Furthermore, in case a list of substituents is disclosed for any group n, m, R14 and R17 specific in a specific embodiment and/or claim, it is understood that one or more substituents may be deleted from the list and that the list of remaining substituents will be considered as an embodiment of the invention.

[0644] It is also understood that the condition presented above in the Summary of the Invention for compounds of formula (I) applies to all relative embodiments of compounds of formula (I) as described above.

[0645] Another aspect of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the invention, as described above, as a stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0646] Another aspect of the invention is a method of treating a disease or a condition associated with NaV1.6 activity in a mammal wherein the disease or condition is epilepsy and/or epileptic seizure disorder and wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of the invention, as described above, as a stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0647] In one embodiment of this aspect, epilepsy or convulsive epileptic disorder is selected from photosensitive epilepsy, self-induced syncope, intractable epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorder, infantile and juvenile absence epilepsy, Dravet, frontal lobe epilepsy, Glut1 deficiency syndrome, hypothalamic hamartoma, infantile spasms/West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), myoclonic absence epilepsy, Ohtahara syndrome , Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsies, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora progressive myoclonus epilepsy, neurocutaneous syndromes, tuberous sclerosis complex, infantile epileptic encephalopathy early onset, early onset epileptic encephalopathy, generalized epilepsy with febrile convulsions +, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia and paroxysmal dyskinesia.

[0648] In one embodiment of this modality, epilepsy or epileptic seizure is selected from Dravet syndrome, infantile spasms/West syndrome, temporal lobe epilepsy, Lennox-Gastaut syndrome (LGS), generalized epilepsy with febrile seizures + and early childhood epileptic encephalopathy.

[0649] Another aspect of the invention is a method of reducing ion flux through NaV1.6 in a mammalian cell, wherein the method comprises placing the cell in contact with a compound of the invention, as defined above, as a stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0650] Another aspect of the invention is a method of selectively inhibiting a first voltage-gated sodium channel through a second voltage-gated sodium channel in a mammal, wherein the method comprises administering to the mammal a modulating amount of a compound of the invention, as described above, as a stereoisomer, enantiomer or tautomer thereof or a mixture thereof; or a pharmaceutically acceptable solvate or prodrug thereof.

[0651] In one embodiment of this aspect, the first voltage-gated sodium channel is NaV1,6.

[0652] In another embodiment of this aspect, the first voltage-gated sodium channel is NaV1.6 and the second voltage-gated sodium channel is NaV1.5.

[0653] In another embodiment of this aspect, the first voltage-gated sodium channel is NaV1.6 and the second voltage-gated sodium channel is NaV1.1.

[0654] Specific embodiments of the compounds of the invention are described in more detail below in the Preparation of Compounds of the Invention.

UTILITY AND TESTING OF THE COMPOUNDS OF THE INVENTION

[0655] The compounds of the invention modulate, preferably inhibit, the flow of ions through a voltage-dependent sodium channel, preferably NaV1.6, in a mammal, especially in a human being. Any such modulation, whether partial or complete inhibition or prevention of ion flow, is sometimes referred to herein as "blocking" and corresponding compounds as "blockers" or "inhibitors". In general, the compounds of the invention modulate the activity of a downstream voltage-gated sodium channel, inhibiting the voltage-gated activity of the sodium channel, and/or reduce or prevent the flow of sodium ions across a cell membrane by preventing sodium channel activity as ion flow.

[0656] The compounds of the invention inhibit the flow of ions through a voltage-dependent sodium channel, preferably NaV1,6. The compounds of the invention are state- or frequency-dependent modifiers of the sodium channel, which have a low affinity in the resting/closed state and a high affinity in the inactivated state. It is likely that these compounds interact with overlapping sites located in the internal cavity of the channel's sodium-conducting pore similar to that described for other state-dependent sodium channel blockers (Cestèle, S., et al., op. cit.). It is also likely that these compounds interact with sites outside the internal cavity and have allosteric effects on the conduction of sodium ions through the channel pore.

[0657] Any of these consequences may ultimately be responsible for the total therapeutic benefit provided by these compounds.

[0658] Consequently, the compounds of the invention are inhibitors of voltage-gated sodium channels, preferably NaV1,6 inhibitors, and are therefore useful in the treatment of diseases and conditions, preferably epilepsy and/or epileptic seizure disorders , in mammals, preferably humans, and other organisms, including all those human diseases and conditions that are the result of abnormal biological activity of voltage-gated sodium channels, preferably abnormal activity of NaV1,6, or that may be improved by modulating the biological activity of voltage-gated sodium channels. In particular, the compounds of the invention, that is, the compounds of formula (I), as set forth above in the Summary of the Invention, as individual stereoisomers, enantiomers or tautomers thereof or mixtures thereof; or as pharmaceutically acceptable salts, solvates or prodrugs thereof, are useful for treating diseases and conditions in mammals, preferably humans, that are the result of abnormal biological activity of voltage-dependent NaV1,6 or that can be ameliorated by modulating, preferably inhibiting, the biological activity of NaV1,6. Preferably, the compounds of the invention selectively inhibit NaV1.6 over NaV1.5 and/or NaV1.1.

[0659] As defined herein, a disease, disorder or condition associated with NaV1.6 activity includes, but is not limited to, epilepsy and/or epileptic seizure disorder. Such epilepsy disorders and/or epileptic seizure disorders include, but are not limited to, photosensitive epilepsy, self-induced syncope, intractable epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorder, infantile and juvenile absence epilepsy, Dravet syndrome, wolf epilepsy frontalis, Glut1 deficiency syndrome, hypothalamic hamartoma, infantile spasms/West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), myoclonic absence epilepsy, Ohtahara syndrome, Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsies, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora progressive myoclonus epilepsy, neurocutaneous syndromes, tuberous sclerosis complex, early infantile epileptic encephalopathy, epileptic encephalopathy of early onset, generalized epilepsy with febrile convulsions +, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia and paroxysmal dyskinesia.

[0660] Therefore, the present invention relates to compounds, pharmaceutical compositions and methods of using the compounds and pharmaceutical compositions for the treatment of diseases or conditions associated with NaV1.6 activity in a mammal, preferably a human being, by administering to the mammal, preferably the human, in need of such treatment, an effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

[0661] The general value of the compounds of the invention in inhibiting the flow of NaV1,6 ions can be determined using the assays described below in the Biological Assays section. Alternatively, the general value of compounds in treating conditions and diseases in humans can be established in industry standard animal models to demonstrate the efficacy of compounds in treating epilepsy and/or epileptic seizure disorder. Animal models of human epileptic conditions have been developed that result in reproducible sensory deficits over a prolonged period of time that can be assessed by sensory testing.

[0662] For example, many rodent models have been developed to assess seizure propensity or epileptiform activity (Klein, B.R. et al., (2016), "Models Currently in Active Use. In: Epilepsy Therapy Screening Program", Vol. 2016, National Institute of Neurological Disorders and Stroke). These include acute chemical or electrical insults that induce seizures, as well as chronic chemical or genetic insults that create seizure-prone animals. These models can be used to determine the relative ability of a compound to promote or prevent seizure activity. The Maximal Electroshock Induced Seizure (MES) Assay and the 6 Hertz (6Hz) Psychomotor Seizure Test are two examples of acute insult seizure assays used to evaluate anticonvulsant interventions (Suzuki, F. et al., Neuroscience ( 1995), Vo. 64, pp. 665 to 674; Barton, M.E. et al., Epilepsy Research (2001), Vol. 47, pp. 217 to 227). Both trials involve an electrical insult applied with electrodes placed on the corneas or ears to provoke an acute seizure. Acute seizures can also be induced chemically, for example, by administration of the proconvulsant ether compound flurotyl (Makinson, C.D. et al., Exp. Neurol. (2016), Vol. 275, Pt 1, pp. 46 to 58 ).

[0663] Genetic epilepsies have been associated with many different genes, including voltage-gated sodium channel genes. Genetically modified mice can be bred to harbor mutations identified in human patients. In some cases, these genetic modifications result in animals that behave much like the human patients in whom the genetic variations were initially identified. The mutant mice could be used to test anticonvulsant interventions. Such experiments may involve the prevention of spontaneous seizures, or may make use of seizure-provoking stimuli similar to those employed in wild-type mice. Animal models of early infantile epileptic encephalopathy (EIEE6), also known as severe myoclonic epilepsy of infancy or Drave syndrome, were created by mutating the SCN1A gene encoding the voltage-gated sodium channel NaV1.1 (Yu, F.H. et al ., Nat. Neurosci. (2006), Vol. 9, pp. 1142 to 1149). EIEE13 models have also been created by mutating the SCN6A gene encoding the NaV1.6 voltage-gated sodium channel (Wagnon, J.L. et al., Human Molecular Genetics (2014)). Both of these mouse strains provide the opportunity to evaluate potential therapeutic interventions that may be useful in clinical patient populations (Martin, M.S. et al., J. Biol. Chem. (2010), Vol. 285, pp. 9823 to 9834; and Martin, M.S. et al., Human Molecular Genetics (2007), Vol. 16, pp. 2892 to 2899).

[0664] The present invention readily provides many different means of identifying NaV1,6 inhibitory agents that are useful as therapeutic agents. Identification of NaV1,6 inhibitors can be assessed using a variety of in vitro and in vivo assays, e.g., current measurement, membrane potential measurement, ion flux measurement, (e.g., sodium or guanidinium), measurement of sodium concentration, measurement of second messengers and transcription levels, and using, for example, voltage-sensitive dyes, radioactive tracers and ion channel clamp electrophysiology.

[0665] Such a protocol involves screening chemical agents for their ability to modulate the activity of a sodium channel, thus identifying them as a modulating agent.

[0666] A typical assay described in Bean et al., J. General Physiology (1983), 83:613 to 642, and Leuwer, M., et al., Br. J. Pharmacol (2004), 141(1) :47 to 54, uses ion channel clamping techniques (patch clamp) to study channel behavior. Such techniques are known to those skilled in the art and can be developed, using current technologies, in low or medium throughput assays to evaluate compounds for their ability to modulate sodium channel behavior.

[0667] The yield of test compounds is an important consideration in choosing the screening assay that will be used. In some strategies, where hundreds of thousands of compounds will be tested, it is not desirable to use low-throughput media. In other cases, however, the low throughput is satisfactory for identifying important differences between a limited number of compounds. It will often be necessary to combine assay types to identify specific sodium channel modulating compounds.

[0668] Electrophysiological assays using ion channel clamping techniques are accepted as a gold standard for the detailed characterization of the interactions of sodium channel compounds, and as described in Bean et al., op. cit. and Leuwer, M., et al., op. cit. There is a low-throughput manual screening (LTS) method that can compare 2 to 10 compounds per day; a newly developed system for automatic medium-throughput screening (MTS) on 20 to 50 patches (i.e., compounds) per day; and a technology from Molecular Devices Corporation (Sunnyvale, CA) that enables automated high-throughput screening (HTS) on 1000 to 3000 patches (i.e., compounds) per day.

[0669] An automatic ion channel clamping system uses flat electrode technology to accelerate the rate of drug discovery. Flat electrodes are capable of achieving high-resistance cell-clamped seals followed by low-noise, stable whole-cell recordings that are comparable to conventional recordings. A suitable instrument is the PatchXpress 7000A (Axon Instruments Inc, Union City, CA). A variety of cell lines and culture techniques, which include adherent cells as well as cells that grow spontaneously in suspension, are classified for sealing success rate and stability. Immortalized cells (e.g. HEK and CHO) that stably express high levels of relative sodium ion channel can be adapted into high-density suspension cultures.

[0670] Other assays may be selected to allow the investigator to identify compounds that block specific states of the channel, such as the open state, closed state, or resting state, or that block the transition from open to closed, closed to rest, or rest. to open. Those skilled in the art are generally familiar with such assays.

[0671] Binding assays are also available. Projects include binding assays based on traditional radioactive filters or the confocal-based fluorescent system available from the Evotec OAI group of companies (Hamburg, Germany), both of which are HTS.

[0672] Radioactive flux assays can also be used. In this assay, channels are stimulated to open with veratridine or aconitine and maintained in a stabilized open state with a toxin, and channel blockers are identified for their ability to prevent ion influx. The assay can use radioactive 22[Na] and 14[C] guanidinium ions as labels. FlashPlate & Cytostar-T plates in live cells avoid separation steps and are suitable for HTS. Scintillation plate technology has also advanced this method for HTS matching. Due to the functional aspects of the assay, the information content is reasonably satisfactory.

[0673] Yet another format measures membrane potential redistribution using the FLIPR System (HTS) membrane potential kit available from Molecular Dynamics (a division of Amersham Biosciences, Piscataway, NJ). This method is limited to slow membrane potential changes. Some problems may result from the fluorescent background of the compounds. Test compounds can also directly influence cell membrane fluidity and lead to an increase in intracellular dye concentrations. Still, due to the functional aspects of the assay, the information content is reasonably satisfactory.

[0674] Sodium dyes can be used to measure the rate or amount of influx of sodium ions through a channel. This type of testing provides a very high information content regarding potential channel blockers. The assay is functional and could measure Na+ influx directly. CoroNa Red, SBFI, and/or crude sodium (Molecular Probes, Inc. Eugene OR) can be used to measure Na influx; all are Na-responsive dyes. They can be used in combination with the FLIPR instrument. The use of these dyes on a screen has not previously been described in the literature. Calcium dyes may also have potential in this format.

[0675] In another assay, FRET-based voltage sensors are used to measure the ability of a test compound to directly block Na influx. Commercially available HTS systems include the VIPR™ II FRET system (Aurora Biosciences Corporation, San Diego, CA, a division of Vertex Pharmaceuticals, Inc.) which can be used in conjunction with FRET dyes, also available from Aurora Biosciences. This assay measures split-second responses to voltage changes. There is no need for a channel function modifier. The assay measures depolarization and hyperpolarizations and provides ratiometric results for quantification. A slightly less expensive MTS version of this assay employs the FLEXstation™ (Molecular Devices Corporation) in conjunction with FRET dyes from Aurora Biosciences. Other methods of testing the compounds disclosed herein are also readily known and available to those skilled in the art.

[0676] These results provide the basis for analyzing the structure-activity relationship (SAR) between the test compounds and the sodium channel. Certain substituents in the core structure of the test compound tend to provide more potent inhibitory compounds. SAR analysis is one of the tools that those skilled in the art can now employ to identify preferred embodiments of the compound of the invention for use as therapeutic agents.

[0677] Modulating agents thus identified are then tested in a variety of in vivo models to determine whether they are useful in treating the disease or condition associated with sodium channel activity of interest, preferably NaV1.6, with minimal adverse events. The assays described below in the Biological Assays Section are useful in evaluating the biological activity of the present compounds.

[0678] Typically, the effectiveness of a compound of the invention is expressed by its IC50 value ("Inhibitory Concentration - 50%"), which is the measurement of the amount of compound required to obtain 50% inhibition of target sodium channel activity during a specific period of time. For example, representative compounds of the present invention demonstrated IC50's ranging from less than 100 nanomolar to less than 10 micromolar in the NaV1,6 ion channel clamp electrophysiology assay described herein.

[0679] In an alternative use of the invention, the compounds of the invention can be used in in vitro or in vivo studies as exemplary agents for comparative purposes to find other compounds also useful in treating or protecting against the various diseases disclosed herein.

[0680] Another aspect of the invention relates to inhibiting the activity of NaV1,6 in a biological sample or a mammal, preferably a human being, such method comprises administering to the mammal, preferably a human being, or placing said biological sample in contact with a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I). The term "biological sample" as used herein includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof.

[0681] Inhibition of NaV1,6 activity in a biological sample is useful for a variety of purposes that are known to those skilled in the art. Examples of such purposes include, but are not limited to, the study of sodium ion channels in biological and pathological phenomena; and the comparative evaluation of new sodium ion channel inhibitors.

[0682] The compounds of the invention, as presented above in the Summary of the Invention, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, and/or the pharmaceutical compositions described in present document comprising a pharmaceutically acceptable excipient and one or more compounds of the invention, as set forth above in the Summary of the Invention, as a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof. same, can be used in the preparation of a medicine for the treatment of diseases or conditions associated with the activity of a voltage-gated sodium channel, preferably NaV1.6, in a mammal.

PHARMACEUTICAL COMPOSITIONS OF THE INVENTION AND ADMINISTRATION

[0683] The present invention also relates to a pharmaceutical composition containing the compounds of the invention disclosed in the present document. In one embodiment, the present invention relates to a composition comprising the compounds of the invention in a pharmaceutically acceptable carrier, excipient or diluent and in an amount effective to modulate, preferably, inhibit the flow of ions through a sodium channel. voltage-dependent to treat sodium channel-mediated diseases, such as epilepsy and/or epileptic seizure disorder, when administered to an animal, preferably a mammal, most preferably a human patient.

[0684] Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in a suitable pharmaceutical composition, can be carried out through any modes of administration of agents accepted to meet similar uses. The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into preparations in solid, semisolid, liquid or gaseous forms, such as tablets, capsules, powders, granules. , ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. Topical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous injection, intramuscular, intrasternal or infusion techniques. The pharmaceutical compositions of the invention are formulated to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions to be administered to an individual or patient take the form of one or more dosage units, wherein, for example, a tablet may be a single dosage unit and a container of a compound of the invention in aerosol form may contain a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art; for example, see The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any case, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or condition of interest in accordance with the teachings of this invention.

[0685] Useful pharmaceutical compositions also contain a pharmaceutically acceptable carrier, including any suitable diluent or excipient, which includes any pharmaceutical agent that does not induce the production of antibodies harmful to the individual receiving the composition, and that can be administered without toxicity undue. Pharmaceutically acceptable carriers include, but are not limited to, liquids such as water, saline, glycerol and ethanol, and the like. A complete discussion of pharmaceutically acceptable carriers, diluents, and other excipients is presented in Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. current edition).

[0686] A pharmaceutical composition of the invention may be in the form of a solid or liquid. In one aspect, the carrier(s) is/are particulate, such that they are, for example, in tablet or powder form. The carrier(s) may be liquid(s), with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful, for example, in administration by inhalation.

[0687] When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, where semisolid suspension, semi-liquid and gel forms are included within the forms considered herein as both solid and liquid.

[0688] As a solid composition for oral administration, the pharmaceutical composition can be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, lozenge or similar form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, corn starch and the like; lubricants such as magnesium stearate; binders such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as mint, methyl salicylate or orange flavoring; and a coloring agent.

[0689] When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

[0690] The pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension. The liquid can be used for oral administration or injection, as two examples. When intended for oral administration, a preferred composition contains, in addition to the present compounds, one or more of a sweetening agent, preservatives, pigment/colorant and flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.

[0691] The liquid compositions of the invention, whether these are solutions, suspensions or other similar form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline solution, Ringer's solution, chloride isotonic sodium, fixed oils such as synthetic mono- or diglycerides that can serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; bactericidal agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting tonicity such as sodium chloride or dextrose. The parenteral preparation can be inserted into ampoules, disposable syringes or multi-dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.

[0692] A liquid pharmaceutical composition of the invention intended for parenteral or oral administration must contain an amount of a compound of the invention such that a suitable dosage is obtained. Typically, this amount is at least 0.01% of a compound of the invention in the composition. When intended for oral administration, this amount can be varied to be between 0.1 and about 70% of the weight of the composition. Preferred oral pharmaceutical compositions contain between about 4% and about 50% of the compound of the invention. Preferred pharmaceutical compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 10% by weight of the compound before dilution of the invention.

[0693] The pharmaceutical composition of the invention may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. Topical formulations may contain a concentration of the compound of the invention from about 0.1 to about 10% w/v (unit weight per volume).

[0694] The pharmaceutical composition of the invention can be intended for administration rectally, in the form, for example, of a suppository, which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable non-irritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.

[0695] The pharmaceutical composition may include various materials, which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a shell coating around the active ingredients. The materials forming the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be enclosed in a gelatin capsule.

[0696] The pharmaceutical composition of the invention in solid or liquid form may include an agent that binds to the compound of the invention and, thus, assists in the application of the compound. Suitable agents that can act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.

[0697] The pharmaceutical composition of the invention can consist of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those of a colloidal nature to systems consisting of pressurized packaging. Application can be done by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds of the invention can be administered in single-phase, two-phase or three-phase systems to deliver the active ingredient(s). The aerosol application includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation, can determine preferred aerosols.

[0698] The pharmaceutical compositions of the invention can be prepared by a methodology well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile distilled water to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that interact non-covalently with the compound of the invention to facilitate the dissolution or homogeneous suspension of the compound in the aqueous delivery system.

[0699] The compounds of the invention, or pharmaceutically acceptable salts thereof, are administered in a therapeutically effective amount, which will vary depending on a variety of factors including the activity of the specific compound employed; the metabolic stability and duration of action of the compound; the patient's age, body weight, general health, sex, and diet; the method and time of administration; the excretion rate; the combination of drugs; the severity of the particular disorder or condition; and the individual undergoing therapy. In general, a therapeutically effective daily dose is (for a 70 kg mammal) from about 0.001 mg/kg (i.e., 0.07 mg) to about 100 mg/kg (i.e., 7.0 g); Preferably, a therapeutically effective dose is (for a 70 kg mammal) from about 0.01 mg/kg (i.e., 0.7 mg) to about 50 mg/kg (i.e., 3.5 g). ; more preferably, a therapeutically effective dose is (for a 70 kg mammal) from about 1 mg/kg (i.e., 70 mg) to about 25 mg/kg (i.e., 1.75 g).

[0700] The effective dose ranges provided herein are not intended to be limiting and represent preferred dose ranges. However, the most preferred dosage will be tailored to the individual, as is understood and determinable by one skilled in the art (see, e.g., Berkow et al., eds., The Merck Manual, 19th edition, Merck and Co., Rahway, N.J. , 2011; Brunton et al. eds., Goodman and Cilman's The Pharmacological Basis of Therapeutics, 12th edition, McGraw-Hill 2011; and Wilkins, Baltimore, MD (1987), Ebadi, Pharmacology, Little, Brown and Co., Boston, (1985); Osolci al., eds., Remington's Pharmaceutical Sciences, current edition, Mack Publishing Co., Easton, PA. ; Katzung, Basic and Clinical Pharmacology, Appleton and Lange, Norwalk, CT (1992)).

[0701] The total dose required for each treatment can be administered in multiple doses or in a single dose throughout the day, if desired. In general, treatment is started with lower dosages, which are lower than the ideal dose of the compound. Thereafter, the dosage is increased in small increments until the optimal effect under the circumstances is obtained. The compound or pharmaceutical composition may be administered alone or in conjunction with other diagnostics and/or drugs directed at the condition, or directed at other symptoms of the condition. Recipients of administration of compounds and/or compositions of the invention can be any vertebrate animal, such as mammals. Among mammals, the preferred receptors are mammals of the Order of Primates (including humans, apes and monkeys), Arteriodactyla (including horses, goats, cows, sheep, pigs), Rodenta (including mice, rats and hamsters), Lagamorpha (including rabbits) and Carnivora (including cats and dogs). Among birds, the preferred recipients are turkeys, chickens and other members of the same order. The most preferred recipients are humans.

[0702] For topical applications, it is preferred to administer an effective amount of a pharmaceutical composition according to the invention to the target area, for example, skin surface, mucous membranes, and the like, which are adjacent to peripheral neurons to be treated. This amount will generally vary from about 0.0001 mg to about 1 g of a compound of the invention per application, depending on the area to be treated, whether the use is diagnostic, prophylactic, or therapeutic, the severity of the symptoms, and the nature of the condition. topical vehicle employed. A preferred topical preparation is an ointment, in which about 0.001 to about 50 mg of active ingredient is used per cc of ointment base. The pharmaceutical composition may be formulated as transdermal compositions of transdermal delivery devices ("patches"). Such compositions include, for example, a backing layer, active compound reservoir, a control membrane, liner and contact adhesive. Such transdermal patches can be used to provide continuous or on-demand pulsatile application of the compounds of the present invention, as desired.

[0703] The compositions of the invention can be formulated to provide rapid, prolonged or delayed release of the active ingredient after administration to the patient using procedures known in the art. Controlled drug release systems include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are provided in US Patent Nos. 3,845,770 and 4,326,525 and in P. J. Kuzma et al., Regional Anesthesia 22 (6): 543 to 551 (1997), all of which are incorporated herein by reference.

[0704] The compositions of the invention can also be applied through an intranasal drug delivery system for local, systemic and rhinocerebral medical therapies. Controlled Particle Dispersion (CPD)™ technology, nasal spray bottles, inhalers or traditional nebulizers are known to those skilled in the art to provide effective local and systemic delivery of drugs by targeting the olfactory region and paranasal sinuses.

[0705] The invention also relates to an intravaginal shell or core drug delivery device suitable for administration to a human or female animal. The device may be comprised of the active pharmaceutical ingredient in a polymeric matrix, surrounded by a sheath, and capable of releasing the compound in a substantially zero order pattern on a daily basis similar to devices used to deliver testosterone as described in the Published Patent Application. PCT No. WO 98/50016.

[0706] Current methods for ocular application include topical administration (eye drops), subconjunctival injections, periocular injections, intravitreal injections, surgical implants and iontophoresis (uses a small electrical current to transport ionized drugs into and through body tissues). Those skilled in the art could combine the most suitable excipients with the compound for safe and effective intraocular administration.

[0707] The most appropriate route will depend on the nature and severity of the condition treated. Those skilled in the art are also familiar with methods of administration (e.g., oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage forms, suitable pharmaceutical excipients, and other matters relevant to applying the compounds to an individual in need. the same.

COMBINATION THERAPY

[0708] The compounds of the invention can be usefully combined with one or more other compounds of the invention or one or more other therapeutic agents or any combination thereof, in the treatment of diseases and conditions associated with the activity of voltage-gated sodium channels. For example, a compound of the invention may be administered simultaneously, sequentially or separately in combination with other therapeutic agents, including, but not limited to: • opiate analgesics, e.g., morphine, heroin, cocaine, oxymorphine, levorphanol, levalorphan, oxycodone, codeine , dihydrocodeine, propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone, meripidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine; • non-opioid analgesics, eg acetaminophen, salicylates (e.g. aspirin); • non-steroidal anti-inflammatory drugs (NSAIDs), e.g. ibuprofen, naproxen, fenoprofen, ketoprofen, celecoxib, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, acid mefenamic, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprene, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin and zomepirac; • anticonvulsants, for example, carbamazepine, oxcarbazepine, lamotrigine, valproate, topiramate, gabapentin and pregabalin; • antidepressants such as tricyclic antidepressants, for example, amitriptyline, clomipramine, despramine, imipramine and nortriptyline; • selective COX-2 inhibitors, for example, celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib and lumiracoxib; • alpha-adrenergics, for example, doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, and 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2- yl)-5-(2-pyridyl)quinazoline; • barbiturate sedatives, e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metarbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, teamylal and thiopental; • tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (aR, 9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8, 9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK -637), 5-[[2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1 ,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy5-(trifluoromethoxy)phenyl]-methylamino]-2 - phenylpiperidine (2S,3S); • tar analgesics, in particular paracetamol; • serotonin reuptake inhibitors, e.g. paroxetine, sertraline, norfluoxetine (desmethyl fluoxetine metabolite), demethylsertraline metabolite, '3 fluvoxamine, paroxetine, citalopram, metabolite of citalopram, desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine, trazodone and fluoxetine; , oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion hydroxy buproprion metabolite, nomifensine and viloxazine (Vivalan®)), especially a selective noradrenaline reabsorption inhibitor such as reboxetine, in particular (S,S)-reboxetine, and sedatives/ neuroleptic anxiolytics venlafaxine and duloxetine; • dual serotonin-norepinephrine reuptake inhibitors such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine; • acetyllinesterase inhibitors such as donepezil; • 5-HT3 antagonists such as ondansetron; • metabotropic glutamate receptor (mGluR) antagonists; • local anesthetic such as mexiletine and lidocaine; • corticosteroid such as dexamethasone; • antiarrhythmics, for example, mexiletine and phenytoin; • muscarinic antagonists, for example, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, temiverine and ipratropium; • cannabinoids; • vanilloid receptor agonists (e.g. resinferatoxin) or antagonists (e.g. capsazepine); • sedatives, for example, glutethimide, meprobamate, methaqualone and dichloralphenazone; • anxiolytics such as benzodiazepines, • antidepressants such as mirtazapine, • topical agents (eg, lidocaine, capsacin and resiniferotoxin); • muscle relaxants such as benzodiazepines, baclofen carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol and orphrenadine; • antihistamines or H1 antagonists; • NMDA receptor antagonists; • 5-HT receptor agonists/antagonists; • PDEV inhibitors; • Tramadol®; • cholinergic (nicotinic) analgesics; • alpha-2-delta ligands; • Subtype E2 prostaglandin antagonists; • leukotriene B4 antagonists; • 5-lipoxygenase inhibitors; and • 5-HT3 antagonists.

[0709] As used herein, "combination" refers to any mixture or permutation of one or more compounds of the invention and one or more other compounds of the invention or one or more additional therapeutic agents. Unless the context makes it clear, "combination" may include simultaneous or sequential application of a compound of the invention with one or more therapeutic agents. Unless the context makes it clear, "combination" may include dosage forms of a compound of the invention with another therapeutic agent. Unless the context makes it clear, "combination" may include routes of administration of a compound of the invention with another therapeutic agent. Unless the context makes it clear, "combination" may include formulations of a compound of the invention with another therapeutic agent. Dosage forms, routes of administration and pharmaceutical compositions include, but are not limited to, those described herein.

PART KITS

[0710] The present invention also provides kits that contain a pharmaceutical composition that includes one or more compounds of the invention. The kit also includes instructions for using the pharmaceutical composition to inhibit the activity of voltage-gated sodium channels, preferably NaV1.6, for the treatment of epilepsy, as well as other uses as disclosed herein. Preferably, a commercial package will contain one or more unit doses of the pharmaceutical composition. For example, such a unit dose may be a sufficient amount for preparing an intravenous injection. It will be apparent to those skilled in the art that compounds that are light and/or sensitive to air may require special packaging and/or formulation. For example, packaging that is opaque to light and/or sealed from contact with ambient air and/or formulated with suitable coatings or excipients may be used. PREPARATION OF THE COMPOUNDS OF THE INVENTION

[0711] The following Reaction Schemes illustrate methods for preparing compounds of this invention, that is, the compound of formula (I), as individual stereoisomers, enantiomers or tautomers thereof or mixtures thereof; or as pharmaceutically acceptable salts, solvates or prodrugs

[0712] It is understood that one skilled in the art could be able to produce the compounds of the invention by similar methods or by methods known to one skilled in the art. It is also understood that one skilled in the art would be able to produce, in a similar manner as described below, other compounds of the invention not specifically illustrated using suitable starting components and modifying the synthesis parameters as necessary. It is also understood that simple functional group transformations (see, e.g., Larock, R.C. Comprehensive Organic Transformations, 2nd edition (Wiley, 1999) can be carried out by methods known to those skilled in the art. In general, the starting components can be obtained from from sources such as Sigma Aldrich, Combi-Blocks, Oakwood Chemicals, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Smith, M.B. and J. March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th edition (Wiley, 2007)) or prepared as described herein.

[0713] It is also understood that, in the following description, combinations of substituents and/or variables of the disclosed formulas are permitted only if such contributions result in stable compounds.

[0714] It will also be appreciated by those skilled in the art that, in the process described below, the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy (i.e., “oxygen protecting groups”) include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino (i.e., “nitrogen protecting groups”) include t-butoxy carbonyl, benzyloxy carbonyl, and the like. Suitable protecting groups for mercapto (i.e., “sulfur protecting groups”) include -C(O)-R” (where R” is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or aryl or arylalkyl esters.

[0715] Protecting groups can be added or removed according to standard techniques, which are known to those skilled in the art and as described herein.

[0716] The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Greene's Protective Groups in Organic Synthesis (2006), 4th Ed., Wiley. The protecting group can also be a polymeric resin, such as a Wang resin or a 2-chlorotrilite chloride resin.

[0717] It will also be understood by those skilled in the art, although such protected derivatives of compounds of this invention may not have pharmacological activity as such, they can be administered to a mammal and thereafter metabolized in the body to form compounds of the invention that are pharmacologically active. Therefore, such derivatives can be described as “prodrugs”. All prodrugs of this invention are included within the scope of the invention.

[0718] The compounds of formula (I) may contain at least one asymmetric carbon atom and, therefore, may present themselves as racemates, enantiomers and/or diastereoisomers. Specific enantiomers or diastereoisomers can be prepared using the appropriate chiral starting material. Alternatively, diastereoisomeric mixtures or racemic mixtures of compounds of formula (I) can be resolved by forming their respective enantiomers or diastereoisomers. Methods for resolving diastereoisomeric or racemic mixtures of the compounds of formula (I), as described herein, or intermediates prepared herein, are well known in the art (e.g., E.L. Eliel and S.H. Wilen, in Stereochemistry of Organic Compounds ; John Wiley & Sons: New York, 1994; Chapter 7, and references cited therein). Suitable processes such as crystallization (e.g. preferential crystallization, preferential crystallization in the presence of additives), asymmetric transformation of racemates, chemical separation (e.g. formation and separation of diastereomers as mixtures of diastereomeric salts or the use of other resolving agents; separation through complexes and inclusion compounds), kinetic resolution (e.g. with titanium tartrate catalyst), enzymatic resolution (e.g. lipase-mediated) and chromatographic separation (e.g. HPLC with chiral stationary phase and/or with simulated moving bed or supercritical fluid chromatography and related techniques) are some examples that can be applied (see, for example, T.J. Ward, Analytical Chemistry, 2002, 2863 to 2872).

PREPARATION OF COMPOUNDS OF FORMULA (I)

[0719] In general, the compounds of formula (I), as described above in the Summary of the Invention, can be synthesized following the general procedure described below in Reaction Scheme 1 in which X, Y, n, m, R1, R2, R3, R4, R5, R6, R7 and R8 are as described above in the Summary of the Invention for compounds of formula (I): REACTION SCHEME 1

[0720] The compounds of formulas (101), (102) and (103) are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. In general, compounds of formula (I) are prepared as described above in Reaction Scheme 1 of the following formula:

[0721] The compound of formula (101) is reacted with sulfonamide (102) (where Z1 is optionally a hydrogen or nitrogen protecting group, for example, but without limitation, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4 -methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl) under standard reaction conditions, such as, but not limited to, the use of a polar aprotic solvent, such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide, in the presence of a base, such as, but not limited to, potassium carbonate or sodium hydride, at a temperature between about 0°C and 80°C, for about 1 to 48 hours to produce a compound of formula (103). The compound of formula (103) is then treated with an acid, such as, but not limited to, trifluoroacetic acid, in a polar aprotic solvent, such as, but not limited to, dichloromethane, at a temperature between about 0°C and room temperature to generate a compound of formula (I), which can be isolated from the reaction mixture by standard techniques. One skilled in the art would also readily recognize that, under certain circumstances, the preparation of a compound of formula (103) can result in a compound of formula (I), which can be isolated from the reaction mixture by standard techniques.

[0722] Alternatively, compounds of formula (I), wherein R4 is hydrogen, as described above in the Summary of the Invention, can be synthesized following the general procedure described below in Reaction Scheme 2 wherein X, Y, n, m , R1, R2, R3, R5, R6, R7 and R8 are as described above in the Summary of the Invention for compounds of formula (I): REACTION SCHEME 2

[0723] The compounds of formulas (201), (202), (203) and (204) are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. In general, compounds of formula (I) are prepared as described above in Reaction Scheme 2 of the following formula:

[0724] The compound of formula (201) (where Z2 is a nitrogen protecting group, for example, but without limitation, tert-butyloxycarbonyl or benzyl) is reacted with sulfonamide (202) (where Z1 is optionally a hydrogen or a nitrogen protecting group, e.g., but not limited to, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl) under standard reaction conditions, such as, but not limited to, the use of a polar aprotic solvent, such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide, in the presence of a base, such as, but not limited to, potassium carbonate or sodium hydride, at a temperature between about 0°C and 80°C for about 1 to 48 hours to produce a compound of formula (203). The compound of formula (203) is then treated with an acid, such as, but not limited to, trifluoroacetic acid, in a polar aprotic solvent, such as, but not limited to, dichloromethane, at a temperature between about 0°C and room temperature to generate a compound of formula (204). The compound of formula (204) is then reacted with, for example, but not limited to, an aldehyde or ketone of formula (205) in the presence of a reducing agent, such as, but not limited to, sodium triacetoxyborohydride, in a mixture of polar aprotic solvent, such as, but not limited to, N,N-dimethylformamide and 1,2-dichloroethane, at a temperature between about 0 °C and room temperature to generate a compound of formula (I), which can be isolated of the reaction mixture by standard techniques.

[0725] The compounds of formula (I) in which R3 is -N(R13)- and R4 is hydrogen, that is, the compounds of formula (I) in which R4 is hydrogen, as described above in the Embodiments of the Invention, can be synthesized following the general procedure described below in Reaction Scheme 3 in which ): REACTION SCHEME 3

[0726] The compounds of formulas (301), (302), (304), (305), (306) and (307) are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed in this document. In general, compounds of formula (Ib) are prepared as described above in Reaction Scheme 3 of the following formula:

[0727] The compound of formula (301) (where Z2 is a nitrogen protecting group, for example, but without limitation, tert-butyloxycarbonyl or benzyl) is reacted with sulfonamide (302) (where Z1 is optionally a hydrogen or a nitrogen protecting group, e.g., but not limited to, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl) under standard reaction conditions, such as, but not limited to, the use of a polar aprotic solvent, such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide, in the presence of a base, such as, but not limited to, potassium carbonate or sodium hydride, at a temperature between about 0°C and 80°C for about 1 to 48 hours to produce a compound of formula (303). The compound of formula (303) can then be alkylated with alkylating agents R13-Z3 (304) (where Z3 is a leaving group such as, but not limited to, bromide, iodide, sulfate), such as, but not limited to, methyl iodide, in the presence of a base such as, but not limited to, lithium bis(trimethylsilyl)amide in a polar aprotic solvent such as, but not limited to, tetrahydrofuran, at a temperature between about -78 °C and room temperature, to provide a compound of formula (305). The compound of formula (305) is then treated with an acid, such as, but not limited to, trifluoroacetic acid, in a polar aprotic solvent, such as, but not limited to, dichloromethane, at a temperature between about 0°C and room temperature to generate a compound of formula (306). The compound of formula (306) is then reacted with, for example, but not limited to, an aldehyde or ketone of formula (307) in the presence of a reducing agent, such as, but not limited to, sodium triacetoxyborohydride, in a mixture of polar aprotic solvent, such as, but not limited to, N,N-dimethylformamide and 1,2-dichloroethane, at a temperature between about 0 °C and room temperature to generate a compound of formula (I), which can be isolated of the reaction mixture by standard techniques.

[0728] Alternatively, the compounds of formula (I) in which R3 is -N(R13)- and R4 is hydrogen, that is, the compounds of formula (I) in which R4 is hydrogen, as described above in the Embodiments of the Invention , can be synthesized following the general procedure described below in Reaction Scheme 4 in which X, Y, n, m, R1, R2, R5, R6, R7, R8 and R13 are as described above in Embodiments of the Invention of the compounds of the formula (Ib): REACTION SCHEME 4

[0729] The compounds of formulas (401), (402), (403) and (404) are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. In general, compounds of formula (Ib) are prepared as described above in Reaction Scheme 4 of the following formula:

[0730] The compound of formula (401) (where Z2 is a protecting group, for example, but without limitation, tert-butyloxycarbonyl or benzyl) is reacted with sulfonamide (402) (where Lg1 is a leaving group, e.g. example, bromine, iodine or trifluorosulfonate and Z1 is hydrogen or a protecting group, for example, but without limitation, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl) under cross-coupling conditions Buchwald-Hartwig standard, such as, but not limited to, the use of a solvent, such as, but not limited to, toluene, in the presence of a base, such as, but not limited to, cesium carbonate, and in the presence of a palladium catalyst compound, for example, but without limitation, of 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene and bis(dibenzylideneacetone)palladium(0), at a temperature between about 0°C and 120°C, for about from 1 to 20 hours to produce a compound of formula (403). The compound of formula (403) is then treated with an acid, such as, but not limited to, trifluoroacetic acid, in a polar aprotic solvent, such as, but not limited to, dichloromethane, at a temperature between about 0°C and room temperature to generate a compound of formula (404). The compound of formula (404) is then reacted with, for example, but not limited to, an aldehyde or ketone of formula (405) in the presence of a reducing agent, such as, but not limited to, sodium triacetoxyborohydride, in a mixture of polar aprotic solvent, such as, but not limited to, N,N-dimethylformamide and 1,2-dichloroethane, at a temperature between about 0 °C and room temperature to generate a compound of formula (I), which can be isolated of the reaction mixture by standard techniques.

[0731] Alternatively, the compounds of formula (I) in which R3 is -N(R13)- and R4 is hydrogen, that is, the compounds of formula (I) in which R4 is hydrogen, as described above in Embodiments of the Invention , can be synthesized following the general procedure described below in Reaction Scheme 5 in which X, Y, n, m, R1, R2, R3, R5, R6, R7, R8 and R13 are as described above in the Embodiments of the Invention of the compounds of formula (Ib): REACTION SCHEME 5

[0732] The compounds of formulas (501), (502), (503), (504), (505), (506) and (507) are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. In general, compounds of formula (Ib) are prepared as described above in Reaction Scheme 5 of the following formula:

[0733] The compound of formula (501) (where Z2 is a protecting group, for example, but without limitation, tert-butyloxycarbonyl or benzyl) is reacted with sulfonamide (502) (where Lg1 is a leaving group, e.g. example, bromine, iodine or trifluorosulfonate and Z1 is hydrogen or a protecting group, for example, but without limitation, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl) under cross-coupling conditions Buchwald-Hartwig standard, such as, but not limited to, the use of a solvent, such as, but not limited to, toluene, in the presence of a base, such as, but not limited to, cesium carbonate, and in the presence of a palladium catalyst compound, for example, but without limitation, of 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene and bis(dibenzylideneacetone)palladium(0), at a temperature between about 0°C and 120°C, for about from 1 to 20 hours to produce a compound of formula (503). The compound of formula (503) can then be alkylated with alkylating agents R13-Z3 (504) (where Z3 is a leaving group such as, but not limited to, bromide, iodide, sulfate), such as, but not limited to, methyl iodide, in the presence of a base such as, but not limited to, lithium bis(trimethylsilyl)amide in a polar aprotic solvent such as, but not limited to, tetrahydrofuran, at a temperature between about -78 °C and room temperature, to provide a compound of formula (505). The compound of formula (505) is then treated with an acid, such as, but not limited to, trifluoroacetic acid, in a polar aprotic solvent, such as, but not limited to, dichloromethane, at a temperature between about 0°C and room temperature to generate a compound of formula (506). The compound of formula (506) is then reacted with, for example, but not limited to, an aldehyde or ketone of formula (507) in the presence of a reducing agent, such as, but not limited to, sodium triacetoxyborohydride, in a mixture of polar aprotic solvent, such as, but not limited to, N,N-dimethylformamide and 1,2-dichloroethane, at a temperature between about 0 °C and room temperature to generate a compound of formula (I), which can be isolated of the reaction mixture by standard techniques.

[0734] Alternatively, the compounds of formula (I), where R3 is -N(R13)-, that is, the compounds of formula (Ib), as described above in the Embodiments of the Invention, can be synthesized following the general procedure described below in Reaction Scheme 6 wherein X, Y, n, m, R1, R2, R3, R4, R5, R6, R7, R8 and R13 are as described above in Embodiments of the Invention for compounds of formula (Ib): REACTION SCHEME 6

[0735] The compounds of formulas (601), (602) and (603) are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. In general, compounds of formula (Ib) are prepared as described above in Reaction Scheme 5 of the following formula:

[0736] The compound of formula (601) is reacted with sulfonamide (602) (wherein Lg1 is a leaving group, for example, but without limitation, bromine, iodine or trifluorosulfonate and Z1 is hydrogen or a protecting group, for example , but not limited to, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl) under standard reaction conditions, such as, but not limited to, the use of a solvent, such as, but not limited to , toluene, in the presence of a base, such as, but not limited to, cesium carbonate, and in the presence of a palladium catalyst comprising, for example, but not limited to, 4,5-bis(diphenylphosphine)-9,9- dimethylxanthene and bis(dibenzylideneacetone)palladium(0), at a temperature between about 0°C and 120°C, for about 1 to 20 hours to generate a compound of formula (Ib), which can be isolated from the reaction mixture by standard techniques.

[0737] Under certain conditions, the above transformations will provide a compound of formula (603) instead of a compound of formula (Ib). In such cases, Z1 can be removed from the compound of formula (603) by methods known in the art, such as, but not limited to, the use of an acid, such as, but not limited to, trifluoroacetic acid, in a polar aprotic solvent, such as, but not limited to, without limitation, dichloromethane, at a temperature between about 0 ° C and room temperature to generate a compound of formula (Ib).

[0738] A compound of formula (Ib) in which R13 is hydrogen can be converted into a compound of formula (Ib) in which R13 is alkyl, such as, but not limited to, methyl, by reaction with an aldehyde, such as, but without limitation, paraformaldehyde, in an acidic solvent, such as, but not limited to, formic acid or trifluoroacetic acid, in the presence of a reducing agent, such as, but not limited to, sodium triacetoxyborohydride or formic acid. The compound of formula (Ib) can then be isolated from the reaction mixture by standard techniques.

[0739] Alternatively, the compounds of formula (I) in which R3 is -N(R13)- and R4 is hydrogen and R7 is alkyl or cycloalkyl, that is, the compounds of formula (Ib) in which R4 is hydrogen and R7 is alkyl or cycloalkyl, as described above in Embodiments of the Invention, can be synthesized following the general procedure described below in Reaction Scheme 7 wherein X, Y, n, m, R1, R2, R3, R5, R6, R8 and R13 are as described above in the Embodiments of the Invention of compounds of formula (Ib) and in which R7 is alkyl or cycloalkyl: REACTION SCHEME 7

[0740] The compounds of formulas (701), (702), (703), (704), (705), (706), (707) and (708) are commercially available or can be prepared according to known methods by one skilled in the art or by methods disclosed herein. In general, compounds of formula (Ib) are prepared as described above in Reaction Scheme 7 of the following formula:

[0741] The compound of formula (701) (where Z2 is a nitrogen protecting group, for example, but without limitation, tert-butyloxycarbonyl or benzyl) is reacted with sulfonamide (702) (where Z1 is optionally a hydrogen or a nitrogen protecting group, for example, but not limited to, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl, and wherein Lg1 is a leaving group, for example, but not limited to , chlorine, bromine or iodine) under standard reaction conditions, such as, but not limited to, the use of a polar aprotic solvent, such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide, in the presence of a base, such as , but without limitation, potassium carbonate or sodium hydride, at a temperature between about 0 ° C and 80 ° C, for about 1 to 48 hours to produce a compound of formula (703). The compound of formula (703) can then be reacted with boronic acid derivatives of formula (704) (wherein Z4 is, for example, but without limitation, B(OH)2 or 4,4,5,5- tetramethyl-1,3,2À2-dioxaborolane and R15 is, for example, but not limited to, methyl, ethyl or cyclopropyl) under standard Suzuki-Miyaura reaction conditions such as, but not limited to, the use of a solvent, such as, but without limitation, 1,4-dioxane, in the presence of a base, such as, but not limited to, tribasic potassium phosphate, and in the presence of a palladium catalyst composed of, for example, but not limited to, palladium acetate and palladium tetrafluoroborate. tricyclohexylphosphine, at a temperature between about room temperature and 120°C, for about 1 to 20 hours to generate a compound of formula (705). The compound of formula (705) can then be alkylated with alkylating agents R13-Z3 (where Z3 is a leaving group such as, but not limited to, bromide, iodide, sulfate), such as, but not limited to, methyl iodide , in the presence of a base such as, but not limited to, lithium bis(trimethylsilyl)amide or sodium hydride, in a polar aprotic solvent such as, but not limited to, tetrahydrofuran or N,N-dimethylformamide, at a temperature between about - 78 °C and room temperature, to provide a compound of formula (706). The compound of formula (706) is then treated with an acid, such as, but not limited to, trifluoroacetic acid, in a polar aprotic solvent, such as, but not limited to, dichloromethane, at a temperature between about 0°C and room temperature to generate a compound of formula (707). The compound of formula (707) is then reacted with, for example, but not limited to, an aldehyde or ketone of formula (708) in the presence of a reducing agent, such as, but not limited to, sodium triacetoxyborohydride, in a mixture of polar aprotic solvent, such as, but not limited to, N,N-dimethylformamide and 1,2-dichloroethane, at a temperature between about 0°C and room temperature to generate a compound of formula (Ib), which can be isolated of the reaction mixture by standard techniques.

[0742] Alternatively, the compounds of formula (I) in which R3 is -N(R13)- and R4 is hydrogen and R7 is alkyl or cycloalkyl, that is, the compounds of formula (Ib) in which R4 is hydrogen and R7 is alkyl or cycloalkyl, as described above in Embodiments of the Invention, can be synthesized following the general procedure described below in Reaction Scheme 8 wherein X, Y, n, m, R1, R2, R3, R5, R6, R8 and R13 are as described above in the Embodiments of the Invention of compounds of formula (Ib) and in which R7 is alkyl or cycloalkyl: REACTION SCHEME 8

[0743] The compounds of formulas (801), (802), (803), (804), (805), (806), (807), (808) and (809) are commercially available or can be prepared from according to methods known to those skilled in the art or methods disclosed herein. In general, compounds of formula (Ib) are prepared as described above in Reaction Scheme 8 of the following formula:

[0744] The compound of formula (801) (where Z2 is a nitrogen protecting group, for example, but without limitation, tert-butyloxycarbonyl) is reacted with sulfonamide (802) (where Z1 is optionally a hydrogen or a nitrogen buffer, e.g., but not limited to, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl, and wherein Lg1 is a leaving group, e.g., but not limited to, chlorine , bromine or iodine) under standard reaction conditions, such as, but not limited to, the use of a polar aprotic solvent, such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide, in the presence of a base, such as, but not limited to without limitation, potassium carbonate or sodium hydride, at a temperature between about 0°C and 80°C, for about 1 to 48 hours to produce a compound of formula (803). The compound of formula (803) can then be reacted with boronic acid derivatives of formula (804) (wherein Z4 is, for example, but without limitation, B(OH)2 or 4,4,5,5- tetramethyl-1,3,2À2-dioxaborolane and R15 is, for example, but not limited to, methyl, ethyl or cyclopropyl) under standard Suzuki-Miyaura reaction conditions such as, but not limited to, the use of a solvent, such as, but without limitation, 1,4-dioxane, in the presence of a base, such as, but not limited to, tribasic potassium phosphate, and in the presence of a palladium catalyst composed of, for example, but not limited to, palladium acetate and palladium tetrafluoroborate. tricyclohexylphosphine, at a temperature between about room temperature and 120°C, for about 1 to 20 hours to generate a compound of formula (805). The compound of formula (805) is then treated with an acid, such as, but not limited to, trifluoroacetic acid, in a polar aprotic solvent, such as, but not limited to, dichloromethane, at a temperature between about 0°C and room temperature to generate a compound of formula (806). The compound of formula (806) is then reacted with, for example, but not limited to, an aldehyde or ketone of formula (807) in the presence of a reducing agent, such as, but not limited to, sodium triacetoxyborohydride, in a mixture of polar aprotic solvent, such as, but not limited to, N,N-dimethylformamide and 1,2-dichloroethane, at a temperature between about 0 ° C and room temperature to provide a compound of formula (808). The compound of formula (808) can then be alkylated to the aniline nitrogen by reaction with an aldehyde of formula (809) (wherein R16 is, for example, but not limited to, hydrogen or methyl) in the presence of a reducing agent , such as, but not limited to, sodium triacetoxyborohydride, in a mixture of polar solvent or solvent, such as, but not limited to, trifluoroacetic acid, at a temperature between about 0°C and room temperature to generate a compound of the formula (Ib ), which can be isolated from the reaction mixture by standard techniques.

[0745] Alternatively, compounds of formula (I), wherein R7 is alkyl or cycloalkyl, as described above in the Summary of the Invention, can be synthesized following the general procedure described below in Reaction Scheme 9 wherein X, Y, n , m, R1, R2, R3, R4, R5, R6 and R8 are as described above in the Summary of the Invention for compounds of formula (I) and R7 is alkyl or cycloalkyl: REACTION SCHEME 9

[0746] The compounds of formulas (901), (902), (903), (904) and (905) are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. In general, compounds of formula (I) are prepared as described above in Reaction Scheme 9 of the following formula:

[0747] The compound of formula (901) is reacted with sulfonamide (902) (where Z1 is optionally a hydrogen or nitrogen protecting group, for example, but without limitation, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4 -methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl and wherein Lg1 is a leaving group, e.g., but not limited to, chlorine, bromine, or iodine) under standard reaction conditions, such as, but not limited to, the use of a solvent polar aprotic acid, such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide, in the presence of a base, such as, but not limited to, potassium carbonate or sodium hydride, at a temperature between about 0°C and 80°C. °C for about 1 to 48 hours to produce a compound of formula (903). The compound of formula (903) can then be reacted with boronic acid derivatives of formula (904) (wherein Z4 is, for example, but without limitation, B(OH)2 or 4,4,5,5- tetramethyl-1,3,2À2-dioxaborolane and R15 is, for example, but not limited to, methyl, ethyl or cyclopropyl) under standard Suzuki-Miyaura reaction conditions such as, but not limited to, the use of a solvent, such as, but not limited to, without limitation, 1,4-dioxane, in the presence of a base, such as, but not limited to, tribasic potassium phosphate, and in the presence of a palladium catalyst composed of, for example, but not limited to, palladium acetate and palladium tetrafluoroborate. tricyclohexylphosphine, at a temperature between about room temperature and 120 ° C, for about 1 to 20 hours to generate a compound of formula (I), which can be isolated from the reaction mixture by standard techniques.

[0748] Alternatively, the compound of formula (903) can be reacted with organotin reagents of formula (904) (wherein Z4 is, for example, but without limitation, trimethylstanyl and R15 is, for example, but without limitation, methyl , under standard Stille coupling conditions, such as, but not limited to, the use of a solvent, such as, but not limited to, N,N-dimethylformamide, in the presence of an additive, such as, but not limited to, lithium chloride, and in the presence of a palladium catalyst, such as, but not limited to, bis(triphenylphosphine)palladium dichloride, at a temperature between about room temperature and 120°C, for about 1 to 20 hours to generate a compound of formula (I ), which can be isolated from the reaction mixture by standard techniques.

[0749] Under certain conditions, the above transformations will provide a compound of formula (905) instead of a compound of formula (I). In such cases, Z1 can be removed from the compound of formula (905) by methods known in the art, such as, but not limited to, the use of an acid, such as, but not limited to, trifluoroacetic acid, in a polar aprotic solvent, such as, but not limited to, without limitation, dichloromethane, at a temperature between about 0°C and room temperature to generate a compound of formula (I).

[0750] Alternatively, compounds of formula (I), wherein R4 is hydrogen, as described above in the Summary of the Invention, can be synthesized following the general procedure described below in Reaction Scheme 10 wherein X, Y, n, m , R1, R2, R3, R5, R6, R7 and R8 are as described above in the Summary of the Invention for compounds of formula (I): REACTION SCHEME 10

[0751] The compounds of formulas (1001), (1002), (1003), (1004), (1005), (1006) and (1007) are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. In general, compounds of formula (I) are prepared as described above in Reaction Scheme 10 of the following formula:

[0752] The compound of formula (1001) (where Z2 is a nitrogen protecting group, for example, but without limitation, tert-butyloxycarbonyl) is reacted with sulfonamide (1002) (where Z1 is optionally a hydrogen or a nitrogen buffer, e.g., but not limited to, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl, and wherein Lg1 is a leaving group, e.g., but not limited to, chlorine , bromine or iodine) under standard reaction conditions, such as, but not limited to, the use of a polar aprotic solvent, such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide, in the presence of a base, such as, but not limited to without limitation, potassium carbonate or sodium hydride, at a temperature between about 0°C and 80°C, for about 1 to 48 hours to produce a compound of formula (1003). The compound of formula (1003) can then be reacted with boronic acid derivatives of formula (1004) (wherein Z4 is, for example, but without limitation, B(OH)2 or 4,4,5,5- tetramethyl-1,3,2À2-dioxaborolane and R15 is, for example, but not limited to, methyl, ethyl or cyclopropyl) under standard Suzuki-Miyaura reaction conditions such as, but not limited to, the use of a solvent, such as, but without limitation, 1,4-dioxane, in the presence of a base, such as, but not limited to, tribasic potassium phosphate, and in the presence of a palladium catalyst composed of, for example, but not limited to, palladium acetate and palladium tetrafluoroborate. tricyclohexylphosphine, at a temperature between about room temperature and 120°C, for about 1 to 20 hours to generate a compound of formula (1005). The compound of formula (1005) is then treated with an acid, such as, but not limited to, trifluoroacetic acid, in a polar aprotic solvent, such as, but not limited to, dichloromethane, at a temperature between about 0°C and room temperature to generate a compound of formula (1006). The compound of formula (1006) is then reacted with, for example, but not limited to, an aldehyde or ketone of formula (1007) in the presence of a reducing agent, such as, but not limited to, sodium triacetoxyborohydride, in a mixture of polar aprotic solvent, such as, but not limited to, N,N-dimethylformamide and 1,2-dichloroethane, at a temperature between about 0°C and room temperature to generate a compound of formula (Ib), which can be isolated of the reaction mixture by standard techniques.

[0753] Alternatively, compounds of formula (I), wherein R4 is hydrogen, as described above in Embodiments of the Invention, can be synthesized following the general procedure described below in Reaction Scheme 11 wherein X, Y, n, m , R1, R2, R3, R5, R6, R7 and R8 are as described above in the Embodiments of the Invention of the compounds of formula (Ib): REACTION SCHEME 11

[0754] The compounds of formulas (1101), (1102), (1103), (1104), (1105), (1106), (1107), (1108) and (1109) are commercially available or can be prepared from according to methods known to those skilled in the art or methods disclosed herein. In general, compounds of formula (Ib) are prepared as described above in Reaction Scheme 11 of the following formula:

[0755] The compound of formula (1101) (where Z2 is a nitrogen protecting group, for example, but not limited to, tert-butyloxycarbonyl) is reacted with sulfonamide (1102) (where Z1 is optionally a hydrogen or a nitrogen buffer, e.g., but not limited to, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl, and wherein Lg1 is a leaving group, e.g., but not limited to, chlorine , bromine or iodine) under standard reaction conditions, such as, but not limited to, the use of a polar aprotic solvent, such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide, in the presence of a base, such as, but not limited to without limitation, potassium carbonate or sodium hydride, at a temperature between about 0°C and 80°C, for about 1 to 48 hours to produce a compound of formula (1103). The compound of formula (1103) is then treated with an acid, such as, but not limited to, trifluoroacetic acid, in a polar aprotic solvent, such as, but not limited to, dichloromethane, at a temperature between about 0°C and room temperature to generate a compound of formula (1104). The compound of formula (1104) is then reacted with, for example, but not limited to, an aldehyde or ketone of formula (1105) in the presence of a reducing agent, such as, but not limited to, sodium triacetoxyborohydride, in a mixture of polar aprotic solvent, such as, but not limited to, N,N-dimethylformamide and 1,2-dichloroethane, at a temperature between about 0 ° C and room temperature to generate a compound of formula (1106). The compound of formula (1106) can then be reacted with boronic acid derivatives of formula (1107) (wherein Z4 is, for example, but without limitation, B(OH)2 or 4,4,5,5- tetramethyl-1,3,2À2-dioxaborolane and R15 is, for example, but not limited to, methyl, ethyl or cyclopropyl) under standard Suzuki-Miyaura reaction conditions such as, but not limited to, the use of a solvent, such as, but not limited to, limitation, 1,4-dioxane, in the presence of a base, such as, but not limited to, tribasic potassium phosphate, and in the presence of a palladium catalyst composed of, for example, but not limited to, palladium acetate and tricyclohexylphosphine tetrafluoroborate , at a temperature between about room temperature and 120°C, for about 1 to 20 hours to generate a compound of formula (1108). The compound of formula (1108) is then reacted with, for example, but not limited to, an aldehyde or ketone of formula (1109) (wherein R16 is, for example, but not limited to, hydrogen or methyl) in the presence of a reducing agent, such as, but not limited to, sodium triacetoxyborohydride, in a mixture of polar aprotic solvent, such as, but not limited to, N,N-dimethylformamide and 1,2-dichloroethane, at a temperature between about 0°C and at room temperature to generate a compound of formula (Ib), which can be isolated from the reaction mixture by standard techniques.

[0756] Alternatively, compounds of formula (I), wherein R4 is hydrogen and R13 is hydrogen or alkyl, as described above in Embodiments of the Invention, can be synthesized following the general procedure described below in Reaction Scheme 12 wherein , Y, n, m, R1, R2, R3, R5, R6, R7 and R8 are as described above in the Embodiments of the Invention of the compounds of formula (Ib) and wherein R13 is hydrogen or alkyl: REACTION SCHEME 12

[0757] The compounds of formulas (1201), (1202), (1203), (1204), (1205) and (1206) are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed in this document. In general, compounds of formula (Ib) are prepared as described above in Reaction Scheme 12 of the following formula:

[0758] The compound of formula (1201) (wherein Z1 is optionally a hydrogen or nitrogen protecting group, for example, but without limitation, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2- ( trimethylsilyl)ethoxymethyl and wherein Lg1 is a leaving group, e.g., but not limited to, chlorine, bromine, or iodine) is reacted with a nitrogen nucleophile, such as, but not limited to, sodium azide, under standard reaction conditions, such as, but not limited to, the use of a polar aprotic solvent, such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide, at a temperature between about 0°C and 80°C, for about 1 to 48 hours. The compound that can be isolated from the reaction mixture by standard techniques is then treated with a reducing agent, such as, but not limited to, zinc powder, in a polar aprotic solvent, such as, but not limited to, tetrahydrofuran, in the presence of a weak acid, such as, but not limited to, aqueous ammonium chloride, to produce a compound of formula (1202).

[0759] Alternatively, Lg1 in the compound of formula (1202) can then be converted to R7 by reaction with boronic acid derivatives of formula (1203) (where Z4 is, for example, but without limitation, B(OH) 2 or 4,4,5,5-tetramethyl-1,3,2À2-dioxaborolane and R15 is, for example, but without limitation, methyl, ethyl or cyclopropyl) under standard Suzuki-Miyaura reaction conditions such as, but without limitation , the use of a solvent, such as, but not limited to, 1,4-dioxane, in the presence of a base, such as, but not limited to, tribasic potassium phosphate, and in the presence of a palladium catalyst composed of, e.g. but without limitation, palladium acetate and tricyclohexylphosphine tetrafluoroborate, at a temperature between about room temperature and 120 ° C, for about 1 to 20 hours to generate a compound of formula (1204).

[0760] Compounds of formula (1202) or compounds of formula (1204) are then reacted with, for example, but without limitation, a ketone of formula (1205) in the presence of a reducing agent, such as, but without limitation , sodium triacetoxyborohydride, in an acidic solvent, such as, but not limited to, trifluoroacetic acid, at a temperature between about 0°C and room temperature, followed by reaction with an aldehyde of formula (1206) (where R16 is, e.g., but not limited to, hydrogen or methyl) in the presence of a reducting agent, such as, but not limited to, sodium triacetoxyborohydride, in an acidic solvent, such as, but not limited to, trifluoroacetic acid, at a temperature between about 0° C and room temperature, to generate a compound of formula (Ib), which can be isolated from the reaction mixture by standard techniques.

[0761] Alternatively, compounds of formula (Ib), as described above in Embodiments of the Invention, can be synthesized following the general procedure described below in Reaction Scheme 13 wherein X, Y, n, m, R1, R2, R3 , R4, R5, R6, R7 and R8 are as described above in the Embodiments of the Invention of the compounds of formula (Ib) and R13 is hydrogen or alkyl: REACTION SCHEME 13

[0762] The compounds of formulas (1301), (1302), (1303), (1304), (1305) and (1306) are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed in this document. In general, compounds of formula (I) are prepared as described above in Reaction Scheme 13 of the following formula:

[0763] The compound of formula (1301) is reacted with sulfonamide (1302) (where Z1 is optionally a hydrogen or nitrogen protecting group, for example, but without limitation, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4 - methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl and wherein Lg1 is a leaving group, e.g., but not limited to, chlorine, bromine, or iodine) under standard reaction conditions, such as, but not limited to, the use of a solvent polar aprotic agent, such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide, in the presence of a base, such as, but not limited to, potassium carbonate or sodium hydride, at a temperature between about 0 °C and 80 °C for about 1 to 48 hours to produce a compound of formula (1303). The compound of formula (1303) can then be reacted with boronic acid derivatives of formula (1304) (wherein Z4 is, for example, but without limitation, B(OH)2 or 4,4,5,5- tetramethyl-1,3,2À2-dioxaborolane and R15 is, for example, but not limited to, methyl, ethyl or cyclopropyl) under standard Suzuki-Miyaura reaction conditions such as, but not limited to, the use of a solvent, such as, but without limitation, 1,4-dioxane, in the presence of a base, such as, but not limited to, tribasic potassium phosphate, and in the presence of a palladium catalyst composed of, for example, but not limited to, palladium acetate and palladium tetrafluoroborate. tricyclohexylphosphine, at a temperature between about room temperature and 120°C, for about 1 to 20 hours to generate a compound of formula (1305). The compound of formula (1305) can then be alkylated to the aniline nitrogen by reaction with an aldehyde of formula (1306) (wherein R16 is, for example, but not limited to, hydrogen or methyl) in the presence of a reducing agent , such as, but not limited to, sodium triacetoxyborohydride, in a mixture of polar solvent or solvent, such as, but not limited to, trifluoroacetic acid, at a temperature between about 0°C and room temperature to generate a compound of the formula (Ib ), which can be isolated from the reaction mixture by standard techniques.

[0764] Alternatively, the compounds of formula (1305) can be alkylated at the aniline nitrogen by reacting with alkylating agents such as, but not limited to, methyl iodide, in the presence of a base, such as, but not limited to, sodium hydride , in a polar aprotic solvent such as, but not limited to, N,N-dimethylformamide, at a temperature between about -5 ° C and room temperature. The alkylated compound is then treated with an acid, such as, but not limited to, trifluoroacetic acid, in a polar aprotic solvent, such as, but not limited to, dichloromethane, at a temperature between about 0°C and room temperature to generate a compound of formula (Ib), which can be isolated from the reaction mixture by standard techniques.

[0765] Alternatively, compounds of formula (Ib), as described above in Embodiments of the Invention, can be synthesized following the general procedure described below in Reaction Scheme 14 wherein X, Y, n, m, R1, R2, R4 , R3, R5, R6, R7, R8 and R13 are as described above in the Embodiments of the Invention of the compounds of formula (Ib): REACTION SCHEME 14

[0766] The compounds of formulas (1401), (1402), (1403), (1404) and (1405) are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. In general, compounds of formula (Ib) are prepared as described above in Reaction Scheme 14 of the following formula:

[0767] The compound of formula (1401) is reacted with sulfonamide (1402) (wherein Lg1 is a leaving group, for example, but without limitation, bromine, iodine or trifluorosulfonate and Z1 is hydrogen or a protecting group, for example , but not limited to, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl) under standard Buchwald reaction conditions, such as, but not limited to, the use of a solvent, such as, but not limited to, without limitation, toluene or 2-methyl-2-butanol, in the presence of a base, such as, but not limited to, cesium carbonate, and in the presence of a palladium catalyst composed of, for example, but not limited to, 4.5 -bis(diphenylphosphine)-9,9-dimethylxanthene and bis(dibenzylideneacetone)palladium(0) or chloro(2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino -1,1'-biphenyl)]palladium(II), at a temperature between about 0°C and 120°C, for about 1 to 20 hours to generate a compound of formula (1403). The compound of formula (1403) can then be alkylated with alkylating agents R13-Z3 (1404) (where Z3 is a leaving group such as, but not limited to, bromide, iodide, sulfate), such as, but not limited to, methyl iodide, in the presence of a base such as, but not limited to, sodium hydride in a polar aprotic solvent such as, but not limited to, N,N-dimethylformamide, at a temperature between about 0°C and room temperature , to provide a compound of formula (1405). The compound of formula (1405) is then treated with an acid, such as, but not limited to, trifluoroacetic acid, in a polar aprotic solvent, such as, but not limited to, dichloromethane, at a temperature between about 0°C and room temperature to generate a compound of formula (Ib), which can be isolated from the reaction mixture by standard techniques.

[0768] The compounds of formula (Ib1), which are the compounds of formula (Ib) in which R4 is hydrogen and at least one R6 is haloalkyl, as described above in the Embodiments of the Invention, can be synthesized following the general procedure described below in Reaction Scheme 15 wherein is haloalkyl: REACTION SCHEME 15

[0769] The compounds of formulas (1501), (1502), (1503), (1504) and (1505) are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. In general, compounds of formula (I) are prepared as described above in Reaction Scheme 15 of the following formula:

[0770] The compound of formula (1501) (where Z2 is a nitrogen protecting group, for example, but without limitation, tert-butyloxycarbonyl or benzyl) is reacted with sulfonamide (1502) (where Z1 is optionally a hydrogen or a nitrogen protecting group, e.g., but not limited to, tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-(trimethylsilyl)ethoxymethyl) under standard reaction conditions, such as, but not limited to, the use of a polar aprotic solvent, such as, but not limited to, dimethyl sulfoxide or N,N-dimethylformamide, in the presence of a base, such as, but not limited to, potassium carbonate or sodium hydride, at a temperature between about 0°C and 80°C for about 1 to 48 hours to produce a compound of formula (1503). The compound of formula (1503) is then treated with a halogenating reagent, such as, but not limited to, diethylaminosulfur trifluoride, in a polar aprotic solvent such as, but not limited to, dichloromethane, at a temperature between about 0°C. and room temperature to generate a compound of formula (1504) wherein R6a is haloalkyl. The compound of formula (1504) is then treated with an acid, such as, but not limited to, trifluoroacetic acid in a polar aprotic solvent, such as, but not limited to, dichloromethane, at a temperature between about room temperature and 120°C. , followed by reaction with, for example, but not limited to, an aldehyde or ketone of formula (1505) in the presence of a reducing agent, such as, but not limited to, N,N-dimethylformamide and dichloromethane, at a temperature between about 0 °C and room temperature to generate a compound of formula (I), which can be isolated from the reaction mixture by standard techniques.

[0771] Alternatively, compounds of formula (I), as described above in the Summary of the Invention, can be synthesized by one skilled in the art by simple functional group transformations. As such, but without limitation, a compound of formula (I) wherein R6 is alkenyl can be converted to a compound of formula (I) wherein R6 is alkyl by treatment with hydrogen in the presence of, but without limitation, palladium on carbon , in solvents such as, but not limited to, methanol and ethyl acetate. Alternatively, but without limitation, a compound of formula (I) wherein R1 is (methoxycarbonyl)phenyl can be converted to a compound of formula (I), while R1 is (2-hydroxypropan-2-yl)phenyl upon reaction with an organometallic reagent, such as, but not limited to, methylmagnesium bromide, in a polar aprotic solvent such as, but not limited to, tetrahydrofuran.

[0772] All compounds described below as being prepared that can be in the form of a free base or acid can be converted into their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid. Salts of the compounds prepared below can be converted to their base or free acid form by standard techniques. Furthermore, all compounds of the invention that contain an acid or an ester group can be converted to the corresponding ester or acid, respectively, by methods known to those skilled in the art or by methods described herein.

[0773] The following Examples, which refer to the synthesis of the compounds of the invention; and the following Biological Examples are provided as a guide to assist in the practice of the invention, and are not intended as a limitation on the scope of the invention.

[0774] In the Examples below, except where otherwise indicated, all temperatures are presented in degrees Celsius. Commercially available reagents were purchased from suppliers such as Aldrich Chemical Company, Combi-Blocks, TCI, or Oakwood Chemicals and were used without further purification except where otherwise noted. The reactions presented below were generally done under a positive pressure of nitrogen or argon or with a drying tube (except where otherwise specified) in anhydrous solvents, and the reaction flasks were typically equipped with rubber septa for the introduction of substrates and reagents via syringe. The glass material was oven dried and/or heat dried. Yields were not optimized. Melting points were determined in a Büchi hot stage apparatus and are uncorrected. 1H NMR, 19F and 13C NMR data were obtained in deuterated CDCI3, DMSO-d6, CD3OD, CD3CN, or acetone-d6 based solvent solutions with chemical shifts (â) reported in parts per million (ppm) in relative to trimethylsilane (TMS) or residual non-deuterated solvent peaks as the reference standard. Data is reported as follows, if applicable: chemical shift, multiplicity, coupling constant in Hz, and number of protons, fluorine, or carbon atoms. When peak multiplicities are reported, the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet, br (wide), dd (doublet of doublets), dt ( doublet of triplets). Coupling constants, when given, are reported in Hz (Hertz).EXAMPLE 1

[0775] Synthesis of 3-chloro-4-((3,3-dimethylpiperidin-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0776] Step 1. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0777] A mixture of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (prepared in accordance with PCT Published Patent Application No. WO 2010/079443, 15.1 g , 60.2 mmol) in anhydrous tetrahydrofuran (200 ml) was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (72.1 ml, 72.1 mmol) at 0 °C and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was cooled to -78 ° C and a solution of 3-chloro-4-fluorobenzenesulfonyl chloride (13.8 g, 60.2 mmol) in anhydrous tetrahydrofuran (40 ml) was added thereto. The reaction mixture was allowed to warm naturally to room temperature, stirred for 2 h, and diluted with ethyl acetate (280 ml). The mixture was washed with saturated ammonium chloride solution (2 x 150 ml), brine (150 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and trituration of the residue in methanol (110 ml) provided the title compound as a colorless solid (14.8 g, 55% yield): 1H NMR (300 MHz, CDCI3) δ 8.22 (s, 1H), 7.71 to 7.65 (m, 2H), 7.20 to 7.13 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6, 36 (dd, J = 8.4, 2.4 Hz, 1H), 6.30 (d, J = 2.4 Hz, 1H), 5.31 (s, 2H), 3.79 (s, 3H ), 3.68 (s, 3H); MS (ES+) m/z 444.0 (M + 1)., 446.0 (M + 1).

[0778] Step 2: Preparation of tert-butyl 4-hydroxy-3,3-dimethylpiperidine-1-carboxylate

[0779] To a solution of 3,3-dimethyl-4-oxopiperidine-1-tert-butyl carboxylate (4.61 g, 20.3 mmol) in anhydrous methanol (75 ml) was added sodium borohydride (0.77 g, 20.3 mmol) at 0 °C. The reaction mixture was allowed to warm naturally to room temperature and stirred for 48 hours. The mixture was diluted with ethyl acetate (300 ml), washed with 0.5 M hydrochloric acid (4 x 80 ml), brine (3 x 60 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave the title compound as a colorless solid (4.59 g, 99% yield): 1H NMR (300 MHz, CDCl3) δ 3.90 to 3.78 (m, 1H), 3 .57 to 3.48 (m, 1H), 3.41 (dd, J = 9.2, 4.2 Hz, 1H), 3.08 to 2.99 (m, 1H), 2.73 (d , J = 13.4 Hz, 1H), 1.85 to 1.71 (m, 2H), 1.62 to 1.55 (m, 1H), 1.42 (s, 9H), 0.95 ( s, 3H), 0.88 (s, 3H); MS (ES+) m/z 230.2 (M + 1).

[0780]Step 3. Preparation of 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)phenoxy)-3, tert-butyl 3-dimethylpiperidine-1-carboxylate

[0781] To a solution of tert-butyl 4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (1.37 g, 5.97 mmol) in anhydrous tetrahydrofuran (180 ml) was added a solution of 1.0 M of lithium bis(trimethylsilyl)amide in tetrahydrofuran (6.0 ml, 6.0 mmol) at -78 °C. The reaction mixture was allowed to warm to room temperature, stirred for 1 h, and cooled to -78 °C. A mixture of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (2.65 g, 5.97 mmol) in anhydrous tetrahydrofuran (10 ml). The reaction mixture was allowed to warm naturally to room temperature, stirred for 4 h, and diluted with ethyl acetate (200 ml). The mixture was washed with saturated ammonium chloride (2 x 200 ml), brine (150 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by column chromatography eluting with 30% ethyl acetate in hexanes. The title compound was obtained as a colorless oil (2.36 g, 61% yield): 1H NMR (300 MHz, CDCl3) δ8.18 (s, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 8.8, 2.3 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.83 (d, J = 8 .8 Hz, 1H), 6.37 to 6.28 (m, 2H), 5.25 (s, 2H), 4.12 (dd, J = 7.1, 4.4 Hz, 1H), 3 .76 (s, 3H), 3.72 (s, 3H), 3.63 to 3.36 (m, 4H), 3.15 (d, J = 13.5 Hz, 1H), 1.94 to 1.86 (m, 1H), 1.48 (s, 9H), 1.06 (s, 3H), 1.03 (s, 3H).

[0782]Step 4. Preparation of 3-chloro-4-((3,3-dimethylpiperidin-4-yl)oxy)-N-(1,2,4-thiadiazol-5-) 2,2,2-trifluoroacetate il)benzenesulfonamide

[0783] To a solution of 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)phenoxy)-3,3 tert-butyl-dimethylpiperidine-1-carboxylate (2.36 g, 3.61 mmol) in dichloromethane (15 ml) trifluoroacetic acid (5 ml) was added and the resulting mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo, triturated in methanol (60 ml) and filtered. Concentration of the filtrate in vacuo gave the title compound as a colorless foam (1.87 g, quantitative yield): 1H NMR (300 MHz, DMSO-d6) δ 8.79 (br s, 1H), 8.64 ( br s, 1H), 8.43 (s, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.70 (dd, J = 8.7, 2.3 Hz, 1H) , 7.38 (d, J = 8.7 Hz, 1H), 4.53 (dd, J = 7.7, 3.0 Hz, 1H), 3.12-2.98 (m, 3H), 2.96 to 2.85 (m, 1H), 2.09 to 1.97 (m, 1H), 1.85 to 1.70 (m, 1H), 1.07 (s, 3H), 1, 02 (s, 3H), NH not observed; MS (ES+) m/z 403.0 (M + 1), 405.0 (M + 1). EXAMPLE 2

[0784] Synthesis of 4-((1-benzyl-3,3-dimethylpiperidin-4-yl)oxy)-3-chloro-N-(1,2,4-thiadiazol-5) 2,2,2-trifluoroacetate -yl)benzenesulfonamide

[0785] A mixture of 3-chloro-4-((3,3-dimethylpiperidin-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl) 2,2,2-trifluoroacetate )benzenesulfonamide (0.20 g, 0.39 mmol) and benzaldehyde (0.08 g, 0.78 mmol) in anhydrous 1,2-dichloroethane (8 ml) was added sodium triacetoxyborohydride (0.17 g, 0. 78 mmol) and the resulting mixture was stirred for 18 h. The mixture was diluted with ethyl acetate (50 ml), washed with saturated ammonium chloride (2 x 30 ml), and the organic phase was concentrated in vacuo. The residue was purified by preparative reverse phase HPLC eluting with a gradient of 10 to 60% acetonitrile in water containing 0.1% trifluoroacetic acid to provide the title compound as a colorless solid (0.075 g, 32% yield). : 1H NMR (300 MHz, DMSO-d6) δ 9.71 (br s, 1H), 8.43 (s, 1H), 7.75 to 7.70 (m, 1H), 7.68 (dd, J = 8.7, 2.3 Hz, 1H), 7.56 to 7.32 (m, 6H), 4.55 to 4.41 (m, 1H), 4.39 to 4.23 (m, 2H), 3.52 to 2.73 (m, 4H), 2.22 to 2.07 (m, 1H), 2.00 to 1.76 (m, 1H), 1.15 (s, 3H) , 0.92 (s, 3H), NH not observed; MS (ES+) m/z 493.0 (M + 1), 495.0 (M + 1).EXAMPLE 3

[0786] Synthesis of 3-chloro-4-((1-(3,5-dimethylbenzyl)-3,3-dimethylpiperidin-4-yl)oxy)-N-(1,2) 2,2,2-trifluoroacetate ,4-thiadiazol-5-yl)benzenesulfonamide

[0787] Following the procedure as described in EXAMPLE 2 and making non-critical variations as necessary to replace benzaldehyde with 3,5-dimethylbenzaldehyde, the title compound was obtained as a colorless solid (0.17 g, 67% yield): 1H NMR (300 MHz, DMSO-d6) δ 9.51 (br s, 1H), 8.43 (s, 1H), 7.74 (d, J = 2.1 Hz, 1H), 7.68 ( dd, J = 8.7, 2.1 Hz, 1H), 7.42 to 7.33 (m, 1H), 7.16 to 7.03 (m, 3H), 4.58 to 4.40 ( m, 1H), 4.29 to 4.13 (m, 2H), 3.45 to 3.02 (m, 3H), 2.99 to 2.78 (m, 1H), 2.26 (s, 6H), 2.19 to 2.05 (m, 1H), 2.01 to 1.75 (m, 1H), 1.16 (d, J = 13.1 Hz, 3H), 0.93 (s , 3H) (Note: NH not observed); MS (ES+) m/z 521.0 (M + 1), 523.0 (M + 1).EXAMPLE 4

[0788] Synthesis of 3-chloro-4-((1-(3,5-dichlorobenzyl)-3,3-dimethylpiperidin-4-yl)oxy)-N-(1,2) 2,2,2-trifluoroacetate ,4-thiadiazol-5-yl)benzenesulfonamide

[0789] Following the procedure as described in EXAMPLE 2 and making non-critical variations as necessary to replace benzaldehyde with 3,5-chlorobenzaldehyde, the title compound was obtained as a colorless solid (0.135 g, 51% yield): 1H NMR (300 MHz, DMSO-d6) δ 9.92 (br s, 1H), 8.44 (s, 1H), 7.76 to 7.62 (m, 5H), 7.37 (d, J = 8 .9 Hz, 1H), 5.56 (br s, 1H), 4.54 to 4.43 (m, 1H), 4.30 (s, 2H), 3.46 to 2.74 (m, 4H ), 2.21 to 2.06 (m, 1H), 1.99 to 1.81 (m, 1H), 1.04 (br s, 6H); MS (ES+) m/z 561.0 (M + 1), 563.0, 564.9 (M + 1).EXAMPLE 5

[0790] Synthesis of 3-chloro-4-((1-(3-(difluoromethoxy)benzyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0791]Step 1. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide

[0792] To a mixture of N-(2,4-dimethoxybenzyl)thiazol-2-amine (prepared according to WO 2013063459, 35.0 g, 140 mmol) in anhydrous tetrahydrofuran (350 ml) was added a solution of 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (182 ml, 182 mmol) at -78 °C and the reaction mixture was warmed to 0 °C and stirred for 30 minutes. The reaction mixture was cooled to -78 ° C and a solution of 3-chloro-4-fluorobenzenesulfonyl chloride (41.6 g, 182 mmol) in anhydrous tetrahydrofuran (100 ml) was added thereto. The reaction mixture was allowed to warm naturally to room temperature, stirred for 2 h, cooled by addition of water (200 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 2 to 20% ethyl acetate in petroleum ether followed by trituration in methanol (2 x 150 ml) provided the title compound as a colorless solid (32.0 g, 50% yield): 1H NMR (300 MHz, CDCla) δ 7.86 (dd, J = 8.0, 2.4 Hz, 1H), 7.78 to 7.71 (m, 1H), 7.47 (d, J = 4.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 12.0 Hz, 1H), 7, 08 (d, J = 4.0 Hz, 1H), 6.41 to 6.35 (m, 2H), 5.07 (s, 2H), 3.79 (s, 3H), 3.71 (s , 3H); MS (ES+) m/z 464.9 (M + 23)., 467.0 (M + 23).

[0793] Step 2. Preparation of 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenoxy)piperidine-1-tert-butyl carboxylate

[0794] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.43 g, 22.0 mmol) in anhydrous tetrahydrofuran (75 ml) was added 1.0 M of a solution of bis(trimethylsilyl)amide lithium in tetrahydrofuran (25.0 ml, 25.0 mmol) at -78 °C. The resulting mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled to -78 °C and 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide (8.86 g, 20.0 mmol ) it was used. The resulting mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was cooled to 0 °C and a dispersion of 60% sodium hydride in mineral oil (0.80 g, 20.0 mmol) was added thereto. The resulting mixture was heated at 45 ° C for 2 days and then cooled to room temperature. The reaction mixture was quenched with the slow addition of water (100 ml) and diluted with ethyl acetate (250 ml). The mixture was washed with saturated ammonium chloride (2 x 150 ml), brine (100 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 60% ethyl acetate in hexanes, provided the title compound which was obtained as a foam (10.68 g, 86 % yield): 1H NMR (300 MHz, CDCla) δ 7.80 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.7, 2.3 Hz, 1H), 7.43 (d, J = 3.6 Hz, 1H), 7.18-7.15 (m, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.94 (d , J = 8.8 Hz, 1H), 6.39 to 6.35 (m, 2H), 5.07 (s, 2H), 4.69 to 4.63 (m, 1H), 3.77 ( s, 3H), 3.73 (s, 3H), 3.67 to 3.49 (m, 4H), 1.95 to 1.82 (m, 4H), 1.49 (s, 9H); MS (ES+) m/z 624.3 (M + 1), 626.3 (M + 1).

[0795]Step 3. Preparation of 3-chloro-4-(piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0796] To a solution of 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenoxy)piperidine-1-tert-butyl carboxylate (10 .68 g, 17.11 mmol) in dichloromethane (80 ml) trifluoroacetic acid (25 ml) was added and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was concentrated in vacuo, and the residue was triturated in methanol (60 ml). Filtration of the mixture and concentration of the filtrate in vacuo provided the title compound as a brown foam (8.35 g, quantitative yield): 1H NMR (300 MHz, DMSO-d6) δ 12.79 (br s, 1H) , 8.71 (br s, 2H), 7.74 (d, J = 2.1 Hz, 1H), 7.68 (dd, J = 8.7, 2.3 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 4.6 Hz, 1H), 6.82 (d, J = 4.6 Hz, 1H), 4.88 to 4 .78 (m, 1H), 3.23 to 3.00 (m, 4H), 2.13 to 2.00 (m, 2H), 1.91 to 1.75 (m, 2H); MS (ES+) m/z 374.1 (M + 1), 376.1 (M + 1).

[0797]Step 4. Preparation of 3-chloro-4-((1-(3-(difluoromethoxy)benzyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[0798] A mixture of 3-(difluoromethoxy)benzaldehyde (0.18 g, 1.04 mmol) and 3-chloro-4-(piperidin-4-yloxy)-N-(2,2,2-trifluoroacetate thiazol-2-yl)benzenesulfonamide (0.25 g, 0.52 mmol) in anhydrous N,N-dimethylformamide (3 ml) and anhydrous 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (0.42 g , 1.04 mmol) and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (50 ml), washed with saturated ammonium chloride (40 ml), saturated sodium bicarbonate (40 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by flash chromatography, eluting with a gradient of 0 to 20% methanol (containing 0.2% ammonium hydroxide) in dichloromethane to give the title compound as a colorless solid. (0.20 g, 73% yield): 1H NMR (300 MHz, DMSO-d6) δ7.71 (d, J = 2.2 Hz, 1H), 7.64 (dd, J = 8.7, 2.3 Hz, 1H), 7.37 to 7.26 (m, 2H), 7.22 (d, J = 4.6 Hz, 1H), 7.20 (t, J = 74.2 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 7.11 to 7.07 (m, 1H), 7.05 to 6.99 (m, 1H), 6.78 (d , J = 4.5 Hz, 1H), 4.64 to 4.55 (m, 1H), 3.50 (s, 2H), 2.66 to 2.54 (m, 2H), 2.36 to 2.25 (m, 2H), 1.96 to 1.84 (m, 2H), 1.74 to 1.60 (m, 2H), NH not observed; MS (ES+) m/z 530.1 (M + 1), 532.1 (M + 1). EXAMPLE 6

[0799] Synthesis of 3-chloro-4-((1-(cyclohexylmethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0800] Following the procedure as described in EXAMPLE 5, Step 4 and making non-critical variations as necessary to replace 3-(difluoromethoxy)benzaldehyde with cyclohexanecarbaldehyde, the title compound was obtained as a colorless solid (0.16 g, 27% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.77 (br s, 1H), 9.16 (br s, 1H), 7.76 to 7.72 (m, 1H), 7, 69 (d, J = 8.6, 2.3 Hz, 1H), 7.42 to 7.31 (m, 1H), 7.25 (d, J = 4.6 Hz, 1H), 6.82 (d, J = 4.5 Hz, 1H), 4.97 to 4.88 (m, 0.5H), 4.77 to 4.64 (m, 0.5H), 3.58 to 3.32 (m, 2H), 3.11 to 2.87 (m, 4H), 2.30 to 1.99 (m, 3H), 1.96 to 1.53 (m, 7H), 1.30 to 1 .04 (m, 3H), 1.00 to 0.82 (m, 2H); MS (ES+) m/z 470.1 (M + 1), 472.1 (M + 1). EXAMPLE 7

[0801] Synthesis of 3-chloro-4-((1-(cyclohexylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0802] Following the procedure as described in EXAMPLE 5, Step 4 and making non-critical variations as necessary to replace 3-(difluoromethoxy)benzaldehyde with cyclohexanone, the title compound was obtained as a colorless solid (0.20 g, 35% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.81 (br s, 1H), 9.76 (br s, 0.5 H), 9.54 (br s, 0.5H), 7.77 to 7.72 (m, 1H), 7.69 (dd, J = 8.7, 2.1 Hz, 1H), 7.41 to 7.33 (m, 1H), 7.25 ( d, J = 4.6 Hz, 1H), 6.82 (d, J = 4.7 Hz, 1H), 5.01 to 4.93 (m, 0.5H), 4.77 to 4.65 (m, 0.5H), 3.45 (d, J = 12.5 Hz, 1H), 3.31 (d, J = 12.0 Hz, 1H), 3.24 to 2.99 (m, 3H), 2.33-1.69 (m, 8H), 1.63 to 0.97 (m, 6H); MS (ES+) m/z 456.1 (M + 1), 458.1 (M + 1). EXAMPLE 8A and 8B

[0803] Synthesis of 4-((cis-1-benzyl-3-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide and 4-((trans-1-benzyl -3-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[0804] Step 1. Preparation of tert-butyl 4-hydroxy-3-methylpiperidine-1-carboxylate

[0805] Following the procedure as described in EXAMPLE 1, Step 2 and making non-critical variations as necessary to replace 3,3-dimethyl-4-oxopiperidine-1-tert-butyl carboxylate with 3-methyl-4-oxopiperidine-1- tert-butyl carboxylate, the title compound was obtained as a colorless oil as a 2:1 mixture of diastereomers (2.83 g, 95% yield). Data reported for the main isomer: 1H NMR (300 MHz, CDCl3) δ 4.09 to 3.86 (m, 2H), 3.28 (td, J = 9.7, 4.2 Hz, 1H), 2 .87 to 2.76 (m, 1H), 2.51 to 2.39 (m, 1H), 2.00 to 1.64 (m, 3H), 1.45 (s, 9H), 0.99 (d, J = 6.6 Hz, 3H), OH not observed; MS (ES+) m/z 216.3 (M + 1).

[0806]Step 2. Preparation of 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenoxy)-3-methylpiperidine-1-tert carboxylate -butyl

[0807] Following the procedure as described in EXAMPLE 5, Step 2 and making non-critical variations as necessary to replace 4-hydroxy-3,3-dimethylpiperidine-1-tert-butyl carboxylate with 4-hydroxy-3-methylpiperidine-1- tert-butyl carboxylate, the title compound was obtained as a colorless foam as a 2:1 mixture of diastereomers (3.29 g, 80% yield). Data reported for the main isomer: 1H NMR (300 MHz, CDCI3) δ 7.80 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.8, 2.3 Hz, 1H ), 7.43 (d, J = 3.6 Hz, 1H), 7.16 (d, J = 9.1 Hz, 1H), 7.04 (s, 1H), 6.93 (d, J = 8.9 Hz, 1H), 6.39 to 6.35 (m, 2H), 5.07 (s, 2H), 4.60 to 4.54 (m, 1H), 3.82 to 3, 72 (m, 8H), 3.26 to 3.14 (m, 2H), 2.05 to 1.92 (m, 2H), 1.79 to 1.69 (m, 1H), 1.49 ( s, 9H), 1.03 (d, J = 6.9 Hz, 3H); MS (ES+) m/z 638.2 (M + 1), 640.2 (M + 1).

[0808] Step 3. Preparation of 3-chloro-4-((3-methylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0809] Following the procedure as described in EXAMPLE 1, Step 4 and making non-critical variations as necessary to replace 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2, 4-thiadiazol-5-yl)sulfamoyl)phenoxy)-3,3-dimethylpiperidine-1-tert-butyl carboxylate by 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol tert-butyl-2-yl)sulfamoyl)phenoxy)-3-methylpiperidine-1-carboxylate, the title compound was obtained as a colorless foam (1.58 g, quantitative yield): MS (ES+) m/z 388, 1 (M + 1), 390.1 (M + 1).

[0810]Step 4. Preparation of 4-((cis-1-benzyl-3-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide and 4-((trans- 1-benzyl-3-methylpiperidin-4-yl)oxy)- 3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[0811] To a mixture of benzaldehyde (0.28 g, 2.60 mmol) and 3-chloro-4-(3-methylpiperidin-4-yloxy)-N-(thiazol-2) 2,2,2-trifluoroacetate -il)benzenesulfonamide (0.65 g, 1.30 mmol) in anhydrous N,N-dimethylformamide (5 ml) and anhydrous 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (0.55 g, 2.0 ml) 60 mmol) and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (50 ml), washed with saturated ammonium chloride (40 ml), and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0 to 20% methanol (containing 0.2% ammonium hydroxide) in dichloromethane to provide the title compounds as diastereomerically pure colorless solids. First eluting isomer (0.20 g, 32% yield): 1H NMR (300 MHz, CD3OD) δ7.81 (d, J = 2.3 Hz, 1H), 7.73 (dd, J = 8, 7, 2.3 Hz, 1H), 7.41 to 7.24 (m, 5H), 7.16 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 4.6 Hz, 1H), 6.68 (d, J = 4.6 Hz, 1H), 4.13 to 4.03 (m, 1H), 3.65 (d, J = 2.0 Hz, 2H), 3.03 to 2.91 (m, 2H), 2.41 to 2.29 (m, 1H), 2.18 to 1.99 (m, 3H), 1.73 to 1.58 (m, 1H ), 0.98 (d, J = 6.0 Hz, 3H), NH not observed; MS (ES+) m/z 478.1 (M + 1), 480.1 (M + 1). Second elution isomer (0.20 g, 32% yield): 1H NMR (300 MHz, CD3OD) δ 7.83 (d, J = 2.2 Hz, 1H), 7.75 (dd, J = 8 .8, 2.3 Hz, 1H), 7.47 to 7.36 (m, 5H), 7.20 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 4, 5 Hz, 1H), 6.69 (d, J = 4.5 Hz, 1H), 4.73 to 4.67 (m, 1H), 4.01 (s, 2H), 3.06 to 2, 94 (m, 2H), 2.87 to 2.70 (m, 2H), 2.30 to 2.17 (m, 1H), 2.15 to 2.05 (m, 1H), 2.01 to 1.87 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H), NH not observed; MS (ES+) m/z 478.1 (M + 1), 480.1 (M + 1). EXAMPLE 9A and 9B

[0812] Synthesis of 3-chloro-4-((cis-3-methyl-1-(3-methylbenzyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide and 3-chloro- 4-((trans-3-methyl-1-(3-methylbenzyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[0813] Following the procedure as described in EXAMPLE 8, Step 4 and making non-critical variations as necessary to replace benzaldehyde with 3,3-dimethylbenzaldehyde, and purification by column chromatography, eluting with a gradient of 0 to 20% methanol ( containing 0.2% ammonium hydroxide) in dichloromethane, the title compounds were obtained as diastereomerically pure colorless solids. First eluting isomer (0.10 g, 16% yield): 1H NMR (300 MHz, CD3OD) δ7.81 (d, J = 2.2 Hz, 1H), 7.72 (dd, J = 8, 6, 2.2 Hz, 1H), 7.24 to 7.03 (m, 6H), 6.67 (d, J = 4.5 Hz, 1H), 4.11 to 4.00 (m, 1H ), 3.57 (d, J = 2.3 Hz, 2H), 3.00 to 2.89 (m, 2H), 2.36 to 2.25 (m, 4H), 2.17 to 1, 96 (m, 3H), 1.72 to 1.57 (m, 1H), 0.97 (d, J = 6.0 Hz, 3H), NH not observed; MS (ES+) m/z 492.1 (M + 1), 494.1 (M + 1). Second elution isomer (0.24 g, 38% yield): 1H NMR (300 MHz, CD3OD) δ 7.84 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 8 .7, 2.3 Hz, 1H), 7.36 to 7.19 (m, 5H), 7.08 (d, J = 4.6 Hz, 1H), 6.70 (d, J = 4, 6 Hz, 1H), 4.77 to 4.72 (m, 1H), 4.19 (d, J = 1.3 Hz, 2H), 3.25 to 3.14 (m, 2H), 3, 07 to 2.92 (m, 2H), 2.36 (s, 3H), 2.34 to 2.25 (m, 1H), 2.22 to 2.12 (m, 1H), 2.08 to 1.95 (m, 1H), 1.04 (d, J = 6.7 Hz, 3H), NH not observed; MS (ES+) m/z 492.1 (M + 1), 494.1 (M + 1). EXAMPLE 10A and 10B

[0814] Synthesis of 3-chloro-4-((cis-1-(2-fluorobenzyl)-3-methylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide and 3-chloro-4 -((trans-1-(2-fluorobenzyl)-3-methylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[0815] Following the procedure as described in EXAMPLE 8, Step 4 and making non-critical variations as necessary to replace benzaldehyde with 2-fluorobenzaldehyde, and purification by column chromatography, eluting with a gradient of 0 to 20% methanol (containing 0 .2% ammonium hydroxide) in dichloromethane, the title compounds were obtained as diastereomerically pure colorless solids. First eluting isomer (0.16 g, 25% yield): 1H NMR (300 MHz, CD3OD) δ7.80 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8, 7, 2.2 Hz, 1H), 7.44 to 7.37 (m, 1H), 7.34 to 7.24 (m, 1H), 7.18 to 7.02 (m, 4H), 6 .68 (d, J = 4.5 Hz, 1H), 4.10 to 3.99 (m, 1H), 3.65 (s, 2H), 2.96 to 2.88 (m, 2H), 2.35 to 2.24 (m, 1H), 2.17 to 1.96 (m, 3H), 1.72 to 1.56 (m, 1H), 0.97 (d, J = 5.8 Hz, 3H), NH not observed; MS (ES+) m/z 496.1 (M + 1), 498.1 (M + 1). Second elution isomer (0.16, 25% yield): 1H NMR (300 MHz, 1:1 CDCl3:CD3OD) δ 7.84 (s, 1H), 7.72 (d, J = 8.6 Hz , 1H), 7.46 to 7.23 (m, 2H), 7.16 to 6.91 (m, 4H), 6.54 (d, J = 4.3 Hz, 1H), 4.54 to 4.49 (m, 1H), 3.73 (s, 2H), 2.78 to 2.65 (m, 2H), 2.59 to 2.39 (m, 2H), 2.21 to 2, 07 (m, 1H), 2.02 to 1.79 (m, 2H), 0.97 (d, J = 6.1 Hz, 3H), NH not observed; MS (ES+) m/z 496.1 (M + 1), 498.1 (M + 1). EXAMPLE 11

[0816] Synthesis of 3-chloro-4-((1-(3-(difluoromethyl)benzyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide;

[0817] Following the procedure as described in EXAMPLE 5, Step 4 and making non-critical variations as necessary to replace 3-(difluoromethoxy)benzaldehyde with 3-(difluoromethyl)benzaldehyde, the title compound was obtained as a colorless solid (0. 20 g, 75% yield): 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J = 2.2 Hz, 1H), 7.64 (dd, J = 8.7, 2, 3 Hz, 1H), 7.50 to 7.47 (m, 1H), 7.46 to 7.40 (m, 3H), 7.29 (d, J = 8.9 Hz, 1H), 7, 22 (d, J = 4.6 Hz, 1H), 6.99 (t, J = 56.0 Hz, 1H), 6.78 (d, J = 4.5 Hz, 1H), 4.65 a 4.55 (m, 1H), 3.54 (s, 2H), 2.66 to 2.54 (m, 2H), 2.37 to 2.25 (m, 2H), 1.97 to 1, 84 (m, 2H), 1.74 to 1.60 (m, 2H), NH not observed; MS (ES+) m/z 514.1 (M + 1), 516.1 (M + 1). EXAMPLE 12

[0818] Synthesis of 3-chloro-N-(thiazol-2-yl)-4-((1-(2-(trifluoromethyl)benzyl)piperidin-4-yl)oxy)benzenesulfonamide

[0819] Following the procedure as described in EXAMPLE 5, Step 4 and making non-critical variations as necessary to replace 3-(difluoromethoxy)benzaldehyde with 2-(trifluoromethyl)benzaldehyde, the title compound was obtained as a colorless solid (0. 21 g, 64% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.65 (br s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.71 ( d, J = 2.3 Hz, 1H), 7,687.58 (m, 3H), 7.45 to 7.38 (m, 1H), 7.31 (d, J = 8.7 Hz, 1H), 7 .23 (d, J = 4.8 Hz, 1H), 6.80 (d, J = 4.6 Hz, 1H), 4.68 to 4.57 (m, 1H), 3.59 (s, 2H), 2.66 to 2.54 (m, 2H), 2.38 to 2.24 (m, 2H), 1.97 to 1.83 (m, 2H), 1.74 to 1.59 ( m, 2H); MS (ES+) m/z 532.1 (M + 1), 534.1 (M + 1). EXAMPLE 13

[0820] Synthesis of 3-chloro-4-((1-(2-chlorobenzyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[0821] Following the procedure as described in EXAMPLE 5, Step 4 and making non-critical variations as necessary to replace 3-(difluoromethoxy)benzaldehyde with 2-chlorobenzaldehyde, the title compound was obtained as a colorless solid (0.14 g, 45% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.71 (br s, 1H), 7.70 (dd, J = 2.3 Hz, 1H), 7.65 (dd, J = 8.6, 2.1 Hz, 1H), 7.46 (dd, J = 7.4, 1.9 Hz, 1H), 7.39 (dd, J = 7.4, 1.7 Hz, 1H), 7.34 to 7.20 (m, 4H), 6.80 (d, J = 4.5 Hz, 1H), 4.67 to 4.56 (m, 1H), 3.56 (s, 2H), 2.69 to 2.58 (m, 2H), 2.41 to 2.29 (m, 2H), 1.97 to 1.85 (m, 2H), 1.73 to 1.60 ( m, 2H); MS (ES+) m/z 498.1 (M + 1), 500.1 (M + 1). EXAMPLE 14

[0822] Synthesis of 3-chloro-4-((1-((4-methylpyridin-2-yl)methyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[0823] Following the procedure as described in EXAMPLE 5, Step 4 and making non-critical variations as necessary to replace 3-(difluoromethoxy)benzaldehyde with 4-methylpicolinaldehyde, the title compound was obtained as a colorless solid (0.09 g, 30% yield): 1H NMR (300 MHz, DMSO-d6) δ 8.31 (d, J = 5.0 Hz, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7 .64 (dd, J = 8.7, 2.3 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 7.26 to 7.23 (m, 1H), 7. 21 (d, J = 4.3 Hz, 1H), 7.08 to 7.03 (m, 1H), 6.78 (d, J = 4.5 Hz, 1H), 4.66 to 4.55 (m, 1H), 3.59 (s, 2H), 2.74 to 2.63 (m, 2H), 2.43 to 2.32 (m, 2H), 2.27 (s, 3H), 1.98 to 1.86 (m, 2H), 1.74 to 1.62 (m, 2H), NH not observed; MS (ES+) m/z 479.1 (M + 1), 481.1 (M + 1). EXAMPLE 15

[0824] Synthesis of 4-(((1R,3r,5S)-8-benzyl-8-azabicyclo[3,2,1]octan-3-yl)oxy)-3-chloro-N-(thiazol-2 -yl)benzenesulfonamide

[0825]Step 1. Preparation of (1R,3r,5S)-3-(2-chloro-4-(N-(2,4-dimethoxybenzyl)- N-(thiazol-2-yl)sulfamoyl)phenoxy)- 8-azabicyclo[3,2,1]octane-8-tert-butyl carboxylate

[0826] Following the procedure as described in EXAMPLE 5, Step 2 and making non-critical variations as necessary to replace 4-hydroxypiperidine-1-tert-butyl carboxylate with (1R,3r,5S)-3-hydroxy-8-azabicyclo[ tert-butyl 3,2,1]octane-8-carboxylate, the title compound was obtained as a colorless foam (0.30 g, 23% yield): 1H NMR (300 MHz, CDCI3) δ 7.82 ( d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.7, 2.3 Hz, 1H), 7.43 (d, 3.6 Hz, 1H), 7.16 ( d, J = 9.0 Hz, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 9.0 Hz, 1H), 6.50 to 6, 46 (m, 1H), 6.39 to 6.34 (m, 2H), 5.07 (s, 2H), 4.76 to 4.72 (m, 1H), 4.26 to 4.13 ( m, 2H), 3.77 (s, 3H), 3.74 (s, 3H), 2.23 to 2.13 (m, 3H), 2.01 to 1.93 (m, 2H), 1 .74 to 1.69 (m, 2H), 1.49 (s, 9H); MS (ES+) m/z 650.1 (M + 1), 652.1 (M + 1).

[0827]Step 2. Preparation of 4-(((1R,3r,5S)-8-benzyl-8-azabicyclo[3,2,1]octan-3-yl)oxy)-3-chloro-N-( thiazol-2-yl)benzenesulfonamide

[0828]A solution of (1R,3r,5S)-3-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenoxy)-8 tert-butyl-azabicyclo[3,2,1]octane-8-carboxylate (0.30 g, 0.46 mmol) in dichloromethane (10 ml) trifluoroacetic acid (2 ml) was added and the resulting mixture was stirred for 1 H. The reaction mixture was concentrated in vacuo. The residue was triturated in methanol (10 ml), filtered, and the filtrate was concentrated in vacuo. To it was then added 1,2-dichloroethane (4 ml), N,N-dimethylformamide (4 ml), benzaldehyde (0.15 g, 1.38 mmol), sodium triacetoxyborohydride (0.29 g, 1 .38 mmol), and the reaction mixture was stirred for 18 h. The mixture was diluted with ethyl acetate (50 ml), washed with saturated ammonium chloride (2 x 30 ml), and the combined organic phase was concentrated in vacuo. Purification of the residue was carried out by column chromatography, eluting with a gradient of 0 to 20% methanol (containing 0.2% ammonium hydroxide) in dichloromethane to give the title compound as a colorless solid (0.03 g , 13% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.65 (br s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.65 (dd, J = 8.7, 2.3 Hz, 1H), 7.51 to 7.45 (m, 2H), 7.38 to 7.27 (m, 3H), 7.20 (d, J = 7, 5 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 4.5 Hz, 1H), 4.83 to 4.77 (m, 1H) , 3.81 (s, 2H), 3.38 (s, 2H), 2.33 to 2.22 (m, 2H), 2.15 to 2.05 (m, 4H), 1.91 (s , 1H), 1.87 (s, 1H); MS (ES+) m/z 490.1 (M + 1), 492.1 (M + 1). EXAMPLE 16

[0829] Synthesis of 4-(((1R,3s,5S)-8-benzyl-8-azabicyclo[3,2,1]octan-3-yl)oxy)-3-chloro-N-(thiazol-2 -yl)benzenesulfonamide

[0830]Step 1. Preparation of (1R,3s,5S)-3-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenoxy)- 8-azabicyclo[3,2,1]octane-8-tert-butyl carboxylate

[0831] Following the procedure as described in EXAMPLE 5, Step 2 and making non-critical variations as necessary to replace 4-hydroxypiperidine-1-tert-butyl carboxylate with (1R,3s,5S)-3-hydroxy-8-azabicyclo[ tert-butyl 3,2,1]octane-8-carboxylate, the title compound was obtained as a colorless foam (0.32 g, 25% yield): 1H NMR (300 MHz, CDCI3) δ 7.78 ( d, J = 2.3 Hz, 1H), 7.70 to 7.65 (m, 1H), 7.42 (d, J = 3.6 Hz, 1H), 7.15 (d, J = 9 .1 Hz, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 6.49 to 6.46 (m, 1H ), 6.38 to 6.34 (m, 2H), 5.06 (s, 2H), 4.82 to 4.71 (m, 1H), 4.40 to 4.28 (m, 3H), 3.77 (s, 3H), 3.72 (m, 2H), 2.17 to 2.09 (m, 2H), 1.99 to 1.82 (m, 2H), 1.74 to 1, 66 (m, 3H), 1.50 (s, 9H); MS (ES+) m/z 650.2 (M + 1), 652.2 (M + 1).

[0832]Step 2. Preparation of 4-(((1R,3s,5S)-8-benzyl-8-azabicyclo[3,2,1]octan-3-yl)oxy)-3-chloro-N-( thiazol-2-yl)benzenesulfonamide

[0833] Following the procedure as described in EXAMPLE 15, Step 2 and making non-critical variations as necessary to replace (1R,3r,5S)-3-(2-chloro-4-(N-(2,4-dimethoxybenzyl) -N-(thiazol-2-yl)sulfamoyl)phenoxy)-8-azabicyclo[3,2,1]octane-8-tert-butyl carboxylate by (1R,3s,5S)-3-(2-chloro-4 -(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenoxy)-8-azabicyclo[3,2,1]octane-8-tert-butyl carboxylate, the title compound was obtained as a colorless solid (0.11 g, 49% yield): 1H NMR (300 MHz, DMSO-d6) δ 7.68 (d, J = 2.2 Hz, 1H), 7.63 (dd, J = 8.7 Hz, 1H), 7.39 to 7.33 (m, 3H), 7.33 to 7.26 (m, 2H), 7.25 to 7.17 (m, 2H), 6 .75 (d, J = 4.3 Hz, 1H), 4.82 to 4.69 (m, 1H), 3.62 (s, 2H), 3.30 to 3.23 (m, 2H), 2.04 to 1.93 (m, 4H), 1.80 to 1.64 (m, 4H), NH not observed; MS (ES+) m/z 490.1 (M + 1), 492.1 (M + 1). EXAMPLE 17

[0834] Synthesis of 4-(((1R,3s,5S)-8-benzyl-8-azabicyclo[3,2,1]octan-3-yl)oxy)-5-chloro-2-fluoro-N- (thiazol-2-yl)benzenesulfonamide

[0835]Step 1. Preparation of 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide

[0836] A solution of N-(2,4-dimethoxybenzyl)thiazol-2-amine (20.86 g, 83.3 mmol, prepared according to WO2013063459) in anhydrous tetrahydrofuran (350 ml) was treated with a 1 M of a solution of bis(trimethylsilyl)amide in tetrahydrofuran (100.0 ml, 100.0 mmol) at -78 °C. The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was cooled to -78 ° C and a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (20.58 g, 83.3 mmol) in anhydrous tetrahydrofuran (75 ml) was added thereto. The reaction mixture was allowed to warm naturally to room temperature, stirred for 2 h, and diluted with ethyl acetate (700 ml). The organic phase was washed with saturated sodium bicarbonate (200 ml), saturated ammonium chloride (2 x 150 ml), brine (2 x 150 ml), (100 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate under reduced pressure gave a residue which was triturated with methanol (80 ml) to give the title compound as a colorless solid (12.7 g, 33% yield): 1H NMR (300 MHz, CDCl3) δ 7.94 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H) 7.21 (d, J = 8.1 Hz, 1H), 7.06 to 6.99 (m, 2H), 6.41 to 6.36 (m, 2H), 5.20 (s, 2H), 3.78 (s, 3H), 3.74 (s, 3H); MS (ES+) m/z 461.0 (M + 1), 463.0 (M + 1).

[0837]Step 2. Preparation of (1R,3s,5S)-3-(2-chloro-4-(N-(2,4- dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-5- fluorophenoxy)-8-azabicyclo[3,2,1]octane-8-tert-butyl carboxylate

[0838]A mixture of (1R,3s,5S)-3-hydroxy-8-azabicyclo[3,2,1]octane-8-tert-butyl carboxylate (1.18 g, 5.21 mmol) and 5 -chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide (2.40 g, 5.21 mmol) in anhydrous dimethyl sulfoxide (35 ml) was Cesium carbonate (2.55 g, 7.82 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (150 ml), washed with water (100 ml), saturated ammonium chloride (80 ml), brine (50 ml), and dried with anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by column chromatography, eluting with 10 to 50% ethyl acetate in hexanes, to give the title compound which was obtained as a colorless foam (1.39 g, 40% yield): 1H NMR (300 MHz, CDCI3) δ 7.86 (d, J = 7.3 Hz, 1H), 7.43 to 7.41 (m, 1H), 7.21 ( d, J = 8.8 Hz, 1H), 7.03 to 7.00 (m, 1H), 6.69 (d, J = 11.3 Hz, 1H), 6.37 to 6.35 (m , 2H), 5.20 (s, 2H), 4.76 to 4.65 (m, 1H), 4.43 to 4.29 (m, 2H), 3.82 to 3.71 (m, 7H ), 2.15 to 2.06 (m, 3H), 1.95 to 1.81 (m, 2H), 1.73 to 1.66 (m, 2H), 1.50 (s, 9H); MS (ES+) m/z 668.1 (M + 1), 670.0 (M + 1).

[0839]Step 3. Preparation of 4-(((1R,3s,5S)-8-azabicyclo[3,2,1]octan-3-yl)oxy)-5-chloro 2,2,2-trifluoroacetate -2-fluoro-N-(thiazol-2-yl)benzenesulfonamide

[0840] To a solution of (1R,3s,5S)-3-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-5-fluorophenoxy )-8-azabicyclo[3,2,1]octane-8-tert-butyl carboxylate (1.39 g, 2.08 mmol) in dichloromethane (40 ml) trifluoroacetic acid (2 ml) was added and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated in vacuo. The residue was suspended in methanol (25 ml) and the mixture was filtered. The filtrate was concentrated in vacuo to provide the title compound as a tan foam (0.81 g, 73% yield): MS (ES+) m/z 418.0 (M + 1), 420.0 ( M+1).

[0841] Step 4. Preparation of 4-(((1R,3s,5S)-8-benzyl-8-azabicyclo[3,2,1]octan-3-yl)oxy 2,2,2-trifluoroacetate) -5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide

[0842]A mixture of benzaldehyde (0.16 g, 1.53 mmol) and 4-(((1R,3s,5S)-8-azabicyclo[3,2,1] 2,2,2-trifluoroacetate octan-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (0.27 g, 0.51 mmol) in anhydrous N,N-dimethylformamide (5 ml) and Anhydrous 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (0.22 g, 1.02 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (50 ml), washed with saturated ammonium chloride (40 ml), saturated sodium bicarbonate (40 ml), and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0 to 20% methanol (containing 0.2% ammonium hydroxide) in dichloromethane, and then by preparative reversed-phase HPLC eluting with a gradient of 10 to 60% acetonitrile in water containing 0.1% trifluoroacetic acid to give the title compound as a colorless solid (0.025 g, 10% yield): 1H NMR (300 MHz, CD3OD) δ 7.84 (d, J = 7.5 Hz, 1H), 7.56 to 7.45 (m, 5H), 7.25 (d, J = 11.5 Hz, 1H), 7.11 (d, J = 4.6 Hz , 1H), 6.74 (d, J = 4.5 Hz, 1H), 5.06 to 4.94 (m, 1H), 4.22 (s, 2H), 4.05 to 3.97 ( m, 2H), 2.52 to 2.37 (m, 4H), 2.32 to 2.22 (m, 2H), 2.10 to 1.94 (m, 2H), NH and COOH not observed; MS (ES+) m/z 508.1 (M + 1), 510.2 (M + 1). EXAMPLE 18

[0843] Synthesis of 5-chloro-4-(((1R,3s,5S)-8-(3-chlorobenzyl)-8-azabicyclo[3,2,1]octan-3 2,2,2-trifluoroacetate -yl)oxy)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide

[0844] Following the procedure as described in EXAMPLE 17, Step 4 and making non-critical variations as necessary to replace benzaldehyde with 3-chlorobenzaldehyde, the title compound was obtained as a colorless solid (0.08 g, 28% yield): 1H NMR (300 MHz, CD3OD) δ 7.83 (d, J = 7.3 Hz, 1H), 7.63 to 7.60 (m, 1H), 7.54 to 7.45 (m, 3H) , 7.24 (d, J = 11.3 Hz, 1H), 7.11 (d, J = 4.8 Hz, 1H), 6.74 (d, J = 4.5 Hz, 1H), 5 .06 to 4.93 (m, 1H), 4.23 (s, 2H), 4.05 to 3.99 (m, 2H), 2.52 to 2.38 (m, 4H), 2.32 at 2.23 (m, 2H), 2.11 to 1.98 (m, 2H), NH and COOH not observed; MS (ES+) m/z 542.1 (M + 1), 544.1 (M + 1). EXAMPLE 19

[0845] Synthesis of 4-((1-benzyl-4-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[0846]Step 1. Preparation of 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenoxy)-4-methylpiperidine-1-tert carboxylate -butyl

[0847] To a solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (0.75 g, 3.49 mmol) in anhydrous N,N-dimethylformamide (12 ml) was added a 60% dispersion of sodium hydride in mineral oil (0.14 g, 3.49 mmol) and the reaction mixture was stirred at room temperature for 45 minutes. To it was added 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide (0.77 g, 1.75 mmol) and the reaction mixture was stirred. at room temperature for 18 h. The reaction mixture was quenched by careful addition of water (50 ml), and extracted with ethyl acetate (100 ml). The organic layer was washed with saturated ammonium chloride (2 x 50 ml), brine (50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by column chromatography, eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give the title compound as a colorless foam (0.98 g, 44% yield): 1H NMR (300 MHz, CDCla) δ 7.82 to 7.79 (m, 1H), 7.66 to 7.61 (m, 1H), 7.46 to 7.41 (m, 1H ), 7.18 to 7.14 (m, 1H), 7.11 to 7.02 (m, 2H), 6.40 to 6.35 (m, 2H), 5.08 (s, 2H), 3.78 to 3.72 (m, 6H), 3.31 to 3.20 (m, 8H), 1.46 (s, 9H), 1.27 (s, 3H); MS (ES+) m/z 638.2 (M + 1), 640.1 (M + 1).

[0848] Step 2. Preparation of 3-chloro-4-((4-methylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0849] Following the procedure as described in EXAMPLE 1, Step 4 and making non-critical variations as necessary to replace 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2, 4-thiadiazol-5-yl)sulfamoyl)phenoxy)-3,3-dimethylpiperidine-1-tert-butyl carboxylate by 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol tert-butyl-2-yl)sulfamoyl)phenoxy)-4-methylpiperidine-1-carboxylate, the title compound was obtained as an off-white foam (0.77 g, quantitative yield): MS (ES+) m/z 388, 1 (M + 1), 390.1 (M + 1).

[0850]Step 3. Preparation of 4-((1-benzyl-4-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[0851] Following the procedure as described in EXAMPLE 2 and making non-critical variations as necessary to replace 3-chloro-4-((3,3-dimethylpiperidin-4-yl)oxy)-N 2,2,2-trifluoroacetate -(1,2,4-thiadiazol-5-yl)benzenesulfonamide by 3-chloro-4-((4-methylpiperidin-4-yl)oxy)-N-(thiazol-2-)-N-(thiazol-2-) il)benzenesulfonamide, and purification by column chromatography, eluting with a gradient of 0 to 20% methanol (containing 0.2% ammonium hydroxide) in dichloromethane, the title compound was obtained as a colorless solid (0.065 g, 26% yield): 1H NMR (300 MHz, DMSO-d6) δ7.72 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.7, 2.3 Hz, 1H ), 7.35 (d, J = 8.8 Hz, 1H), 7.30 to 7.19 (m, 6H), 6.78 (d, J = 4.6 Hz, 1H), 3.55 (s, 2H), 2.60 to 2.50 (m, 2H), 2.49 to 2.38 (m, 2H), 2.08 to 1.98 (m, 2H), 1.78 to 1 .65 (m, 2H), 1.35 (s, 3H), NH not observed; MS (ES+) m/z 478.1 (M + 1), 480.1 (M + H). EXAMPLE 20

[0852] Synthesis of 3-chloro-4-((1-(3-chlorobenzyl)-4-methylpiperidin-4-yl)oxy)-N- (thiazol-2-yl)benzenesulfonamide

[0853] To a mixture of 3-chlorobenzaldehyde (0.15 g, 1.04 mmol) and 3-chloro-4-(4-methylpiperidin-4-yloxy)-N-(thiazole) 2,2,2-trifluoroacetate -2-yl)benzenesulfonamide (0.20 g, 0.52 mmol) in anhydrous N,N-dimethylformamide (4 ml) and anhydrous 1,2-dichloroethane (4 ml) was added sodium triacetoxyborohydride (0.22 g, 1.04 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (50 ml), washed with saturated ammonium chloride (40 ml), and concentrated in vacuo. The residue was carried out by column chromatography, eluting with a gradient of 0 to 20% methanol (containing 0.2% ammonium hydroxide) in dichloromethane to give the title compound as a colorless solid (0.065 g, 24% yield): 1H NMR (300 MHz, DMSO-d6) δ7.72 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.6, 2.2 Hz, 1H), 7 .37 to 7.20 (m, 6H), 6.79 (d, J = 4.6 Hz, 1H), 3.48 (s, 2H), 2.53 to 2.31 (m, 4H), 2.07 to 1.97 (m, 2H), 1.76 to 1.64 (m, 2H), 1.35 (s, 3H), NH not observed; MS (ES+) m/z 512.0 (M + 1), 514.0 (M + 1). EXAMPLE 21

[0854] Synthesis of 3-chloro-4-((1-(3-(difluoromethyl)benzyl)-4-methylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[0855] Following the procedure as described in EXAMPLE 21 and making non-critical variations as necessary to replace 3-chlorobenzaldehyde with 3-(difluoromethyl)benzaldehyde, the title compound was obtained as a colorless solid (0.095 g, 35% yield) : 1H NMR (300 MHz, DMSO-d6) δ 7.72 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.6, 2.3 Hz, 1H), 7, 49-7.39 (m, 4H), 7.35 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 4.6 Hz, 1H), 6.98 (t, J = 56.3 Hz, 1H), 6.79 (d, J = 4.5 Hz, 1H), 3.54 (s, 2H), 2.55-2.33 (m, 4H), 2.08 at 1.97 (m, 2H), 1.77 to 1.63 (m, 2H), 1.36 (s, 3H), NH not observed; MS (ES+) m/z 528.1 (M + 1), 530.1 (M + 1). EXAMPLE 22

[0856] Synthesis of fluorobenzyl 2,2,2-trifluoroacetate)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[0857]A mixture of 3-chloro-4-(piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate (0.30 g, 0.62 mmol) and 4-fluorobenzaldehyde (0.13 ml, 1.2 mmol) in N,N-dimethylformamide (1.5 ml) and 1,2-dichloroethane (1.5 ml) was added sodium triacetoxyborohydride (0.26 g, 1 .23 mmol) and the mixture was stirred for 17 h. The reaction mixture was diluted with dichloromethane (4 ml) and water (4 ml) and the layers were separated. The aqueous phase was extracted with dichloromethane (2 x 5 ml) and the combined organic extracts were washed with brine (2 x 5 ml), dried with anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative reversed-phase HPLC using acetonitrile in water containing 0.1% trifluoroacetic acid as eluent provided the title compound as a colorless solid (0.10 g, 34% yield ): 1H NMR (300 MHz, CD3OD) δ 7.90 to 7.85 (m, 1H), 7.82 to 7.76 (m, 1H), 7.67 to 7.53 (m, 2H), 7.32 to 7.21 (m, 3H), 7.12 (d, J = 4.8 Hz, 1H), 6.74 (d, J = 4.5 Hz, 1H), 4.97 (br s, 1H), 4.39 (s, 2H), 3.66 to 3.50 (m, 1H), 3.49 to 3.34 (m, 3H), 2.49 to 1.88 (m, 4H); NH and COOH not observed 19F NMR (282 MHz, CD3OD) δ -78.5, -114.1; MS (ES+) m/z 482.0 (M + 1), 484.0 (M + 1). EXAMPLE 23

[0858] Synthesis of 3-chloro-N-(thiazol-2-yl)-4-((1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)oxy)benzenesulfonamide 2,2,2-trifluoroacetate

[0859] Following the procedure as described in Example 22 and making non-critical variations as necessary to replace 4-fluorobenzaldehyde with 4-(trifluoromethyl)benzaldehyde, the title compound was obtained as a colorless solid (0.078 g, 15% yield) : 1H NMR (300 MHz, CD3OD) δ 7.85 (d, J = 2.1Hz, 1H), 7.82 to 7.78 (m, 3H), 7.76 to 7.72 (m, 2H) , 7.26 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 4.8 Hz, 1H), 6.72 (d, J = 4.5 Hz, 1H), 4 .95 (br s, 1H), 4.47 (s, 2H), 3.68 to 3.34 (m, 3H), 2.49 to 1.91 (m, 5H); NH and COOH not observed; 19F NMR (282 MHz, CD3OD) δ -61.4, -77.1; MS (ES+) m/z 531.9 (M + 1), 533.9 (M + 1). EXAMPLE 24

[0860] Synthesis of 3-chloro-N-(thiazol-2-yl)-4-((1-(4-(methylbenzyl)piperidin-4-yl)oxy)benzenesulfonamide 2,2,2-trifluoroacetate

[0861] Following the procedure as described in Example 22 and making non-critical variations as necessary to replace 4-fluorobenzaldehyde with 4-methylbenzaldehyde, the title compound was obtained as a colorless solid (0.29 g, 60% yield): 1H NMR (300 MHz, CD3OD) δ 7.84 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.7, 2.4 Hz, 1H), 7.38 (d , J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.27 to 7.19 (m, 1H), 7.09 (d, J = 4, 5 Hz, 1H), 6.71 (d, J = 4.5 Hz, 1H), 4.94 (s, 1H), 4.31 (s, 2H), 3.64 to 3.48 (m, 1H), 3.46 to 3.34 (m, 2H), 3.21 to 3.06 (m, 1H), 2.37 (s, 3H), 2.24 to 1.79 (m, 4H) ; NH and COOH not observed; MS (ES+) m/z 478.1 (M + 1), 480.0 (M + 1). EXAMPLE 25

[0862] Synthesis of 4-((1-benzyl-3-methylazetidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0863]Step 1. Preparation of 4-((1-benzyl-3-methylazetidin-3-yl)amino)-3-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl) benzenesulfonamide

[0864] To a solution of 3-amino-3-methyl-N-benzylazetidine (0.25 g, 1.42 mmol) and 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N- (thiazol-2-yl)benzenesulfonamide (0.63 g, 1.42 mmol) in anhydrous dimethyl sulfoxide (3 ml) was added potassium carbonate (0.39 g, 2.84 mmol) and the reaction mixture was heated to 70 to 75 °C for 24 h. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (150 ml) and water (15 ml). The organic phase was washed with water (15 ml), brine (15 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 100% ethyl acetate in hexanes provided the title compound as a colorless amorphous solid (0.26 g, 31% yield): MS (ES+) m/z 599.1 (M + 1), 601.1 (M + 1).

[0865] Step 2. Preparation of 4-((1-benzyl-3-methylazetidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0866]A mixture of 4-((1-benzyl-3-methylazetidin-3-yl)amino)-3-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.26 g, 0.44 mmol) in anhydrous dichloromethane (10 ml) trifluoroacetic acid (0.5 ml) was added at 0 °C and the reaction mixture was stirred at 0 °C for 30 minutes. The reaction mixture was concentrated in vacuo and methanol (10 ml) was added thereto. The mixture was filtered and the filtrate was concentrated in vacuo. Trituration of the residue in diethyl ether (15 ml) provided the title compound as an off-white solid (0.26 g, quantitative yield): 1H NMR (300 MHz, CDCI3) δ 7.64 (d, J = 2 .1 Hz, 1H), 7.53 to 7.42 (m, 6H), 7.26 (d, J = 4.6 Hz, 1H), 6.82 (d, J = 4.6 Hz, 1H ), 6.75 to 6.67 (m, 1H), 6.48 (d, J = 8.2 Hz, 1H), 4.41 (s, 2H), 4.27 (d, J = 10, 5 Hz, 2H), 4.19 (d, J = 10.6 Hz, 2 H), 1.56 (s, 3H), NH and COOH not observed; MS (ES+) m/z 449.0 (M + 1), 451.0 (M + 1). EXAMPLE 26

[0867] Synthesis of 4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide trifluoroacetate

[0868]Step 1. Preparation of 4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5- il)benzenesulfonamide:

[0869]A mixture of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.25 g, 0.56 mmol) and 1-benzylpyrrolidin-3-amine (0.096 ml, 0.56 mmol) in anhydrous dimethyl sulfoxide (5 ml) was added potassium carbonate (0.19 g, 1.35 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (5 ml) and water (5 ml) and the aqueous phase was extracted with ethyl acetate (3x 5 ml). The combined organic phase was washed with brine (1 x 5 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography, eluting with 6 to 50% ethyl acetate in hexanes provided the title compound as a yellow oil (0.33 g, 97% yield): 1H NMR (300 MHz, CDCI3) δ 8.11 (s, 1H), 7.56 to 7.46 (m, 2H), 7.36 to 7.21 (m, 6H), 7.01 (d, J = 9.0 Hz, 1H ), 6.45 (d, J = 9.3 Hz, 1H), 6.34 to 6.26 (m, 2H), 5.16 (s, 2H), 4.05 to 3.92 (m, 1H), 3.72 (s, 3H), 3.69 (s, 3H), 3.64 (s, 2H), 2.89 to 2.71 (m, 2H), 2.51 to 2.42 (m, 1H), 2.40 to 2.25 (m, 1H), 1.72 to 1.56 (m, 2H).

[0870]Step 2. Preparation of 4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl) 2,2,2-trifluoroacetate benzenesulfonamide

[0871]A mixture of 4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl )benzenesulfonamide (0.33 g, 0.55 mmol) in dichloromethane (8 ml) trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated in vacuo and the residue triturated in methanol (10 ml). The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a colorless solid (0.27 g, 85% yield): 1H NMR (300 MHz, CDCl3) δ 10.04 (s, 1H) , 8.40 (s, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.51 to 7.47 (m, 2H), 7.46 to 7.41 (m, 3H), 6.84 (d, J = 8.4 Hz, 1H), 6.47 to 6.21 (m, 1H), 6.17 to 5.89 (m, 1H), 4.38 (s, 2H), 3.59 to 3.10 (m, 4H), 2, 51 (s, 1H), 2.10 to 1.83 (m, 1H); MS (ES+) m/z 449.9 (M + 1), 451.9 (M + 1). EXAMPLE 27

[0872] Synthesis of (S)-3-chloro-4-((1-(3-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)- N-(thiazol-2-yl)benzenesulfonamide

[0873]Step 1. Preparation of (S)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenyl)amino)pyrrolidine- 1-tert-butyl carboxylate

[0874]A mixture of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide (3.39 g, 7.65 mmol) and (S) tert-butyl-3-aminopyrrolidine-1-carboxylate (1.71 g, 9.18 mmol) in anhydrous dimethyl sulfoxide (40 ml) was added potassium carbonate (2.11 g, 15.3 mmol) and the mixture reaction mixture was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate (200 ml), washed with water (200 ml), saturated ammonium chloride (100 ml), brine (100 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by column chromatography, eluting with a gradient of 10 to 80% ethyl acetate in hexanes to give the title compound as a colorless foam (3.95 g, 85% yield): 1H NMR (300 MHz, CDCl3) δ7.67 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 3.6, 1 .1 Hz, 1H), 7.17 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 3.6 Hz, 1H), 6.63 (d, J = 8.6 Hz, 1H), 6.41 to 6.53 (m, 2H), 5.07 (s, 2H), 4.86 (d, J = 6.4 Hz, 1H), 4.13 to 4.06 (m, 1H), 3.79 to 3.69 (m, 7H), 3.56 to 3.49 (m, 2H), 3.39 to 3.22 (m, 1H), 2.33 to 2 .21 (m, 1H), 2.00 to 1.93 (m, 1H), 1.46 (s, 9H); MS (ES+) m/z 609.2 (M + 1), 611.2 (M + 1).

[0875]Step 2. Preparation of (S)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenyl)(methylamino)pyrrolidine -1-tert-butyl carboxylate

[0876] To a solution of (S)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenyl)amino)pyrrolidine-1 -tert-butyl carboxylate (2.44 g, 4.00 mmol) in anhydrous tetrahydrofuran (35 ml) was added 1.0 M of a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (4.8 ml, 4. 8 mmol) at 0 °C. The reaction mixture was stirred for 1.5 h at 0 °C, cooled to -78 °C, and 1.0 M solution of methyl iodide in tetrahydrofuran (4.4 ml, 4.4 mmol) was added to it. . The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was diluted with ethyl acetate (100 ml), washed with saturated ammonium chloride (2 x 80 ml), brine (2 x 50 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by column chromatography, eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give the title compound as a colorless foam (1.75 g, 70% yield): 1H NMR (300 MHz, CDCI3) δ 7.75 (s, 1H), 7.68 to 7.61 (m, 1H), 7.43 (d, J = 3.6 Hz, 1H) , 7.17 (dd, J = 9.0, 4.4 Hz, 1H), 7.06 to 7.03 (m, 2H), 6.40 to 6.33 (m, 2H), 5.08 (s, 2H), 4.12 to 4.06 (m, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 3.67 to 3.52 (m, 2H), 3.37 to 3.26 (m, 2H), 2.79 (s, 3H), 2.04 to 2.01 (m, 2H), 1.47 (s, 9H); MS (ES+) m/z 623.2 (M + 1), 625.2 (M + 1).

[0877]Step 3. Preparation of (S)-3-chloro-4-(methyl(pyrrolidin-3-yl)amino)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0878] Following the procedure as described in EXAMPLE 1, Step 4 and making non-critical variations as necessary to replace 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2, 4-thiadiazol-5-yl)sulfamoyl)phenoxy)-3,3-dimethylpiperidine-1-tert-butyl carboxylate by (S)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl) -N-(thiazol-2-yl)sulfamoyl)phenyl)(methyl)amino)tert-butylpyrrolidine-1-carboxylate, the title compound was obtained as a beige foam (1.37 g, quantitative yield): MS ( ES+) m/z 373.1 (M + 1), 375.1 (M + 1).

[0879]Step 4. Preparation of (S)-3-chloro-4-((1-(3-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide

[0880]A mixture of 3-chlorobenzaldehyde (0.15 g, 1.08 mmol) and (S)-3-chloro-4-(methyl(pyrrolidin-3-yl)amino 2,2,2-trifluoroacetate )-N-(thiazol-2-yl)benzenesulfonamide (0.20 g, 0.54 mmol) in anhydrous N,N-dimethylformamide (4 ml) and anhydrous 1,2-dichloroethane (4 ml) was added sodium triacetoxyborohydride (0.23 g, 1.08 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (50 ml), washed with saturated ammonium chloride (40 ml), and concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 20% methanol (containing 0.2% ammonium hydroxide) in dichloromethane provided the title compound as a colorless solid (0.11 g, 41% yield): 1H NMR (300 MHz, DMSO-d6) δ 7.64 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.6, 2.2 Hz, 1H) , 7.34 to 7.15 (m, 6H), 6.77 (d, J = 4.6 Hz, 1H), 4.09 to 3.97 (m, 1H), 3.61 (d, J = 13.4 Hz, 1H), 3.5 (d, J = 13.4 Hz, 1H), 2.68 (s, 3H), 2.66 to 2.53 (m, 3H), 2.42 at 2.31 (m, 1H), 2.02 to 1.92 (m, 1H), 1.81 to 1.67 (m, 1H), NH not observed; MS (ES+) m/z 497.0 (M + 1), 499.0 (M + 1). EXAMPLE 28

[0881] Synthesis of (S)-3-chloro-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide

[0882] Following the procedure as described in EXAMPLE 27, Step 4 and making non-critical variations as necessary to replace 3-chlorobenzaldehyde with 3-(difluoromethyl)benzaldehyde, the title compound was obtained as a colorless solid (0.195 g, 70% yield): 1H NMR (300 MHz, DMSO-d6) δ 7.64 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.5, 2.2 Hz, 1H) , 7.50 to 7.40 (m, 4H), 7.21 (d, J = 4.5 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 6.99 ( t, J = 56.0 Hz, 1H), 6.77 (d, J = 4.5 Hz, 1H), 4.10 to 3.98 (m, 1H), 3.69 (d, J = 13 .3 Hz, 1H), 3.55 (d, J = 13.3 Hz, 1H), 2.68 (s, 3H), 2.67 to 2.53 (m, 3H), 2.43 to 2 .32 (m, 1H), 2.07 to 1.93 (m, 1H), 1.81 to 1.68 (m, 1H), NH not observed; MS (ES+) m/z 513.1 (M + 1), 515.1 (M + 1). EXAMPLE 29

[0883] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl) hydrochloride salt benzenesulfonamide

[0884]Step 1. Preparation of (S)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl) phenyl)amino)pyrrolidine-1-tert-butyl carboxylate

[0885]A mixture of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (12.46 g, 28.07 mmol) in anhydrous dimethyl sulfoxide (100 ml) was added (S)-3-aminopyrrolidine-1-tert-butyl carboxylate (15.69 g, 84.21 mmol) and the reaction mixture was heated to 50 °C for 6 p.m. The reaction mixture was allowed to cool to room temperature and stirred for 18 h. The reaction mixture was diluted with ethyl acetate (550 ml), washed with saturated ammonium chloride (2 x 200 ml), brine (100 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 100% ethyl acetate in hexanes provided the title compound as a colorless foam (17.13 g, 31% yield ): 1H NMR (300 MHz, CDCla) δ 8.16 (s, 1H), 7.65 to 7.61 (m, 2H), 7.06 (d, J = 9.0 Hz, 1H), 6 .58 (d, J = 8.6 Hz, 1H), 6.37 to 6.33 (m, 2H), 5.21 (s, 2H), 4.93 (d, J = 6.6 Hz, 1H), 4.10 to 4.05 (m, 1H), 3.78 to 3.72 (m, 7H), 3.56 to 3.47 (m, 2H), 3.37 to 3.22 ( m, 1H), 2.34 to 2.18 (m, 1H), 1.99 to 1.90 (m, 1H), 1.48 (s, 9H); MS (ES+) m/z 610.1 (M + 1), 612.1 (M + 1).

[0886]Step 2. Preparation of (S)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl) tert-butyl phenyl)(methyl)amino)pyrrolidine-1-carboxylate

[0887] To a solution of (S)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)phenyl tert-butyl amino)pyrrolidine-1-carboxylate (10.26 g, 16.82 mmol) in anhydrous tetrahydrofuran (100 ml) was added 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (20.2 ml, 20.2 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 40 minutes, cooled to -78 °C, and methyl iodide (1.15 ml, 18.50 mmol) was added thereto. The reaction mixture was stirred at -78°C for 30 minutes, allowed to warm to room temperature and stirred for 4 h. The reaction mixture was diluted with ethyl acetate (250 ml), washed with saturated ammonium chloride (2 x 150 ml), brine (100 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 100% ethyl acetate in hexanes provided the title compound as a colorless foam (6.50 g, 62% yield ): 1H NMR (300 MHz, CDCla) δ8.19 (s, 1H), 7.64 to 7.58 (m, 2H), 7.07 (d, J = 8.3 Hz, 1H), 6, 99 (d, J = 8.2 Hz, 1H), 6.35 to 6.32 (m, 1H), 6.30 (d, J = 2.3 Hz, 1H), 5.27 (s, 2H ), 4.09 to 4.03 (m, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 3.64 to 3.55 (m, 2H), 3.36 to 3.26 (m, 2H), 2.79 (s, 3H), 2.05 to 1.98 (m, 2H), 1.48 (s, 9H); MS (ES+) m/z 624.1 (M + 1), 626.1 (M + 1).

[0888]Step 3. Preparation of (S)-3-chloro-4-(methyl(pyrrolidin-3-yl)amino)-N-(1,2,4-thiadiazol-5) 2,2,2-trifluoroacetate -yl)benzenesulfonamide

[0889] To a solution of (S)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)phenyl Tert-butyl )(methyl)amino)pyrrolidine-1-carboxylate (3.0 g, 4.8 mmol) in dichloromethane (60 ml) was added 2,2,2-trifluoroacetic acid (18 ml). The reaction mixture was stirred at room temperature for 40 minutes and then concentrated in vacuo. The residue was triturated with methanol (40 ml) containing activated charcoal (1.0 g), and the resulting mixture was filtered. The filtrate was concentrated in vacuo to provide the title compound as a brownish oil (2.1 g, 91% yield): 1H NMR (300 MHz, DMSO-d6) δ9.03 to 8.83 (m, 2H) , 8.46 (s, 1H), 7.75 to 7.74 (m, 1H), 7.72 to 7.68 (m, 1H), 7.37 (d, J = 8.5 Hz, 1H ), 4.26 to 4.16 (m, 1H), 3.44 to 3.23 (m, 2H), 3.20 to 3.06 (m, 2H), 2.72 (s, 3H), 2.11 to 1.88 (m, 2H), an NH not observed.

[0890]Step 4. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0891] A mixture of (S)-3-chloro-4-(methyl(pyrrolidin-3-yl)amino)-N-(1,2,4-thiadiazol-5-) 2,2,2-trifluoroacetate il)benzenesulfonamide (0.80 g, 1.6 mmol) in anhydrous N,N-dimethylformamide (8 ml) and anhydrous 1,2-dichloroethane (8 ml) benzaldehyde (0.2 ml, 2 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes and then sodium triacetoxyborohydride (0.68 g, 3.2 mmol) was added thereto. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted in water (30 ml), saturated ammonium chloride solution (10 ml) and ethyl acetate (50 ml). The aqueous phase was extracted with ethyl acetate (2 x 30 ml) and dichloromethane (10 x 15 ml). The combined organic phases were washed with brine (30 ml), dried over anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 20% methanol (containing 0.1% ammonium hydroxide) in dichloromethane gave a residue which was triturated in methanol (10 ml) to give the title compound as a colorless solid (0.355 g, 77% yield): 1H NMR (300 MHz, DMSO-d6) δ 10.07 (br s, 1H), 7.90 (s, 1H ), 7.68 (d, J = 2.1 Hz, 1H), 7.62 (dd, J = 8.4, 2.1 Hz, 1H), 7.52 to 7.40 (m, J = 2.7 Hz, 5H), 7.27 (d, J = 8.5 Hz, 1H), 4.33 (s, 2H), 4.24 to 4.15 (m, 1H), 3.51 to 3.15 (m, 4H), 2.69 (s, 3H), 2.15 to 1.97 (m, 2H); MS (ES+) m/z 464.0 (M + 1), 466.0 (M + 1).

[0892]Step 5. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl) hydrochloride )benzenesulfonamide

[0893]A (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.334 g, 0.720 mmol) a 5 to 10% solution of hydrogen chloride in methanol (2 ml) was added and the reaction mixture was stirred at room temperature for 30 minutes. Concentration in vacuo gave the title compound as a colorless solid (0.339 g, 94% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.33 to 10.82 (m, 1H), 8.43 (s, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.68 (dd, J = 8.4, 2.1 Hz, 1H), 7.62 to 7.53 ( m, 2H), 7.47 to 7.41 (m, J = 3.2 Hz, 3H), 7.33 (d, J = 8.6 Hz, 1H), 4.49 to 4.16 (m , 3H), 3.54 to 3.00 (m, 5H), 2.76 (s, 3H), 2.20 to 2.00 (m, 2H); MS (ES+) m/z 464.0 (M + 1), 466.0 (M + 1). EXAMPLE 30

[0894] Synthesis of (S)-3-chloro-4-((1-(3-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)- N-(1,2,4-thiadiazol-5-yl )benzenesulfonamide

[0895] Following the procedure as described in EXAMPLE 29, Step 4 and making non-critical variations as necessary to replace benzaldehyde with 3-chlorobenzaldehyde, and purification by column chromatography, eluting with 0 to 20% methanol (containing 0.2% of ammonium hydroxide) in dichloromethane, the title compound was obtained as a colorless solid (0.12 g, 47% yield): 1H NMR (300 MHz, DMSO-d6) δ 10.22 (br s, 1H) , 7.85 (s, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.59 (dd, J = 8.4, 2.1 Hz, 1H), 7.47 ( s, 1H), 7.41 to 7.34 (m, 3H), 7.20 (s, 1H), 4.12 to 4.04 (m, 1H), 3.98 to 3.89 (m, 2H), 3.04 to 2.75 (m, 4H), 2.67 (s, 3H), 2.11 to 1.99 (m, 1H), 1.93 to 1.81 (m, 1H) ; MS (ES+) m/z 498.0 (M + 1), 500.0 (M + 1). EXAMPLE 31

[0896] Synthesis of (S)-3-chloro-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazole- 5-yl)benzenesulfonamide

[0897] Following the procedure as described in EXAMPLE 29, Step 4 and making non-critical variations as necessary to replace benzaldehyde with 3-(difluoromethyl)benzaldehyde, and purification by column chromatography, eluting with 0 to 20% methanol (containing 0 .2% ammonium hydroxide) in dichloromethane, the title compound was obtained as a colorless solid (0.085 g, 32% yield): 1H NMR (300 MHz, DMSO-d6) δ 10.22 (br s, 1H ), 7.87 (s, 1H), 7.66 to 7.54 (m, 6H), 7.25 (s, 1H), 7.05 (t, J = 51.4 Hz, 1H), 4 .19 to 4.09 (m, 3H), 3.46 to 3.32 (m, 1H), 3.22 to 2.93 (m, 3H), 2.68 (s, 3H), 2.14 to 2.03 (m, 1H), 1.98 to 1.86 (m, 1H); MS (ES+) m/z 514.0 (M + 1), 516.0 (M + 1). EXAMPLE 32

[0898] Synthesis of (S)-3-chloro-4-((1-(3-chloro-2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazole -5-yl)benzenesulfonamide

[0899] Following the procedure as described in EXAMPLE 29, Step 4 and making non-critical variations as necessary to replace benzaldehyde with 3-chloro-2-fluorobenzaldehyde, and purification by column chromatography, eluting with 0 to 20% methanol (containing 0.2% ammonium hydroxide) in dichloromethane, the title compound was obtained as a colorless solid (0.145 g, 55% yield): 1H NMR (300 MHz, DMSO-d6) δ 7.89 (s, 1H ), 7.64 (d, J = 2.1 Hz, 1H), 7.61 to 7.54 (m, 2H), 7.49 to 7.44 (m, 1H), 7.26 (dd, J = 7.9, 0.8 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 4.12 to 4.07 (m, 1H), 3.98 (s, 2H ), 3.05 to 2.74 (m, 4H), 2.67 (s, 3H), 2.10 to 1.98 (m, 1H), 1.91 to 1.79 (m, 1H), NH not observed; MS (ES+) m/z 516.0 (M + 1), 518.0 (M + 1). EXAMPLE 33

[0900] Synthesis of (S)-3-chloro-4-((1-(5-chloro-2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-2,2,2-trifluoroacetate (1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0901] Following the procedure as described in EXAMPLE 29, Step 4 and making non-critical variations as necessary to replace benzaldehyde with 5-chloro-2-fluorobenzaldehyde, and purification by reversed-phase preparative HPLC, eluting with a gradient from 10 to 60% acetonitrile in water containing 0.1% trifluoroacetic acid, the title compound was obtained as a colorless solid (0.085 g, 26% yield): 1H NMR (300 MHz, CD3OD) δ 8.08 (s, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.75 (dd, J = 8.5, 2.2 Hz, 1H), 7.55 (dd, J = 6.2 , 2.6 Hz, 1H), 7.47 (ddd, J = 8.9, 4.5, 2.7 Hz, 1H), 7.26 to 7.16 (m, 2H), 4.42 ( s, 2H), 4.40 to 4.33 (m, 1H), 3.67 to 3.61 (m, 1H), 3.51 to 3.36 (m, 3H), 2.77 (s, 3H), 2.30 to 2.16 (m, 2H), NH and COOH not observed; MS (ES+) m/z 516.0 (M + 1), 518.0 (M + 1). EXAMPLE 34

[0902] Synthesis of (S)-3-chloro-4-((1-(2-fluoro-3-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-2,2,2-trifluoroacetate (1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0903] Following the procedure as described in EXAMPLE 29, Step 4 and making non-critical variations as necessary to replace benzaldehyde with 2-fluoro-3-methylbenzaldehyde, and purification by reversed-phase preparative HPLC, eluting with a gradient from 10 to 60% acetonitrile in water containing 0.1% trifluoroacetic acid, the title compound was obtained as a colorless solid (0.085 g, 22% yield, check): 1H NMR (300 MHz, CD3OD) δ 8.19 ( s, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.76 (dd, J = 8.5, 2.2 Hz, 1H), 7.42 to 7.31 (m , 3H), 7.16 (t, J = 7.6 Hz, 1H), 4.49 (s, 2H), 4.42 to 4.32 (m, 1H), 3.70 to 3.63 ( m, 1H), 3.54 to 3.41 (m, 3H), 2.79 (s, 3H), 2.31 to 2.22 (m, 5H), NH and COOH not observed; MS (ES+) m/z 496.0 (M + 1), 498.0 (M + 1). EXAMPLE 35

[0904] Synthesis of (S)-3-chloro-4-((1-(2-fluoro-5-methylbenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2,4-thiadiazole -5-yl)benzenesulfonamide

[0905] Following the procedure as described in EXAMPLE 29, Step 4 and making non-critical variations as necessary to replace benzaldehyde with 2-fluoro-5-methylbenzaldehyde, and purification by column chromatography, eluting with 0 to 20% methanol (containing 0.2% ammonium hydroxide) in dichloromethane, the title compound was obtained as a colorless solid (0.085 g, 32% yield): 1H NMR (300 MHz, DMSO-d6) δ 7.89 (s, 1H ), 7.66 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 8.4, 2.1 Hz, 1H), 7.32 (dd, J = 7.2, 1.8 Hz, 1H), 7.27 to 7.22 (m, 2H), 7.14 (dd, J = 9.1, 9.1 Hz, 1H), 4.18 to 4.15 (m , 3H), 3.32 to 3.25 (m, 1H), 3.13 to 3.04 (m, 3H), 2.68 (s, 3H), 2.28 (s, 3H), 2, 12 to 2.04 (m, 1H), 1.98 to 1.91 (m, 1H), NH and COOH not observed; MS (ES+) m/z 496.1 (M + 1), 498.1 (M + 1). EXAMPLE 36

[0906] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(ethyl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0907]Step 1. Preparation of (S)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl) tert-butyl phenyl)(ethyl)amino)pyrrolidine-1-carboxylate

[0908] To a solution of (S)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)phenyl tert-butyl)amino)pyrrolidine-1-carboxylate (0.94 g, 1.54 mmol) in anhydrous dimethyl sulfoxide (21 ml) was added anhydrous cesium carbonate (1.0 g, 3.08 mmol). The reaction mixture was stirred at room temperature for 2 h, and then iodoethane (0.19 ml, 2.31 mmol) was added dropwise thereto. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate (50 ml), washed with water (50 ml), brine (3 x 50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 100% ethyl acetate in hexanes gave the title compound as a colorless solid (0.77 mg, 78% yield ). 1H NMR (300 MHz, CDCla) δ 8.16 (s, 1H), 7.61 to 7.56 (m, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.31 to 6.28 (m, 2H), 5.26 (s, 2H), 4.01 to 3.93 (m, 1H), 3.73 (s, 3H), 3.69 (s, 3H), 3.66 to 3.43(m, 2H), 3.30 to 3.09 (m, 4H), 2.00 to 1.94 (m, 1H), 1.90 to 1.77 (m, 1H ), 1.43 (s, 9H), 0.92 to 0.88 (m, 3H); MS (ES+) m/z 638.2 (M + 1), 640.1 (M + 1).

[0909]Step 2. Preparation of (S)-3-chloro-4-(ethyl(pyrrolidin-3-yl)amino)-N-(1,2,4-thiadiazol-5) 2,2,2-trifluoroacetate -yl)benzenesulfonamide

[0910] Following the procedure as described in EXAMPLE 29, Step 3 and making non-critical variations as necessary to replace (S)-3-((2-chloro- 4-(N-(2,4-dimethoxybenzyl)-N- tert-butyl (1,2,4-thiadiazol-5-yl)sulfamoyl)phenyl)(methyl)amino)pyrrolidine-1-carboxylate by (S)-3-((2-chloro-4-(N-(2 ,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)phenyl)(ethyl)amino)pyrrolidine-1-tert-butyl carboxylate, the title compound was obtained as a brown foam ( 0.61 g, quantitative yield): 1H NMR (300 MHz, CD3OD) δ 8.20 (s, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.77 (dd, J = 8.4, 2.2 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 4.30 to 4.20 (m, 1H), 3.45 to 3.34 ( m, 2H), 3.26 to 3.17 (m, 4H), 2.21 to 2.06 (m, 1H), 2.02 to 1.90 (m, 1H), 0.92 (t, J = 7.1 Hz, 3H), NH and COOH not observed; MS (ES+) m/z 388.0 (M + 1), 390.0 (M + 1).

[0911]Step 3. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(ethyl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0912]A mixture of benzaldehyde (0.15 g, 1.08 mmol) and (S)-3-chloro-4-(ethyl(pyrrolidin-3-yl)amino)-2,2,2-trifluoroacetate N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.30 g, 0.60 mmol) in anhydrous N,N-dimethylformamide (4 ml) and anhydrous 1,2-dichloroethane (4 ml) was Sodium triacetoxyborohydride (0.32 g, 1.50 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate (50 ml), washed with saturated ammonium chloride (40 ml), and concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 20% methanol (containing 0.2% ammonium hydroxide) in dichloromethane provided the title compound as a colorless solid (0.11 g, 38% yield): 1H NMR (300 MHz, DMSO-d6) δ 10.11 (br s, 1H), 7.85 (s, 1H), 7.67 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 8.2, 2.1 Hz, 1H), 7.45 to 7.36 (m, 5H), 7.31 (d, J = 8.4 Hz, 1H), 4 .24 (s, 2H), 4.16 to 4.03 (m, 1H), 3.14 to 3.30 (m, 2H), 3.24 to 3.00 (m, 4H), 2.14 at 2.00 (m, 1H), 1.93 to 1.79 (m, 1H), 0.77 (t, J = 7.01 Hz, 3H); MS (ES+) m/z 478.1 (M + 1), 480.1 (M + 1). EXAMPLE 37

[0913] Synthesis of (S)-3-chloro-4-(ethyl(1-(3-methylbenzyl)pyrrolidin-3-yl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0914] Following the procedure as described in EXAMPLE 17, Step 3 and making non-critical variations as necessary to replace benzaldehyde with 3-methylbenzaldehyde, the title compound was obtained as a colorless solid (0.11 g, 37% yield): 1H NMR (300 MHz, DMSO-d6) δ 10.02 (br s, 1H), 7.85 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.60 ( dd, J = 8.4, 2.0 Hz, 1H), 7.34 to 7.16 (m, 5H), 4.21 (s, 2H), 4.15 to 4.03 (m, 1H) , 3.42 to 3.31 (m, 1H), 3.27 to 2.97 (m, 5H), 2.26 (s, 3H), 2.12 to 1.99 (m, 1H), 1 .92 to 1.78 (m, 1H), 0.77 (t, J = 6.6 Hz, 3H); MS (ES+) m/z 492.1 (M + 1), 494.1 (M + 1). EXAMPLE 38

[0915] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-) 2,2,2-trifluoroacetate il)benzenesulfonamide

[0916]Step 1. Preparation of tert-butyl ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate

[0917] To a solution of tert-butyl thiazol-4-ylcarbamate (160.0 g, 799.0 mmol) in anhydrous tetrahydrofuran (1500 ml) was added lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 1120 ml) at -78 °C. The reaction mixture was heated to 5 °C, stirred for 30 minutes, and cooled to -78 °C. A solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (355.3 g, 1440 mmol) in anhydrous tetrahydrofuran (500 ml) was then added dropwise to it at - 78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 12h. Saturated ammonium chloride (200 ml) was then added to it, and the mixture was extracted with ethyl acetate (3 x 1000 ml). The combined organic phase was washed with brine (3 x 1000 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and trituration of the residue with methanol (500 ml) provided the title compound as a colorless solid (220.0 g, 67% yield): 1H NMR (400MHz, DMSO-d6) δ 9, 14 (d, J = 2.2 Hz, 1H), 8.25 (t, J = 7.6 Hz, 1H), 8.06 to 7.94 (m, 2H), 1.28 (s, 9H ); MS (ES+) m/z 310.8 (M - 99), 312.8 (M - 99).

[0918]Step 2. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol) 2,2,2-trifluoroacetate -4-yl)benzenesulfonamide

[0919]A mixture of tert-butyl ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (prepared according to WO2010079443, 0.28 g, 0.67 mmol) in Anhydrous dimethyl sulfoxide (3 ml) was added (S)-1-benzyl-N-methylpyrrolidin-3-amine (0.26 g, 1.34 mmol) and the reaction mixture was heated to 80 °C in a tube sealed for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 ml), washed with saturated ammonium chloride (30 ml), brine (30 ml), dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The obtained residue was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (5 ml) was added thereto. The reaction mixture was stirred at room temperature for 20 minutes and concentrated in vacuo. Purification of the residue by preparative reversed-phase HPLC eluting with a gradient of 10 to 50% acetonitrile in water containing 0.1% trifluoroacetic acid provided the title compound as a colorless solid (0.125 g, 39% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.36 (br s, 1H), 10.61 (br s, 0.5H), 10.35 (br s, 0.5H), 8.87 (d , J = 2.2 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.51 to 7.38 (m, 5H), 7.21 to 7.13 (m, 1H), 7.04 (d, J = 2.2 Hz, 1H), 4.61 to 4.20 (m, 3H), 3.61 to 3.01 (m, 4H), 2.73 (d , J = 20.0 Hz, 3H), 2.17 to 1.89 (m, 2H); MS (ES+) m/z 481.1 (M + 1), 483.1 (M + 1). EXAMPLE 39

[0920] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide bis(acid) salt trifluoroacetic acid)

[0921] Following the procedure as described in EXAMPLE 38, STEP 2 and making non-critical variations as necessary to replace ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate with 5 -chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide, and purification by column chromatography, eluting with 0 to 20% methanol (containing 0.2 % ammonium hydroxide) in dichloromethane, the title compound was obtained as a colorless solid (0.40 g, 56% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.93 (br s, 1H ), 10.98 (br s, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.53 to 7.44 (m, 5H), 7.32 (d, J = 4 .6 Hz, 1H), 7.21 (d, J = 11.9 Hz, 1H), 6.89 (d, J = 4.6 Hz, 1H), 4.40 to 4.33 (m, 2H ), 3.79 to 3.69 (m, 2H), 3.57 to 3.49 (m, 1H), 3.37 to 3.29 (m, 2H), 2.75 (s, 3H), 2.17 to 2.07 (m, 2H), an exchangeable proton not observed; 19F NMR (282 MHz, DMSO-d6) δ -73.65 (s, 6F), -109.18 (s, 1F); MS (ES+) m/z 481.1 (M + 1), 483.0 (M + 1). EXAMPLE 40

[0922] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide bis salt (trifluoroacetic acid)

[0923]Step 1. Preparation of 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide

[0924] To a solution of N-(2,4-dimethoxybenzyl)-6-fluoropyridin-2-amine (prepared according to WO2014066490, 20.00 g, 76.25 mmol) in anhydrous tetrahydrofuran (200 ml) was added 1.6 M methyl lithium solution in diethyl ether (66.7 ml, 106.7 mmol) dripped at -78 °C. The reaction mixture was allowed to warm to 0°C and stirred for 30 minutes. The reaction mixture was cooled to -78 °C and a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (33.9 g, 137.3 mmol) in anhydrous tetrahydrofuran (100 ml) was added dropwise thereto. . The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The mixture was diluted with water (200 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and trituration of the residue in a mixture of methanol and dichloromethane (20:1, 2 * 150 ml) gave the title compound as a colorless solid (12.1 g, 32% yield): 1H NMR (300 MHz, CDCl3) δ8.02 (t, J = 8.0 Hz, 1H), 7.77 to 7.66 (m, 1H), 7.27 to 7.15 (m, 2H), 7, 01 (t, J = 8.0 Hz, 1H), 6.72 (dd, J = 8.0, 2.8 Hz, 1H), 6.43 to 6.35 (m, 2H), 5.07 (s, 2H), 3.78 (s, 3H), 3.73 (s, 3H).

[0925]Step 2. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide salt bis(trifluoroacetic acid)

[0926] Following the procedure as described in EXAMPLE 38, STEP 2 and making non-critical variations as necessary to replace ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate with 5 -chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide, and purification by flash chromatography, (0 to 20% methanol (+0.2 % ammonium hydroxide) in dichloromethane), the title compound was obtained as a colorless solid (0.40 g, 56% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (br s, 1H), 10.63 (br s, 1H), 7.92 to 7.83 (m, 2H), 7.53 to 7.44 (m, 5H), 7.19 (d, J = 12.4 Hz, 1H), 6.90 (dd, J = 7.9, 2.1 Hz, 1H), 6.75 (dd, J = 8.0, 2.5 Hz, 1H), 4.53 to 4 .32 (m, 3H), 3.58 to 3.51 (m, 2H), 3.42 to 3.27 (m, 2H), 2.78 (s, 3H), 2.21 to 2.07 (m, 2H), an unobserved exchangeable proton; 19F NMR (282 MHz, DMSO-d6) δ -69.00 (s, 1F), -73.61 (s, 6F), -110.18 (s, 1F); MS (ES+) m/z 493.1 (M + 1), 495.1 (M + 1). EXAMPLE 41

[0927] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0928]Step 1. Preparation of tert-butyl ((3-chloro-4-fluorophenyl)sulfonyl)(thiazol-5-yl)carbamate

[0929] To a solution of tert-butyl thiazol-4-ylcarbamate (8.87 g, 44.3 mmol) in anhydrous tetrahydrofuran (220 ml) was added 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran ( 48.7 ml, 48.7 mmol) at -78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was cooled to -78 ° C, and a solution of 3-chloro-4-fluorobenzenesulfonyl chloride (6.93 ml, 48.7 mmol) in anhydrous tetrahydrofuran (17 ml) was added thereto. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was diluted with ethyl acetate (350 ml), washed with saturated ammonium chloride (2 x 200 ml), brine (2 x 150 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 100% ethyl acetate in hexanes provided the title compound as a colorless solid (13.9 g, 80% yield ). 1H NMR (300 MHz, CDCla) δ 8.83 to 8.81 (m, 1H), 8.30 to 8.25 (m, 1H), 8.14 to 8.07 (m, 1H), 7, 58 to 7.55 (m, 1H), 7.39 to 7.28 (m, 1H), 1.38 (s, 9H); MS (ES+) m/z 393.0 (M + 1), 395.0 (M + 1).

[0930]Step 2. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(thiazol-4-yl) 2,2,2-trifluoroacetate )benzenesulfonamide

[0931] Following the procedure as described in EXAMPLE 38, STEP 2 and making non-critical variations as necessary to replace ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate with ( tert-butyl (3-chloro-4-fluorophenyl)sulfonyl)(thiazol-5-yl)carbamate, the title compound was obtained as a colorless solid (0.40 g, 56% yield): 1H NMR (300 MHz , CD3OD) δ 8.71 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 0.6 Hz, 1H), 7.72 (dd, J = 8.5, 2, 2 Hz, 1H), 7.51 to 7.44 (m, 5H), 7.07 (d, J = 2.2 Hz, 1H), 4.43 to 4.40 (m, 2H), 4, 38 to 4.28 (m, 2H), 3.64 to 3.38 (m, 4H), 2.79 to 2.77 (m, 3H), 2.35 to 2.10 (m, 2H), NH and COOH not observed; MS (ES+) m/z 463.1 (M + 1), 465.1 (M + 1). EXAMPLE 42

[0932] Synthesis of 3-chloro-4-(methyl((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl)benzenesulfonamide

[0933]Step 1. Preparation of (S)-2-((tert-butoxycarbonyl)amino)butane-1,4-di-yl dimethanesulfonate

[0934] To a solution of (S)-(1,4-dihydroxybutan-2-yl) tert-butyl carbamate (5.0 g, 24.36 mmol) and triethylamine (17.0 ml, 121.8 mmol) in anhydrous dichloromethane (120 ml) was added methanesulfonyl chloride (4.15 ml, 53.59 mmol) at 0°C. The reaction mixture was stirred for 1 h at 0 °C and then quenched by addition of water (50 ml) and saturated ammonium chloride (120 ml). The aqueous layer was extracted with dichloromethane (100 ml) and the combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo provided the title compound as a colorless solid (8.70 g, 99% yield): 1H NMR (300 MHz, DMSO-d6) δ7.08 (d, J = 8.4 Hz, 1H), 4.26 to 4.06 (m, 4H), 3.18 (s, 3H), 3.16 (s, 3H), 1.97 to 1.86 (m, 1H), 1.83 at 1.71 (m, 1H), 1.39 (s, 9H), NH not observed; MS (ES+) m/z 362.1 (M + 1).

[0935]Step 2. Preparation of tert-butyl ((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl)carbamate

[0936]A mixture of dimethanesulfonate (S)-2-((tert-butoxycarbonyl)amino)butane-1,4-diyl (2.63 g, 7.28 mmol) and N,N-diisopropylethylamine (6 .34 ml, 36.4 mmol) in anhydrous dimethyl sulfoxide (12 ml) was added (S)-1-phenylethan-1-amine (0.93 ml, 7.28 mmol) and the reaction mixture was heated until 40 °C in a sealed tube for 18 h. The reaction mixture was diluted with ethyl acetate (130 ml), washed with saturated ammonium chloride (3 x 100 ml), brine (50 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with 5% methanol (containing 0.2% ammonium hydroxide) in dichloromethane gave the title compound as a colorless solid (0.76 g, 36% yield). 1H NMR (300 MHz, CDCl3) δ 7.36 to 7.25 (m, 5H), 4.86 to 4.81 (m, 1H), 4.18 to 4.07 (m, 1H), 3, 22 (q, J = 6.6 Hz, 1H), 2.97 to 2.88 (m, 1H), 2.57 (dd, J = 9.9, 6.6 Hz, 1H), 2.36 to 2.20 (m, 3H), 1.71 to 1.57 (m, 1H), 1.43 (s, 9H), 1.39 (d, J = 6.6 Hz, 3H); MS (ES+) m/z 291.2 (M + 1).

[0937]Step 3. Preparation of (S)-N-methyl-1-((S)-1-phenylethyl)pyrrolidin-3-amine

[0938] To a solution of tert-butyl ((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl)carbamate (0.76 g, 2.62 mmol) in anhydrous tetrahydrofuran (40 ml ) 1.0 M lithium aluminum hydride solution in tetrahydrofuran (5.24 ml, 5.24 mmol) was added and the reaction mixture was heated to reflux for 4 h. The reaction mixture was cooled to 0 °C and quenched by slow addition of 2.0 M sodium hydroxide (50 ml). The mixture was extracted with diethyl ether (2 x 60 ml). The combined organic phase was washed with 2.0 M sodium hydroxide (20 ml), brine (3 x 20 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave the title compound as a colorless oil (0.46 g, 85% yield): 1H NMR (300 MHz, CDCla) δ 7.36 to 7.20 (m, 5H), 3 .24 to 3.14 (m, 2H), 2.78 to 2.65 (m, 2H), 2.40 to 2.32 (m, 4H), 2.27 (dt, J = 9.6, 4.5 Hz, 1H), 2.14 to 1.99 (m, 1H), 1.62 to 1.45 (m, 2H), 1.38 (d, J = 6.6 Hz, 3H); MS (ES+) m/z 205.2 (M + 1).

[0939]Step 4. Preparation of Synthesis of 3-chloro-4-(methyl((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl)amino)-N-(thiazol-2- il)benzenesulfonamide

[0940]A mixture of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide (0.22 g, 0.50 mmol) and (S) -N-methyl-1-((S)-1-phenylethyl)pyrrolidin-3-amine (0.10 g, 0.5 mmol) in anhydrous dimethyl sulfoxide (5 ml) was added potassium carbonate (0.14 g, 1.0 mmol) and the reaction mixture was at 80 °C for 18 h. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (50 ml). The mixture was washed with saturated ammonium chloride (2 x 150 ml), brine (30 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue, which was dissolved in dichloromethane (20 ml). Trifluoroacetic acid (8 ml) was added to it and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and methanol (20 ml) was added thereto. Filtration and concentration of the filtrate in vacuo gave a residue which was purified by column chromatography, eluting with 5% methanol (containing 0.2% ammonium hydroxide) in dichloromethane to give the title compound as a colorless solid (0 .07 g, 29% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.13 (br s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.63 (dd, J = 8.5, 2.2 Hz, 1H), 7.44 to 7.31 (m, 5H), 7.27 (d, J = 4.6 Hz, 1H), 7.23 ( d, J = 8.5 Hz, 1H), 6.84 (d, J = 4.6 Hz, 1H), 4.20 to 4.10 (m, 1H), 3.81 to 3.75 (m , 2H), 3.08 to 3.03 (m, 2H), 2.78 to 2.69 (m, 4H), 2.06 to 2.01 (m, 1H), 1.95 to 1.84 (m, 1H), 1.43 (d, J = 6.6 Hz, 3H); MS (ES+) m/z 477.1 (M + 1), 479.1 (M + 1). EXAMPLE 43

[0941] Synthesis of 3-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((S)-1-((S)-1-2,2,2-trifluoroacetate phenylethyl)pyrrolidin-3-yl)amino)benzenesulfonamide

[0942] Following the procedure as described in EXAMPLE 42, Step 4 and making non-critical variations as necessary to replace 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2- il)benzenesulfonamide by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide, and purification by reversed-phase preparative HPLC, eluting with a gradient from 10 to 50% acetonitrile in water containing 0.1% trifluoroacetic acid, the title compound was obtained as a colorless solid (0.11 g, 43% yield): 1H NMR (300 MHz, CD3OD) δ 8 .01 to 7.98 (m, 1H), 7.76 (dd, J = 8.1, 8.1 Hz, 1H), 7.51 to 7.46 (m, 5H), 7.09 to 7 .06 (m, 1H), 6.92 (dd, J = 7.9, 1.9 Hz, 1H), 6.61 (dd, J = 8.1, 2.6 Hz, 1H), 4, 47 to 4.40 (m, 2H), 4.07 to 3.85 (m, 1H), 3.26 to 3.07 (m, 1H), 2.86 to 2.72 (m, 3H), 2.34 to 2.10 (m, 2H), 1.72 (d, J = 6.8 Hz, 3H), NH and COOH not observed; MS (ES+) m/z 507.1 (M + 1), 509.1 (M + 1). EXAMPLE 44

[0943] Synthesis of 3-chloro-4-(methyl((S)-1-((R)-1-phenylethyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl)benzenesulfonamide

[0944]Step 1. Preparation of tert-butyl ((S)-1-((R)-1-phenylethyl)pyrrolidin-3-yl)carbamate

[0945] Following the procedure as described in EXAMPLE 42, Step 2 and making non-critical variations as necessary to replace (S)-1-phenylethan-1-amine with (R)-1-phenylethan-1-amine, the compound of title was obtained as a colorless solid (1.39 g, 66% yield): 1H NMR (300 MHz, CDCI3) δ7.35 to 7.23 (m, 5H), 4.96 to 4.79 (m, 1H), 4.39 to 4.26 (m, 1H), 4.22 to 4.06 (m, 1H), 3.26 to 3.19 (m, 1H), 2.69 to 2.54 ( m, 2H), 2.31 to 2.18 (m, 1H), 2.10 to 1.98 (m, 1H), 1.59 to 1.52 (m, 1H), 1.45 (s, 9H), 1.38 (d, J = 6.5 Hz, 3H); MS (ES+) m/z 291.2 (M + 1).

[0946]Step 2. Preparation of (S)-N-methyl-1-((R)-1-phenylethyl)pyrrolidin-3-amine

[0947] Following the procedure as described in EXAMPLE 42, Step 2 and making non-critical variations as necessary to replace ((S)-1-((S)-1-phenylethyl)-pyrrolidin-3-yl) tert-butyl carbamate by tert-butyl ((S)-1-((R)-1-phenylethyl)pyrrolidin-3-yl)carbamate, the title compound was obtained as a colorless oil (0.63 g, 64% yield): 1H NMR (300 MHz, CDCI3) δ7.35 to 7.24 (m, 5H), 3.23 to 3.12 (m, 2H), 2.64 to 2.45 (m, 4H), 2.35 (s, 3H), 2.16 to 2.05 (m, 2H), 1.58 to 1.46 (m, 1H), 1.38 (d, J = 6.6 Hz, 3H); MS (ES+) m/z 205.2 (M + 1).

[0948]Step 3. Preparation of 3-chloro-4-(methyl((S)-1-((R)-1-phenylethyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl) benzenesulfonamide

[0949] Following the procedure as described in EXAMPLE 42, Step 4 and making non-critical variations as necessary to replace (S)-N-methyl-1- ((S)-1-phenylethyl)pyrrolidin-3-amine with (S )-N-methyl-1-((R)-1-phenylethyl)pyrrolidin-3-amine, the title compound was obtained as a colorless solid (0.11 g, 46% yield): 1H NMR (300 MHz , DMSO-d6) δ 12.03 (br s, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.65 (dd, J = 8.5, 2.2 Hz, 1H ), 7.51 to 7.40 (m, 5H), 7.31 to 7.28 (m, 2H), 6.85 (d, J = 4.6 Hz, 1H), 4.39 to 4, 21 (m, 2H), 3.45 to 3.38 (m, 1H), 3.33 to 3.26 (m, 2H), 3.10 to 3.02 (m, 1H), 2.72 ( s, 3H), 2.10 to 2.02 (m, 2H), 1.59 (d, J = 6.7 Hz, 3H); MS (ES+) m/z 477.1 (M + 1), 479.1 (M + 1). EXAMPLE 45

[0950] Synthesis of 5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(methyl((S)-1-((R)-1) 2,2,2-trifluoroacetate -phenylethyl)pyrrolidin-3-yl)amino)benzenesulfonamide

[0951]A mixture of 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (0.22 g, 0.5 mmol) and (S)-N-methyl-1-((S)-1-phenylethyl)pyrrolidin-3-amine (0.10 g, 0.5 mmol) in anhydrous dimethyl sulfoxide (5 ml) was added potassium carbonate (0.14 g, 1.0 mmol) and the reaction mixture was heated at 80 °C for 18 h. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (50 ml). The mixture was washed with saturated ammonium chloride (2 x 150 ml), brine (30 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative reverse phase HPLC eluting with a gradient of 10 to 50% acetonitrile in water (containing 0.1% trifluoroacetic acid) provided the title compound as a colorless solid ( 0.10 g, 39% yield): 1H NMR (300 MHz, CD3OD) δ 8.02 (d, J = 7.4 Hz, 1H), 7.78 (dd, J = 8.1, 8, 1 Hz, 1H), 7.48 to 7.43 (m, 5H), 7.13 to 7.05 (m, 1H), 6.94 (dd, J = 7.9, 2.0 Hz, 1H ), 6.63 (dd, J = 8.1, 2.6 Hz, 1H), 4.57 to 4.28 (m, 2H), 3.89 to 3.44 (m, 2H), 3, 15 to 3.03 (m, 2H), 2.85 to 2.74 (m, 3H), 2.31 to 2.09 (m, 2H), 1.74 (d, J = 6.8 Hz, 3H), NH and COOH not observed; MS (ES+) m/z 507.1 (M + 1), 509.1 (M + 1). EXAMPLE 46

[0952] Synthesis of 4-((1-benzylpiperidin-4-yl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0953]Step 1. Preparation of 4-((1-benzylpiperidin-4-yl)amino)-3-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5- il)benzenesulfonamide

[0954] To a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.20 g, 0.45 mmol) and 1-benzylpiperidin-4-amine (0.09 ml, 0.45 mmol) in anhydrous dimethyl sulfoxide (1.8 ml) was added potassium carbonate (0.149 g, 1.1 mmol) and the mixture of reaction was stirred at room temperature for 17 h. The mixture was diluted with ethyl acetate (5 ml) and water (5 ml) and the aqueous phase was extracted with ethyl acetate (2 x 5 ml). The combined organic extracts were washed with brine (2 x 5 ml), dried with anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 30 to 50% ethyl acetate in hexanes followed by 5% methanol in dichloromethane provided the title compound as a colorless oil (0.158 g, 57% yield). : 1H NMR (300 MHz, CDCl3) δ8.13 (s, 1H), 7.57 to 7.50 (m, 2H), 7.38 to 7.25 (m, 5H), 7.03 (d, J = 9.1 Hz, 1H), 6.53 (d, J = 8.5 Hz, 1H), 6.36 to 6.29 (m, 2H), 5.18 (s, 2H), 4, 83 (d, J = 7.7 Hz, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.53 (s, 2H), 3.45 to 3.29 (m , 1H), 2.90 to 2.78 (m, 2H), 2.25 to 2.11 (m, 2H), 2.05 to 1.94 (m, 2H), 1.65 to 1.50 (m, 2H); MS (ES+) m/z 614.2 (M + 1), 616.2 (M + 1).

[0955] Step 2. Preparation of 4-((1-benzylpiperidin-4-yl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl) 2,2,2-trifluoroacetate benzenesulfonamide

[0956] To a solution of 4-((1-benzylpiperidin-4-yl)amino)-3-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl )benzenesulfonamide (0.158 g, 0.26 mmol) in dichloromethane (4 ml) trifluoroacetic acid (0.5 ml, 7 mmol) was added and the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated in vacuo and methanol (4 ml) was added to the residue. The resulting mixture was filtered and the filtrate was concentrated in vacuo to provide the title compound as a colorless solid (0.100 g, 68% yield): 1H NMR (300 MHz, DMSO-d6) δ 9.68 (br s, 1H), 8.45 (s, 1H), 7.69 to 7.43 (m, 7H), 6.93 (d, J = 8.9 Hz, 1H), 6.02 (d, J = 7 .6 Hz, 1H), 4.31 (s, 2H), 3.63 (br s, 1H), 3.44 (d, J = 11.7 Hz, 2H), 3.13 to 2.95 ( m, 2H), 2.15 to 2.01 (m, 2H), 1.87 to 1.67 (m, 2H), NH not observed; MS (ES+) m/z 464.0 (M + 1), 466.0 (M + 1). EXAMPLE 47

[0957] Synthesis of 4-((1-benzylpiperidin-4-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0958] To a solution of 1-benzylpiperidin-4-ol (0.21 g, 1.09 mmol) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazole -2-yl)benzenesulfonamide (0.50 g, 1.09 mmol) in dimethyl sulfoxide (4.4 ml) was added cesium carbonate (0.86 g, 2.64 mmol) and the reaction mixture was stirred at room temperature for 17 h. The mixture was diluted with ethyl acetate (10 ml) and water (10 ml), and the aqueous phase was extracted with ethyl acetate (2 x 10 ml). The combined organic extracts were washed with brine (2 x 10 ml), dried with anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane (12 ml) and trifluoroacetic acid (2.0 ml, 26 mmol) was added thereto. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated in vacuo. The residue was triturated in methanol (7 ml) and the suspension obtained was filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with 0 to 10% methanol in dichloromethane gave the title compound as a colorless solid (0.27 g, 41% yield). 1H NMR (300 MHz, DMSO-d6) δ 12.86 (br s, 1H), 10.13 (br s, 1H), 7.77 (d, J = 7.1 Hz, 1H), 7.59 at 7.38 (m, 6H), 7.32 (d, J = 3.7 Hz, 1H), 6.89 (d, J = 3.7 Hz, 1H), 4.86 (br s, 1H ), 4.37 (s, 2H), 3.19 (br s, 4H), 2.09 (br s, 4H); MS (ES+) m/z 482.0 (M + 1), 484.0 (M + 1). EXAMPLE 48

[0959] Synthesis of 3-chloro-4-((1-(4-methoxybenzyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[0960] Following the procedure as described in Example 22, and making non-critical variations as necessary to replace 4-fluorobenzaldehyde with 4-methoxybenzaldehyde, and purification by column chromatography, eluting with 0 to 20% methanol, the title compound was obtained as a colorless solid (0.122 g, 40% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.01 (br s, 1H), 7.74 (d, J = 2.3 Hz, 1H ), 7.71 to 7.65 (m, 1H), 7.37 to 7.24 (m, 4H), 6.94 (s, 1H), 6.91 (s, 1H), 6.83 ( d, J = 4.6 Hz, 1H), 4.74 to 4.64 (m, 1H), 3.74 (s, 3H), 3.70 (s, 2H), 2.87 to 2.71 (m, 2H), 2.63 to 2.52 (m, 2H), 2.07 to 1.92 (m, 2H), 1.85 to 1.69 (m, 2H); MS (ES+) m/z 494.0 (M + 1), 496.0 (M + 1). EXAMPLE 49

[0961] Synthesis of 3-chloro-4-((1-(2,3-dihydro-1H-inden-1-yl)piperidin-4-yl)oxy)-N 2,2,2-trifluoroacetate -(thiazol-2-yl)benzenesulfonamide

[0962]Step 1. Preparation of 1-(2,3-dihydro-1H-inden-1-yl)piperidin-4-ol

[0963]A mixture of piperidin-4-ol (1.00 g, 9.90 mmol) and 2,3-dihydro-1H-inden-1-one (0.65 g, 4.9 mmol) In anhydrous tetrahydrofuran (40 ml) titanium(IV) isopropoxide (4.35 ml, 14.85 mmol) was added and the reaction mixture was heated to reflux for 4 h. The reaction mixture was allowed to cool to room temperature, sodium triacetoxyborohydride (4.20 g, 19.80 mmol) was added thereto, and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched by adding 2.0 M sodium hydroxide (20 ml) and filtered. The filtrate was diluted with ethyl acetate (100 ml), washed with brine (3 x 60 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0-20% methanol (containing 0.2% ammonium hydroxide) in dichloromethane provided the title compound as a clear oil (0 .99 g, 93% yield). 1H NMR (300 MHz, CDCla) δ 7.43 to 7.37 (m, 1H), 7.24 to 7.20 (m, 3H), 4.44 to 4.38 (m, 1H), 3, 74 to 3.67 (m, 1H), 2.99 to 2.78 (m, 3H), 2.72 to 2.66 (m, 1H), 2.41 to 2.33 (m, 2H), 2.16 to 2.07 (m, 2H), 1.98 to 1.91 (m, 2H), 1.69 to 1.55 (m, 3H); MS (ES+) m/z 218.2 (M + 1).

[0964]Step 2. Preparation of 3-chloro-4-((1-(2,3-dihydro-1H-inden-1-yl)piperidin-4-yl)oxy 2,2,2-trifluoroacetate )-N-(thiazol-2-yl)benzenesulfonamide

[0965]A mixture of 1-(2,3-dihydro-1H-inden-1-yl)piperidin-4-ol (0.33 g, 1.50 mmol) and 3-chloro-N-( 2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide (0.44 g, 1.00 mmol) in anhydrous dimethyl sulfoxide (6 ml) was added cesium carbonate (0.49 g, 1.50 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (80 ml), washed with brine (2 x 60 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue, which was dissolved in dichloromethane (20 ml). To this mixture was added trifluoroacetic acid (5 ml) and the reaction mixture was stirred at room temperature for 40 minutes. The mixture was concentrated in vacuo and the residue suspended in methanol (10 ml). Filtration and concentration of the filtrate provided a residue. The residue was purified by preparative reverse phase HPLC eluting with a gradient of 10 to 50% acetonitrile in water containing 0.1% trifluoroacetic acid to give the title compound as a colorless solid (0.04 g, 14% yield): 1H NMR (300 MHz, CD3OD) δ 7.82 (d, J = 2.1 Hz, 1H), 7.78 to 7.70 (m, 1H), 7.62 to 7.56 (m , 1H), 7.47 to 7.30 (m, 3H), 7.23 (d, J = 8.9 Hz, 1H), 7.08 (d, J = 4.6 Hz, 1H), 6 .70 (d, J = 4.6 Hz, 1H), 5.03 to 4.93 (m, 2H), 3.62 to 3.44 (m, 1H), 3.39 to 3.31 (m , 1H), 3.26 to 3.12 (m, 2H), 3.09 to 2.94 (m, 2H), 2.68 to 2.32 (m, 3H), 2.29 to 2.03 (m, 3H), NH and COOH not observed; MS (ES+) m/z 490.0 (M + 1), 492.0 (M + 1). EXAMPLE 50

[0966] Synthesis of 4-((1-benzylazetidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0967]Step 1. Preparation of 3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenyl)amino)azetidine-1-tert carboxylate -butyl

[0968] Following the procedure as described in Example 25, Step 1 and making non-critical variations as necessary to replace 3-amino-3-methyl-N-benzylazetidine with 3-aminoazetidine-1-tert-butyl carboxylate, the title compound was obtained as a colorless foam (1.3 g, 75% yield): 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 8.7, 2.1 Hz, 1H), 7.42 (d, J = 3.6 Hz, 1H), 7.19 to 7.16 (m, 1H), 7.02 (d, J = 3.6 Hz, 1H), 6.39 to 6.36 (m, 3H), 5.12 to 5.10 (m, 1H), 5.06 (s, 2H), 4.40 to 4.34 (m, 2H), 4.29 to 4.25 (m, 1H), 3.85 to 3.79 (m, 2H), 3.78 (s, 3H), 3.75 (s, 3H), 1.47 (s, 9H).

[0969] Step 2. Preparation of 4-((1-benzylazetidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0970] To a solution of 3-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenyl)amino-azetidine-1-tert-butyl carboxylate (0.30 g, 0.504 mmol) in dichloromethane (6 ml) trifluoroacetic acid (3 ml) was added and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and the residue was triturated in methanol (5 ml), and the suspension was obtained. The filtrate was concentrated in vacuo to provide an oil which was dissolved in tetrahydrofuran (2 ml). To this solution were added benzaldehyde (0.040 ml, 0.39 mmol) and sodium triacetoxyborohydride (0.105 g, 0.498 mmol). The reaction mixture was stirred at room temperature for 17 h and was then quenched by the addition of water (5 ml). The mixture was extracted with ethyl acetate (2 x 5 ml). The combined organic phase was washed with brine (5 ml), dried over anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative reverse phase HPLC eluting with a gradient of 20 to 80% acetonitrile in water containing 0.1% trifluoroacetic acid provided the title compound as a colorless solid (0.014 g , 5% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.68 (br s, 1H), 10.28 (br s, 1H), 7.65 (d, J = 2.1 Hz , 1H), 7.59 to 7.52 (m, 1H), 7.52 to 7.42 (m, 4H), 7.26 (d, J = 4.6 Hz, 1H), 6.85 to 6.79 (m, 1H), 6.79 to 6.61 (m, 2H), 4.72 to 4.30 (m, 5H), 4.29 to 4.11 (m, 2H), 3, 70 to 3.35 (m, 1H); MS (ES+) m/z 435.1 (M + 1), 437.1 (M + 1). EXAMPLE 51

[0971] Synthesis of 3-chloro-4-((1-(naphthalen-2-ylmethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[0972] Following the procedure as described in EXAMPLE 22 and making non-critical variations as necessary to replace 4-fluorobenzaldehyde with 2-naphthaldehyde, the title compound was obtained as a colorless solid (0.177 g, 46% yield): 1H NMR (300 MHz, CDCI3) δ 8.73 (br s, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.86 to 7.68 (m, 5H), 7.55 to 7.42 (m, 3H), 7.13 (d, J = 4.6 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 6.51 (d, J = 4 .6 Hz, 1H), 4.55 (s, 1H), 3.83 (s, 2H), 2.90 to 2.76 (m, 2H), 2.63 (br s, 2H), 2, 18-2.02 (m, 2H), 2.01-1.87 (m, 2H), NH not observed; MS (ES+) m/z 514.0 (M + 1)., 516.0 (M + 1). EXAMPLE 52

[0973] Synthesis of 3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[0974]Step 1. Preparation of 1-(1-phenylethyl)piperidin-4-ol

[0975] To a solution of piperidin-4-ol (1.0 g, 10 mmol) and acetophenone (0.78 ml, 6.7 mmol) in dichloromethane (2 ml) was added titanium(IV) isopropoxide (2 .8 ml, 9.4 mmol). The reaction mixture was heated to 45 °C for 17 h and then 1 M solution of sodium cyanoborohydride in tetrahydrofuran (14.7 ml, 14.7 mmol) was added thereto. The reaction mixture was stirred at 45 °C for a further 3 h, allowed to cool to room temperature, and quenched with water (250 ml). The resulting mixture was filtered and the filtrate extracted with dichloromethane (3 x 50 ml). The combined organic phase was washed with brine (50 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification of the residue by column chromatography, eluting with 0 to 15% methanol (containing 2% ammonium hydroxide) in dichloromethane gave the title compound as a yellow oil (0.710 g, 35% yield): 1H NMR ( 300 MHz, CDCla) δ 7.31 (s, 5H), 3.72 to 3.57 (m, 1H), 3.55 to 3.41 (m, 1H), 2.95 to 2.81 (m , 1H), 2.80 to 2.65 (m, 1H), 2.27 to 2.09 (m, 2H), 2.05 (br s, 1H), 2.00 to 1.81 (m, 2H), 1.69 to 1.47 (m, 2H), 1.41 (d, J = 6.1 Hz, 3H); MS (ES+) m/z 206.2 (M + 1).

[0976]Step 2. Preparation of 3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[0977] To a solution of 1-(1-phenylethyl)piperidin-4-ol (0.133 g, 0.650 mmol) and 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol- 2-yl)benzenesulfonamide (0.288 g, 0.650 mmol) in dimethyl sulfoxide (2.6 ml) was added cesium carbonate (0.509 g, 1.56 mmol) and the reaction mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with ethyl acetate (5 ml) and water (5 ml) and the aqueous phase was extracted with ethyl acetate (2 x 5 ml). The combined organic phase was washed with brine (2 x 5 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane (7 ml) and trifluoroacetic acid (0.18 ml, 2.3 mmol) was added thereto at 0°C. The reaction mixture was stirred for 20 minutes at 0 °C and then concentrated in vacuo. The residue was triturated in methanol (7 ml) and the resulting mixture was filtered. Concentration of the filtrate in vacuo and purification by preparative reverse phase HPLC eluting with a gradient of 20 to 80% acetonitrile in water containing 0.1% trifluoroacetic acid yielded the title compound as a colorless solid (0.011 g, 4 % yield): 1H NMR (300 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.61 (dd, J = 2 .2, 8.6 Hz, 1H), 7.33 to 7.29 (m, 4H), 7.24 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 4, 3 Hz, 1H), 6.65 (d, J = 4.3 Hz, 1H), 4.57 to 4.45 (m, 1H), 3.51 (q, J = 6.8 Hz, 1H) , 2.75 to 2.55 (m, 2H), 2.32 to 2.18 (m, 2H), 1.96 to 1.83 (m, 2H), 1.71 to 1.56 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H), NH not observed; MS (ES+) m/z 478.1 (M + 1), 480.1 (M + 1). EXAMPLE 53

[0978] Synthesis of 4-((1-benzylpiperidin-4-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide

[0979] Following the procedure as described in EXAMPLE 47 and making non-critical variations as necessary to replace 1-benzylpiperidin-4-ol with 1-benzyl-N-methylpiperidin-4-amine, the title compound was obtained as a colorless solid (0.077 g, 24% yield): 1H NMR (300 MHz, DMSO-d6) δ 7.69 (d, J = 7.4 Hz, 1H), 7.40 to 7.31 (m, 5H), 7.29 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 12.2 Hz, 1H), 6.86 (d, J = 4.6 Hz, 1H), 3, 70 (s, 2H), 3.47 to 3.32 (m, 1H), 3.00 (d, J = 11.5 Hz, 2H), 2.67 (s, 3H), 2.28 (t , J = 11.1 Hz, 2H), 1.95 to 1.74 (m, 2H), 1.74 to 1.60 (m, 2H), NH not observed; MS (ES+) m/z 495.1 (M + 1)., 497.1 (M + 1). EXAMPLE 54

[0980] Synthesis of 5-chloro-2-fluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[0981] Following the procedure as described in EXAMPLE 52, Step 2, and making non-critical variations as necessary to replace 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl )benzenesulfonamide by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide, the title compound was obtained as a colorless solid (0.017 g, 5% yield): 1H NMR (300 MHz, DMSO-d6) δ8.14 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.35 to 7.19 (m, 6H ), 6.77 (d, J = 4.5 Hz, 1H), 4.63 to 4.52 (m, 1H), 3.55 (q, J = 6.6 Hz, 1H), 2.75 to 2.56 (m, 2H), 2.38 to 2.20 (m, 2H), 1.97 to 1.84 (m, 2H), 1.73 to 1.56 (m, 2H), 1 .31 (d, J = 6.8 Hz, 3H), NH not observed; MS (ES+) m/z 496.1 (M + 1), 498.1 (M + 1). EXAMPLE 55

[0982] Synthesis of (R)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl) 2,2,2-trifluoroacetate benzenesulfonamide

[0983]Step 1. Preparation of 1-ethyl-1-methyl-4-oxopiperidin-1-ium iodide

[0984] To a solution of 1-methylpiperidin-4-one (13.8 ml, 120 mmol) in butan-2-one (70 ml) was added iodoethane (10.6 ml, 132 mmol) and the reaction mixture was stirred at room temperature for 4 d. The mixture was filtered and the resulting solid was dried in vacuo to give the title compound as an orange solid (27.8 g, 86% yield): 1H NMR (300 MHz, D2O) δ 3.52 to 3.38 (m, 6H), 3.05 (s, 3H), 2.17 to 1.99 (m, 4H), 1.34 (t, J = 7.3 Hz, 3H); MS (ES+) m/z 142.2 (M + 1).

[0985]Step 2. Preparation of (R)-1-(1-phenylethyl)piperidin-4-one

[0986] To a hot mixture of (R)-1-phenylethan-1-amine (0.7 ml, 6 mmol) and potassium carbonate (0.05 g, 0.37 mmol) in ethanol (6 ml) added A solution of 1-ethyl-1-methyl-4-oxopiperidin-1-ium iodide (1.0 g, 3.7 mmol) in water (2.6 ml) was added and the reaction mixture was heated to reflux for 1.5 h. The reaction mixture was allowed to cool to room temperature and was then diluted in water (6 ml) and ethyl acetate (15 ml). The aqueous phase was extracted with ethyl acetate (2 x 10 ml). The combined organic phase was washed with water (2 x 10 ml), brine (10 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography, eluting with a gradient of 0 to 80% ethyl acetate (containing 10% isopropanol and 10% triethylamine) in hexanes, to give the title compound as an oil (0.583 g, 77% yield): 1H NMR (300 MHz, CDCla) δ 7.41 to 7.18 (m, 5H), 3.62 (q, J = 6.8 Hz, 1H), 2.84 to 2.65 (m, 4H), 2.42 (t, J = 6.0 Hz, 4H), 1.42 (d, J = 6.8 Hz, 3H); MS (ES+) m/z 204.3 (M + 1).

[0987]Step 3. Preparation of (R)-1-(1-phenylethyl)piperidin-4-ol

[0988] To a solution of (R)-1-(1-phenylethyl)piperidin-4-one (0.55 g, 2.71 mmol) in ethanol (27 ml) was added sodium borohydride (0.21 g, 5.42 mmol) and the reaction mixture was stirred at room temperature for 17 h. The reaction mixture was concentrated in vacuo, saturated ammonium chloride (5 ml) was slowly added to the residue, and the obtained mixture was extracted with ethyl acetate (3 x 5 ml). The combined organic phase was washed with brine (5 ml), dried over anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo gave the title compound as a yellow oil (0.51 g, 91% yield): 1H NMR (300 MHz, CDCl3) δ 7.37 to 7.20 (m, 5H), 3 .73 to 3.57 (m, 1H), 3.47 (q, J = 6.8 Hz, 1H), 2.94 to 2.82 (m, 1H), 2.79 to 2.67 (m , 1H), 2.24 to 2.07 (m, 2H), 1.99 to 1.82 (m, 2H), 1.70 to 1.47 (m, 2H), 1.41 (d, J = 6.8 Hz, 3H), OH not observed; MS (ES+) m/z 206.3 (M + 1).

[0989]Step 4. Preparation of (R)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-2)-2,2,2-trifluoroacetate -yl)benzenesulfonamide

[0990] Following the procedure as described in EXAMPLE 52, Step 2, and making non-critical variations as necessary to replace 1-(1-phenylethyl)piperidin-4-ol with (R)-1-(1-phenylethyl)piperidin- 4-ol, the title compound was obtained as a colorless solid (0.046 g, 12% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.86 (br s, 1H), 7.74 to 7 .63 (m, 2H), 7.46 to 7.30 (m, 6H), 7.27 (d, J = 4.6 Hz, 1H), 6.84 (d, J = 4.6 Hz, 1H), 4.77 to 4.64 (m, 1H), 4.17 to 3.97 (m, 1H), 2.98 to 2.61 (m, 4H), 2.11 to 1.94 ( m, 2H), 1.90 to 1.72 (m, 2H), 1.49 (d, J = 6.7 Hz, 3H), an exchangeable proton not observed; 19F NMR (282 MHz, DMSO-d6) δ -77.4; MS (ES+) m/z 478.0 (M + 1), 480.0 (M + 1). EXAMPLE 56

[0991] Synthesis of (R)-5-chloro-2-fluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-)2,2,2-trifluoroacetate 2-yl)benzenesulfonamide

[0992]Step 1. Preparation of (R)-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)- N-(thiazol-2-yl)benzenesulfonamide

[0993] To a solution of -1-(1-phenylethyl)piperidin-4-ol (0.13 g, 0.65 mmol) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4- difluoro-N-(thiazol-2-yl)benzenesulfonamide (0.30 g, 0.65 mmol) in anhydrous dimethyl sulfoxide (3 ml) was added cesium carbonate (0.51 g, 1.6 mmol) and to Reaction mixture was stirred at room temperature for 17 h. The mixture was diluted with ethyl acetate (5 ml) and water (5 ml) and the aqueous phase was extracted with ethyl acetate (2 x 5 ml). The combined organic phase was washed with brine (5 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography, eluting with 0 to 95% ethyl acetate in hexanes to give the title compound as a yellow oil (0.065 g, 15% yield): MS (ES+) m/z 646, 1 (M + 1), 648.1 (M + 1).

[0994]Step 2. Preparation of (R)-5-chloro-2-fluoro-4- ((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-2,2,2-trifluoroacetate (thiazol-2-yl)benzenesulfonamide

[0995]A mixture of (R)-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N -(thiazol-2-yl)benzenesulfonamide in dichloromethane (2 ml) was added trifluoroacetic acid (0.02 ml, 0.30 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes and then concentrated in vacuo. To the residue, methanol (5 ml) was added and the mixture was filtered. Concentration of the filtrate in vacuo gave the title compound as a colorless solid (0.043 g, 88% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.97 (br s, 1H), 9.79 ( br s, 1H), 7.81 to 7.66 (m, 1H), 7.62 to 7.35 (m, 6H), 7.31 (d, J = 4.6 Hz, 1H), 6, 88 (d, J = 4.6 Hz, 1H), 5.04 to 4.88 (m, 1H), 4.74 to 4.59 (m, 1H), 3.79 to 3.63 (m, 2H), 3.57 to 3.39 (m, 2H), 2.99 to 2.69 (m, 2H), 2.16 to 1.95 (m, 2H), 1.68 (d, J = 6.9Hz, 3H); MS (ES+) m/z 496.1 (M + 1), 498.1 (M + 1). EXAMPLE 57

[0996] Synthesis of (R)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl) 2,2,2-trifluoroacetate benzenesulfonamide

[0997]Step 1. Preparation of tert-butyl ((3-chloro-4-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate

[0998] To a solution of tert-butyl thiazol-4-ylcarbamate (30.0 g, 150 mmol) in anhydrous tetrahydrofuran (400 ml) was added lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofurans, 210. 0 ml, 210.0 mmol) at -78 °C. The reaction mixture was heated to 0 °C, stirred for 1 h, and cooled to -78 °C. To it was then added dropwise a solution of 3-chloro-4-fluorobenzenesulfonyl chloride (51.5 g, 225.0 mmol) in anhydrous tetrahydrofuran (100 ml) at -78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was then diluted with water (500 ml) and extracted with ethyl acetate (3 x 400 ml). The combined organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and trituration of the residue with methanol (2 x 200 ml) gave the title compound as a colorless solid (47.0 g, 80% yield): 1H NMR (400 MHz, CDCla) δ8, 83 (d, J = 2.0 Hz, 1 H), 8.28 (dd, J = 6.4, 2.0 Hz, 1 H), 8.13 to 8.08 (m, 1 H), 7.57 (d, J = 2.0 Hz, 1 H), 7.35 (t, J = 8.4 Hz, 1 H), 1.38 (s, 9 H); MS (ES+) m/z 415.0 (M +23), 417.0 (M + 23).

[0999]Step 2. Preparation of 3-chloro-4-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01000] To a solution of ((3-chloro-4-fluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate (1.0 g, 2.5 mmol) in dichloromethane (5 ml) was added acid trifluoroacetic acid (1.0 ml, 13 mmol) and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo and the residue was triturated in diethyl ether (5 ml) to provide a colorless solid (0.55 g, 74% yield): 1H NMR (300 MHz, DMSO-d6) δ 11, 22 (s, 1H), 8.91 (d, J = 2.2 Hz, 1H), 8.01 (dd, J = 2.2, 6.8 Hz, 1H), 7.87 to 7.80 (m, 1H), 7.64 (t, J = 8.9 Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H); MS (ES-) m/z 291.1 (M - 1), 293.0 (M - 1).

[01001]Step 3. Preparation of (R)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4)-2,2,2-trifluoroacetate -yl)benzenesulfonamide

[01002]A mixture of 3-chloro-4-fluoro-N-(thiazol-4-yl)benzenesulfonamide (0.06 g, 0.21 mmol) in anhydrous dimethyl sulfoxide (1.2 ml) and (R )-1-(1-phenylethyl)piperidin-4-ol (0.06 g, 0.30 mmol) was added cesium carbonate (0.51 g, 1.56 mmol) and a dispersion of sodium hydride at 60 % in mineral oil (0.025 g, 0.63 mmol). The reaction mixture was stirred at room temperature for 2 h and then quenched by addition of water (5 ml) and saturated ammonium chloride (5 ml). The mixture was extracted with ethyl acetate (3 x 5 ml) and the organic phase was washed with brine (5 ml), dried over anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative reverse phase HPLC eluting with a gradient of 12 to 54% acetonitrile in water containing 0.1% trifluoroacetic acid yielded the title compound as a colorless solid (0.030 g , 17% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.93 to 9.64 (m, 1H), 8.88 (s, 1H), 7 .86 to 7.76 (m, 1H), 7.75 to 7.65 (m, 1H), 7.59 to 7.45 (m, 5H), 7.44 to 7.31 (m, 1H) , 7.11 to 7.05 (m, 1H), 4.98 (s, 1H), 4.75 to 4.57 (m, 1H), 3.56 to 3.24 (m, 2H), 2 .99 to 2.69 (m, 2H), 2.34 to 2.18 (m, 1H), 2.14 to 1.96 (m, 2H), 1.93 to 1.74 (m, 1H) , 1.68 (d, J = 6.8 Hz, 3H); MS (ES+) m/z 478.1 (M + 1), 480.1 (M + 1). EXAMPLE 58

[01003] Synthesis of (S)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl) 2,2,2-trifluoroacetate benzenesulfonamide

[01004]Step 1. Preparation of (S)-1-(1-phenylethyl)piperidin-4-one

[01005] Following the procedure as described in EXAMPLE 55, Step 2 and making non-critical variations as necessary to replace (R)-1-phenylethan-1-amine with (S)-1-phenylethan-1-amine, the compound of title was obtained as a yellow oil (1.17 g, 78% yield): 1H NMR (300 MHz, CDCl3) δ 7.38 to 7.21 (m, 5H), 3.62 (q, J = 6 .8 Hz, 1H), 2.84 to 2.64 (m, 4H), 2.41 (t, J = 6.0 Hz, 4H), 1.41 (d, J = 6.8 Hz, 3H ); MS (ES+) m/z 204.3 (M + 1).

[01006]Step 2. Preparation of (S)-1-(1-phenylethyl)piperidin-4-ol

[01007] Following the procedure as described in EXAMPLE 55, Step 3, and making non-critical variations as necessary to replace (R)-1-(1-phenylethyl)piperidin-4-one with (S)-1-(1- phenylethyl)piperidin-4-one, the title compound was obtained as a yellow oil (1.15 g, 97% yield): 1H NMR (300 MHz, CDCl3) δ 7.38 to 7.17 (m, 5H ), 3.69 to 3.55 (m, 1H), 3.43 (q, J = 6.8 Hz, 1H), 2.93 to 2.80 (m, 1H), 2.76 to 2, 64 (m, 1H), 2.19 to 2.04 (m, 2H), 1.95 to 1.78 (m, 2H), 1.67 to 1.45 (m, 2H), 1.38 ( d, J = 6.8 Hz, 3H), OH not observed; MS (ES+) m/z 206.3 (M + 1).

[01008]Step 3. Preparation of (S)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-2)-2,2,2-trifluoroacetate -yl)benzenesulfonamide

[01009] To a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide (0.300 g, 0.676 mmol) and (S)-1-( 1-phenylethyl)piperidin-4-ol (0.137 g, 0.668 mmol) in N,N-dimethylformamide (6.5 ml) was added 60% sodium hydride in mineral oil (0.052 g, 1.3 mmol) and to reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with the slow addition of saturated ammonium chloride (5 ml) and extracted with ethyl acetate (3 x 5 ml). The combined organic phase was washed with brine (5 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue obtained was dissolved in dichloromethane (4 ml) and trifluoroacetic acid (0.6 ml, 6 mmol) was added thereto. The reaction mixture was stirred at room temperature for 10 minutes, concentrated in vacuo, and methanol was added to the residue. The mixture was filtered and the filtrate was concentrated in vacuo. Purification of the residue by preparative reverse phase HPLC eluting with a gradient of 20 to 85% acetonitrile in water containing 0.1% trifluoroacetic acid afforded the title compound as a colorless solid (0.05 g, 13% yield ): 1H NMR (300 MHz, DMSO-d6) δ 12.81 (br s, 1H), 10.03 to 9.56 (m, 1H), 7.78 to 7.64 (m, 2H), 7 .60 to 7.44 (m, 5H), 7.42 to 7.31 (m, 1H), 7.28 (d, J = 4.6 Hz, 1H), 6.85 (d, J = 4 .6 Hz, 1H), 5.04 to 4.87 (m, 1H), 4.77 to 4.55 (m, 1H), 3.58 to 3.25 (m, 2H), 3.01 to 2.67 (m, 2H), 2.37 to 2.16 (m, 1H), 2.15 to 1.95 (m, 3H), 1.68 (d, J = 6.9 Hz, 3H) ; MS (ES+) m/z 478.0 (M + 1), 480.0 (M + 1). EXAMPLE 59

[01010] Synthesis of 3-chloro-4-((1-(2-phenylpropan-2-ill)piperidin-4-yl)oxy)-N-(thiazol-2-yl) 2,2,2-trifluoroacetate benzenesulfonamide

[01011]Step 1. Preparation of 1-(2-phenylpropan-2-yl)piperidin-4-one

[01012] Following the procedure as described in EXAMPLE 55, Step 2 and making non-critical variations as necessary to replace (R)-1-phenylethan-1-amine with 2-phenylpropan-2-amine, the title compound was obtained as a yellow oil (0.56 g, 70% yield): 1H NMR (300 MHz, CDCI3) δ 7.63 to 7.54 (m, 2H), 7.38 to 7.20 (m, 3H), 2.77 (t, J = 5.9 Hz, 4H), 2.41 (t, J = 6.0 Hz, 4H), 1.40 (s, 6H); MS (ES+) m/z 218.3 (M + 1).

[01013]Step 2. Preparation of 1-(2-phenylpropan-2-yl)piperidin-4-ol

[01014] Following the procedure as described in EXAMPLE 55, Step 3, and making non-critical variations as necessary to replace (R)-1-(1-phenylethyl)piperidin-4-one with 1-(-2-phenylpropan-2 -yl)piperidin-4-one, the title compound was obtained as a yellow oil (0.50 g, 88% yield): 1H NMR (300 MHz, CDCl3) δ 7.63 to 7.46 (m, 2H), 7.36 to 7.26 (m, 2H), 7.25 to 7.16 (m, 1H), 3.78 to 3.56 (m, 1H), 2.87 to 2.63 ( m, 2H), 2.32 to 2.10 (m, 2H), 1.96 to 1.77 (m, 2H), 1.62 to 1.43 (m, 2H), 1.35 (s, 6H), OH not observed; MS (ES+) m/z 220.3 (M + 1).

[01015]Step 3. Preparation of 3-chloro-4-((1-(2-phenylpropan-2-yl)piperidin-4-yl)oxy)-N-(thiazol-2)-2,2,2-trifluoroacetate -yl)benzenesulfonamide

[01016] Following the procedure as described in EXAMPLE 52, Step 2, and making non-critical variations as necessary to replace 1-(1-phenylethyl)piperidin-4-ol with 1-(2-phenylpropan-2-yl)piperidin- 4-ol, the title compound was obtained as a colorless solid (0.116 g, 28% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.80 (br s, 1H), 9.40 (br s, 1H), 7.74 to 7.65 (m, 4H), 7.56 to 7.44 (m, 3H), 7.39 to 7.30 (m, 1H), 7.28 (d, J = 4.6 Hz, 1H), 6.85 (d, J = 4.6 Hz, 1H), 5.03 to 4.92 (m, 1H), 3.51 to 3.28 (m, 2H ), 3.00 to 2.73 (m, 2H), 2.32 to 2.17 (m, 1H), 2.13 to 1.97 (m, 3H), 1.82 (s, 6H); MS (ES+) m/z 492.1 (M + 1), 494.1 (M + 1). EXAMPLE 60

[01017] Synthesis of 5-chloro-2-fluoro-4-((1-(2-phenylpropan-2-yl)piperidin-4-yl)oxy)-N-(thiazol-) 2,2,2-trifluoroacetate 2-yl)benzenesulfonamide

[01018]Step 1. Preparation of 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-((1- (2-phenylpropan-2-yl)piperidin-4-yl)oxy)- N-(thiazol-2-yl)benzenesulfonamide

[01019] To a solution of 1-(-2-phenylpropan-2-yl)piperidin-4-ol (0.14 g, 0.65 mmol) and 5-chloro-N-(2,4-dimethoxybenzyl)- 2,4-Difluoro-N-(thiazol-2-yl)benzenesulfonamide (0.30 g, 0.65 mmol) in anhydrous dimethyl sulfoxide (3 ml) was added cesium carbonate (0.51 g, 1.6 mmol) and the reaction mixture was stirred at room temperature for 17 h. The mixture was diluted with ethyl acetate (5 ml) and water (5 ml) and the aqueous phase was extracted with ethyl acetate (2 x 5 ml). The combined organic phase was washed with brine (5 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography, eluting with 0 to 90% ethyl acetate in hexanes to give the title compound as a yellow oil (0.174 g, 40% yield): MS (ES+) m/z 660, 2 (M + 1), 662.1 (M + 1).

[01020]Step 2. Preparation of 5-chloro-2-fluoro-4-((1-(2-phenylpropan-2-ill)piperidin-4-yl)oxy)-N-2,2,2-trifluoroacetate (thiazol-2-yl)benzenesulfonamide

[01021]A mixture of 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-((1-(2-phenylpropan-2-yl)piperidin-4-yl)oxy)-N -(thiazol-2-yl)benzenesulfonamide in dichloromethane (5 ml) trifluoroacetic acid (0.26 ml, 3.4 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes and then concentrated in vacuo. To the residue, methanol (5 ml) was added and the mixture was filtered. Concentration of the filtrate in vacuo provided a residue which was purified by preparative reverse phase HPLC eluting with a gradient of 20 to 80% acetonitrile in water containing 0.1% trifluoroacetic acid to yield the title compound as a colorless solid ( 0.053 g, 40% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.96 (s, 1H), 9.48 to 9.31 (m, 1H), 7.80 to 7.65 ( m, 3H), 7.57 to 7.45 (m, 3H), 7.45 to 7.35 (m, 1H), 7.32 (d, J = 4.6 Hz, 1H), 6.89 (d, J = 4.6 Hz, 1H), 5.02 to 4.91 (m, 1H), 3.56 to 3.43 (m, 1H), 3.41 to 3.28 (m, 1H ), 2.94 to 2.73 (m, 2H), 2.32 to 2.18 (m, 1H), 2.14 to 1.97 (m, 3H), 1.83 (s, 6H); MS (ES+) m/z 510.1 (M + 1), 512.1 (M + 1). EXAMPLE 61

[01022] Synthesis of 4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[01023]Step 1. Preparation of 4-bromo-3-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide

[01024] Following the procedure as described in EXAMPLE 1, Step 1 and making non-critical variations as necessary to replace 3-chloro-4-fluorobenzenesulfonyl chloride with 4-bromo-3-chlorobenzenesulfonyl chloride, and purification by column chromatography, eluting with 20% ethyl acetate in hexanes, the title compound was obtained as a colorless solid (0.50 g, 50% yield): 1H NMR (400 MHz, CDCI3) δ7.84 (d, J = 2 .0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.56 (dd, J = 8.0, 2.0 Hz, 1H), 7.48 (d, J = 4.0 Hz, 1H), 7.16 to 7.14 (m, 1H), 7.09 (d, J =4.0 Hz, 1H), 6.39 to 6.36 (m, 2H) , 5.07 (s, 2H), 3.79 (s, 3H), 3.71 (s, 3H).

[01025]Step 2. Preparation of 4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl) benzenesulfonamide

[01026]A mixture of 1-benzyl-3-methylpyrrolidin-3-amine (prepared according to WO2007117559, 0.10 g, 0.53 mmol) and 4-bromo-3-chloro-N-(2.4 - dimethoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.27 g, 0.53 mmol) in anhydrous toluene (5 ml) was added 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.091 g, 0.158 mmol), bis(dibenzylideneacetone)palladium(0) (0.060 g, 0.105 mmol), and cesium carbonate (0.17 g, 0.53 mmol) and the reaction mixture was heated to 100 °C for 12 H. The reaction mixture was poured into water (20 ml), and the mixture was extracted with ethyl acetate (3 x 20 ml). The combined organic phase was washed with brine (2 x 20 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative thin layer chromatography, eluting with 20% ethyl acetate in hexanes gave the title compound as a beige solid (0.25 g, 54% yield): MS (ES+) m/z 613.1 (M + 1), 615.1 (M + 1).

[01027]Step 3. Preparation of 4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[01028]A mixture of 4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.20 g, 0.33 mmol) in anhydrous dichloromethane (10 ml) trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred at room temperature for 12 h. Concentration in vacuo and purification of the residue by reverse phase preparative HPLC, eluting with a gradient of acetonitrile in water containing 0.2% formic acid, gave the title compound as a colorless solid (0.12 g, 77% yield): 1H NMR (400 MHz, DMSO-d6) δ7.63 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 8.0, 2.0 Hz, 1H), 7.43 to 7.39 (m, 5H), 7.26 (d, J = 4.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.83 (d , J = 4.0 Hz, 1H), 5.63 (s, 1H), 4.11 (s, 2H), 3.142.89 (m, 4H), 2.40 (m, 1H), 2.13 at 2.08 (m, 1H), 1.50 (s, 3H), NH not observed; MS (ES+) m/z 463.1 (M + 1), 465.1 (M + 1). EXAMPLE 62

[01029] Synthesis of (S)-3-chloro-4-(methyl(1-(2-phenylpropan-2-yl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide

[01030]Step 1. Preparation of tert-butyl (S)-(1-(2-phenylpropan-2-yl)pyrrolidin-3-yl)carbamate

[01031] Following the procedure as described in EXAMPLE 42, Step 2 and making non-critical variations as necessary to replace (S)-1-phenylethan-1-amine with 2-phenylpropan-2-amine, and purification by trituration with sodium acetate ethyl (10 ml), the title compound was obtained as a colorless solid (1.95 g, 73% yield): 1H NMR (300 MHz, CDCI3) δ 7.52 to 7.50 (m, 2H), 7.38 to 7.31 (m, 2H), 7.26 to 7.20 (m, 1H), 4.84 to 4.79 (m, 1H), 4.38 to 4.25 (m, 2H ), 4.12 to 4.05 (m, 1H), 3.07 (s, 3H), 3.06 (s, 3H), 2.73 to 2.68 (m, 1H), 2.48 to 2.42 (m, 1H), 2.15 to 1.97 (m, 2H), 1.45 (s, 9H); MS (ES+) m/z 305.4 (M + 1).

[01032]Step 2. Preparation of (S)-N-methyl-1-(2-phenylpropan-2-yl)pyrrolidin-3-amine

[01033] Following the procedure as described in EXAMPLE 42, Step 3 and making non-critical variations as necessary to replace ((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl) tert-butyl carbamate with tert-butyl (S)-(1-(2-phenylpropan-2-yl)pyrrolidin-3-yl)carbamate, the title compound was obtained as a colorless oil (0.55 g, 39% yield): MS (ES+) m/z 219.2 (M + 1).

[01034]Step 3. Preparation of tert-butyl ((4-bromo-3-chlorophenyl)sulfonyl)(thiazol-4-yl)carbamate

[01035] To a solution of tert-butyl thiazol-4-ylcarbamate (25.0 g, 124.9 mmol) in anhydrous tetrahydrofuran (250 ml) was added 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran ( 174.8 ml, 174.8 mmol) at -78 °C. The reaction mixture was allowed to warm to 0°C, stirred for 30 minutes at 0°C, and cooled to -78°C. To it was added a solution of 4-bromo-3-chlorobenzenesulfonyl chloride (47.1 g, 162.3 mmol) in anhydrous tetrahydrofuran (50 ml) at -78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was diluted in water (500 ml) and extracted with ethyl acetate (3 x 500 ml). The combined organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and trituration of the residue with methanol (3 x 150 ml) gave the title compound as a colorless solid (28.0 g, 49% yield): 1H NMR (400 MHz, CDCl3) δ 8 .73 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.87 to 7.81 (m, 1H), 7.78 to 7, 73 (m, 1H), 7.48 (d, J = 4.0 Hz, 1H), 1.29 (s, 9H).

[01036]Step 4. Preparation of 4-bromo-3-chloro-N-(thiazol-4-yl)benzenesulfonamide

[01037] To ((4-bromo-3-chlorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate (20.0 g, 44.1 mmol) 4 M hydrogen chloride solution in acetate was added of ethyl (200 ml) and the mixture was stirred at room temperature for 72 h. Filtration and concentration of the filtrate in vacuo gave a residue, which was triturated with ethyl acetate (2 x 100 ml) to give the title compound as a colorless solid (15.1 g, 97% yield): 1H NMR ( 400 MHz, CD3OD) δ 8.84 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.87 (d, J = 8.0 Hz , 1H), 7.65 (dd, J = 12.0, 4.0 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), NH not observed; MS (ES+) m/z 352.9 (M + 1), 355.0 (M + 1).

[01038]Step 5. Preparation of (S)-3-chloro-4-(methyl(1-(2-phenylpropan-2-yl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl) benzenesulfonamide

[01039]A mixture of 4-bromo-3-chloro-N-(thiazol-4-yl)benzenesulfonamide (0.89 g, 2.52 mmol), (S)-N-methyl-1-(2- phenylpropan-2-yl)pyrrolidin-3-amine (0.55 g, 2.52 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.29 g, 0.50 mmol), and Sodium tert-butoxide (0.73 g, 7.56 mmol) in anhydrous dioxane (32 ml) tris(dibenzylideneacetone)dipalladium(0) (0.23 g, 0.25 mmol) was added. The resulting mixture was degassed by passing nitrogen through it and then heated to reflux for 18 h. The reaction mixture was concentrated in vacuo and the residue dissolved in methanol (40 ml). To this mixture was added 6.0 M hydrochloric acid (40 ml) and the reaction mixture was stirred for 30 minutes. Filtration and concentration of the filtrate in vacuo provided a residue that was purified by column chromatography, eluting with 0 to 20% methanol (containing 0.2% ammonium hydroxide) in dichloromethane. The residue obtained was then purified by preparative reverse phase HPLC eluting with a gradient of 10 to 45% acetonitrile in water (containing 0.1% formic acid) to provide the title compound as a colorless solid (0.020 g , 2% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.31 (br s, 1H), 8.89 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.62 (dd, J = 8.6, 2.3 Hz, 1H), 7.48 (dt, J = 8.3, 1.7 Hz, 2H), 7.33 to 7.28 (m, 2H), 7.22 to 7.17 (m, 2H), 7.05 (d, J = 2.2 Hz, 1H), 4.04 to 3.97 ( m, 1H), 2.75 (s, 3H), 2.69 to 2.59 (m, 2H), 2.55 to 2.52 (m, 1H), 2.43 to 2.35 (m, 1H), 2.02 to 1.91 (m, 1H), 1.79 to 1.67 (m, 1H), 1.34 (s, 6H); MS (ES+) m/z 491.1 (M + 1), 493.1 (M + 1). EXAMPLE 63

[01040] Synthesis of 3-chloro-4-((1-(pyridin-4-ylmethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[01041] Following the procedure as described in Example 22, and making non-critical variations as necessary to replace 4-fluorobenzaldehyde with isonicotinaldehyde, and purification by column chromatography, eluting with 0 to 20% methanol, the title compound was obtained as a colorless solid (0.17 g, 36% yield): 1H NMR (300 MHz, DMSO-d6) ^ 12.67 (br s, 1H), 8.48 to 8.46 (m, 2H), 7 .70 (d, J = 2.2 Hz, 1H), 7.64 (dd, J = 8.7, 2.3 Hz, 1H), 7.32 to 7.29 (m, 3H), 7. 24 to 7.22 (m, 1H), 6.80 to 6.78 (m, 1H), 4.64 to 4.60 (m, 1H), 3.51 (s, 2H), 2.61 to 2.56 (m, 2H), 2.33 to 2.28 (m, 2H), 1.95 to 1.88 (m, 2H), 1.74 to 1.63 (m, 2H); MS (ES+) m/z 465.0 (M + 1), 467.0 (M + 1). EXAMPLE 64

[01042] Synthesis of 3-chloro-4-((1-(pyridin-3-ylmethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[01043] Following the procedure as described in Example 22, and making non-critical variations as necessary to replace 4-fluorobenzaldehyde with nicotinaldehyde, and purification by column chromatography, eluting with 0 to 20% methanol, the title compound was obtained as a colorless solid (0.18 mg, 39% yield): 1H NMR (300 MHz, DMSO-d6) δ8.47 to 8.42 (m, 2H), 7.70 to 7.66 (m, 2H) , 7.64 (dd, J = 8.7, 2.3 Hz, 1H), 7.34 to 7.28 (m, 2H), 7.21 (d, J = 4.6 Hz, 1H), 6.78 (d, J = 4.6 Hz, 1H), 4.64 to 4.57 (m, 1H), 3.51 (s, 2H), 2.61 to 2.55 (m, 2H) , 2.33 to 2.26 (m, 2H), 1.93 to 1.87 (m, 2H), 1.71 to 1.61 (m, 2H), NH not observed; MS (ES+) m/z 465.0 (M + 1), 467.0 (M + 1). EXAMPLE 65

[01044] Synthesis of 3-chloro-4-((1-(pyridin-2-ylmethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[01045] Following the procedure as described in Example 22, and making non-critical variations as necessary to replace 4-fluorobenzaldehyde with picolinaldehyde, and purification by column chromatography, eluting with 0 to 20% methanol, the title compound was obtained as a colorless solid (0.20 mg, 43% yield), 1H NMR (300 MHz, DMSO-d6) δ 12.48 (br s, 1H), 8.47 to 8.45 (m, 1H), 7 .77 to 7.70 (m, 2H), 7.64 (dd, J = 8.7, 2.3 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7, 31 (d, J = 8.9 Hz, 1H), 7.25 to 7.21 (m, 2H), 6.78 (s, J = 4.6 Hz, 1H), 4.65 to 4.58 (m, 1H), 3.63 (s, 2H), 2.71 to 2.64 (m, 2H), 2.42 to 2.34 (m, 2H), 1.97 to 1.90 (m , 2H), 1.74 to 1.63 (m, 2H); MS (ES+) m/z 465.0 (M + 1), 467.0 (M + 1). EXAMPLE 66

[01046] Synthesis of (R)-4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl) 2,2,2-trifluoroacetate )benzenesulfonamide

[01047]Step 1. Preparation of (R)-4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro- N-(2,4-dimethoxybenzyl)-N-(1,2,4- thiadiazol-5-yl)benzenesulfonamide

[01048]A mixture of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.40 g, 0.90 mmol) and anhydrous potassium carbonate (0.31 g, 2.25 mmol) in anhydrous dimethyl sulfoxide (2 ml) was added (R)-1-benzylpyrrolidin-3-amine (0.16 g, 0.90 mmol ) and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate (50 ml), washed with water (20 ml), brine (3 x 50 ml), dried over anhydrous sodium sulfate and filtered. Concentration in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 5% methanol in dichloromethane provided the title compound as a colorless solid (0.54 g, quantitative yield). 1H NMR (300 MHz, CD3OD) δ8.16 (s, 1H), 7.43 (dd, J = 8.8, 2.3 Hz, 1H), 7.34 to 7.22 (m, 6H), 6.90 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 8.9 Hz, 1H), 6.29 to 6.25 (m, 2H), 5.21 (s , 2H), 4.13 to 4.05 (m, 1H), 3.69 (s, 3H), 3.66 (s, 2H), 3.60 (s, 3H), 2.88 to 2, 80 (m, 2H), 2.61 (dd, J = 10.1, 3.8 Hz, 1H), 2.54 to 2.46 (m, 1H), 2.42 to 2.31 (m, 1H), 1.77 to 1.66 (m, 1H), NH not observed; MS (ES+) m/z 600.1 (M + 1), 602.1 (M + 1).

[01049]Step 2. Preparation of (R)-4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro-N-(1,2,4-thiadiazole) 2,2,2-trifluoroacetate 5-yl)benzenesulfonamide

[01050] To a solution of (R)-4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazole -5-yl)benzenesulfonamide (0.14 g, 0.23 mmol) in dichloromethane (1.4 ml) trifluoroacetic acid (0.8 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo. To the residue, methanol (20 ml) was added and the suspension obtained was filtered. The filtrate was concentrated in vacuo to provide the title compound as a beige solid (0.11 g, 82% yield). 1H NMR (300 MHz, CD3OD) δ 8.14 (s, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.64 (dd, J = 8.7, 2.1 Hz , 1H), 7.51 to 7.45 (m, 5H), 6.78 (d, J = 8.8 Hz, 1H), 4.48 to 4.44 (m, 1H), 4.43 to 4.42 (m, 2H), 3.77 to 3.68 (m, 1H), 3.63 to 3.51 (m, 1H), 3.48 to 3.37 (m, 2H), 2, 67 to 2.56 (m, 1H), 2.18 to 2.07 (m, 1H), 2 NH and COOH not observed; MS (ES+) m/z 450.0 (M + 1) 452.0 (M + 1). EXAMPLE 67

[01051] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro-N-(1,2,4-thiadiazol-5-yl) 2,2,2-trifluoroacetate )benzenesulfonamide

[01052] Step 1. Preparation of (S)-(1-benzylpyrrolidin-3-yl) tert-butyl carbamate

[01053] To a solution of (S)-pyrrolidin-3-ylcarbamate tert-butyl (0.30 g, 1.60 mmol) in anhydrous 1,2-dichloroethane (2 ml) and anhydrous N,N-dimethylformamide (2 ml) benzaldehyde (0.26 g, 2.40 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes and then sodium triacetoxyborohydride (0.68 g, 3.20 mmol) was added thereto. The reaction mixture was stirred at room temperature for 5 h. After dilution with ethyl acetate (50 ml), the mixture was washed with brine (3 x 50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo provided the title compound as a colorless oil (0.37 g, 84% yield). 1H NMR (300 MHz, CDCl3) δ 7.58 to 7.53 (m, 2H), 7.46 to 7.39 (m, 3H), 4.55 to 4.49 (m, 1H), 4, 16 (s, 2H), 3.67 to 3.52 (m, 1H), 3.40 to 3.36 (m, 1H), 3.12 to 3.06 (m, 1H), 2.91 to 2.81 (m, 1H), 2.52 to 2.40 (m, 1H), 2.25 to 2.12 (m, 1H), 1.39 (s, 9H), NH not observed; MS (ES+) m/z 277.2 (M + 1).

[01054]Step 2. Preparation of (S)-1-benzylpyrrolidin-3-amine

[01055] To a solution of (S)-(1-benzylpyrrolidin-3-yl) tert-butyl carbamate (0.37 g, 1.34 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid (4.0 ml ). The reaction mixture was stirred at room temperature for 1.5 h and concentrated in vacuo to yield the title compound as a beige oil 0.39 g, quantitative yield): MS (ES+) m/z 177.2 (M + 1 ).

[01056]Step 3. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro-N- (2,4-dimethoxybenzyl)-N-(1,2,4- thiadiazol-5-yl)benzenesulfonamide

[01057] Following the procedure as described in Example 66, Step 1 and making non-critical variations as necessary to replace (R)-1-benzylpyrrolidin-3-amine with (S)-1-benzylpyrrolidin 2,2,2-trifluoroacetate -3-amine, the title compound was obtained as a white solid (0.43 g, 79% yield): 1H NMR (300 MHz, CD3OD) δ8.20 (s, 1H), 7.47 (dd, J = 8.9, 2.3 Hz, 1H), 7.39 to 7.33 (m, 5H), 7.32 to 7.26 (m, 2H), 6.94 (d, J = 8, 1 Hz, 1H), 6.64 (d, J = 8.9 Hz, 1H), 6.33 to 6.28 (m, 2H), 5.25 (s, 2H), 4.17 to 4, 09 (m, 1H), 3.73 (s, 3H), 3.69 (s, 2H), 3.63 (s, 3H), 2.89 to 2.84 (m, 2H), 2.65 (dd, J = 10.1, 3.8 Hz, 1H), 2.54 (d, J = 7.5 Hz, 1H), 2.40 (d, J = 8.3 Hz, 1H), sulfonamide NH not observed; MS (ES+) m/z 600.1 (M + 1), 602.1 (M + 1).

[01058]Step 4. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro-N-(1,2,4-thiadiazole) 2,2,2-trifluoroacetate 5-yl)benzenesulfonamide

[01059] Following the procedure as described in Example 66 Step 2 and making non-critical variations as necessary to replace (R)-4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro-N-(2, 4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide by (S)-4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro-N-(2, 4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, the title compound was obtained as a colorless solid 0.10 mg, quantitative yield): 1H NMR (300 MHz, CD3OD) δ8 .14 (s, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.64 (dd, J = 8.7, 2.1 Hz, 1H), 7.51 to 7, 45 (m, 5H), 6.78 (d, J = 8.8 Hz, 1H), 4.49 to 4.45 (m, 1H), 4.42 to 4.42 (m, 2H), 3 .77 to 3.68 (m, 1H), 3.63 to 3.52 (m, 1H), 3.49 to 3.35 (m, 2H), 2.67 to 2.54 (m, 1H) , 2.18 to 2.06 (m, 1H), 2 NH and COOH not observed; MS (ES+) m/z 450.0 (M + 1), 452.0 (M + 1). EXAMPLE 68

[01060] Synthesis of (R)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(1,2,4-thiadiazole) 2,2,2-trifluoroacetate 5-yl)benzenesulfonamide

[01061]Step 1. Preparation of (R)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2 ,4-thiadiazol-5-yl)benzenesulfonamide

[01062]A mixture of (R)-4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazole -5-yl)benzenesulfonamide (0.37 g, 0.62 mmol) in anhydrous tetrahydrofuran (9.0 ml) was added to a dispersion of 60% sodium hydride in mineral oil (0.027 g, 0.68 mmol) to 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 1h. The reaction mixture was then cooled to 0 °C and 0.5 M iodomethane solution in anhydrous tetrahydrofuran (1.0 ml, 0.50 mmol) was added thereto. The reaction mixture was allowed to warm to room temperature, stirred for 16 h, and quenched by addition of water (10 ml). After dilution with ethyl acetate (50 ml), the organic phase was washed with brine (3 x 50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC eluting with a gradient of 15 to 92% acetonitrile in water (containing 0.2% ammonium hydroxide) to give the title compound as a colorless solid (0.012 g, 3% yield): MS (ES+) m/z 614.1 (M + 1), 616.1 (M + 1).

[01063]Step 2. Preparation of (R)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N-(1,2,4) 2,2,2-trifluoroacetate -thiadiazol-5-yl)benzenesulfonamide

[01064] Following the procedure as described in Example 66 Step 2 and making non-critical variations as necessary to replace (R)-4-((1-benzylpyrrolidin-3-yl)amino)-3-chloro-N-(2, 4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide by (R)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N- (2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, the title compound was obtained as a colorless solid 0.02 g, quantitative yield): 1H NMR (300 MHz, CD3OD) δ8.16 (br s, 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.75 (dd, J = 8.5, 2.1 Hz, 1H), 7, 45 (s, 5H), 7.32 (d, J = 8.5 Hz, 1H), 4.39 (s, 2H), 4.34 to 4.28 (m, 1H), 3.61 to 3 .52 (m, 1H), 3.48 to 3.34 (m, 2H), 3.24 to 3.20 (m, 1H), 2.77 (s, 3H), 2.29 to 2.12 (m, 2H), NH and COOH not observed; MS (ES+) m/z 464.0 (M + 1), 466.0 (M + 1). EXAMPLE 69

[01065] Synthesis of (R)-3-chloro-4-((1-(3-chlorobenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl) benzenesulfonamide

[01066]Step 1. Preparation of (R)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenyl)amino)pyrrolidine- 1-tert-butyl carboxylate

[01067] To a suspension of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl) benzenesulfonamide (1.08 g, 2.44 mmol) and (R) tert-butyl-3-aminopyrrolidine-1-carboxylate (0.500 g, 2.68 mmol) in anhydrous dimethyl sulfoxide (10 ml) was added potassium carbonate (0.843 g, 6.10 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (50 ml) and water (20 ml) and the aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic phases were washed with brine (3 x 20 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 50% ethyl acetate in hexanes provided the title compound as a colorless foam (0.72 g, 48% yield ): MS (ES+) m/z 609.1 (M + 1), 611.1 (M + 1).

[01068]Step 2. Preparation of (R)-3-chloro-4-(pyrrolidin-3-ylamino)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01069] To a solution of (R)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl) phenyl)amino)pyrrolidine-1 -tert-butyl carboxylate (0.72 g, 1.17 mmol) in anhydrous dichloromethane (7.5 ml) trifluoroacetic acid (3 ml) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue was suspended in methanol (20 ml). The mixture was stirred at room temperature for 16 h, filtered and the residue was washed with methanol (2 x 15 ml). Concentration of the filtrate in vacuo yielded (R)-3-chloro-4-(pyrrolidin-3-ylamino)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate as a beige foam (0. 52 g, 94% yield): MS (ES+) m/z 359.0 (M + 1), 361.0 (M + 1).

[01070]Step 3. Preparation of (R)-3-chloro-4-((1-(3-chlorobenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl) benzenesulfonamide ci

[01071] To a solution of (R)-3-chloro-4-(pyrrolidin-3-ylamino)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate (0.170 g, 0.36 mmol) in anhydrous 1,2-dichloroethane (2 ml) and anhydrous N,N-dimethylformamide (2 ml) 3-chlorobenzaldehyde (0.15 g, 1.08 mmol) was added. The reaction mixture was stirred for 15 minutes and then sodium triacetoxyborohydride (0.23 g, 1.08 mmol) was added thereto. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with brine (2 x 25 ml). The combined aqueous layers were extracted with ethyl acetate (3 x 75 ml). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was carried out by column chromatography, eluting with a gradient of 0 to 5% methanol (containing 0.2% ammonium hydroxide) in dichloromethane to give the title compound as a colorless solid (0.136 g, 78% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.53 (br s, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.52 (dd, J = 2, 1, 8.5 Hz, 1H), 7.38 to 7.35 (m, 1H), 7.32 to 7.26 (m, 2H), 7.23 (d, J = 4.6 Hz, 1H ), 6.82 to 6.77 (m, 2H), 5.72 (d, J = 7.0 Hz, 1H), 4.09 to 4.02 (m, 1H), 3.63 (s, 2H), 3.41 to 3.28 (m, 1H), 2.83 (dd, J = 6.7, 9.4 Hz, 1H), 2.72 to 2.64 (m, 1H), 2 .53 to 2.44 (m, 2H), 2.29 to 2.17 (m, 1H), 1.81 to 1.71 (m, 1H); (ES-) m/z 481.0 (M - 1), 483.0 (M - 1). EXAMPLE 70

[01072] Synthesis of (R)-3-chloro-4-((1-(3-methylbenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl) benzenesulfonamide

[01073] Following the procedure as described in Example 69 Step 3 and making non-critical variations as necessary to replace 3-chlorobenzaldehyde with 3-methylbenzaldehyde, the title compound was obtained as a colorless solid (0.085 g, 51% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.44 (br s, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.51 (dd, J = 2.1, 8 .6 Hz, 1H), 7.22 to 7.04 (m, 4H), 6.82 to 6.75 (m, 2H), 5.70 (d, J = 7.0 Hz, 1H), 4 .10 to 3.99 (m, 1H), 3.60 (s, 2H), 3.43 to 3.24 (m, 1H), 2.88 to 2.79 (m, 1H), 2.74 to 2.63 (m, 1H), 2.57 to 2.41 (m, 2H), 2.34 to 2.23 (m, 1H), 2.27 (s, 3H), 1.81 to 1 .70 (m, 1H); MS (ES+) m/z 463.0 (M + 1), 465.0 (M + 1). EXAMPLE 71

[01074] Synthesis of (R)-3-chloro-4-((1-(2-fluorobenzyl)pyrrolidin-3-yl)amino)-N-(thiazol-2-yl) benzenesulfonamide

[01075] Following the procedure as described in Example 69 Step 3 and making non-critical variations as necessary to replace 3-fluorobenzaldehyde with 2-methylbenzaldehyde, the title compound was obtained as a colorless solid (0.138 g, 82% yield): 1H NMR (300 MHz, DMSO-d6) δ 1H NMR (300 MHz, DMSO-d6) δ 12.44 (br s, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7, 52 (dd, J = 2.2, 8.6 Hz, 1H), 7.44 to 7.38 (m, 1H), 7.35 to 7.27 (m, 1H), 7.15 to 7, 12 (m, 2H), 6.80 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 4.6 Hz, 1H), 5.72 (d, J = 7.0 Hz, 1H), 4.08 to 4.00 (m, 1H), 3.67 (s, 2H), 3.38 to 3.30 (m, 1H), 2.89 to 2.84 (m, 1H), 2.73 to 2.65 (m, 1H), 2.53 to 2.46 (m, 2H), 2.28 to 2.16 (m, 1H), 1.81-1.70 ( m, 1H); MS (ES+) m/z 467.0 (M + 1), 469.0 (M + 1). EXAMPLE 72

[01076] Synthesis of 4-((cis-1-benzyl-2-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[01077]Step 1. Preparation of tert-butyl cis-4-hydroxy-2-methylpiperidine-1-carboxylate

[01078] To a solution of 2-methyl-4-oxopiperidine-1-tert-butyl carboxylate (1.5 g, 7.03 mmol) in anhydrous tetrahydrofuran (110 ml) was added 1.0 M of tri- lithium sec-butylborohydride in tetrahydrofuran (8.10 ml, 8.1 mmol) at -78 °C. The reaction mixture was stirred at -78°C for 20 minutes before being quenched by addition of methanol (15 ml). The reaction mixture was diluted in water (300 ml) and dichloromethane (300 ml) and allowed to warm to room temperature. The aqueous layer was extracted with dichloromethane (2 x 150 ml). The combined organic phases were washed with brine (50 ml), dried with anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0 to 40% ethyl acetate in hexanes to give the title compound as a colorless solid (1.08 g, 71% yield): 1H NMR (300 MHz, CDCI3) δ 4.32 to 4.23 (m, 1H), 4.20 to 4.13 (m, 1H), 3.84 to 3.77 (m, 1H), 3.24 (ddd, J = 13.6, 11.1, 4.7 Hz, 1H), 1.84 (ddd, J = 14.4, 6.6, 3.3 Hz, 1H), 1.77 to 1.60 ( m, 3H), 1.58 to 1.51 (m, 1H), 1.44 (s, 9H), 1.31 (d, J = 7.1 Hz, 3H); MS (ES+) m/z 216.3.

[01079]Step 2. Preparation of cis-4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenoxy)-2-methylpiperidine-1- tert-butyl carboxylate

[01080]A mixture of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl) benzenesulfonamide (1.1 g, 2.49 mmol) and cis-4 tert-butyl-hydroxy-2-methylpiperidine-1-carboxylate (0.535 g, 2.49 mmol) in anhydrous dimethyl sulfoxide (15 ml) was added cesium carbonate (2.03 g, 6.23 mmol) and the mixture reaction was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (50 ml) and water (20 ml). The aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic phases were washed with brine (3 x 20 ml), dried with anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0 to 50% ethyl acetate in hexanes to give the title compound as a yellowish foam (1.14 g, 72% yield): MS (ES+) m/z 638.1 (M + 1).

[01081] Step 3. Preparation of 3-chloro-4-((cis-2-methylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01082] To a solution of cis-4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenoxy)-2-methylpiperidine-1-carboxylate tert-butyl (1.14 g, 1.79 mmol) in dichloromethane (12 ml) trifluoroacetic acid (5 ml) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue was diluted with methanol (20 ml). The mixture was stirred at room temperature for 16 hours and filtered. The residue was rinsed with methanol (2 x 15 ml) and the filtrate was concentrated in vacuo to give the title compound as a beige solid (0.90 g, quantitative yield): MS (ES+) m/z 388.2 ( M + 1), 390.2 (M + 1).

[01083]Step 4. Preparation of 4-((cis-1-benzyl-2-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[01084] To a solution of 3-chloro-4-((cis-2-methylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate (0.4 g, 0.825 mmol) in anhydrous 1,2-dichloroethane (5 ml) and anhydrous N,N-dimethylformamide (5 ml) benzaldehyde (0.21 ml, 2.06 mmol) was added. The reaction mixture was stirred for 15 minutes and then sodium triacetoxyborohydride (0.525 g, 2.49 mmol) was added to it. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (75 ml) and washed with brine (2 x 50 ml). The combined aqueous layers were extracted with ethyl acetate (3 x 100 ml). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was carried out by column chromatography, eluting with a gradient of 0 to 5% methanol (containing 0.2% ammonium hydroxide) in dichloromethane to give the title compound as a colorless solid (0.214 g, 54% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.26 (br s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.66 (dd, J = 8, 7, 2.3 Hz, 1H), 7.38 to 7.21 (m, 7H), 6.82 (d, J = 4.5 Hz, 1H), 4.57 to 4.47 (m, 1H ), 4.03 (d, J = 13.6 Hz, 1H), 3.24 (d, J = 13.6 Hz, 1H), 2.78 (dt, J = 12.1, 3.7 Hz , 1H), 2.54 to 2.46 (m, 1H), 2.17 to 1.95 (m, 3H), 1.55 to 1.38 (m, 2H), 1.20 (d, J = 6.2 Hz, 3H); MS (ES+) m/z 478.0 (M + 1), 480.0 (M + 1). EXAMPLE 73

[01085] Synthesis of 4-((trans-1-benzyl-2-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[01086]Step 1. Preparation of tert-butyl trans-4-hydroxy-2-methylpiperidine-1-carboxylate

[01087] To a solution of 2-methyl-4-oxopiperidine-1-tert-butyl carboxylate (1.5 g, 7.03 mmol) in anhydrous ethanol (30 ml)) was added sodium borohydride (0.4 g , 10.55 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was diluted in water (15 ml) and a mixture of hexanes and ethyl acetate (1:1, 30 ml). The aqueous layer was extracted with a mixture of hexanes and ethyl acetate (1:1, 3 x 50 ml). The combined organic phases were washed with brine (50 ml), dried with anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 40% ethyl acetate in hexanes gave the title compound as a colorless solid (0.627 g, 41% yield); 1H NMR (300 MHz, CDCI3) δ 4.51 to 4.42 (m, 1H), 4.06 to 3.87 (m, 2H), 2.85 (dt, J = 13.5, 2.8 Hz, 1H), 2.14 to 1.96 (m, 1H), 1.94 to 1.77 (m, 2H), 1.56 to 1.45 (m, 1H), 1.42 (s, 9H), 1.41 to 1.22 (m, 1H), 1.12 (d, J = 7.1 Hz, 3H); MS (ES+) m/z 216.3 (M + 1).

[01088]Step 2. Preparation of trans-4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenoxy)-2-methylpiperidine-1- tert-butyl carboxylate

[01089] Following the procedure as described in Example 72, Step 2 and making non-critical variations as necessary to replace cis-4-hydroxy-2-methylpiperidine-1-tert-butyl carboxylate with trans-4-hydroxy-2-methylpiperidine- 1- tert-butyl carboxylate, the title compound was obtained as a yellowish foam (1.02 g, 71% yield): MS (ES+) m/z 638.1 (M + 1).

[01090]Step 3. Preparation of 3-chloro-4-((trans-2-methylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01091] Following the procedure as described in Example 72, Step 3 and making non-critical variations as necessary to replace cis-4-(2-chloro-4- (N-(2,4-dimethoxybenzyl)-N-(thiazol- tert-butyl 2-yl)sulfamoyl)phenoxy)-2-methylpiperidine-1-carboxylate by trans-4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl )sulfamoyl)phenoxy)-2-methylpiperidine-1-tert-butylcarboxylate, the title compound was obtained as a beige solid (0.925 g, quantitative yield): MS (ES+) m/z 388.2 (M + 1) , 390.2 (M + 1).

[01092]Step 4. Preparation of 4-((trans-1-benzyl-2-methylpiperidin-4-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[01093] Following the procedure as described in Example 72, Step 4 and making non-critical variations as necessary to replace 3-chloro-4-((cis-2-methylpiperidin-4-yl)oxy)-N-(thiazol-2 -yl)benzenesulfonamide 2,2,2-trifluoroacetate by 3-chloro-4-((trans-2-methylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)-N-(thiazol-2-yl) benzenesulfonamide, the title compound was obtained as a colorless solid (0.095 g, 24% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.17 (br s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 8.6, 2.3 Hz, 1H), 7.45 to 7.31 (m, 6H), 7.26 (d, J = 4.6 Hz, 1H), 6.83 (d, J = 4.6 Hz, 1H), 4.90 to 4.89 (m, 1H), 4.18 (d, J = 13.5 Hz, 1H), 3.65 (d, J = 13.5 Hz, 1H), 3.07 to 3.01 (m, 1H), 2.78 to 2.73 (m, 1H), 2.64 to 2 .56 (m, 1H), 2.01 to 1.78 (m, 4H), 1.28 (d, J = 6.3 Hz, 3H); MS (ES+) m/z 478.0 (M + 1), 480.0 (M + 1). EXAMPLE 74

[01094] Synthesis of 4-((trans-1-benzyl-4-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[01095]Step 1. Preparation of trans-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenyl)amino)-4-methylpyrrolidine -1-tert-butyl carboxylate

[01096] Following the procedure as described in Example 72, Step 2 and making non-critical variations as necessary to replace cis-4-hydroxy-2-methylpiperidine-1-tert-butyl carboxylate with trans-3-amino-4-methylpyrrolidine- 1- tert-butyl carboxylate, the title compound was obtained as a yellowish foam (0.927 g, 66% yield): MS (ES+) m/z 623.1 (M + 1), 625.1 (M + 1 ).

[01097]Step 2. Preparation of 3-chloro-4-((trans-4-methylpyrrolidin-3-yl)amino)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01098] Following the procedure as described in Example 72, Step 3 and making non-critical variations as necessary to replace cis-4-(2-chloro-4- (N-(2,4-dimethoxybenzyl)-N-(thiazol- tert-butyl 2-yl)sulfamoyl)phenoxy)-2-methylpiperidine-1-carboxylate by trans-3-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl )sulfamoyl)phenyl)amino)-4-methylpyrrolidine-1-tert-butylcarboxylate, the title compound was obtained as a beige solid (0.734 g, quantitative yield): MS (ES+) m/z 373.0 (M + 1), 375.0 (M + 1).

[01099]Step 3. Preparation of 4-((trans-1-benzyl-4-methylpyrrolidin-3-yl)amino)- 3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[01100] Following the procedure as described in Example 72, Step 4 and making non-critical variations as necessary to replace 3-chloro-4-((cis-2-methylpiperidin-4-yl)oxy)-N-(thiazol-2 -yl)benzenesulfonamide 2,2,2-trifluoroacetate by 3-chloro-4-((trans-4-methylpyrrolidin-3-yl)amino)-N-(thiazol-2-yl)-N-(thiazol-2-yl) benzenesulfonamide, the title compound was obtained as a colorless solid (0.059 g, 20% yield): 1H NMR (300 MHz, DMSO-d6) δ7.57 (d, J = 2.2 Hz, 1H), 7, 52 (dd, J = 8.6, 2.1 Hz, 1H), 7.32 to 7.28 (m, 4H), 7.27 to 7.20 (m, 2H), 6.79 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 4.6 Hz, 1H), 5.72 (d, J = 7.5 Hz, 1H), 3.85-3.11 ( m, 1H), 3.68 to 3.55 (m, 2H), 2.98 to 2.89 (s, 1H), 2.88 to 2.80 (m, 1H), 2.58 to 2, 51 (m, 1H), 2.34 to 2.26 (m, 1H), 2.11 to 2.06 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H), sulfonamide NH not observed; MS (ES+) m/z 463.0 (M + 1), 465.0 (M + 1). EXAMPLE 75

[01101] Synthesis of 4-((cis-1-benzyl-4-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[01102]Step 1. Preparation of cis-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenyl)amino)-4-methylpyrrolidine -1-tert-butyl carboxylate

[01103] Following the procedure as described in Example 72, Step 2 and making non-critical variations as necessary to replace cis-4-hydroxy-2-methylpiperidine-1-tert-butyl carboxylate with cis-3-amino-4-methylpyrrolidine- 1- tert-butyl carboxylate, the title compound was obtained as a yellowish foam (0.683 g, 48% yield): MS (ES+) m/z 623.1 (M + 1), 625.1 (M + 1 ).

[01104]Step 2. Preparation of 3-chloro-4-(((3R,4S)-4-methylpyrrolidin-3-yl)amino)-N-(thiazol-2-yl) 2,2,2-trifluoroacetate benzenesulfonamide

[01105] Following the procedure as described in Example 72, Step 3 and making non-critical variations as necessary to replace cis-4-(2-chloro-4- (N-(2,4-dimethoxybenzyl)-N-(thiazol- tert-butyl 2-yl)sulfamoyl)phenoxy)-2-methylpiperidine-1-carboxylate by cis-3-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl )sulfamoyl)phenyl)amino)-4-methylpyrrolidine-1-tert-butylcarboxylate, the title compound was obtained as a beige solid (0.561 g, quantitative yield): MS (ES+) m/z 373.0 (M + 1), 375.1 (M + 1).

[01106]Step 3. Preparation of 4-((cis-1-benzyl-4-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[01107] Following the procedure as described in Example 72, Step 4 and making non-critical variations as necessary to replace 3-chloro-4-((cis-2-methylpiperidin-4-yl)oxy)-N-(thiazol-2 -yl)benzenesulfonamide 2,2,2-trifluoroacetate by 2,2,2-trifluoroacetate 3-chloro-4-((3R,4S)-4-methylpyrrolidin-3-yl)amino)-N-(thiazol-2 -il)benzenesulfonamide, the title compound was obtained as a colorless solid (0.032 g, 11% yield): 1H NMR (300 MHz, DMSO-d6) δ7.58 (d, J = 2.2 Hz, 1H) , 7.51 (dd, J = 8.7, 2.1 Hz, 1H), 7.34 to 7.30 (m, 4H), 7.29 to 7.21 (m, 2H), 6.87 (d, J = 8.9 Hz, 1H), 6.78 (d, J = 4.6 Hz, 1H), 5.57 (d, J = 8.4 Hz, 1H), 4.19 to 4 .09 (m, 1H), 3.70 to 3.57 (m, 2H), 3.68 to 3.12 (m, 1H), 3.02 (dd, J = 9.3, 7.0 Hz , 1H), 2.95 to 2.89 (m, 1H), 2.61 to 2.53 (m, 1H), 2.19 (dd, J = 8.9, 7.6 Hz, 1H), 0.77 (d, J = 7.1 Hz, 3H), sulfonamide NH not observed; MS (ES+) m/z 463.0 (M + 1), 465.0 (M + 1). EXAMPLE 76

[01108] Synthesis of 4-((1-benzylazetidin-3-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[01109]Step 1. Preparation of 3-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)phenoxy)azetidine-1-tert-butyl carboxylate

[01110] To a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide (1.02 g, 2.31 mmol) and 3-hydroxyazetidine tert-butyl-1-carboxylate (0.400 g, 2.31 mmol) in anhydrous N,N-dimethylformamide (20 ml) was added to a dispersion of 60% sodium hydride in mineral oil (0.185 g, 4.62 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then slowly added to a rapidly stirred saturated ammonium chloride solution (150 ml). The resulting slurry was filtered and the precipitate was dried in vacuo to yield the title compound as a pale yellow solid (1.43 g, quantitative yield): 1H-NMR (300 MHz, DMSO-d6): δ 7.81 (d, J = 2.3 Hz, 1H), 7.72 (dd, J = 8.7, 2.3 Hz, 1H), 7.46 (q, J = 4.3 Hz, 2H), 7 .04 (dd, J = 15.3, 8.6 Hz, 2H), 6.48 (d, J = 2.3 Hz, 1H), 6.42 (dd, J = 8.5, 2.3 Hz, 1H), 5.19 to 5.15 (m, 1H), 4.97 (s, 2H), 4.37 to 4.31 (m, 2H), 3.87 to 3.83 (m, 2H), 3.71 (s, 3H), 3.67 (s, 3H), 1.39 (s, 9H); MS (ES+) m/z 596.0 (M + 1), 597.0 (M + 1).

[01111] Step 2. Preparation of 4-(azetidin-3-yloxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01112] Following the procedure as described in Example 72, Step 3 and making non-critical variations as necessary to replace cis-4-(2-chloro-4- (N-(2,4-dimethoxybenzyl)-N-(thiazol- tert-butyl 2-yl)sulfamoyl)phenoxy)-2-methylpiperidine-1-carboxylate by 3-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl )phenoxy)azetidine-1-tert-butyl carboxylate, the title compound was obtained as a beige foam (0.729 g, quantitative yield): MS (ES+) m/z 346.0 (M + 1), 348.0 ( M+1).

[01113]Step 3. Preparation of 4-((1-benzylazetidin-3-yl)oxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide

[01114] Following the procedure as described in Example 72, Step 4 and making non-critical variations as necessary to replace 3-chloro-4-((cis-2-methylpiperidin-4-yl)oxy 2,2,2-trifluoroacetate )-N-(thiazol-2-yl)benzenesulfonamide by 4-(azetidin-3-yloxy)-3-chloro-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate, the title compound was obtained as a colorless solid (0.073 g, 31% yield): 1H-NMR (300 MHz, DMSO-d6): δ 7.76 (d, J = 2.2 Hz, 1H), 7.66 (dd , J = 8.6, 2.3 Hz, 1H), 7.35 to 7.23 (m, 6H), 7.05 (d, J = 8.7 Hz, 1H), 6.83 (d, J = 4.6 Hz, 1H), 5.00 to 4.93 (m, 1H), 3.82 to 3.77 (m, 2H), 3.69 (s, 2H), 3.18 to 3 .13 (m, 2H), sulfonamide NH not observed; MS (ES+) m/z 436.0 (M + 1), 438.0 (M + 1). EXAMPLE 77

[01115] Synthesis of 4-((1-benzylpiperidin-4-yl)oxy)-3-chloro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01116]Step 1. Synthesis of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide

[01117] Following the procedure as described in Example 40, Step 1 and making non-critical variations as necessary to replace 5-chloro-2,4-difluorobenzenesulfonyl chloride with 3-chloro-4-fluorobenzenesulfonyl and purification by column chromatography, eluting with a gradient of 5 to 20% ethyl acetate in hexanes, the title compound was obtained as a yellowish oil (2.71 g, 75% yield): 1H NMR (300 MHz, CDCI3) δ7.84 (ddd , J = 6.7, 2.3 Hz, 1H), 7.78 to 7.68 (m, 2H), 7.28 to 7.24 (m, 1H), 7.20 (d, J = 8 .2 Hz, 2H), 6.77 to 6.73 (m, 1H), 6.41 to 6.35 (m, 2H), 4.95 (s, 2H), 3.78 (s, 3H) , 3.67 (s, 3H); 19F NMR (282 MHz, CDCl3) δ -67.5 (s, 1F), -107.1 (s, 1F); MS (ES+) m/z 477.1 (M + 23), 479.0 (M + 23).

[01118] Step 2. Synthesis of 4-((1-benzylpiperidin-4-yl)oxy)-3-chloro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01119] To a mixture of 1-benzylpiperidin-4-ol (0.231 g, 1.21 mmol) in anhydrous N,N-dimethylformamide (10 ml) was added a dispersion of 60% sodium hydride in mineral oil (0.054 g, 1.32 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. After cooling to 0 °C, 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide (0.50 g, 1.1 mmol) was added to it. The reaction mixture was allowed to warm to room temperature, stirred for 3 h, and quenched by addition of water (10 ml). The mixture was extracted with ethyl acetate (50 ml) and the organic layer was washed with brine (3 x 50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue which was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (4 ml) was added thereto. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. To the residue, methanol (10 ml) was added and the mixture was filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative reverse phase HPLC eluting with a gradient of 10 to 40% acetonitrile in water containing 0.1% trifluoroacetic acid yielded the title compound as a colorless solid (0.333 g , 51% yield): 1H NMR (300 MHz, CD3OD) δ8.01 (s, 1H), 7.89 (dd, J = 8.8, 2.3 Hz, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.53 to 7.47 (m, 5H), 7.31 to 7.25 (m, 1H), 6.94 (d, J = 7.9 Hz, 1H ), 6.59 (d, J = 8.0 Hz, 1H), 4.96 (br s, 1H), 4.36 (s, 2H), 3.61 to 3.39 (m, 2H), 3.25 to 3.11 (m, 2H), 2.43 to 2.36 (m, 1H), 2.26 to 2.01 (m, 2H), 2.00 to 1.86 (m, 1H ), sulfonamide NH and CF3COOH not observed; 19F NMR (282 MHz, CD3OD) δ 70.5 (s, 1F), 76.8 (s, 3F); MS (ES+) m/z 476.0 (M + 1), 478.0 (M + 1). EXAMPLE 78

[01120] Synthesis of 4-((1-benzylpiperidin-4-yl)oxy)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01121] Following the procedure as described in Example 77, Step 2 and making non-critical variations as necessary to replace 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(6-fluoropyridin-2- il)benzenesulfonamide by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide, the title compound was obtained as a colorless solid (0.015 g , 3% yield): 1H NMR (300 MHz, CD3OD) δ8.15 (s, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.56 to 7.48 (m, 5H), 7.26 (s, 1H), 6.93 (d, J = 7.9 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 4.99 (br s , 1H), 4.33 (s, 2H), 3.60 to 3.51 (m, 2H), 3.36 to 3.21 (m, 2H), 2.32 to 2.26 (m, 2H ), 2.10 to 1.99 (m, 2H), sulfonamide NH and CF3COOH not observed; 19F NMR (282 MHz, CD3OD) δ 70.4 (s, 1F), 77.0 (s, 3F), 105.0 (s, 1F); MS (ES+) m/z 494.0 (M + 1), 496.0 (M + 1). EXAMPLES 79 TO 100

[01122] In a similar way as described in the Examples and Reaction Schemes above, with the use of appropriately substituted starting materials and intermediates, the following compounds were prepared: EXAMPLE 101

[01123] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide formate

[01124]Step 1. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenyl)amino)pyrrolidine -1-tert-butyl carboxylate

[01125] To a solution of tert-butyl ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (7.49 g, 18.3 mmol) in anhydrous dimethyl sulfoxide (37 ml) triethylamine (3.1 ml, 21.9 mmol) was added followed by (S)-3-aminopyrrolidine-1-tert-butyl carboxylate (4.08 g, 21.9 mmol). The reaction mixture was stirred at room temperature for 16 h and then diluted with water (150 ml). The resulting solid was filtered off and rinsed with water (300 ml) to yield the title compound as a tan solid, which was used without further purification (yield not determined). An analytically pure sample was obtained by purification by column chromatography, eluting with a gradient of 20 to 80% ethyl acetate in hexanes to yield the title compound as a colorless solid: 1H-NMR (300 MHz, CDCI3) δ 8.81 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 7.1 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 6, 42 (d, J = 12.2 Hz, 1H), 5.05-5.02 (m, 1H), 4.09 to 4.06 (m, 1H), 3.79 to 3.77 (m, 1H), 3.58 to 3.54 (m, 2H), 3.43 to 3.28 (m, 1H), 2.34 to 2.27 (m, 1H), 2.03 to 1.96 ( m, 1H), 1.50 (s, 9H), 1.40 (s, 9H); MS (ES+) m/z 577.3 (M + 1), 579.3 (M + 1).

[01126]Step 2. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-5-fluoro-2-methylphenyl)amino)pyrrolidine -1-tert-butyl carboxylate

[01127]A mixture of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenyl)amino)pyrrolidine- 1-tert-butyl carboxylate (12.0 g, 13.2 mmol) in 1,4-dioxane (132 ml) was added methylboronic acid (7.89 g, 131.6 mmol), palladium acetate (0.44 g, 2.0 mmol), potassium phosphate (14.00 g, 65.8 mmol), and tricyclohexylphosphonium tetrafluoroborate (1.45 g, 4.0 mmol). The resulting mixture was degassed by passing a flow of dry argon through it for 15 minutes and then heated at 90 °C for 4 h. The reaction mixture was allowed to cool to room temperature and filtered through a Celite filter. The filter plug was washed with ethyl acetate (300 ml) and the combined filtrate concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 15 to 65% ethyl acetate in hexanes, provided the title compound as a colorless solid (5.1 g, 70% yield): 1H-NMR ( 300 MHz, CDCI3) δ 8.80 (d, J = 2.3 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 2.2 Hz , 1H), 6.34 (d, J = 12.7 Hz, 1H), 4.22 (d, J = 5.2 Hz, 1H), 4.08 to 4.05 (m, 1H), 3 .79 to 3.75 (m, 1H), 3.55 to 3.50 (m, 2H), 3.41 to 3.24 (m, 1H), 2.34 to 2.23 (m, 1H) , 2.13 (s, 3H), 1.99 to 1.94 (m, 1H), 1.49 (s, 9H), 1.37 (s, 9H); MS(ES+) m/z 557.3 (M + 1).

[01128]Step 3. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-5-fluoro-2-methylphenyl)(methyl) amino)pyrrolidine-1-tert-butylcarboxylate

[01129] To a solution of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-5-fluoro-2-methylphenyl)amino)pyrrolidine- tert-Butyl 1-carboxylate (5.0 g, 9.0 mmol) in anhydrous N,N-dimethylformamide (18 ml) was added methyl iodide (1.1 ml, 18.2 mmol) followed by sodium hydride ( 0.55 g of a 60% dispersion in mineral oil, 13.6 mmol), and the reaction mixture was stirred at room temperature for 18 h. HPLC analysis showed incomplete conversion, and further methyl iodide (1.0 ml, 16.1 mmol), followed by sodium hydride (0.50 g of a 60% dispersion in mineral oil, 12.5 mmol ) was added to the reaction mixture. After 2h, the reaction mixture was quenched by addition of saturated ammonium chloride and extracted with dichloromethane (3 x 75 ml). The combined organic extracts were washed with 5% aqueous lithium chloride solution (2 x 75 ml), dried with anhydrous magnesium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 5 to 45% ethyl acetate in hexanes provided the title compound as an orange oil (4.1 g, 80% yield ): MS (ES+) m/z 571.3 (M + 1).

[01130]Step 4. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide formate

[01131] A solution of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-5-fluoro-2-methylphenyl)(methyl)amino) tert-butyl pyrrolidine-1-carboxylate (4.12 g, 8.8 mmol) in anhydrous dichloromethane (10 ml) was treated with trifluoroacetic acid (6.8 ml, 87.8 mmol), and the resulting mixture was stirred at room temperature for 16 h. Concentration in vacuo gave a brown solid, which was suspended in N,N-dimethylformamide (18 ml). An 11 ml aliquot of this solution was treated with benzaldehyde (1.1 g, 10.4 mmol) and sodium triacetoxyborohydride (3.32 g, 15.7 mmol). The reaction mixture was stirred at room temperature for 16 h, then quenched by addition of 5% aqueous lithium chloride and extracted with ethyl acetate (3 x 75 ml). The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative reverse phase HPLC eluting with a gradient of acetonitrile in water containing 0.5% formic acid, provided the title compound as a colorless solid (0.54 g, 14 % yield): 1H-NMR (300 MHz, DMSO-d6) δ8.87 (d, J = 2.1 Hz, 1H), 8.17 (s, 0.12H), 7.58 (d, J = 8.5 Hz, 1H), 7.38 to 7.34 (m, 5H), 6.98 to 6.96 (m, 1H), 6.95 (d, J = 11.0 Hz, 1H) , 4.04 to 3.89 (m, 3H), 3.02 to 2.96 (m, 2H), 2.91 to 2.86 (m, 1H), 2.80 to 2.76 (m, 1H), 2.64 (s, 3H), 2.20 (s, 3H), 2.07 to 2.02 (m, 1H), 1.91 to 1.84 (m, 1H), NH and COOH not observed; 13C NMR (75 MHz, DMSO-d6) δ 157.44 (d, J = 252.6 Hz), 157.8 (d, J = 8.4 Hz), 153.5, 147.9, 135.5 , 132.5 (d, J = 4.6 Hz), 129.8, 129.0, 128.5, 127.5 (d, J = 3.0 Hz), 120.2 (d, J = 14 .2 Hz), 108.8 (d, J = 22.0 Hz), 103.0, 60.2, 58.9, 55.7, 53.0, 36.6, 27.6, 18.6 ; MS (ES+) m/z 461.2 (M + 1). EXAMPLE 102

[01132] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide formate

[01133]Step 1. Preparation of Trifluorobenzenesulfonyl Chloride

[01134] To chlorosulfonic acid (18.0 ml, 270.3 mmol) was added 2-chloro-1,3,5-trifluorobenzene (7.20 g, 43.3 mmol) at 0 °C. The resulting mixture was stirred for 18 h at room temperature and then heated to 65 °C. The reaction mixture was allowed to cool to room temperature and then added dropwise to a mixture of ice (400 g) and concentrated hydrochloric acid (125 ml), maintaining a temperature below 5 °C. After the addition was complete, the mixture was vigorously stirred at 0 °C for 1 h. The precipitate was removed by filtration and rinsed with water (250 ml) to give the title compound as a colorless amorphous solid (8.02 g, 70% yield): 1H NMR (300 MHz, CDCI3) δ7.07 (ddd , J = 9.8, 8.3, 2.3 Hz, 1H).

[01135]Step 2. Preparation of tert-butyl ((3-chloro-2,4-trifluorophenyl)sulfonyl)(thiazol-4-yl)carbamate

[01136] To a solution of tert-butyl thiazol-4-ylcarbamate (3.32 g, 16.6 mmol) in anhydrous tetrahydrofuran (210 ml) was added 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran ( 16.6 ml, 16.6 mmol) at 0 °C. The reaction mixture was stirred at 0°C for 1 h, cooled to -78°C, and 3-chloro-2,4,6-fluorobenzenesulfonyl chloride solution (4.00 ml, 15.09 mmol) in Anhydrous tetrahydrofuran (15 ml) was added dropwise thereto. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was concentrated in vacuo to a volume of approximately 50 ml. After dilution with ethyl acetate (160 ml), the organic layer was washed with saturated ammonium chloride (150 ml), saturated sodium bicarbonate (150 ml), brine (50 ml), and dried with anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave a residue which was purified by column chromatography, eluting with a gradient of 10 to 50% ethyl acetate in hexanes to give the title compound as a colorless solid (3.35 g, 52% yield): 1H NMR (300 MHz, CDCl3) δ8.83 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 6.99 ( ddd, J = 10.0, 8.2, 2.0 Hz, 1H), 1.40 (s, 9H); MS (ES+) m/z 329.0 (M - 100), 331.0 (M - 100).

[01137]Step 3. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-3,5-difluorophenyl)amino )tert-butyl pyrrolidine-1-carboxylate

[01138] To a solution of tert-butyl ((3-chloro-2,4,6-trifluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (1.53 g, 3.57 mmol) in N,N- anhydrous dimethylformamide (25 ml) was added cesium carbonate (1.16 g, 3.57 mmol) and (S)-3-aminopyrrolidine-1-tert-butyl carboxylate (0.66 g, 3.57 mmol) to - 42°C. The reaction mixture was stirred at -42 °C for 1 h and then at 0 °C for 2 h. The reaction mixture was diluted with ethyl acetate (80 ml), washed with saturated ammonium chloride (2 x 50 ml), brine (50 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 60% ethyl acetate in hexanes provided the title compound as a colorless foam (1.54 g, 73% yield ): 1H NMR (300 MHz, CDCl3) δ 8.80 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 6.30 (dd, J = 12.6, 1.6 Hz, 1H), 5.17 to 5.13 (m, 1H), 4.09 to 4.05 (m, 1H), 3.81 to 3.74 (m, 1H ), 3.58 to 3.49 (m, 2H), 3.42 to 3.29 (m, 1H), 2.36 to 2.24 (m, 1H), 2.02 to 1.97 (m , 1H), 1.49 (s, 9H), 1.40 (s, 9H); MS (ES-) m/z 593.4 (M - 1), 595.4 (M - 1).

[01139]Step 4. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-3,5-difluorophenyl)( tert-butyl methyl)amino)pyrrolidine-1-carboxylate

[01140] To a solution of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-3,5-difluorophenyl)amino) tert-butyl pyrrolidine-1-carboxylate (1.50 g, 2.52 mmol) and methyl iodide (0.19 ml, 3.02 mmol) in anhydrous N,N-dimethylformamide (20 ml) was added to a dispersion of 60% sodium hydride in mineral oil (0.21 g, 30.2 mmol) at 0 °C. The resulting mixture was stirred at 0°C for 1 h and then quenched by slow addition of water (5 ml). The mixture was diluted with ethyl acetate (80 ml), washed with saturated ammonium chloride (2 x 50 ml), brine (30 ml), and dried with anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave a residue which was purified by column chromatography, eluting with a gradient of 10 to 60% ethyl acetate in hexanes to give the title compound as a colorless foam (1.26 g, 82% yield): 1H NMR (300 MHz, CDCl3) δ 8.81 (d, J = 2.3 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 6.65 (dd, J = 12.4, 1.4 Hz, 1H), 4.33 to 4.27 (m, 1H), 3.67 to 3.59 (m, 2H), 3.38 to 3.30 (m, 2H), 2.88 (s, 3H), 2.14 to 2.08 (m, 2H), 1.48 (s, 10H), 1.40 (s, 9H); MS (ES+) m/z 631.4 (M + 23), 633.4 (M + 23).

[01141]Step 5. Preparation of (S)-3-chloro-2,6-difluoro-4-(methyl(pyrrolidin-3-yl)amino)-N-(thiazol-4) 2,2,2-trifluoroacetate -yl)benzenesulfonamide

[01142] To a solution of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-3,5-difluorophenyl)(methyl tert-butyl amino)pyrrolidine-1-carboxylate (1.26 g, 2.07 mmol) in dichloromethane (10 ml) trifluoroacetic acid (10 ml) was added. The resulting mixture was stirred for 2 h and then concentrated in vacuo to provide the title compound as a yellowish foam (1.08 g, quantitative yield): MS (ES+) m/z 409.2 (M + 1), 411.2 (M + 1).

[01143]Step 6. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-2,6-difluoro-N-(thiazol-4-yl) formate )benzenesulfonamide

[01144]A mixture of (S)-3-chloro-2,6-difluoro-4-(methyl(pyrrolidin-3-yl)amino)-N-(thiazol-4-) 2,2,2-trifluoroacetate il)benzenesulfonamide (0.40 g, 0.76 mmol) and benzaldehyde (0.16 ml, 1.52 mmol) in dichloromethane (5 ml) and N,N-dimethylformamide (5 ml) was added sodium triacetoxyborohydride (0 .32 g, 1.52 mmol). The reaction mixture was stirred at room temperature for 16 h, then quenched by addition of 2 M sodium hydroxide (15 ml), and extracted with ethyl acetate (50 ml). The aqueous layer was diluted with saturated ammonium chloride (30 ml) and extracted with ethyl acetate (50 ml). The organic layers were washed with saturated ammonium chloride (30 ml), brine (30 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo produced a residue that was purified by column chromatography, eluting with a gradient of 10 to 65% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in hexanes. The purified residue was then dissolved in methanol (15 ml) and formic acid (0.5 ml). Filtration and concentration of the filtrate gave the title compound as a colorless foam (0.09 g, 22% yield): 1H NMR (300 MHz, DMSO-d6 + 25% CD3OD) δ 8.81 (d, J = 2.2 Hz, 1H), 8.12 (s, 0.6 H), 7.30 (d, J = 4.2 Hz, 4H), 7.27 to 7.21 (m, 1H), 6 .94 (d, J = 2.2 Hz, 1H), 6.84 to 6.77 (m, 1H), 4.29 to 4.25 (m, 1H), 3.69 (d, J = 12 .9 Hz, 1H), 3.57 (d, J = 13.1 Hz, 1H), 2.83 (s, 3H), 2.80 to 2.70 (m, 2H), 2.65 to 2 .58 (m, 1H), 2.43 to 2.34 (m, 1H), 2.16 to 2.05 (m, 1H), 1.91 to 1.79 (m, 1H), NH and COOH not observed; MS (ES+) m/z 499.1 (M + 1), 501.1 (M + 1). EXAMPLE 103

[01145] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(thiazol-) 2,2,2-trifluoroacetate 4-yl)benzenesulfonamide

[01146]Step 1. Preparation of (S)-3-((3,5-difluoro-2-methyl-4-(N-(thiazol-4-yl)sulfamoyl)phenyl)amino)tert pyrrolidine-1-carboxylate -butyl

[01147]A mixture of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-3,5-difluorophenyl)amino) tert-butyl pyrrolidine-1-carboxylate (2.04 g, 3.43 mmol) and methylboronic acid (4.11 g, 68.6 mmol) in anhydrous 1,4-dioxane (35 ml) tribasic potassium phosphate was added (7.28 g, 34.3 mmol), and the mixture was degassed by passing a stream of nitrogen through it for 15 minutes. To the mixture was then added tricyclohexylphosphine tetrafluoroborate (0.76 g, 2.05 mmol) and palladium acetate (0.23 g, 1.03 mmol), and the resulting mixture was heated to reflux for 16 h. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (100 ml) and saturated ammonium chloride (100 ml), and filtered. The filtrate was collected and the layers were separated. The organic layer was washed with saturated ammonium chloride (80 ml), brine (50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 65% ethyl acetate in hexanes gave the title compound as a brownish foam (1.25 g, 77% yield ): 1H NMR (300 MHz, CDCI3) δ 11.06 (s, 1H), 8.77 (d, J = 2.3 Hz, 1H), 6.98 (d, J = 2.1 Hz, 1H ), 6.15 to 6.03 (m, 1H), 4.28 to 4.26 (m, 1H), 4.03 to 3.99 (m, 1H), 3.76 to 3.66 (m , 1H), 3.54 to 3.43 (m, 2H), 3.35 to 3.22 (m, 1H), 2.29 to 2.16 (m, 1H), 1.99 to 1.88 (m, 4H), 1.47 (s, 9H); MS (ES-) m/z 473.2 (M - 1).

[01148] Step 2. Preparation of (S)-2,6-difluoro-3-methyl-4-(pyrrolidin-3-ylamino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01149] Following the procedure as described in Example 102, Step 5 and making non-critical variations as necessary to replace (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl )sulfamoyl)-2-chloro-3,5-difluorophenyl)(methyl)amino)tert-butylpyrrolidine-1-carboxylate by (S)-3-((3,5-difluoro-2-methyl-4-(N tert-butyl-(thiazol-4-yl)sulfamoyl)phenyl)amino)pyrrolidine-1-carboxylate, the title compound was obtained as a yellowish foam (1.28 g, quantitative yield): MS (ES+) m/z 375.2 (M + 1).

[01150]Step 3. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide

[01151] Following the procedure as described in Example 102, Step 6 and making non-critical variations as necessary to replace 2,2,2-(S)-3-chloro-2,6-difluoro-4-(methyl()trifluoroacetate pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide by (S)-2,6-difluoro-3-methyl-4-(pyrrolidin-3-ylamino) 2,2,2-trifluoroacetate )-N-(thiazol-4-yl)benzenesulfonamide, the title compound was obtained as a colorless foam (0.34 g, 89% yield): MS (ES+) m/z 465.3 (M + 1) .

[01152]Step 4. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-2,2,2-trifluoroacetate (thiazol-4-yl)benzenesulfonamide

[01153] To a solution of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide (0.19 g, 0.40 mmol) in trifluoroacetic acid (1.8 ml) was added sodium triacetoxyborohydride (0.25 g, 1.20 mmol) at 0 °C. The resulting mixture was stirred at 0°C for 10 minutes and then paraformaldehyde (24 mg, 0.80 mmol) was added thereto. The reaction mixture was stirred at 0 °C for 15 minutes and then concentrated in vacuo. To the residue were added 2M sodium hydroxide (15 ml) and brine (15 ml), and the mixture was extracted with ethyl acetate (50 ml). The aqueous layer was diluted with saturated ammonium chloride (50 ml) and then extracted with ethyl acetate (50 ml). The organic layers were washed with saturated ammonium chloride (30 ml), brine (30 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative reverse phase HPLC eluting with a gradient of 7 to 50% acetonitrile in water containing 0.1% trifluoroacetic acid yielded the title compound as a colorless solid (0.045 g , 19% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.48 (br s, 1H), 10.59 (br s, 1H), 8.91 (d, J = 2.1 Hz , 1H), 7.50 to 7.45 (m, 5H), 6.99 (d, J = 2.2 Hz, 1H), 6.89 to 6.83 (m, 1H), 4.40 to 4.34 (m, 3H), 4.08 to 3.89 (m, 4H), 2.70 to 2.63 (m, 3H), 2.16 to 1.98 (m, 5H); MS (ES+) m/z 479.3 (M + 1). EXAMPLE 104

[01154] Synthesis of (S)-2,6-difluoro-3-methyl-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N formate -(thiazol-4-yl)benzenesulfonamide

[01155] To a solution of (S)-2,6-difluoro-3-methyl-4-(pyrrolidin-3-ylamino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate ( 0.63 g, 1.30 mmol) and 6-methylpicolinaldehyde (0.17 g, 1.43 mmol) in dichloromethane (20 ml) and isopropanol (5 ml) was added sodium triacetoxyborohydride (0.55 g, 2.0 ml) 60 mmol). The resulting mixture was stirred for 1 h and then concentrated in vacuo. The residue was dissolved in trifluoroacetic acid (5 ml), cooled to 0 °C, and sodium triacetoxyborohydride (2.20 g, 10.4 mmol) was added thereto. The reaction mixture was stirred for 10 minutes at 0 °C and then paraformaldehyde (0.16 g, 5.20 mmol) was added to it. The resulting mixture was stirred at 0°C for 15 minutes and then concentrated in vacuo. To the residue were added 2M sodium hydroxide (50 ml) and dichloromethane (15 ml), and the mixture was extracted with ethyl acetate (75 ml). The aqueous layer was diluted with saturated ammonium chloride (50 ml) and extracted with ethyl acetate (75 ml). The organic layers were washed with saturated ammonium chloride (50 ml), brine (50 ml), dried with anhydrous sodium sulfate and filtered. Filtration and concentration of the filtrate in vacuo provided a residue which was purified by preparative reverse phase HPLC eluting with a gradient of 7 to 50% acetonitrile in water containing 0.5% formic acid, to yield the title compound as a colorless solid (0.045 g, 19% yield): 1H NMR (300 MHz, DMSO-d6) δ 8.89 (d, J = 2.2 Hz, 1H), 8.17 (s, 0.8H), 7.64 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 6, 93 (d, J = 2.2 Hz, 1H), 6.72 (dd, J = 13.4, 1.4 Hz, 1H), 4.03 to 3.93 (m, 1H), 3.72 (d, J = 14.0 Hz, 1H), 3.62 (d, J = 14.0 Hz, 1H), 2.81 to 2.80 (m, 1H), 2.71 (s, 3H) , 2.68 to 2.59 (m, 2H), 2.46 to 2.37 (m, 4H), 2.11 to 1.99 (m, 4H), 1.86 to 1.75 (m, 1H), NH and COOH not observed; MS (ES+) m/z 494.3 (M + 1). EXAMPLE 105

[01156] Synthesis of 4-((1-benzylpiperidin-4-yl)oxy)-3-chloro-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide formate

[01157]Step 1. Preparation of ((4-((1-benzylpiperidin-4-yl)oxy)-3-chloro-2,6-difluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate

[01158] To a solution of 1-benzylpiperidin-4-ol (0.94 g, 4.90 mmol) and ((3-chloro-2,4,6-trifluorophenyl)sulfonyl)(thiazol-4-yl)carbamate tert-butyl (2.10 g, 4.90 mmol) in anhydrous N,N-dimethylformamide (25 ml) was added a dispersion of 60% sodium hydride in mineral oil (0.20 g, 4.90 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h, diluted with ethyl acetate (80 ml) and then quenched by slow addition of water (50 ml). The mixture was washed with saturated ammonium chloride (2 x 50 ml), brine (2 x 30 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 65% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in dichloromethane, provided the compound of the title as a colorless foam (0.62 g, 21% yield). 1H NMR (300 MHz, CDCla) δ 8.82 (d, J = 2.3 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 4 .3 Hz, 4H), 7.33 to 7.29 (m, 1H), 6.62 (dd, J = 12.2, 1.9 Hz, 1H), 4.57 to 4.49 (m, 1H), 3.58 (s, 2H), 2.77 to 2.69 (m, 2H), 2.49 to 2.43 (m, 2H), 2.11 to 2.02 (m, 2H) , 2.00 to 1.91 (m, 2H), 1.40 (s, 9H); MS (ES+) m/z 600.2 (M + 1), 602.2 (M + 1).

[01159]Step 2. Preparation of 4-((1-benzylpiperidin-4-yl)oxy)-3-chloro-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide formate

[01160] To a solution of ((4-((1-benzylpiperidin-4-yl)oxy)-3-chloro-2,6-difluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate (0, 21 g, 0.35 mmol) in dichloromethane (3 ml) trifluoroacetic acid (2 ml) was added and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo, and the residue purified by preparative reverse phase HPLC, eluting with a gradient of 7 to 50% acetonitrile in water containing 0.5% formic acid, to yield the title compound as a colorless solid. (0.045 g, 19% yield): 1H NMR (300 MHz, DMSO-d6) δ8.89 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.35 to 7 .24 (m, 6H), 7.00 (d, J = 2.2 Hz, 1H), 4.76 to 4.69 (m, 1H), 3.60 (s, 2H), 2.70 to 2.64 (m, 2H), 2.46 to 2.39 (m, 2H), 1.99 to 1.91 (m, 2H), 1.78 to 1.68 (m, 2H), NH and COOH not observed; MS (ES+) m/z 500.2 (M + 1), 502.2 (M + 1). EXAMPLE 106

[01161] Synthesis of 4-((1-benzylpiperidin-4-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide formate

[01162]A mixture of ((4-((1-benzylpiperidin-4-yl)oxy)-3-chloro-2,6-difluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate (0, 62 g, 1.03 mmol) and methylboronic acid (0.62 g, 10.3 mmol) in anhydrous 1,4-dioxane (16 ml) tribasic potassium phosphate (1.09 g, 5.15 mmol) was added and the mixture was degassed by passing a stream of nitrogen through it for 15 minutes. To the mixture was then added tricyclohexylphosphine tetrafluoroborate (0.15 g, 0.41 mmol) and palladium acetate (0.046 g, 0.21 mmol), and the resulting mixture was heated to reflux for 6 h. The mixture was diluted with saturated ammonium chloride (50 ml) and extracted with ethyl acetate (80 ml). The organic layer was washed with saturated ammonium chloride (50 ml), brine (50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography, eluting with a gradient of 10 to 65% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in hexanes. Further purification by preparative reverse phase HPLC eluting with a gradient of 7 to 50% acetonitrile in water containing 0.5% formic acid afforded the title compound as a colorless solid (0.14 g, 27% yield). : 1H NMR (300 MHz, DMSO-d6) δ8.89 (d, J = 2.2 Hz, 1H), 8.17 (s, 1H), 7.36 to 7.29 (m, 4H), 7 .25 (dddd, J = 5.2, 5.0, 2.4, 1.8 Hz, 1H), 7.00 (dd, J = 13.1, 1.3 Hz, 1H), 6.94 (d, J = 2.2 Hz, 1H), 4.65 to 4.57 (m, 1H), 3.52 (s, 2H), 2.63 to 2.55 (m, 2H), 2, 37 to 2.30 (m, 2H), 1.98 (d, J = 1.8 Hz, 3H), 1.94 to 1.88 (m, 2H), 1.71 to 1.64 (m, 2H), NH and COOH not observed; MS (ES+) m/z 480.3 (M + 1). EXAMPLE 107

[01163] Synthesis of (S)-2-fluoro-4-((1-((2-isopropylthiazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino) 2,2,2-trifluoroacetate -5-methyl-N-(thiazol-4-yl)benzenesulfonamide

[01164]Step 1. Preparation of 5-chloro-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide

[01165] A solution of tert-butyl ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (37.0 g, 90.1 mmol) in dichloromethane (400 ml) was Trifluoroacetic acid (200 ml) was added and the reaction mixture was stirred at room temperature for 1 h. Concentration in vacuo gave a residue which was triturated in ethyl acetate (100 ml) to yield the title compound as a colorless solid (25.0 g, 89% yield): 1H NMR (400 MHz, CDCl3) δ 8 .75 (s, 1H), 8.00 (t, J = 7.2 Hz, 1H), 7.07 (s, 1H), 7.02 (t, J = 8.8 Hz, 1H), NH not observed.

[01166]Step 2. Preparation of 5-chloro-2,4-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide

[01167] To a solution of 5-chloro-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide (50.00 g, 161.00 mmol) in anhydrous N,N-dimethylformamide (500 ml), 4-methoxybenzyl chloride (30.20 g, 193.40 mmol) and sodium bicarbonate (69.08 g, 803.85 mmol) were added. The resulting solution was stirred at 50 °C for 16 h and then cooled to room temperature and diluted with cold water (2000 ml). The supernatant was decanted, and the residue was stirred with water (1000 ml) for 2 h until a yellow solid was formed. The solid was collected by filtration and dried in vacuo to obtain the title compound as a pale yellow solid (63.80 g, 92% yield): 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 7.7, 7.1 Hz, 1H), 7.22 (d, J = 14.5 Hz, 2H), 7.18 (d, J = 2.3 Hz, 1H), 7.03 (t, J = 8.8 Hz, 1H), 6.81-6.76 (m, 2H), 5.01 (s, 2H), 3, 76 (d, J = 10.2 Hz, 3H).

[01168]Step 3. Preparation of (S)-3-((2-chloro-5-fluoro-4-(N-(4-methoxybenzyl)- N-(thiazol-4-yl)sulfamoyl)phenyl)amino) tert-butyl pyrrolidine-1-carboxylate

[01169] To a solution of 5-chloro-2,4-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide (15.00 g, 34.95 mmol) and potassium carbonate (15.00 g, 108.62 mmol) in anhydrous N,N-dimethylformamide (100 ml) was added a solution of (S)-1-tert-butoxycarbonyl-3-aminopyrrolidine (6.50 g, 34.90 mmol ) by dripping at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 24 h. The reaction mixture was poured onto ice to provide a gum, which was triturated in water (400 ml) and then dissolved in ethyl acetate (100 ml). The organic phase was washed with water (3 x 150 ml), brine (3 x 100 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo provided a pale yellow solid, which was used directly without further purification (18.60 g, 89% yield).

[01170]Step 5. Preparation of (S)-3-((5-fluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)-2-methylphenyl)amino)pyrrolidine -1-tert-butyl carboxylate

[01171] To a solution of (S)-3-((2-chloro-5-fluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)phenyl)amino)pyrrolidine tert-butyl-1-carboxylate (12.80 g, 21.50 mmol) in anhydrous 1,4-dioxane (425 ml) was added palladium(II) acetate (0.48 g, 2.15 mmol), tetrafluoroborate of tricyclohexylphosphonium (1.58 g, 4.30 mmol), methylboronic acid (10.15 g, 169.44 mmol) and tripotassium phosphate (18.20 g, 85.74 mmol). The mixture was degassed by spraying with argon and then heated to reflux for 6 h. After cooling to room temperature, the mixture was filtered through a Celite filter. The filter was washed with ethyl acetate (500 ml) and the filtrate was concentrated to a volume of about 150 ml. The organic phase was washed with saturated ammonium chloride (2 x 250 ml), brine (100 ml), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo provided the title compound as a brown foam, which was used without further purification (13.0 g, quantitative yield): MS (ES-) m/z 575.2 (M - 1) .

[01172]Step 6. Preparation of (S)-3-((5-fluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)-2-methylphenyl)(methyl) amino)pyrrolidine-1-tert-butylcarboxylate

[01173] To a solution of (S)-3-((5-fluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)-2-methylphenyl)amino)pyrrolidine- tert-Butyl 1-carboxylate (3.26 g, 5.66 mmol) in N,N-dimethylformamide (28 ml) was added iodomethane (0.70 ml, 11.32 mmol) followed by sodium hydride (0.45 g, 11.32 mmol). The solution was stirred for 1 h, then diluted with saturated ammonium chloride (30 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were washed with brine (50 ml), dried with anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 50% ethyl acetate in heptane, provided the title compound as a light brown solid (2.77 g, 83% income). 1H-NMR (300 MHz, CDCl3) δ8.56 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.29 to 7.20 (m , 3H), 6.81 to 6.75 (m, 3H), 5.03 (s, 2H), 3.81 to 3.71 (m, 4H), 3.65 to 3.47 (m, 2H ), 3.34 to 3.19 (m, 2H), 2.65 (s, 3H), 2.22 (s, 3H), 2.04 to 1.88 (m, 2H), 1.47 ( s, 9H); MS (ES+) m/z 591.2 (M + 1).

[01174]Step 7. Preparation of (S)-2-fluoro-5-methyl-4-(methyl(pyrrolidin-3-yl)amino)-N-(thiazol-4-yl) 2,2,2-trifluoroacetate )benzenesulfonamide

[01175] To a solution of (S)-3-((5-fluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)-2-methylphenyl)(methyl)amino )tert-butyl pyrrolidine-1-carboxylate (2.77 g, 4.70 mmol) in dichloromethane (32 ml) trifluoroacetic acid (3.60 ml, 46.98 mmol) was added and the solution was stirred for 2 h. The volatiles were removed in vacuo and the resulting residue was triturated in methanol (50 ml). Filtration and concentration of the filtrate in vacuo provided a residue which was triturated in diethyl ether (50 ml) to give the title compound as a tan solid (2.16 g, 95% yield): MS (ES+) m /z 371.1 (M + 1).

[01176]Step 8. Preparation of (S)-2-fluoro-4-((1-((2-isopropylthiazol-4-yl)methyl)pyrrolidin-3-yl)(methyl) 2,2,2-trifluoroacetate )amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide

[01177] To a solution of (S)-2-fluoro-5-methyl-4-(methyl(pyrrolidin-3-yl)amino)-N-(thiazol-4-yl) 2,2,2-trifluoroacetate benzenesulfonamide (0.081 g, 0.17 mmol) in anhydrous N,N-dimethylformamide (1.7 ml) and anhydrous 1,2-dichloroethane (1.0 ml) was added 2-isopropylthiazol-4-carbaldehyde (0.039 g, 0 .25 mmol) and sodium triacetoxyborohydride (0.071 g, 0.33 mmol). The reaction mixture was stirred at room temperature for 18 hours. The mixture was then diluted with 1 M sodium hydroxide (0.30 ml) and stirred for 1 h. The mixture was diluted with saturated ammonium chloride (6 ml) and extracted with ethyl acetate (2x5 ml). The combined compounds were concentrated in vacuo and purified by reverse phase HPLC, eluting with a gradient of acetonitrile in water containing 0.1% trifluoroacetic acid, to give the title compound as a colorless solid (0.052 g, 49% yield ): 1H NMR (300 MHz, DMSO-d6) δ 11.25 (s, 1H), 10.47 to 10.30 (m, 1H), 8.89 (d, J = 2.2 Hz, 1H) , 7.64 to 7.57 (m, 2H), 7.05 (d, J = 12.4 Hz, 1H), 7.00 (d, J = 2.1 Hz, 1H), 4.42 to 4.37 (m, 2H), 4.19 to 4.11 (m, 2H), 3.51 to 3.34 (m, 5H), 2.62 (s, 3H), 2.45 to 2, 42 (m, 1H), 2.22 (s, 3H), 2.07 to 2.00 (m, 2H), 1.16 to 1.12 (m, 2H), 0.94 (dt, J = 2.6, 2.1Hz, 2H); MS (ES+) m/z 510.1 (M + 1). EXAMPLES 108 TO 127

[01178] In a similar way as described in EXAMPLE 107, with the use of appropriately substituted starting materials and intermediates, the following compounds were prepared: EXAMPLES 128 TO 154

[01179] In a similar way as described in EXAMPLE 107, with the use of appropriately substituted starting materials and intermediates, the following compounds were prepared: EXAMPLE 155

[01180] Synthesis of (S)-2-fluoro-4-((1-(2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide

[01181]Step 1. Preparation of (S)-3-((5-fluoro-2-methyl-4-(N-(thiazol-4-yl)sulfamoyl)phenyl)amino)tert-butylpyrrolidine-1-carboxylate

[01182] To a solution of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenyl)amino)pyrrolidine- 1-tert-butyl carboxylate (8.58 g, 14.87 mmol) in anhydrous 1,4-dioxane (149 ml) was added methylboronic acid (10.15 g, 169.44 mmol) and tripotassium phosphate (18. 20 g, 85.74 mmol). The mixture was degassed by sparging with argon before palladium(II) acetate (0.48 g, 2.15 mmol) and tricyclohexylphosphonium tetrafluoroborate (1.58 g, 4.30 mmol) were added thereto. The resulting suspension was heated to 115°C for 4 h. After cooling to room temperature, the mixture was filtered through a Celite filter. The filter plug was washed with ethyl acetate (200 ml) and the combined filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate (100 ml) and then washed with water (50 ml) and brine (50 ml). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0 to 60% ethyl acetate (containing 10% isopropyl alcohol and 10% triethylamine) in hexanes to yield (S)-3-((4-( N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-5-fluoro-2-methylphenyl)amino)tert-butylpyrrolidine-1-carboxylate as a pale brown solid (5.13 g, 62 % yield) and the title compound as a pale brown solid (1.84 g, 27% yield). Characterization data of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-5-fluoro-2-methylphenyl)amino)pyrrolidine-1-carboxylate tert-butyl: 1H-NMR (300 MHz, CDCI3) δ 8.79 (d, J = 2.3 Hz, 1H), 7.70 (dd, J = 8.0, 0.8 Hz, 1H), 7.51 (dd, J = 2.3, 0.5 Hz, 1H), 6.33 (d, J = 12.7 Hz, 1H), 4.08 to 4.03 (m, 1H), 3 .79 to 3.73 (m, 1H), 3.54 to 3.48 (m, 2H), 3.33 to 3.27 (m, 1H), 2.34 (d, J = 7.8 Hz , 1H), 2.12 (s, 3H), 1.92 (dt, J = 0.8, 0.4 Hz, 1H), 1.48 (s, 9H), 1.35 (s, 9H) , NH not observed; MS (ES+) m/z 557.2 (M + 1), 558.3 (M + 1). Characterization data of (S)-3-((5-fluoro-2-methyl-4-(N-(thiazol-4-yl)sulfamoyl)phenyl)amino)pyrrolidine-1-tert-butylcarboxylate: 1H NMR ( 300 MHz, CDCl3) δ8.66 (td, J = 1.1, 0.6 Hz, 1H), 7.51 (dd, J = 8.0, 0.7 Hz, 1H), 6.98 (dt , J = 1.6, 0.4 Hz, 1H), 6.29 (d, J = 12.8 Hz, 1H), 4.05 to 3.98 (m, 1H), 3.76 to 3, 70 (m, 1H), 3.54 to 3.47 (m, 2H), 3.30 to 3.25 (m, 1H), 2.29 to 2.20 (m, 1H), 2.07 ( s, 3H), 1.96 to 1.89 (m, 1H), 1.48 (s, 9H), NH not observed; MS (ES+) m/z 457.1 (M + 1), 458.1 (M + 1); MS (ES-) m/z 455.3 (M - 1), 456.2 (M - 1).

[01183]Step 2. Preparation of (S)-2-fluoro-5-methyl-4-(pyrrolidin-3-ylamino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01184] To a solution of (S)-3-((5-fluoro-2-methyl-4-(N-(thiazol-4-yl))sulfamoyl) phenyl)amino) tert-butyl pyrrolidine-1-carboxylate (0.900 g, 1.97 mmol) in dichloromethane (30 ml) trifluoroacetic acid (7 ml) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether (10 ml). The resulting suspension was filtered to give the title compound as a pale yellow solid (0.805 g, 87% yield) which was used without further purification: MS (ES+) m/z 357.2 (M + 1), 358. 2 (M + 1).

[01185]Step 3. Preparation of (S)-2-fluoro-4-((1-(2-fluorobenzyl)pyrrolidin-3-yl)amino)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide

[01186] To a solution of (S)-2-fluoro-5-methyl-4-(pyrrolidin-3-ylamino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate (0.250 g , 0.531 mmol) in anhydrous 1,2-dichloroethane (4.5 ml) and anhydrous N,N-dimethylformamide (4.5 ml) 2-fluorobenzaldehyde (0.170 ml, 1.59 mmol) was added. After 15 minutes, sodium triacetoxyborohydride (0.338 g, 1.59 mmol) was added and the reaction was stirred at room temperature for 16 h. The reaction was diluted with ethyl acetate (50 ml) and washed with brine (2 x 25 ml). The aqueous layers were extracted with ethyl acetate (3 x 75 ml). The combined organic layers were dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 5% methanol (containing 2% ammonium hydroxide) in dichloromethane gave the title compound as a pale yellow solid (0.209 g, 85% yield). MS (ES+) m/z 465.2 (M + 1), 466.1 (M + 1); (ES-) m/z 463.2 (M - 1), 464.2 (M - 1).

[01187]Step 4. Preparation of (S)-2-fluoro-4-((1-(2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-5-methyl-N-(thiazol-4- il)benzenesulfonamide

[01188] To a cooled (0 °C) solution of (S)-2-fluoro-4-((1-(2-fluorobenzyl)pyrrolidin-3-yl)amino)-5-methyl-N-(thiazol- 4-yl)benzenesulfonamide (0.209 g, 0.450 mmol) in trifluoroacetic acid (4.5 ml) was added sodium triacetoxyborohydride (0.286 g, 1.35 mmol). The resulting mixture was stirred at 0°C for 10 minutes before paraformaldehyde (0.020 g, 0.68 mmol) was added thereto. The reaction mixture was stirred at 0 °C for 45 minutes and then concentrated in vacuo. To the residue were added 2M sodium hydroxide (15 ml) and brine (15 ml), and the mixture was extracted with ethyl acetate (50 ml). The aqueous layer was diluted with saturated ammonium chloride (50 ml) and then extracted with ethyl acetate (50 ml). The organic layers were washed with saturated ammonium chloride (30 ml), brine (30 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 5% methanol (containing 2% ammonium hydroxide in dichloromethane, provided the title compound as a pale yellow solid (0.093 g, 43% yield) 1H NMR (300 MHz, CDCI3) δ8.71 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.4, 0.5 Hz, 1H) , 7.48 to 7.43 (m, 1H), 7.31 to 7.24 (m, 1H), 7.13 (td, J = 7.5, 1.2 Hz, 1H), 7.04 (ddd, J = 9.9, 8.4, 1.3 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6.63 (d, J = 12.3 Hz, 1H), 3.96 to 3.88 (m, 1H), 3.88 to 3.75 (m, 2H), 2.93 to 2.68 (m, 4H), 2.64 (s, 3H) , 2.21 (d, J = 4.3 Hz, 3H), 2.16 to 2.04 (m, 1H), 1.90 to 1.83 (m, 1H), NH not observed (ES+; ) m/z 479.2 (M + 1); MS (ES-) m/z 477.3 (M - 1).

[01189] In a similar manner as described in EXAMPLE 155, Step 3 to Step 4, with the use of appropriately substituted starting materials and intermediates, the following compounds were prepared: EXAMPLE 158

[01190] Synthesis of (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide formate

[01191]Step 1. Preparation of (S)-1-benzyl-3-methylpyrrolidin-3-ol

[01192]A mixture of benzaldehyde (3.0 g, 29.7 mmol) and (S)-3-methylpyrrolidin-3-ol (1.0 g, 9.90 mmol) in anhydrous N,N-dimethylformamide ( 10 ml) and anhydrous 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (6.29 g, 29.7 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was cooled to 0 °C and quenched with methanol (5 ml) and 1 M hydrochloric acid (10 ml). Dithyl ether (30 ml) and water (30 ml) were added to it. The aqueous layer was adjusted with 1 M sodium hydroxide solution to pH 9 to 10 and extracted with ethyl acetate (3 x 30 ml). The combined organic phase was washed with brine (40 ml) and concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 80% ethyl acetate (containing 10% 2-propanol and 10% triethylamine) in heptane, provided the title compound as a pink oil (1 .4 g, 76% yield): 1H NMR (300 MHz, CDCI3) δ 7.33 to 7.24 (m, 5H), 3.66 (s, 2H), 3.03 to 2.96 (m , 1H), 2.75 (dd, J = 9.6, 0.6 Hz, 1H), 2.41 to 2.33 (m, 1H), 2.28 to 2.25 (m, 1H), 1.93 to 1.87 (m, 2H), 1.34 (s, 3H), OH not observed; MS (ES+) m/z 192.3 (M + 1).

[01193]Step 2. Preparation of (S)-((4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-3-chloro-2,6-difluorophenyl)sulfonyl)(thiazol-4- il) tert-butyl carbamate

[01194] Following the procedure as described in Example 105, Step 1 and making non-critical variations as necessary to replace 1-benzylpiperidin-4-ol with (S)-1-benzyl-3-methylpyrrolidin-3-ol, the compound of title was obtained as an orange oil (0.15 g, 17% yield): MS (ES+) m/z 600.1 (M + 1), 602.1 (M + 1).

[01195]Step 3. Preparation of (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-) formate il)benzenesulfonamide

[01196]A mixture of (S)-((4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-3-chloro-2,6-difluorophenyl)sulfonyl)(thiazol-4-yl ) tert-butyl carbamate (0.15 g, 0.25 mmol) and methylboronic acid (0.081 g, 13.6 mmol) in anhydrous 1,4-dioxane (5 ml) tribasic potassium phosphate (0.16 g) was added , 0.74 mmol) and the mixture was degassed by passing a flow of argon through it for 15 minutes. To the mixture was then added tricyclohexylphosphine tetrafluoroborate (0.027 g, 0.07 mmol) and palladium(II) acetate (0.008 g, 0.04 mmol), and the resulting mixture was heated in a microwave at 101 °C for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue obtained was dissolved in ethyl acetate (30 ml) and the mixture was diluted with saturated ammonium chloride (50 ml). The aqueous phase was extracted with ethyl acetate (2 x 30 ml). The combined organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide (S)-((4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methylphenyl)sulfonyl)(thiazol-4- il) tert-butyl carbamate which was used directly without further purification. To a mixture of (S)-((4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methylphenyl)sulfonyl)(thiazol-4-yl) tert carbamate -butyl acid (0.064 g, 0.11 mmol) in anhydrous dichloromethane (2 ml) trifluoroacetic acid (0.17 ml, 2.2 mmol) was added and the reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo, and the residue purified by preparative reverse phase HPLC, eluting with a gradient of acetonitrile in water containing 0.5% formic acid, to give the title compound as a colorless solid (0.012 g, 5 % yield in 2 steps): 1H NMR (300 MHz, DMSO-d6) δ8.82 (d, J = 2.1 Hz, 1H), 8.19 (s, 0.5H), 7.35 to 7 .20 (m, 5H), 7.08 to 7.03 (m, 1H), 6.75 to 6.74 (m, 1H), 3.64 (d, J = 13.2 Hz, 1H), 3.53 (d, J = 13.2 Hz, 1H), 2.91 (d, J = 10.6 Hz, 1H), 2.79 to 2.70 (m, 1H), 2.59 (d , J = 10.4 Hz, 1H), 2.55 to 2.47 (m, 1H), 2.28 to 2.18 (m, 1H), 2.04 to 1.99 (m, 1H), 1.94 (d, J = 2.0 Hz, 3H), 1.53 (s, 3H), NH and COOH not observed; MS (ES+) m/z 480.1 (M + 1). EXAMPLE 159

[01197] Synthesis of (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide formate

[01198]Step 1. Preparation of (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01199] To a solution of (S)-1-benzyl-3-methylpyrrolidin-3-ol (0.30 g, 1.57 mmol) and ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazole -4-yl) tert-butyl carbamate (0.58 g, 1.42 mmol) in anhydrous N,N-dimethylformamide (14 ml) was added to a dispersion of 60% sodium hydride in mineral oil (0.11 g , 2.85 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h, diluted with ethyl acetate (40 ml) and then quenched by slow addition of water (15 ml) and saturated ammonium chloride (20 ml). . The aqueous phase was extracted with ethyl acetate (2 x 40 ml) and the organic phase was washed with brine (2 x 30 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 80% ethyl acetate (containing 10% triethylamine and 10% 2-propanol) in heptane, provided the title compound. as an orange oil (0.45 g, 54% yield). MS (ES+) m/z 482.0 (M + 1), 484.1 (M + 1).

[01200]Step 2. Preparation of (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2-fluoro-5-methyl-N-(thiazol-4-yl) formate benzenesulfonamide

[01201] A mixture of (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl) tert-benzenesulfonamide butyl (0.45 g, 0.94 mmol) and methylboronic acid (0.31 g, 51.5 mmol) in anhydrous 1,4-dioxane (9 ml) tribasic potassium phosphate (0.79 g, 3 .74 mmol) and the mixture was degassed by passing a stream of argon through it for 15 minutes. To the mixture was then added tricyclohexiphosphine tetrafluoroborate (0.10 g, 0.28 mmol) and palladium(II) acetate (0.032 g, 0.14 mmol), and the resulting mixture was heated in a micro- waves up to 101 °C for 2 h. The reaction mixture was allowed to cool to room temperature, and methylboronic acid (0.31 g, 51.5 mmol) was added to it. The reaction mixture was degassed by passing a flow of argon through it for 15 minutes, and tricyclohexylphosphine tetrafluoroborate (0.10 g, 0.28 mmol) and palladium(II) acetate (0.032 g, 0.14 mmol) were added to it. The reaction mixture was then heated in a microwave reactor to 101 °C for 90 minutes. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuo to provide a residue, which was dissolved in ethyl acetate (30 ml). Saturated ammonium chloride (50 ml) was added to it, and the mixture was extracted with ethyl acetate (2 x 30 ml). The combined organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by preparative reverse phase HPLC, eluting with a gradient of acetonitrile in water containing 0.5% formic acid, to give the title compound as a colorless solid (0.020 g, 4% yield): 1H NMR (300 MHz, DMSO-d6): δ 8.85 (d, J = 2.2 Hz, 1H), 8.20 (s, 0.4H), 7.58 (dd, J = 8.7, 0.6 Hz, 1H), 7.30 to 7.17 (m, 6H), 6.86 (d, J = 2.2 Hz, 1H), 3.63 (d, J = 13.0 Hz, 1H), 3.54 (d, J = 13.0 Hz, 1H), 2.92 to 2.89 (m, 1H), 2.77 to 2.69 (m, 1H), 2.63 to 2.53 (m, 1H), 2.56 to 2.48 (m, 1H), 2.28 to 2.18 (m, 1H), 2.07 (s, 3H), 2, 04 to 1.96 (m, 1H), 1.53 (s, 3H), NH and COOH not observed; MS (ES+) m/z 462.1 (M + 1). EXAMPLE 160

[01202] Synthesis of (S)-5-chloro-4-((1-((6-(difluoromethyl)pyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro- N-(thiazol-4-yl)benzenesulfonamide

[01203]Step 1. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenyl)(methyl) amino)pyrrolidine-1-tert-butylcarboxylate

[01204] Following the procedure as described in EXAMPLE 101, Step 4 and making non-critical variations as necessary to replace (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl )sulfamoyl)-5-fluoro-2-methylphenyl)amino)pyrrolidine-1-tert-butyl carboxylate by (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl )sulfamoyl)-2-chloro-5-fluorophenyl)amino)pyrrolidine-1-tert-butylcarboxylate, the title compound was obtained as a colorless foam (3.36 g, 85% yield): 1H NMR (300 MHz , CDCl3) δ8.81 (d, J = 2.3 Hz, 1H), 8.07 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H) , 6.83 (d, J = 11.8 Hz, 1H), 4.27 to 4.23 (m, 1H), 3.65 to 3.58 (m, 2H), 3.35 to 3.31 (m, 2H), 2.85 (s, 3H), 2.09 (td, J = 7.9, 2.7 Hz, 2H), 1.48 (s, 9H), 1.39 (s, 9H); MS (ES+) m/z 613.4 (M + 23), 615.4 (M + 23).

[01205]Step 2. Preparation of (S)-5-chloro-2-fluoro-4-(methyl(pyrrolidin-3-yl)amino)-N-(thiazol-4-yl) 2,2,2-trifluoroacetate )benzenesulfonamide

[01206] Following the procedure as described in EXAMPLE 253, Step 2 and making non-critical variations as necessary to replace (S)-3-((2-chloro-4-(N-(thiazol-4-yl)sulfamoyl)phenyl tert-butyl )(methyl)amino)pyrrolidine-1-carboxylate with (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro- tert-butyl 5-fluorophenyl)(methyl)amino)pyrrolidine-1-carboxylate, the title compound was obtained as a colorless foam (1.68 g, quantitative yield): MS (ES+) m/z 391.2 (M +1), 393.2 (M + 1).

[01207]Step 3. Preparation of 2-bromo-6-(difluoromethyl)pyridine

[01208] To a solution of 6-bromopicolinaldehyde (2.10 g, 11.29 mmol) in dichloromethane (20 ml) was added diethylaminosulfur trifluoride (1.94 ml, 14.68 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 18 h and then poured into an ice-cold saturated sodium bicarbonate solution (300 ml). The mixture was extracted with ethyl acetate (2 x 120 ml). The combined organic phase was washed with sodium bicarbonate (80 ml), brine (2 x 50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo yielded the title compound as a brown oil (2.17 g, 89% yield): 1H NMR (300 MHz, CDCI3) δ 7.75 to 7.70 (m, 1H), 7 .65 to 7.60 (m, 2H), 6.60 (t, J = 55.1 Hz, 1H).

[01209]Step 4. Preparation of 6-(difluoromethyl)picolinaldehyde

[01210] To a solution of 2-bromo-6-(difluoromethyl)pyridine (2.17 g, 10.53 mmol) in anhydrous tetrahydrofuran (50 ml) was added 1.3 M solution of isopropylmagnesium chloride complex and lithium in tetrahydrofuran (54.24 ml, 41.72 mmol) at - 42 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h, then cooled to -42 °C, and anhydrous N,N-dimethylformamide (50 ml) was added thereto. The reaction mixture was allowed to warm naturally to room temperature, stirred for 18 h, and then diluted with ethyl acetate (140 ml). The mixture was washed with 1 M aqueous hydrochloric acid (2 x 60 ml), saturated ammonium chloride (60 ml), brine (60 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo yielded the title compound as a brown oil (1.55 g, 95% yield): 1H NMR (300 MHz, CDCl3) δ 10.08 (s, 1H), 8.09 to 8 .05 (m, 2H), 7.91 to 7.85 (m, 1H), 6.73 (t, J = 55.1 Hz, 2H).

[01211]Step 5. Preparation of (S)-5-chloro-4-((1-((6-(difluoromethyl)pyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2 -fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01212]A mixture of (S)-5-chloro-2-fluoro-4-(methyl(pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate (0.51 g, 1.00 mmol) and 6-(difluoromethyl)picolinaldehyde (0.24 g, 1.5 mmol) in dichloromethane (8 ml) and N,N-dimethylformamide (8 ml) were added sodium triacetoxyborohydride (0.42 g, 2.00 mmol). The reaction mixture was stirred for 3 h, and then diluted with ethyl acetate (60 ml). The mixture was washed with a 1:1 mixture of 1 M aqueous sodium hydroxide and brine (60 ml), saturated ammonium chloride (30 ml), brine (30 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 60% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in dichloromethane, produced the compound of the title as a colorless solid (0.32 g, 60% yield). 1H NMR (300 MHz, DMSO-d6) δ8.76 (d, J = 2.3 Hz, 1H), 7.86 to 7.80 (m, 2H), 7.54 (d, J = 7.7 Hz, 2H), 6.92 (d, J = 2.3 Hz, 1H), 6.82 to 6.44 (m, 2H), 4.32 to 4.22 (m, 1H), 3.90 (d, J = 14.1 Hz, 1H), 3.75 (d, J = 14.0 Hz, 1H), 2.93 to 2.90 (m, 1H), 2.85 (s, 3H) , 2.81 to 2.67 (m, 2H), 2.61 to 2.50 (m, 1H), 2.22 to 2.11 (m, 1H), 2.00 to 1.88 (m, 1H), NH not observed; MS (ES+) m/z 532.4 (M + 1), 534.2 (M + 1). EXAMPLE 161

[01213] Synthesis of (S)-5-chloro-2-fluoro-4-((1-(3-(2-hydroxypropan-2-yl)benzyl)pyrrolidin-3-yl)(methyl)amino formate -N-(thiazol-4-yl)benzenesulfonamide

[01214]Step 1. Preparation of (S)-methyl-3-((3-((2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenyl)(methyl)amino )pyrrolidin-1-yl)methyl)benzoate

[01215]A mixture of methyl 3-formylbenzoate (0.0900 g, 0.548 mmol), (S)-5-chloro-2-fluoro-4-(methyl(pyrrolidin-3-yl)amino hydrochloride salt )-N-(thiazol-4-yl)benzenesulfonamide (0.195 g, 0.456 mmol) in tetrahydrofuran (2 ml) was added sodium triacetoxyborohydride (0.193 g, 0.913 mmol) and the reaction mixture was stirred at room temperature for 2 h . Additional sodium triacetoxyborohydride (0.097 g, 0.456 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. Concentration in vacuo and purification of the residue by preparative reversed-phase HPLC, using acetonitrile in water containing 0.225% formic acid as eluent, gave the title compound as a colorless solid (0.129 g, 52% yield): MS (ES+ ) m/z 539.0 (M + 1), 541.0 (M + 1).

[01216]Step 2. Preparation of (S)-5-chloro-2-fluoro-4-((1-(3-(2-hydroxypropan-2-yl)benzyl)pyrrolidin-3-yl)(methyl formate )amino)-N-(thiazol-4-yl)benzenesulfonamide

[01217] To a solution of methylmagnesium bromide (3 M in tetrahydrofuran, 0.717 ml, 2.15 mmol) was added a solution of (S)-methyl 3-((3-((2-chloro-5-fluoro- 4-(N-(thiazol-4-yl)sulfamoyl)phenyl)(methyl)amino)pyrrolidin-1-yl)methyl)benzoate (0.129 g, 0.239 mmol) in anhydrous tetrahydrofuran (2 ml) at 0 °C. The reaction mixture was allowed to warm to room temperature, stirred for 2 h and then quenched with aqueous ammonium chloride (5 ml). The mixture was extracted with ethyl acetate (2 x 30 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. Purification of the residue by preparative reversed-phase HPLC, using acetonitrile in water containing 0.225% formic acid as eluent, provided the title compound as a colorless solid (0.089 g, 68% yield): 1H NMR (400 MHz, CD3OD ) δ 8.73 (d, J = 2.0 Hz, 1H), 8.45 (br s, 0.75H), 7.82 (d, J = 7.2 Hz, 1H), 7.59 ( s, 1H), 7.52 (br d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.29 (br d, J = 7.2 Hz, 1H), 7.08 to 7.02 (m, 2H), 4.62 (br s, 1H), 4.36 to 4.33 (m, 1H), 4.08 (q, J = 12 .8 Hz, 2H), 3.30 to 2.98 (m, 5H), 2.84 (s, 3H), 2.31 to 2.00 (m, 2H), 1.55 (s, 6H) , NH and COOH not observed; MS (ES+) m/z 539.0 (M + 1), 541.0 (M + 1). EXAMPLE 162

[01218] Synthesis of 5-chloro-4-(((3R,4S)-1-(3-(difluoromethyl)benzyl)-3-fluoropiperidin-4-yl)oxy)-2-fluoro-N-(thiazol- 4-yl)benzenesulfonamide

[01219] Step 1. Preparation of 5-chloro-2-fluoro-4- (((3R,4S)-3-fluoropiperidin-4-yl)oxy)-N-(thiazol-) 2,2,2-trifluoroacetate 4-yl)benzenesulfonamide

[01220] To a solution of (3R,4S)-3-fluoro-4-hydroxypiperidine-1-tert-butyl carboxylate (0.267 g. 1.22 mmol) and ((5-chloro-2,4-difluorophenyl)sulfonyl )(tert-butyl thiazol-4-yl)carbamate (0.500 g, 1.22 mmol) in anhydrous N,N-dimethylformamide (10 ml) was added sodium hydride (60% dispersion in mineral oil, 0.146 g, 3 .65 mmol) and the suspension was stirred at room temperature for 1 h. Saturated ammonium chloride solution (10 ml) was added followed by water (10 ml) and ethyl acetate (20 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate (3 x 20 ml). The combined organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo provided a residue which was purified by column chromatography eluting with a gradient of -60% ethyl acetate in hexanes. The purified residue was then dissolved in dichloromethane (10 ml) and trifluoroacetic acid (2 ml) was added thereto. The reaction mixture was stirred at room temperature for 20 h. Concentration in vacuo gave the title compound as a colorless oil (0.664 g, quantitative yield): MS (ES+) m/z 408.2 (M + 1), 410.2 (M + 1).

[01221]Step 2. Preparation of 5-chloro-4-(((3R,4S)-1-(3-(difluoromethyl)benzyl)- 3-fluoropiperidin-4-yl)oxy)-2-fluoro-N- (thiazol-4-yl)benzenesulfonamide

[01222] To a solution of 5-chloro-2-fluoro-4-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-N-(thiazol-4) 2,2,2-trifluoroacetate -yl)benzenesulfonamide (0.332 g, 0.637 mmol) and 3-(difluoromethyl)benzaldehyde (0.100 g, 0.637 mmol) in anhydrous tetrahydrofuran (4 ml) was added sodium triacetoxyborohydride (0.268 g, 1.27 mmol). The mixture was stirred at room temperature for 2 h. An aqueous ammonium chloride solution (5 ml) and ethyl acetate (5 ml) were added to the mixture and the layers were separated. The aqueous phase was extracted with ethyl acetate (3 x 5 ml). The combined organic phase was washed with brine (5 ml), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 20% methanol in dichloromethane, gave the title compound as a colorless solid (0.152 g, 43% yield): 1H -NMR (300 MHz, DMSO-d6) δ 8.90 (s, 1H), 7.95 to 7.91 (m, 1H), 7.63 to 7.44 (m, 5H), 7.36 to 6.80 (m, 1H), 7.23 to 7.06 (m, 1H), 5.35 to 4.49 (m, 1H), 4.97 to 4.83 (m, 1H), 3, 80 (s, 2H), 2.88 to 2.73 (m, 1H), 2.72 to 2.54 (m, 2H), 2.54 to 2.22 (m, 1H), 1.85 to 1.68 (m, 2H), NH not observed; MS (ES+) m/z 548.2 (M + 1), 550.2 (M + 1). EXAMPLE 163

[01223] Synthesis of (S)-5-chloro-4-((1-((6-(difluoromethyl)-3-fluoropyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino formate -2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01224]Step 1. Preparation of (6-bromo-5-fluoropyridin-2-yl)methanol

[01225] To a solution of 6-bromo-5-fluoropicolinic acid (4.50 g, 20.5 mmol) in anhydrous tetrahydrofuran (60 ml) was added a borane dimethylsulfide complex (10 M, 5.11 ml, 51.1 mmol) at 0 °C. The mixture was then heated to 80 °C for 2 h. After cooling to room temperature, the reaction mixture was quenched with methanol (30 ml) and concentrated in vacuo to provide the title compound as a colorless oil (4.0 g, 95% yield): MS (ES+ ) m/z 205.9 (M + 1), 207.9 (M + 1).

[01226]Step 2. Preparation of 6-bromo-5-fluoropicolinaldehyde

[01227] To a solution of (6-bromo-5-fluoropyridin-2-yl)methanol (4.00 g, 19.4 mmol) in chloroform (60 ml) was added manganese dioxide (8.44 g, 97 .1 mmol) and the resulting mixture was heated to reflux for 12 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography, eluting with a gradient of 2 to 10% ethyl acetate in petroleum ether, provided the title compound as a yellow solid (3.00 g, 76% yield): 1H NMR (400 MHz, CDCI3) δ 10.00 (s, 1H), 8.00 (ddd, J = 1.6, 3.6, 8.4 Hz, 1H), 7.68 to 7.54 (m, 1H).

[01228]Step 3. Preparation of 2-bromo-6-(difluoromethyl)-3-fluoropyridine

[01229] To a solution of 6-bromo-5-fluoropicolinaldehyde (2.90 g, 14.2 mmol) in dichloromethane (50 ml) was added diethylaminosulfur trifluoride (4.58 g, 28.4 mmol) in portions 0°C. The reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was slowly poured into ice water (50 ml) and extracted with dichloromethane (2 x 50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with 2% ethyl acetate in petroleum ether, to give the title compound as a pale yellow oil (2.00 g, 62% yield): 1H NMR (400 MHz , CDCI3) δ7.73 to 7.63 (m, 1H), 7.63 to 7.49 (m, 1H), 6.62 (t, J = 55.0 Hz, 1H).

[01230]Step 4. Preparation of methyl 6-(difluoromethyl)-3-fluoropicolinate

[01231] To a solution of 2-bromo-6-(difluoromethyl)-3-fluoropyridine (1.80 g, 7.96 mmol) in methanol (30 ml) was added [1,1'-bis(diphenyphosphino)ferrocene ]dichloropalladium(II) (0.291 g, 0.398 mmol) and N,N-diisopropylethylamine (2.06 g, 15.9 mmol, 2.78 ml). The resulting mixture was heated to 60°C under a CO atmosphere (50 psi) for 12 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, eluting with 17% ethyl acetate in petroleum ether, to give the title compound as a yellow oil (1.30 g, 79% yield): 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 3.6, 8.8 Hz, 1H), 7.79 to 7.68 (m, 1H), 6.74 (t, J = 54.8 Hz, 1H ), 4.05 (s, 3H).

[01232]Step 5. Preparation of (6-(difluoromethyl)-3-fluoropyridin-2-yl)methanol

[01233] To a cooled solution (0 °C) of methyl 6-(difluoromethyl)-3-fluoropicolinate (1.30 g, 6.34 mmol) and calcium chloride (1.76 g, 15.9 mmol) in anhydrous methanol (20 ml) and anhydrous tetrahydrofuran (10 ml) sodium borohydride (4.41 g, 117 mmol) was added in portions. The resulting mixture was stirred at 0°C for 2 h and then water (10 ml) was added thereto. Concentration in vacuo gave a residue which was dissolved in water (10 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were dried with anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo gave the title compound as a colorless oil (1.00 g, 89% yield): 1H NMR (400 MHz, CDCla) δ 7.66 (dd, J = 3.8, 8. 4 Hz, 1H), 7.60 to 7.51 (m, 1H), 6.68 (t, J = 55.2 Hz, 1H), 4.90 (d, J = 4.4 Hz, 2H) , 3.60 (t, J = 5.2 Hz, 1H).

[01234]Step 6. Preparation of 6-(difluoromethyl)-3-fluoropicolinaldehyde

[01235] To a solution of (6-difluoromethyl)-3-fluoropyridin-2-yl)methanol (1.00 g, 5.65 mmol) in chloroform (30 ml) was added manganese dioxide (2.46 g, 28.3 mmol) and the mixture was heated to reflux for 12 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, eluting with a gradient of 5 to 9% ethyl acetate in petroleum ether, to give the title compound as a yellow oil (0.70 g, 71% yield): 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 7.95 (dd, J = 3.6, 8.8 Hz, 1H), 7.77 (t, J = 9.2 Hz, 1H), 6.75 (t, J = 55.0 Hz, 1H).

[01236]Step 7. Preparation of (S)-5-chloro-4-((1-((6-(difluoromethyl)-3-fluoropyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl) formate )amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01237] To a solution of (S)-5-chloro-2-fluoro-4-(methyl(pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide (0.100 g, 0.234 mmol) and 6-(difluoromethyl)-3-fluoropicolinaldehyde (0.102 g, 0.585 mmol) in dichloromethane (5 ml) was added acetic acid (0.50 ml) and sodium triacetoxyborohydride (0.148 g, 0.702 mmol) in parts and the resulting mixture was stirred at room temperature for 1 h. Concentration in vacuo and purification of the residue by preparative phase HPLC, using acetonitrile in water containing 0.225% formic acid as eluent, gave the title compound as a colorless solid (0.017 g, 13% yield): 1H NMR (400 MHz, CD3OD) δ 8.74 (d, J = 2.2 Hz, 1H), 8.40 (br s, 0.8H), 7.83-7.71 (m, 3H), 7.04 ( d, J = 2.2 Hz, 1H), 7.00 (d, J = 12.0 Hz, 1H), 6.75 (t, J = 55.2 Hz, 1H), 4.35 to 4, 26 (m, 1H), 4.16 to 4.02 (m, 2H), 3.09 to 2.96 (m, 3H), 2.92 to 2.84 (m, 1H), 2.83 ( s, 3H), 2.22 to 2.12 (m, 1H), 2.05 to 1.92 (m, 1H), NH and COOH not observed; MS (ES+) m/z 549.9 (M + 1), 551.9 (M + 1). EXAMPLES 164 TO 194

[01238] In a similar way as described in EXAMPLE 163, with the use of appropriately substituted starting materials and intermediates, the following compounds were prepared: EXAMPLES 195 TO 220

[01239] In a similar way as described in EXAMPLE 163, with the use of appropriately substituted starting materials and intermediates, the following compounds were prepared: EXAMPLE 221

[01240] Synthesis of (S)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(1,2,4-) 2,2,2-trifluoroacetate thiadiazol-5-yl)benzenesulfonamide

[01241] Following the procedure as described in EXAMPLE 58, Step 3 and making non-critical variations as necessary to replace 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl) benzenesulfonamide by 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, the title compound was obtained as a colorless solid (0.025 g , 6% yield): 1H NMR (300 MHz, DMSO-d6) δ9.87 (br s, 1H), 7.78 to 7.66 (m, 2H), 7.60 to 7.44 (m, 6H), 7.44 to 7.29 (m, 1H), 5.05 to 4.92 (m, 1H), 4.76 to 4.58 (m, 1H), 3.82 to 3.23 ( m, 2H), 3.02 to 2.70 (m, 2H), 2.40 to 1.76 (m, 4H), 1.68 (d, J = 7.0 Hz, 3H), NH not observed ; MS (ES+) m/z 479.0 (M + 1), 481.0 (M + 1). EXAMPLE 222

[01242] Synthesis of (R)-5-chloro-2-fluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-) 2,2,2-trifluoroacetate 4-yl)benzenesulfonamide

[01243] Following the procedure as described in EXAMPLE 57, Step 3 and making non-critical variations as necessary to replace 3-chloro-4-fluoro-N-(thiazol-4-yl)benzenesulfonamide with 5-chloro-2,4- difluoro-N-(thiazol-4-yl)benzenesulfonamide, the title compound was obtained as a colorless solid (0.04 g, 9% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.37 a 11.35 (m, 1H), 9.93 to 9.68 (m, 1H), 8.89 (d, J = 2.2 Hz, 1H), 7.81 to 7.74 (m, 1H) , 7.62 to 7.40 (m, 5H), 7.07 (s, 1H), 4.98 to 4.96 (m, 1H), 4.69 to 4.62 (m, 1H), 3 .74 to 3.68 (m, 1H), 3.59 to 3.28 (m, 2H), 2.92 to 2.71 (m, 2H), 2.31 to 2.22 (m, 1H) , 2.13 to 1.99 (m, 2H), 1.68 (d, J = 6.9 Hz, 3H); MS (ES+) m/z 496.1 (M + 1), 498.1 (M + 1). EXAMPLE 223

[01244] Synthesis of 4-((1-benzylpiperidin-4-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01245]Step 1. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(thiazol-2-yl)benzenesulfonamide

[01246] To a solution of N-(2,4-dimethoxybenzyl)thiazol-2-amine (4.11 g, 16.4 mmol) in anhydrous tetrahydrofuran (150 ml) was added 1.0 M bis( lithium trimethylsilyl)amide in tetrahydrofuran (16.40 ml, 16.40 mmol) at -78 °C. The reaction mixture was allowed to warm to room temperature, stirred for 1 h, and then cooled to −78 °C. To it was added a solution of 3-chloro-2,4,6-trifluorobenzenesulfonyl chloride (3.96 g, 14.90 mmol) in tetrahydrofuran (75 ml) -78 °C. The reaction mixture was stirred at -78 °C for 1 h and then at room temperature for 18 h. The mixture was diluted with saturated ammonium chloride (100 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic fractions were washed with brine (100 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography, eluting with a gradient of 0 to 30% ethyl acetate in pentane, to give the title compound as a colorless solid (3.48 g, 49% yield): 1H NMR (300 MHz, CDCI3) δ7.44 (d, J = 3.6 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 3.6 Hz, 1H), 6.90 to 6.82 (m, 1H), 6.39 to 6.36 (m, 2H), 5.21 (s, 2H), 3.76 (s, 3H), 3.74 (s, 3H).

[01247]Step 2. Preparation of 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-3,5-dilfluorophenoxy)piperidine-1- tert-butyl carboxylate

[01248] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.42 g, 2.10 mmol) and 3-chloro-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro -N-(thiazol-2-yl)benzenesulfonamide (1.00 g, 2.10 mmol) in anhydrous N,N-dimethylformamide (20 ml) was added to a dispersion of 60% sodium hydride in mineral oil (0. 17 g, 4.2 mmol) at room temperature. The reaction mixture was stirred for 18 h and then quenched with saturated ammonium chloride (80 ml). The mixture was extracted with ethyl acetate (3 x 80 ml). The combined organic fractions were washed with brine (2 x 80 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and purified by column chromatography, eluting with a gradient of 0 to 50% ethyl acetate in heptane, to give the title compound as a colorless solid (0.97 g, 70% yield). : 1H NMR (300 MHz, CDCl3) δ 7.43 to 7.42 (m, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.01 (d, J = 3.6 Hz, 1H), 6.53 to 6.47 (m, 1H), 6.39 to 6.36 (m, 2H), 5.23 (s, 2H), 4.60 to 4.56 (m, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 3.58 to 3.51 (m, 4H), 1.94 to 1.81 (m, 4H), 1.47 (s, 9H).

[01249]Step 3. Preparation of 4-(4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-3,5-difluoro-2-methylphenoxy)piperidine-1- tert-butyl carboxylate

[01250]A mixture of 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-3,5-difluorophenoxy)piperidine-1-carboxylate tert-butyl (0.97 g, 1.50 mmol), methylboronic acid (0.88 g, 14.7 mmol), and potassium phosphate (1.59 g, 7.50 mmol) in anhydrous dioxane (30 ml ) palladium acetate (0.10 g, 0.44 mmol) and tricyclohexylphosphonium tetrafluoroborate (0.32 g, 0.88 mmol) were added. The resulting mixture was degassed and sparged with nitrogen and heated to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature and stirred for 18 h. After concentration in vacuo, the residue was diluted in water (100 ml) and the mixture was extracted with ethyl acetate (4 x 50 ml). The combined organic fractions were washed with brine (100 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography, eluting with a gradient of 0 to 6% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in heptane, to yield the title compound as a grayish oil (0.93 g, 97% yield): MS (ES+) m/z 640.5 (M + 1).

[01251]Step 4. Preparation of 2,6-difluoro-3-methyl-4-(piperidin-4-yloxy)-N-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01252] To a solution of 4-(4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)- 3,5-difluoro-2-methylphenoxy)piperidine-1-carboxylate tert-butyl (0.93 g, 1.45 mmol) in dichloromethane (4 ml) trifluoroacetic acid (4 ml) was added. The mixture was stirred for 4 h and then concentrated in vacuo. The residue was triturated with methanol (20 ml). Filtration and concentration of the filtrate in vacuo produced a pink solid (0.73 g, quantitative yield): MS (ES+) m/z 390.2 (M + 1).

[01253]Step 5. Preparation of 4-((1-benzylpiperidin-4-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-2-yl) 2,2,2-trifluoroacetate benzenesulfonamide

[01254] Following the procedure as described in EXAMPLE 2 and making non-critical variations as necessary to replace 2,2,2-3-chloro-4-((3,3-dimethylpiperidin-4-yl)oxy)-N trifluoroacetate -(1,2,4-thiadiazol-5-yl)benzenesulfonamide by 2,6-difluoro-3-methyl-4-(piperidin-4-yloxy)-N-(thiazol-2)-2-trifluoroacetate -yl)benzenesulfonamide, the title compound was produced as a colorless solid (0.05 g, 14% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.97 to 12.88 (m, 1H) , 9.81 to 9.62 (m, 1H), 7.63 to 7.47 (m, 5H), 7.35 to 7.28 (m, 1H), 7.06 to 6.88 (m, 2H), 4.38 (t, J = 0.4 Hz, 2H), 3.50 to 3.42 (m, 1H), 3.34 to 3.00 (m, 4H), 2.28 to 1 .72 (m, 7H); MS (ES+) m/z 480.3 (M + 1). EXAMPLE 224

[01255] Synthesis of (S)-2,6-difluoro-3-methyl-4-(methyl(1-((6-(trifluoromethyl)trifluoromethyl)pyridin-2-yl)methyl)pyrrolidin 2,2,2-trifluoroacetate -3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide

[01256]Step 1. Preparation of 3-bromo-2,4,6-trifluorobenzene-1-sulfonyl chloride

[01257] To 2-bromo-1,3,5-trifluorobenzene (50.00 g, 236.00 mmol) chlorosulfonic acid (250 ml) was added and the reaction mixture was heated to 80 ° C for 12 h. The mixture was poured into ice water and extracted with ethyl acetate (2 x 500 ml). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. Purification of the residue was carried out by column chromatography, eluting with petroleum ether, to give the title compound as a yellow oil (51.00 g, 70% yield): 1H NMR (400 MHz, CDCl3) δ7.03 (ddd, J = 9.8, 7.8, 2.2 Hz, 1H).

[01258]Step 2. Preparation of tert-butyl ((3-bromo-2,4-trifluorophenyl)sulfonyl)(thiazol-4-yl)carbamate

[01259] To a solution of tert-butyl thiazol-4-ylcarbamate (26.90 g, 134.00 mmol) in anhydrous tetrahydrofuran (500 ml) was added lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran 168 ml, 168.0 mmol) at -78 °C. The reaction mixture was stirred at -78°C for 20 minutes, after which a solution of 3-bromo-2,4,6-trifluorobenzene-1-sulfonyl chloride (50.00 g, 161.00 mmol) in Anhydrous tetrahydrofuran (100 ml) was added dropwise at -78°C. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (3 x 400 ml). The organic phase was washed with water (3 x 400 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and trituration of the residue in methanol (100 ml) gave the title compound as a colorless solid (40.00 g, 62% yield): 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 2.3 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 6.97 (ddd, J = 9.8, 8.0, 2.2 Hz, 1H), 1.47 to 1.34 (m, 9H); MS (ES+) m/z 496.9 (M + 23).

[01260]Step 3. Preparation of (S)-3-((2-bromo-4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-3,5-difluorophenyl)amino )tert-butyl pyrrolidine-1-carboxylate

[01261] To a solution of tert-butyl ((3-bromo-2,4,6-trifluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (38.1 g, 80.6 mmol) and triethylamine (34, 0 ml, 241.8 mmol) in anhydrous N,N-dimethylformamide (250 ml) was added (S)-3-aminopyrrolidine-1-tert-butyl carboxylate (15.0 g, 80.6 mmol). The reaction mixture was stirred for 18 h, and then diluted with ethyl acetate (1000 ml). The mixture was washed with saturated ammonium chloride (2 x 250 ml), brine (2 x 100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography, eluting with a gradient of 10 to 80% ethyl acetate in hexanes, to give the title compound as a colorless solid (12.6 g, 25% yield): MS (ES+) m/z 639.2 (M + 1), 641.2 (M + 1).

[01262]Step 4. Preparation of (S)-3-bromo-2,6-difluoro-4-(pyrrolidin-3-ylamino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01263] To a solution of (S)-3-((2-bromo-4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-3,5-difluorophenyl)amino) tert-butyl pyrrolidine-1-carboxylate (12.6 g, 19.70 mmol) in dichloromethane (50 ml) trifluoroacetic acid (25 ml) was added. The mixture was stirred for 4 h and then concentrated in vacuo. The residue was triturated with methanol (75 ml) to give the title compound as an off-white solid (8.20 g, 75% yield): MS (ES+) m/z 439.0 (M + 1), 441.0 (M + 1).

[01264]Step 5. Preparation of (S)-3-bromo-2,6-difluoro-N-(thiazol-4-yl)-4-((1-((6-(trifluoromethyl)pyridin-2-yl )methyl)pyrrolidin-3-yl)amino)benzenesulfonamide

[01265] A mixture of (S)-3-bromo-2,6-difluoro-4-(pyrrolidin-3-ylamino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate ( 0.80 g, 1.45 mmol) and 6-(trifluoromethyl)picolinaldehyde (0.38 g, 2.18 mmol) in anhydrous N,N-dimethylformamide (5 ml) and anhydrous dichloromethane (5 ml) were added. sodium (0.46 g, 2.18 mmol). The mixture was stirred at room temperature for 18 h and then quenched with 2M aqueous sodium hydroxide (8 ml) and brine (8 ml). The mixture was extracted with ethyl acetate (3 x 25 ml). The combined organic phase was washed with brine (25 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as an orange oil (0.87 g, quantitative yield): 1H NMR (300 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.90 ( d, J = 2.2 Hz, 1H), 8.12 to 8.04 (m, 2H), 7.79 to 7.74 (m, 4H), 6.96 (d, J = 2.2 Hz , 1H), 6.63 (dd, J = 14.0, 1.4 Hz, 1H), 6.21 to 6.18 (m, 1H), 4.14 to 4.11 (m, 1H), 3.83 (s, 2H), 2.30 to 2.19 (m, 2H), 1.82 to 1.72 (m, 1H); MS (ES+) m/z 598.2 (M + 1), 600.3 (M + 1).

[01266]Step 6. Preparation of (S)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)-4-((1-((6-(trifluoromethyl)pyridin-2-yl )methyl)pyrrolidin-3-yl)amino)benzenesulfonamide

[01267]A mixture of (S)-3-bromo-2,6-difluoro-N-(thiazol-4-yl)-4-((1-((6-(trifluoromethyl)pyridin-2-yl) methyl)pyrrolidin-3-yl)amino)benzenesulfonamide (0.87 g, 1.45 mmol), methylboronic acid (0.52 g, 8.70 mmol), and potassium phosphate (0.92 g, 4.35 mmol) in anhydrous dioxane (14 ml) tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) was added. The reaction mixture was degassed by sparging with nitrogen and heated to reflux for 6 h. After cooling to room temperature, additional methylboronic acid (0.52 g, 8.70 mmol), potassium phosphate (0.92 g, 4.35 mmol), and tetrakis(triphenylphosphine)palladium(0) (0. 16 g, 0.14 mmol) was added. The reaction mixture was heated to reflux for 6 h and then allowed to cool to room temperature. The mixture was filtered through a celite filter and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 10% methanol in dichloromethane provided the title compound as a grayish oil (0.72 g, quantitative yield). MS (ES+) m/z 534.4 (M + 1).

[01268]Step 7. Preparation of (S)-2,6-difluoro-3-methyl-4-(methyl(1-((6-(trifluoromethyl)pyridin-2-yl) 2,2,2-trifluoroacetate methyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide

[01269] Following the procedure as described in EXAMPLE 155, Step 4 and making non-critical variations as necessary to substitute (S)-2-fluoro-4- ((1-(2-fluorobenzyl)pyrrolidin-3-yl)amino) -5-methyl-N-(thiazol-4-yl)benzenesulfonamide by (S)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)-4-(((1-((6- (trifluoromethyl)pyridin-2-yl)methyl)pyrrolidin-3-yl)amino)benzenesulfonamide, and purification by reversed-phase preparative HPLC, eluting with a gradient of 10 to 50% acetonitrile in water containing 0.1% trifluoroacetic acid, gave the title compound as a colorless solid (0.070 g, 6% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.49 (d, J = 0.4 Hz, 1H), 10 .58 to 10.40 (m, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.23 (td, J = 0.4, 7.8 Hz, 1H), 7, 99 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H), 6.90 a 6.85 (m, 1H), 4.73 to 4.67 (m, 2H), 4.30 to 4.07 (m, 1H), 3.76 to 3.12 (m, 4H), 2, 70 to 2.66 (m, 3H), 2.28 to 2.01 (m, 5H); MS (ES+) m/z 548.2 (M + 1).

[01270] EXAMPLE 225

[01271] Synthesis of (R)-4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide formate

[01272]Step 1. Preparation of tert-butyl ((4-bromo-3-chlorophenyl)sulfonyl(thiazol-4-yl)carbamate

[01273] To a mixture of tert-butyl thiazol-4-ylcarbamate (26.5 g, 132.3 mmol) in anhydrous tetrahydrofuran (300 ml) was added a 1 M solution of bis(trimethylsilyl)amide in tetrahydrofuran (185 .3 ml, 185.3 mmol) at -78 °C. The reaction mixture was allowed to warm to 0°C and stirred for 1 h. After cooling the reaction mixture to -78 ° C, a solution of 4-bromo-3-chlorobenzenesulfonyl chloride (49.88 g, 172.0 mmol) in anhydrous tetrahydrofuran (200 ml) was added thereto. The reaction mixture was allowed to warm to room temperature, stirred for 3 h and then quenched by addition of saturated sodium bicarbonate solution (100 ml). The mixture was diluted with water (300 ml) and extracted with ethyl acetate (3 x 300 ml). The combined organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and trituration of the residue in methanol (200 ml) provided the title compound as a colorless solid (35.0 g, 58% yield): 1H NMR (400 MHz, CDCI3) δ8.85 a 8.78 (d, J = 2.0 Hz, 1H), 8.28 to 8.21 (d, J = 4.0 Hz, 1H), 7.95 to 7.89 (m, 1H), 7 .87 to 7.83 (m, 1H), 7.59 to 7.55 (d, J = 4.0 Hz, 1H), 1.38 (s, 9H); MS (ES+) m/z 352.9 (M - 99), 354.9 (M - 99).

[01274]Step 2. Preparation of (R)-((4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chlorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate

[01275]A mixture of (R)-1-benzyl-3-methylpyrrolidin-3-amine (prepared according to WO 2013063459, 0.230 g, 1.2 mmol) and (4-bromo-3-chlorophenyl)sulfonyl( tert-butyl thiazol-4-yl)carbamate and (0.548 g, 1.2 mmol) in anhydrous toluene (5 ml) was added 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.21 g, 0.363 mmol), cesium carbonate (1.20 g, 3.6 mmol), and bis(dibenzylideneacetone)palladium(0) (0.139 g, 0.242 mmol) and the reaction mixture was heated to 100 °C for 12 h. After cooling to room temperature, water (10 ml) was added and the mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic layers were washed with brine (3 x 10 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 50% ethyl acetate in petroleum ether, provided the title compound as a yellow solid (0.400 g, 54% performance). MS (ES+) m/z 563.2 (M + 1), 565.2 (M + 1)..

[01276]Step 3. Preparation of (R)-4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide formate

[01277]A (R)-((4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chlorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate (0.400 g, 0.71 mmol) 4 M hydrogen chloride solution in dioxane (10 ml) was added and the reaction mixture was stirred at room temperature for 12 h. Concentration in vacuo and purification of the residue by preparative reversed-phase HPLC, eluting with a gradient of acetonitrile in water containing 0.225% formic acid, provided the title compound as a colorless solid (0.021 g, 6% yield): 1H NMR (400 MHz, DMSO-d6) δ8.87 (d, J = 2.0 Hz, 1H), 8.23 (s, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.54 (dd, J = 2.4, 8.8 Hz, 1H), 7.30 (d, J = 4.4 Hz, 4H), 7.23 (qd, J = 4.2, 8, 4 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 5.48 (s, 1H), 3.65 to 3.53 (m, 1H), 2.78 (d, J = 9.6 Hz, 1H), 2.73 to 2.65 (m, 1H), 2.58 to 2.52 (m, 3H ), 2.19 to 2.08 (m, 1H), 1.86 (ddd, J = 5.2, 7.2, 12.6 Hz, 1H), 1.44 (s, 3H), NH and COOH not observed; MS (ES+) m/z 463.0. EXAMPLE 226

[01278] Synthesis of (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide formate

[01279]Step 1. Preparation of (S)-N-(1-benzyl-3-methylpyrrolidin-3-yl)acetamide (2R,3R)-2,3-bis((4-methoxybenzoyl)oxy)succinate

[01280] To a solution of (-)-O,O'-di-p-toluoyl-L-tartaric acid (11.5 g, 27.7 mmol) in ethanol (200 ml) was added N-(1- benzyl-3-methylpyrrolidin-3-yl)acetamide (9.0 g, 38.7 mmol). The mixture was stirred at 10°C for 15 minutes and then heated to 70°C for 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 48 h. The resulting solid was removed by filtration, the filter cake washed with ethanol (100 ml) and dried under reduced pressure to provide a colorless solid. The solid was dissolved in ethanol (100 ml), heated to reflux for 30 minutes, and allowed to cool to room temperature. The precipitate obtained was removed by filtration to yield a colorless solid. The recrystallization step was repeated twice to provide the title compound as a colorless solid (20.9 g, 33% yield): 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.94 (d, J = 8.8 Hz, 4H), 7.44 to 7.38 (m, 2H), 7.36 to 7.25 (m, 3H), 7.06 (d, J = 8.8 Hz, 4H), 5.69 (s, 2H), 4.12 to 4.02 (m, 2H), 3.83 (s, 6H), 3.24 (d, J = 11.4 Hz, 1H), 3.10 (d, J = 6.4 Hz, 2H), 2.97 (d, J = 11.4 Hz, 1H), 2.14 (td, J = 12.8, 6 .4 Hz, 1H), 1.88 to 1.77 (m, 1H), 1.74 (s, 3H), 1.29 (s, 3H), two COOH not observed.

[01281]Step 2. Preparation of (S)-N-(1-benzyl-3-methylpyrrolidin-3-yl)acetamide

[01282]A mixture of (S)-N-(1-benzyl-3-methylpyrrolidin-3-yl)acetamide (2R,3R)-2,3-bis((4-methoxybenzoyl)oxy)succinate (6, 0 g, 9.2 mmol) in water (40 ml) was added potassium carbonate (3.8 g, 27.6 mmol) and the mixture was stirred at 10 °C for 2 h. The mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic phase was washed with brine (3 x 50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate under reduced pressure yielded (S)-N-(1-benzyl-3-methylpyrrolidin-3-yl)acetamide as a yellow solid (2.0 g, 93% yield, 100% ee). Enantiopurity was determined by supercritical fluid chromatography, using 5 to 40% isopropanol (containing 0.05% diethylamine) in supercritical carbon dioxide as eluent at a flow rate of 3 ml/min and a Chiralpak IC-3 column. (100 x 4.6 mm, 3 μm). Data for (S)-N-(1-benzyl-3-methylpyrrolidin-3-yl)acetamide: 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.33 to 7.26 (m, 4H), 7.25 to 7.19 (m, 1H), 3.59 to 3.46 (m, 2H), 2.65 to 2.60 (m, 1H), 2.59 to 2 .51 (m, 2H), 2.49 to 2.43 (m, 1H), 2.07 to 1.95 (m, 1H), 1.75 (s, 3H), 1.74 to 1.66 (m, 1H), 1.33 (s, 3H).

[01283]Step 3. Preparation of (S)-1-benzyl-3-methylpyrrolidin-3-amine

[01284] To a (S)-N-(1-benzyl-3-methylpyrrolidin-3-yl)acetamide (1.5 g, 6.4 mmol) 6 M hydrochloric acid (5 ml) was added and the mixture was heated to 100 °C for 36 h. After cooling to room temperature, the mixture was adjusted to pH 11 to 12 with sodium hydroxide and then extracted with ethyl acetate (3 x 10 ml). The combined organic phase was washed with brine (3 x 10 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave the title compound as a dark oil (1.0 g, 83% yield): 1H iMR (400 MHz, CDCl3) δ7.30 to 7.16 (m, 5H), 3. 60 to 3.50 (m, 2H), 2.80 (dt, J = 8.8, 5.2 Hz, 1H), 2.44 (d, J = 9.0 Hz, 1H), 2.37 (dt, J = 9.0, 6.8 Hz, 1H), 2.26 (d, J = 9.0 Hz, 1H), 1.78 (ddd, J = 13.2, 8.4, 5 .0 Hz, 1H), 1.69 to 1.60 (m, 1H), 1.20 (s, 3H), iH not observed.

[01285]Step 4. Preparation of (S)-((4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chlorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate

[01286] Following the procedure as described in EXAMPLE 225, Step 2 and making non-critical variations to replace (R)-1-benzyl-3-methylpyrrolidin-3-amine with (S)-1-benzyl-3-methylpyrrolidin-3 -amine, the title compound was obtained as a yellow solid (0.015 g, 5% yield): MS (ES+) m/z 563.1 (M + 1), 565.1 (M + 1).

[01287]Step 5. Preparation of (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide formate

[01288] Following the procedure as described in EXAMPLE 225, Step 3 and making non-critical variations to replace (R)-((4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chlorophenyl) tert-butyl sulfonyl)(thiazol-4-yl)carbamate by (S)-((4-((1-benzyl- 3-methylpyrrolidin-3-yl)amino)-3-chlorophenyl)sulfonyl)(thiazol-4- il) tert-butyl carbamate, the title compound was obtained as a colorless solid (0.027 g, 54% yield): 1H NMR (400 MHz, DMSO-d6) δ8.87 (d, J = 2.1 Hz, 1H), 8.25 (s, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.54 (dd, J = 2.0, 8.8 Hz, 1H), 7, 31 (d, J = 4.4 Hz, 4H), 7.27 to 7.20 (m, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.97 (s, 1H ), 5.48 (s, 1H), 3.68 to 3.51 (m, 1H), 2.78 (d, J = 9.8 Hz, 1H), 2.73 to 2.68 (m, 1H), 2.59 to 2.53 (m, 2H), 2.18 to 2.09 (m, 1H), 1.90 to 1.82 (m, 1H), 1.44 (s, 3H) , NH and COOH not observed; MS (ES+) m/z 463.2 (M + 1), 465.2 (M + 1). EXAMPLE 227

[01289] Synthesis of (R)-3-chloro-2-fluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide formate

[01290]Step 1. Preparation of tert-butyl ((3-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate

[01291] To a solution of tert-butyl N-thiazol-4-ylcarbamate (110 g, 549 mmol) in anhydrous tetrahydrofuran (1000 ml) was added lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 659 ml, 659 mmol) at -78 °C. The mixture was warmed to 5°C before a cooled (-78°C) solution of 3-chloro-2,4-difluorobenzenesulfonyl chloride (163 g, 659 mmol) in tetrahydrofuran (300 ml) was added dropwise. the same. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. After dilution with saturated aqueous ammonium chloride (200 ml), the mixture was extracted with ethyl acetate (3 x 1000 ml). The combined organic layers were washed with brine (3 x 1000 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and trituration of the residue with methanol (300 ml) gave the title compound as a colorless solid (75 g, 33% yield) 1H NMR (400 MHz, CDCla) δ 9.14 (s, 1H ), 8.26 to 8.09 (m, 1H), 8.03 (s, 1H), 7.66 (t, J = 8.6 Hz, 1H), 1.27 (s, 9H); MS (ES+) m/z 432.8 (M + 23), 434.8 (M + 23).

[01292]Step 2. Preparation of 3-chloro-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide

[01293] A solution of tert-butyl ((3-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (2.50 g, 6.09 mmol) in dichloromethane (15 ml) was Trifluoroacetic acid (7 ml) was added and the reaction mixture was stirred at room temperature for 2 h. Concentration in vacuo and trituration of the residue with diethyl ether (25 ml) provided the title compound as a pale yellow solid (1.74 g, 92% yield) which was used without further purification: MS (ES+) m/z 311.1 (M + 1), 313.1 (M + 1).

[01294]Step 3. Preparation of (R)-3-chloro-2-fluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl) formate )benzenesulfonamide

[01295] To a solution of 3-chloro-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide (0.241 g, 0.774 mmol) and (R)-1-(1-phenylethyl)piperidin-4- ol (0.159 g, 0.774 mmol) in anhydrous N,N-dimethylformamide (3 ml), a dispersion of 60% sodium hydride in mineral oil (0.092 g, 2.32 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then slowly added to the rapidly stirred saturated aqueous ammonium chloride solution (100 ml). The resulting slurry was filtered and the solid obtained purified by reverse phase HPLC using a gradient of acetonitrile in water (containing 0.5% formic acid) to yield the title compound as a colorless solid (0.010 g, 2. 6% yield) 1H NMR (300 MHz, DMSO-d6) δ 8.75 (d, J = 2.1 Hz, 1H), 8.20 (s, 1H), 7.64 (t, J = 8 .6 Hz, 1H), 7.32 to 7.30 (m, 4H), 7.25 to 7.21 (m, 1H), 7.11 to 7.08 (m, 1H), 6.62 ( t, J = 0.3 Hz, 1H), 4.60 to 4.54 (m, 1H), 3.53 to 3.46 (m, 1H), 2.73 to 2.55 (m, 2H) , 2.30 to 2.19 (m, 2H), 1.94 to 1.86 (m, 2H), 1.69 to 1.59 (m, 2H), 1.30 (d, J = 6, 8 Hz, 3H), NH and COOH not observed; MS (ES+) m/z 496.2 (M + 1), 498.2 (M + 1). EXAMPLE 228

[01296] Synthesis of rac-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-2) 2,2,2-trifluoroacetate -yl)benzenesulfonamide

[01297]Step 1. Preparation of rac-3-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-3,5-difluorophenoxy)-3 tert-butyl-methylpyrrolidine-1-carboxylate

[01298]A mixture of tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate (prepared according to WO 2015035278, 1.19 g, 5.91 mmol) and 3-chloro-N-(2.4 - dimethoxybenzyl)-2,4,6-trifluoro-N-(thiazol-2-yl)benzenesulfonamide (2.83 g, 5.91 mmol) in anhydrous N,N-dimethylformamide (10 ml) was added sodium hydride ( 60% dispersion in mineral oil, 0.496 g, 12.41 mmol) at 0 °C. The mixture was stirred at room temperature for 48 h, cooled to 0 °C, and diluted with saturated ammonium solution (40 ml). The mixture was extracted with ethyl acetate (3 x 60 ml). The combined organic layers were washed with water (80 ml), brine (80 ml), dried with anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0% to 50% acetone in heptane, provided the title compound as a colorless solid (0.22 g, 6% yield ): MS (ES-) m/z 508.2 (M - 151), 510.2 (M - 151).

[01299]Step 2. Preparation of 3-(4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-3,5-difluoro-2-methylphenoxy)-3-methylpyrrolidine -1-tert-butyl carboxylate

[01300]A mixture of 3-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-3,5-difluorophenoxy)-3-methylpyrrolidine- tert-butyl 1-carboxylate (0.22 g, 0.33 mmol) and methylboronic acid (0.11 g, 1.83 mmol) in anhydrous 1,4-dioxane (10 ml) was added tribasic potassium phosphate (0 .21 g, 0.99 mmol) and the mixture was degassed by spraying with argon for 15 minutes. Tricyclohexylphosphine tetrafluoroborate (0.049 g, 0.132 mmol) and palladium(II) acetate (0.015 g, 0.07 mmol) were then added to it and the reaction mixture was heated in a microwave reactor to 101 ° C for 12 minutes. The reaction mixture was then removed from the microwave reactor and then heated to 100 °C for 4 h. The reaction mixture was allowed to cool to room temperature, and filtered through a diatomaceous earth filter. The filter plug was washed with ethyl acetate (2 x 15 ml) and the combined filtrate was concentrated in vacuo. The residue was diluted with saturated aqueous ammonium chloride (15 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with brine (25 ml), dried over anhydrous magnesium sulfate and filtered. Concentration of the residue in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 50% ethyl acetone in heptane, provided the title compound as a colorless solid (0.065 g, 31% yield). : MS (ES+) m/z 640.3 (M + 1).

[01301] Step 3. Preparation of rac-2,6-difluoro-3-methyl-4-((3-methylpyrrolidin-3-yl)oxy)-N-(thiazol-2-) il)benzenesulfonamide

[01302] Following the procedure as described in EXAMPLE 1, Step 4 and making non-critical variations as necessary to replace 4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2, 4-thiadiazol-5-yl)sulfamoyl)phenoxy)-3,3-dimethylpiperidine-1-tert-butyl carboxylate by 3-(4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl )sulfamoyl)-3,5-difluoro-2-methylphenoxy)-3-methylpyrrolidine-1-tert-butylcarboxylate, the title compound was obtained as a colorless solid (0.051 g, quantitative yield): MS (ES+) m/ z 390.1 (M + 1).

[01303]Step 4. Preparation of rac4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol- 2-yl)benzenesulfonamide

[01304] Following the procedure as described in EXAMPLE 36, Step 3 and making non-critical variations as necessary to replace 2,2,2,- (S)-3-chloro-4-(ethyl(pyrrolidin-3-yl) trifluoroacetate )amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide by 2,6-difluoro-3-methyl-4-((3-methylpyrrolidin-3-yl) 2,2,2-trifluoroacetate )oxy)-N-(thiazol-2-yl)benzenesulfonamide, and purification by the title compound was carried out by reverse phase preparative HPLC, eluting with a gradient of acetonitrile in water containing 0.1% trifluoroacetic acid, the compound of the title was obtained as a colorless solid (0.026 g, 43% yield): 1H NMR (300 MHz, DMSO-d6) £12.96 (s, 1H), 10.51 (s, 1H), 7.60 to 7.39 (m, 5H), 7.33 (d, J = 4.6 Hz, 1H), 6.98 to 6.86 (m, 2H), 4.40 (s, 2H), 4, 00 to 3.20 (m, 4H), 2.68 to 2.09 (m, 2H), 2.03 to 1.94 (m, 3H), 1.61 (s, 3H); MS (ES +) m/z 480.3 (M + 1). EXAMPLE 229

[01305] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isoxazol-3-yl)-5 2,2,2-trifluoroacetate -methylbenzenesulfonamide

[01306]Step 1. Preparation of tert-butyl ((5-chloro-2,4-difluorophenyl)sulfonyl)(isoxazol-3-yl)carbamate

[01307] To a solution of tert-butyl isoxazol-3-ylcarbamate (10.00 g, 54.30 mmol) in anhydrous tetrahydrofuran (200 ml) was added 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran ( 81.5 ml, 81.50 mmol) at -78 °C. The reaction was stirred for 30 minutes at -78°C and then a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (13.40 g, 54.30 mmol) in anhydrous tetrahydrofuran (50 ml) was added. same by drip. The reaction solution was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with ethyl acetate (200 ml) and then washed with saturated ammonium chloride (100 ml) and brine (100 ml). The organic layer was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting residue was triturated with diethyl ether (75 ml) to give the title compound as a pale yellow solid (6.21 g, 29% yield): 1H NMR (300 MHz, DMSO- de) δ9.15 (d, J = 2.2 Hz, 1H), 8.25 (dd, J = 7.5, 7.5 Hz, 1H), 8.05 (dd, J = 10.0, 9.5 Hz, 1H), 6.92 (s, 1H), 1.31 (s, 9H); MS (ES+) m/z 395.1 (M + 1), 396.1 (M + 1).

[01308]Step 2. Preparation of (S)-((4-((1-benzylpyrrolidin-3-yl)amino)-5-chloro-2-fluorophenyl)sulfonyl)(isoxazol-3-yl) tert-butyl carbamate

[01309] To a solution of tert-butyl ((5-chloro-2,4-difluorophenyl)sulfonyl)(isoxazol-3-yl)carbamate (6.21 g, 15.80 mmol) in anhydrous N,N-dimethylformamide (200 ml) N,N-diisopropylethylamine (8.20 ml, 47.30 mmol) was added followed by (S)-1-benzylpyrrolidin-3-amine (2.78 g, 15.80 mmol) at 0 °C over a period of 30 minutes. The reaction mixture was stirred at room temperature for 16 h and then diluted with ethyl acetate (200 ml) and washed with saturated ammonium chloride (3 x 100 ml) and brine (200 ml). The organic layer was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography, eluting with a gradient of 20 to 60% ethyl acetate in heptane, to give the title compound as a brown gum (4.82 g, 56% yield): MS (ES+) m/z 551.2 (M + 1), 553.2 (M + 1).

[01310]Step 3. Preparation of (S)-((4-((1-benzylpyrrolidin-3-yl)amino)-2-fluoro-5-methylphenyl)sulfonyl)(isoxazol-3-yl) tert-butyl carbamate

[01311]A mixture of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-3,5-difluorophenyl)amino) tert-butyl pyrrolidine-1-carboxylate (4.82 g, 8.76 mmol), methylboronic acid (4.13 g, 70.10 mmol), tribasic potassium phosphate (7.43 g, 35.10 mmol), tricyclohexylphosphine tetrafluoroborate (0.64 g, 1.75 mmol) and palladium acetate (0.19 g, 0.08 mmol) were added to 1,4-dioxane (150 ml). The resulting mixture was degassed by sparging with nitrogen for 15 minutes and then heated to reflux for 8 h. After cooling to room temperature, the reaction mixture was filtered through a Celite filter. The filtrate was diluted with ethyl acetate (150 ml), washed with saturated ammonium chloride (100 ml) and brine (100 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 20 to 60% ethyl acetate in heptane, gave the title compound as a brown gum (3.50 g, 75% yield): MS (ES+) m/z 531.2 (M + 1).

[01312]Step 4. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isoxazol-3-yl) 2,2,2-trifluoroacetate )-5-methylbenzenesulfonamide

[01313] Following the procedure as described in EXAMPLE 103, Step 4 and making non-critical variations to replace (S)-4-((1-benzylpyrrolidin-3-yl)amino)- 2,6-difluoro-3-methyl- N-(thiazol-4-yl)benzenesulfonamide by (S)-((4-((1-benzylpyrrolidin-3-yl)amino)-2-fluoro-5-methylphenyl)sulfonyl)(isoxazol-3-yl)carbamate tert-butyl, the title compound was obtained as a colorless solid (0.039 g, 9% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.80 (br s, 1H), 10.36 to 10 .16 (m, 1H), 8.73 (d, J = 1.8 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.50 to 7.45 (m, 5H), 7.07 (d, J = 12.6 Hz, 1H), 6.38 (d, J = 1.8 Hz, 1H), 4.41 to 4.35 (m, 2H), 4, 24 to 4.04 (m, 1H), 3.42 to 3.20 (m, 4H), 2.69 to 2.62 (m, 3H), 2.35 to 2.15 (m, 3H), 2.15 to 2.03 (m, 2H); MS (ES+) m/z 445.4 (M + 1). EXAMPLE 230

[01314] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-bromo-2-fluoro-N-(thiazol-4-) 2,2,2-trifluoroacetate il)benzenesulfonamide

[01315]Step 1. Preparation of tert-butyl ((5-bromo-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate

[01316] Following the procedure as described in EXAMPLE 102, Step 2 and making non-critical variations as necessary to replace 3-chloro-2,4,6-trifluorobenzenesulfonyl chloride with 5-bromo-2,4-difluorobenzenesulfonyl chloride and purification by trituration with methanol (50 ml), the title compound was obtained as a colorless solid (7.75 g, 75% yield): 1H NMR (300 MHz, CDCI3) δ8.82 (d, J = 2.3 Hz, 1H), 8.39 (t, J = 7.3 Hz, 1H), 7.55 (dd, J = 2.2, 0.6 Hz, 1H), 7.09 (dd, J = 9 .3, 7.9 Hz, 1H), 1.39 (s, 9H).

[01317]Step 2. Preparation of 5-bromo-2,4-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide

[01318] A solution of tert-butyl ((5-bromo-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (7.75 g, 17.02 mmol) in dichloromethane (10 ml) was trifluoroacetic acid (10 ml) was added. The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was dissolved in anhydrous N,N-dimethylformamide (50 ml). To this mixture was then added sodium bicarbonate (7.15 g, 85.11 mmol) and 1-(chloromethyl)-4-methoxybenzene (4.62 ml, 34.04 mmol). The reaction mixture was heated to 45 °C for 18 h, and then diluted with ethyl acetate (180 ml). The organic phase was washed with water (150 ml), saturated ammonium chloride (2 x 50 ml), brine (100 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and trituration of the residue with methanol (60 ml) gave the title compound as a colorless solid (6.57 g, 81% yield): 1H NMR (300 MHz, CDCl3) δ 8.59 (d, J = 2.3 Hz, 1H), 7.96 (t, J = 7.2 Hz, 1H), 7.25 to 7.19 (m, 3H), 7.01 (dd, J = 9.3, 8.0 Hz, 1H), 6.81 to 6.77 (m, 2H), 5.02 (s, 2H), 3.78 (s, 3H); MS (ES+) m/z 475.2 (M + 1), 477.2 (M + 1).

[01319]Step 3. Preparation of (S)-3-((2-bromo-5-fluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)phenyl)amino) tert-butyl pyrrolidine-1-carboxylate

[01320] To a solution of 5-bromo-2,4-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide (10.00 g, 21.01 mmol) in N,N -dimethylformamide (200 ml) was added potassium carbonate (7.26 g, 52.50 mmol) and (S)-1-benzylpyrrolidin-3-amine (3.91 g, 21.00 mmol). The solution was stirred at 40 °C for 16 h and then diluted with water (800 ml). The resulting precipitate was collected by filtration, washed with water (500 ml), and dried under vacuum to give the title compound as a brown gum (9.80 g, 73% yield): MS (ES+) m/z 681.1 (M + 1), 683.1 (M + 1).

[01321]Step 4. Preparation of (S)-3-((2-bromo-5-fluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)phenyl)(methyl )amino)pyrrolidine-1-tert-butyl carboxylate

[01322] To a solution of (S)-3-((2-bromo-5-fluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)phenyl)amino)pyrrolidine tert-butyl-1-carboxylate (0.50 g, 0.78 mmol) in N,N-dimethylformamide (2 ml) was added iodomethane (0.49 ml, 7.80 mmol), followed by sodium hydride (0.094 g, 2.34 mmol). The reaction mixture was stirred at room temperature for 16 h and then quenched by addition of water (5 ml). The precipitated solid was removed by filtration and then suspended in ethyl acetate (50 ml). The resulting mixture was dried over anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo yielded the title compound as a brown solid (0.51 g, quantitative yield), which was used without further purification: MS (ES+) m/z 655.1 (M + 1), 657. 1 (M + 1).

[01323]Step 5. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-bromo-2-fluoro-N-(thiazol) 2,2,2-trifluoroacetate -4-yl)benzenesulfonamide o

[01324] To a solution of (S)-3-((2-bromo-5-fluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)phenyl)(methyl) tert-butyl amino)pyrrolidine-1-carboxylate (0.51 g, 0.78 mmol) in dichloromethane (1 ml) trifluoroacetic acid (2.1 ml) was added and the resulting solution was heated to reflux for 1.5 H. The reaction mixture was cooled to room temperature and then concentrated in vacuo to provide a residue. To the residue were added N,N-dimethylformamide (2 ml), benzaldehyde (0.16 g, 1.56 mmol) and sodium triacetoxyborohydride (0.50 g, 2.34 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then quenched by adding 5% aqueous lithium chloride (10 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic extracts were dried with anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by reverse phase HPLC eluting with a gradient of acetonitrile in water containing 0.1% trifluoroacetic acid, provided the title compound as a colorless solid (0.050 g, 10% yield ): 1H NMR (300 MHz, DMSO-d6) δ 11.41 (s, 1H), 9.97 (s, 1H), 8.92 (d, J = 2.2 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.48 to 7.46 (m, 5H), 7.30 (s, 1H), 7.10 (d, J = 2.1 Hz, 1H) , 4.45 to 4.35 (m, 3H), 3.55 to 3.37 (m, 4H), 2.85 to 2.60 (m, 3H), 2.21 to 2.12 (m, 2H); MS (ES+) m/z: 525.0 (M + 1), 527.0 (M + 1). EXAMPLE 231

[01325] Synthesis of 4-(((3S,5S)-1-benzyl-5-methylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-) formate il)benzenesulfonamide

[01326]Step 1. Preparation of (2S,4S)-4-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenyl)amino )-2-methylpyrrolidine-1-carboxylate tert-butyl

[01327] To a solution of tert-butyl ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (1.71 g, 4.16 mmol) in anhydrous dimethyl sulfoxide (8 ml) tert-butyl (2S,4S)-4-amino-2-methylpyrrolidine-1-carboxylate (1.00 g, 4.99 mmol) was added followed by triethylamine (0.70 ml, 4.99 mmol). The resulting solution was stirred at room temperature for 16 h. The crude reaction mixture was purified by column chromatography, eluting with 0 to 100% ethyl acetate in heptane, to provide the title compound as a colorless solid (1.62 g, 55% yield).

[01328]Step 2. Preparation of (2S,4S)-4-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenyl)( methyl)amino)-2-methylpyrrolidine-1-tert-butyl carboxylate

[01329] Following the procedure as described in EXAMPLE 101, Step 3 and making non-critical variations to replace (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl )-5-fluoro-2-methylphenyl)amino)pyrrolidine-1-tert-butyl carboxylate by (2S, 4S)-4-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl )sulfamoyl)-2-chloro-5-fluorophenyl)amino)-2-methylpyrrolidine-1-tert-butylcarboxylate, the title compound was obtained as a brown solid (1.08 g, 65% yield): MS ( ES+) m/z 605.3 (M + 1), 607.4 (M + 1).

[01330]Step 3. Preparation of 4-(((3S,5S)-1-benzyl-5-methylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazole) formate -4-yl)benzenesulfonamide

[01331] Following the procedure as described in EXAMPLE 101, Step 4 and making non-critical variations to replace (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl )-5-fluoro-2-methylphenyl)amino)pyrrolidine-1-tert-butyl carboxylate by (2S, 4S)-4-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl )sulfamoyl)-2-chloro-5-fluorophenyl)(methyl)amino)-2-methylpyrrolidine-1-tert-butylcarboxylate, the title compound was obtained as a colorless solid (0.46 g, 31% yield) : 1H NMR (300 MHz, DMSO-d6) δ8.90 (d, J = 2.1 Hz, 1H), 8.14 (s, 1H), 7.72 (d, J = 7.5 Hz, 1H ), 7.44 to 7.39 (m, 5H), 7.17 (d, J = 12.0 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 4.36 (d, J = 12.5 Hz, 1H), 4.25 to 4.20 (m, 1H), 3.97 to 3.91 (m, 1H), 3.43 to 3.27 (m, 2H ), 3.00 to 2.94 (m, 1H), 2.74 (s, 3H), 2.25 to 2.20 (m, 1H), 1.89 to 1.78 (m, 1H), 1.26 (d, J = 6.1 Hz, 3H), NH and COOH not observed; MS(ES+) m/z 495.2, 497.2 (M + 1). Note: acidic protons not observed. EXAMPLE 232

[01332] Synthesis of 3-chloro-4-((1-(3-(difluoromethyl)benzyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide formate

[01333]Step 1. Preparation of tert-butyl 4-hydroxy piperidine-1-carboxylate

[01334] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.00 g, 10.0 mmol) in methanol (2 ml) was added a solution of sodium borohydride (0.45 g, 12.0 mmol) 1 mmol) in methanol (2 ml) at 0 °C. The mixture was stirred at 0°C for 1 h, quenched by addition of water (10 ml), and extracted with dichloromethane (3 x 20 ml). The combined organic extracts were washed with brine (2 x 10 ml), dried with anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain the title compound as a yellow oil (1.70 g, 85% yield): 1H NMR (400 MHz, CD3OD) δ3.87 to 3.79 (m, 2H), 3.78 to 3.72 (m, 1H), 3.03 (br s, 2H), 1.86 to 1.76 (m, 2H), 1.45 (s, 9H), 1.44 to 1.33 ( m, 2H), OH not observed.

[01335]Step 2. Preparation of 4-(4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chlorophenoxy)piperidine-1-tert-butyl carboxylate

[01336] To a mixture of a dispersion of 60% sodium hydride in mineral oil (0.087 g, 2.19 mmol) in anhydrous N,N-dimethylformamide (4 ml) was added a solution of 4-hydroxypiperidine-1- tert-butyl carboxylate (0.40 g, 1.99 mmol) in N,N-dimethylformamide (4 ml) at 0 °C. The solution was stirred for 30 minutes at room temperature and then a solution of tert-butyl (3-chloro-4-fluorophenyl)sulfonyl(thiazol-4-yl)carbamate (0.86 g, 2.19 mmol) in N,N-dimethylformamide (4 ml) was added thereto dropwise. The mixture was stirred for 1 h at room temperature and then the reaction was quenched by addition of saturated ammonium chloride (10 ml). The mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine (2 x 20 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 25% ethyl acetate in petroleum ether, provided the title compound as a yellow solid (0.17 g, 15 % yield). MS (ES+) m/z 596.0 (M + 23), 598.0 (M + 23).

[01337]Step 3. Preparation of 3-chloro-4-(piperidin-4-yloxy)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01338] To the mixture of 4-(4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chlorophenoxy) piperidine-1-tert-butyl carboxylate (0.17 g, 0.30 mmol) and dichloromethane (5 ml) trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was then concentrated in vacuo to provide the title compound as a yellow solid (0.071 g, quantitative yield): MS (ES+) m/z 374.0 (M + 1), 376.0 (M + 1 ).

[01339]Step 4. Preparation of 3-chloro-4-((1-(3-(difluoromethyl)benzyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide formate

[01340] To a solution of 3-chloro-4-(piperidin-4-yloxy)- N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate (0.48 g, 1.00 mmol) in anhydrous N,N-dimethylformamide (2.50 ml) was added 3-(difluoromethyl)benzaldehyde (0.23 g, 1.50 mmol) followed by sodium triacetoxyborohydride (0.64 g, 3.00 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The resulting residue was purified by column chromatography, eluting with a gradient of 10 to 100% ethyl acetate in hexanes. Further purification by reverse phase HPLC eluting with a gradient of 20 to 50% acetonitrile in water (containing 0.1% formic acid), yielded the title compound as a colorless solid (0.26 g, 51% yield): 1H NMR (300 MHz, DMSO-de) δ 8.89 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.72 (dd, J = 8.8, 2.3 Hz, 1H), 7.64 (s, 1H), 7.59 to 7.54 (m, 3H), 7.39 (d, J = 9.0 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 7.05 (t, J = 55.8 Hz, 1H), 4.77 to 4 .75 (m, 1H), 3.98 (s, 2H), 2.94 to 2.87 (m, 2H), 2.77 to 2.71 (m, 2H), 2.03 to 2.00 (m, 2H), 1.86 to 1.80 (m, 2H), NH and COOH not observed; MS (ES+) m/z 513.9 (M + 1), 515.9 (M + 1). EXAMPLE 233

[01341] Synthesis of 4-((1-benzyl-3-methylazetidin-3-yl)amino)-2,6-difluoro-3-methyl- N-(thiazol-4-yl)benzenesulfonamide 2,2,2- trifluoroacetate

[01342]Step 1. Preparation of ((4-((1-benzyl-3-methylazetidin-3-yl)amino)-3-bromo-2,6-difluorophenyl)sulfonyl)(thiazol-4-yl) tert carbamate -butyl

[01343] To a solution of tert-butyl ((3-bromo-2,4,6-trifluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (1.07 g, 2.26 mmol) in anhydrous dimethyl sulfoxide (11 ml) potassium carbonate (0.47 g, 3.39 mmol) and 1-benzyl-3-methylazetidin-3-amine (0.40 g, 2.26 mmol) were added. The reaction mixture was stirred at room temperature for 16 h, after which additional 1-benzyl-3-methylazetidin-3-amine (0.30 g, 1.70 mmol) was added. The reaction mixture was then heated to 50 °C for 2 h. After cooling to room temperature, the mixture was diluted with brine (50 ml) and extracted with diethyl ether (5 x 50 ml). The combined organic extracts were washed with brine (50 ml), dried with anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 20 to 100% ethyl acetate in heptane, provided the title compound as a colorless solid (1.02 g, 72% yield): MS (ES+) m/z 629.2 (M + 1), 631.3 (M + 1).

[01344]Step 2. Preparation of ((4-((1-benzyl-3-methylazetidin-3-yl)amino)-2,6-difluoro-3-methylphenyl)sulfonyl)(thiazol-4-yl) tert carbamate -butyl

[01345] Following the procedure as described in EXAMPLE 224, Step 6 and making non-critical variations to replace (S)-3-bromo-2,6-difluoro-N-(thiazol-4-yl)-4-((1 -((6-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolidin-3-yl)amino)benzenesulfonamide by ((4-((1-benzyl-3-methylazetidin-3-yl)amino)-3-bromo tert-butyl-2,6-difluorophenyl)sulfonyl)-(thiazol-4-yl)carbamate, the title compound was obtained as a brown solid (0.45 g, 50% yield): MS (ES+) m/ z 565.2 (M + 1).

[01346]Step 3. Preparation of 4-((1-benzyl-3-methylazetidin-3-yl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide 2,2 ,2-trifluoroacetate

[01347] To a solution of ((4-((1-benzyl-3-methylazetidin-3-yl)amino)-2,6-difluoro-3-methylphenyl)sulfonyl)(thiazol-4-yl) tert-carbamate butyl acid (0.45 g, 0.80 mmol) in anhydrous dichloromethane (8 ml) trifluoroacetic acid (0.61 ml) was added. The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The residue was triturated with methanol (2 ml) and filtered. Concentration of the filtrate in vacuo and purification of the residue by reverse phase HPLC eluting with a gradient of acetonitrile in water (containing 0.1% trifluoroacetic acid) provided the title compound as a colorless solid (0.050 g, 11% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.29 (d, J = 0.5 Hz, 1H), 10.80 to 10.59 (m, 1H), 8.91 (d, J = 2.1 Hz, 1H), 7.48 to 7.43 (m, 5H), 6.91 (d, J = 2.1 Hz, 1H), 5.96 to 5.91 (m, 1H) , 4.41 to 4.40 (m, 2H), 4.26 to 4.21 (m, 4H), 1.96 (d, J = 1.7 Hz, 3H), 1.54 (d, J = 4.9 Hz, 3H), NH not observed; MS (ES+) m/z 465.2 (M + 1). EXAMPLE 234

[01348] Synthesis of 3-chloro-4-((1-phenethylpiperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide

[01349] Following the procedure as described in EXAMPLE 5, Step 4 and making non-critical variations as necessary to replace 3-(difluoromethoxy)benzaldehyde with 2-phenylacetaldehyde, the title compound was obtained as a colorless solid (0.12 g, 41% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.13 (br s, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.65 (dd, J = 8.7, 2.2 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.28 to 7.13 (m, 6H), 6.78 (d, J = 4.5 Hz, 1H), 4.68 to 4.61 (m, 1H), 2.86 to 2.74 (m, 4H), 2.70 to 2.65 (m, 2H), 2.60 to 2.52 (m, 2H), 2.00 to 1.93 (m, 2H), 1.77 to 1.67 (m, 2H); MS (ES+) m/z: 478.0 (M + 1), 480.0 (M + 1). EXAMPLE 235

[01350] Synthesis of (S)-2,6-difluoro-4-((1-(3-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-3-methyl-N-(thiazol-4) formate -yl)benzenesulfonamide

[01351]Step 1. Preparation of (S)-2,6-difluoro-4-((1-(3-fluorobenzyl)pyrrolidin-3-yl)amino)-3-methyl-N-(thiazol-4-yl )benzenesulfonamide

[01352]A mixture of (S)-2,6-difluoro-3-methyl-4-(pyrrolidin-3-ylamino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate (0 .20 g, 0.41 mmol) and 3-fluorobenzaldehyde (0.087 ml, 0.82 mmol) in dichloromethane (2 ml) and N,N-dimethylformamide (1 ml) was added sodium triacetoxyborohydride (0.173 g, 0.82 mmol) and the reaction mixture was stirred at room temperature for 16 h. After addition of 2 M sodium hydroxide (3 ml) and brine (3 ml), the mixture was extracted with ethyl acetate (4 ml). The aqueous layer was diluted with saturated ammonium chloride (5 ml) and extracted with ethyl acetate (2 x 5 ml). The organic layers were washed with saturated ammonium chloride (2 ml), brine (3 ml), dried with anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo provided a residue that was purified by column chromatography, eluting with a gradient of 0 to 60% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in hexanes, to provide the title compound as a colorless foam (0.18 g, 91% yield). MS (ES+) m/z 483.2 (M + 1).

[01353]Step 2. Preparation of (S)-2,6-difluoro-4-((1-(3-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-3-methyl-N-( formate thiazol-4-yl)benzenesulfonamide

[01354]A mixture of (S)-2,6-difluoro-4-((1-(3-fluorobenzyl)pyrrolidin-3-yl)amino)-3-methyl-N-(thiazol-4-yl) benzenesulfonamide (0.152 g, 0.32 mmol) in 1,2-dichloroethane (1.5 ml) and trifluoroacetic acid (3.0 ml) was added sodium triacetoxyborohydride (0.208 g, 0.98 mmol) and the reaction mixture was stirred at room temperature for three days. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography, eluting with a gradient of 0 to 100% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in hexanes. Further purification by preparative reverse phase HPLC eluting with a gradient of acetonitrile in water containing 0.5% formic acid yielded the title compound as a colorless solid (0.034 g, 20% yield): 1H NMR (300 MHz, DMSO-d6) δ 8.89 (d, J = 2.2 Hz, 1H), 8.15 (s, 0.9H), 7.38 to 7.32 (m, 1H), 7.18 to 7 .03 (m, 3H), 6.93 (d, J = 2.2 Hz, 1H), 6.71 (dd, J = 13.4, 1.4 Hz, 1H), 4.01 to 3, 91 (m, 1H), 3.63 (d, J = 13.3 Hz, 1H), 3.53 (d, J = 13.5 Hz, 1H), 2.76 to 2.53 (m, 6H ), 2.38 to 2.28 (m, 1H), 2.10 to 1.98 (m, 4H), 1.85 to 1.72 (m, 1H), NH and COOH not observed; MS (ES+) m/z 497.3 (M + 1). EXAMPLE 236

[01355] Synthesis of (S)-2,6-difluoro-4-((1-(2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-3-methyl-N-(thiazol-4) formate -yl)benzenesulfonamide

[01356] Following the procedure as described in EXAMPLE 235, Step 3 to 4, and making non-critical variations as necessary to replace 3-fluorobenzaldehyde with 2-fluorobenzaldehyde, the title compound was obtained as a colorless solid (0.043 g, 28% yield): 1H NMR (300 MHz, DMSO-d6) δ 8.89 (d, J = 2.2 Hz, 1H), 8.14 (s, 1.3H), 7.41 (td, J = 7.6, 1.8 Hz, 1H), 7.35 to 7.28 (m, 1H), 7.21 to 7.12 (m, 2H), 6.95 (d, J = 2.2 Hz , 1H), 6.71 (dd, J = 13.5, 1.4 Hz, 1H), 4.00 to 3.91 (m, 1H), 3.66 (d, J = 13.7 Hz, 1H), 3.61 (d, J = 13.7 Hz, 1H), 2.76 to 2.56 (m, 6H), 2.43 to 2.33 (m, 1H), 2.08 to 1 .96 (m, 4H), 1.83 to 1.71 (m, 1H), NH and COOH not observed; MS (ES+) m/z 497.4 (M + 1). EXAMPLE 237

[01357] Synthesis of (S)-4-((1-(2,3-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(thiazol) formate -4-yl)benzenesulfonamide

[01358] Following the procedure as described in EXAMPLE 235, Step 3 to 4, and making non-critical variations as necessary to replace 3-fluorobenzaldehyde with 2,3-difluorobenzaldehyde, the title compound was obtained as a colorless solid (0.046 g, 29% yield): 1H NMR (300 MHz, DMSO-dε) δ8.88 (d, J = 2.2 Hz, 1H), 8.15 (s, 0.6H), 7.35 to 7.16 (m, 3H), 6.92 (d, J = 2.2 Hz, 1H), 6.71 (dd, J = 13.4, 1.3 Hz, 1H), 3.99 to 3.90 ( m, 1H), 3.68 (dd, J = 13.4, 1.2 Hz, 1H), 3.62 (dd, J = 13.5, 1.1 Hz, 1H), 2.74 to 2 .54 (m, 6H), 2.40 to 2.30 (m, 1H), 2.07 to 1.96 (m, 4H), 1.82 to 1.70 (m, 1H), NH and COOH not observed; MS (ES+) m/z 515.3 (M + 1). EXAMPLE 238

[01359] Synthesis of 4-((1-benzylpiperidin-4-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01360]Step 1. Preparation of ((4-((1-benzylpiperidin-4-yl)oxy)-5-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate

[01361]A mixture of ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (0.821 g, 2.0 mmol) and 1-benzyl-4-hydroxypiperidine (0.383 g, 2.0 mmol) in anhydrous N,N-dimethylformamide (5 ml) was added to a dispersion of 60% sodium hydride in mineral oil (0.088 g, 2.2 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. After addition of saturated ammonium chloride solution (15 ml), the mixture was extracted with ethyl acetate (100 ml). The organic phase was washed with water (15 ml), brine (15 ml), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo provided a residue. Purification of the residue by column chromatography, eluting with a gradient of 0 to 100% ethyl acetate (containing 10% isopropanol and 10% triethylamine) in hexanes, provided the title compound as a colorless solid (0.850 g, 73% yield): MS (ES+) m/z 582.5 (M + 1), 584.4 (M + 1).

[01362] Step 2. Preparation of 4-((1-benzylpiperidin-4-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01363]A mixture of tert-butyl ((4-((1-benzylpiperidin-4-yl)oxy)-5-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (0.150 g, 0 .26 mmol) in dichloromethane (2 ml) trifluoroacetic acid (2 ml) was added and the reaction mixture was stirred at room temperature for 16 h. Concentration in vacuo and trituration of the residue in diethyl ether (25 ml) gave the title compound as a colorless solid (0.115 g, 92% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.10 (br s, 1H), 10.00 (br s, 1H), 8.91 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.57 to 7.44 (m, 6H), 7.08 (d, J = 2.2 Hz, 1H), 5.00 to 4.69 (m, 1H), 4.36 (s, 2H), 3, 58 to 2.63 (m, 4H), 2.25 to 1.79 (m, 4H); MS (ES+) m/z 482.3 (M + 1), 484.3 (M + 1). EXAMPLE 239

[01364] Synthesis of 4-((1-benzylpiperidin-4-yl)oxy)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide

[01365] A mixture of ((4-((1-benzylpiperidin-4-yl)oxy)-5-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate (0.70 g , 1.2 mmol) and methylboronic acid (0.359 g, 6.0 mmol) in anhydrous 1,4-dioxane (10 ml) was added tribasic potassium phosphate (1.27 g, 6.0 mmol), tricyclohexiphosphine tetrafluoroborate (0.177 g, 0.48 mmol) and palladium acetate (0.054 g, 0.24 mmol), and the mixture was degassed by passing a stream of nitrogen through it for 15 minutes. The resulting mixture was heated to 90 to 100 °C for 24 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 ml) and filtered through a Celite filter. The filter plug was washed with ethyl acetate (50 ml) and the combined filtrate concentrated in vacuo. The residue was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (6 ml) was added thereto. The reaction mixture was stirred at room temperature for 6 h and then concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 100% ethyl acetate (containing 10% isopropanol and 10% triethylamine) in hexanes, provided the title compound as an off-white solid (0.248 g, 45% yield): 1H NMR (300 MHz, DMSO-d6) δ8.82 (d, J = 2.2 Hz, 1H), 7.57 (dd, J = 8.6, 0.7 Hz , 1H), 7.35 to 7.22 (m, 5H), 7.05 (d, J = 12.7 Hz, 1H), 6.77 (d, J = 2.2 Hz, 1H), 4 .57 to 4.52 (m, 1H), 3.48 (s, 2H), 2.76 (q, J = 7.2 Hz, 3H), 2.61 to 2.53 (m, 2H), 2.33 to 2.26 (m, 2H), 2.09 (s, 3H), 1.93 to 1.85 (m, 2H), 1.71 to 1.61 (m, 2H), 1, 05 (t, J = 7.2 Hz, 4.5H), NH not observed; MS (ES+) m/z 462.3 (M + 1). EXAMPLE 240

[01366] Synthesis of (S)-4-((1-(2,5-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3- 2,2,2-trifluoroacetate methyl-N-(thiazol-4-yl)benzenesulfonamide

[01367]Step 1. Preparation of (S)-4-((1-(2,5-difluorobenzyl)pyrrolidin-3-yl)amino)-2,6-difluoro-3-methyl-N-(thiazol-4 -yl)benzenesulfonamide

[01368] To a solution of (S)-2,6-difluoro-3-methyl-4-(pyrrolidin-3-ylamino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate ( 0.40 g, 0.82 mmol) and 2,5-difluorobenzaldehyde (0.23 g, 1.64 mmol) in anhydrous N,N-dimethylformamide (2 ml) and anhydrous dichloromethane (8 ml) were added sodium triacetoxyborohydride (0.34 g, 1.62 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then quenched by adding 2 M sodium hydroxide (10 ml) and brine (30 ml). The mixture was extracted with ethyl acetate (2 x 60 ml). The organic fractions were washed with saturated ammonium chloride (30 ml), brine (30 ml), dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography, eluting with a gradient of 10 to 60% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in hexanes, to produce the title compound as a colorless solid (0.27 g, 66% yield): MS (ES+) m/z 501.2 (M + H).

[01369]Step 2. (S)-4-((1-(2,5-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3 2,2,2-trifluoroacetate -methyl-N-(thiazol-4-yl)benzenesulfonamide

[01370] Following the procedure as described in EXAMPLE 103, Step 4 and making non-critical variations as necessary to substitute (S)-4-((1-benzylpyrrolidin-3-yl)amino)-2,6-difluoro-3- methyl-N-(thiazol-4-yl)benzenesulfonamide by (S)-4-((1-(2,5-difluorobenzyl)pyrrolidin-3-yl)amino)-2,6-difluoro-3-methyl-N -(thiazol-4-yl)benzenesulfonamide, and purification by preparative reversed-phase HPLC, eluting with a gradient of 7 to 50% acetonitrile in water containing 0.1% trifluoroacetic acid, yielded the title compound as a solid colorless (0.095 g, 38% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.48 (s, 1H), 10.90 (s, 1H), 8.91 (d, J = 2, 2 Hz, 1H), 7.53 to 7.47 (m, 1H), 7.40 (td, J = 6.4, 1.5 Hz, 2H), 6.99 (d, J = 2.2 Hz, 1H), 6.86 (d, J = 13.0 Hz, 1H), 4.44 to 4.41 (m, 2H), 4.31 to 4.04 (m, 1H), 3.57 to 3.43 (m, 3H), 2.74 to 2.62 (m, 3H), 2.19 to 2.00 (m, 6H); MS (ES+) m/z 515.3 (M + H). EXAMPLE 241

[01371] Synthesis of 4-((1-benzyl-3-methylpyrrolidin-3-yl)(methyl)amino)-3-chloro-N- (thiazol-2-yl)benzenesulfonamide

[01372]A mixture of 4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.180 g, 0.293 mmol) in formic acid (2 ml) paraformaldehyde (2.18 g, 26.86 mmol) was added and the reaction mixture was heated to 90 °C for 12 h. Concentration in vacuo and purification of the residue by preparative reversed-phase HPLC, eluting with a gradient of 20 to 80% acetonitrile in water (containing 0.05% ammonium hydroxide), yielded the title compound as a colorless solid ( 0.015 g, 15% yield): 1H NMR (400 MHz, CDCI3) δ7.90 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 2.0, 8.6 Hz, 1H), 7.33 to 7.29 (m, 5H), 7.26 to 7.22 (m, 1H), 7.14 (d, J = 4.6 Hz, 1H), 6.54 (d , J = 4.6 Hz, 1H), 3.69 to 3.55 (m, 2H), 2.79 to 2.70 (m, 5H), 2.68 to 2.61 (m, 1H), 2.59 to 2.56 (m, 1H), 2.21 to 2.10 (m, 1H), 1.82 to 1.71 (m, 1H), 1.44 (s, 3H), NH no observed; MS (ES+) m/z 477.0 (M + 1)

[01373] EXAMPLE 242

[01374] Synthesis of 5-chloro-2-fluoro-4-(methyl((S)-1-((S)-1-phenylpropyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl )benzenesulfonamide

[01375]Step 1. Preparation of tert-butyl ((S)-1-((S)-1-phenylpropyl)pyrrolidin-3-yl)carbamate

[01376] Following the procedure as described in EXAMPLE 42, Step 2 and making non-critical variations as necessary to replace (S)-1-phenylethan-1-amine with (S)-1-phenylpropan-1-amine, the compound of title was obtained as a yellow syrup (1.42 g, 58% yield): MS (ES+) m/z 305.2 (M + 1).

[01377]Step 2. Preparation of (S)-N-methyl-1-((S)-1-phenylpropyl)pyrrolidin-3-amine

[01378] Following the procedure as described in EXAMPLE 42, Step 3 and making non-critical variations as necessary to replace ((S)-1-((S)-1-phenylethyl)-pyrrolidin-3-yl) tert-butyl carbamate by tert-butyl ((R)-1-((R)-1-phenylpropyl)pyrrolidin-3-yl)carbamate, the title compound was obtained as a light yellow syrup (0.76 g, 74% yield) : MS (ES+) m/z 219.3 (M + 1).

[01379]Step 3. Preparation of 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide

[01380] To a solution of 5-chloro-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide (29.0 g, 93.3 mmol), (2,4-dimethoxyphenyl)methanol (19, 6 g, 117 mmol) and tri-n-butylphosphine (28.3 g, 140 mmol) in anhydrous tetrahydrofuran (300 ml) was added a solution of 1,1'-(azodicarbonyl)dipiperidine (35.3 g, 140 mmol ) in tetrahydrofuran (100 ml). The reaction mixture was stirred at room temperature for 2 h and then heated to 60 °C for 10 h. After cooling to room temperature, the reaction mixture was diluted with water (500 ml) and extracted with dichloromethane (3 * 400 ml). The combined organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate, and filtered. Concentration in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 20% ethyl acetate in petroleum ether, provided the title compound as a colorless solid (19.0 g, 44% performance). 1H NMR (400 MHz, CDCla) δ 8.58 (d, J = 2.4 Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.22 to 7.17 (m , 2H), 7.04 (t, J = 8.0 Hz, 1H), 6.43 to 6.35 (m, 2H), 5.04 (s, 2H), 3.79 (s, 3H) , 3.71 (s, 3H); MS (ES+) m/z 461.0 (M + 1), 463.0 (M + 1).

[01381]Step 4. Preparation of 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4- (methyl((S)-1-((S)-1-phenylpropyl)pyrrolidin-3- yl)amino)-N-(thiazol-4-yl)benzenesulfonamide

[01382] To a solution of (S)-N-methyl-1-((S)-1-phenylpropyl)pyrrolidin-3-amine (0.20 g, 0.92 mmol) and 5-chloro-N-( 2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide (0.41 g, 0.88 mmol) in anhydrous dimethyl sulfoxide (5 ml) was added N,N-diisopropylethylamine (0.80 ml, 4.6 mmol). The solution was heated to 80 °C for 22 h, then cooled to room temperature and diluted with ethyl acetate (150 ml). The mixture was washed with saturated aqueous ammonium chloride (100 ml), brine (100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0 to 30% ethyl acetate (containing 10% triethylamine and 10% isopropanol) in hexanes, to provide the title compound as a light yellow syrup (0 .26 g, 44% yield): 1H NMR (300 MHz, CDCI3) δ8.54 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.38 to 7.26 (m, 5H), 7.22 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 6.63 (d , J = 12.2 Hz, 1H), 6.40 to 6.34 (m, 2H), 5.02 (s, 2H), 4.24 to 4.14 (m, 1H), 3.77 ( s, 3H), 3.69 (s, 3H), 3.01 to 2.95 (m, 2H), 2.85 (s, 3H), 3.60 to 2.46 (m, 2H), 2 .29 to 2.10 (m, 2H), 1.98 to 1.85 (m, 2H), 1.75 to 1.65 (m, 1H), 0.70 (t, J = 7.4 Hz , 3H); MS (ES+) m/z 659.3 (M + 1), 661.3 (M + 1).

[01383]Step 5. Preparation of 5-chloro-2-fluoro-4-(methyl((S)-1-((S)-1-phenylpropyl)pyrrolidin-3-yl)amino)-N-(thiazol- 4-yl)benzenesulfonamide

[01384] To a solution of 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(methyl((S)- 1-((S)-1-phenylpropyl)pyrrolidin-3-yl )amino)-N-(thiazol-4-yl)benzenesulfonamide (0.26 g, 0.39 mmol) in dichloromethane (10 ml) trifluoroacetic acid (3 ml) was added. The solution was stirred at room temperature for 15 h, then concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0 to 10% methanol in dichloromethane, to give the title compound as a colorless solid (0.052 g, 26% yield): 1H NMR (300 MHz, DMSO -dε) δ 11.26 (br s, 1H), 8.88 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.35 a 7.23 (m, 5H), 7.04 to 7.00 (m, 2H), 4.18 to 4.09 (m, 1H), 3.07 to 3.01 (m, 1H), 2, 91 to 2.83 (m, 1H), 2.77 (s, 3H), 2.47 to 2.42 (m, 2H), 2.21 to 2.13 (m, 1H), 2.10 to 1.99 (m, 1H), 1.93 to 1.73 (m, 2H), 1.66 to 1.55 (m, 1H), 0.61 (t, J = 7.3 Hz, 3H) ; MS (ES+) m/z 509.1 (M + 1), 511.1 (M + 1). EXAMPLE 243

[01385] Synthesis of 5-chloro-2-fluoro-4-(methyl((S)-1-((R)-1-phenylpropyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl )benzenesulfonamide

[01386]Step 1. Preparation of tert-butyl ((S)-1-((R)-1-phenylpropyl)pyrrolidin-3-yl)carbamate

[01387] Following the procedure as described in EXAMPLE 42, Step 2 and making non-critical variations as necessary to replace (S)-1-phenylethan-1-amine with (R)-1-phenylpropan-1-amine, the compound of title was obtained as a yellow solid (1.65 g, 68% yield): MS (ES+) m/z 305.3 (M + 1).

[01388]Step 2. Preparation of (S)-N-methyl-1-((R)-1-phenylpropyl)pyrrolidin-3-amine

[01389] Following the procedure as described in EXAMPLE 42, Step 3 and making non-critical variations as necessary to replace ((S)-1-((S)-1-phenylethyl)-pyrrolidin-3-yl) tert-butyl carbamate by tert-butyl ((S)-1-((R)-1-phenylpropyl)pyrrolidin-3-yl)carbamate, the title compound was obtained as a light yellow oil (0.96 g, 81% yield) : MS (ES+) m/z 219.3 (M + 1).

[01390]Step 3. Preparation of 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4- (methyl((S)-1-((R)-1-phenylpropyl)pyrrolidin-3- yl)amino)-N-(thiazol-4-yl)benzenesulfonamide

[01391] Following the procedure as described in EXAMPLE 242, Step 4 and making non-critical variations as necessary to replace (S)-N-methyl-1- ((S)-1-phenylpropyl)pyrrolidin-3-amine with (S )-N-methyl-1-((R)-1-phenylpropyl)pyrrolidin-3-amine, the title compound was obtained as a yellow syrup (0.29 g, 48% yield): 1H NMR (300 MHz , CDCI3) £8.56 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.38 to 7.26 (m, 5H), 7 .23 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 6.72 (d, J = 12.2 Hz, 1H), 6.40 to 6.35 (m, 2H), 5.04 (s, 2H), 4.26 to 4.16 (m, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 3.01 (dd, J = 3.9, 9.4 Hz, 1H), 2.89 (s, 3H), 2.84 (dd, J = 4.4, 10.0 Hz, 1H), 2 .66 to 2.50 (m, 2H), 2.35 (q, J = 8.4 Hz, 1H), 1.96 to 1.65 (m, 4H), 0.70 (t, J = 7 .4Hz, 3H); MS (ES+) m/z 659.2 (M + 1), 661.2 (M + 1).

[01392]Step 4. Preparation of 5-chloro-2-fluoro-4-(methyl((S)-1-((R)-1-phenylpropyl)pyrrolidin-3-yl)amino)-N-(thiazol- 4-yl)benzenesulfonamide

[01393] Following the procedure as described in EXAMPLE 242, Step 5 and making non-critical variations as necessary to replace 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(methyl((S)- 1-((S)-1-phenylpropyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide by 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4 -(methyl((S)-1-((R)-1-phenylpropyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide, the title compound was obtained as a colorless solid ( 0.10 g, 47% yield): 1H NMR (300 MHz, DMSO-d6) £11.39 (br s, 1H), 8.92 to 8.89 (m, 1H), 7.78 to 7 .71 (m, 1H), 7.50 to 7.43 (m, 5H), 7.23 to 7.14 (m, 1H), 7.09 to 7.06 (m, 1H), 4.48 to 4.10 (m, 2H), 3.79 to 3.60 (m, 2H), 3.08 to 2.98 (m, 1H), 2.91 to 2.83 (m, 1H), 2 .80 to 2.70 (m, 3H), 2.22 to 1.88 (m, 4H), 0.62 (t, J = 7.3 Hz, 3H); MS (ES+) m/z 509.1 (M + 1), 511.1 (M + 1). EXAMPLE 244

[01394] Synthesis of (S)-5-chloro-2-fluoro-4-((1-(1-(2-fluorophenyl)cyclobutyl)pyrrolidin-3-yl)(methyl)amino)-N-( thiazol-4-yl)benzenesulfonamide

[01395]Step 1. Preparation of tert-butyl (S)-(1-(1-(2-fluorophenyl)cyclobutyl)pyrrolidin-3-yl)carbamate

[01396] To a solution of (S)-2-((tert-butoxycarbonyl)amino)butane-1,4-diyl dimethanesulfonate (2.19 g, 6.05 mmol) in anhydrous dimethyl sulfoxide (12 ml) 1-(2-fluorophenyl)cyclobutan-1-amine (1.00 g, 6.05 mmol) and N,N-diisopropylethylamine (3.30 ml, 24.21 mmol) were added and the resulting solution was heated up to 50 °C for 16 h. The reaction mixture was then cooled to room temperature and diluted with saturated ammonium chloride and extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide the title compound as a colorless oil (2.0 g, 99% yield), and used without further purification: MS (ES+) m /z 335.3 (M + 1).

[01397]Step 2. Preparation of (S)-1-(1-(2-fluorophenyl)cyclobutyl)-N-methylpyrrolidin-3-amine

[01398] To a solution of (S)-(1-(1-(2-fluorophenyl)cyclobutyl)pyrrolidin-3-yl) tert-butyl carbamate (2.00 g, 5.98 mmol) in anhydrous tetrahydrofuran (20 ml) 1 M solution of lithium aluminum hydride in tetrahydrofuran (12.10 ml, 12.10 mmol) was added and the resulting solution was heated to reflux for 3 h and then stirred at room temperature for 16 h. The reaction mixture was cooled to 0°C and quenched by addition of 1 M sodium hydroxide (50 ml) and extracted with diethyl ether (3 x 50 ml). The combined organic extracts were washed with water (25 ml), dried with anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo gave the title compound as a colorless oil (0.72 g, 48% yield): MS (ES+) m/z 249.1 (M + 1).

[01399]Step 3. Preparation of (S)-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4- ((1-(1-(2-fluorophenyl)cyclobutyl)pyrrolidin-3- yl)(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide

[01400] To a solution of (S)-1-(1-(2-fluorophenyl)cyclobutyl)-N-methylpyrrolidin-3-amine (0.72 g, 2.91 mmol) in anhydrous dimethyl sulfoxide (5 ml ) N,N-diisopropylethylamine (1.70 ml, 9.72 mmol) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide were added (1.12 g, 2.43 mmol) and the resulting solution was heated to 70 °C for 16 h. The reaction mixture was purified by column chromatography, eluting with a gradient of 10 to 100% ethyl acetate in heptane, to provide the title compound as a pale yellow oil (0.20 g, 10% yield): 1H NMR (300 MHz, CDCI3) δ8.56 (d, J = 2.3 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.21 to 7.02 (m, 6H), 6.70 (d, J = 12.3 Hz, 1H), 6.37 (td, J = 6.7, 2.3 Hz, 2H), 5.03 (s, 2H), 4, 11 to 4.05 (m, 1H), 3.85 to 3.67 (m, 6H), 2.89 to 2.79 (m, 4H), 2.45 to 2.39 (m, 5H), 2.23 to 2.17 (m, 2H), 2.07 to 2.01 (m, 2H), 1.86 to 1.80 (m, 2H); MS (ES+) m/z 689.3 (M + 1), 691.3 (M + 1).

[01401] Step 4. (S)-5-chloro-2-fluoro-4-((1-(1-(2-fluorophenyl)cyclobutyl)pyrrolidin-3-yl)(methyl)amino)-N- formate (thiazol-4-yl)benzenesulfonamide

[01402] To a solution of (S)-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-((1-(1- (2-fluorophenyl)cyclobutyl)pyrrolidin-3-yl )(methyl)amino)-N-(thiazol-4-yl)benzenesulfonamide (0.20 g, 0.29 mmol) in anhydrous dichloromethane (5 ml) was added trifluoroacetic acid (0.22 ml, 2.90 mmol) . The resulting solution was heated for 3 hours at reflux and then concentrated in vacuo. Purification of the residue by reverse phase HPLC eluting with a gradient of acetonitrile in water containing 0.1% formic acid, provided the title compound as a colorless solid (0.033 g, 19% yield): 1H NMR (300 MHz , DMSO-d6) δ 8.89 (d, J = 2.1 Hz, 1H), 8.15 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.31 to 7.27 (m, 1H), 7.17 to 7.02 (m, 5H), 4.05 to 4.02 (m, 1H), 2.76 (s, 3H), 2.70 to 2 .60 (m, 2H), 2.43 to 2.26 (m, 5H), 2.13 to 1.97 (m, 3H), 1.77 to 1.69 (m, 2H), NH and COOH not observed; MS (ES+) m/z 537.2 (M + 1), 539.2 (M + 1). EXAMPLE 245

[01403] Synthesis of (S)-4-((1-((2,5-dimethyloxazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2 2,2,2-trifluoroacetate -fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide

[01404]Step 1. Preparation of (S)-4-((1-(2,5-dimethyloxazol-4-carbonyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(4- methoxybenzyl)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide

[01405] To a solution of (S)-2-fluoro-N-(4-methoxybenzyl)-5-methyl-4- (methyl(pyrrolidin-3-yl)amino)-N-(thiazol-4-yl) benzenesulfonamide (0.25 g, 0.50 mmol) in dichloromethane (5 ml) was added 2,5-dimethyloxazol-4-carboxylic acid (0.105 g, 0.75 mmol), N-(3-dimethylaminopropyl)-hydrochloride N-ethylcarbodiimide (0.286 g, 1.50 mmol) and 4-(dimethylamino)pyridine (0.244 g, 2.0 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate (20 ml), washed with saturated ammonium chloride (2 x 20 ml), brine (10 ml), dried with anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 60% ethyl acetate in hexanes, provided the title compound as a colorless solid (0.20 g, 65% performance). MS (ES+) m/z 614.4 (M + 1).

[01406]Step 2. Preparation of (S)-4-((1-((2,5-dimethyloxazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N- (4-methoxybenzyl)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide

[01407] To a solution of (S)-4-((1-(2,5-dimethyloxazol-4-carbonyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(4-methoxybenzyl )-5-methyl-N-(thiazol-4-yl)benzenesulfonamide (0.15 g, 0.24 mmol) in anhydrous tetrahydrofuran (5 ml) was added 1 M lithium aluminum hydride solution in tetrahydrofuran (1 .22 ml, 1.22 mmol) by drip at 0 °C. The reaction mixture was stirred at 0°C for a further 15 minutes and then cooled by slow addition of sodium sulfate decahydrate (1.22 g). The mixture was stirred at room temperature for 4 hours and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 8% methanol in dichloromethane, provided the title compound as a colorless solid (0.055 g, 38% yield): MS (ES+) m/z 600.2 (M + 1).

[01408]Step 3. Preparation of (S)-4-((1-((2,5-dimethyloxazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino 2,2,2-trifluoroacetate )-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide

[01409] To a solution of (S)-4-((1-((2,5-dimethyloxazol-4-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-( 4-methoxybenzyl)-5-methyl-N-(thiazol-4-yl)benzenesulfonamide (0.055 g, 0.091 mmol) in dichloromethane (4 ml) was added trifluoroacetic acid (2 ml). The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 10% methanol in dichloromethane provided the title compound as a colorless solid (0.039 g, 89% yield). MS (ES+) m/z 480.2 (M + 1). EXAMPLE 246

[01410] Synthesis of 5-chloro-4-(((S)-1-((R)-2,3-dihydro- 1H-inden-1-yl)pyrrolidin- 2,2,2-trifluoroacetate 3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01411]Step 1. Preparation of tert-butyl ((S)-1-((R)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)carbamate

[01412] Following the procedure as described in EXAMPLE 42, Step 2 and making non-critical variations as necessary to replace (S)-1-phenylethan-1-amine with (R)-2,3-dihydro-1H-inden -1-amine, the title compound was obtained as a brown syrup (1.44 g, 58% yield): MS (ES+) m/z 303.3 (M + 1).

[01413]Step 2. Preparation of (S)-1-((R)-2,3-dihydro-1H-inden-1-yl)-N-methylpyrrolidin-3-amine

[01414] Following the procedure as described in EXAMPLE 42, Step 3 and making non-critical variations as necessary to replace ((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl) tert-butyl carbamate with ((S)-1-((R)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl) tert-butyl carbamate, the title compound was obtained as a brown oil ( 0.86 g, 83% yield): MS (ES+) m/z 217.2 (M + 1).

[01415]Step 3. Preparation of 5-chloro-4-(((S)-1-((R)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)( methyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01416] Following the procedure as described in EXAMPLE 242, Step 4 and making non-critical variations as necessary to replace (S)-N-methyl-1- ((S)-1-phenylpropyl)pyrrolidin-3-amine with (S )-1-((R)-2,3-dihydro-1H-inden-1-yl)-N-methylpyrrolidin-3-amine, the title compound was obtained as a light brown syrup (0.28 g , 47% yield): 1H NMR (300 MHz, CDCI3) δ 8.56 (d, J = 2.3 Hz, 1H), 7.68 (d, J = 7.4 Hz, 1H), 7, 36 to 7.34 (m, 1H), 7.26 to 7.19 (m, 5H), 6.68 (d, J = 12.2 Hz, 1H), 6.40 to 6.34 (m, 2H), 5.03 (s, 2H), 4.28 to 4.18 (m, 2H), 3.77 (s, 3H), 3.69 (s, 3H), 3.10 to 2.99 (m, 1H), 2.93 to 2.78 (m, 4H), 2.74 to 2.53 (m, 4H), 2.17 to 2.07 (m, 3H), 1.96 to 1 .84 (m, 1H); MS (ES+) m/z 657.3 (M + 1), 659.3 (M + 1).

[01417]Step 4. Preparation of 5-chloro-4-(((S)-1-((R)-2,3-dihydro-1H-inden-1-yl 2,2,2-trifluoroacetate )pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01418] Following the procedure as described in EXAMPLE 242, Step 5 and making non-critical variations as necessary to replace 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(methyl((S)- 1-((S)-1-phenylpropyl)pyrrolidin-3-yl)amino)-N-(thiazol- 4-yl)benzenesulfonamide by 5-chloro-4-(((S)-1-((R)- 2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)(methyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-4-yl )benzenesulfonamide, the title compound was obtained as a colorless solid (0.21 g, 79% yield): 1H NMR (300 MHz, DMSO-d6) £11.39 (br s, 1H), 10.39 ( br s, 0.5H), 10.20 (br s, 0.5H), 8.91 (d, J = 2.2 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H ), 7.65 to 7.58 (m, 1H), 7.42 to 7.38 (m, 2H), 7.34 to 7.28 (m, 1H), 7.24 to 7.18 (m , 1H), 7.08 (d, J = 2.2 Hz, 1H), 4.98 to 4.85 (m, 1H), 4.53 to 4.42 (m, 0.5H), 4, 33 to 4.22 (m, 0.5H), 3.62 to 3.46 (m, 3H), 3.38 to 3.08 (m, 2H), 2.94 to 2.84 (m, 1H ), 2.76 (s, 3H), 2.43 to 2.35 (m, 2H), 2.21 to 1.99 (m, 2H); MS (ES+) m/z 507.1 (M + 1), 509.1 (M + 1). EXAMPLE 247

[01419] Synthesis of 3-chloro-4-(((S)-1-((S)-2,3-dihydro- 1H-inden-1-yl)pyrrolidin- 2,2,2-trifluoroacetate 3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01420]Step 1. Preparation of tert-butyl ((3-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate

[01421] To a solution of tert-butyl thiazol-4-ylcarbamate (110.00 g, 549.3 mmol) in anhydrous tetrahydrofuran (1000 ml) was added 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran in tetrahydrofuran (659 ml, 659 mmol) at -78 °C. The reaction mixture was warmed to 5°C, stirred for 30 minutes, and cooled to -78°C. To it was added a solution of 3-chloro-2,4-difluoro-benzenesulfonyl chloride (162.8 g, 659 mmol) in anhydrous tetrahydrofuran (300 ml) at -78 °C. The reaction mixture was allowed to warm to room temperature, stirred for 12 h and then quenched by addition of saturated ammonium chloride (200 ml). The mixture was extracted with ethyl acetate (3 x 1000 ml), washed with brine (3 x 1000 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and trituration of the residue in methanol (300 ml) gave the title compound as a colorless solid (75.0 g, 33% yield): 1H NMR (400 MHz, CDCla) δ 9.14 (s, 1H), 8.26 to 8.09 (m, 1H), 8.03 (s, 1H), 7.66 (br t, J = 8.6 Hz, 1H), 1.27 (s , 9H); MS (ES+) m/z 432.8 (M + 23), 434.8 (M + 23).

[01422]Step 2. Preparation of 3-chloro-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide

[01423] Following the procedure as described in EXAMPLE 107, Step 1 and making non-critical variations as necessary to replace ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate with ( tert-butyl (3-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate, the title compound was obtained as a colorless solid (2.83 g, 87% yield): MS (ES+ ) m/z 311.0 (M + 1), 313.0 (M + 1).

[01424]Step 3. Preparation of 3-chloro-2,4-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide

[01425] To a solution of 3-chloro-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide (2.83 g, 9.11 mmol) in anhydrous dimethyl sulfoxide (10 ml) was added bicarbonate sodium (3.87 g, 46.1 mmol) and 1-(chloromethyl)-4-methoxybenzene (1.35 ml, 9.96 mmol). The mixture was stirred at 55 °C for 1 h, then cooled and filtered. The filtrate was purified by column chromatography, eluting with a gradient of 0 to 30% ethyl acetate in hexanes, to give the title compound as a colorless solid (3.08 g, 78% yield): 1H NMR ( 300 MHz, CDCI3) δ 8.56 (d, J = 2.3 Hz, 1H), 7.70 (ddd, J = 5.8, 7.4, 9.0 Hz, 1H), 7.25 a 7.20 (m, 2H), 7.18 (d, J = 2.3 Hz, 1H), 7.04 (ddd, J = 1.7, 7.6, 9.1 Hz, 1H), 6 .82 to 6.77 (m, 2H), 5.03 (s, 2H), 3.77 (s, 3H); MS (ES+) m/z 431.1 (M + 1), 433.1 (M + 1).

[01426]Step 4. Preparation of 3-chloro-4-(((S)-1-((S)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)( methyl)amino)-2-fluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide

[01427] To a solution of 3-chloro-2,4-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide (0.48 g, 1.12 mmol) and (S) -1-((S)-2,3-dihydro-1H-inden-1-yl)-N-methylpyrrolidin-3-amine (0.25 g, 1.16 mmol) in anhydrous dimethyl sulfoxide (5 ml) N,N-diisopropylethylamine (0.80 ml, 4.6 mmol) was added. The solution was heated to 80 °C for 21 h, then cooled to room temperature and diluted with ethyl acetate (150 ml). The mixture was washed with saturated aqueous ammonium chloride (100 ml), brine (100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0 to 50% ethyl acetate (containing 10% triethylamine and 10% isopropanol) in hexanes to give the title compound as a light yellow syrup (0. 23 g, 32% yield): 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J = 2.3 Hz, 1H), 7.52 (dd, J = 7.8, 8.8 Hz , 1H), 7.37 to 7.34 (m, 1H), 7.28 to 7.18 (m, 6H), 6.81 to 6.76 (m, 2H), 6.72 (dd, J = 1.4, 8.9 Hz, 1H), 5.04 (s, 2H), 4.30 to 4.26 (m, 1H), 4.24 to 4.13 (m, 1H), 3, 77 (s, 3H), 3.09 to 2.99 (m, 1H), 2.89 to 2.75 (m, 7H), 2.71 to 2.63 (m, 1H), 2.20 to 2.08 (m, 3H), 1.94 to 1.82 (m, 1H); MS (ES+) m/z 627.3 (M + 1), 629.3 (M + 1).

[01428]Step 5. Preparation of 3-chloro-4-(((S)-1-((S)-2,3-dihydro-1H-inden-1-yl 2,2,2-trifluoroacetate )pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01429] To a solution of 3-chloro-4-(((S)-1-((S)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)(methyl )amino)-2-fluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide (0.11 g, 0.17 mmol) in dichloromethane (5 ml) trifluoroacetic acid (10 ml) was added ). The solution was heated for 6 h at reflux, then allowed to cool to room temperature and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0 to 10% methanol in dichloromethane, to give the title compound as a colorless solid (0.091 g, 87% yield): 1H NMR (300 MHz, DMSO -d6) δ 11.42 (br s, 1H), 10.55 (br s, 0.5H), 10.20 (br s, 0.5H), 8.90 (d, J = 2.2 Hz , 1H), 7.72 to 7.60 (m, 2H), 7.44 to 7.38 (m, 2H), 7.34 to 7.28 (m, 1H), 7.13 to 7.09 (m, 1H), 7.06 (d, J = 2.1 Hz, 1H), 4.97 to 4.92 (m, 1H), 4.51 to 4.24 (m, 1H), 3, 87 to 3.42 (m, 3H), 3.30 to 3.05 (m, 2H), 2.93 to 2.76 (m, 4H), 2.46 to 2.36 (m, 2H), 2.21 to 1.98 (m, 2H); MS (ES+) m/z 507.1 (M + 1), 509.1 (M + 1). EXAMPLE 248

[01430] Synthesis of 5-chloro-4-(((S)-1-((S)-1-(2-chlorophenyl)propyl)pyrrolidin-3-yl)(methyl) 2,2,2-trifluoroacetate amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01431]Step 1. Preparation of tert-butyl ((S)-1-((S)-1-(2-chlorophenyl)propyl)pyrrolidin-3-yl)carbamate

[01432] Following the procedure as described in EXAMPLE 42, Step 2 and making non-critical variations as necessary to replace (S)-1-phenylethan- 1-amine with (S)-1-(2-chlorophenyl)propan hydrochloride 1-amine, the title compound was obtained as a yellow solid (1.12 g, 68% yield): MS (ES+) m/z 339.3 (M + 1), 341.3 (M + 1) .

[01433]Step 2. Preparation of (S)-1-((S)-1-(2-chlorophenyl)propyl)-N-methylpyrrolidin-3-amine

[01434] Following the procedure as described in EXAMPLE 42, Step 3 and making non-critical variations as necessary to replace ((S)-1-((S)-1-phenylethyl)-pyrrolidin-3-yl) tert-butyl carbamate by tert-butyl ((S)-1-((S)-1-(2-chlorophenyl)propyl)pyrrolidin-3-yl)carbamate, the title compound was obtained as a light yellow oil (0.63 g, 78% yield): MS (ES+) m/z 253.3 (M + 1), 255.3 (M + 1).

[01435]Step 3. Preparation of 5-chloro-4-(((S)-1-((S)- 1-(2-chlorophenyl)propyl)pyrrolidin-3-yl) 2,2,2-trifluoroacetate (methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01436] To a solution of (S)-1-((S)-1-(2-chlorophenyl)propyl)-N-methylpyrrolidin-3-amine (0.56 g, 2.20 mmol) and 5-chloro -N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide (0.98 g, 2.12 mmol) in anhydrous dimethyl sulfoxide (5 ml) was added N ,N-diisopropylethylamine (1.4 ml, 7.7 mmol). The solution was heated to 80 °C for 22 h, then cooled to room temperature and diluted with ethyl acetate (150 ml). The mixture was washed with saturated aqueous ammonium chloride (100 ml), brine (100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was partially purified by column chromatography, eluting with a gradient of 0 to 30% ethyl acetate (containing 10% triethylamine and 10% isopropanol) in hexanes. The partially purified compound was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (30 ml) and heated to reflux. After 5 minutes, the mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by reverse phase HPLC, eluting with a gradient of 20 to 80% acetonitrile in water (containing 0.1% trifluoroacetic acid) to give the title compound as a colorless solid (0.047 g, 33% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.42 to 11.36 (m, 1H), 10.79 (br s, 0.5H), 10.53 (br s, 0.5H) , 8.92 to 8.89 (m, 1H), 7.78 to 7.45 (m, 5H), 7.26 to 7.05 (m, 2H), 4.94 to 4.72 (m, 1H), 4.55 to 4.31 (m, 1H), 4.04 to 3.86 (m, 1H), 3.64 to 3.33 (m, 1H), 3.14 to 2.95 ( m, 2H), 2.85 to 2.67 (m, 3H), 2.30 to 1.86 (m, 4H), 0.63 (t, J = 7.3 Hz, 3H); MS (ES+) m/z 543.1 (M + 1), 545.1 (M + 1). EXAMPLE 249

[01437] Synthesis of 5-chloro-4-(((S)-1-((S)-2,3-dihydro- 1H-inden-1-yl)pyrrolidin- 2,2,2-trifluoroacetate 3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01438]Step 1. Preparation of tert-butyl ((S)-1-((S)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)carbamate

[01439] Following the procedure as described in EXAMPLE 42, Step 2 and making non-critical variations as necessary to replace (S)-1-phenylethan-1-amine with (S)-2,3-dihydro-1H-inden -1-amine, the title compound was obtained as a brown syrup (1.39 g, 58% yield): MS (ES+) m/z 303.3 (M + 1).

[01440]Step 2. Preparation of (S)-1-((S)-2,3-dihydro-1H-inden-1-yl)-N-methylpyrrolidin-3-amine

[01441] Following the procedure as described in EXAMPLE 42, Step 3 and making non-critical variations as necessary to replace ((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl) tert-butyl carbamate with ((S)-1-((S)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl) tert-butyl carbamate, the title compound was obtained as a brown oil ( 0.84 g, 85% yield): MS (ES+) m/z 217.3 (M + 1).

[01442]Step 3. Preparation of 5-chloro-4-(((S)-1-((S)-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)( methyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01443] Following the procedure as described in EXAMPLE 242, Step 4 and making non-critical variations as necessary to replace (S)-N-methyl-1- ((S)-1-phenylpropyl)pyrrolidin-3-amine with (S )-1-((S)-2,3-dihydro-1H-inden-1-yl)-N-methylpyrrolidin-3-amine, the title compound was obtained as a light brown syrup (0.33 g , 55% yield): 1H NMR (300 MHz, CDCI3) δ 8.56 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7, 36 to 7.33 (m, 1H), 7.27 to 7.20 (m, 5H), 6.70 (d, J = 12.2 Hz, 1H), 6.40 to 6.34 (m, 2H), 5.03 (s, 2H), 4.28 to 4.24 (m, 1H), 4.21 to 4.15 (m, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 3.09 to 2.99 (m, 1H), 2.91 to 2.74 (m, 7H), 2.67 to 2.59 (m, 1H), 2.19 to 2 .08 (m, 3H), 1.92 to 1.80 (m, 1H); MS (ES+) m/z 657.3 (M + 1), 659.3 (M + 1).

[01444]Step 4. Preparation of 5-chloro-4-(((S)-1-((S)-2,3-dihydro-1H-inden-1-yl 2,2,2-trifluoroacetate )pyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01445] Following the procedure as described in EXAMPLE 242, Step 5 and making non-critical variations as necessary to replace 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(methyl((S)- 1-((S)-1-phenylpropyl)pyrrolidin-3-yl)amino)-N-(thiazol- 4-yl)benzenesulfonamide by 5-chloro-4-(((S)-1-((S)- 2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)(methyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-4-yl )benzenesulfonamide, the title compound was obtained as a colorless solid (0.23 g, 74% yield): 1H NMR (300 MHz, DMSO-dε) δ 11.40 (br s, 1H), 10.43 ( br s, 0.5H), 10.10 (br s, 0.5H), 8.92 (d, J = 2.1 Hz, 1H), 7.76 (d, J = 7.4 Hz, 1H ), 7.65 to 7.60 (m, 1H), 7.42 to 7.38 (m, 2H), 7.34 to 7.28 (m, 1H), 7.23 (d, J = 12 .2 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 4.97 to 4.91 (m, 1H), 4.51 to 4.43 (m, 0.5H) , 4.32 to 4.25 (m, 0.5H), 3.86 to 3.40 (m, 3H), 3.27 to 3.04 (m, 2H), 2.94 to 2.72 ( m, 4H), 2.46 to 2.35 (m, 2H), 2.19 to 2.04 (m, 2H); MS (ES+) m/z 507.1 (M + 1), 509.1 (M + 1). EXAMPLE 250

[01446] Synthesis of 3-chloro-4-(methyl((S)-1-((S)-1-phenylethyl)pyrrolidin-3-yl)amino)-N-(thiazole) 2,2,2-trifluoroacetate -4-yl)benzenesulfonamide

[01447] Following the procedure as described in EXAMPLE 62, Step 5 and making non-critical variations as necessary to replace (S)-N-methyl-1-(2-phenylpropan-2-yl)pyrrolidin-3-amine with (S )-N-methyl-1-((S)-1-phenylethyl)pyrrolidin-3-amine and purification by reverse phase preparative HPLC, eluting with a gradient of 10 to 60% acetonitrile in water containing 0.1% trifluoroacetic acid, the title compound was obtained as a colorless solid (0.045 g, 8% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.17 to 11.07 (br s, 1H), 10, 56 to 10.24 (br s, 1H), 8.94 to 8.87 (m, 1H), 7.84 to 7.75 (m, 1H), 7.74 to 7.61 (m, 1H) , 7.54 to 7.42 (m, 5H), 7.37 to 7.22 (m, 1H), 7.12 to 7.06 (m, 1H), 4.58 to 4.20 (m, 2H), 4.00 to 3.45 (m, 1H), 3.35 to 3.03 (m, 2H), 2.97 to 2.83 (m, 1H), 2.81 to 2.64 ( m, 3H), 2.35 to 1.95 (m, 2H), 1.66 to 1.54 (m, 3H); MS (ES+) m/z 477.1 (M + 1), 479.1 (M + 1). EXAMPLE 251

[01448] Synthesis of 3-chloro-4-(methyl((S)-1-((R)-1-phenylethyl)pyrrolidin-3-yl)amino)-N-(thiazol) 2,2,2-trifluoroacetate -4-yl)benzenesulfonamide

[01449] Following the procedure as described in EXAMPLE 62, Step 5 and making non-critical variations as necessary to replace (S)-N-methyl-1-(2-phenylpropan-2-yl)pyrrolidin-3-amine with (S )-N-methyl-1-((R)-1-phenylethyl)pyrrolidin-3-amine and purification by reverse phase preparative HPLC, eluting with a gradient of 10 to 60% acetonitrile in water containing 0.1% trifluoroacetic acid, the title compound was obtained as a colorless solid (0.018 g, 3% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.15 to 11.12 (m, 1H), 10.35 to 10.19 (m, 1H), 8.92 to 8.89 (m, 1H), 7.84 to 7.78 (m, 1H), 7.74 to 7.64 (m, 1H), 7 .51 to 7.43 (m, 5H), 7.34 to 7.25 (m, 1H), 7.11 to 7.08 (m, 1H), 4.43 to 4.39 (m, 2H) , 4.20 to 4.15 (m, 1H), 3.74 to 3.61 (m, 1H), 3.07 to 2.90 (m, 2H), 2.76 to 2.70 (m, 3H), 2.19 to 2.08 (m, 2H), 1.64 to 1.57 (m, 3H); MS (ES+) m/z 477.1 (M + 1), 479.1 (M + 1). EXAMPLE 252

[01450] Synthesis of (S)-3-chloro-4-((1-(2-chlorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(1,2) 2,2,2-trifluoroacetate ,4-thiadiazol-5-yl)benzenesulfonamide

[01451] Following the procedure as described in EXAMPLE 29, Step 4 and making non-critical variations as necessary to replace benzaldehyde with 2-chlorobenzaldehyde, and purification by reversed-phase preparative HPLC, eluting with a gradient of 10 to 60% acetonitrile in water containing 0.1% trifluoroacetic acid, the title compound was obtained as a colorless solid (0.060 g, 32% yield): 1H NMR (300 MHz, DMSO-d6) δ 10.51 (br s, 2H ), 8.53-8.47 (m, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.72 to 7.68 (m, 2H), 7.61 to 7, 58 (m, 1H), 7.53 to 7.43 (m, 2H), 7.35 (d, J = 8.5 Hz, 1H), 4.57 (s, 2H), 4.37 to 4 .34 (m, 1H), 3.67 to 3.59 (m, 1H), 3.45 to 3.38 (m, 3H), 2.77 (s, 3H), 2.15 to 2.12 (m, 2H); MS (ES+) m/z 498.0 (M + 1), 500.0 (M + 1). EXAMPLE 253

[01452] Synthesis of (S)-3-chloro-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl) formate benzenesulfonamide

[01453]Step 1. Preparation of (S)-3-((2-chloro-4-(N-(thiazol-4-yl)sulfamoyl)phenyl)(methyl)amino)pyrrolidine-1-tert-butyl carboxylate

[01454] Following the procedure as described in EXAMPLE 62, Step 5 and making non-critical variations as necessary to replace (S)-N-methyl-1-(2-phenylpropan-2-yl)pyrrolidin-3-amine with (S )-3-(methylamino)pyrrolidine-1-tert-butyl carboxylate and purification by column chromatography, eluting with a gradient of 0 to 60% ethyl acetate in hexanes, the title compound was obtained as a beige solid (0 .92 g, 49% yield): MS (ES+) m/z 473.0 (M + 1), 475.0 (M + 1).

[01455]Step 2. Preparation of (S)-3-chloro-4-(methyl(pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01456] To a solution of (S)-3-((2-chloro-4-(N-(thiazol-4-yl)sulfamoyl)phenyl)- (methyl)amino)pyrrolidine-1-tert-butyl carboxylate ( 0.92 g, 1.95 mmol) in dichloromethane (50 ml) trifluoroacetic acid (15 ml) was added. The reaction mixture was stirred for 30 minutes. Concentration in vacuo gave the title compound as a beige foam (0.94 g, quantitative yield): 373.0 (M + 1), 375.0 (M + 1).

[01457]Step 3. Preparation of (S)-3-chloro-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4) formate -yl)benzenesulfonamide

[01458]A mixture of (S)-3-chloro-4-(methyl(pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate (0.36 g, 0.75 mmol) and 3-(difluoromethyl)benzaldehyde (0.23 g, 1.50 mmol) in 1,2-dichloroethane (5 ml) and N,N-dimethylformamide (5 ml) sodium triacetoxyborohydride was added (0.32 g, 1.50 mmol). The reaction mixture was stirred for 5 h at room temperature, and then diluted with ethyl acetate (60 ml). The mixture was washed with saturated ammonium chloride (2 x 30 ml), brine (150 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography, eluting with a gradient of 0 to 20% methanol (containing 0.2% ammonium hydroxide) in dichloromethane. Further purification by preparative reverse phase HPLC eluting with a gradient of 10 to 55% acetonitrile in water containing 0.1% formic acid afforded the title compound as a colorless solid (0.050 g, 12% yield): 1H NMR (300 MHz, DMSO-d6) £11.56 (s, 2H), 8.89 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.63 (dd, J = 8.6, 2.3 Hz, 1H), 7.51 to 7.44 (m, 4H), 7.21 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 2.1 Hz, 1H), 7.03 (t, J = 55.9 Hz, 1H), 4.17 to 4.07 (m , 1H), 3.70 (d, J = 13.4 Hz, 1H), 3.57 (d, J = 13.3 Hz, 1H), 2.76 (s, 3H), 2.73 to 2 .66 (m, 1H), 2.60 (d, J = 6.4 Hz, 2H), 2.43 to 2.33 (m, 1H), 2.11 to 1.99 (m, 1H), 1.85 to 1.73 (m, 1H); MS (ES+) m/z 513.1 (M + 1), 515.0 (M + 1). EXAMPLE 254

[01459] Synthesis of (S)-3-chloro-4-((1-(5-chloro-2-fluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl) formate )benzenesulfonamide

[01460] Following the procedure as described in EXAMPLE 253, Step 3 and making non-critical variations as necessary to replace 3-(difluoromethyl)benzaldehyde with 5-chloro-2-fluorobenzaldehyde, the title compound was obtained as a colorless solid (0.080 g, 19% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.64 (dd, J = 8.6, 2.3 Hz, 1H), 7.46 (dd, J = 6.3 , 2.7 Hz, 1H), 7.37 (ddd, J = 8.7, 4.5, 2.8 Hz, 1H), 7.23 (t, J = 8.8 Hz, 2H), 7 .06 (d, J = 2.2 Hz, 1H), 4.15 to 4.06 (m, 1H), 3.67 to 3.55 (m, 2H), 2.74 (s, 3H), 2.70 to 2.58 (m, 3H), 2.43 to 2.35 (m, 1H), 2.10 to 1.98 (m, 1H), 1.83 to 1.71 (m, 1H ), COOH not observed; MS (ES+) m/z 515.0 (M +1), 517.0 (M + 1). EXAMPLE 255

[01461] Synthesis of 4-((1-benzyl-3-methylazetidin-3-yl)amino)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01462]A mixture of tert-butyl ((3-chloro-4-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (0.56 g, 1.42 mmol) and 1-benzyl-3-methylazetidin- 3-amine (0.25 g, 1.42 mmol) in anhydrous dimethyl sulfoxide (3 ml) was added potassium carbonate (0.39 g, 2.84 mmol). The reaction mixture was heated to 50 °C under nitrogen for 18 h, and then diluted with ethyl acetate (150 ml). The mixture was washed with water (15 ml), brine (15 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (2 ml) was added. The mixture was stirred for 18 h at room temperature and then concentrated in vacuo. The residue was purified by preparative reverse phase HPLC eluting with a gradient of 8 to 60% acetonitrile in water containing 0.1% trifluoroacetic acid to provide the title compound as a colorless solid (0.035 g, 4% yield). : 1H NMR (300 MHz, CD3OD) δ 8.72 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.62 (dd, J = 8.7, 2.2 Hz, 1H), 7.49 (s, 5H), 7.04 (d, J = 2.2 Hz, 1H), 6.47 to 6.39 (m, 1H), 4.45 (s, 2H), 4.38 to 4.28 (m, 4H), 1.67 (s, 3H), NH and COOH not observed; MS (ES+) m/z 449.1 (M +1), 451.0 (M + 1). EXAMPLE 256

[01463] Synthesis of 3-chloro-4-(((1R,3s,5S)-8-(3-(difluoromethyl)benzyl)-8-azabicyclo[3,2,1]octan-3-yl)oxy) -N-(thiazol-4-yl)benzenesulfonamide

[01464]Step 1. Preparation of (1R,3s,5S)-3-(2-chloro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)-8-azabicyclo[3,2,1] tert-butyl octane-8-carboxylate

[01465] Following the procedure as described in EXAMPLE 57, Step 3 and making non-critical variations as necessary to replace (R)-1-(1-phenylethyl)piperidin-4-ol with (1R,3s,5S)-3- tert-butyl hydroxy-8-azabicyclo[3,2,1]octane-8-carboxylate and purification by trituration with diethyl ether (25 ml), the title compound was obtained as a colorless solid (2.01 g, 83% yield): MS (ES-) m/z 498.4 (M -1), 500.4 (M - 1).

[01466]Step 2. Preparation of 4-(((1R,3s,5S)-8-azabicyclo[3,2,1]octan-3-yl)oxy)-3-chloro 2,2,2-trifluoroacetate -N-(thiazol-4-yl)benzenesulfonamide

[01467] Following the procedure as described in EXAMPLE 253, Step 2 and making non-critical variations as necessary to replace (S)-3-((2-chloro-4-(N-(thiazol-4-yl)sulfamoyl)phenyl tert-butyl )(methyl)amino)pyrrolidine-1-carboxylate by (1R,3s,5S)-3-(2-chloro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)-8-azabicyclo [3,2,1]octane-8-tert-butyl carboxylate, the title compound was obtained as a colorless foam (2.06 g, quantitative yield): MS (ES+) m/z 400.2 (M +1 ), 402.2 (M + 1).

[01468]Step 3. Preparation of 3-chloro-4-(((1R,3s,5S)-8-(3-(difluoromethyl)benzyl)-8-azabicyclo[3,2,1]octan-3-yl )oxy)-N-(thiazol-4-yl)benzenesulfonamide

[01469] Following the procedure as described in EXAMPLE 257, Step 3 and making non-critical variations as necessary to replace 2,2,2-(S)-3-chloro-4-(methyl(pyrrolidin-3-yl) trifluoroacetate amino)-N-(thiazol-4-yl)benzenesulfonamide by 4-(((1R,3s,5S)-8-azabicyclo[3,2,1]octan-3-yl) 2,2,2-trifluoroacetate oxy)-3-chloro-N-(thiazol-4-yl)benzenesulfonamide, and purification by column chromatography, eluting with a gradient of 0 to 15% methanol (containing 0.1% ammonium hydroxide) in dichloromethane, the title compound was obtained as a colorless solid (0.12 g, 38% yield): 1H NMR (300 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.75 to 7.67 (m, 3H), 7.54 (t, J = 5.1 Hz, 2H), 7.49 (d, J = 9.0 Hz, 1H), 7.25 to 6.88 (m, 2H), 4.97 to 4.86 (m, 1H), 4.00 to 3 .93 (m, 2H), 3.58 to 3.50 (m, 2H), 2.17 to 2.12 (m, 4H), 1.99 to 1.91 (m, 4H); MS (ES+) m/z 540.1 (M +1), 542.1 (M + 1). EXAMPLE 257

[01470] Synthesis of (S)-5-chloro-2-fluoro-4-(methyl(1-(2-phenylpropan-2-yl)pyrrolidin-3-yl)amino)-N-(thiazol-4) formate -yl)benzenesulfonamide

[01471] A mixture of 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide (0.38 g, 0.82 mmol) and ( S)-N-methyl-1-(2-phenylpropan-2-yl)pyrrolidin-3-amine (0.18 g, 0.82 mmol) in anhydrous dimethyl sulfoxide (6 ml) was added cesium carbonate (0 .53 g, 1.64 mmol). The resulting mixture was stirred for 18 h at room temperature, and then diluted with ethyl acetate (60 ml). The mixture was washed with water (50 ml), saturated ammonium chloride (2 x 150 ml), brine (30 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue which was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (2 ml) was added thereto. The reaction mixture was stirred for 20 minutes at room temperature and then concentrated in vacuo. The residue was triturated in methanol (20 ml). Filtration and concentration of the filtrate in vacuo provided a residue which was dissolved in ethyl acetate (25 ml). The organic phase was washed with saturated sodium bicarbonate (2 x 25 ml), brine (25 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue was purified by preparative reversed-phase HPLC eluting with a gradient of 7 to 60% acetonitrile in water containing 0.1% formic acid, yielding the title compound as a colorless solid. (0.020 g, 4% yield): 1H NMR (300 MHz, DMSO-d6) δ 8.82 (d, J = 2.2 Hz, 1H), 8.23 to 8.17 (m, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.50 to 7.46 (m, 2H), 7.33 to 7.28 (m, 2H), 7.22 to 7.17 ( m, 1H), 7.03 (d, J = 12.3 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 4.11 to 4.01 (m, 1H), 2.77 (s, 3H), 2.68 to 2.53 (m, 3H), 2.40 to 2.32 (m, 1H), 2.03 to 1.92 (m, 1H), 1, 79 to 1.69 (m, 1H), 1.34 (s, 6H), NH and COOH not observed; MS (ES+) m/z 509.2 (M +1), 511.2 (M + 1). EXAMPLE 258

[01472] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide formate

[01473]Step 1. Preparation of (S)-5-chloro-2-fluoro-4-(pyrrolidin-3-ylamino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01474] Following the procedure as described in EXAMPLE 253, Step 2 and making non-critical variations as necessary to replace (S)-3-((2-chloro-4-(N-(thiazol-4-yl)sulfamoyl)phenyl tert-butyl )(methyl)amino)pyrrolidine-1-carboxylate with (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro- tert-butyl 5-fluorophenyl)amino)pyrrolidine-1-carboxylate, the title compound was obtained as a colorless foam (2.53 g, quantitative yield): MS (ES+) m/z 377.2 (M +1) , 379.2 (M + 1).

[01475]Step 2. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide formate

[01476] Following the procedure as described in EXAMPLE 29, Step 4 and making non-critical variations as necessary to replace 2,2,2-(S)-3-chloro-4-(methyl(pyrrolidin-3-yl) trifluoroacetate amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide by (S)-5-chloro-2-fluoro-4-(pyrrolidin-3-ylamino)-2,2,2-trifluoroacetate N-(thiazol-4-yl)benzenesulfonamide and purification by reverse phase preparative HPLC, eluting with a gradient of 10 to 60% acetonitrile in water containing 0.1% formic acid, the title compound was obtained as a solid colorless (0.140 g, 22% yield): 1H NMR (300 MHz, DMSO-d6) δ8.88 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 7.59 ( d, J = 7.4 Hz, 1H), 7.33 to 7.22 (m, 5H), 6.95 (d, J = 2.2 Hz, 1H), 6.75 (d, J = 13 .3 Hz, 1H), 6.14 (dd, J = 7.1, 1.4 Hz, 1H), 4.10 to 4.03 (m, 1H), 3.61 (s, 2H), 2 .80 (dd, J = 9.4, 6.9 Hz, 1H), 2.71 to 2.63 (m, 1H), 2.45 to 2.40 (m, 2H), 2.27 to 2 .17 (m, 1H), 1.80 to 1.70 (m, 1H), NH and COOH not observed; MS (ES+) m/z 467.2 (M + 1), 469.2 (M + 1). EXAMPLE 259

[01477] Synthesis of (S)-5-chloro-2-fluoro-4-(methyl(1-(1-phenylcyclopropyl)pyrrolidin-3-yl)amino)-N-(thiazol) 2,2,2-trifluoroacetate -4-yl)benzenesulfonamide

[01478]Step 1. Preparation of (S)-(1-(1-phenylcyclopropyl)pyrrolidin-3-yl) tert-butyl carbamate

[01479] Following the procedure as described in EXAMPLE 42, Step 2 and making non-critical variations as necessary to replace (S)-1-phenylethan-1-amine with 1-phenylcyclopropan-1-amine and purification by trituration with ethyl acetate (35 ml), the title compound was obtained as a colorless oil (2.73 g, 65% yield): MS (ES+) m/z 303.2 (M + 1).

[01480]Step 2. Preparation of (S)-N-methyl-1-(1-phenylcyclopropyl)pyrrolidin-3-amine

[01481] Following the procedure as described in EXAMPLE 42, Step 3 and making non-critical variations as necessary to replace ((S)-1-((S)-1-phenylethyl)-pyrrolidin-3-yl) tert-butyl carbamate by tert-butyl (S)-(1-(1-phenylcyclopropyl)pyrrolidin-3-yl)carbamate, the title compound was obtained as a colorless oil (1.36 g, 70% yield): MS (ES+) m/z 217.3 (M + 1).

[01482]Step 3. Preparation of (S)-5-chloro-2-fluoro-4-(methyl(1-(1-phenylcyclopropyl)pyrrolidin-3-yl)amino)-N 2,2,2-trifluoroacetate -(thiazol-4-yl)benzenesulfonamide

[01483] Following the procedure as described in EXAMPLE 257 and making non-critical variations as necessary to replace (S)-N-methyl-1-(2-phenylpropan-2-yl)pyrrolidin-3-amine with (S)-N -methyl-1-(1-phenylcyclopropyl)pyrrolidin-3-amine, and purification by reversed-phase preparative HPLC, eluting with a gradient of 10 to 60% acetonitrile in water containing 0.1% trifluoroacetic acid, the compound of title was obtained as a colorless solid (0.045 g, 7% yield): 1H NMR (300 MHz, CD3OD) δ8.73 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 7 .4 Hz, 1H), 7.64 (dt, J = 5.3, 2.1 Hz, 2H), 7.53 to 7.46 (m, 4H), 7.05 (d, J = 2, 2 Hz, 1H), 7.02 (d, J = 11.7 Hz, 1H), 4.20 to 4.07 (m, 1H), 3.83 to 3.76 (m, 1H), 3, 55 to 3.41 (m, 2H), 2.63 to 2.57 (m, 3H), 2.12 to 1.96 (m, 2H), 1.59 to 1.55 (m, 2H), 1.31 to 1.27 (m, 2H), NH and COOH not observed; MS (ES+) m/z 507.3 (M + 1), 509.3 (M + 1). EXAMPLE 260

[01484] Synthesis of (S)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(methyl(1-(2-phenylpropan-2) 2,2,2-trifluoroacetate -yl)pyrrolidin-3- yl)amino)benzenesulfonamide

[01485] Following the procedure as described in EXAMPLE 257 and making non-critical variations as necessary to replace 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide, and purification by reversed-phase preparative HPLC, eluting with a gradient from 10 to 60% acetonitrile in water containing 0.1% trifluoroacetic acid, the title compound was obtained as a colorless solid (0.34 g, 54% yield): 1H NMR (300 MHz, CD3OD) δ7.99 (d , J = 7.1 Hz, 1H), 7.78 (q, J = 8.1 Hz, 1H), 7.71 to 7.65 (m, 2H), 7.56 to 7.45 (m, 3H), 7.07 (d, J = 11.8 Hz, 1H), 6.93 (dd, J = 7.8, 1.9 Hz, 1H), 6.62 (dd, J = 7.9 , 2.4 Hz, 1H), 4.34 to 4.24 (m, 1H), 3.63 to 3.56 (m, 1H), 3.43 to 3.35 (m, 1H), 3, 29 to 3.21 (m, 2H), 2.82 to 2.66 (m, 3H), 2.18 to 2.08 (m, 2H), 1.87 (s, 6H), NH and COOH no observed; MS (ES+) m/z 521.3 (M + 1), 523.3 (M + 1). EXAMPLE 261

[01486] Synthesis of (R)-4-((1-benzylpyrrolidin-3-yl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01487]Step 1. Preparation of (R)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenyl)amino)pyrrolidine -1-tert-butyl carboxylate

[01488] Following the procedure as described in EXAMPLE 101, Step 1 and making non-critical variations as necessary to replace (S)-3-tert-butyl aminopyrrolidine-1-carboxylate with (R)-3-tert-aminopyrrolidine-1-carboxylate -butyl, the title compound was obtained as a colorless foam (2.04 g, 68% yield): 1H NMR (300 MHz, CDCl3) δ 8.81 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 7.1 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 6.42 (d, J = 12.2 Hz, 1H), 5, 05 to 5.01 (m, 1H), 4.08 to 4.06 (m, 1H), 3.81 to 3.76 (m, 1H), 3.57 to 3.52 (m, 2H), 3.39 to 3.30 (m, 1H), 2.36 to 2.25 (m, 1H), 2.02 to 1.98 (m, 1H), 1.50 (s, 9H), 1, 40 (s, 9H); MS (ES-) m/z 575.4 (M - 1), 577.4 (M - 1).

[01489] Step 2. Preparation of (R)-5-chloro-2-fluoro-4-(pyrrolidin-3-ylamino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01490] Following the procedure as described in EXAMPLE 253, Step 2 and making non-critical variations as necessary to replace (S)-3-((2-chloro-4-(N-(thiazol-4-yl)sulfamoyl)phenyl tert-butyl )(methyl)amino)pyrrolidine-1-carboxylate with (R)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro- tert-butyl 5-fluorophenyl)amino)pyrrolidine-1-carboxylate, the title compound was obtained as a colorless foam (0.51 g, quantitative yield): MS (ES+) m/z 377.2 (M +1) , 379.2 (M + 1).

[01491]Step 3. Preparation of (R)-4-((1-benzylpyrrolidin-3-yl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01492] Following the procedure as described in EXAMPLE 29, Step 4 and making non-critical variations as necessary to replace 2,2,2-(S)-3-chloro-4-(methyl(pyrrolidin-3-yl) trifluoroacetate amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide by (R)-5-chloro-2-fluoro-4-(pyrrolidin-3-ylamino)-2,2,2-trifluoroacetate N-(thiazol-4-yl)benzenesulfonamide and purification by column chromatography, eluting with a gradient of 0 to 60% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in hexanes, the title compound was obtained as a colorless solid (0.35 g, 75% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.88 (d, J = 2 .2 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.33 to 7.29 (m, 4H), 7.28 to 7.21 (m, 1H), 6 .96 (d, J = 2.2 Hz, 1H), 6.75 (d, J = 13.3 Hz, 1H), 6.14 to 6.11 (m, 1H), 4.12 to 4, 00 (m, 1H), 3.61 (s, 2H), 2.80 (dd, J = 9.4, 6.9 Hz, 1H), 2.71 to 2.64 (m, 1H), 2 .45 to 2.40 (m, 2H), 2.27 to 2.15 (m, 1H), 1.80 to 1.70 (m, 1H); MS (ES+) m/z 467.2 (M + 1), 469.2 (M + 1). EXAMPLE 262

[01493] Synthesis of (R)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01494]Step 1. Preparation of (R)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenyl)(methyl) amino)pyrrolidine-1-tert-butylcarboxylate

[01495] Following the procedure as described in EXAMPLE 101, Step 3 and making non-critical variations as necessary to replace (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl )sulfamoyl)-5-fluoro-2-methylphenyl)amino)pyrrolidine-1-tert-butyl carboxylate by (R)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl )sulfamoyl)-2-chloro-5-fluorophenyl)amino)pyrrolidine-1-tert-butylcarboxylate, the title compound was obtained as a colorless foam (0.47 g, 33% yield): 1H NMR (300 MHz , CDCI3) δ8.82 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H) , 6.84 (d, J = 11.8 Hz, 1H), 4.28 to 4.24 (m, 1H), 3.63 to 3.59 (m, 2H), 3.36 to 3.32 (m, 2H), 2.86 (s, 3H), 2.10 (dd, J = 7.8, 5.1 Hz, 2H), 1.49 (s, 9H), 1.40 (s, 9H); MS (ES+) m/z 467.2 (M + 23), 469.2 (M + 23).

[01496]Step 2. Preparation of (R)-5-chloro-2-fluoro-4-(methyl(pyrrolidin-3-yl)amino)-N-(thiazol-4-yl) 2,2,2-trifluoroacetate )benzenesulfonamide

[01497] Following the procedure as described in EXAMPLE 253, Step 2 and making non-critical variations as necessary to replace (S)-3-((2-chloro-4-(N-(thiazol-4-yl)sulfamoyl)phenyl tert-butyl )(methyl)amino)pyrrolidine-1-carboxylate with (R)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro- tert-butyl 5-fluorophenyl(methyl)amino)pyrrolidine-1-carboxylate, the title compound was obtained as a colorless foam (0.32 g, quantitative yield): MS (ES+) m/z 391.2 (M + 1), 393.2 (M + 1).

[01498]Step 3. Preparation of (R)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01499] Following the procedure as described in EXAMPLE 29, Step 4 and making non-critical variations as necessary to replace 2,2,2-(S)-3-chloro-4-(methyl(pyrrolidin-3-yl) trifluoroacetate amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide by (R)-5-chloro-2-fluoro-4-(methyl)pyrrolidin-3-yl 2,2,2-trifluoroacetate )amino)-N-(thiazol-4-yl)benzenesulfonamide and purification by column chromatography, eluting with a gradient of 0 to 60% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in hexanes, the title compound was obtained as a colorless solid (0.14 g, 29% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.89 (d , J = 2.2 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.33 to 7.28 (m, 4H), 7.28 to 7.21 (m, 1H), 7.07 (d, J = 12.5 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H), 4.24 to 4.15 (m, 1H), 3, 64 (d, J = 13.1 Hz, 1H), 3.52 (d, J = 13.0 Hz, 1H), 2.80 (s, 3H), 2.77 to 2.53 (m, 3H ), 2.38 to 2.30 (m, 1H), 2.13 to 2.02 (m, 1H), 1.86 to 1.74 (m, 1H); MS (ES+) m/z 481.2 (M + 1), 483.2 (M + 1). EXAMPLE 263

[01500] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(ethyl)amino)-5-chloro-2-fluoro- N-(thiazol-4-yl)benzenesulfonamide

[01501]Step 1. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenyl)(ethyl) amino)pyrrolidine-1-tert-butylcarboxylate

[01502] To a solution of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenyl)amino)pyrrolidine- tert-butyl 1-carboxylate (1.67 g, 2.89 mmol) and iodoethane (0.70 ml, 8.67 mmol) in anhydrous N,N-dimethylformamide (12 ml) was added to a dispersion of sodium hydride. 60% in mineral oil (0.35 g, 8.67 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. After quenching with saturated ammonium chloride (50 ml), the mixture was extracted with ethyl acetate (80 ml). The organic layer was washed with saturated ammonium chloride (40 ml), brine (40 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 25 to 50% ethyl acetate in hexanes provided the title compound as a colorless foam (1.23 g, 70% yield ): 1H NMR (300 MHz, CDCI3) δ8.83 (d, J = 2.3 Hz, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 6.93 (d, J = 11.5 Hz, 1H), 4.09 to 4.06 (m, 1H), 3.65 to 3.60 (m, 2H), 3.37 to 3.18 (m, 4H), 2.11 to 2.09 (m, 1H), 2.00 to 1.90 (m, 1H), 1.47 (s, 9H), 1, 39 (s, 9H), 1.03 to 0.98 (m, 3H); MS (ES+) m/z 627.4 (M + 23), 629.4 (M + 23).

[01503]Step 2. Preparation of (S)-5-chloro-4-(ethyl(pyrrolidin-3-yl)amino)-2-fluoro-N-(thiazol-4-yl) 2,2,2-trifluoroacetate )benzenesulfonamide

[01504] Following the procedure as described in EXAMPLE 253, Step 2 and making non-critical variations as necessary to replace (S)-3-((2-chloro-4-(N-(thiazol-4-yl)sulfamoyl)phenyl tert-butyl )(methyl)amino)pyrrolidine-1-carboxylate by (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro- tert-butyl 5-fluorophenyl(ethyl)amino)pyrrolidine-1-carboxylate, the title compound was obtained as a colorless foam (1.05 g, quantitative yield): MS (ES+) m/z 405.2 (M + 1), 407.2 (M + 1).

[01505]Step 3. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(ethyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01506] To a solution of (S)-5-chloro-4-(ethyl(pyrrolidin-3-yl)amino)-2-fluoro-N-(thiazol-4-yl) 2,2,2-trifluoroacetate benzenesulfonamide (0.55 g, 1.06 mmol) and benzaldehyde (0.22 ml, 2.12 mol) in anhydrous dichloromethane (20 ml) were added sodium triacetoxyborohydride (0.45 g, 2.12 mmol). The mixture was stirred at room temperature for 3 h and then quenched by addition of 2 M sodium hydroxide (50 ml). The mixture was extracted with ethyl acetate (80 ml). The organic layer was washed with saturated ammonium chloride (50 ml), brine (30 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo produced a residue that was purified by column chromatography, eluting with a gradient of 0 to 60% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in hexanes. The purified compound was then dissolved in ethanol (10 ml) containing 0.1% formic acid, filtered and concentrated in vacuo to give the title compound as a colorless solid (0.23 g, 40% yield): 1H NMR (300 MHz, DMSO-d6) δ 8.88 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H ), 7.33 to 7.24 (m, 5H), 7.02 (d, J = 2.2 Hz, 1H), 4.19 to 4.10 (m, 1H), 3.76 (d, J = 13.0 Hz, 1H), 3.65 (d, J = 13.0 Hz, 1H), 3.41 to 3.20 (m, 2H), 2.83 to 2.74 (m, 2H ), 2.65 (dd, J = 10.0, 5.6 Hz, 1H), 2.57 to 2.51 (m, 2H), 2.12 to 2.01 (m, 1H), 1, 80 to 1.68 (m, 1H), 0.84 (t, J = 7.0 Hz, 3H), NH and COOH not observed; MS (ES+) m/z 495.1 (M + 1), 497.1 (M + 1). EXAMPLE 264

[01507] Synthesis of (S)-4-((5-benzyl-5-azaspiro[2,4]heptan-7-yl)amino)-5-chloro-2-fluoro- 2,2,2-trifluoroacetate N-(thiazol-4-yl)benzenesulfonamide

[01508] Following the procedure as described in EXAMPLE 257 and making non-critical variations as necessary to replace (S)-N-methyl-1-(2-phenylpropan-2-yl)pyrrolidin-3-amine with (S) hydrochloride -5-benzyl-5-azaspiro[2,4]heptan-7-amine, and purification by reversed-phase preparative HPLC, eluting with a gradient of 10 to 60% acetonitrile in water containing 0.1% trifluoroacetic acid, the title compound was obtained as a colorless solid (0.060 g, 22% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.17 (s, 1H), 10.71 (s, 0.5H) , 10.24 (s, 0.5H), 8.89 (d, J = 2.2 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.52 to 7, 46 (m, 5H), 7.00 (d, J = 2.2 Hz, 1H), 6.90 to 6.71 (m, 1H), 6.55 to 6.46 (m, 0.5H) , 6.20 to 6.14 (m, 0.5H), 4.52 to 4.25 (m, 2H), 4.12 to 4.03 (m, 1H), 3.79 to 3.54 ( m, 1H), 3.42 to 3.28 (m, 2H), 0.90 to 0.69 (m, 4H), NH not observed; MS (ES+) m/z 493.2 (M + 1), 495.2 (M + 1). EXAMPLE 265

[01509] Synthesis of (S)-4-((5-benzyl-5-azaspiro[2,4]heptan-7-yl)(methyl)amino)-5-chloro-2 2,2,2-trifluoroacetate -fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01510]Step 1. Preparation of tert-butyl (S)-(5-benzyl-5-azaspiro[2,4]heptan-7-yl)carbamate

[01511] To a mixture of (S)-5-benzyl-5-azaspiro[2,4]heptan-7-amine hydrochloride (0.70 g, 2.55 mmol) and 2 M sodium hydroxide (25 .5 mmol, 12.75 ml) in tetrahydrofuran (30 ml) di-tert-butyl dicarbonate (1.11 g, 5.10 mmol) was added at 0°C. The mixture was allowed to warm to room temperature, stirred for 18 h and then diluted with ethyl acetate (85 ml). The mixture was washed with water (50 ml), brine (2 x 50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 50% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in dichloromethane, produced the compound of the title as a colorless oil (0.74 g, 96% yield). 1H NMR (300 MHz, CDCla) δ 7.35- to 7.31 (m, 5H), 4.98 to 4.92 (m, 1H), 3.83 (ddd, J = 9.1, 6, 0, 3.1 Hz, 1H), 3.69-3.55 (m, 2H), 2.92 (dd, J = 9.6, 5.9 Hz, 1H), 2.71 to 2.65 (m, 2H), 2.35 (d, J = 9.0 Hz, 1H), 1.44 (s, 9H), 0.82 to 0.73 (m, 2H), 0.60 (ddd, J = 9.3, 5.6, 3.7 Hz, 1H), 0.46 (ddd, J = 9.5, 5.7, 3.9 Hz, 1H); MS (ES+) m/z 303.4 (M + 1).

[01512]Step 2. Preparation of (S)-5-benzyl-N-methyl-5-azaspiro[2,4]heptan-7-amine

[01513] Following the procedure as described in EXAMPLE 42, Step 3 and making non-critical variations as necessary to replace ((S)-1-((S)-1-phenylethyl)-pyrrolidin-3-yl) tert-butyl carbamate by tert-butyl (S)-(5-benzyl-5-azaspiro[2,4]heptan-7-yl)carbamate, the title compound was obtained as a colorless oil (0.52 g, 98% yield) : MS (ES+) m/z 217.3 (M + 1).

[01514]Step 3. Preparation of (S)-4-((5-benzyl-5-azaspiro[2,4]heptan-7-yl)(methyl)amino)-5- 2,2,2-trifluoroacetate chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01515] Following the procedure as described in EXAMPLE 257 and making non-critical variations as necessary to replace (S)-N-methyl-1-(2-phenylpropan-2-yl)pyrrolidin-3-amine with (S)-5 -benzyl-N-methyl-5-azaspiro[2,4]heptan-7-amine, and purification by reversed-phase preparative HPLC, eluting with a gradient of 10 to 60% acetonitrile in water containing 0.1% acid trifluoroacetic acid, the title compound was obtained as a colorless solid (0.15 g, 3% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.37 (s, 1H), 10.74 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.53 to 7.49 (m, 2H), 7, 46 to 7.43 (m, 3H), 7.21 (d, J = 12.2 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 4.46 to 4.44 (m, 2H), 4.16 to 4.10 (m, 1H), 3.90 to 3.83 (m, 1H), 3.62 to 3.56 (m, 1H), 3.48 to 3 .42 (m, 1H), 3.03 to 2.98 (m, 1H), 2.94 (s, 3H), 0.96 to 0.71 (m, 4H); MS (ES+) m/z 507.2 (M + 1), 509.2 (M + 1). EXAMPLE 266

[01516] Synthesis of (S)-3-chloro-4-((1-(2-fluoro-5-methylbenzyl)-3-methylpyrrolidin-3-yl)amino)-N-(thiazol-4-yl) formate )benzenesulfonamide

[01517]Step 1. Preparation of (S)-N-(3-methylpyrrolidin-3-yl)acetamide

[01518]To (S)-N-(1-benzyl-3-methylpyrrolidin-3-yl)acetamide (1.0 g, 4.3 mmol) and 10% Pd/C (0.46 mg) was added methanol (10 ml) and the mixture was heated to 40 °C under a hydrogen atmosphere (50 psi) for 24 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to yield the title compound as a colorless oil (0.600 g, 98% yield): 1H NMR (400 MHz, CDCI3) δ 5 .67 (s, 1H), 3.22 (d, J = 11.6 Hz, 1H), 3.11 (ddd, J = 11.2, 8.0, 5.9 Hz, 1H), 2, 94 (ddd, J = 11.2, 8.2, 6.5 Hz, 1H), 2.76 (d, J = 11.6 Hz, 1H), 2.21 (br s, 1H), 2, 19 to 2.10 (m, 1H), 1.95 (s, 3H), 1.76 (ddd, J = 13.1, 8.2, 5.9 Hz, 1H), 1.46 (s, 3H).

[01519]Step 2. Preparation of (S)-N-(1-(2-fluoro-5-methylbenzyl)-3-methylpyrrolidin-3-yl)acetamide

[01520] To a solution of (S)-N-(3-methylpyrrolidin-3-yl)acetamide (0.240 g, 1.6 mmol) and 2-fluoro-5-methyl-benzaldehyde (0.233 g, 1.6 mmol ) in dichloromethane (2 ml) acetic acid (0.101 g, 1.6 mmol) was added, followed by addition of sodium acetoxy borohydride (0.358 g, 1.6 mmol). The reaction mixture was stirred at room temperature for 12 h. water (10 ml) was added thereto, and the mixture was extracted with ethyl acetate (3 x 20 ml). The combined organic phase was washed with brine (3 x 10 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by reversed-phase column chromatography, eluting with a gradient of acetonitrile in water containing 0.1% ammonium hydroxide, provided the title compound as a colorless oil (0.200 g, 0.757 mmol): 1H NMR (400 MHz, CDCI3) δ7.45 (d, J = 6.8 Hz, 1H), 7.23 to 7.12 (m, 2H), 4.18 to 4.06 (m , 2H), 3.76 (d, J = 11.2 Hz, 1H), 3.64 to 3.53 (m, 1H), 3.05 (dt, J = 10.2, 4.4 Hz, 1H), 2.84 to 2.74 (m, 1H), 2.70 (d, J = 11.2 Hz, 1H), 2.27 (s, 3H), 1.98 (td, J = 13 .6, 8.8 13.6 Hz, 1H), 1.91 (s, 3H), 1.59 (s, 3H), NH not observed; MS (ES+) m/z 265.1 (M + 1)

[01521]Step 3. Preparation of (S)-1-(2-fluoro-5-methylbenzyl)-3-methylpyrrolidin-3-amine

[01522] Following the procedure as described in EXAMPLE 226, Step 3 and making non-critical variations to replace (S)-N-(1-benzyl-3-methylpyrrolidin-3-yl)acetamide with (S)-N-(1 -(2-fluoro-5-methylbenzyl)-3-methylpyrrolidin-3-yl)acetamide, the title compound was obtained as a yellow oil (0.135 g, 80% yield): 1H NMR (400 MHz, CDCl3) δ 7.24 to 7.16 (m, 1H), 7.07 to 6.99 (m, 1H), 6.95 to 6.89 (m, 1H), 3.72 to 3.59 (m, 2H ), 2.90 (dt, J = 8.8, 5.2 Hz, 1H), 2.56 (d, J = 9.0 Hz, 1H), 2.53 to 2.45 (m, 1H) , 2.38 (d, J = 9.2 Hz, 1H), 2.33 (s, 3H), 1.86 (ddd, J = 13.2, 8.4, 5.0 Hz, 1H), 1.79-1.74 (m, 1H), 1.28 (s, 3H), NH not observed.

[01523]Step 4. Preparation of (S)-((3-chloro-4-((1-(2-fluoro-5-methylbenzyl)-3-methylpyrrolidin-3-yl)amino)phenyl)sulfonyl)(thiazole -4-yl) tert-butyl carbamate

[01524] Following the procedure as described in EXAMPLE 225, Step 2 and making non-critical variations to replace (R)-1-benzyl-3-methylpyrrolidin-3-amine with (S)-1-(2-fluoro-5- methylbenzyl)-3-methylpyrrolidin-3-amine, the title compound was obtained as a yellow solid (0.150 g, 41% yield): MS (ES+) m/z 595.1 (M + 1), 597.1 (M + 1).

[01525]Step 5. Preparation of (S)-3-chloro-4-((1-(2-fluoro-5-methylbenzyl)-3-methylpyrrolidin-3-yl)amino)-N-(thiazole) formate 4-yl)benzenesulfonamide

[01526] Following the procedure as described in EXAMPLE 225, Step 3 and making non-critical variations to replace (R)-((4-((1-benzyl-3-methylpyrrolidin-3-yl)amino)-3-chlorophenyl) tert-butyl sulfonyl)(thiazol-4-yl)carbamate by (S)-((3-chloro-4-((1- 2-fluoro-5-methylbenzyl)-3-methylpyrrolidin-3-yl)amino)phenyl )sulfonyl)(thiazol-4-yl)tert-butylcarbamate, the title compound was obtained as a colorless solid (0.052 g, 41% yield): 1H NMR (400 MHz, DMSO-d6) δ 8.87 ( d, J = 2.0 Hz, 1H), 8.20 (s, 0.4H), 7.66 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 8.8 , 2.2 Hz, 1H), 7.22 to 7.18 (m, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.10 to 7.06 (m, 1H) , 7.06 to 7.00 (m, 1H), 6.96 (d, J = 2.0 Hz, 1H), 5.47 (s, 1H), 3.67 to 3.57 (m, 2H ), 2.84 (d, J = 9.8 Hz, 1H), 2.78 to 2.70 (m, 1H), 2.59 to 2.53 (m, 2H), 2.25 (s, 3H), 2.19 to 2.07 (m, 1H), 1.90 to 1.80 (m, 1H), 1.44 (s, 3H), NH and COOH not observed; MS (ES+) m/z 495.0 (M + 1), 497.0 (M + 1). EXAMPLE 267

[01527] Synthesis of (S)-3-chloro-2,6-difluoro-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)amino)-N-( thiazol-4-yl)benzenesulfonamide

[01528] Following the procedure as described in EXAMPLE 102, Step 6 and making non-critical variations as necessary to replace benzaldehyde with 6-methylpicolinaldehyde, the title compound was obtained as a colorless solid (0.26 g, 67% yield) : 1H NMR (300 MHz, DMSO-d6) δ 8.88 (d, J = 2.2 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 2.2 Hz, 1H), 6.88 (dd, J = 13.3, 1.4 Hz, 1H), 4.32 to 4.23 (m, 1H), 3.76 (d, J = 14.0 Hz, 1H), 3.64 (d, J = 13 .9 Hz, 1H), 2.90 to 2.75 (m, 5H), 2.66 (dd, J = 9.9, 8.2 Hz, 1H), 2.46 to 2.34 (m, 4H), 2.18 to 2.06 (m, 1H), 1.92 to 1.77 (m, 1H), NH not observed; MS (ES+) m/z 514.2 (M + 1), 516.2 (M + 1). EXAMPLE 268

[01529] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)oxy)-3-chloro-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide hydrochloride

[01530]Step 1. Preparation of (S)-((4-((1-benzylpyrrolidin-3-yl)oxy)-3-chloro-2,6-difluorophenyl)sulfonyl)(thiazol-4-yl) tert carbamate -butyl

[01531]A mixture of (S)-1-benzylpyrrolidin-3-ol (0.87 g, 4.66 mmol) and ((3-chloro-2,4,6-trifluorophenyl)sulfonyl)(thiazol-4 -yl) tert-butyl carbamate (2.00 g, 4.66 mmol) in anhydrous N,N-dimethylformamide (25 ml) was added to a dispersion of 60% sodium hydride in mineral oil (0.19 g, 4 .66 mmol) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then quenched by adding water (20 ml) and extracted with ethyl acetate (80 ml). The organic layer was washed with saturated ammonium chloride (2 x 50 ml), brine (2 x 50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 60% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in dichloromethane, produced the compound of the title as a colorless foam (0.97 g, 36% yield). 1H NMR (300 MHz, CDCI3) δ 8.82 (d, J = 2.3 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.38 to 7.34 (m , 4H), 7.33 to 7.29 (m, 1H), 6.53 (dd, J = 11.9, 1.9 Hz, 1H), 4.94 to 4.88 (m, 1H), 3.78 to 3.69 (m, 2H), 3.11 (dd, J = 10.8, 6.1 Hz, 1H), 2.88 to 2.78 (m, 2H), 2.76 to 2.68 (m, 1H), 2.47 to 2.35 (m, 1H), 2.12 to 2.02 (m, 1H), 1.40 (s, 9H); MS (ES+) m/z 586.4 (M + 1), 588.4 (M + 1).

[01532]Step 2. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)oxy)-3-chloro-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide hydrochloride

[01533]A (S)-((4-((1-benzylpyrrolidin-3-yl)oxy)-3-chloro-2,6-difluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate (0 .19 g, 0.32 mmol) 4 M hydrochloric acid in dioxane (10 ml) was added. The mixture was stirred at room temperature for 5 h and then concentrated in vacuo. The residue was treated with ethanol (20 ml) and 3 M aqueous hydrochloric acid (0.3 ml). The mixture was filtered and the filtrate was concentrated in vacuo to provide the title compound as a colorless solid (0.15 g, 89% yield): 1H NMR (300 MHz, CD3OD) δ 8.82 to 8.75 ( m, 1H), 7.62 to 7.48 (m, 5H), 7.10 to 7.02 (m, 2H), 5.39 to 5.37 (m, 1H), 4.58 to 4, 48 (m, 2H), 3.76 to 3.59 (m, 3H), 3.53 to 3.45 (m, 1H), 2.91 to 2.75 (m, 0.5H), 2, 52 to 2.41 (m, 1H), 2.37 to 2.21 (m, 0.5H), HCl and NH not observed; MS (ES+) m/z 486.1 (M + 1), 488.1 (M + 1). EXAMPLE 269

[01534] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)oxy)-2,6-difluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide hydrochloride

[01535] A mixture of (S)-((4-((1-benzylpyrrolidin-3-yl)oxy)-3-chloro-2,6-difluorophenyl)sulfonyl)(thiazol-4-yl) tert-carbamate butyl (0.97 g, 1.66 mmol), methylboronic acid (0.99 g, 16.60 mmol), and potassium phosphate (1.76 g, 8.30 mmol) in anhydrous dioxane (20 ml) were palladium acetate (0.075 g, 0.33 mmol) and tricyclohexylphosphonium tetrafluoroborate (0.25 g, 0.66 mmol) were added. The resulting mixture was degassed and heated at reflux for 6 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 ml) and saturated ammonium chloride (50 ml) and filtered. The organic layer of the filtrate was washed with saturated ammonium chloride (30 ml), brine (2 x 20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 60% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in hexanes, provided a residue , which was treated with ethanol (10 ml) and 3 M aqueous hydrochloric acid (0.3 ml). Filtration and concentration of the filtrate in vacuo gave the title compound as a colorless solid (0.30 g, 36% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 0.5H) , 11.85 (s, 0.5H), 11.50 (s, 0.5H), 11.46 (s, 0.5H), 8.91 (dd, J = 5.4, 2.2 Hz , 1H), 7.71 to 7.61 (m, 2H), 7.42 (ddd, J = 7.8, 5.5, 2.4 Hz, 3H), 7.04 to 6.99 (m , 2H), 5.28 to 5.19 (m, 1H), 4.44 to 4.35 (m, 2H), 3.94 to 3.86 (m, 0.5H), 3.59 to 3 .39 (m, 2H), 3.33 to 3.19 (m, 1.5H), 2.68 to 2.56 (m, 0.5H), 2.35 to 2.09 (m, 1, 5H), 2.10 to 1.99 (m, 3H); MS (ES+) m/z 466.1 (M + 1). EXAMPLE 270

[01536] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-(difluoromethyl)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide formate

[01537]Step 1. Preparation of 2,4-difluoro-5-formyl-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide

[01538] To a solution of 5-bromo-2,4-difluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide (2.73 g, 5.74 mmol) in anhydrous tetrahydrofuran ( 45 ml) was added 1.3 M lithium isopropylmagnesium chloride complex solution in tetrahydrofuran (5.74 ml, 7.47 mmol) at -42 °C. The reaction mixture was stirred at -42 °C for 1 h and then N,N-dimethylformamide (1.11 ml, 14.35 mmol) was added thereto. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. After quenching with saturated ammonium chloride (60 ml), the mixture was extracted with ethyl acetate (80 ml). The organic layer was washed with saturated ammonium chloride (60 ml), brine (50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 50% ethyl acetate in hexanes provided the title compound as a colorless solid (1.07 g, 44% yield ): 1H NMR (300 MHz, CDCI3) δ 10.23 (s, 1H), 8.56 (d, J = 2.3 Hz, 1H), 8.30 (t, J = 7.7 Hz, 1H ), 7.25 to 7.19 (m, 3H), 7.05 (t, J = 9.5 Hz, 1H), 6.81 to 6.75 (m, 2H), 5.01 (s, 2H), 3.77 (s, 3H); MS (ES+) m/z 425.2 (M + 1).

[01539]Step 2. Preparation of (S)-3-((5-fluoro-2-formyl-4-(N-(4-methoxybenzyl)- N-(thiazol-4-yl)sulfamoyl)phenyl)(methyl )amino)pyrrolidine-1-tert-butyl carboxylate

[01540] To a solution of 2,4-difluoro-5-formyl-N-(4-methoxy benzyl)-N-(thiazol-4-yl)benzenesulfonamide (1.07 g, 2.52 mmol) in sodium sulfoxide anhydrous dimethyl (20 ml) tert-butyl (S)-3-(methylamino)pyrrolidine-1-carboxylate (1.01 g, 5.04 mmol) was added. The reaction mixture was heated at 80 °C for 30 minutes. After cooling to room temperature, the mixture was diluted with ethyl acetate (80 ml). The organic layer was washed with saturated ammonium chloride (2 x 50 ml), brine (50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave the title compound as a beige oil (1.45 g, 95% yield): 1H NMR (300 MHz, CDCla) δ 9.89 (s, 1H), 8.56 (d , J = 2.3 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.25 to 7.21 (m, 3H), 6.81 to 6.71 (m, 3H), 5.02 (s, 2H), 4.15 to 4.09 (m, 1H), 3.76 (s, 3H), 3.64 to 3.59 (m, 1H), 3.46 to 3.32 (m, 2H), 2.92 (s, 3H), 2.21 to 2.12 (m, 2H), 1.72 to 1.70 (m, 1H), 1.49 (s , 9H); MS (ES+) m/z 605.5 (M + 1).

[01541] Step 3. Preparation of (S)-3-((2-difluoromethyl)-5-fluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)phenyl)( tert-butyl methyl)amino)pyrrolidine-1-carboxylate

[01542] To a solution of (S)-3-((5-fluoro-2-formyl-4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)phenyl)(methyl) tert-butylamino)pyrrolidine-1-carboxylate (1.45 g, 2.40 mmol) in dichloromethane (25 ml) was added diethylaminosulfur trifluoride (0.63 ml, 4.80 mmol) at 0°C. The mixture was stirred at 0°C for 2 h and then at room temperature for 18 h. The reaction mixture was poured into ice-cold saturated sodium bicarbonate (300 ml) and extracted with ethyl acetate (110 ml). The organic layer was washed with saturated sodium bicarbonate (100 ml), saturated ammonium chloride (50 ml), brine (50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 45% ethyl acetate in hexanes provided the title compound as a colorless solid (1.00 g, 66% yield ): 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J = 0.3 Hz, 1H), 8.00 (d, J = 7.4 Hz, 1H), 7.26 to 7.22 (m, 3H), 6.97 (d, J = 11.3 Hz, 1H), 6.84 to 6.66 (m, 3H), 5.03 (s, 2H), 3.76 (s, 3H), 3.73 to 3.69 (m, 1H), 3.62 to 3.52 (m, 2H), 3.36 to 3.21 (m, 2H), 2.72 (s, 3H) , 2.04 to 2.00 (m, 1H), 1.89 (dq, J = 12.6, 8.5 Hz, 1H), 1.47 (s, 9H); MS (ES+) m/z 627.3 (M + 1).

[01543]Step 4. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-(difluoromethyl)-2-fluoro-N-(thiazol-4-yl) formate )benzenesulfonamide

[01544] To a solution of (S)-3-((2-(difluoromethyl)-5-fluoro-4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)phenyl)( tert-butyl methyl)amino)pyrrolidine-1-carboxylate (1.00 g, 1.60 mmol) in dichloromethane (10 ml) trifluoroacetic acid (10 ml) was added and the reaction mixture was heated at reflux for 5 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (5 ml) and N,N-dimethylformamide (5 ml). To this mixture was then added benzaldehyde (0.33 ml, 3.2 mmol) and sodium triacetoxyborohydride (0.68 g, 3.2 mmol). The reaction mixture was stirred at room temperature for 18 h and then quenched by addition of 2 M sodium hydroxide (30 ml). The mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated ammonium chloride (50 ml), brine (50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo produced a residue that was purified by column chromatography, eluting with a gradient of 10 to 60% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in hexanes. Further purification by preparative reverse phase HPLC eluting with a gradient of 7 to 50% acetonitrile in water containing 0.5% formic acid afforded the title compound as a colorless solid (0.045 g, 5% yield): 1H NMR (300 MHz, DMSO-d6) δ8.86 (d, J = 2.2 Hz, 1H), 8.16 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.35 to 7.22 (m, 5H), 7.16 (d, J = 12.7 Hz, 1H), 7.09 (t, J = 54.4 Hz, 1H), 6.99 (d , J = 2.2 Hz, 1H), 3.99 to 3.90 (m, 1H), 3.64 (d, J = 13.1 Hz, 1H), 3.52 (d, J = 13, 0 Hz, 1H), 2.77 (s, 3H), 2.74 to 2.66 (m, 1H), 2.60 (d, J = 6.2 Hz, 2H), 2.42 to 2, 34 (m, 1H), 2.13 to 2.02 (m, 1H), 1.81-1.69 (m, 1H), NH and COOH not observed; MS (ES+) m/z 497.2 (M + 1). EXAMPLE 271

[01545] Synthesis of (R)-4-((1-benzylpyrrolidin-3-yl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide formate

[01546]Step 1. Preparation of (R)-((4-((1-benzylpyrrolidin-3-yl)amino)-5-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate

[01547] To a solution of tert-butyl ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (2.46 g, 6.00 mmol) in anhydrous N,N-dimethylformamide (10 ml) (R)-1-benzylpyrrolidin-3-amine (1.20 g, 6.81 mmol) was added at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was diluted with water (100 ml) and the resulting precipitate was filtered off and rinsed with water (50 ml) to give the title compound as a gray solid (3.10 g, 91% yield): 1H NMR (300 MHz, CDCI3) δ 8.80 (d, J = 2.3 Hz, 1H), 7.95 (d, J = 7.1 Hz, 1H), 7.52 (dd, J = 2.3 , 0.4 Hz, 1H), 7.38 to 7.33 (m, 5H), 6.36 (d, J = 12.4 Hz, 1H), 5.31 to 5.28 (m, 1H) , 4.04 to 3.99 (m, 1H), 3.70 (s, 2H), 2.95 to 2.87 (m, 1H), 2.85 to 2.80 (m, 1H), 2 .70 to 2.65 (m, 1H), 2.55 to 2.46 (m, 1H), 2.44 to 2.35 (m, 1H), 1.81 to 1.73 (m, 1H) , 1.40 (s, 9H); MS (ES+) m/z 567.4 (M + 1), 569.4 (M + 1).

[01548] Step 2. Preparation of (R)-4-((1-benzylpyrrolidin-3-yl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide formate

[01549] Following the procedure as described in EXAMPLE 269 and making non-critical variations as necessary to replace (S)-((4-((1-benzylpyrrolidin-3-yl)oxy)-3-chloro-2,6-difluorophenyl )sulfonyl)(thiazol-4-yl) tert-butyl carbamate by (R)-((4-((1-benzylpyrrolidin-3-yl)amino)-5-chloro-2-fluorophenyl)sulfonyl)(thiazol- 4 -yl) tert-butyl carbamate, 0.68 g of a 4:1 mixture of (R)-((4-((1-benzylpyrrolidin-3-yl)amino)-2-fluoro-5-methylphenyl) was produced tert-butyl sulfonyl)(thiazol-4-yl)carbamate (MS (ES+) m/z 547.4 (M + 1)) and the title compound. An aliquot of the mixture (0.10 g) was stirred in formic acid (10 ml) for 30 minutes and then purified by preparative reverse phase HPLC, eluting with a gradient of 7 to 50% acetonitrile in water containing 0. 5% formic acid, to give the title compound as a colorless solid (0.070 g): 1H NMR (300 MHz, DMSO-d6) δ 8.85 (d, J = 2.2 Hz, 1H), 8, 19 (s, 1H), 7.36 to 7.29 (m, 5H), 7.25 (dtd, J = 8.1, 5.2, 2.9 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.40 (d, J = 13.8 Hz, 1H), 5.78 to 5.74 (m, 1H), 4.04 to 3.93 (m, 1H ), 3.62 (s, 2H), 2.87 (dd, J = 9.4, 7.2 Hz, 1H), 2.69 to 2.61 (m, 1H), 2.54 to 2, 44 (m, 2H), 2.27 to 2.16 (m, 1H), 2.05 (s, 3H), 1.79 to 1.68 (m, 1H), NH and COOH not observed; MS (ES+) m/z 447.1 (M + 1). EXAMPLE 272

[01550] Synthesis of (R)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl- N-(thiazol-4-yl)benzenesulfonamide

[01551] Following the procedure as described in EXAMPLE 103, Step 4 and making non-critical variations as necessary to substitute (S)-4-((1-benzylpyrrolidin-3-yl)amino)-2,6-difluoro-3- methyl-N-(thiazol-4-yl)benzenesulfonamide by (R)-((4-((1-benzylpyrrolidin-3-yl)amino)-2-fluoro-5-methylphenyl)sulfonyl)(thiazol-4-yl ) tert-butyl carbamate, and purification by column chromatography, eluting with a gradient of 10 to 60% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in hexanes, produced the compound of title as a colorless solid (0.37 g, 76% yield): 1H NMR (300 MHz, DMSO-d6) £11.09 (s, 1H), 8.87 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 1.8 Hz, 4H), 7.23 (ddd, J = 8.5, 5.3 , 3.3 Hz, 1H), 6.94 (d, J = 2.2 Hz, 1H), 6.88 (d, J = 12.8 Hz, 1H), 3.96 to 3.87 (m , 1H), 3.63 (d, J = 13.1 Hz, 1H), 3.51 (d, J = 13.0 Hz, 1H), 2.70 to 2.62 (m, 4H), 2 .57 (d, J = 6.2 Hz, 2H), 2.37 (q, J = 8.1 Hz, 1H), 2.19 (s, 3H), 2.06-1.95 (m, 1H), 1.80 to 1.69 (m, 1H); MS (ES+) m/z 461.3 (M + 1). EXAMPLE 273

[01552] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)oxy)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01553]Step 1. Preparation of (S)-((4-((1-benzylpyrrolidin-3-yl)oxy)-5-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate

[01554] Following the procedure as described in EXAMPLE 268, Step 1 and making non-critical variations as necessary to replace ((3-chloro-2,4,6-trifluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate by tert-butyl ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate, the title compound was produced as a colorless solid (2.35 g, 63% yield) : 1H NMR (300 MHz, CDCl3) £ 8.81 (d, J = 2.2 Hz, 1H), 8.12 (d, J = 7.4 Hz, 1H), 7.53 (dd, J = 2.3, 0.4 Hz, 1H), 7.38 to 7.32 (m, 5H), 6.66 (d, J = 11.4 Hz, 1H), 4.92 to 4.86 (m , 1H), 3.75 to 3.71 (m, 2H), 3.15 to 3.10 (m, 1H), 2.87 to 2.71 (m, 3H), 2.40 (dq, J = 14.0, 7.1 Hz, 1H), 2.12 to 2.07 (m, 1H), 1.39 (s, 9H).

[01555]Step 2. Preparation of (S)-((4-((1-benzylpyrrolidin-3-yl)oxy)-2-fluoro-5-methylphenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate

[01556] Following the procedure as described in EXAMPLE 101, Step 2 and making non-critical variations as necessary to replace (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl )sulfamoyl)-2-chloro-5-fluorophenyl)amino)pyrrolidine-1-tert-butyl carboxylate by (S)-((4-((1-benzylpyrrolidin-3-yl)oxy)-5-chloro-2- tert-butyl fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate, the title compound was obtained as a colorless solid (1.16 g, 51% yield): MS (ES+) m/z 461.3 (M + 1).

[01557]Step 3. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)oxy)-2-fluoro-5-methyl-N-(thiazol-4-) 2,2,2-trifluoroacetate il)benzenesulfonamide

[01558] To a solution of (S)-((4-((1-benzylpyrrolidin-3-yl)oxy)-2-fluoro-5-methylphenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate ( 1.30 g, 2.37 mmol) in dichloromethane (10 ml) trifluoroacetic acid (10 ml) was added. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. Purification of the residue by preparative reverse phase HPLC eluting with a gradient of 7 to 50% acetonitrile in water containing 0.1% trifluoroacetic acid afforded the title compound as a colorless solid (0.22 g, 17% yield ): 1H NMR (300 MHz, DMSO-d6) δ 11.24 (s, 1H), 11.02-10.97 (m, 1H), 8.88 (d, J = 1.8 Hz, 1H) , 7.65 to 7.59 (m, 1H), 7.54 to 7.49 (m, 2H), 7.49 to 7.41 (m, 3H), 7.11 (d, J = 12, 3 Hz, 1H), 6.98 (s, 1H), 5.24 to 5.22 (m, 1H), 4.50 to 4.37 (m, 2H), 4.29 to 4.15 (m , 2H), 3.59 to 3.53 (m, 2H), 2.68 to 2.62 (m, 1H), 2.12 to 2.05 (m, 4H); MS (ES+) m/z 448.3 (M + 1). EXAMPLE 274

[01559] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)oxy)-3-bromo-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide hydrochloride

[01560]Step 1. Preparation of (S)-((4-((1-benzylpyrrolidin-3-yl)oxy)-3-bromo-2,6-difluorophenyl)sulfonyl)(thiazol-4-yl) tert carbamate -butyl

[01561] Following the procedure as described in EXAMPLE 268, Step 1 and making non-critical variations as necessary to replace ((3-chloro-2,4,6-trifluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate by tert-butyl ((3-bromo-2,4,6-trifluorophenyl)sulfonyl)(thiazol-4-yl)carbamate, the title compound was obtained as a colorless solid (1.15 g, 53% yield) : 1H NMR (300 MHz, CDCI3) δ 8.82 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.37 to 7.35 ( m, 4H), 7.32 (ddd, J = 8.0, 3.5, 1.7 Hz, 1H), 6.52 (dd, J = 11.9, 1.9 Hz, 1H), 4 .95 to 4.89 (m, 1H), 3.80 to 3.71 (m, 2H), 3.18 to 3.12 (m, 1H), 2.87 to 2.75 (m, 3H) , 2.47 to 2.35 (m, 1H), 2.13 to 2.08 (m, 1H), 1.40 (s, 9H); MS (ES+) m/z 630.4 (M + 1), 632.4 (M + 1).

[01562]Step 2. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)oxy)-3-bromo-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide hydrochloride

[01563] Following the procedure as described in EXAMPLE 273, Step 3 and making non-critical variations as necessary to replace (S)-((4-((1-benzylpyrrolidin-3-yl)oxy)-2-fluoro-5- tert-butyl methylphenyl)sulfonyl)(thiazol-4-yl)carbamate by (S)-((4-((1-benzylpyrrolidin-3-yl)oxy)-3-bromo-2,6-difluorophenyl)sulfonyl)( tert-butyl thiazol-4-yl)carbamate, and purification by preparative reversed-phase HPLC, eluting with a gradient of 7 to 50% acetonitrile in water containing 0.5% formic acid, provided the title compound as a colorless solid (0.045 g, 49% yield): 1H NMR (300 MHz, DMSO-d6) δ 8.89 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7, 35 to 7.30 (m, 4H), 7.28 to 7.21 (m, 1H), 7.09 (dd, J = 12.7, 1.8 Hz, 1H), 6.99 (d, J = 2.2 Hz, 1H), 5.09 to 5.03 (m, 1H), 3.65 (d, J = 13.1 Hz, 1H), 3.62 (d, J = 13.0 Hz, 1H), 2.91 (dd, J = 11.0, 6.0 Hz, 1H), 2.75 to 2.66 (m, 2H), 2.47 to 2.29 (m, 2H) , 1.85 to 1.75 (m, 1H); NH and COOH not observed; MS (ES+) m/z 530.1 (M + 1), 532.1 (M + 1). EXAMPLE 275

[01564] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)oxy)-2,6-difluoro-N-(thiazol-4-yl)-3- 2,2,2-trifluoroacetate vinylbenzenesulfonamide

[01565] A mixture of (S)-((4-((1-benzylpyrrolidin-3-yl)oxy)-3-bromo-2,6-difluorophenyl)sulfonyl)(thiazol-4-yl) tert-carbamate butyl acid (1.00 g, 1.59 mmol), pinacol vinylboronic acid ester (0.81 ml, 4.77 mmol), and potassium phosphate (1.69 g, 7.95 mmol) in anhydrous dioxane (24 ml) palladium acetate (0.071 g, 0.32 mmol) and tricyclohexylphosphonium tetrafluoroborate (0.24 g, 0.64 mmol) were added. The resulting mixture was degassed with nitrogen and then heated at reflux for 4 h. The mixture was allowed to cool to room temperature. To it were then added 2 M aqueous sodium carbonate (3 ml, 6.00 mmol), vinylboronic acid pinacol ester (0.81 ml, 4.77 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol) and the reaction mixture was heated at reflux for 18 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (80 ml). The mixture was washed with saturated ammonium chloride (2 x 60 ml), brine (30 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo produced a residue that was purified by column chromatography, eluting with a gradient of 10 to 65% ethyl acetate (containing 20% ethanol and 0.1% ammonium hydroxide) in hexanes. Further purification by preparative reverse phase HPLC eluting with a gradient of 7 to 50% acetonitrile in water containing 0.1% trifluoroacetic acid afforded the title compound as a colorless solid (0.75 g, 80% yield). : 1H NMR (300 MHz, DMSO-d6) δ 11.53 (s, 1H), 10.90 (s, 1H), 8.92 (d, J = 2.1 Hz, 1H), 7.57 a 7.43 (m, 5H), 7.11 (s, 1H), 7.05 (d, J = 2.2 Hz, 1H), 6.65 (dd, J = 18.0, 11.8 Hz , 1H), 5.88 (d, J = 18.0 Hz, 1H), 5.60 to 5.55 (m, 1H), 5.29 to 5.26 (m, 1H), 4.48 to 4.40 (m, 2H), 3.59 to 3.50 (m, 4H), 2.31 to 2.12 (m, 2H); MS (ES+) m/z 478.2 (M + 1). EXAMPLE 276

[01566] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)oxy)-3-ethyl-2,6-difluoro-N-(thiazol-4-yl) 2,2,2-trifluoroacetate )benzenesulfonamide

[01567]A mixture of (S)-4-((1-benzylpyrrolidin-3-yl)oxy)-2,6-difluoro-N-(thiazol-4-yl)-3-vinylbenzenesulfonamide (0.37 g , 0.77 mmol) in methanol (30 ml) and ethyl acetate (20 ml) 10% palladium on carbon (0.20 g) was added and the mixture was stirred under a hydrogen atmosphere (1 bar) for 4 H. Filtration through a Celite filter and concentration of the filtrate in vacuo provided a residue. Purification of the residue by preparative reverse phase HPLC eluting with a gradient of 7 to 50% acetonitrile in water containing 0.1% trifluoroacetic acid afforded the title compound as a colorless solid (0.15 g, 32% yield ): 1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H), 11.25 (s, 1H), 8.91 (d, J = 2.1 Hz, 1H), 7.55 to 7.43 (m, 5H), 7.05 to 7.00 (m, 2H), 5.28 to 5.21 (m, 1H), 4.50 to 4.38 (m, 2H), 3 .62 to 3.51 (m, 4H), 2.56 to 2.51 (m, 2H), 2.35 to 2.13 (m, 2H), 1.08 to 0.90 (m, 3H) ; MS (ES+) m/z 480.3 (M + 1). EXAMPLE 277

[01568] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isothiazol-3-yl)-5 2,2,2-trifluoroacetate -methylbenzenesulfonamide

[01569]Step 1. Preparation of tert-butyl isothiazol-3-ylcarbamate

[01570] To a slurry of isothiazol-3-carboxylic acid (5.0 g, 38.7 mmol) in tert-butanol (194 ml) was added triethylamine (4.3 g, 42.6 mmol) followed by diphenylphosphoryl azide (11.9 g, 43.3 mmol). The reaction mixture was heated at reflux for 9 hours. Concentration under reduced pressure gave a residue which was dissolved in ethyl acetate (300 ml). The organic layer was washed with water (100 ml), 1N sodium hydroxide solution (50 ml), water (100 ml) and brine (50 ml). The organic layer was dried with anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 10% ethyl acetate in heptane, provided the title compound as a colorless solid (6.16 g, 79% yield): 1H NMR (300 MHz, CDCl3) δ 9.03 to 8.98 (m, 1H), 8.58 (d, J = 4.9 Hz, 1H), 7.70 (d, J = 4.9 Hz, 1H), 1.53 (d, J = 0.7 Hz, 9H).

[01571] Step 2. Preparation of tert-butyl ((5-chloro-2,4-difluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate

[01572] To a solution of tert-butyl isothiazol-3-ylcarbamate (1.0 g, 5.0 mmol) in anhydrous tetrahydrofuran (13 ml) was added 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran ( 5 ml, 5 mmol) at -78 °C. The reaction mixture was stirred at -78°C for 10 minutes, then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was then cooled to -78°C, and a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (1.23 ml, 5 mmol) in anhydrous tetrahydrofuran (2.8 ml) was added. the same. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was quenched by adding saturated ammonium chloride solution (50 ml), and the mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried with anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo gave the title compound as a brown solid (2.0 g, 97% yield): MS (ES+) m/z 311.0 (M + 1), 313.0 (M + 1 ).

[01573]Step 3. Preparation of (S)-((4-((1-benzylpyrrolidin-3-yl)amino)-5-chloro-2-fluorophenyl)sulfonyl)(isothiazol-3-yl) tert-butyl carbamate

[01574] To a solution of tert-butyl ((5-chloro-2,4-difluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate (2.0 g, 4.86 mmol) in anhydrous N,N-dimethylformamide (25 ml) was added (S)-1-benzylpyrrolidin-3-amine (1.06 g, 6.0 mmol) followed by N,N-diisopropylethylamine (3.23 g, 25 mmol). The reaction mixture was heated to 50 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (150 ml). The organic layer was washed with water (3 x 50 ml), brine (50 ml), and dried over anhydrous magnesium sulfate. The solution was filtered and the filtrate was concentrated in vacuo to provide the title compound as a beige solid (2.6 g, 94% yield): MS (ES+) m/z 567.0 (M + 1), 569 .0 (M + 1).

[01575]Step 4. Preparation of (S)-((4-((1-benzylpyrrolidin-3-yl)amino)-2-fluoro-5-methylphenyl)sulfonyl)(isothiazol-3-yl) tert-butyl carbamate

[01576] A solution of (S)-((4-((1-benzylpyrrolidin-3-yl)amino)-5-chloro-2-fluorophenyl)sulfonyl)(isothiazol-3-yl) tert-butyl carbamate (2 .6 g, 4.58 mmol) in anhydrous 1,4-dioxane (53 ml) was sprayed with argon for 10 minutes. To the solution was then added methylboronic acid (1.8 g, 30 mmol), tribasic potassium phosphate (3.18 g, 15 mmol), palladium acetate (0.112 g, 0.5 mmol), and tricyclohexylphosphonium tetrafluoroborate. (0.368 g, 1.06 mmol). The reaction mixture was sparged with argon for 5 min and then heated at reflux for 12 h. The reaction mixture was allowed to cool to room temperature and filtered through a Celite filter. The filter plug was washed with ethyl acetate (3 x 30 ml) and the combined organic layer was concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 10 to 100% ethyl acetate in heptane, provided the title compound as a brown solid (0.91 g, 36% yield): MS (ES+) m/z 547.4 (M + 1).

[01577]Step 5. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isothiazol-3-yl) 2,2,2-trifluoroacetate )-5-methylbenzenesulfonamide

[01578] To a solution of (S)-((4-((1-benzylpyrrolidin-3-yl)amino)-2-fluoro-5-methylphenyl)sulfonyl)(isothiazol-3-yl) tert-butyl carbamate ( 0.91 g, 1.66 mmol) in trifluoroacetic acid (3.5 ml) paraformaldehyde (0.150 g, 4.98 mmol) was added. The reaction mixture was stirred for 10 minutes before sodium triacetoxyborohydride (1.4 g, 6.64 mmol) was added thereto. The reaction mixture was stirred for 1 h at room temperature, and then diluted with ethyl acetate (50 ml) and water (50 ml). Sodium bicarbonate was carefully added until gas evolution ceased. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 30 ml). The organic layers were washed with water (30 ml), brine (30 ml), and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate in vacuo produced a residue that was purified by column chromatography, eluting with a gradient of 5 to 50% ethyl acetate (containing 20% ethanol and 1% ammonium hydroxide) in heptane. The solid was further purified by preparative reverse phase HPLC, using a gradient of 5 to 95% acetonitrile in water with 0.1% trifluoroacetic acid, affording the title compound as a colorless solid (0.159 g, 21% yield ): 1H NMR (300 MHz, DMSO-d6) δ 11.86 to 11.73 (m, 1H), 10.37 to 10.04 (m, 1H), 8.97 to 8.90 (m, 1H ), 7.75 to 7.64 (m, 1H), 7.56 to 7.43 (m, 5H), 7.09 to 7.00 (m, 1H), 6.99 to 6.94 (m , 1H), 4.46 to 3.97 (m, 3H), 3.57 to 3.07 (m, 4H), 2.72 to 2.56 (m, 3H), 2.30 to 2.21 (m, 3H), 2.20 to 1.87 (m, 2H); 19F NMR (282 MHz, DMSO-d6) δ -74.1 (s, 3F), -112.2(s, 1F); MS (ES+) m/z 461.2 (M + 1). EXAMPLE 278

[01579] Synthesis of (S)-2-fluoro-5-methyl-4-(methyl(1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)amino)-N-2,2,2-trifluoroacetate (thiazol-4-yl)benzenesulfonamide

[01580]Step 1. Preparation of (S)-5-chloro-2-fluoro-4-((1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)amino)- 2,2,2-trifluoroacetate N-(thiazol-4-yl)benzenesulfonamide

[01581] Following the procedure as described in EXAMPLE 258, Step 3 and making non-critical variations as necessary to replace benzaldehyde with picolinaldehyde, and purification by reversed-phase preparative HPLC, eluting with a gradient of 10 to 50% acetonitrile in water containing 0.1% trifluoroacetic acid, gave the title compound as a colorless solid (0.125 g, 13% yield): MS (ES+) m/z 468.2 (M + 1), 470.1 (M + 1).

[01582]Step 2. Preparation of (S)-2-fluoro-5-methyl-4-((1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)amino)-N-(thiazol-4-yl )benzenesulfonamide

[01583]A mixture of (S)-5-chloro-2-fluoro-4-((1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)amino)-N 2,2,2-trifluoroacetate -(thiazol-4-yl)benzenesulfonamide (0.125 g, 0.21 mmol), methylboronic acid (0.16 g, 2.7 mmol), and potassium phosphate (0.28 g, 1.30 mmol) in dioxane anhydrous (5 ml) palladium acetate (0.018 g, 0.08 mmol) and tricyclohexylphosphonium tetrafluoroborate (0.059 g, 0.16 mmol) were added. The resulting mixture was degassed by spraying with nitrogen and then heated at reflux for 4 h. After cooling to room temperature, the mixture was diluted in water (15 ml) and extracted with ethyl acetate (3 x 15 ml). The combined organic fractions were washed with brine (10 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound as a gray solid (0.87 g, 98% yield): MS (ES+) m/z 448.3 (M + 1).

[01584]Step 3. Preparation of (S)-2-fluoro-5-methyl-4-(methyl(1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)amino) 2,2,2-trifluoroacetate -N-(thiazol-4-yl)benzenesulfonamide

[01585] Following the procedure as described in EXAMPLE 155, Step 4 and making non-critical variations as necessary to substitute (S)-2-fluoro-4- ((1-(2-fluorobenzyl)pyrrolidin-3-yl)amino) -5-methyl-N-(thiazol-4-yl)benzenesulfonamide (S)-2-fluoro-5-methyl-4-((1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)amino)-N -(thiazol-4-yl)benzenesulfonamide, and purification by reversed-phase preparative HPLC, eluting with a gradient of 8 to 50% acetonitrile in water containing 0.1% trifluoroacetic acid, provided the title compound as a solid colorless (0.009 g, 7% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.24 (s, 1H), 10.54-10.43 (m, 1H), 8.88 (d, J = 2.2 Hz, 1H), 8.65 (ddd, J = 0.9, 1.6, 4.8 Hz, 1H), 7.92 (td, J = 1.8, 7.7 Hz , 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.51 to 7.44 (m, 2H), 7.04 (d, J = 12.5 Hz, 1H), 6 .99 (d, J = 2.2 Hz, 1H), 4.60 to 4.55 (m, 2H), 4.17 to 4.12 (m, 1H), 3.57 to 3.50 (m , 2H), 3.38 to 3.31 (m, 2H), 2.63 (s, 3H), 2.23 (s, 3H), 2.18 to 2.04 (m, 2H); MS (ES+) m/z 462.2 (M + 1). EXAMPLE 279

[01586] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(isothiazol-3-yl) 2,2,2-trifluoroacetate -3-methylbenzenesulfonamide

[01587]Step 1. Preparation of 3-bromo-2,4,6-Trifluorobenzenesulfonyl chloride

[01588] To 4-bromo-1,3,5-trifluorobenzene (25 g, 0.118 mmol) chlorosulfonic acid (24 ml) was added and the reaction mixture was heated to 80 ° C for 72 h. The reaction mixture was allowed to cool to room temperature and very slowly added to ice. The resulting solid was removed by filtration and dissolved in dichloromethane (200 ml). The organic phase was washed with water (2 x 50 ml), brine (50 ml), and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate in vacuo gave the title compound as a colorless solid (28.6 g, 78% yield): 1H NMR (300 MHz, CDCla) δ7.06 (ddd, J = 9.9.7 .8, 2.2 Hz, 1H).

[01589]Step 2. Preparation of tert-butyl ((3-bromo-2,4-trifluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate

[01590] To a solution of tert-butyl isothiazol-3-ylcarbamate (0.9 g, 4.49 mmol) in anhydrous tetrahydrofuran (12 ml) was added 1 M of a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (4.94 ml, 4.94 mmol) at -78 °C. The reaction mixture was stirred at -78°C for 10 minutes, allowed to warm for 1 hour. The solution was then cooled to -78°C and a solution of 5-bromo-2,4,6-trifluorobenzenesulfonyl chloride (1.39 g, 4.49 mmol) in anhydrous tetrahydrofuran (2.6 ml) was added to it. The reaction mixture was allowed to warm to room temperature, stirred for 12 h and quenched by addition of saturated ammonium chloride solution (50 ml). The aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried with anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 5% ethyl acetate in heptane, gave the title compound as a beige solid (1.08 g, 97% yield): 1H NMR (300 MHz, CDCl3) δ8.76 (d, J = 4.7 Hz, 1H), 7.33 (d, J = 4.7 Hz, 1H), 6.99 (ddd, J = 9.9, 7.9, 2.1 Hz, 1H), 1.44 to 1.35 (m, 9H).

[01591]Step 3. Preparation of (S)-((4-((1-benzylpyrrolidin-3-yl)amino)-3-bromo-2,6-difluorophenyl)sulfonyl)(isothiazol-3-yl) tert carbamate -butyl

[01592] To a solution of tert-butyl ((3-bromo-2,4,6-trifluorophenyl)sulfonyl)(isothiazol-3-yl)carbamate (1.08 g, 2.28 mmol) in N,N- Anhydrous dimethylformamide (12 ml) was added (S)-1-benzylpyrrolidin-3-amine (0.48 g, 2.74 mmol) followed by N,N-diisopropylethylamine (0.59 g, 4.56 mmol). The reaction mixture was heated to 50 °C for 3 h, and then diluted with ethyl acetate (150 ml). The organic layer was washed with water (2 x 50 ml), brine (50 ml), and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate in vacuo provided a residue. Purification of the residue by column chromatography, using a gradient of 5 to 60% ethyl acetate (containing 20% ethanol and 1% ammonium hydroxide) in heptane, provided the title compound as a colorless solid (1. 02 g, 71% yield): 1H NMR (300 MHz, CDCl3) δ 8.75 to 8.71 (m, 1H), 7.40 to 7.29 (m, 6H), 6.26 to 6, 20 (m, 1H), 5.52 to 5.46 (m, 1H), 4.07 to 3.97 (m, 1H), 3.76 to 3.64 (m, 2H), 2.97 to 2.88 (m, 1H), 2.82 to 2.74 (m, 1H), 2.72 to 2.66 (m, 1H), 2.53 to 2.34 (m, 2H), 1, 82 to 1.71 (m, 1H), 1.38 to 1.34 (s, 9H).

[01593]Step 4. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-2,6-difluoro-3-methylphenyl)sulfonyl)(isothiazol-3-yl) tert-butyl carbamate

[01594]A mixture of (S)-((4-((1-benzylpyrrolidin-3-yl)amino)-3-bromo-2,6-difluorophenyl)sulfonyl)(isothiazol-3-yl) tert-carbamate butyl acid (1.02 g, 1.62 mmol) in anhydrous 1,4-dioxane (16 ml) was added methylboronic acid (0.58 g, 9.7 mmol), tribasic potassium phosphate (1.03 g, 4 .86 mmol), palladium acetate (0.036 g, 0.16 mmol), and tricyclohexylphosphonium tetrafluoroborate (0.119 g, 0.32 mmol). The slurry was degassed with argon and then heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature and filtered through a Celite filter. The filter plug was washed with ethyl acetate (3 x 30 ml) and the combined organic phase was concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 10% methanol in dichloromethane provided the title compound as a brown solid (0.89 g, 97% yield). MS (ES+) m/z 565.4 (M + 1).

[01595]Step 5. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(isothiazol-3) 2,2,2-trifluoroacetate -yl)-3- methylbenzenesulfonamide

[01596] To a solution of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-2,6-difluoro-3-methylphenyl)sulfonyl)(isothiazol-3-yl) tert-butyl carbamate ( 0.89 g, 1.63 mmol) in trifluoroacetic acid (3 ml) paraformaldehyde (0.120 g, 4.26 mmol) was added. The reaction mixture was stirred for 10 minutes before sodium triacetoxyborohydride (0.92 g, 4.2 mmol) was added thereto. The reaction mixture was stirred at room temperature for 1 h and subsequently diluted with ethyl acetate (50 ml) and water (50 ml). Sodium bicarbonate was then added to the mixture until the bubbling stopped. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 30 ml). The combined organic layers were washed with water (30 ml), brine (30 ml), dried over anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo provided a residue that was purified by column chromatography eluting with a gradient of 0 to 10% methanol in dichloromethane. Further purification by preparative reverse phase HPLC eluting with a gradient of 5 to 95% acetonitrile in water containing 0.1% trifluoroacetic acid afforded the title compound as a colorless solid (0.136 g, 14% yield): 1H NMR (300 MHz, DMSO-d6) δ 12.09 to 11.96 (m, 1H), 10.36 to 9.94 (m, 1H), 8.93 (d, J = 4.8 Hz, 1H ), 7.61 to 7.43 (m, 5H), 6.95 (d, J = 4.8 Hz, 1H), 6.93 to 6.85 (m, 1H), 4.47 to 4, 30 (m, 2H), 4.30 to 3.92 (m, 2H), 3.62-3.08 (m, 2H), 2.77-2.59 (m, 3H), 2.07 ( m, 5H); 19F NMR (282 MHz, DMSO-d6) δ -73.5 (s, 3F), -108.1 (s, 1F), -111.5 (s, 1F); MS (ES+) m/z 479.1 (M + 1). EXAMPLE 280

[01597] Synthesis of (R)-5-chloro-2-fluoro-4-(methyl(1-(1-phenylethyl)piperidin-4-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide formate

[01598]Step 1. Preparation of tert-butyl ((4-amino-5-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate

[01599] To a solution of tert-butyl ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (3.0 g, 7.3 mmol) in anhydrous N,N-dimethylformamide (37 ml) sodium azide (0.570 g, 8.8 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. Water (50 ml) was added to the reaction mixture and the precipitate formed was collected by filtration. The solid obtained was dissolved in tetrahydrofuran (94 ml) and the mixture cooled to 0 °C. Zinc powder (1.43 g, 21.8 mmol) and saturated ammonium chloride (31 ml) were then added to the mixture. The reaction mixture was allowed to warm to room temperature, stirred for 18 h and then filtered through a Celite filter. The filter plug was washed with tetrahydrofuran (2 x 30 ml). The combined organic phase was washed with brine (50 ml), dried over anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo gave the title compound as a colorless solid (2.67 g, 90% yield): MS (ES+) m/z 408.2 (M + 1), 410.2 (M + 1 ).

[01600]Step 2. Preparation of (R)-1-(1-phenylethyl)piperidin-4-one

[01601] To a mixture of (R)-1-phenylethan-1-amine (9.7 g, 80.4 mmol) in a mixture of denatured ethanol (287 ml) and water (72 ml) was added potassium carbonate (24.4 g, 176.8 mmol) and the mixture was heated to reflux. A solution of 1,1-dimethyl-4-oxopiperidin-1-ium in water (75 ml) was added dropwise to the hot mixture over 1 h. After complete addition, heating of the reaction mixture at reflux continued for 3 h. The solution was then cooled to room temperature and concentrated under reduced pressure. The remaining aqueous mixture was extracted with diethyl ether (2 x 150 ml). The organic phase was dried with anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with diethyl ether as eluent, provided the title compound as a yellowish oil (10.5 g, 64% yield): 1H NMR (300 MHz, CDCI3) δ 7.39 to 7.25 (m, 5H), 3.65 (q, J = 6.7 Hz, 1H), 2.84 to 2.69 (m, 4H), 2.44 (t , J = 6.1 Hz, 4H), 1.44 (d, J = 6.7 Hz, 3H).

[01602]Step 3. Preparation of (R)-5-chloro-2-fluoro-4-(methyl(1-(1-phenylethyl)piperidin-4-yl)amino)-N-(thiazol-4-) formate il)benzenesulfonamide

[01603]A mixture of tert-butyl ((4-amino-5-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (1.0 g, 2.5 mmol) and (R)- 1-(1-phenylethyl)piperidin-4-one (0.55 g, 2.7 mmol) trifluoroacetic acid (4.2 ml) was added. The mixture was stirred at room temperature for 10 minutes and then sodium triacetoxyborohydride (0.74 g, 3.5 mmol) was added thereto. The reaction mixture was stirred at room temperature for 10 minutes and then paraformaldehyde (0.225 g, 7.5 mmol) was added thereto, followed by trifluoroacetic acid (1 ml). The reaction mixture was stirred at room temperature for 10 minutes and then sodium triacetoxyborohydride (1.06 g, 5 mmol) was added thereto. After stirring for a further 30 minutes, the reaction mixture was diluted with dichloromethane (125 ml). The mixture was washed with brine (50 ml), dried over anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo produced a residue that was purified by column chromatography, eluting with a gradient of 10 to 60% ethyl acetate (containing 20% ethanol and 1% ammonium hydroxide) in heptane. Further purification by preparative reverse phase HPLC eluting with a gradient of 5 to 95% acetonitrile in water containing 0.5% formic acid gave the title compound as a colorless solid (0.195 g, 15% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.75 to 11.03 (m, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.14 (s, 0.45H), 7.68 (d, J = 7.6 Hz, 1H), 7.38 to 7.26 (m, 5H), 7.09 (d, J = 12.6 Hz, 1H), 7.03 (d , J = 2.2 Hz, 1H), 3.74 to 3.68 (m, 1H), 3.39 to 3.30 (m, 1H), 3.17 to 3.10 (m, 1H), 2.93 to 2.88 (m, 1H), 2.73 to 2.67 (m, 3H), 2.18 to 2.01 (m, 2H), 1.87 to 1.57 (m, 4H ), 1.37 to 1.33 (m, 3H), COOH not observed; 19F NMR (282 MHz, DMSO-d6) δ -110.1 (s, 1F); MS (ES+) m/z 509.1 (M + 1), 511.0 (M + 1). EXAMPLE 281

[01604] Synthesis of (R)-2-fluoro-5-methyl-4-(methyl(1-(1-phenylethyl)piperidin-4-yl)amino)-N-(thiazol) 2,2,2-trifluoroacetate -4-yl)benzenesulfonamide

[01605] Step 1. Preparation of tert-butyl ((4-amino-2-fluoro-5-methylphenyl)sulfonyl)(thiazol-4-yl)carbamate.

[01606] To a solution of tert-butyl ((4-amino-5-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (1.0 g, 2.46 mmol) in 1,4- anhydrous dioxane (25 ml) was added methylboronic acid (0.88 g, 15 mmol), tribasic potassium phosphate (1.66 g, 7.8 mmol), palladium acetate (0.55 g, 0.25 mmol) , and tricyclohexylphosphonium tetrafluoroborate (0.18 g, 0.49 mmol). The resulting slurry was degassed with argon and then heated at reflux for 18 h. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (25 ml) and filtered through a Celite filter. The filter plug was washed with ethyl acetate (2 x 30 ml) and the combined organic phase was concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 20 to 100% ethyl acetate (containing 20% ethanol and 1% ammonium hydroxide) in heptane, provided the title compound as a brown solid (0.496 g, 70% yield): MS (ES+) m/z 388.2 (M + 1).

[01607]Step 2. Preparation of (R)-2-fluoro-5-methyl-4-(methyl(1-(1-phenylethyl)piperidin-4-yl)amino)-N 2,2,2-trifluoroacetate -(thiazol-4-yl)benzenesulfonamide.

[01608] Following the procedure as described in EXAMPLE 280, Step 3, and making non-critical variations as necessary to replace ((4-amino-5-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl) tert-carbamate butyl by ((4-amino-2-fluoro-5-methylphenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate, and purification by reversed-phase preparative HPLC, eluting with a gradient of 5 to 95% of Acetonitrile in water containing 0.1% trifluoroacetic acid gave the title compound as a colorless solid (0.074 g, 7% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.23 to 11.19 ( m, 1H), 9.61 to 9.51 (m, 1H), 8.90 to 8.85 (m, 1H), 7.66 to 7.36 (m, 6H), 7.03 to 6, 93 (m, 2H), 4.55 to 4.43 (m, 1H), 3.67 to 3.55 (m, 1H), 3.33 to 3.19 (m, 1H), 2.93 to 2.71 (m, 2H), 2.63 to 2.57 (m, 3H), 2.20 to 2.14 (m, 3H), 2.13 to 1.89 (m, 3H), 1, 84 to 1.70 (m, 2H), 1.68 to 1.55 (m, 3H); MS (ES+) 489.1 m/z (M+1). EXAMPLE 282

[01609] Synthesis of (R)-2,6-difluoro-3-methyl-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(2,2,2-trifluoroacetate thiazol-4-yl)benzenesulfonamide

[01610]Step 1. Preparation of (R)-1-(1-phenylethyl)piperidin-4-ol

[01611] To a solution of (R)-1-(1-phenylethyl)piperidin-4-one (5.5 g, 27.1 mmol) in methanol (68 ml) was added sodium borohydride (1.4 g , 37.9 mmol) and the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with ethyl acetate (150 ml). The organic layer was washed with water (50 ml), saturated ammonium chloride (50 ml), water (2 x 50 ml), brine (50 ml) and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate in vacuo gave the title compound as a yellowish oil (5.5 g, quantitative yield): 1H NMR (300 MHz, CDCla) δ 7.36 to 7.23 (m, 5H), 3 .65 to 3.62 (m, 1H), 3.44 (q, J = 6.8 Hz, 1H), 2.91 to 2.85 (m, 1H), 2.74 to 2.68 (m , 1H), 2.16 to 2.04 (m, 2H), 1.94 to 1.82 (m, 2H), 1.66 to 1.49 (m, 2H), 1.41 to 1.36 (m, 3H), OH not observed.

[01612]Step 2. Preparation of (R)-((3-bromo-2,6-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)(thiazol- 4-yl) tert-butyl carbamate

[01613] To a solution of tert-butyl ((3-bromo-2,4,6-trifluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (3.1 g, 6.6 mmol) and (R)- 1-(1-phenylethyl)piperidin-4-ol (4.04 g, 19.7 mmol) in anhydrous N,N-dimethylformamide (44 ml) was added sodium hydride (60% suspension in mineral oil) (1 .31 g, 32.8 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then cooled to -78 °C and slowly added to a 1:10 mixture of 1 M hydrochloric acid and water at 0 °C. After dilution with ethyl acetate (75 ml), the layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with water (2 x 30 ml), brine (50 ml), and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate in vacuo provided a residue that was purified by column chromatography, eluting with a gradient of 10 to 60% ethyl acetate (containing 20% ethanol and 1% ammonium hydroxide) in heptane, to provide the title compound as an orange oil (2.2 g, 51% yield). MS (ES+) m/z 658.4 (M + 1), 660.4 (M + 1).

[01614] Step 3. Preparation of (R)-2,6-difluoro-3-methyl-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)- 2,2,2-trifluoroacetate N-(thiazol-4-yl)benzenesulfonamide.

[01615] To a solution of (R)-((3-bromo-2,6-difluoro-4-((1-(1-phenylethyl)-piperidin-4-yl)oxy)phenyl)sulfonyl)(thiazol- tert-butyl 4-yl)carbamate (2.2 g, 3.4 mmol) in anhydrous N,N-dimethylformamide (61 ml) was added lithium chloride (0.43 g, 10.0 mmol), bis dichloride (triphenylphosphine)palladium (0.47 g, 0.67 mmol) and tetramethyltin (1.80 g, 10.0 mmol). The mixture was degassed with argon and heated to 100 °C for 5 h. The reaction mixture was concentrated in vacuo and the residue diluted with ethyl acetate (130 ml). The organic layer was washed with water (2 x 30 ml), brine (30 ml), dried over anhydrous magnesium sulfate and filtered. Concentration of the filtrate in vacuo and purification by column chromatography, eluting with a gradient of 10 100% ethyl acetate (containing 20% ethanol and 1% ammonium hydroxide) in heptane, produced an orange oil. The oil was dissolved in dichloromethane (15 ml) and trifluoroacetic acid (6 ml) was added thereto. The reaction mixture was stirred at room temperature for 4 h and then concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 10 to 100% ethyl acetate (containing 20% ethanol and 1% ammonium hydroxide) in heptane, followed by purification by reversed-phase preparative HPLC, eluting with a gradient of 5 to 95% acetonitrile in water containing 0.1% trifluoroacetic acid, gave the title compound as a colorless solid (0.403 g, 19% yield): 1H NMR (601 MHz, DMSO-dε) δ 11.41 to 11.40 (m, 1H), 10.08 to 9.83 (m, 1H), 8.89 (d, J = 2.1 Hz, 1H), 7.57 to 7.49 (m, 5H), 7.10 to 6.98 (m, 2H), 4.77 (m, 2H), 3.71 to 3.54 (m, 1H), 3.46 to 3.20 (m , 1H), 2.92 to 2.76 (m, 2H), 2.28 to 2.22 (m, 1H), 2.10 to 1.97 (m, 3H), 1.89 to 1.77 (m,3H), 1.69 (d, J = 7.0 Hz, 3H); 19F NMR (565 MHz, DMSO-d6) δ - 73.9 (s, 3F), -109.6 (s, 1F), -110.5 (s, 1F); MS (ES+) m/z 494.1 (M + 1). EXAMPLE 283

[01616] Synthesis of (R)-2,6-difluoro-3-methyl-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl) trifluoroacetic formate )benzenesulfonamide

[01617]Step 1. Preparation of (R)-((3-chloro-2,6-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)(thiazol- 4-yl) tert-butyl carbamate

[01618] Following the procedure as described in EXAMPLE 282, Step 2 and making non-critical variations as necessary to replace ((3-bromo-2,4,6-trifluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate by tert-butyl ((3-chloro-2,4,6-trifluorophenyl)sulfonyl)(thiazol-4-yl)carbamate, the title compound was obtained as a colorless solid (1.3 g, 38% yield) : MS (ES+) m/z 614.1 (M + 1), 616.1 (M + 1).

[01619] Step 2. Preparation of (R)-3-chloro-2,6-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy 2,2,2-trifluoroacetate formate )-N-(thiazol-4-yl)benzenesulfonamide

[01620]A mixture of (R)-((3-chloro-2,6-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)(thiazol-4 -yl) tert-butyl carbamate (0.40 g, 0.65 mmol) in dichloromethane (2 ml) trifluoroacetic acid (3 ml) was added and the reaction mixture was stirred at room temperature for 4 h. Concentration in vacuo provided a residue that was purified by column chromatography, eluting with a gradient of 10 to 100% ethyl acetate (containing 20% ethanol and 1% ammonium hydroxide) in heptane, and then by HPLC. reverse phase preparation, eluting with a gradient of 5 to 95% acetonitrile in water containing 0.5% formic acid, to yield the title compound as a colorless solid (0.403 g, 19% yield): 1H NMR ( 300 MHz, DMSO-d6) δ 11.83 to 10.99 (m, 2H), 8.90 (d, J = 2.2 Hz, 1H), 8.14 (s, 0.4H), 7, 39 to 7.28 (m, 6H), 7.03 (d, J = 2.1 Hz, 1H), 4.71 to 4.65 (m, 1H), 3.79 to 3.74 (m, 1H), 2.80 to 2.69 (m, 2H), 2.47 to 2.34 (m, 2H), 2.00 to 1.91 (m, 2H), 1.77 to 1.66 ( m, 2H), 1.40 to 1.36 (m, 3H), COOH not observed; 19F NMR (282 MHz, DMSO-d6) δ -73.4 (s, 0.6F), -106.9 (s, 1F), -107.8 (s, 1F); MS (ES+) m/z 514.0 (M + 1), 516.0 (M + 1). EXAMPLE 284

[01621] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-methyl-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01622]Step 1. Preparation of (S)-3-((2-chloro-4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)phenyl)amino)pyrrolidine-1- tert-butyl carboxylate

[01623] To a mixture of 3-chloro-4-fluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide (prepared analogously to EXAMPLE 107, Step 1 and 2, 0.70 g, 1.69 mmol) and (S)-3-aminopyrrolidine-1-tert-butyl carboxylate (0.35 g, 1.89 mmol) in anhydrous dimethyl sulfoxide (10 ml) was added potassium carbonate (0. 70 g, 5.07 mmol) and the reaction mixture was heated to 60 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml), washed with saturated ammonium chloride (2 x 20 ml), brine (20 ml), dried with anhydrous sodium sulfate and filtered. . Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 40% ethyl acetate in hexanes provided the title compound as a colorless foam (0.90 g, 92% yield ): MS (ES+) m/z 579.3 (M + 1), 581.3 (M + 1).

[01624]Step 2. Preparation of (S)-3-((4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)-2-methylphenyl)amino)pyrrolidine-1-carboxylate tert-butyl

[01625]A mixture of (S)-3-((2-chloro-4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)phenyl)amino)pyrrolidine-1-carboxylate tert-butyl (0.90 g, 1.55 mmol) in 1,4-dioxane (10 ml) was added methylboronic acid (0.28 g, 4.67 mmol), palladium acetate (0.10 g, 0 .31 mmol), potassium phosphate (1.30 g, 6.20 mmol), and tricyclohexylphosphonium tetrafluoroborate (0.23 g, 0.62 mmol). The resulting mixture was degassed by passing an argon flow through it for 15 minutes and then heated at 110 °C for 2 h. The reaction mixture was allowed to cool to room temperature and filtered through a Celite filter. The filter plug was washed with ethyl acetate (20 ml) and the combined filtrate concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 50% ethyl acetate in hexanes, provided the title compound as a colorless solid (0.60 g, 69% yield): MS (ES+) m/z 559.3 (M + 1).

[01626]Step 3. Preparation of (S)-N-(4-methoxybenzyl)-3-methyl-4-(pyrrolidin-3-ylamino)-N-(thiazol-4-yl) 2,2,2-trifluoroacetate )benzenesulfonamide

[01627] To a solution of (S)-3-((4-(N-(4-methoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)-2-methylphenyl)amino)pyrrolidine-1-tert carboxylate -butyl (0.60 g, 1.08 mmol) in dichloromethane (4 ml) trifluoroacetic acid (2 ml) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to provide the title compound as a beige solid (0.56 g, quantitative yield): MS (ES+) m/z 459.3 (M + 1).

[01628]Step 4. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-N-(4-methoxybenzyl)-3-methyl-N-( thiazol-4-yl)benzenesulfonamide

[01629]A mixture of benzaldehyde (0.07 g, 0.63 mmol) and (S)-N-(4-methoxybenzyl)-3-methyl-4-(pyrrolidin-3) 2,2,2-trifluoroacetate -ylamino)-N-(thiazol-4-yl)benzenesulfonamide (0.30 g, 0.53 mmol) in anhydrous N,N-dimethylformamide (4 ml) was added sodium triacetoxyborohydride (0.17 g, 0.79 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (30 ml), washed with saturated ammonium chloride (20 ml) and concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 5% methanol (containing 0.2% trifluoroacetic acid) in dichloromethane provided the title compound as a colorless solid (0.20 g, 57% yield): MS (ES+) m/z 549.3 (M + 1).

[01630]Step 5. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-methyl-N-(thiazol-4-yl) 2,2,2-trifluoroacetate )benzenesulfonamide

[01631] To a solution of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-N-(4-methoxy benzyl)-3-methyl-N-( thiazol-4-yl)benzenesulfonamide (0.20 g, 0.30 mmol) in trifluoroacetic acid (2.0 ml) was added sodium triacetoxyborohydride (0.19 g, 0.90 mmol) at 0 °C. The resulting mixture was stirred at 0°C for 10 minutes and then paraformaldehyde (14 mg, 0.45 mmol) was added thereto. The reaction mixture was stirred at 0 °C for 15 minutes and then concentrated in vacuo. To the residue were added 2M sodium hydroxide (15 ml) and brine (15 ml), and the mixture was extracted with ethyl acetate (30 ml). The aqueous layer was diluted with saturated ammonium chloride (30 ml) and then extracted with ethyl acetate (50 ml). The organic layers were washed with saturated ammonium chloride (30 ml), brine (30 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0.10% methanol (containing 0.2% trifluoroacetic acid) in dichloromethane gave the title compound as a colorless solid (0.067 g , 40% yield). 1H NMR (300 MHz, DMSO-d6) £11.02 (s, 1H), 10.39 (br s, 0.5H), 10.24 (br s, 0.5H), 8.88 (d, J = 2.2 Hz, 1H), 7.65 to 7.59 (m, 2H), 7.49 to 7.45 (m, 5H), 7.18 (d, J = 8.4 Hz, 1H ), 7.02 (d, J = 2.2 Hz, 1H), 4.39 to 4.31 (m, 2H), 4.21 to 3.92 (m, 1H), 3.55 to 3, 08 (m, 4H), 2.65 to 2.54 (m, 3H), 2.27 (s, 3H), 2.22 to 1.84 (m, 2H); MS (ES+) m/z 443.1 (M + 1). EXAMPLE 285

[01632] Synthesis of (S)-4-((1-(2,5-difluorobenzyl)pyrrolidin-3-yl)(methyl)amino)-3-methyl-N-(thiazol) 2,2,2-trifluoroacetate -4-yl)benzenesulfonamide

[01633] Following the procedure as described in EXAMPLE 284, Step 3 to 5, and making non-critical variations as necessary to replace benzaldehyde with 2,5-difluorobenzaldehyde, the title compound was obtained as a colorless solid (0.045 g, 17% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.88 (d, J = 2.2 Hz, 1H), 7.65 to 7.59 (m, 2H), 7.52 to 7.47 (m, 1H), 7.39 (t, J = 6.4 Hz, 2H), 7.18 (d, J = 8.5 Hz, 1H), 7, 02 (d, J = 2.2 Hz, 1H), 4.41 (s, 2H), 4.23 to 3.94 (m, 1H), 3.54 to 3.09 (m, 4H), 2 .60 (s, 3H), 2.27 (s, 3H), 2.20 to 1.86 (m, 2H), NH not observed; MS (ES+) m/z 479.2 (M + 1). EXAMPLE 286

[01634] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide formate

[01635]Step 1. Preparation of tert-butyl thiazol-4-yl((2,4,6-trifluorophenyl)sulfonyl)carbamate

[01636] To a solution of tert-butyl thiazol-4-ylcarbamate (0.96 g, 4.8 mmol) in anhydrous tetrahydrofuran (20 ml) was added 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran ( 5.76 ml, 5.76 mmol) at -78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was cooled to -78 ° C, and a solution of 2,4,6-trifluorobenzenesulfonyl chloride (1.32 ml, 5.76 mmol) in anhydrous tetrahydrofuran (10 ml) was added thereto. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was diluted with ethyl acetate (35 ml), washed with saturated ammonium chloride (2 x 30 ml), brine (2 x 30 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 50% ethyl acetate in hexanes, provided the title compound as a colorless solid (0.67 g, 47% performance). MS (ES+) m/z 395.0 (M + 1).

[01637]Step 2. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-3,5-difluorophenyl)amino)pyrrolidine-1 -tert-butyl carboxylate

[01638] Following the procedure as described in EXAMPLE 284, Step 2 and making non-critical variations as necessary to replace 3-chloro-4-fluoro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)benzenesulfonamide with tert-butyl thiazol-4-yl((2,4,6-trifluorophenyl)sulfonyl)carbamate, the title compound was obtained as a colorless solid (0.36 g, 40% yield): 1H NMR (300 MHz, CDCI3) δ 8.77 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 6.15 (d, J = 11.7 Hz, 2H) , 4.00 to 3.92 (m, 1H), 3.67 to 3.62 (m, 1H), 3.49 to 3.42 (m, 2H), 2.25 to 2.12 (m, 1H), 1.97 to 1.87 (m, 2H), 1.45 (s, 9H), 1.37 (s, 9H), NH not observed; MS (ES-) m/z 559 (M - 1).

[01639]Step 3. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-3,5-difluorophenyl)amino)pyrrolidine-1 -tert-butyl carboxylate

[01640] To a solution of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-3,5-difluorophenyl)amino)pyrrolidine-1- tert-butyl carboxylate (0.20 g, 0.36 mmol) and dimethyl sulfate (0.10 ml, 1.07 mmol) in anhydrous N,N-dimethylformamide (20 ml) a dispersion of sodium hydride was added to 60% in mineral oil (0.025 g, 1.07 mmol) at 0 °C. The resulting mixture was stirred at 0°C for 1 h and then quenched by slow addition of water (5 ml). The mixture was diluted with ethyl acetate (20 ml), washed with saturated ammonium chloride (2 x 20 ml), brine (15 ml), and dried with anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave a residue which was purified by column chromatography, eluting with a gradient of 0 to 60% ethyl acetate in hexanes to give the title compound as a colorless foam (0.13 g, 63% yield): 1H NMR (300 MHz, CDCl3): δ 8.78 (d, J = 2.3 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H), 6, 30 (d, J = 12.7 Hz, 2H), 4.40 to 4.28 (m, 1H), 3.68 to 3.52 (m, 1H), 3.45 to 3.31 (m, 2H), 2.95 to 2.87 (m, 3H), 2.19 to 2.08 (m, 2H), 1.67 (s, 1H), 1.47 (s, 9H), 1.38 (s, 9H); MS (ES+) m/z 575.1 (M + 1).

[01641]Step 4. Preparation of (S)-2,6-difluoro-4-(methyl(pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01642] To a solution of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-3,5-difluorophenyl)amino)pyrrolidine-1- tert-butyl carboxylate (0.13 g, 0.22 mmol) in dichloromethane (4 ml) trifluoroacetic acid (2 ml) was added. The resulting mixture was stirred for 2 h and then concentrated in vacuo to provide the title compound as a yellowish foam (0.14 g, quantitative yield): MS (ES+) m/z 375.1 (M + 1).

[01643]Step 5. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(thiazol-4-yl)benzenesulfonamide formate

[01644]A mixture of benzaldehyde (0.056 g, 0.45 mmol) and (S)-2,6-difluoro-4-(methyl(pyrrolidin-3-yl)amino)-2,2,2-trifluoroacetate N-(thiazol-4-yl)benzenesulfonamide (0.14 g, 0.37 mmol) in anhydrous N,N-dimethylformamide (4 ml) was added sodium triacetoxyborohydride (0.24 g, 1.11 mmol) and to Reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (20 ml), washed with saturated ammonium chloride (20 ml) and concentrated in vacuo. The residue obtained was purified by preparative reverse phase HPLC eluting with a gradient of 10 to 60% acetonitrile in water containing 0.5% formic acid to provide the title compound as a colorless solid (0.020 g, 11% yield ): 1H NMR (300 MHz, DMSO-d6) δ 8.83 (d, J = 2.2 Hz, 1H), 8.22 (s, 1H), 7.36 to 7.31 (m, 4H) , 7.31 to 7.23 (m, 1H), 7.12 to 7.04 (m, 2H), 6.79 (d, J = 2.2 Hz, 1H), 3.83 to 3.76 (m, 1H), 3.68 (d, J = 13.0 Hz, 1H), 3.59 (d, J = 12.9 Hz, 1H), 2.74 (d, J = 12.2 Hz , 1H), 2.65 to 2.54 (m, 5H), 2.31 (q, J = 7.8 Hz, 1H), 1.95 to 1.83 (m, 1H), 1.74 to 1.60 (m, 1H), NH and COOH not observed; MS (ES+) m/z 465.2 (M+1). EXAMPLE 287

[01645] Synthesis of (S)-4-((1-(3-(difluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N 2,2,2-trifluoroacetate -(thiazol-4-yl)benzenesulfonamide

[01646] Following the procedure as described in EXAMPLE 286, Step 5 and making non-critical variations as necessary to replace 3-(difluoromethyl)benzaldehyde with 3-(difluoromethyl)benzaldehyde, the title compound was obtained as a colorless solid (0.035 g , 36% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.89 to 8.88 (m, 1H), 7.52 to 7.46 (m, 5H), 6.89 to 6.89 (m, 1H), 6.51 (d, J = 13.6 Hz, 2H), 4.57 to 4.50 (m, 1H), 3.65 (q , J = 16.0 Hz, 2H), 2.96 to 2.83 (m, 5H), 2.68 to 2.64 (m, 1H), 2.30 to 2.16 (m, 2H), 1.72 to 1.58 (m, 1H), NH not observed; MS (ES+) m/z 515.3 (M + 1).

[01647] EXAMPLE 288

[01648] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01649] To a mixture of benzaldehyde (0.27 g, 2.58 mmol) and (S)-N-(-2-methoxybenzyl)-5-methyl-4-(pyrrolidin-) 2,2,2-trifluoroacetate 3-ylamino)-N-(thiazol-4-yl)benzenesulfonamide (0.77 g, 2.15 mmol) in anhydrous N,N-dimethylformamide (8 ml) was added sodium triacetoxyborohydride (0.68 g, 3. 22 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (30 ml), washed with saturated ammonium chloride (20 ml) and concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 10% methanol (containing 0.2% trifluoroacetic acid) in dichloromethane provided the title compound as a colorless solid (0.12 g, 12% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.54 (s, 1H), 8.86 (d, J = 2.2 Hz, 1H), 7, 54 to 7.38 (m, 5H), 6.89 (d, J = 2.2 Hz, 1H), 6.57 to 6.45 (m, 1H), 6.12 to 5.68 (m, 1H), 4.41 (s, 2H), 4.22 to 3.75 (m, 2H), 3.60 to 3.31 (m, 3H), 3.26 to 3.14 (m, 1H) , 2.59 to 2.25 (m, 1H), 2.10 to 1.91 (m, 4H); MS (ES+) m/z 447.2 (M + 1). EXAMPLE 289

[01650] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-cyclopropyl-2-fluoro-N-(thiazol-4-) 2,2,2-trifluoroacetate il)benzenesulfonamide

[01651]Step 1. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-cyclopropyl-5-fluorophenyl)(methyl) amino)pyrrolidine-1-tert-butylcarboxylate

[01652]A mixture of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenyl)methyl)pyrrolidine- 1-tert-butyl carboxylate (0.35 g, 0.60 mmol) in 1,4-dioxane (5 ml) was added cyclopropylboronic acid (0.15 g, 1.8 mmol), palladium acetate (0.027 g, 0.12 mmol), potassium phosphate (0.50 g, 2.40 mmol), and tricyclohexylphosphonium tetrafluoroborate (0.088 g, 0.24 mmol). The resulting mixture was degassed by passing an argon flow through it for 15 minutes and then heated at 100 °C for 4 h. The reaction mixture was allowed to cool to room temperature and filtered through a Celite filter. The filter plug was washed with ethyl acetate (30 ml) and the combined filtrate was concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 70% ethyl acetate in hexanes, provided the title compound as a colorless solid (0.30 g, 85% yield): MS(ES+) m/z 483.2 (M + 1).

[01653] Step 2. Preparation of (S)-5-cyclopropyl-2-fluoro-4-(pyrrolidin-3-ylamino)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate

[01654] To a solution of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-cyclopropyl-5-fluorophenyl)(methyl)amino ) tert-butyl pyrrolidine-1-carboxylate (0.30 g, 0.51 mmol) in dichloromethane (4 ml) trifluoroacetic acid (2 ml) was added. The resulting mixture was stirred for 2 h and then concentrated in vacuo to provide the title compound as a yellowish foam (0.32 g, quantitative yield): MS (ES+) m/z 383.2 (M + 1).

[01655]Step 3. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-5-cyclopropyl-2-fluoro-N-(thiazol-4-) 2,2,2-trifluoroacetate il)benzenesulfonamide

[01656]A mixture of benzaldehyde (0.13 g, 1.27 mmol) and (S)-N-(-5-cyclopropyl)-2-fluoro-4-(pyrrolidin-) 2,2,2-trifluoroacetate 3-ylamino)-N-(thiazol-4-yl)benzenesulfonamide (0.30 g, 1.06 mmol) in anhydrous N,N-dimethylformamide (4 ml) was added sodium triacetoxyborohydride (0.34 g, 1. 59 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (30 ml), washed with saturated ammonium chloride (20 ml) and concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 5% methanol (containing 0.2% trifluoroacetic acid) in dichloromethane provided the title compound as a colorless solid (0.10 g, 19% yield): MS (ES+) m/z 473.1 (M + 1).

[01657]Step 4. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-cyclopropyl-2-fluoro-N-(thiazol) 2,2,2-trifluoroacetate -4- yl)benzenesulfonamide

[01658] To a solution of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-5-cyclopropyl-2-fluoro-N-(thiazol-4-yl) 2,2,2-trifluoroacetate )benzenesulfonamide (0.10 g, 0.21 mmol) in trifluoroacetic acid (2.0 ml) was added sodium triacetoxyborohydride (0.13 g, 0.63 mmol) at 0 °C. The resulting mixture was stirred at 0°C for 10 minutes and then paraformaldehyde (9 mg, 0.32 mmol) was added thereto. The reaction mixture was stirred at 0 °C for 15 minutes and then concentrated in vacuo. To the residue were added 2M sodium hydroxide (10 ml) and brine (10 ml), and the mixture was extracted with ethyl acetate (30 ml). The aqueous layer was diluted with saturated ammonium chloride (30 ml) and then extracted with ethyl acetate (20 ml). The organic layers were washed with saturated ammonium chloride (30 ml), brine (30 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative reverse phase HPLC eluting with a gradient of 10 to 50% acetonitrile in water containing 0.1% trifluoroacetic acid yielded the title compound as a colorless solid (0.040 g , 39% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.24 (s, 1H), 10.48 (br s, 0.5H), 10.29 (br s, 0.5H) , 8.90 (d, J = 2.1 Hz, 1H), 7.52 to 7.45 (m, 5H), 7.20 (dd, J = 7.9, 3.2 Hz, 1H), 7.06 to 7.01 (m, 2H), 4.41 (s, 2H), 4.29 to 4.22 (m, 1H), 3.57 to 3.08 (m, 4H), 2.777 to 2.66 (m, 3H), 2.29 to 1.90 (m, 3H), 1.02 to 0.99 (m, 2H), 0.62 to 0.60 (m, 2H); MS (ES+) m/z 487.2 (M + 1). EXAMPLE 290

[01659] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-ethyl-2-fluoro-N-(thiazol-4-) 2,2,2-trifluoroacetate il)benzenesulfonamide

[01660] Following the procedure as described in EXAMPLE 289, Step 1 to 5, and making non-critical variations as necessary to replace cyclopropylboronic acid with ethylboronic acid, the title compound was obtained as a colorless solid (0.015 g, 5% yield ): 1H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.87 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 8.3 Hz , 1H), 7.44 to 7.28 (m, 5H), 7.08 to 6.99 (m, 2H), 3.96 to 3.71 (m, 2H), 2.92 to 2.77 (m, 2H), 2.66 to 2.56 (m, 4H), 2.07 to 1.64 (m, 4H), 1.23 (s, 2H), 1.12 (t, J = 7 .5 Hz, 3H), NH not observed; MS (ES+) m/z 475.2 (M + 1). EXAMPLE 291

[01661] Synthesis of (R)-2,6-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-) 2,2,2-trifluoroacetate il)benzenesulfonamide

[01662]Step 1. Preparation of (R)-((2,6-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate

[01663] To a solution of (R)-1-(1-phenylethyl)piperidin-4-ol (0.70 g, 3.41 mmol) in anhydrous N,N-dimethylformamide (10 ml) was added a dispersion of 60% sodium hydride in mineral oil (0.40 g, 10.2 mmol) and the reaction mixture was stirred at room temperature for 45 minutes. To it was added tert-butyl thiazol-4-yl((2,4,6-trifluorophenyl)sulfonyl)carbamate (1.60 g, 4.09 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched by careful addition of water (50 ml), and extracted with ethyl acetate (100 ml). The organic layer was washed with saturated ammonium chloride (2 x 50 ml), brine (50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by column chromatography, eluting with a gradient of 0 to 5% methanol in dichloromethane, to give the title compound as a colorless foam (0.52 g, 22% yield): MS (ES+) m/z 580.1 (M + 1).

[01664]Step 2. Preparation of (R)-2,6-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol) 2,2,2-trifluoroacetate -4-yl)benzenesulfonamide

[01665] To a solution of (R)-((2,6-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)(thiazol-4-yl)carbamate tert-butyl (0.52 g, 0.89 mmol) in dichloromethane (6 ml) trifluoroacetic acid (3 ml) was added. The resulting mixture was stirred for 2 h and then concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 10% methanol (containing 0.2% trifluoroacetic acid) in dichloromethane provided the title compound as a colorless foam (0.41 g, 95% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.45 (s, 1H), 10.09 (s, 1H), 8.90 (s, 1H), 7.56 to 7.48 (m , 5H), 7.01 to 6.87 (m, 3H), 4.85 (s, 0.5H), 4.58 (s, 1.5H), 3.50 to 3.35 (m, 1H ), 3.07 to 2.67 (m, 3H), 2.27 to 1.75 (m, 4H), 1.67 (d, J = 7.2 Hz, 3H); MS (ES+) m/z 480.2 (M + 1). EXAMPLE 292

[01666] Synthesis of (R)-3-chloro-4-((1-(1-(5-difluoromethyl)-2-fluorophenyl)ethyl)piperidin-4-yl)oxy)-N-(thiazole) formate 4-yl)benzenesulfonamide

[01667]Step 1. Preparation of 5-(difluoromethyl)-2-fluorobenzonitrile

[01668] To a solution of 2-fluoro-5-formylbenzonitrile (5.15 g, 34.5 mmol) in anhydrous 1,2-dichloroethane (200 ml) was added diethylaminosulfur trifluoride (5.86 ml, 44.4 mmol). The reaction mixture was stirred at room temperature for 16 h and then quenched by addition of saturated sodium bicarbonate solution (100 ml) to 0 °C. The organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by column chromatography, eluting with a gradient of 0 to 20% ethyl acetate in hexanes to give the title compound as a colorless oil (5.10 g, 86% yield): 1H-NMR (300 MHz, CDCl3) δ 7.82 to 7.75 (m, 2H), 7.34 (t, J = 8.5 Hz, 1H), 6.66 (t, J = 55.9 Hz, 1H).

[01669]Step 2. Preparation of 1-(5-(difluoromethyl)-2-fluorophenyl)ethan-1-one

[01670] To a solution of 5-(difluoromethyl)-2-fluorobenzonitrile (1.80 g, 10.5 mmol) in anhydrous tetrahydrofuran (70 ml) was added 3 M solution of methylmagnesium bromide in diethyl ether (7. 0 ml, 21.0 mmol) by drip at -78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was diluted with 1 M hydrochloric acid (200 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by column chromatography, eluting with a gradient of 0 to 20% ethyl acetate in hexanes to give the title compound as a colorless oil (0.70 g, 35% yield): 1H-NMR (300 MHz, CDCla) δ 8.03 (d, J = 6.8 Hz, 1H), 7.73 to 7.68 (m, 1H), 7.25 (t, J = 9.5 Hz, 1H), 6.65 (t, J = 56.1 Hz, 1H), 2.67 (d, J = 5.0 Hz, 3H).

[01671]Step 3. Preparation of (R)-1-(5-(difluoromethyl)-2-fluorophenyl)ethan-1-ol

[01672] To a solution of 1-(5-(difluoromethyl)-2-fluorophenyl)ethan-1-one (0.70 g, 3.68 mmol) in anhydrous tetrahydrofuran (10 ml) was added 1 M solution of (S)-(-)-2-methyl-CBS-oxazaborolidine in tetrahydrofuran (3.68 ml, 3.68 mmol) by drip at -78 °C followed by slow addition of borane dimethylsulfide complex (0.35 ml , 3.68 mmol). The reaction mixture was stirred at -78°C for 20 minutes, allowed to warm to room temperature, and stirred for 20 minutes. After quenching by slow addition of MeOH (20 ml), the reaction mixture was concentrated in vacuo. To the residue was added 1 M hydrochloric acid (20 ml), and the mixture was extracted with ethyl acetate (2 x 20 ml). The combined organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by column chromatography, eluting with a gradient of 0 to 20% ethyl acetate in hexanes to give the title compound as a colorless oil (0.60 g, 87% yield): 1H-NMR (300 MHz, CDCI3): δ 7.68 (d, J = 6.9 Hz, 1H), 7.44 to 7.39 (m, 1H), 7.11 (d, J = 9.7 Hz, 1H), 6.63 (t, J = 56.4 Hz, 1H), 5.22 (qd, J = 6.4, 5.2 Hz, 1H), 1.52 ( d, J = 7.0 Hz, 3H), OH not observed.

[01673]Step 4. Preparation of (R)-1-(5-(difluoromethyl)-2-fluorophenyl)ethyl methanesulfonate

[01674] A solution of (R)-1-(5-(difluoromethyl)-2-fluorophenyl)ethan-1-ol (0.60 g, 3.12 mmol) in methyl and isobutyl ketone (5 ml) was A methanesulfonic anhydride (0.90 g, 5.31 mmol) was added at 0 °C followed by dropwise addition of triethylamine (0.87 ml, 6.24 mmol). After 20 minutes, the reaction was quenched by the addition of saturated ammonium chloride (10 ml) and extracted with methyl and isobutyl ketone (2 x 10 ml). The combined organic extracts were carried out in the next step. MS (ES+) m/z 269.1 (M + 1).

[01675]Step 5. Preparation of (R)-4-(benzyloxy)-1-(1-(5-(difluoromethyl)-2-fluorophenyl)ethyl)-piperidine

[01676] To a solution of (R)-1-(5-(difluoromethyl)-2-fluorophenyl)ethyl methanesulfonate (3.12 mmol) in methyl and isobutyl ketone (25 ml) and water (3 ml) was added 4-(benzyloxy)piperidine (0.59 g, 3.12 mmol) and potassium carbonate (0.64 g, 4.68 mmol) and the reaction mixture was heated to 75 °C for 16 h. After cooling to room temperature, saturated ammonium chloride (15 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (2 x 20 ml). The organic phase was washed with water (15 ml), brine (15 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 15% ethyl acetate in hexanes provided the title compound as a yellow oil (0.61 g, 53% yield ): MS (ES+) m/z 364.0 (M + 1).

[01677]Step 6. Preparation of (R)-1-(1-(5-(difluoromethyl)-2-fluorophenyl)ethyl)piperidin-4-ol

[01678] To a solution of (R)-4-(benzyloxy)-1-(1-(5-(difluoromethyl)-2-fluorophenyl)-ethyl)piperidine (0.12 g, 0.33 mmol) in tetrahydrofuran (3 ml) and 1 M hydrochloric acid (1 ml) palladium hydroxide in activated charcoal (0.03 g) was added. The reaction mixture was then stirred under a hydrogen atmosphere (1 atm) at room temperature for 2 h. After addition of saturated sodium bicarbonate solution (10 ml), the mixture was extracted with ethyl acetate (2 x 20 ml). The organic phase was washed with brine (15 ml), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 40% ethyl acetate in hexanes gave the title compound as a yellow oil (0.08 g, 88% yield ): MS (ES+) m/z 274.0 (M + 1).

[01679]Step 7. Preparation of (R)-3-chloro-4-((1-(1-(5-difluoromethyl)-2-fluorophenyl)ethyl)piperidin-4-yl)oxy)-N-formate (thiazol-4-yl)benzenesulfonamide

[01680]A mixture of (R)-1-(1-(5-(difluoromethyl)-2-fluorophenyl)ethyl)piperidin-4-ol (0.08 g, 0.29 mmol) and 3-chloro- 4-fluoro-N-(thiazol-4-yl)benzenesulfonamide (0.085 g, 0.29 mmol) in anhydrous dimethyl sulfoxide (4 ml) was added potassium carbonate (0.10 g, 0.73 mmol) and to reaction mixture was heated to 60 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 ml), washed with saturated ammonium chloride (2 x 15 ml), brine (15 ml), dried with anhydrous sodium sulfate and filtered. . Concentration of the filtrate in vacuo and purification of the residue by preparative reverse phase HPLC eluting with a gradient of 20 to 60% acetonitrile in water containing 0.1% formic acid, yielded the title compound as a colorless solid (0.078 g, 48% yield): 1H NMR (300 MHz, DMSO-d6) δ 8.88 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.69 to 7.65 (m, 2H), 7.55 to 7.50 (m, 1H), 7.30 (d, J = 13.9 Hz, 2H ), 7.05 (d, J = 2.7 Hz, 2H), 4.62 to 4.55 (m, 1H), 3.93 (q, J = 6.9 Hz, 1H), 2.71 to 2.57 (m, 2H), 2.30 to 2.21 (m, 2H), 1.95 to 1.86 (m, 2H), 1.70 to 1.60 (m, 2H), 1 .34 (d, J = 6.9 Hz, 3H), NH and COOH not observed; MS (ES+) m/z 546.0 (M + 1), 548.0 (M + 1). EXAMPLE 293

[01681] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,5-difluoro-N-(thiazol-4-yl) 2,2,2-trifluoroacetate benzenesulfonamide

[01682]Step 1. Preparation of tert-butyl thiazol-4-yl((2,4,5-trifluorophenyl)sulfonyl)carbamate

[01683] To a solution of tert-butyl thiazol-4-ylcarbamate (1.47 g, 7.35 mmol) in anhydrous tetrahydrofuran (10 ml) was added 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran ( 10.3 ml, 10.3 mmol) at -78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was then cooled to -78 °C, and a solution of 2,4,5-trifluorobenzenesulfonyl chloride (1.22 ml, 8.82 mmol) in anhydrous tetrahydrofuran (10 ml) was added to it. . The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was diluted with ethyl acetate (50 ml), washed with saturated ammonium chloride (2 x 30 ml), brine (2 x 30 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 50% ethyl acetate in hexanes, provided the title compound as a colorless solid (2.0 g, 68% performance). MS (ES+) m/z 395.0 (M + 1).

[01684]Step 2. Preparation of (S)-((4-((1-benzylpyrrolidin-3-yl)amino)-2,5-difluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate

[01685]A mixture of tert-butyl thiazol-4-yl((2,4,5-trifluorophenyl)sulfonyl)carbamate (0.18 g, 0.46 mmol) and (S)-1-benzylpyrrolidin-3- amine (0.08 g, 0.46 mmol) in anhydrous dimethyl sulfoxide (10 ml) was added potassium carbonate (0.19 g, 1.38 mmol) and the reaction mixture was stirred at room temperature for 2 h . The reaction mixture was diluted with ethyl acetate (30 ml), washed with saturated ammonium chloride (2 x 20 ml), brine (20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 8% methanol in dichloromethane, provided the title compound as a colorless foam (0.22 g, 86% yield). : MS (ES+) m/z 551.0 (M + 1).

[01686]Step 3. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,5-difluoro-N-(thiazol-4) 2,2,2-trifluoroacetate -yl)benzenesulfonamide

[01687] To a solution of (S)-((4-((1-benzylpyrrolidin-3-yl)amino)-2,5-difluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate (0, 22 g, 0.40 mmol) in trifluoroacetic acid (2.0 ml) was added sodium triacetoxyborohydride (0.20 g, 0.97 mmol) at 0 °C. The resulting mixture was stirred at 0°C for 10 minutes and then paraformaldehyde (29 mg, 0.97 mmol) was added thereto. The reaction mixture was stirred at 0 °C for 15 minutes and then concentrated in vacuo. To the residue were added 2M sodium hydroxide (10 ml) and brine (10 ml), and the mixture was extracted with ethyl acetate (30 ml). The aqueous layer was diluted with saturated ammonium chloride (30 ml) and then extracted with ethyl acetate (20 ml). The organic layers were washed with saturated ammonium chloride (30 ml), brine (30 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 10% methanol in dichloromethane, gave the title compound as a colorless solid (0.098 g, 42% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.29 (s, 1H), 10.37-10.31 (m, 1H), 8.89 (d, J = 2.2 Hz, 1H), 7, 53 to 7.45 (m, 6H), 7.02 to 6.92 (m, 2H), 4.64 (s, 1H), 4.41 (s, 2H), 3.56 to 3.12 ( m, 4H), 2.84 (s, 3H), 2.18 (s, 2H); MS (ES+) m/z 465.2 (M + 1). EXAMPLE 294

[01688] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)-3-(trifluoromethyl)benzenesulfonamide formate

[01689] Step 1. Preparation of tert-butyl (4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl(thiazol-4-yl)carbamate

[01690] To a mixture of tert-butyl thiazol-4-ylcarbamate (0.500 g, 2.50 mmol) in tetrahydrofuran (8 ml) was added 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (3 .25 ml, 3.25 mmol) at -78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was then cooled to -78°C and a solution of 4-fluoro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.985 g, 3.75 mmol) in anhydrous tetrahydrofuran (1 ml) was slowly added. The reaction mixture was stirred at -78 °C for 30 minutes, allowed to warm to room temperature and stirred for 11 h. The mixture was then poured into ice water (20 ml) and the aqueous phase was extracted with ethyl acetate (3 x 30 ml). The combined organic phase was washed with brine (30 ml), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 12.5% ethyl acetate in petroleum ether, provided the title compound as a yellow solid (0.400 g, 38 % yield). 1H NMR (400 MHz, CDCI3) δ8.80 (d, J = 2.4 Hz, 1H), 8.49 to 8.44 (m, 1H), 8.44 to 8.37 (m, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.42 (t, J = 9.2 Hz, 1H), 1.36 (s, 9H); MS (ES+) m/z 326.6 (M - 99).

[01691] Step 2. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-(trifluoromethyl)phenyl)amino)pyrrolidine- 1-tert-butyl carboxylate

[01692] A mixture of tert-butyl (4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl(thiazol-4-yl)carbamate (0.200 g, 0.469 mmol) and (S)-3-aminopyrrolidine-1-carboxylate tert-butyl (0.105 g, 0.563 mmol) in anhydrous dimethyl sulfoxide (1 ml) N,N-diisopropylethylamine (0.073 g, 0.563 mmol) was added and the reaction mixture was heated to 36 ° C for 12 h. The residue was poured into ice water (20 ml) and the aqueous phase was extracted with ethyl acetate (3 x 50 ml) (3 x 30 ml). The combined organic phase was washed with brine (30 ml), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by thin layer chromatography, eluting with a 3:1 mixture of petroleum ether and ethyl acetate, gave the title compound as a colorless oil (0.140 g, 49% yield ); 1H NMR (400 MHz, CDCI3) δ 8.80 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H), 8.12 (br s, 1H), 7.53 (s, 1H), 6.85 (d, J = 9.0 Hz, 1H), 4.92 (br s, 1H), 4.25 to 4.17 (m, 1H), 3.81 (br s, 1H ), 3.56 (br s, 2H), 3.42 to 3.22 (m, 1H), 2.33 (s, 1H), 1.99 (br s, 1H), 1.50 (s, 9H), 1.40 (s, 9H); MS (ES+) m/z 615.4 (M + 23).

[01693]Step 3. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-(trifluoromethyl)phenyl)(methyl)amino )tert-butyl pyrrolidine-1-carboxylate

[01694]A mixture of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-(trifluoromethyl)phenyl)amino)pyrrolidine-1 -tert-butyl carboxylate (0.300 g, 0.506 mmol) and iodomethane (0.144 g, 1.01 mmol) in N,N-dimethylformamide (8 ml) was added sodium hydride (60% dispersion in mineral oil, 0.020 g, 0.506 mmol) at 0 °C. The mixture was stirred at 0°C for 30 minutes and at room temperature for 1 h. The residue was poured into ice water (30 ml) and the aqueous phase was extracted with ethyl acetate (3 x 40 ml). The combined organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 9 to 25% ethyl acetate in petroleum ether, gave the title compound as a yellow oil (0.250 g, 81% performance). 1H NMR (400 MHz, CDCI3) δ8.81 (d, J = 2.4 Hz, 1H), 8.42 (br s, 1H), 8.31 (br s, 1H), 7.56 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 3.82 (br s, 1H), 3.67 to 3.48 (m, 2H), 3.32 to 3.11 ( m, 2H), 2.74 (s, 3H), 2.02 to 1.84 (m, 2H), 1.45 (s, 9H), 1.36 (s, 9H); MS (ES+) m/z 629.0 (M + 23).

[01695]Step 4. Preparation of (S)-4-(methyl(pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)-3-(trifluoromethyl)benzenesulfonamide

[01696]A (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-(trifluoromethyl)phenyl)(methyl)amino)pyrrolidine- tert-Butyl 1-carboxylate (0.250 g, 0.412 mmol) was added to a solution of hydrogen chloride in methanol (25 ml) and the reaction mixture was stirred at room temperature for 12 h. Concentration of the mixture in vacuo and purification of the residue by preparative reversed-phase HPLC, using acetonitrile in water containing 0.225% formic acid as eluent, provided the title compound as a yellow solid (0.120 g, 66% yield): 1H NMR (400 MHz, CD3OD) δ 8.76 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.14 to 8.09 (m , 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 2.2 Hz, 1H), 4.13 to 4.02 (m, 1H), 3 .50 to 3.38 (m, 2H), 3.32 to 3.25 (m, 1H), 3.17 (dd, J = 6.4, 12.4 Hz, 1H), 2.71 (s , 3H), 2.15 (qd, J = 6.6, 13.4 Hz, 1H), 1.95 (qd, J = 7.0, 13.8 Hz, 1H), NH not observed; MS (ES+) m/z 406.9 (M + 1).

[01697]Step 5. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-N-(thiazol-4-yl)-3-(trifluoromethyl)benzenesulfonamide formate

[01698] To a solution of (S)-4-(methyl(pyrrolidin-3-yl)amino)-N-(thiazol-4-yl)-3-(trifluoromethyl) benzenesulfonamide (0.070 g, 0.172 mmol) and benzaldehyde (0.037 g, 0.344 mmol) in tetrahydrofuran (2 ml) trifluoroacetic acid (0.001 g, 0.009 mmol) and sodium triacetoxyborohydride (0.109 g, 0.517 mmol) were added and the mixture was stirred at room temperature for 1.5 h. Concentration in vacuo and purification of the residue by preparative reversed-phase HPLC, using acetonitrile in water containing 0.225% formic acid as eluent, gave the title compound as a colorless solid (0.026 g, 30% yield): 1H NMR (400 MHz, CD3OD) δ 8.72 (d, J = 2.0 Hz, 1H), 8.45 (br s, 1H), 8.13 (d, J = 2.0 Hz, 1H), 8 .06 (dd, J = 2.2, 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.44 (s, 5H), 7.11 (d, J = 2.2 Hz, 1H), 4.20 to 4.10 (m, 2H), 4.09 to 4.00 (m, 1H), 3.39 to 3.35 (m, 1H), 3 .17 (dt, J = 2.8, 7.0 Hz, 2H), 3.00 (dd, J = 6.8, 11.2 Hz, 1H), 2.69 (s, 3H), 2, 16 (qd, J = 7.2, 13.7 Hz, 1H), 1.93 (qd, J = 6.8, 13.8 Hz, 1H), NH and COOH not observed; MS (ES+) m/z 497.1 (M + 1), 499.1 (M + 1). EXAMPLE 295

[01699] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(1,2,4-thiadiazol-5- il)benzenesulfonamide

[01700]Step 1. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-bromo-N-(2,4-dimethoxybenzyl)-2,6-difluoro- N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[01701] A mixture of 3-bromo-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (1.00 g , 1.91 mmol) and (S)-1-benzyl-N-methylpyrrolidin-3-amine (0.363 g, 1.91 mmol) in N,N-dimethylformamide (5 ml) was added cesium carbonate (1.24 g, 3.82 mmol) and the reaction mixture was stirred at room temperature for 2 h. Water (20 ml) and ethyl acetate (20 ml) were added to the mixture, the layers were separated, and the aqueous phase was extracted with ethyl acetate (3 x 20 ml). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography, eluting with a gradient of 5 to 25% ethyl acetate in petroleum ether, to give the title compound as a light brown gum (0.450 g, 34% yield): 1H NMR (400 MHz, CDCla) δ 8.20 to 8.11 (m, 1H), 7.27 to 7.18 (m, 5H), 7.14 (d, J = 8.4 Hz, 1H), 6.28 to 6.20 (m, 2H), 6.06 (d, J = 2.4 Hz, 1H), 5.32 (s, 2H), 4.18 to 4.09 (m, 1H) , 3.70 to 3.60 (m, 7H), 2.81 (s, 2H), 2.80 (s, 3H), 2.65 (dd, J = 3.8, 10.4 Hz, 1H ), 2.47 (dd, J = 8.2, 10.2 Hz, 1H), 2.30 (q, J = 8.2 Hz, 1H), 2.16 to 2.05 (m, 1H) , 1.88-1.77 (m, 1H).

[01702]Step 2. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-N-(2,4-dimethoxybenzyl)-2,6-difluoro-3-methyl- N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[01703]A mixture of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-bromo-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N -(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.240 g, 0.346 mmol), methylboronic acid (0.041 g, 0.691 mmol), and potassium phosphate (0.220 g, 1.04 mmol) in anhydrous toluene ( 5 ml) palladium(II) acetate (0.016 g, 0.069 mmol) and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (0.029 g, 0.069 mmol) were added and the reaction mixture was heated to 110 °C for 12 H. Concentration of the mixture in vacuo and purification of the residue by column chromatography, eluting with a gradient of 5 to 25% ethyl acetate in petroleum ether, gave the title compound as a light brown solid (0.060 g, 40% income).

[01704]Step 3. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-2,2,2-trifluoroacetate (1,2,4-thiadiazol-5-yl)benzenesulfonamide

[01705]A mixture of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-N-(2,4-dimethoxybenzyl)-2,6-difluoro-3-methyl-N -(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.070 g, 0.114 mmol) in dichloromethane (1 ml) trifluoroacetic acid (0.046 g, 0.405 mmol) was added. The resulting mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was purified by preparative reverse phase HPLC eluting with a gradient of 15 to 45% acetonitrile in water containing 0.1% trifluoroacetic acid to provide the title compound as a light brown solid (0.017 g, 30% yield ): 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.51 (s, 5H), 6.87 (d, J = 12.4 Hz, 1H), 4.42 (br s, 2H), 4.30 to 4.01 (m, 1H), 3.80 to 3.35 (m, 4H), 2.71 (br s, 3H), 2.19 (d, J = 2 .8Hz, 5H); NH and COOH not observed; MS (ES+) m/z 480.4 (M + 1). EXAMPLE 296

[01706] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-(1, 2,2,2-trifluoroacetate) 2,4-thiadiazol-5-yl)benzenesulfonamide

[01707]Step 1. Preparation of 3-bromo-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[01708] To a solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (0.665 g, 2.65 mmol) in anhydrous tetrahydrofuran (10 ml) was added 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.91 ml, 2.91 mmol) at -78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. A solution of 3-bromo-2,4,6-trifluorobenzene-1-sulfonyl chloride (1.00 g, 3.23 mmol) in anhydrous tetrahydrofuran (10 ml) was then added to it at - 78 °C. . The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Water (20 ml) was added to the mixture which was then extracted with ethyl acetate (3 x 40 ml). The combined organic phase was washed with brine (3 x 20 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 5 to 10% ethyl acetate in petroleum ether, provided the title compound as a colorless solid (1.00 g, 72 % yield). 1H NMR (400 MHz, CDCla) δ 8.27 (s, 1H), 7.37 to 7.18 (m, 1H), 6.74 (ddd, J = 9.8, 7.8, 2.2 Hz, 1H), 6.36 (dd, J = 8.6, 2.4 Hz, 1H), 6.19 (d, J = 2.4 Hz, 1H), 5.46 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H).

[01709]Step 2. Preparation of (S)-3-((2-bromo-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl) tert-butyl -3,5-difluorophenyl)amino)pyrrolidine-1-carboxylate

[01710]A mixture of 3-bromo-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (1.00 g , 1.91 mmol) and (3S)-3-aminopyrrolidine-1-tert-butyl carboxylate (0.284 g, 1.53 mmol) in N,N-dimethylformamide (5 ml) was added cesium carbonate (1.24 g, 3.81 mmol) and the reaction mixture was stirred at room temperature for 12 h. Water (20 ml) was added and the mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic phase was washed with brine (3 x 20 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 5 to 50% ethyl acetate in petroleum ether, provided the title compound as a colorless solid (0.600 g, 45% performance). 1H NMR (400 MHz, CDCla) δ 8.14 (s, 1H), 7.13 (d, J = 8.6 Hz, 1H), 6.25 (dd, J = 8.4, 2.4 Hz , 1H), 6.16 (d, J = 2.4 Hz, 1H), 5.98 (dd, J = 12.8, 1.2 Hz, 1H), 5.31 (d, J = 2, 8 Hz, 2H), 5.02 (br d, J = 6.2 Hz, 1H), 3.90 (br s, 1H), 3.66 (d, J = 1.2 Hz, 6H), 3 .46 (br s, 2H), 3.33 to 3.13 (m, 1H), 2.25 to 2.12 (m, 1H), 1.86 (br s, 1H), 1.41 (s , 9H), NH not observed.

[01711]Step 3. Preparation of (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-3,5 tert-butyl-difluoro-2-methylphenyl)amino)pyrrolidine-1-carboxylate

[01712] To a solution of (S)-3-((2-bromo-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)- 3,5-difluorophenyl)amino)pyrrolidine-1-tert-butyl carboxylate (0.600g, 0.869 mmol), methylboronic acid (0.104 g, 1.74 mmol), palladium(II) acetate (0.0975 g, 0.434. mmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (0.178 g, 0.434 mmol) in anhydrous toluene (10 ml) and anhydrous tetrahydrofuran (10 ml) was added potassium phosphate (0.369 g, 1.74 mmol). The reaction mixture was heated to 110 °C for 1 h using a microwave. After cooling to room temperature, the mixture was concentrated in vacuo. Water (15 ml) was added to the residue which was then extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (3 x 10 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 9 to 20% ethyl acetate in petroleum ether, provided the title compound as a colorless solid (0.300 g, 30% performance). 1H NMR (400 MHz, CDCI3) δ 8.19 (d, J = 2.0 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.39 to 6.35 (m , 1H), 6.31 (d, J = 2.3 Hz, 1H), 6.11 to 6.01 (m, 1H), 5.37 to 5.31 (m, 2H), 4.02 ( br s, 1H), 3.78 to 3.73 (m, 6H), 3.72 to 3.71 (m, 1H), 3.60 to 3.46 (m, 3H), 3.38 to 3 .16 (m, 1H), 2.34 to 2.17 (m, 1H), 1.89 (s, 3H), 1.50 (s, 9H), NH not observed.

[01713]Step 4. Preparation of (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-3,5 tert-butyl-difluoro-2-methylphenyl)(methyl)amino)pyrrolidine-1-carboxylate

[01714] To a solution of (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-3,5- tert-butyl difluoro-2-methylphenyl)amino)pyrrolidine-1-carboxylate (0.270 g, 0.432 mmol), iodomethane (32 μl, 0.518 mmol) in anhydrous N,N-dimethylformamide (3 ml) was added sodium hydride (60 % dispersion in mineral oil 0.035 g, 0.863 mmol) at 0 °C. The resulting mixture was allowed to warm to room temperature and stirred for 2 h. Water (15 ml) was added and the aqueous phase was extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (3 x 10 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 5 to 33% ethyl acetate in petroleum ether, provided the title compound as a pale yellow solid (0.070 g, 23% income). 1H NMR (400 MHz, CDCI3) δ 8.22 (s, 1H), 7.24 (d, J = 8.6 Hz, 1H), 6.53 to 6.44 (m, 1H), 6.35 (dd, J = 8.4, 2.2 Hz, 1H), 6.25 (d, J = 2.2 Hz, 1H), 5.39 (s, 2H), 3.85-3.79 ( m, 1H), 3.75 (d, J = 3.4 Hz, 6H), 3.70 to 3.47 (m, 3H), 3.41 to 3.17 (m, 3H), 2.69 (s, 3H), 2.05 (br d, J = 2.4 Hz, 3H), 1.49 (s, 9H).

[01715]Step 5. Preparation of (S)-3-chloro-2,6-difluoro-4-(methyl(pyrrolidin-3-yl)amino)-N-(1,2,4-thiadiazol-5) hydrochloride -yl)benzenesulfonamide

[01716] To a solution of (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-3,5- tert-butyl difluoro-2-methylphenyl)(methyl)amino)pyrrolidine-1-carboxylate (0.040 g, 0.0625 mmol) in dichloromethane (1 ml) was added 4 M hydrogen chloride solution in dioxane (0.100 ml, 0.40 mmol) at 0 °C. The resulting mixture was stirred for 2 h at room temperature and was then concentrated in vacuo to provide the title compound as a light brown solid (0.025 g, 94% yield), which was used without further purification.

[01717]Step 6. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-3-methyl-N-2,2,2-trifluoroacetate (1,2,4-thiadiazol-5-yl)benzenesulfonamide

[01718] To a solution of (S)-3-chloro-2,6-difluoro-4-(methyl(pyrrolidin-3-yl)amino)-N-(1,2,4-thiadiazole) hydrochloride salt 5-yl)benzenesulfonamide (0.0240 g, 0.0616 mmol) and 6-methylpicolinaldehyde (0.00896 g, 0.0739 mmol) in methanol (2 ml) were added sodium cyanoborohydride (0.00775 g, 0.123 mmol ) and acetic acid (0.07 ml) at 0 °C. The resulting mixture was allowed to warm to room temperature and stirred for 2 h. Concentration in vacuo and purification of the residue by preparative reversed-phase HPLC, eluting with a gradient of 10 to 40% acetonitrile in water containing 0.1% trifluoroacetic acid, yielded the title compound as a light brown solid (0.011 g, 34% yield): 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.30 (dd, J = 16.2, 7.6 Hz, 2H), 6.88 (br d, J = 11.8 Hz, 1H), 4.62 to 4.47 (m, 2H), 4.22 (quin, J = 6.8 Hz, 1H), 3.72 to 3.58 (m, 2H), 3.58 to 3.46 (m, 2H), 2.74 (s, 3H), 2.57 (s, 3H ), 2.37 (qd, J = 13.4, 6.8 Hz, 1H), 2.28 to 2.17 (m, 4H), NH and COOH not observed; MS (ES+) m/z 495.4 (M + 1). EXAMPLE 297

[01719] Synthesis of (S)-3-chloro-2,6-difluoro-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin-3- 2,2,2-trifluoroacetate yl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[01720]Step 1. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[01721] Following the procedure as described in EXAMPLE 102, Step 2 and making non-critical variations as necessary to replace tert-butyl thiazol-4-ylcarbamate with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazole- 5-amine, the title compound was obtained as a colorless solid (0.538 g, 56% yield): 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.83-6.69 (m, 1H), 6.36 (dd, J = 2.3, 8.6 Hz, 1H), 6.19 (d, J = 2 .4Hz, 1H), 5.45 (s, 2H), 3.76 (s, 3H), 3.70 (s, 3H).

[01722]Step 2. Preparation of (S)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl) tert-butyl -3,5-difluorophenyl)amino)pyrrolidine-1-carboxylate

[01723] Following the procedure as described in EXAMPLE 296, Step 2 and making non-critical variations as necessary to replace 3-bromo-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(1, 2,4-thiadiazol-5-yl)benzenesulfonamide by 3-chloro-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide , the title compound was obtained as a colorless solid (0.130 g, 22% yield): 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.23 (d, J=8.4 Hz, 1H), 6.35 (dd, J = 8.4, 2.4 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 6.08 (d, J = 11 .8 Hz, 1H), 5.40 (d, J = 2.6 Hz, 2H), 5.06 (br d, J = 5.8 Hz, 1H), 4.00 (br s, 1H), 3.75 (d, J = 1.6 Hz, 6H), 3.55 (br s, 2H), 3.42 to 3.18 (m, 1H), 2.34 to 2.20 (m, 1H ), 1.96 (br s, 1H), 1.50 (s, 9H), NH not observed.

[01724]Step 3. Preparation of (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-3,5 tert-butyl-difluoro-2-methylphenyl)amino)pyrrolidine-1-carboxylate

[01725] Following the procedure as described in EXAMPLE 296, Step 4 and making non-critical variations as necessary to replace (S)-3-((4-(N-(2,4-dimethoxy-benzyl)-N-(1 ,2,4-thiadiazol-5-yl)sulfamoyl)-3,5-difluoro-2-methylphenyl)amino)-tert-butyl pyrrolidine-1-carboxylate by (S)-3-((2-chloro-4- tert-butyl (N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-3,5-difluorophenyl)amino)pyrrolidine-1-carboxylate, the title compound was obtained as a yellow solid (0.070 g, 64% yield): 1H NMR (400 MHz, CDCI3) δ 8.16 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.31 (br d, J = 11.8 Hz, 1H), 6.25 (dd, J = 8.4, 2.2 Hz, 1H), 6.08 (d, J = 2.2 Hz, 1H), 5.34 (d, J = 6.2 Hz, 2H), 4.07 (s, 1H), 3.66 (s, 3H), 3.62 (s, 3H), 3.56 a 3.43 (m, 2H), 3.25 (br s, 2H), 2.73 (s, 3H), 1.85 (br s, 2H), 1.40 (s, 9H).

[01726]Step 4. Preparation of (S)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-) hydrochloride salt tert-butyl yl)sulfamoyl)-3,5-difluorophenyl)(methyl)amino)pyrrolidine-1-carboxylate

[01727] Following the procedure as described in EXAMPLE 296, Step 5 and making non-critical variations as necessary to replace (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(1,2 tert-butyl,4-thiadiazol-5-yl)sulfamoyl)-3,5-difluoro-2-methylphenyl)-(methyl)amino)-pyrrolidine-1-carboxylate by (S)-3-((2-chloro- 4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-3,5-difluorophenyl)amino)pyrrolidine-1-tert-butyl carboxylate, the compound of the title was obtained as a light brown solid, which was used without further purification (0.095 g, 94% yield):

[01728]Step 5. Preparation of (S)-3-chloro-2,6-difluoro-4-(methyl(1-((6-methylpyridin-2-yl)methyl)pyrrolidin 2,2,2-trifluoroacetate -3-yl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[01729] Following the procedure as described in EXAMPLE 296, Step 6 and making non-critical variations as necessary to substitute (S)-3-chloro-2,6-difluoro-4-(methyl(pyrrolidin-3-) hydrochloride salt yl)amino)-N-(1,2,4-thiadiazol-5- yl)benzenesulfonamide by (S)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)) hydrochloride salt -N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-3,5-difluorophenyl)(methyl)amino)pyrrolidine-1-tert-butylcarboxylate, the title compound was obtained as a colorless solid ( 0.0340 g, 23% yield): 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.31 (dd , J = 17.8, 7.8 Hz, 2H), 6.98 (br d, J = 11.2 Hz, 1H), 4.64 to 4.50 (m, 3H), 3.79 to 3 .68 (m, 1H), 3.64 to 3.44 (m, 3H), 2.90 (s, 3H), 2.59 (s, 3H), 2.42 to 2.27 (m, 2H ), NH and COOH not observed; MS (ES+) m/z 515.3 (M + 1). EXAMPLE 298

[01730] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-3-methylbenzenesulfonamide formate

[01731] Step 1. Preparation of 3-bromo-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro- N-(6-fluoropyridin-2-yl)benzenesulfonamide

[01732] To a solution of N-(2,4-dimethoxybenzyl)-6-fluoropyridin-2-amine (2.50 g, 9.53 mmol) in anhydrous tetrahydrofuran (10 ml) was added methyl lithium (1.6 M, 7.15 ml, 11.44) at -78 °C. The mixture was heated to 0°C and stirred for 30 minutes. The reaction mixture was then cooled to -78 °C, and a solution of 3-bromo-2,4,6-trifluorobenzene-1-sulfonyl chloride (3.54 g, 11.4 mmol) in anhydrous tetrahydrofuran (2 ml) was added thereto by drip. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The mixture was diluted with saturated aqueous ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (3 x 20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 25% ethyl acetate in petroleum ether, provided the title compound as a yellow oil (2.30 g, 45 % yield). 1H NMR (400 MHz, CDCl3) δ 7.69 (q, J = 8.0 Hz, 1H), 7.26 to 7.22 (m, 1H), 7.09 (dd, J = 1.6, 7.8 Hz, 1H), 6.94 to 6.83 (m, 1H), 6.70 (dd, J = 2.8, 8.0 Hz, 1H), 6.43 to 6.40 (m , 1H), 6.40 (s, 1H), 5.11 (s, 2H), 3.76 (d, J = 9.6 Hz, 6H).

[01733]Step 2. Preparation of (S)-3-((2-bromo-4-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)sulfamoyl)-3,5 tert-butyl-difluorophenyl)amino)pyrrolidine-1-carboxylate

[01734] Following the procedure as described in EXAMPLE 296, Step 2 and making non-critical variations as necessary to replace 3-bromo-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(1, 2,4-thiadiazol-5-yl)benzenesulfonamide by 3-bromo-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide, the compound of title was obtained as a colorless solid (2.00 g, 66% yield): 1H NMR (400 MHz, CDCI3) δ 7.73 to 7.61 (m, 1H), 7.30 to 7.25 (m , 2H), 7.23 (br d, J = 8.0 Hz, 1H), 6.66 (dd, J = 2.4, 7.8 Hz, 1H), 6.42 to 6.36 (m , 2H), 6.20 (br d, J = 12.4 Hz, 1H), 5.11 (s, 2H), 5.06 (br d, J = 6.2 Hz, 1H), 4.03 (br s, 1H), 3.75 (d, J = 6.8 Hz, 6H), 3.52 (br d, J = 17.2 Hz, 2H), 3.42 to 3.21 (m, 1H), 2.34 to 2.20 (m, 1H), 2.05 to 1.88 (m, 1H), 1.49 (s, 9H); MS (ES+) m/z 701.1 (M + 1), 703.1 (M + 1).

[01735]Step 3. Preparation of (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)sulfamoyl)-3,5-difluoro-2 tert-butyl-methylphenyl)amino)pyrrolidine-1-carboxylate

[01736] To a solution of (S)-3-((2-bromo-4-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)sulfamoyl)- 3,5- tert-butyl difluorophenyl)amino)pyrrolidine-1-carboxylate (1.70 g, 2.42 mmol) in N,N-dimethylformamide (5 ml) was added tetramethyltin (1.30 g, 7.27 mmol), lithium (0.30 g, 7.27 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.34 g, 0.484 mmol). The resulting mixture was heated to 80°C for 12 h. After cooling to room temperature, the mixture was diluted with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (3 x 20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 50% ethyl acetate in petroleum ether, gave the title compound as a yellow oil (1.30 g, 84 % yield). 1H NMR (400 MHz, CDCI3) δ 7.67 (q, J = 8.1 Hz, 1H), 7.33 to 7.27 (m, 2H), 6.62 (dd, J = 2.8, 8.0 Hz, 1H), 6.44 to 6.31 (m, 2H), 6.17 to 6.07 (m, 1H), 5.19 to 5.09 (m, 2H), 4.20 (br d, J = 5.8 Hz, 1H), 4.03 (br s, 1H), 3.78 to 3.76 (m, 1H), 3.78 (s, 3H), 3.75 ( s, 3H), 3.60 to 3.44 (m, 2H), 3.37 to 3.16 (m, 1H), 2.31 to 2.18 (m, 1H), 1.94 (s, 3H), 1.48 (s, 9H), NH not observed; MS (ES+) m/z 637.3 (M + 1).

[01737]Step 4. Preparation of (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)sulfamoyl)-3,5-difluoro-2 -methylphenyl)(methyl)amino)pyrrolidine-1- tert-butyl carboxylate

[01738] Following the procedure as described in EXAMPLE 296, Step 4 and making non-critical variations as necessary to replace (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(1,2 tert-butyl,4-thiadiazol-5-yl)sulfamoyl)-3,5-difluoro-2-methylphenyl)amino)pyrrolidine-1-carboxylate by (S)-3-((4-(N-(2,4 - tert-butyl dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)sulfamoyl)-3,5-difluoro-2-methylphenyl)amino)pyrrolidine-1-carboxylate, the title compound was obtained as a yellow oil ( 0.80 g, 71% yield): 1H NMR (400 MHz, CDCl3) δ 7.69 (q, J = 8.2 Hz, 1H), 7.31 (s, 2H), 6.66 (dd , J = 2.9, 8.0 Hz, 1H), 6.60 (d, J = 12.4 Hz, 1H), 6.44 to 6.37 (m, 2H), 5.15 (s, 2H), 3.86 to 3.79 (m, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.70 to 3.47 (m, 2H), 3.40 to 3.17 (m, 2H), 2.70 (s, 3H), 2.14 (d, J = 2.8 Hz, 3H), 2.06 to 1.90 (m, 2H), 1, 49 (s, 9H); MS (ES+) m/z 673.3 (M + 23).

[01739]Step 5. Preparation of (S)-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-3-methyl-4-(methyl(pyrrolidin -3-yl)amino)benzenesulfonamide

[01740] A (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)sulfamoyl)-3,5-difluoro-2-methylphenyl)( tert-butyl methyl)amino)pyrrolidine-1-carboxylate (0.30 g, 0.46 mmol) was added to 4 M hydrogen chloride solution in dioxane (20 ml, 80 mmol) and the resulting mixture was heated to 45 °C for 4 h. The mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC, eluting with a gradient of 5 to 60% acetonitrile in water containing 0.1% ammonium hydroxide, to give the title compound as a solid. colorless (0.10 g, 56% yield): 1H NMR (400MHz, CD3OD) δ 7.46 to 7.38 (m, 1H), 6.73 to 6.64 (m, 2H), 6.17 (dd, J = 2.4, 7.8 Hz, 1H), 4.51 (br s, 1H), 3.94 (quin, J = 6.5 Hz, 1H), 3.36 to 3.26 (m, 3H), 3.09 to 3.01 (m, 1H), 2.56 to 2.54 (m, 3H), 2.14 to 2.03 (m, 1H), 1.99 (d , J = 2.7 Hz, 3H), 1.97 to 1.90 (m, 1H), NH not observed; MS (ES+) m/z 401.2 (M + 1).

[01741]Step 6. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-formate 3-methylbenzenesulfonamide

[01742] To a solution of (S)-2,6-difluoro-N-(6-fluoropyridin-2-yl)-3-methyl-4- (methyl(pyrrolidin-3-yl) amino)benzenesulfonamide (0. 09 g, 0.2 mmol) in anhydrous tetrahydrofuran (2 ml) was added benzaldehyde (0.047 g, 0.45 mmol) and sodium triacetoxyborohydride (0.095 g, 0.45 mmol). The resulting mixture was stirred at room temperature for 10 minutes. The mixture was concentrated in vacuo, and the residue purified by preparative reversed-phase HPLC, using acetonitrile in water containing 0.225% formic acid as eluent, to give the title compound as a colorless solid (0.363 g, 32% yield). : 1H-NMR (400 MHz, DMSO-d6) δ 8.17 (s, 0.4H), 7.75 (q, J = 8.3 Hz, 1H), 7.32 to 7.30 (m, 4H), 7.28 to 7.22 (m, 1H), 6.82 (dd, J = 8.0, 2.1 Hz, 1H), 6.71 (d, J = 12.9 Hz, 1H ), 6.57 (dd, J = 7.9, 2.4 Hz, 1H), 3.97 to 3.92 (m, 1H), 3.66 (d, J = 13.1 Hz, 1H) , 3.56 (d, J = 13.0 Hz, 1H), 2.76 to 2.70 (m, 1H), 2.68 (s, 3H), 2.66 to 2.60 (m, 2H ), 2.42 to 2.36 (m, 1H), 2.05 to 2.01 (m, 4H), 1.83 to 1.75 (m, 1H), NH and COOH not observed; 19F NMR (376.5 MHz, DMSO-d6) - 68.9 (s, 1F), -108.2 (s, 1F), -111.8 (s, 1F); MS (ES+) m/z 491.1 (M + 1). EXAMPLE 299

[01743] Synthesis of 4-((1-benzylpiperidin-4-yl)oxy)-2-fluoro-3-methyl- N-(thiazol-4-yl)benzenesulfonamide hydrochloride

[01744]Step 1. Preparation of tert-butyl ((3-chloro-2,4-difluorophenyl)sulfonyl(thiazol-4-yl)carbamate

[01745] To a solution of tert-butyl N-thiazol-4-ylcarbamate (110.0 g, 549.3 mmol) in anhydrous tetrahydrofuran (1000 ml) was added lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 659.1 ml, 659.1 mmol) at -78 °C. The mixture was heated to 5°C, stirred for 30 minutes and then cooled to -78°C. To it was then added a solution of 3-chloro-2,4-difluorobenzenesulfonyl chloride (162.8 g, 659.2 mmol) in anhydrous tetrahydrofuran (300 ml) at -78 °C. The mixture was allowed to warm to room temperature and stirred for 12 h. The mixture was diluted with saturated ammonium chloride (200 ml) and extracted with ethyl acetate (3 x 1000 ml). The combined organic phase was washed with brine (3 x 1000 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and trituration of the residue with methanol (300 ml) provided the title compound as a colorless solid (75.00 g, 33% yield): 1H NMR (400 MHz, CDCI3) δ 9.14 (s, 1H), 8.26 to 8.09 (m, 1H), 8.03 (s, 1H), 7.66 (t, J = 8.6 Hz, 1H), 1.27 (s, 9H); MS (ES+) m/z 432.8 (M + 23), 434.8 (M + 23).

[01746]Step 2. Preparation of ((4-((1-benzylpiperidin-4-yl)oxy)-3-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate

[01747]A mixture of tert-butyl (3-chloro-2,4-difluorophenyl)sulfonyl(thiazol-4-yl)carbamate (2.70 g, 6.57 mmol) and 1-benzylpiperidin-4-ol ( 1.01 g, 5.26 mmol) in anhydrous dimethyl sulfoxide (4 ml) cesium carbonate (4.28 g, 13.14 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. Water (20 ml) was added to the mixture and the aqueous phase was extracted with ethyl acetate (4 x 30 ml). The combined organic extracts were washed with brine (3 x 20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 66% ethyl acetate in petroleum ether, provided the title compound as a yellow oil (1.00 g, 26 % yield). 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 9.1, 6.1 Hz, 1H), 7.47 (d , J = 2.3 Hz, 1H), 7.26 to 7.15 (m, 5H), 6.98 (dd, J = 7.7, 9.0 Hz, 1H), 4.62 to 4, 48 (m, 1H), 3.39 (s, 2H), 2.73 (br d, J = 12.0 Hz, 2H), 1.95 to 1.85 (m, 2H), 1.79 to 1.65 (m, 4H), 1.26 (s, 9H).

[01748]Step 3. Preparation of ((4-((1-benzylpiperidin-4-yl)oxy)-2-fluoro-3-methylphenyl)sulfonyl)(thiazol-4-yl) tert-butyl carbamate

[01749]A mixture of tert-butyl (4-((1-benzylpiperidin-4-yl)oxy)-3-chloro-2-fluorophenyl)sulfonyl(thiazol-4-yl)carbamate (0.200 g, 0.344 mmol) and methylboronic acid (0.031 g, 0.52 mmol) in anhydrous tetrahydrofuran (5 ml) and toluene (5 ml) was added potassium phosphate (0.146 mg, 0.687 mmol), palladium(II) acetate (0.015 g, 0.069 mmol ) and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (0.028 g, 0.069 mmol). The resulting mixture was heated to 110 °C for 1 h using a microwave reactor. Concentration in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 25% ethyl acetate in petroleum ether, gave the title compound as a light brown gum (0.150 g, 78% yield ). MS (ES+) m/z 562.2 (M + 1).

[01750]Step 4. Preparation of 4-((1-benzylpiperidin-4-yl)oxy)-2-fluoro-3-methyl-N-(thiazol-4-yl)benzenesulfonamide hydrochloride

[01751]A mixture of tert-butyl (4-((1-benzylpiperidin-4-yl)oxy)-2-fluoro-3-methylphenyl)sulfonyl(thiazol-4-yl)carbamate (0.130 g, 0.231 mmol) in tert-butanol (10 ml) potassium tert-butoxide (0.0779 g, 0.694 mmol) was added and the reaction was stirred at room temperature for 1 h. Concentration in vacuo and purification of the residue by reverse phase preparative HPLC, eluting with a gradient of 20 to 40% acetonitrile in water containing 0.05% hydrochloric acid, gave the title compound as a colorless solid (0.040 g , 37% yield): 1H NMR (400 MHz, CD3OD) δ 8.75 to 8.69 (m, 1H), 7.76 to 7.66 (m, 1H), 7.62 to 7.50 ( m, 5H), 6.98 (d, J = 2.1 Hz, 1H), 6.97 to 6.87 (m, 1H), 4.93 (br s, 1H), 4.45 to 4, 37 (m, 2H), 3.66 to 3.38 (m, 2H), 3.31 to 3.17 (m, 2H), 2.46 to 2.15 (m, 3H), 2.15 to 2.08 (m, 3H), 2.03 to 1.86 (m, 1H), NH and HCl not observed; MS (ES+) m/z 462.1 (M + 1). EXAMPLE 300

[01752] Synthesis of (R)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(pyrimidin-4-yl)benzenesulfonamide

[01753]Step 1. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide

[01754] To a solution of N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (prepared according to WO2013064983, 15.0 g, 61.2 mmol) and 1,4-diazabicyclo[2,2,2 ]octane (13.7 g, 122.0 mmol) in anhydrous acetonitrile (150 ml) was added a solution of 3-chloro-4-fluorobenzene-1-sulfonyl chloride (21.0 g, 91.7 mmol) in anhydrous acetonitrile (100 ml) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The mixture was then diluted with water (200 ml) and extracted with ethyl acetate (2 x 300 ml). The combined organic phase was washed with brine (50 ml), dried over sodium sulfate and filtered. Concentration in vacuo and trituration of the residue with methanol (2 x 200 ml) gave the title compound as a pale yellow solid (20.0 g, 75% yield): 1H NMR (400 MHz, CDCI3) δ 8, 88 (d, J = 0.8 Hz, 1 H), 8.53 (d, J = 5.6 Hz, 1 H), 7.89 (dd, J = 6.8, 2.0 Hz, 1 H), 7.86 to 7.81 (m, 1 H), 7.24 (t, J = 8.4 Hz, 1 H), 7.20 (dd, J = 5.6, 1.2 Hz , 1 H), 7.17 (d, J = 8.0 Hz, 1 H), 6.46-6.39 (m, 2 H), 5.20 (s, 2 H), 3.80 ( s, 3 H), 3.71 (s, 3 H); MS (ES+) m/z 460.1 (M + 23), 462.1 (M + 1).

[01755]Step 2. Preparation of (R)-3-chloro-N-(2,4-dimethoxybenzyl)-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(pyrimidinyl -4-yl)benzenesulfonamide

[01756] To a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.100 g, 0.228 mmol) in anhydrous dimethyl sulfoxide (5 ml ) cesium carbonate (0.149 g, 0.457 mmol) and (R)-1-(1-phenylethyl)piperidin-4-ol (0.056 g, 0.274 mmol) were added and the reaction mixture was stirred at room temperature for 12 h . The reaction mixture was diluted in water (10 ml) and extracted with ethyl acetate (2 x 10 ml). The combined organic extracts were washed with brine (10 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo gave the title compound as a yellow oil (0.120 g, 84% yield): MS (ES+) m/z 623.2 (M + 1).

[01757]Step 3. Preparation of (R)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)- N-(pyrimidin-4-yl)benzenesulfonamide

[01758] To a solution of (R)-3-chloro-N-(2,4-dimethoxybenzyl)-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(pyrimidin- 4-yl)benzenesulfonamide (0.100 mg, 0.160 mmol) in dichloromethane (10 ml) trifluoroacetic acid (1 ml) was added. The mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was purified by preparative reverse phase HPLC eluting with acetonitrile in water containing 0.05% ammonium hydroxide, to give the title compound as a colorless solid (0.030 g, 40% yield): 1H NMR (400 MHz , CDCI3) δ 8.79 (s, 1H), 8.42 (d, J = 6.0 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.78 (dd , J = 8.8, 2.4 Hz, 1H), 7.34 to 7.38 (m, 4H), 7.29 to 7.33 (m, 1H), 7.17 (d, J = 6 .0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.52 (br s, 1H), 3.75 (d, J = 7.2 Hz, 1H), 2 .75 to 2.90 (m, 2H), 2.49 to 2.75 (m, 2H), 2.12 (d, J = 9.2 Hz, 2H), 1.95 (br s, 2H) , 1.51 (d, J = 6.8 Hz, 3H), NH not observed; MS (ES+) m/z 473.1 (M + 1). EXAMPLE 301

[01759] Synthesis of (S)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(pyrimidin-4-yl)benzenesulfonamide

[01760]Step 1. Preparation of (S)-3-chloro-N-(2,4-dimethoxybenzyl)-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(pyrimidinyl -4-yl)benzenesulfonamide

[01761] Following the procedure as described in EXAMPLE 300, Step 2 and making non-critical variations as necessary to replace (R)-1-(1-phenylethyl)piperidin-4-ol with (S)-1-(1-phenylethyl )piperidin-4-ol, the title compound was obtained as a brown oil (0.320 g, 8% yield) which was used without purification: MS (ES+) m/z 623.1 (M + 1).

[01762]Step 2. Preparation of (S)-3-chloro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)- N-(pyrimidin-4-yl)benzenesulfonamide

[01763] Following the procedure as described in EXAMPLE 300, Step 3 and making non-critical variations as necessary to replace (R)-3-chloro-N- (2,4-dimethoxybenzyl)-4-((1-(1- phenylethyl)piperidin-4-yl)oxy)-N-(pyrimidin-4-yl)benzenesulfonamide by (S)-3-chloro-N-(2,4-dimethoxybenzyl)-4-((1-(1-phenylethyl) )piperidin-4-yl)oxy)-N-(pyrimidin-4-yl)benzenesulfonamide, the title compound was obtained as a colorless solid (0.073 g, 30% yield): 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 8 .4 Hz, 1H), 7.30 to 7.45 (m, 5H), 7.12 (d, J = 5.2 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H ), 4.53 (br s, 1H), 3.89 (br s, 1H), 2.64 to 3.02 (m, 4H), 2.07 to 2.28 (m, 2H), 1, 97 (d, J = 3.6 Hz, 2H), 1.56 (d, J = 6.8 Hz, 3H), NH not observed; MS (ES+) m/z 473.1 (M + 1). EXAMPLE 302

[01764] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(5-fluoropyridin-2-yl)-3-methylbenzenesulfonamide formate

[01765]Step 1. Preparation of 3-bromo-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide

[01766] Following the procedure as described in EXAMPLE 298, Step 1 and making non-critical variations as necessary to replace N-(2,4-dimethoxybenzyl)-6-fluoropyridin-2-amine with N-(2,4-dimethoxybenzyl) -5-fluoropyridin-2-amine (prepared according to WO 2012004743), the title compound was obtained as a yellow solid (0.500 g, 38% yield): 1H NMR (400 MHz, CDCl3) δ 8.14 ( d, J = 2.9 Hz, 1H), 7.38 to 7.31 (m, 1H), 7.27 to 7.23 (m, 1H), 7.16 (d, J = 8.9 Hz , 1H), 6.85 (ddd, J = 9.9, 8.1, 2.1 Hz, 1H), 6.38 to 6.33 (m, 2H), 5.03 (s, 2H), 3.75 (s, 3H), 3.69 (s, 3H); MS (ES+) m/z 559.2 (M + 23).

[01767]Step 2. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-3-bromo-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-( 5-fluoropyridin-2-yl)benzenesulfonamide

[01768] To a solution of 3-bromo-N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (0.40, 0.75 mmol ) and (S)-1-benzylpyrrolidin-3-amine (0.16 g, 0.90 mmol) in N,N-dimethylformamide (5 ml) was added N,N-diisopropylethylamine (0.19 g, 1.5 mmol), and the mixture was heated to 35 °C for 12 h. After dilution with saturated ammonium chloride (20 ml), the mixture was extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (3 x 20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 50% ethyl acetate in petroleum ether, gave the title compound as a yellow oil (0.50 g, 96 % yield). 1H NMR (400 MHz, CDCI3) δ8.16 (d, J = 2.8 Hz, 1H), 7.43 to 7.30 (m, 7H), 7.22 (d, J = 8.9 Hz, 1H), 6.40 to 6.31 (m, 2H), 6.13 (dd, J = 13.1, 1.4 Hz, 1H), 5.35 (br d, J = 7.0 Hz, 1H), 5.05 (s, 2H), 4.03 to 3.92 (m, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.70 to 3.66 (m, 2H), 2.96 to 2.85 (m, 1H), 2.85 to 2.75 (m, 1H), 2.67 (br d, J = 7.3 Hz, 1H), 2 .55 to 2.45 (m, 1H), 2.45 to 2.29 (m, 1H), 1.83 to 1.69 (m, 1H).

[01769]Step 3. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(5-fluoropyridin- 2-yl)-3-methylbenzenesulfonamide

[01770] To a solution of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-3-bromo-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(5 -fluoropyridin-2-yl)benzenesulfonamide (0.40 g, 0.58 mmol) in anhydrous toluene (5 ml) was added methylboronic acid (0.35 g, 5.8 mmol), potassium phosphate (0.37 g , 1.7 mmol), palladium(II) acetate (0.013 g, 0.58 mmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (0.048 g, 0.12 mmol) and the mixture was degassed by purging with nitrogen for 3 minutes. The resulting mixture was heated at 120 °C for 1 h in a microwave reactor. After cooling to room temperature, the mixture was diluted with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (3 x 20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 50% ethyl acetate in petroleum ether, provided the title compound as a yellow oil (0.3 g, 82 % yield). 1H NMR (400 MHz, CDCI3) δ 8.15 to 8.11 (m, 1H), 7.47 to 7.42 (m, 1H), 7.36 to 7.31 (m, 5H), 7, 23 (d, J = 8.8 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.39 to 6.32 (m, 2H), 6.01 (d, J = 13.0 Hz, 1H), 5.07 (s, 2H), 4.67 (br s, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 2.94 ( br d, J = 3.6 Hz, 1H), 2.77 to 2.70 (m, 2H), 2.50 to 2.31 (m, 2H), 2.07 (s, 1H), 1, 93 (d, J = 1.3 Hz, 3H), 1.77 to 1.70 (m, 2H), 1.62 to 1.51 (m, 1H); MS (ES+) m/z 627.3 (M + 1).

[01771]Step 4. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(5 -fluoropyridin-2-yl)-3-methylbenzenesulfonamide

[01772] To a solution of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(5-fluoropyridin-2 -yl)-3-methylbenzenesulfonamide (0.1 g, 0.2 mmol) in N,N-dimethylformamide (1 ml) was added sodium hydride (60% dispersion in mineral oil, 0.006 g, 0.2 mmol) at -5°C. Iodomethane (0.020 g, 143 umol) was then added and the mixture was stirred at room temperature for 1 h. The mixture was diluted with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (3 x 20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative reverse phase HPLC eluting with acetonitrile in water containing 0.05% ammonium hydroxide, gave the title compound as a colorless solid (0.029 g, 28% yield). : 1H NMR (400 MHz, CDCl3) δ8.13 (d, J = 2.8 Hz, 1H), 7.46 to 7.40 (m, 1H), 7.37 to 7.27 (m, 6H) , 7.23 (d, J = 8.4 Hz, 1H), 6.43 (dd, J = 12.9, 1.4 Hz, 1H), 6.38 to 6.33 (m, 2H), 5.07 (s, 2H), 3.96 to 3.86 (m, 1H), 3.75 (s, 3H), 3.73 to 3.65 (m, 4H), 3.53 (d, J = 12.9 Hz, 1H), 2.82 to 2.75 (m, 1H), 2.74 (s, 3H), 2.69 to 2.57 (m, 2H), 2.51 to 2 .42 (m, 1H), 2.16 to 2.09 (m, 1H), 2.08 (d, J = 3.0 Hz, 3H), 1.94 to 1.83 (m, 1H); MS (ES+) m/z 641.5 (M + 1).

[01773]Step 5. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,6-difluoro-N-(5-fluoropyridin-2-yl)-formate 3-methylbenzenesulfonamide

[01774] To a solution of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-N-(2,4- dimethoxybenzyl)- 2,6-difluoro-N-(5- fluoropyridin-2-yl)-3-methylbenzenesulfonamide (0.060 g, 0.093 mmol) in dichloromethane (5 ml) trifluoroacetic acid (1 ml) was added and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo, and the residue was purified by reversed-phase preparative HPLC, using acetonitrile in water containing 0.225% formic acid as eluent, to give the title compound as a colorless solid (0.042 g, 83% yield ): 1H NMR (400MHz, CD3OH) δ 8.22 (br s, 1H), 8.03 (d, J = 2.8 Hz, 1H), 7.56 to 7.50 (m, 1H), 7 .47 (s, 5H), 7.16 (dd, J = 9.2, 3.7 Hz, 1H), 6.81 (dd, J = 12.4, 1.3 Hz, 1H), 4, 34 (s, 2H), 4.14 (quin, J = 7.2 Hz, 1H), 3.56 to 3.48 (m, 1H), 3.46 to 3.38 (m, 1H), 3 .36 to 3.32 (m, 1H), 3.30 to 3.26 (m, 1H), 2.68 (s, 3H), 2.33 to 2.23 (m, 1H), 2.15 (d, J = 2.8 Hz, 3H), 2.15 to 2.07 (m, 1H), NH and COOH not observed; MS (ES+) m/z 491.3 (M + 1). EXAMPLE 303

[01775] Synthesis of 3-chloro-4-((1-(1-phenylcyclopropyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide

[01776]Step 1. Preparation of 1-(1-phenylcyclopropyl)piperidin-4-one

[01777] To a solution of 1-phenylcyclopropanamine hydrochloride (0.300 mg, 1.77 mmol) in ethanol (10 ml) was added potassium carbonate (0.0367 g, 0.265 mmol) and a mixture of 1-dimethyl iodide -4-oxopiperidin-1-io (0.451 g, 1.77 mmol) in water (5 ml). The reaction mixture was heated to 80°C for 3 h and was then concentrated in vacuo, quenched with water (20 ml) and extracted with dichloromethane (2 x 50 ml). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0 to 10% ethyl acetate in petroleum ether, to give the title compound as a yellow solid (0.200 g, 53% yield): 1H NMR ( 400 MHz, CDCI3) δ7.26 to 7.36 (m, 5H), 2.82 (t, J = 6.0 Hz, 4H), 2.39 (t, J = 6.0 Hz, 4H), 1.01 to 1.06 (m, 2H), 0.88 to 0.94 (m, 2H).

[01778]Step 2. Preparation of 1-(1-phenylcyclopropyl)piperidin-4-ol

[01779] To a solution of 1-(1-phenylcyclopropyl)piperidin-4-one (0.200 mg, 0.929 mmol) in methanol (5 ml) was added sodium borohydride (0.070 g, 1.86 mmol). The reaction mixture was stirred at room temperature for 3 h and was then concentrated in vacuo, diluted with water (10 ml) and extracted with dichloromethane (2 x 30 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless solid (0.180 g, 89% yield): 1H NMR (400 MHz, CDCl3) δ 7.27- 7.34 (m, 4H), 7.23 to 7.27 (m, 1H), 3.40 to 3.53 (m, 1H), 2.78 to 2.95 (m, 2H), 2, 12 to 2.26 (m, 2H), 1.79 to 1.93 (m, 2H), 1.42 to 1.53 (m, 2H), 1.26 (d, J = 5.2 Hz, 1H), 0.90 to 0.96 (m, 2H), 0.76 to 0.86 (m, 2H).

[01780]Step 3. Preparation of 3-chloro-4-((1-(1-phenylcyclopropyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide

[01781] To a solution of 1-(1-phenylcyclopropyl)piperidin-4-ol (0.150 g, 0.690 mmol) in anhydrous N,N-dimethylformamide (5 ml) was added sodium hydride (60% dispersion in mineral oil , 0.055 g, 1.38 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then tert-butyl (3-chloro-4-fluorophenyl)sulfonyl(thiazol-4-yl)carbamate (0.298 g, 0.759 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 h and then quenched with water (20 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were washed with brine (3 x 20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative reversed-phase HPLC using acetonitrile in water containing 0.225% formic acid as eluent gave the title compound as a colorless solid (0.021 g, 6% yield): 1H NMR (400 MHz, CDCl3) δ8.61 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 8.8, 2.4 Hz, 1H), 7.27 to 7.39 (m, 5H), 7.05 (d, J = 2.2 Hz, 1H), 6.80 (d, J = 9.2 Hz, 1H), 4.18 to 4.41 (m, 1H), 2.82 to 3.03 (m, 2H), 2.33 to 2.66 (m, 2H), 1.89 to 2.20 ( m, 4H), 0.99 to 1.35 (m, 2H), 0.79 to 0.95 (m, 2H), NH not observed; MS (ES+) m/z 490.1 (M + 1 EXAMPLE 304

[01782] Synthesis of (R)-3-chloro-N-(5-fluoropyrimidin-2-yl)-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)benzenesulfonamide

[01783]Step 1. Preparation of N-(2,4-dimethoxybenzyl)-5-fluoropyrimidin-2-amine

[01784] To a solution of 5-fluoropyrimidin-2-amine (1.20 g, 10.6 mmol) in dichloromethane (30 ml) was added 2,4-dimethoxybenzaldehyde (1.94 g, 11.7 mmol). The reaction was stirred at room temperature for 2 h and then chloro(triisopropoxy)titanium (4.15 g, 15.9 mmol, 5.32 ml) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 12 h and then diluted with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (3 x 20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 25% ethyl acetate in petroleum ether, gave the title compound as a yellow oil (1.30 g, 47 % yield). 1H NMR (400 MHz, CDCI3) δ 8.15 (s, 2H), 7.22 (d, J = 8.3 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.41 (dd, J = 8.2, 2.1 Hz, 1H), 5.59 (br s, 1H), 4.49 (d, J = 6.0 Hz, 2H), 3.82 ( s, 3H), 3.79 (s, 3H).

[01785]Step 2. Preparation of 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(5-fluoropyrimidin-2-yl)benzenesulfonamide

[01786] Following the procedure as described in EXAMPLE 41, Step 1 and making non-critical variations as necessary to replace tert-butyl thiazol-4-ylcarbamate with N-(2,4-dimethoxybenzyl)-5-fluoropyrimidin-2-amine, the title compound was obtained as a colorless solid (0.800 g, 92% yield): 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 2H), 7.86 to 7.79 (m, 1H) , 7.75 to 7.68 (m, 1H), 7.18 to 7.06 (m, 2H), 6.42 (d, J = 8.4 Hz, 1H), 6.28 (s, 1H ), 5.39 (s, 2H), 3.79 (s, 3H), 3.43 (s, 3H).

[01787]Step 3. Preparation of (R)-3-chloro-N-(2,4-dimethoxybenzyl)-N-(5-fluoropyrimidin-2-yl)-4-((1-(1-phenylethyl)piperidin -4-yl)oxy)benzenesulfonamide

[01788] To a solution of (R)-1-(1-phenylethyl)piperidin-4-ol (0.100 g, 0.487 mmol) in anhydrous dimethyl sulfoxide (5 ml) was added 3-chloro-N-(2, 4-dimethoxybenzyl)-4-fluoro-N-(5-fluoropyrimidin-2-yl) benzenesulfonamide (0.222 g, 0.487 mmol) and cesium carbonate (0.317 g, 0.974 mmol). The reaction mixture was heated to 80 °C for 12 h and then diluted with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 × 10 ml). The combined organic extracts were washed with brine (3 x 10 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative reversed-phase HPLC using acetonitrile in water containing 0.1% formic acid as eluent provided the title compound as a yellow oil (0.030 g, 10% yield): 1H NMR (400 MHz, CDCI3) δ 8.36 (s, 2H), 7.78 to 7.72 (m, 2H), 7.42 to 7.35 (m, 5H), 7.10 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.41 to 6.35 (m, 1H), 6.28 (d, J = 2.0 Hz, 1H), 5.35 (s, 2H), 4.61 (br s, 1H), 4.03 (d, J = 6.8 Hz, 1H), 3.76 (s, 3H), 3 .50 (s, 3H), 3.05 (br s, 1H), 2.96 to 2.78 (m, 3H), 2.27 (d, J = 12.0 Hz, 2H), 1.97 (d, J = 11.3 Hz, 2H), 1.64 (d, J = 6.8 Hz, 3H).

[01789]Step 4. Preparation of (R)-3-chloro-N-(5-fluoropyrimidin-2-yl)-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)benzenesulfonamide

[01790] Following the procedure as described in EXAMPLE 41, Step 2 and making non-critical variations as necessary to substitute (R)-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-((1 -(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide by (R)-3-chloro-N-(2,4-dimethoxybenzyl)-N-(5-fluoropyrimidin -2-yl)-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)benzenesulfonamide the title compound was obtained as a colorless solid (0.012 g, 48% yield): 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 2H), 8.10 (d, J = 2.3 Hz, 1H), 7.98 to 7.89 (m, 1H), 7.39 to 7.27 (m, 5H), 6.94 (d, J = 9.2 Hz, 1H), 4.54 (br s, 1H), 3.71 (d, J = 5.6 Hz, 1H), 2, 86 to 2.55 (m, 4H), 2.13 (br s, 2H), 1.93 (br s, 2H), 1.51 (d, J = 6.4 Hz, 3H), NH not observed ; MS (ES+) m/z 491.1 (M + 1). EXAMPLE 305

[01791] Synthesis of (R)-3-chloro-N-(isoxazol-3-yl)-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)benzenesulfonamide formate

[01792]Step 1. Preparation of 3-chloro-4-fluoro-N-(isoxazol-3-yl)benzenesulfonamide

[01793]A mixture of isoxazol-3-amine (0.500 g, 5.95 mmol), 4-dimethylaminopyridine (0.0727 g, 0.595 mmol) and pyridine (0.941 g, 11.9 mmol) in dichloromethane (2 ml ) a solution of 3-chloro-4-fluorobenzene-1-sulfonyl chloride (1.64 g, 7.14 mmol) in dichloromethane (1 ml) was added at 0 °C. The mixture was stirred at room temperature for 12 h and was then diluted with water (20 ml) and extracted with dichloromethane (2 x 30 ml). The combined organic extracts were washed with water (20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative reversed-phase HPLC using acetonitrile in water containing 0.1% formic acid as eluent provided the title compound as a colorless solid (0.250 g, 15% yield): 1H NMR (400 MHz, CDCI3) δ 8.31 (d, J = 1.8 Hz, 1 H), 7.92 to 7.90 (m, 1 H), 7.76 to 7.74 (m, 1H), 7.22 (t, J = 8.5 Hz, 1 H), 6.62 (s, 1 H), NH not observed; MS (ES+) m/z 276.9 (M + 1).

[01794]Step 2. Preparation of (R)-3-chloro-N-(isoxazol-3-yl)-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)benzenesulfonamide formate

[01795] To a solution of (R)-1-(1-phenylethyl)piperidin-4-ol (0.089 g, 0.433 mmol) in N,N-dimethylformamide (1.50 ml) was added sodium hydride (60% dispersion in mineral oil, 0.029 g, 0.723 mmol) and the mixture was stirred at room temperature for 30 minutes. To it was then added 3-chloro-4-fluoro-N-(isoxazol-3-yl)benzenesulfonamide (0.100 g, 0.361 mmol) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then quenched with water (20 ml) and extracted with ethyl acetate (2 x 30 ml). The combined organic extracts were washed with brine (20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative reversed-phase HPLC using acetonitrile in water containing 0.1% formic acid as eluent provided the title compound as a colorless solid (0.072 g, 43% yield): 1H NMR (400 MHz, CDCI3) δ 8.58 (s, 1H), 8.19 (s, 1H), 7.83 (d, J = 1.7 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.42 (s, 5H), 6.89 (d, J = 8.6 Hz, 1H), 6.52 (s, 1H), 4.67 (br s, 1H), 4.32 (br s, 1H), 3.27 (br s, 1H), 3.14 (br s, 1H), 3.04 to 2.93 (m, 2H), 2.43 to 2.40 (m, 2H), 2.02 (br s, 2H), 1.76-1.74 (d, J = 6.5 Hz, 3H), NH and COOH not observed. EXAMPLE 306

[01796] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(5-fluoropyridin-2-yl)-5-methylbenzenesulfonamide

[01797]Step 1. Preparation of 4-bromo-2-fluoro-5-methylbenzenesulfonyl chloride

[01798] To 4-bromo-2-fluoro-5-methylaniline (5.00 g, 24.5 mmol) concentrated hydrochloric acid (20 ml) was added at 0 °C. The mixture was stirred at 0°C for 30 minutes and then a solution of sodium nitride (2.54 g, 36.7 mmol) in water (8 ml) was added dropwise at 0°C. In a separate flask, sulfur dioxide (15 psi) was bubbled through acetic acid (25 ml) at 0°C for 30 minutes. To this solution was then added cuprous chloride (0.72 g, 7.35 mmol) at 0 °C followed by dropwise addition of the mixture prepared from 4-bromo-2-fluoro-5-methylaniline and nitrite. sodium to hydrochloric acid. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with brine (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic fractions were washed with brine (3 x 20 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 2 to 17% ethyl acetate in petroleum ether, provided the title compound as a yellow solid (5.00 g, 70 % yield). 1H NMR (400 MHz, CDCla) δ 7.82 (d, J = 7.2 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 2.48 (s, 3H).

[01799]Step 2. Preparation of 4-bromo-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(5-fluoropyridin-2-yl)-5-methylbenzenesulfonamide

[01800] To a solution of N-(2,4-dimethoxybenzyl)-5-fluoropyridin-2-amine (1.00 g, 3.81 mmol) in anhydrous tetrahydrofuran (30 ml) was added methyl lithium (1.6 M, 3.10 ml, 4.96 mmol) at -78°C. The reaction mixture was stirred at 0°C for 30 minutes. After cooling to -78 °C, a solution of 4-bromo-2-fluoro-5-methylbenzene-1-sulfonyl chloride (1.42 g, 4.95 mmol) in anhydrous tetrahydrofuran (10 ml) was added by dripping at -78°C. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was then diluted with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (3 x 20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 9 to 25% ethyl acetate in petroleum ether, provided the title compound as a yellow solid (1.00 g, 51 % yield). 1H NMR (400 MHz, CDCla) δ 8.15 (d, J = 2.6 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.40 to 7.31 (m , 3H), 7.18 (d, J = 8.2 Hz, 1H), 6.38 to 6.32 (m, 2H), 4.99 (s, 2H), 3.76 (s, 3H) , 3.67 (s, 3H), 2.39 (s, 3H); MS (ES+) m/z 536.8 (M + 23).

[01801]Step 3. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(5-fluoropyridin-2- yl)-5-methylbenzenesulfonamide

[01802] To a solution of (S)-1-benzylpyrrolidin-3-amine (0.31 g, 1.8 mmol) and 4-bromo-N-(2,4-dimethoxybenzyl)-2-fluoro-N- (5-fluoropyridin-2-yl)-5-methylbenzenesulfonamide (0.60 g, 1.2 mmol) in 2-methyl-2-butanol (5 ml) was added chlorine(2-dicyclohexylphosphine-2',6-diisopropoxy -1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (0.091 g, 0.12 mmol) and cesium carbonate (1.14 g, 3.64 mmol) . The mixture was heated to 90 °C for 12 h and then diluted with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (3 x 20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 9 to 50% ethyl acetate in petroleum ether, provided the title compound as a yellow solid (0.650 g, 91% performance). 1H NMR (400 MHz, CDCI3) δ 8.13 (d, J = 2.9 Hz, 1H), 7.46 (dd, J = 8.8, 4.1 Hz, 1H), 7.40 (d , J = 7.9 Hz, 1H), 7.36 to 7.26 (m, 7H), 7.22 (d, J = 8.0 Hz, 1H), 6.38 to 6.31 (m, 2H), 6.18 (d, J = 12.9 Hz, 1H), 4.99 (s, 2H), 4.36 (br d, J = 7.0 Hz, 1H), 4.01 to 3 .91 (m, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 3.66 (s, 2H), 2.87 (dt, J = 8.6, 4.5 Hz, 1H), 2.77 (dd, J = 9.7, 6.3 Hz, 1H), 2.63 (dd, J = 9.7, 2.9 Hz, 1H), 2.50 to 2 .42 (m, 1H), 2.40 to 2.29 (m, 2H), 1.77 to 1.64 (m, 2H); MS (ES+) m/z 609.4 (M + 1).

[01803]Step 4. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(5-fluoropyridin -2-yl)-5-methylbenzenesulfonamide

[01804] Following the procedure as described in EXAMPLE 296, Step 4 and making non-critical variations as necessary to replace (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(1,2 tert-butyl,4-thiadiazol-5-yl)sulfamoyl)-3,5-difluoro-2-methylphenyl)amino)pyrrolidine-1-carboxylate by (S)-4-((1-benzylpyrrolidin-3-yl)amino )-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(5-fluoropyridin-2-yl)-5-methylbenzenesulfonamide, the title compound was obtained as a yellow oil (0.12 g, 58% yield): 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 3.0 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.44 (dd , J = 8.8, 4.0 Hz, 1H), 7.38 to 7.27 (m, 6H), 7.21 (d, J = 8.2 Hz, 1H), 6.62 (d, J = 12.4 Hz, 1H), 6.38 to 6.30 (m, 2H), 5.00 (s, 2H), 3.95 to 3.84 (m, 1H), 3.79 to 3 .69 (m, 5H), 3.67 (s, 3H), 2.71 (s, 3H), 2.63 (br s, 1H), 2.53 (br s, 1H), 2.22 ( s, 3H), 2.14 to 2.04 (m, 1H), 1.86 (td, J = 6.6, 3.2 Hz, 2H), 1.62 (br s, 1H); MS (ES+) m/z 623.5 (M + 1).

[01805]Step 5. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(5-fluoropyridin-2-yl)-5-methylbenzenesulfonamide

[01806] Following the procedure as described in EXAMPLE 295, Step 3 and making non-critical variations as necessary to replace (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-N-(2, 4-dimethoxybenzyl)-2,6-difluoro-3-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide by (S)-4-((1-benzylpyrrolidin-3-yl)(methyl )amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(5-fluoropyridin-2-yl)-5-methylbenzenesulfonamide, the title compound was obtained as a colorless solid (0.0498 g, 49% yield): 1H NMR (400 MHz, CD3OD) δ8.02 (d, J = 3.0 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.49 ( dt, J = 8.6, 3.0 Hz, 1H), 7.44 (s, 5H), 7.18 (dd, J = 9.0, 3.6 Hz, 1H), 6.94 (d , J = 12.2 Hz, 1H), 4.23 (br s, 2H), 4.08 (br s, 1H), 3.39 (br s, 1H), 3.30 to 3.12 (m , 3H), 2.65 (s, 3H), 2.30 (s, 3H), 2.27 to 2.18 (m, 1H), 2.12 to 1.99 (m, 1H), NH no observed; MS (ES+) m/z 473.1 (M + 1). EXAMPLE 307

[01807] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isothiazol-4-yl)-5-methylbenzenesulfonamide formate

[01808]Step 1. Preparation of 4-bromo-2-fluoro-N-(isothiazol-4-yl)-5-methylbenzenesulfonamide

[01809] To a solution of isothiazol-4-amine (0.45 g, 4.5 mmol) in dichloromethane (2 ml) was added 4-(dimethylamino)pyridine (0.05 g, 0.45 mmol), pyridine (0.71 mg, 9.0 mmol) and then 4-bromo-2-fluoro-5-methylbenzene-1-sulfonyl chloride (1.55 g, 5.39 mmol). The mixture was stirred at room temperature for 12 h and then concentrated in vacuo. The mixture was diluted with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (3 x 20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 9 to 50% ethyl acetate in petroleum ether, provided the title compound as a colorless solid (1.3 g, 82 % yield). 1H NMR (400 MHz, CDCla) δ 8.34 (s, 1H), 8.30 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.44 (d, J = 9.4 Hz, 1H), 7.00 (s, 1H), 2.38 (s, 3H).

[01810]Step 2. Preparation of 4-bromo-2-fluoro-N-(isothiazol-4-yl)-5-methyl-N- ((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide

[01811]A mixture of 4-bromo-2-fluoro-N-(isothiazol-4-yl)-5-methylbenzenesulfonamide (0.40 g, 1.1 mmol) in anhydrous N,N-dimethylformamide (5 ml) Potassium carbonate (0.47 g, 3.4 mmol) was added and the reaction mixture was heated to 40 ° C for 30 minutes. The reaction mixture was cooled to 0 °C and 2-(chloromethoxy)ethyltrimethylsilane (0.19 g, 1.14 mmol) was added thereto. The reaction mixture was allowed to warm to room temperature, stirred for 12 h, and was then diluted with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (3 x 20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 9 to 50% ethyl acetate in petroleum ether, provided the title compound as a yellow oil (0.5 g, 91 % yield). 1H NMR (400 MHz, CDCl3) δ8.50 (s, 1H), 8.38 (s, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.41 (d, J = 9.4 Hz, 1H), 5.13 (s, 2H), 3.74 to 3.63 (m, 2H), 2.37 (s, 3H), 0.96 to 0.85 (m, 2H ), 0.01 (s, 9H); MS (ES+) m/z 483.2 (M + 1).

[01812]Step 3. Preparation of (S)-3-((5-fluoro-4-(N-(isothiazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-2 tert-butyl-methylphenyl)amino)pyrrolidine-1-carboxylate

[01813] To a solution of 4-bromo-2-fluoro-N-(isothiazol-4-yl)-5-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (1.13 g, 2 .34 mmol) in anhydrous toluene (1 ml) was added (S)-3-aminopyrrolidine-1-tert-butyl carboxylate (0.48 g, 2.6 mmol), bis(dibenzylideneacetone)palladium (0.27 g, 0.47 mmol), cesium carbonate (2.29 g, 7.03 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.27 g, 0.47 mmol). The mixture was degassed by spraying with nitrogen and then heated to 80 °C for 12 h. After cooling to room temperature, the mixture was diluted with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with brine (3 x 20 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 9 to 33% ethyl acetate in petroleum ether, provided the title compound as a yellow oil (1.0 g, 72 % yield). 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.38 (s, 1H), 7.36 (br d, J = 8.1 Hz, 1H), 6.28 (d, J = 13.0 Hz, 1H), 5.16 (br s, 2H), 4.17 to 4.11 (m, 2H), 4.03 (br s, 1H), 3.82 to 3.63 (m, 3H), 3.51 (br s, 2H), 3.40 to 3.18 (m, 1H), 2.30 to 2.21 (m, 1H), 1.49 (s, 9H) , 1.28 (dd, J = 7.2 Hz, 2H), 0.97 to 0.88 (m, 2H), 0.02 (s, 9H), NH not observed; MS (ES+) m/z 610.9 (M + 23).

[01814]Step 4. Preparation of (S)-3-((5-fluoro-4-(N-(isothiazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-2 tert-butyl-methylphenyl)(methyl)amino)pyrrolidine-1-carboxylate

[01815] Following the procedure as described in EXAMPLE 296, Step 4 and making non-critical variations as necessary to replace (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(1,2 tert-butyl,4-thiadiazol-5-yl)sulfamoyl)-3,5-difluoro-2-methylphenyl)amino)pyrrolidine-1-carboxylate by (S)-3-((5-fluoro-4-(N- (isothiazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-2-methylphenyl)amino)pyrrolidine-1-tert-butyl carboxylate, the title compound was obtained as a yellow oil ( 0.2 g, 48% yield): 1H NMR (400 MHz, CDCI3) δ 8.48 (br s, 1H), 8.38 (s, 1H), 7.52 (br d, J = 8, 2 Hz, 1H), 6.78 (d, J = 12.2 Hz, 1H), 5.16 (s, 2H), 3.77 (br d, J = 6.1 Hz, 1H), 3, 74 to 3.68 (m, 2H), 3.66 to 3.45 (m, 2H), 3.38 to 3.16 (m, 2H), 2.67 (s, 3H), 2.23 ( s, 3H), 2.04 to 1.88 (m, 2H), 1.47 (s, 9H), 0.97 to 0.89 (m, 2H), 0.03 to 0.01 (m, 9H).

[01816]Step 5. Preparation of (S)-2-fluoro-N-(isothiazol-4-yl)-5-methyl-4- (methyl(pyrrolidin-3-yl)amino)benzenesulfonamide

[01817] Following the procedure as described in EXAMPLE 295, Step 3 and making non-critical variations as necessary to replace (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-N-(2, 4-dimethoxybenzyl)-2,6-difluoro-3-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide by (S)-3-((5-fluoro-4-(N-( isothiazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)sulfamoyl)-2-methylphenyl)(methyl)amino)pyrrolidine-1-tert-butyl carboxylate, the title compound was obtained as an oil yellow (0.1 g, 58% yield): MS (ES+) m/z 371.1 (M + 1).

[01818]Step 6. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(isothiazol-4-yl)-5-methylbenzenesulfonamide formate

[01819] To a solution of (S)-2-fluoro-N-(isothiazol-4-yl)-5-methyl-4- (methyl(pyrrolidin-3-yl)amino)benzenesulfonamide (0.08 g, 0 .22 mmol) in anhydrous tetrahydrofuran (3 ml) benzaldehyde (0.023 g, 0.22 mmol) and acetic acid (0.039 g, 0.65 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.091 g, 0.43 mmol) was then added and the mixture was stirred at room temperature for 12 h. Concentration in vacuo and purification of the residue by preparative reversed-phase HPLC, using acetonitrile in water containing 0.225% formic acid as eluent, gave the title compound as a colorless solid (0.053 g, 46% yield): 1H NMR (400 MHz, CDCI3) δ8.43 (s, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7 .39 (s, 5H), 6.77 (d, J = 12.0 Hz, 1H), 4.15 to 3.98 (m, 3H), 3.37 (br dd, J = 10.8, 7.7 Hz, 1H), 3.18 to 3.00 (m, 2H), 2.94 (br dd, J = 10.6, 6.6 Hz, 1H), 2.63 (s, 3H) , 2.29 to 2.21 (m, 1H), 2.20 (s, 3H), 1.98 (qd, J = 13.8, 6.9 Hz, 1H), NH and COOH not observed; MS (ES+) m/z 461.3 (M + 1). EXAMPLE 308

[01820] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(6-fluoropyridin-2-yl)-5-methylbenzenesulfonamide

[01821]Step 1. Preparation of 4-bromo-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-5-methylbenzenesulfonamide

[01822] Following the procedure as described in EXAMPLE 306, Step 2 and making non-critical variations as necessary to replace N-(2,4-dimethoxybenzyl)-5-fluoropyridin-2-amine with N-(2,4-dimethoxybenzyl) -6-fluoropyridin-2-amine, the title compound was obtained as a yellow solid (0.550 g, 94% yield): 1H NMR (400 MHz, CDCl3) δ7.78 (d, J = 7.2 Hz, 1H), 7.70 (q, J = 8.0 Hz, 1H), 7.38 (d, J = 9.6 Hz, 1H), 7.27 to 7.21 (m, 2H), 6, 69 (dd, J = 7.6, 3.2 Hz, 1H), 6.42 to 6.37 (m, 2H), 5.06 (s, 2H), 3.78 (s, 3H), 3 .73 (s, 3H), 2.42 (s, 3H).

[01823]Step 2. Preparation of (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)sulfamoyl)-5-fluoro-2-methylphenyl )amino)pyrrolidine-1-tert-butyl carboxylate

[01824] Following the procedure as described in EXAMPLE 307, Step 3 and making non-critical variations as necessary to replace 4-bromo-2-fluoro-N-(isothiazol-4-yl)-5-methyl-N-((2 -(trimethylsilyl)ethoxy)methyl)benzenesulfonamide by 4-bromo-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(6-fluoropyridin-2-yl)-5-methylbenzenesulfonamide, the title compound was obtained as a yellow oil (0.514 g, 94% yield): 1H NMR (400 MHz, CDCI3) δ 7.68 (q, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.33 (br d, J = 8.0 Hz, 1H), 7.29 (br s, 1H), 6.63 (dd, J = 7.6, 3.2 Hz, 1H ), 6.43 to 6.34 (m, 2H), 6.27 (d, J = 12.8 Hz, 1H), 5.08 (s, 2H), 4.16 to 4.01 (m, 2H), 3.77 (s, 3H), 3.75 (s, 3H), 3.60 to 3.40 (m, 2H), 3.39 to 3.14 (m, 1H), 2.34 at 2.19 (m, 1H), 2.09 (s, 3H), 1.96 (br s, 1H), 1.62 (s, 9H), NH not observed; MS (ES+) m/z 519.0 (M - 99).

[01825]Step 3. Preparation of (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)sulfamoyl)-5-fluoro-2-methylphenyl tert-butyl )(methyl)amino)pyrrolidine-1-carboxylate

[01826]Following the procedure as described in EXAMPLE 296, Step 4 and making non-critical variations as necessary to replace (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(1,2 tert-butyl,4-thiadiazol-5-yl)sulfamoyl)-3,5-difluoro-2-methylphenyl)amino)pyrrolidine-1-carboxylate by (S)-3-((4-(N-(2,4 - tert-butyl dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)sulfamoyl)-5-fluoro-2-methylphenyl)amino)pyrrolidine-1-carboxylate, the title compound was obtained as a yellow oil (0.520 g , 91% yield): 1H NMR (400 MHz, CDCl3) δ 7.68 (dd, J = 8.4, 5.6 Hz, 2H), 7.34 to 7.29 (m, 2H), 6 .77 (d, J = 11.6 Hz, 1H), 6.66 (dd, J = 8.0, 2.8 Hz, 1H), 6.42 to 6.36 (m, 2H), 5. 08 (s, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.49 to 3.61 (m, 2H), 3.31 (br d, J = 8.4 Hz, 2H), 2.67 (s, 3H), 2.27 (s, 3H), 2.04 to 1.88 (m, 3H), 1.48 (s, 9H). MS (ES+) m/z 655.0 (M + 23).

[01827]Step 4. Preparation of (S)-2-fluoro-N-(6-fluoropyridin-2-yl)-5-methyl-4- (methyl(pyrrolidin-3-yl)amino)benzenesulfonamide

[01828]A (S)-3-((4-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)sulfamoyl)-5-fluoro-2-methylphenyl)(methyl) tert-butyl amino)pyrrolidine-1-carboxylate (0.320 g, 0.506 mmol) was added 4 M hydrogen chloride solution in dioxane (4.0 ml, 16.0 mmol) and the mixture was stirred at room temperature for 2 H. Water (30 ml) was added and the mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic extracts were washed with brine (3 x 30 ml), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by preparative reversed-phase HPLC using acetonitrile in water containing 0.225% formic acid as eluent gave the title compound as a colorless solid (0.140 g, 72% yield): 1H NMR (400 MHz, CDCla) δ 8.44 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.63 (q, J = 8.0 Hz, 1H), 7, 09 to 7.05 (m, 1H), 6.76 (d, J = 12.0 Hz, 1H), 6.51 (dd, J = 8.0, 2.4 Hz, 1H), 4.04 to 3.94 (m, 1H), 3.47 to 3.33 (m, 3H), 3.09 (br dd, J = 12.0, 6.4 Hz, 1H), 2.63 (s, 3H), 2.26 (s, 3H), 2.23 to 2.15 (m, 2H), an NH not observed.

[01829]Step 5. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-N-(6-fluoropyridin-2-yl)-5-methylbenzenesulfonamide

[01830] To a solution of (S)-2-fluoro-N-(6-fluoropyridin-2-yl)-5-methyl-4(methyl(pyrrolidin-3-yl)amino)benzenesulfonamide (0.070 g, 0. 18 mmol), benzaldehyde (0.023 g, 0.22 mmol) and acetic acid (0.0003 g, 0.005 mmol) in methanol (3 ml) was added sodium cyanoborohydride (0.0230 g, 0.366 mmol) and the mixture of reaction was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure to yield a residue. Purification of the residue by preparative reverse phase HPLC eluting with a gradient of 5 to 60% acetonitrile in water containing 0.05% ammonium hydroxide, yielded the title compound as a colorless solid (0.251 g, 29% yield ): 1H NMR (400 MHz, CDCI3) δ7.71 to 7.62 (m, 2H), 7.36 to 7.30 (m, 4H), 7.28 to 7.25 (m, 1H), 7 .16 (dd, J = 8.0, 1.6 Hz, 1H), 6.65 (d, J = 12.8 Hz, 1H), 6.56 (dd, J = 8.0, 2.4 Hz, 1H), 3.98 to 3.85 (m, 1H), 3.76 to 3.66 (m, 1H), 3.56 (d, J = 12.8 Hz, 1H), 2.79 to 2.72 (m, 1H), 2.70 (s, 3H), 2.69 to 2.59 (m, 2H), 2.58 to 2.51 (m, 1H), 2.25 (s , 3H), 2.13 to 2.02 (m, 1H), 1.90 to 1.80 (m, 1H), NH not observed; MS (ES+) m/z 473.2 (M + 1). EXAMPLE 309

[01831] Synthesis of rac-4-(((2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl)(methyl)amino)- 5-chloro-2-fluoro-N-(thiazol-4- il)benzenesulfonamide

[01832]Step 1. Preparation of rac-(2R,3R)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)-5 tert-butyl-fluorophenyl)amino)-2-methylpyrrolidine-1-carboxylate

[01833]A suspension of 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide (1.04 g, 2.35 mmol) and cis -3-amino-1-Boc-2-methylpyrrolidine (0.470 g, 2.35 mmol) in anhydrous dimethylsulfoxide (10 ml) was added potassium carbonate (0.974 g, 7.05 mmol). The reaction mixture was stirred at room temperature for 18 hours and then heated to 50 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 ml) and water (20 ml) and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic phase was washed with brine (3 x 20 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 50% ethyl acetate in hexanes provided the title compound as a yellowish foam (0.556 g, 37% yield): MS (ES+) m/z 641.2 (M + 1), 643.5 (M + 1).

[01834]Step 2. Preparation of rac-(2R,3R)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)-5 -fluorophenyl)(methyl)amino)-2-methylpyrrolidine-1-tert-butyl carboxylate

[01835] To a solution of rac-(2R,3R)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)-5- tert-butyl fluorophenyl)amino)-2-methylpyrrolidine-1-carboxylate (0.377 g, 0.588 mmol) and methyl iodide (0.040 ml, 0.70 mmol) in anhydrous N,N-dimethylformamide (6 ml) was added to a dispersion of sodium hydride in mineral oil (0.035 g, 0.88 mmol) at 0 °C. The resulting mixture was warmed to room temperature, stirred for 2 hours and then quenched by slow addition of water (100 ml). Filtration of the resulting suspension provided the title compound as a yellowish solid (0.458 g) which was dried in vacuo and used without further purification: MS (ES+) m/z 655.3 (M + 1), 667.3 (M + 1).

[01836]Step 3. Preparation of rac-5-chloro-2-fluoro-4-(((2R,3R)-2-methylpyrrolidin-3-yl)amino)-N-(2,2,2-trifluoroacetate thiazol-4-yl)benzenesulfonamide

[01837] To a cooled solution (0°C) of rac-(2R,3R)-3-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-4-yl )sulfamoyl)-5-fluorophenyl)(methyl)amino)-2-methylpyrrolidine-1-tert-butyl carboxylate (0.458 g, 0.588 mmol) in dichloromethane (7 ml) was added trifluoroacetic acid (1.4 ml, 18.3 mmol). The reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was concentrated and the residue triturated with methanol (30 ml). The precipitate was removed by filtration and the filtered residue rinsed with methanol (2 x 25 ml). The combined filtrate was concentrated in vacuo to give the title compound as a yellow oil (0.340 g) which was used without further purification: MS (ES+) m/z 405.1 (M + 1), 407.1 (M + 1).

[01838]Step 4. Preparation of rac-4-(((2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-N-(thiazole -4-yl)benzenesulfonamide

[01839] To a solution of rac-5-chloro-2-fluoro-4-2,2,2-trifluoroacetate (((2R,3R)-2-methylpyrrolidin-3-yl)amino)-N-(thiazole -4-yl)benzenesulfonamide (0.340 g, 0.588 mmol) in anhydrous 1,2-dichloroethane and anhydrous N,N-dimethylformamide (3 ml) benzaldehyde (0.178 ml, 1.76 mmol) was added. After 15 minutes, sodium triacetoxyborohydride (0.373 g, 1.76 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with brine (2 x 25 ml). The combined aqueous layers were extracted with ethyl acetate (3 x 75 ml). The combined organic layers were dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 5% methanol (containing 2% ammonium hydroxide) in dichloromethane, provided the title compound as a colorless solid (0.119 g, 41% yield) 1H NMR (300 MHz, DMSO-d6) δ 11.13 to 11.06 (m, 1H), 8.91 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.37 to 7.28 (m, 5H), 7.16 (s, 1H), 7.06 (d, J = 2.2 Hz, 1H) , 4.32 to 4.25 (m, 1H), 4.13 to 4.07 (m, 1H), 3.37 to 3.24 (m, 2H), 2.98 to 2.82 (m, 4H), 2.04 to 1.83 (m, 3H), 1.19 to 1.17 (m, 3H); MS (ES+) m/z 495.1 (M + 1), 497.1 (M + 1). EXAMPLE 310

[01840] Synthesis of rac-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01841]Step 1. Preparation of rac-tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate

[01842] To a cooled (0 °C) solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (0.975 g, 5.26 mmol) in anhydrous diethyl ether (20 ml) was added 3 M methylmagnesium bromide solution in diethyl ether (3.50 ml, 10.53 mmol). The reaction was allowed to warm to room temperature, stirred for 1 hour and then cooled to 0 °C and quenched by addition of saturated aqueous ammonium chloride (15 ml). The aqueous layer was separated and extracted with ethyl acetate (3 x 100 ml). The combined organic phases were washed with brine (50 ml), dried over magnesium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 40% ethyl acetate in hexanes, provided the title compound as a yellowish oil (0.735 g, 69% yield). 1H NMR (300 MHz, CDCl3) δ 3.54 to 3.44 (m, 2H), 3.42 to 3.33 (m, 1H), 3.28 to 3.20 (m, 1H), 1, 93 to 1.79 (m, 2H), 1.60 to 1.56 (m, 1H), 1.46 (s, 9H), 1.42 (s, 3H); MS (ES+) m/z 202.3 (M + 1).

[01843]Step 2. Preparation of 3-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)-5-fluorophenoxo)-3-methylpyrrolidine-1 -rac-tert-butyl carboxylate

[01844] To a solution of 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-4-yl)benzenesulfonamide (0.500 g, 1.13 mmol) and 3-hydroxy -3-methylpyrrolidine-1-tert-butyl carboxylate (0.250 g, 1.24 mmol) in anhydrous N,N-dimethylformamide (8 ml) was added to a dispersion of 60% sodium hydride in mineral oil (0.185 g, 4 .62 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then slowly added to rapidly stirred saturated aqueous ammonium chloride (150 ml). The resulting slurry was filtered and the precipitate obtained was purified by column chromatography, eluting with a gradient of 0 to 60% ethyl acetate in hexanes, to yield the title compound as a pale yellow solid (0.323 g, 45% yield): MS (ES+) m/z 664.3 (M + 23), 666.3 (M + 23).

[01845]Step 3. Preparation of rac-5-chloro-2-fluoro-4-((3-methylpyrrolidin-3-yl)oxy)-N-(thiazol-4-yl) 2,2,2-trifluoroacetate benzenesulfonamide

[01846] To a solution of 3-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-4-yl)sulfamoyl)-5-fluorophenoxy)-3-methylpyrrolidine-1- rac-tert-butyl carboxylate (0.323 g, 0.503 mmol) in dichloromethane (6 ml) trifluoroacetic acid (0.554 ml, 7.23 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue triturated with methanol (10 ml). The precipitate was removed by filtration and rinsed with methanol (2 x 15 ml). The combined filtrate was concentrated in vacuo to give the title compound as a yellow foam (0.364 g, quantitative yield) which was used without further purification:

[01847]Step 4. Preparation of rac-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01848] To a solution of rac-5-chloro-2-fluoro-4-((3-methylpyrrolidin-3-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate (0.364 g) in anhydrous 1,2-dichloroethane (4 ml) and N,N-dimethylformamide (4 ml) benzaldehyde (0.218 ml, 2.16 mmol) was added. After 15 minutes, sodium triacetoxyborohydride (0.457 g, 2.16 mmol) was added thereto and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (75 ml) and washed with brine (2 x 50 ml). The combined aqueous layers were extracted with ethyl acetate (3 x 100 ml). The combined organic phase was dried with sodium sulfate, filtered and the filtrate concentrated in vacuo. Purification of the residue by column chromatography, eluting with a gradient of 0 to 5% methanol (containing 2% ammonium hydroxide) in dichloromethane provided the title compound as a pale yellow solid (0.100 g, 41% yield). : 1H NMR (300 MHz, DMSO-d6) £11.39 to 11.34 (m, 1H), 8.91 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 7 .6 Hz, 1H), 7.59 (d, J = 12.3 Hz, 1H), 7.33 to 7.23 (m, 5H), 7.05 (d, J = 2.2 Hz, 1H ), 3.67 to 3.54 (m, 2H), 3.00 to 2.96 (m, 1H), 2.81 to 2.75 (m, 1H), 2.64 to 2.61 (m , 1H), 2.56 to 2.52 (m, 1H), 2.31 to 2.21 (m, 1H), 2.09 to 2.02 (m, 1H), 1.56 (s, 3H ); MS (ES+) m/z 482.1 (M + 1), 484.1 (M + 1). EXAMPLE 311A AND 311B

[01849] Synthesis of (S)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide and (R) -4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01850] The resolution of rac-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide (0.090 g) by supercritical fluid chromatography, using 30% ethanol (containing 0.1% ammonium hydroxide) in supercritical carbon dioxide as eluent and a Chiralcel AS-H column (250 x 25 mm, 10 μm), gave (S)- 4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide (0.030 g, 97% ee) as the first enantiomer eluting and (R)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide (0.036 g, 96% ee) and as the second enantiomer. The absolute setting was arbitrarily assigned. Data for (R)-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide 1H-NMR (400 MHz, CDCl3) δ 8.65 (d, J = 2.2 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 12.0 Hz, 1H) , 7.35 to 7.31 (m, 4H), 7.30 to 7.24 (m, 1H), 7.03 (d, J = 2.3 Hz, 1H), 3.70 (d, J = 12.9 Hz, 1H), 3.60 (d, J = 13.8 Hz, 1H), 3.09 (d, J = 10.5 Hz, 1H), 2.98 to 2.90 (m , 1H), 2.64 to 2.54 (m, 2H), 2.47 to 2.37 (m, 1H), 2.01 to 1.92 (m, 1H), 1.62 (s, 3H ), NH not observed; MS (ES+) m/z 481.9 (M + 1), 483.9 (M + 1). EXAMPLE 312

[01851] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(ethyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-) 2,2,2-trifluoroacetate il)benzenesulfonamide

[01852]Step 1. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-5-fluoro-2-methylphenyl)(ethyl) amino)pyrrolidine-1-tert-butylcarboxylate

[01853] To a cooled (0 °C) solution of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-5-fluoro-2- tert-butyl methylphenyl)amino)pyrrolidine-1-carboxylate (0.300 g, 0.539 mmol) in anhydrous N,N-dimethylformamide (6 ml) was added to a dispersion of 60% sodium hydride in mineral oil (0.032 g, 0.808 mmol ). The resulting suspension was stirred at 0°C for 15 minutes before iodoethane (0.052 ml, 0.647 mmol) was added thereto. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with ethyl acetate (100 ml) and saturated aqueous ammonium chloride (50 ml) and the layers were separated. The aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic phase was washed with brine (3 x 20 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 50% ethyl acetate in hexanes provided the title compound as a yellow oil (0.085 g, 27% yield): MS (ES+) m/z 585.3 (M + 1).

[01854]Step 2. Preparation of (S)-4-(ethyl(pyrrolidin-3-yl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl) 2,2,2-trifluoroacetate )benzenesulfonamide

[01855] To a solution of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-5-fluoro-2-methylphenyl)(ethyl)amino )tert-butyl pyrrolidine-1-carboxylate (0.085 g, 0.145 mmol) in dichloromethane (2 ml) trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred at room temperature for 16 h. Concentration in vacuo gave the title compound as a yellow oil (0.190 g, quantitative yield) which was used without further purification: MS (ES+) m/z 385.2 (M + 1).

[01856]Step 3. (S)-4-((1-benzylpyrrolidin-3-yl)(ethyl)amino)-2-fluoro-5-methyl-N-(thiazol-4) 2,2,2-trifluoroacetate -yl)benzenesulfonamide

[01857] To a solution of (S)-4-(ethyl(pyrrolidin-3-yl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl) 2,2,2-trifluoroacetate benzenesulfonamide (0.190 g) in anhydrous 1,2-dichloroethane (3 ml) and anhydrous N,N-dimethylformamide (3 ml) benzaldehyde (0.115 ml, 1.14 mmol) was added. After 15 minutes, sodium triacetoxyborohydride (0.242 g, 1.14 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with brine (2 x 25 ml). The combined aqueous layers were extracted with ethyl acetate (3 x 100 ml). The organic phase was dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by reverse phase HPLC, eluting with a gradient of acetonitrile in water (containing 0.1% trifluoroacetic acid) provided the title compound as a pale yellow solid (0.037 g, 53 % yield) 1H NMR (300 MHz, DMSO-d6) δ 10.39 to 10.17 (m, 1H), 8.89 (d, J = 2.2 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.49 to 7.45 (m, 5H), 7.20 (d, J = 12.2 Hz, 1H), 7.01 (d, J = 2.2 Hz, 1H), 4.39 to 4.31 (m, 2H), 4.18 (td, J = 1.4, 0.8 Hz, 1H), 3.95 to 3.94 (m, 1H) , 3.60 to 3.03 (m, 5H), 2.25 to 2.15 (m, 3H), 2.08 to 1.81 (m, 2H), 0.79 to 0.77 (m, 3H), NH not observed; MS (ES+) m/z 475.1 (M + 1), 476.1 (M + 1). EXAMPLE 313

[01858] Synthesis of (R)-2,3-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide formate

[01859]Step 1. Preparation of tert-butyl thiazol-4-yl((2,3,4-trifluorophenyl)sulfonyl)carbamate

[01860] To a cooled solution (-50 °C) of tert-butyl N-thiazol-4-ylcarbamate (2.87 g, 14.3 mmol) in tetrahydrofuran (50 ml) was added lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 14.3 ml, 14.3 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The resulting suspension was cooled to 0°C and then added dropwise to a cooled (-78°C) solution of 2,3,4-trifluorobenzenesulfonyl chloride (1.82 ml, 13.0 mmol) in tetrahydrofuran ( 60 ml). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was then diluted with saturated aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine (2 x 50 ml), dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 30% ethyl acetate in hexanes provided the title compound as a colorless solid (4.34 g, 85% yield ). MS (ES+) m/z 395.1 (M + 1).

[01861] Step 2. Preparation of 2,3,4-trifluoro-N-(thiazol-4-yl)benzenesulfonamide

[01862] To a solution of tert-butyl thiazol-4-yl((2,3,4-trifluorophenyl)sulfonyl)carbamate (2.50 g, 6.34 mmol) in dichloromethane (13 ml) was added trifluoroacetic acid ( 3.88 ml, 50.7 mmol) and the reaction mixture was stirred at room temperature for 5 h. Concentration in vacuo and trituration of the residue in diethyl ether (25 ml) gave the title compound as a pale yellow solid (1.68 g, 90% yield) which was used without further purification: MS (ES+) m/ z 295.1 (M + 1).

[01863]Step 3. Preparation of (R)-2,3-difluoro-4-((1-(1-phenylethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl)benzenesulfonamide formate

[01864] To a solution of 2,3,4-trifluoro-N-(thiazol-4-yl)benzenesulfonamide (0.265 g, 0.901 mmol) and (R)-1-(1-phenylethyl)piperidin-4-ol ( 0.185 g, 0.901 mmol) in anhydrous N,N-dimethylformamide (4 ml) a dispersion of 60% sodium hydride in mineral oil (0.108 g, 2.70 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then slowly added to rapidly stirred saturated ammonium chloride (150 ml). The resulting slurry was filtered and the solid obtained purified by reverse phase HPLC using a gradient of acetonitrile in water (containing 0.5% formic acid) to yield the title compound as a colorless solid (0.023 g, % yield) 1H NMR (300 MHz, DMSO-d6) δ8.83 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 7.50 (td, J = 8.5, 1 .9 Hz, 1H), 7.35 to 7.13 (m, 6H), 6.88 (d, J = 2.1 Hz, 1H), 4.55 to 4.47 (m, 1H), 3 .55 to 3.48 (m, 1H), 2.75 to 2.61 (m, 2H), 2.23 to 2.17 (m, 2H), 1.95 to 1.89 (m, 2H) , 1.70 to 1.55 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H), NH and COOH not observed; MS (ES+) m/z 480.3 (M + 1). EXAMPLE 314

[01865] Synthesis of (S)-5-chloro-2-fluoro-4-((1-((3-fluoro-6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl)amino) -N-(thiazol-4-yl)benzenesulfonamide

[01866]Step 1. Preparation of 3-fluoro-6-methylpicolinaldehyde

[01867] To a solution of 2-bromo-3-fluoro-6-methylpyridine (2.00 g, 10.53 mmol) in anhydrous tetrahydrofuran (35 ml) was added 1.3 M solution of isopropylmagnesium chloride complex and lithium in tetrahydrofuran (16.20 ml, 21.06 mmol) at 0 °C. The mixture was stirred at 0 °C for 5 h, then cooled to -42 °C, and anhydrous N,N-dimethylformamide (3 ml) was added thereto. The reaction mixture was stirred at -42 °C for 2 h and then diluted with ethyl acetate. The mixture was washed with saturated ammonium chloride (2 x 60 ml), brine (50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as an orange oil (1.47 g, quantitative yield): 1H NMR (300 MHz, CDCla) δ 10.18 (s, 1H), 7.50 to 7. 38 (m, 2H), 2.63 (s, 3H); MS (ES+) m/z: 140.1 (M + 1).

[01868]Step 2. Preparation of (S)-5-chloro-2-fluoro-4-((1-((3-fluoro-6-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl )amino)-N-(thiazol-4-yl)benzenesulfonamide

[01869] Following the procedure as described in EXAMPLE 160, Step 5 and making non-critical variations as necessary to replace 6-(difluoromethyl)picolinaldehyde with 3-fluoro-6-methylpicolinaldehyde, the title compound was obtained as a colorless solid (0 .22 g, 43% yield): 1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 7.68 ( d, J = 7.6 Hz, 1H), 7.53 (dd, J = 9.7, 8.6 Hz, 1H), 7.21 (dd, J = 8.4, 3.7 Hz, 1H ), 7.07 (s, 1H), 7.00 (d, J = 2.2 Hz, 1H), 4.20 to 4.11 (m, 1H), 3.76 to 3.64 (m, 2H), 2.77 to 2.67 (m, 6H), 2.47 to 2.39 (m, 4H), 2.08 to 1.99 (m, 1H), 1.80 to 1.68 ( m, 1H); MS (ES+) m/z: 514.2 (M + 1), 516.2 (M + 1). EXAMPLE 315

[01870] Synthesis of (R)-3-chloro-4-((1-(1-(5-chloro-2-fluorophenyl)ethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl )benzenesulfonamide

[01871]Step 1. Preparation of (S,E)-N-(5-chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide

[01872] To a solution of (S)-2-methylpropane-2-sulfinamide (3.87 g, 31.91 mmol) and 5-chloro-2-fluorobenzaldehyde (4.60 g, 29.01 mmol) in dichloromethane anhydrous (100 ml) titanium(IV) isopropoxide (17.10 ml, 58.02 mmol) was added. The mixture was stirred at room temperature for 18 h and then quenched by slow addition of 2 M sodium hydroxide (80 ml). The resulting slurry was filtered and the filter cake was rinsed with dichloromethane (200 ml). The combined filtrate was concentrated in vacuo to provide the title compound as an orange solid (7.52 g, 99% yield): 1H NMR (300 MHz, CDCl3) δ 8.83 (s, 1H), 7.97 to 7.94 (m, 1H), 7.48 to 7.42 (m, 1H), 7.15 to 7.09 (m, 1H), 1.28 (s, 9H).

[01873]Step 2. Preparation of (S)-N-((R)-1-(5-chloro-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

[01874] To a solution of (S,E)-N-(5-chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (3.14 g, 12.00 mmol) in anhydrous dichloromethane (45 ml) 3.0 M methylmagnesium bromide solution in diethyl ether (5.20 ml, 15.60 mmol) was added at -78°C. The reaction mixture was stirred at -78 °C for 1 h and was then warmed to room temperature for 1 h. The reaction mixture was quenched with water (5 ml) and diluted with ethyl acetate (100 ml). The mixture was washed with saturated ammonium chloride (2 x 75 ml), brine (50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography, eluting with a gradient of 10 to 80% ethyl acetate in hexanes, to give the title compound as a colorless solid (2.38 g, 71% yield): 1H NMR (300 MHz, CDCla) δ 7.34 (dd, J = 6.3, 2.7 Hz, 1H), 7.21 (ddd, J = 8.7, 4.4, 2, 7 Hz, 1H), 6.99 (dd, J = 9.7, 8.8 Hz, 1H), 4.88 to 4.80 (m, 1H), 3.37 (d, J = 4.4 Hz, 1H), 1.57 (d, J = 6.8 Hz, 3H), 1.22 (s, 9H); MS (ES+) m/z: 287.2 (M + 1), 280.2 (M + 1).

[01875]Step 3. Preparation of (R)-1-(5-chloro-2-fluorophenyl)ethan-1-amine hydrochloride

[01876] To a 4M hydrogen chloride solution in dioxane (10 ml) was added (S)-N-((R)-1-(5-chloro-2-fluorophenyl)ethyl)-2-methylpropane-2 -sulfinamide (2.38 g, 8.57 mmol). The mixture was stirred at room temperature for 2 h and then concentrated in vacuo to provide the title compound as a colorless solid 1.80 g, quantitative yield): MS (ES+) m/z 174.2 (M + 1), 176.2 (M + 1).

[01877]Step 4. Preparation of (R)-1-(1-(5-chloro-2-fluorophenyl)ethyl)piperidin-4-one

[01878]A mixture of (R)-1-(5-chloro-2-fluorophenyl)ethan-1-amine hydrochloride (2.54 g, 12.09 mmol) and 1-ethyl-1-methyl iodide -4-oxopiperidin-1-ium (3.25 g, 12.09 mmol) in ethanol (19 ml) and water (6 ml) was added potassium carbonate (1.84 g, 13.30 mmol) and the mixture reaction was heated at reflux for 3h. After cooling to room temperature, the reaction mixture was diluted with water (80 ml) and extracted with ethyl acetate (3 x 60 ml). The combined organic fractions were washed with brine (3 x 30 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography, eluting with a gradient of 0 to 5% methanol (containing 0.1% ammonium hydroxide) in dichloromethane, to give the title compound. as a colorless solid (2.41 g, 78% yield): 1H NMR (300 MHz, CDCla) δ 7.43 (dd, J = 6.2, 2.7 Hz, 1H), 7.19 (ddd , J = 8.7, 4.5, 2.7 Hz, 1H), 6.98 (dd, J = 9.5, 8.8 Hz, 1H), 4.01 (q, J = 6.8 Hz, 1H), 2.74 (qd, J = 11.4, 6.0 Hz, 4H), 2.44 (dd, J = 7.0, 5.3 Hz, 4H), 1.41 (d , J = 6.8 Hz, 3H); MS (ES+) m/z 256.1 (M + 1), 258.1 (M + 1).

[01879]Step 5. Preparation of (R)-1-(1-(5-chloro-2-fluorophenyl)ethyl)piperidin-4-ol

[01880] To a solution of (R)-1-(1-(5-chloro-2-fluorophenyl)ethyl)piperidin-4-one (2.41 g, 9.42 mmol) in anhydrous methanol (75 ml) sodium borohydride (0.36 g, 9.42 mmol) was added at 0°C. The mixture was stirred at 0 °C for 2 h and then quenched with saturated ammonium hydroxide (50 ml). The mixture was concentrated in vacuo. The residue was diluted with 2M sodium hydroxide (110 ml) and extracted with dichloromethane (3 x 80 ml). The combined organic layers were washed with brine (80 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a colorless oil (2.32 g, 96% yield): 1H NMR (300 MHz, CDCl3) δ 7.39 (dd, J = 6.1, 2 .7 Hz, 1H), 7.16 (ddd, J = 8.7, 4.4, 2.7 Hz, 1H), 6.96 (dd, J = 9.4, 8.8 Hz, 1H) , 3.84 (q, J = 6.8 Hz, 1H), 3.64 (tt, J = 8.9, 4.4 Hz, 1H), 2.91 to 2.87 (m, 1H), 2.74 to 2.67 (m, 1H), 2.18 to 2.05 (m, 2H), 1.94 to 1.81 (m, 2H), 1.66 to 1.51 (m, 2H ), 1.35 (d, J = 6.8 Hz, 3H), OH not observed; MS (ES+) m/z 258.2 (M + 1), 260.2 (M + 1).

[01881]Step 6. Preparation of (R)-3-chloro-4-((1-(1-(5-chloro-2-fluorophenyl)ethyl)piperidin-4-yl)oxy)-N-(thiazol- 4-yl)benzenesulfonamide

[01882] To a solution of (R)-1-(1-(5-chloro-2-fluorophenyl)ethyl)piperidin-4-ol (0.39 g, 1.51 mmol) and 3-chloro-4- fluoro-N-(thiazol-4-yl)benzenesulfonamide (0.44 g, 1.51 mmol) in anhydrous N,N-dimethylformamide (10 ml) was added to a dispersion of 60% sodium hydride in mineral oil (0 .18 g, 4.53 mmol) mmol) at 0 °C. The mixture was allowed to warm to room temperature, stirred for 2 h and then heated to 75 °C for 3 h. The mixture was cooled to 0 °C, quenched by addition of water (5 ml), and diluted with saturated ammonium chloride (80 ml). The mixture was extracted with ethyl acetate (2 x 60 ml). The organic phase was washed with saturated ammonium chloride (30 ml), brine (30 ml), dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative reverse phase HPLC eluting with a gradient of 10 to 60% acetonitrile in water containing 0.1% formic acid, to give the title compound as a solid. colorless (0.20 g, 25% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.04 (br s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.8, 2.3 Hz, 1H), 7.46 (dd, J = 6.1, 2, 7 Hz, 1H), 7.39 to 7.32 (m, 2H), 7.23 (dd, J = 9.7, 8.8 Hz, 1H), 7.07 (d, J = 2.1 Hz, 1H), 4.60 to 4.54 (m, 1H), 3.89 (q, J = 6.8 Hz, 1H), 2.66 to 2.60 (m, 2H), 2.30 to 2.22 (m, 2H), 1.94 to 1.88 (m, 2H), 1.67 to 1.60 (m, 2H), 1.33 (d, J = 6.9 Hz, 3H ); MS (ES+) m/z 530.1 (M +1), 532.1 (M + 1). EXAMPLE 316

[01883] Synthesis of 3-chloro-4-(((1R,3s,5S)-8-(5-chloro-2-fluorobenzyl)-8-azabicyclo[3,2,1]octan-3-yl formate )oxy)-N-(thiazol-4-yl)benzenesulfonamide

[01884] To a solution of 4-(((1R,3s,5S)-8-azabicyclo[3,2,1]octan-3-yl)oxy)-3-chloro- N-(thiazol-4-yl)benzenesulfonamide (0.30 g, 0.58 mmol) and 5-chloro-2-fluorobenzaldehyde (0.18 g, 1.16 mol) in anhydrous N,N-dimethylformamide (5 ml ) and anhydrous dichloromethane (5 ml) sodium triacetoxyborohydride (0.25 g, 1.16 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The mixture was then diluted with saturated ammonium chloride (50 ml) and extracted with ethyl acetate (2 x 40 ml). The combined organic phase was washed with brine (30 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography, eluting with a gradient of 0 to 15% methanol (containing 0.1% ammonium hydroxide) in dichloromethane. Further purification by preparative reverse phase HPLC eluting with a gradient of 10 to 55% acetonitrile in water containing 0.1% formic acid afforded the title compound as a colorless solid (0.10 g, 29% yield). : 1H NMR (300 MHz, DMSO-d6) δ8.89 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H ), 7.69 (dd, J = 8.8, 2.3 Hz, 1H), 7.57 (dd, J = 6.3, 2.7 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.35 (ddd, J = 8.7, 4.5, 2.8 Hz, 1H), 7.22 (dd, J = 9.6, 8.8 Hz, 1H ), 7.07 (d, J = 2.2 Hz, 1H), 4.85 to 4.74 (m, 1H), 3.59 (s, 2H), 3.28 to 3.20 (m, 2H), 2.05 to 1.96 (m, 4H), 1.80 to 1.64 (m, 4H), NH and COOH not observed; MS (ES+) m/z 542.1 (M +1), 544.1 (M + 1). EXAMPLE 317

[01885] Synthesis of (S)-4-((1-((6-(azetidin-1-yl)pyridin-2-yl)methyl)pyrrolidin-3-yl)(methyl) 2,2,2-trifluoroacetate )amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01886]Step 1. Preparation of 6-(azetidin-1-yl)picolinaldehyde

[01887] To a solution of 6-chloropicolinaldehyde (1.00 g, 7.06 mmol) in anhydrous dimethyl sulfoxide (12 ml) was added azetidine (1.05 ml, 15.54 mmol) and the mixture was heated until 120 °C for 1 h. The mixture was diluted with ethyl acetate (80 ml), washed with brine (2 x 60 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide the title compound as a dark red oil (1.14 g, quantitative yield): MS (ES+) m/z 163.3 (M + 1).

[01888]Step 2. Preparation of (S)-4-((1-((6-(azetidin-1-yl)pyridin-2-yl)methyl)pyrrolidin-3-yl 2,2,2-trifluoroacetate )(methyl)amino)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[01889] Following the procedure as described in EXAMPLE 160, Step 5 and making non-critical variations as necessary to replace 6-(difluoromethyl)picolinaldehyde with 6-(azetidin-1-yl)picolinaldehyde, and purification by reverse phase preparative HPLC , eluting with a gradient of 7 to 50% acetonitrile in water containing 0.5% formic acid, gave the title compound as a colorless solid (0.020 g, 10% yield): 1H NMR (300 MHz, DMSO- d6) δ 11.40 (s, 1H), 10.19 (s, 1H), 8.91 (d, J = 2.2 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.57 (dd, J = 8.3, 7.2 Hz, 1H), 7.23 (d, J = 12.1 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.68 (d, J = 7.1 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 4.45 to 4.35 (m, 3H), 3.95 (t, J = 7.4 Hz, 4H), 3.69 to 3.61 (m, 1H), 3.53 to 3.35 (m, 3H), 2.79 (s, 3H) , 2.38 to 2.27 (m, 2H), 2.20 to 2.10 (m, 2H); MS (ES+) m/z 537.3 (M + 1), 539.3 (M + 1). EXAMPLE 318

[01890] Synthesis of 4-(((1R,3s,5S)-8-benzyl-8-azabicyclo[3,2,1]octan-3-yl)oxy)-3-chloro-N-(thiazol-4 -yl)benzenesulfonamide

[01891] Following the procedure as described in EXAMPLE 29, and making non-critical variations as necessary to replace 5-chloro-2-fluorobenzaldehyde with benzaldehyde, and purification by column chromatography, eluting with a gradient of 0 to 15% methanol (containing 0.1% ammonium hydroxide) in dichloromethane, yielded the title compound was obtained as a colorless solid (0.21 g, 74% yield): 1H NMR (300 MHz, DMSO-d6) δ 11, 07 (s, 1H), 8.88 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 8.8 , 2.3 Hz, 1H), 7.42 (d, J = 9.0 Hz, 1H), 7.39 to 7.29 (m, 4H), 7.25 to 7.20 (m, 1H) , 7.04 (d, J = 2.2 Hz, 1H), 4.85 to 4.74 (m, 1H), 3.58 (s, 2H), 3.24 to 3.21 (m, 2H ), 2.01 to 1.96 (m, 4H), 1.78 to 1.65 (m, 4H); MS (ES+) m/z 490.1 (M +1), 492.1 (M + 1). EXAMPLE 319

[01892] Synthesis of 3-chloro-4-(((1R,3s,5S)-8-(3-chloro-4-fluorobenzyl)-8-azabicyclo[3,2,1]octan-3-yl formate )oxy)-N-(thiazol-4-yl)benzenesulfonamide

[01893] Following the procedure as described in EXAMPLE 316 and making non-critical variations as necessary to replace 5-chloro-2-fluorobenzaldehyde with 3-chloro-4-fluorobenzaldehyde, produced the title compound as a colorless solid (0.11 g , 32% yield): 1H NMR (300 MHz, DMSO-d6) δ 8.89 (d, J = 2.1 Hz, 1H), 8.16 (s, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.8, 2.3 Hz, 1H), 7.56 (dd, J = 7.4, 1.9 Hz, 1H), 7 .44 to 7.31 (m, 3H), 7.06 (d, J = 2.1 Hz, 1H), 4.85 to 4.73 (m, 1H), 3.56 (s, 2H), 3.21 to 3.17 (m, 2H), 2.03 to 1.93 (m, 4H), 1.79 to 1.64 (m, 4H), NH and COOH not observed; MS (ES+) m/z 542.1 (M +1), 544.1 (M + 1). EXAMPLE 320

[01894] Synthesis of (R)-3-chloro-4-((1-(1-(5-cyclopropyl-2-fluorophenyl)ethyl)piperidin-4-yl)oxy)-N-(thiazol-4-yl )benzenesulfonamide

[01895]Step 1. Preparation of (R)-1-(1-(5-cyclopropyl-2-fluorophenyl)ethyl)piperidin-4-ol

[01896]A mixture of (R)-1-(1-(5-chloro-2-fluorophenyl)ethyl)piperidin-4-ol (1.93 g, 5.04 mmol), cyclopropylboronic acid (0.87 g, 10.01 mmol), and potassium phosphate (4.28 g, 20.16 mmol) in toluene (60 ml) and water (6 ml) palladium acetate (0.11 g, 0.50 mmol) was added ) and tricyclohexylphosphonium tetrafluoroborate (0.37 g, 1.00 mmol). The resulting mixture was degassed by spraying with nitrogen and then heated at reflux for 18 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml) and filtered. The filtrate was washed with saturated ammonium chloride (50 ml), brine (50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography, eluting with a gradient of 0 to 10% methanol (containing 0.2% ammonium hydroxide) in dichloromethane, to give the title compound as a colorless oil. (0.71 g, 53% yield): 1H NMR (300 MHz, CDCI3) δ 7.13 (dd, J = 6.9, 2.0 Hz, 1H), 6.92 to 6.87 (m , 2H), 3.87 (q, J = 6.8 Hz, 1H), 3.69 to 3.60 (m, 1H), 2.95 to 2.89 (m, 1H), 2.79 to 2.72 (m, 1H), 2.19 to 2.05 (m, 2H), 1.96 to 1.84 (m, 3H), 1.69 to 1.52 (m, 3H), 1, 39 (d, J = 6.8 Hz, 3H), 0.99 to 0.93 (m, 2H), 0.68 to 0.63 (m, 2H); MS (ES+) m/z 264.2 (M + 1).

[01897]Step 2. Preparation of (R)-3-chloro-4-((1-(1-(5-cyclopropyl-2-fluorophenyl)ethyl)piperidin-4-yl)oxy)-N-(thiazol- 4-yl)benzenesulfonamide

[01898] Following the procedure as described in EXAMPLE 315, Step 6 and making non-critical variations as necessary to replace (R)-1-(1-(5-chloro-2-fluorophenyl)ethyl)-piperidin-4-ol with (R)-1-(1-(5-cyclopropyl-2-fluorophenyl)ethyl)piperidin-4-ol, and purification by column chromatography, eluting with a gradient of 0 to 10% methanol (containing 0.2 % ammonium hydroxide) in dichloromethane, gave the title compound as a colorless solid (0.35 g 49% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.03 (br s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 8.8, 2.3 Hz, 1H ), 7.34 (d, J = 9.1 Hz, 1H), 7.14 (dd, J = 6.9, 2.3 Hz, 1H), 7.07 (d, J = 2.2 Hz , 1H), 7.01 (dd, J = 10.1, 8.5 Hz, 1H), 6.92 (ddd, J = 8.2, 5.3, 2.6 Hz, 1H), 4, 59 to 4.53 (m, 1H), 3.86 (q, J = 6.8 Hz, 1H), 2.73 to 2.62 (m, 2H), 2.29 to 2.20 (m, 2H), 1.96 to 1.87 (m, 3H), 1.70 to 1.59 (m, 2H), 1.33 (d, J = 6.9 Hz, 3H), 0.95 to 0 .88 (m, 2H), 0.68 to 0.56 (m, 2H), MS (ES+) m/z 536.3 (M + 1), 538.3 (M + 1). EXAMPLE 321

[01899] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-3-methyl-N-(thiazol-4-) 2,2,2-trifluoroacetate il)benzenesulfonamide

[01900]Step 1. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-3-fluorophenyl)amino)pyrrolidine -1-tert-butyl carboxylate

[01901] To a solution of tert-butyl ((3-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (7.50 g, 18.27 mmol) in anhydrous dimethyl sulfoxide (44 ml) triethylamine (3.10 ml, 21.92 mmol) and (S)-3-aminopyrrolidine-1-tert-butyl carboxylate (4.10 g, 21.92 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. Concentration in vacuo and purification of the residue by column chromatography, eluting with a gradient of 5 to 50% ethyl acetate in hexanes, gave the title compound as a colorless solid (6.67 g, 64% yield). : 1H NMR (300 MHz, CDCI3) δ8.79 (d, J = 2.3 Hz, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 2 .2 Hz, 1H), 6.53 (d, J = 9.2 Hz, 1H), 5.01 (d, J = 6.5 Hz, 1H), 4.174.11 (m, 1H), 3, 78 to 3.75 (m, 1H), 3.53 to 3.50 (m, 2H), 3.35 to 3.23 (m, 1H), 2.33 to 2.22 (m, 1H), 1.97 to 1.93 (m, 1H), 1.46 (s, 9H), 1.34 (s, 9H); MS (ES+) m/z 577.3 (M + 1), 579.3 (M + 1).

[01902]Step 2. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-3-fluoro-2-methylphenyl)amino)pyrrolidine -1-tert-butyl carboxylate

[01903] To a solution of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-3-fluorophenyl)amino)pyrrolidine- tert-butyl 1-carboxylate (6.80 g, 11.71 mmol), methylboronic acid (7.05 g, 117.10 mmol), palladium acetate (0.40 g, 1.76 mmol), and tricyclohexyl phosphonium (1.30 g, 3.51 mmol) in anhydrous 1,4-dioxane (117 ml) was added potassium phosphate (12.49 g, 59.00 mmol). The reaction mixture was degassed by sparging with nitrogen for 5 min and then heated to 90 °C for 4 h. After cooling to room temperature, the reaction mixture was filtered through a Celite filter. The filter plug was washed with ethyl acetate (150 ml) and the combined filtrate concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 10 to 50% ethyl acetate in hexanes to give the title compound as a colorless solid (6.23 g, 96% yield): MS (ES+) m/z 557.3 (M + 1).

[01904]Step 3. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-3-fluoro-2-methylphenyl)(methyl) amino)pyrrolidine-1-tert-butylcarboxylate

[01905] To a solution of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-3-fluoro-2-methylphenyl)amino)pyrrolidine- tert-Butyl 1-carboxylate (6.23 g, 11.20 mmol) in anhydrous N,N-dimethylformamide (22 ml) was added iodomethane (1.40 ml, 22.41 mmol), followed by sodium hydride (0 .67 g, 16.80 mmol). The reaction mixture was stirred at room temperature for 16 h and then quenched by addition of methanol (5 ml). Concentration in vacuo and purification of the residue by column chromatography, eluting with a gradient of 10 to 50% ethyl acetate in hexanes, gave the title compound as a light brown foam (5.84 g, 91% yield ): MS (ES+) m/z 571.2 (M + 1).

[01906]Step 4. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-3-methyl-N-(thiazol) 2,2,2-trifluoroacetate -4-yl)benzenesulfonamide

[01907] To a solution of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-3-fluoro-2-methylphenyl)(methyl)amino )tert-butyl pyrrolidine-1-carboxylate (5.30 g, 9.36 mmol) in dichloromethane (10 ml) trifluoroacetic acid (5 ml) was added and the reaction mixture was stirred at room temperature for 16 h. Concentration in vacuo provided a residue, which was used without further purification. The residue was dissolved in anhydrous N,N-dimethylformamide (18 ml), and benzaldehyde (1.99 g, 18.73 mmol) and sodium triacetoxyborohydride (5.96 g, 28.10 mmol) were added thereto. The reaction mixture was stirred at room temperature for 16 h and then quenched by addition of 5% aqueous lithium chloride (25 ml). The mixture was extracted with ethyl acetate (7 x 25 ml), and the combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and a portion of the residue purified by preparative reverse phase HPLC, eluting with water in acetonitrile to obtain the title compound as a colorless solid (0.31 g, 6% yield): 1H NMR (300 MHz, DMSO-d6) δ 11.27 (t, J = 0.7 Hz, 1H), 8.89 (d, J = 2.2 Hz, 1H), 7.60 (t, J = 8.0 Hz, 3H), 7.43 to 7.43 (m, 3H), 6.97 (q, J = 2.7 Hz, 2H), 4.38 to 4.31 (m, 2H), 4.23 to 4.07 (m, 1H), 3.38 (s, 4H), 2.66 (s, 3H), 2.14 to 2.06 (m, 5H); MS (ES+) m/z 461.2 (M + 1). Note: acidic protons not observed. EXAMPLES 322 TO 324

[01908] In a similar manner as described in EXAMPLE 321, Step 4, with the use of appropriately substituted starting materials and intermediates, the following compounds were prepared: EXAMPLES 325 TO 327

[01909] In a similar way as described in EXAMPLE 29, Step 4, with the use of appropriately substituted starting materials and intermediates, the following compounds were prepared: EXAMPLE 328

[01910] Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-2-fluoro-N-(thiazol-4-) 2,2,2-trifluoroacetate il)benzenesulfonamide

[01911]Step 1. Preparation of (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-3-fluorophenyl)(methyl) amino)pyrrolidine-1-tert-butylcarboxylate

[01912] Following the procedure as described in EXAMPLE 321, Step 3 and making variations as necessary to replace (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl )-3-fluoro-2-methylphenyl)amino)pyrrolidine-1-tert-butyl carboxylate by (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl )-2-chloro-3-fluorophenyl)amino)pyrrolidine-1-tert-butylcarboxylate, the title compound was obtained as a colorless solid (0.70 g, 86% yield): 1H NMR (300 MHz, CDCl3 ) δ8.81 to 8.80 (m, 1H), 7.96 to 7.91 (m, 1H), 7.55 (d, J = 2.3 Hz, 1H), 6.98 to 6.94 (m, 1H), 4.24 to 4.19 (m, 1H), 3.68 to 3.54 (m, 2H), 3.38 to 3.28 (m, 2H), 2.87 (s , 3H), 2.11 to 2.03 (m, 2H), 1.47 (s, 9H), 1.35 (s, 9H).

[01913]Step 2. Preparation of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-3-chloro-2-fluoro-N-(thiazol) 2,2,2-trifluoroacetate -4-yl)benzenesulfonamide

[01914] Following the procedure as described in EXAMPLE 321, Step 4 and making variations as necessary to replace (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl )-3-fluoro-2-methylphenyl)amino)pyrrolidine-1-tert-butyl carboxylate by (S)-3-((4-(N-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl )- tert-butyl 2-chloro-3-fluorophenyl)(methyl)amino)pyrrolidine-1-carboxylate, the title compound was obtained as a colorless solid (0.12 g, 45% yield): 1H-NMR ( 300 MHz, DMSO-d6) δ 8.87 (d, J = 2.2 Hz, 1H), 7.61 (t, J = 8.5 Hz, 1H), 7.32 to 7.22 (m, 5H), 6.98 to 6.96 (m, 2H), 5.76 (s, 1H), 4.22 to 4.12 (m, 1H), 3.68 to 3.49 (m, 2H) , 2.81 (s, 3H), 2.77 to 2.54 (m, 3H), 2.39 to 2.30 (m, 1H), 2.12 to 2.04 (m, 1H), 1 .88 to 1.76 (m, 1H), NH not observed; MS (ES+) m/z 481.0 (M + 1), 483.0 (M + 1).

BIOLOGICAL TESTS

[01915] Various techniques are known for testing the activity of the compound of the invention or determining its solubility in known pharmaceutically acceptable excipients. In order that the invention described herein may be more fully understood, the following biological assays are presented. It should be understood that these examples are for illustrative purposes only and should not be construed in any way as limiting this invention.

BIOLOGICAL EXAMPLE 1 Electrophysiological Assay (in vitro Assay)

[01916] Ion channel clamp electrophysiology allows direct measurement and quantification of voltage-gated sodium channels (NaV's), and allows the determination of time dependence and block voltage that has been interpreted as differential binding to resting states, open and inactive sodium channel (Hille, B., Journal of General Physiology (1977), 69: 497 to 515).

[01917] The following ion channel clamping electrophysiology studies were performed on representative compounds of the invention using human embryonic kidney (HEK) cells, permanently transfected with an expression vector containing the full-length cDNA encoding the channel α subunit. desired human sodium in culture medium containing 10% FBS, 1% PSG and 0.5 mg/ml G418 at 37 °C with 5% CO2. HEK cells used for electrophysiology (EP) recordings had a passage number of less than 40 for all studies and were used within three days from the time of plating. The cDNAs of NaV1.1, NaV1.5, and NaV1.6 (NM_001165964 (SCN1A), NM_000335 (SCN5A), and NM_014191 (SCN8A), respectively) were stably expressed in HEK-293 cells.

[01918] Sodium currents were measured using the ion channel clamping technique in the whole cell configuration using a PatchXpress automatic voltage clamp or manually using an Axopatch 200B (Axon Instruments) or Model 2400 (A-M systems) amplifier. The manual voltage clamping protocol was as follows: Borosilicate glass micropipettes were fire polished to a tip diameter, producing a resistance of 2 to 4 Mohms in the working solutions. The pipette was loaded with a solution comprising: 5 mM NaCl, 10 mM CsCl, 120 mM CsF, 0.1 mM CaCl2, 2 mM MgCl2, 10 mM HEPES, 10 mM EGTA; and adjusted to pH 7.2 with CsOH. The external solution had the following composition: 140 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES; and adjusted to 7.4 with NaOH. In some studies, external sodium was reduced by equimolar substitution for choline. The osmolarity in the external CsF and NaCl solutions was adjusted to 300 mOsm/kg and 310 mOsm/kg with glucose, respectively. All recordings were performed at room temperature in a bath chamber with a volume of 150 μl. Control sodium currents were measured in 0.5% DMSO. Controls and compounds representative of the invention were applied to the recording chamber via a 4-clamp or 8-clamp valve bath perfusion system produced by ALA Scientific Instruments.

[01919] Currents were recorded at a sampling frequency of 40 kHz, filtered at 5 Hz, and stored using a Digidata-1322A analog/digital interface with pClamp software (Axon Instruments). A series resistance compensation was applied (60 to 80%). Cells are rejected if the currents show inadequate voltage control (as judged by the IV ratio during gradual activation). All statistics in these studies are provided as the mean ± SD.

[01920] The membrane potential was maintained at a voltage at which channel inactivation is complete. The voltage is then stepped back to a very negative voltage (Vhold = -150mV) for 20 ms and then a test pulse is applied to quantify the compound block. The brief 20 ms repolarization was long enough for the compound-free channels to fully recover from the rapid inactivation, but the compound-bound channels recovered more slowly so that negligible recovery could occur during this interval. The percentage reduction in sodium current after compound washing was used as the percentage of sodium channel blockade.

[01921] The representative compounds of the invention, when tested in this assay, demonstrated the IC50's as shown in Table 9.

BIOLOGICAL EXAMPLE 2 Sodium Influx Assay (in vitro Assay)

[01922] This sodium influx assay employs the use of the cell-permeable, sodium-sensitive ANG2 dye to quantify the influx of sodium ions that are maintained in an open state by the use of sodium channel modulators. This high-throughput sodium influx assay allows for rapid profiling and characterization of sodium channel blockers.

[01923] In general, Trex HEK293 cells were stably transfected with an inducible expression vector containing the full-length cDNA encoding the desired human sodium channel subunit and with an expression vector containing the full-length cDNA encoding the β1 subunit. Sodium channel expressing cell lines were induced with tetracycline (1μg/ml) and seeded in PDL-coated 384-well plates at a density of 25K to 30K cells/well in culture medium (DMEM, containing 10% FBS and 1% L-glutamine). After overnight incubation (37°C, 5% CO2), the culture medium was removed and cells were loaded with 5uM ANG2 dye for 1 to 1.5h in Buffer 1 (155mM NMDG, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM glucose, adjusted with Tris to pH 7.4). Access dye was removed and cells were incubated with test compounds for 1 h in buffer 1 containing sodium channel modulator(s) at room temperature. Hamamatsu FDSS μCell was used to perform a 1:1 addition of Na/K challenge buffer (140 mM NaCl, 20 mM HEPES, 1 mM CaCl2, 15 mM KCl, 1 mM MgCl2, 10 mM glucose, adjusted with Tris at pH 7.4) and plates simultaneously read at an excitation wavelength of 530 nm and an emission wavelength adjusted at 558 nm. The percentage inhibition of sodium ion influx was calculated for each test compound at each test concentration to determine IC50 values.

[01924] The representative compounds of the invention, when tested in this model, demonstrated affinities with the inactivated state of NaV1.6, NaV1.5 and NaV1.1 as shown below in Table 9.

[01925] The Example numbers provided in Table 1 below correspond to the Examples in this document, "Flow" refers to the Sodium Influx Assay and "EP" refers to the Electrophysiological Assay. The IC50 values mentioned are arithmetic mean values. :TABLE 1: Inhibition of Nav1.6, Nav1.5 and Nav1.1

BIOLOGICAL EXAMPLE 3 Electrical Stimulation Seizure Trials

[01926] Many electrical stimulation tests have been used to identify compounds with anticonvulsant activity, that is, which raise the seizure threshold. Two examples of electrical stimulation seizure assays frequently used in the field are the 6Hz psychomotor seizure assay (6Hz) and the Maximum Electroshock Induced Seizure (MES). The 6Hz assay is considered a model of partial seizures observed in humans (Loscher, W and Schmidt, D., Epilepsy Res. (1988), Vol. 2, pp 145 to 81; Barton, M.E. et al., Epilepsy Res (2001), Vol. 47, pp. 217-27). The MES assay is a model of generalized tonic-clonic seizures in humans and provides an indication of the ability of a compound to prevent seizure spread when all neuronal circuits in the brain are maximally activated. These seizures are highly reproducible and are electrophysiologically compatible with human seizures (Toman et al., 1946; Piredda et al., 1984; White et al., 1995). Experiments can be performed with healthy animals, or with seizure-prone animals that have been genetically modified to model genetic epilepsy syndromes (Piredda, S. G. et al., J. Pharmacol. Exp. Ther. (1985), Vol. 232, pp 741 to 5; Toman, J. E. et al., J. Neurol. Vol. 16 (1 to 2), pp. 73 to 7).

[01927] To facilitate testing, mice can be pretreated with the test compound or appropriate vehicle prior to application of electroshock. Each treatment group (n = 4 to 8 mice/group) is examined for anticonvulsant effects at different time points after compound and vehicle administration. The eyes of the mice are first anesthetized with a topical application of 0.5% Alcaine (proparacaine hydrochloride), one drop in each eye 30 minutes before stimulation. Seizures are then induced by placing electrodes in the eyes that release a transcorneal current.

The 6Hz Psychomotor Seizure test

[01928] After pretreatment, each mouse is challenged with low-frequency stimulation (6 Hz, 0.3 ms pulse width) for 3 seconds delivered through corneal electrodes at various intensities (12 to 44 mA) . Animals are manually restrained and released immediately after stimulation and observed for the presence or absence of seizure activity. Typically, 6 Hz stimulation results in a seizure characterized by a minimal clonic phase that is followed by stereotyped automatic behaviors, including spasms of the vibrissae and Straub's tail, or by a generalized tonic-clonic seizure. The presence, type, and seizure latency (in seconds) after current application are monitored. Animals that do not exhibit a generalized tonic-clonic seizure are considered “protected.” All animals are euthanized at the end of the trial. Plasma and brain samples are collected.

Maximum Electroshock Test (MES):

[01929] After pretreatment, each mouse is challenged with an alternating current (60 Hz, 0.4 to 0.6 ms pulse width) for 0.2 to 0.5 seconds delivered through corneal electrodes in intensities (44 to 55 mA).

[01930] Typically, MES stimulation results in a generalized tonic seizure that may be followed by a clonic seizure, automatic behaviors and Straub's tail. The presence, type, and seizure latency (in seconds) after current application are monitored. An animal is considered “protected” against MES-induced seizures by abolishing the tonic hindlimb extensor component of the seizure. After the seizure, mice are expected to resume normal exploratory behavior within 1 to 4 minutes. Latency to seizure is recorded with a cutoff value of 1 minute, after which all animals are euthanized.* * * * *

[01931] All US patents, US patent application publications, US patent applications, foreign patents, foreign patent applications and non-patent publications mentioned are incorporated herein by reference in their entirety.

[01932] Although the previous invention has been described in some detail to facilitate understanding, it will be evident that certain changes and modifications can be made within the scope of the attached claims. Accordingly, the described embodiments should be considered as illustrative and not restrictive, and the invention should not be limited to the details presented herein, but may be modified within the scope and equivalents of the appended claims.

Claims (9)

1. Compound, CHARACTERIZED by the fact that it is (S)-4-((1-benzylpyrrolidin- 3-yl)(methyl)amino)-2-fluoro-5-methyl-N-(thiazol-4-yl)benzenesulfonamide , or a pharmaceutically acceptable salt or solvate thereof. 2. Pharmaceutical composition, CHARACTERIZED by the fact that it comprises a pharmaceutically acceptable excipient and the compound or a pharmaceutically acceptable salt or solvate thereof, as defined in claim 1. 3. Use of a compound or a pharmaceutically acceptable salt or solvate thereof, as defined in claim 1, CHARACTERIZED by the fact that it is for the preparation of a medicament for the treatment of epilepsy and/or epileptic seizure disorder in a mammal. 4. Compound, according to claim 1, CHARACTERIZED by the fact that it is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-( thiazol-4-yl)benzenesulfonamide, or a pharmaceutically acceptable salt thereof. 5. Pharmaceutical composition, CHARACTERIZED by the fact that it comprises a pharmaceutically acceptable excipient and the compound or a pharmaceutically acceptable salt thereof, as defined in claim 4. 6. Use of a compound or a pharmaceutically acceptable salt thereof, as defined in claim 4, CHARACTERIZED by the fact that it is for the preparation of a medicament for the treatment of epilepsy and/or epileptic seizure disorder in a mammal. 7. Compound, according to claim 1, CHARACTERIZED by the fact that it is (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2-fluoro-5-methyl-N-( thiazol-4-yl)benzenesulfonamide. 8. Pharmaceutical composition, CHARACTERIZED by the fact that it comprises a pharmaceutically acceptable excipient and the compound as defined in claim 7. 9. Use of a compound, as defined in claim 7, CHARACTERIZED by the fact that it is for the preparation of a medicament for the treatment of epilepsy and/or epileptic seizure disorder in a mammal.