DIARYLSULFONE SULFONAMIDES AND USE THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. application serial number

60/681,080, filed May 13, 2005, and U.S. application serial number , filed May

10, 2006, which are incorporated herein in their entireties.

FIELD OF THE INVENTION

[0002] The present invention relates to novel diarylsulfone sulfonamides that act, for example, as modulators of secreted frizzled-related protein- 1. The present invention also relates to processes for the preparation of diarylsulfone sulfonamides and to their use in treating various diseases and disorders.

BACKGROUND OF THE INVENTION

[0003] Bone remodeling, the process by which the adult human skeleton is continuously renewed, is carried out by osteoclasts and osteoblasts, two specialized cell types that originate from hematopoietic and mesenchymal progenitors of the bone marrow, respectively. A continuous and orderly supply of these cells is believed to be essential for skeletal homeostasis, as increased or decreased production of osteoclasts or osteoblasts and/or changes in the rate of their apoptosis are largely responsible for the imbalance between bone resorption and formation that underlies several systemic or localized bone diseases. For example, enhanced osteoclast activity has been found to play a major role in the pathogenesis of

postmenopausal osteoporosis, Paget's disease, lytic bone metastases, multiple myeloma, hyperparathyroidism, rheumatoid arthritis, periodontitis, and hypercalcemia of malignancy.

[0004] Numerous genes and gene families (and the polypeptides encoded by them) that participate in the regulation of bone cell production and apoptosis have been identified. Wnt proteins have been identified as a family of growth factors consisting of more than a dozen structurally related molecules that are involved in the regulation of fundamental biological processes such as apoptosis, embryogenesis, organogenesis, morphogenesis and tumorigenesis (Nusse and Varmus, Cell 1992, 69:1073-1087). Wnt polypeptides are multipotent factors and have biological activities similar to those of other secretory proteins such as transforming growth factor (TGF)-β, fibroblast growth factors (FGFs), nerve growth factor (NGF), and bone morphogenetic proteins (BMPs).

[0005] Studies indicate that certain Wnt proteins interact with a family of proteins named "frizzled" that act as receptors for Wnt proteins or as components of a Wnt receptor complex (in Moon et al, Cell 1997, 88:725-728; Barth et al, Curr. Opin. Cell Biol. 1997, 9:683- 690). Frizzled proteins contain an amino terminal signal sequence for secretion, a cysteine-rich domain (CRD) that is thought to bind Wnt, seven putative transmembrane domains that resemble a G-protein coupled receptor, and a cytoplasmic carboxyl terminus. The Frizzled receptors form a signaling complex with another family of membrane receptors known as the low-density lipoprotein (LDL) receptor-related proteins (LRP) (in Logan & Nusse, Annual Review of Cell & Developmental Biology 2004, 20:781-810; Moon et al, Nature Reviews Genetics 2004, 5:691- 701).

[0006] The first secreted frizzled-related protein (SFRP) was named "Frzb" (for "frizzled motif in bone development") and was purified and cloned from bovine articular cartilage extracts based on its ability to stimulate in vivo chondrogenic activity in rats (Hoang et al, J. Biol Chem. 1996, 271 :26131-26137; Jones & Jomary, Bioessays 2002, 24:811-820). The human homologue of the bovine gene has also been cloned. Unlike the frizzled proteins, however, Frzb does not contain a serpentine transmembrane domain, and appears to be a secreted receptor for Wnt. The Frzb cDNA encodes a 325 amino acid/36,000 dalton protein and is predominantly expressed in the appendicular skeleton. The highest level of expression is in developing long bones and corresponds to epiphyseal chondroblasts; expression declines and disappeares toward the ossification center.

[0007] Studies indicate that SFRPs participate in apoptosis. Some SFRPs have thus been identified as "SARPs" for secreted apoptosis related proteins. Additional members of the SFRP family have been identified, and have been shown to be antagonists of Wnt action. There are currently at least five known human SFRP/SARP genes: SFRP-l/FrzA/FRP-l/SARP-2, SFRP-2/SDF-5/SARP-1, SFRP-3/Frzb-l/FrzB/Fritz, SFRP-4 and SFRP-5/SARP-3 (Leimeister et ah, Mechanisms of Development 1998, 75:29-42). Secreted frizzled related protein-1 (SFRP- 1) is a Wnt antagonist and is expressed in osteoblasts and osteocytes. Although the precise role that SARPs/SFRPs play in apoptosis is not yet clear, these proteins appear to either suppress or enhance the programmed cell death process. Deletion of SFRP-I in mice has been shown to lead to decreased osteoblast/osteocyte apoptosis and to increased bone formation. (Bodine, P.V.N, et al, MoL Endocrinol, 2004, 18(5) 1222-1237.)

[0008] A need exists in the art for the identification of modulators of SFRP-I that can be used as novel agents for the treatment of bone disorders, including bone resorption disorders such as osteoporosis, and for regulation of bone formation in humans.

SUMMARY OF THE INVENTION

[0009] The present invention relates to certain diarylsulfone sulfonamides and to their use, for example, in medical treatment. In one aspect, the invention relates to diarylsulfone sulfonamides that act as modulators of secreted frizzled related protein-1. The compounds can be used, for example, to treat bone disorders such as osteoporosis.

[0010] In certain aspects, the present invention is directed to compounds of Formula

(1):

(1) or a pharmaceutically acceptable salt thereof, wherein

R ₁ is

and each R ₁ group is optionally substituted with up to three R ₈ groups;

Y is O, S, or NR ₉ ;

R ₈ is alkyl, arylalkyl, perfluoroalkyl, alkenyl, arylalkenyl, alkynyl, arylalkynyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, aryl, alkylaryl, heteroaryl, alkoxy, perfluoroalkoxy, arylalkoxy, alkylcarbonyl, arylcarbonyl, halogen, cyano, azido, hydroxyl, carboxy, alkoxycarbonyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaniinocarbonyl, alkylcarbonylamino, alkylcarbonylalkylamino, hydroxyalkylamino, nitro, alkylcarbonyloxime, alkylsulfonyl, alkylsulfinyl, alkylthio, perfluoroalkylthio, arylthio, tertiary alkylcarbinol, tertiary alkylcycloalkylcarbinol, or tertiary arylalkylcarbinol;

R ₉ is hydrogen, alkyl, aryl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, or spirocycloalkyl;

X is oxygen or an electron pair;

R ₂ is hydrogen, alkyl, alkoxy, cycloalkyl, perfluoroalkyl, perfluoroalkylalkyl, perfluoroalkoxy, dialkylamino, or halogen;

R ₄ is hydrogen, halogen, alkyl, cycloalkyl, alkoxy, perfluoroalkyl, or perfluoroalkoxy; or R ₂ and R ₄ , together with the carbon atoms to which they are attached, form a cycloalkyl ring of 5 to 7 carbon atoms that is optionally substituted with 1 to 3 R groups; each R is, independently, hydrogen, alkyl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, spirocycloalkyl, aryl, arylalkyl, or alkoxyalkyl;

R ₅ , and R ₆ are, independently, hydrogen, alkyl, aryl, alkoxy, halogen, or perfluoroalkyl;

R ₃ and R ₇ are each, independently, hydrogen or an optionally substituted alkyl, cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, heteroarylalkyl, alkylaryl, alkylheteroaryl, alkenyl, alkynyl, fused cycloalkylaryl, fused heterocycloalkylaryl, cycloalkylcarbonyl, or heterocycloalkylcarbonyl group;

or Ra and R ₇ , together with the nitrogen atom to which they are attached, form a five or six membered heterocycloalkyl ring optionally substituted with 1 to 5 substituents selected from alkyl, aryl, heterocycloalkyl, heterocycloalkylalkyl, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonylalkyl, and heterocycloalkylcarbonylalkyl.

[0011] In other embodiments, the invention relates to compositions comprising at least one compound of Formula 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents, or carriers.

[0012] The present invention also provides methods for treating patients suffering from osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, or leiomyoma that comprise administering to the patients a therapeutically effective amount of at least one compound of Formula 1.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0013] The term "alkyl," as used herein, refers to an optionally substituted aliphatic hydrocarbon chain having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 4 carbon atoms. The term "alkyl" includes straight and branched chains. Straight chain alkyl groups have 1 to 8 carbon atoms and branched chain alkyl groups have 3 to 12 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl groups.

[0014] The term "hydroxyalkyl," as used herein, refers to the group -alkyl-OH where alkyl is an alkyl group as previously defined.

[0015] The term "carboxyalkyl," as used herein, refers to the group -alkyl-C(O)OH where alkyl is an alkyl group as previously defined.

[0016] The term "haloalkyl," as used herein, refers to the group -alkyl-halo where halo is a halogen atom and alkyl is an alkyl group as previously defined.

[0017] The term "perfluoroalkyl," as used herein, refers to an optionally substituted straight or branched aliphatic hydrocarbon chain of 1 to 8 carbon atoms and preferably 1 to 3 carbon atoms, in which all hydrogens are replaced with fluorine.

[0018] The term "perfluoroalkylalkyl," as used herein, refers to the group -alkyl- perfluoroalkyl where alkyl and perfluoroalkyl are as previously defined.

[0019] The term "alkenyl," as used herein, refers to an optionally substituted aliphatic straight or branched hydrocarbon chain having 2 to 12 carbon atoms that contain 1 to 3 double

bonds. Straight chain alkenyl groups have 2 to 8 carbon atoms and branched chain alkenyl groups have 3 to 12 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, prop-1-enyl, allyl, but-1-enyl, but-2-enyl, but-3-enyl, 3,3-dimethylbut-l-enyl, or 2- methylvinyl.

[0020] The term "alkynyl," as used herein, refers to an optionally substituted aliphatic straight or branched hydrocarbon chain having 2 to 8 carbon atoms that contains 1 to 3 triple bonds. Straight chain alkynyl groups have 2 to 8 carbon atoms and branched chain alkynyl groups have 5 to 12 carbon atoms.

[0021] The term "cycloalkyl," as used herein, refers to an optionally substituted hydrocarbon ring containing 3 to 12 carbon atoms and preferably 3 to 6 carbon atoms. Cycloalkyl groups may be monocyclic or bicyclic, and may be saturated or partially saturated. The term "bicycloalkyl," as used herein, refers to a bicyclic cycloalkyl group of 8 to 12 ring carbon atoms. "Bridged" cycloalkyl groups contain at least one carbon-carbon bond between two non-adjacent carbon atoms of the cycloalkyl ring.

[0022] The term "alkylcycloalkyl," as used herein, refers to the group -cycloalkyl- (alkyl)n in which n is 1 to 3, cycloalkyl is a cycloalkyl group as previously defined, and alkyl is an alkyl group as previously defined.

[0023] The term "cycloalkylalkyl," as used herein, refers to the group -alkyl-cycloalkyl in which alkyl is an alkyl group as previously defined and cycloalkyl is a cycloalkyl group as previously defined.

[0024] The term "spirocycloalkyl," as used herein, refers to two optionally substituted cycloalkyl groups as previously defined that are joined by a single sp3 carbon atom that is the only common member of the two joined rings.

[0025] The term "heterocycloalkyl," as used herein, refers to a 3 to 12 membered, and more preferably 5 to 7 membered optionally substituted cycloalkyl group in which one to three carbon atoms of the cycloalkyl group are replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur, including sulfoxide and sulfonyl. The heterocycloalkyl group may be saturated or partially saturated, and may be monocyclic or bicyclic. The term "heterobicycloalkyl" refers to the bicyclic structure formed when a heterocycloalkyl group is fused to another heterocycloalkyl group, to a cycloalkyl group, to an aryl group, or to a heteroaryl group. Heterobicycloalkyl groups have 8 to 12 ring atoms. "Bridged"

heterocycloalkyl groups contain at least one carbon-carbon bond between non-adjacent carbon atoms of the heterocycloalkyl ring.

[0026] The term "alkylheterocycloalkyl," as used herein, refers to the group -heterocycloalkyl-(alkyl) _n in which n is 1 to 3, heterocycloalkyl is a heterocycloalkyl group as previously defined, and alkyl is an alkyl group as previously defined.

[0027] The term "heterocycloalkylalkyl," as used herein, refers to the group -R'-heterocycloalkyl where R' is an alkyl group as previously defined and heterocycloalkyl is a heterocycloalkyl group as previously defined.

[0028] The term "aryl," as used herein refers to an optionally substituted carbocyclic aromatic ring. Aryl groups may be monocyclic or bicyclic. Exemplary aryl groups include phenyl and naphthyl.

[0029] The term "carboxyaryl," as used herein, refers to the group -aryl-C(O)OH, where aryl is an aryl group as previously defined.

[0030] The term "heteroaryl," as used herein refers to an optionally substituted 5 to 10 membered monocyclic or bicyclic carbon containing aromatic ring having 1 to 3 of its ring members independently selected from nitrogen, sulfur and oxygen. Monocyclic rings preferably have 5 to 6 members and bicyclic rings preferably have 8 to 10 membered ring structures. Examples of heteroaryls include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, quinolyl, isoquinolyl, quinoxalinyl, and quinazolinyl.

[0031] The term "alkylheteroaryl," as used herein, refers to the group -heteroaryl-alkyl wherein heteroaryl is a heteroaryl group as previously defined and alkyl is an alkyl group as previously defined.

[0032] The term "arylcarbonylalkyl," as used herein, refers to the group R'-C(O)-aryl where R' is an alkyl group as previously defined and aryl is an aryl group as previously defined.

[0033] The term, "fused cycloalkylaryl," as used herein, refers to a cycloalkyl group as previously defined fused to an aryl group of five or six carbon atoms as previously defined or fused to a heteroaryl group of five or six atoms as previously defined. The point of attachment can occur at any generally acceptable position.

[0034] The term, "fused cycloalkylarylaminocarbonyl," as used herein, refers to the group -C(O)-NH-fused cycloalkylaryl where fused cycloalkylaryl is a fused cycloalkylaryl group as previously defined.

[0035] The term, "fused hetercycloalkylaryl," as used herein, refers to a heterocycloalkyl group as previously defined fused to an aryl group of five or six carbon atoms as previously defined or fused to a heteroaryl group of five or six atoms as previously defined. The point of attachment can occur at any generally acceptable position.

[0036] The term "fused hetercycloalkylarylcarbonyl," as used herein, refers to the group -C(O)- fused hetercycloalkylaryl where fused hetercycloalkylaryl is a fused hetercycloalkylaryl group as previously defined.

[0037] The term "alkylcarbonyl," as used herein, refers to the group -C(O)R' where R' is an alkyl group as previously defined.

[0038] The term "alkylthioalkylcarbonyl," as used herein, refers to the group -C(O)-R' -S-R' where R' is an alkyl group as previously defined.

[0039] The term "alkylcarbonylamino," as used herein, refers to the group -NHC(O)R' where R' is an alkyl group as previously defined.

[0040] The term "alkoxycarbonylamino," as used herein, refers to the group -NHC(O)OR' where R' is an alkyl group as previously defined.

[0041] The term "alkylcarbonylalkylamino," as used herein, refers to the group -NH-R' -C(O)R' where R' is an alkyl group as previously defined.

[0042] The term "alkylsulfonylamino," as used herein, refers to the group -NH ₂ -S(O) ₂ -R' where R' is an alkyl group as previously defined.

[0043] The term "carboxyarylsulfonylamino," as used herein, refers to the group -NH ₂ -S(O) ₂ -aryl-C(O)OH where aryl is an aryl group as previously defined.

[0044] The term "alkylcarbonyloxime," as used herein, refers to the group -C(N=OR' )R' where R' is an alkyl group as previously defined.

[0045] The term "alkoxy," as used herein, refers to the group -O-R' where R' is an alkyl group as previously defined.

[0046] The term "perfluoroalkoxy," as used herein, refers to the group -O-R" where R" is a perfluoroalkyl group as previously defined.

[0047] The terms "amino," "alkylamino," "dialkylamino," and "imino," as used herein, refer to the groups -NH ₂ , -NHR', -N(R') ₂ , and -C=NH, respectively, where each R' is, independently, an alkyl group as previously defined.

[0048] The term "aminoalkyl," as used herein, refers to the group -R ⁵ NH ₂ where R' is an alkyl group as previously defined.

[0049] The term "alkylcarbinol," as used herein, refers to an alkyl group as previously defined substituted with a hydroxy 1 group.

[0050] The term "carboxy," as used herein, refers to the group -COOH.

[0051] The term "carbonyl," as used herein, refers to a bivalent carbon atom that is further bonded to an oxygen atom through a double bond.

[0052] The term "thiocarbonyl," as used herein, refers to a bivalent carbon atom that is further bonded to a sulfur atom through a double bond.

[0053] The terms "halogen" or "halo," as used herein, refer to chlorine, bromine, fluorine or iodine.

[0054] The term "cyano" or "cyanoalkyl," as used herein, refers to the group -CN or -R'-CN where R' is an alkyl group as previously defined.

[0055] The term "alkoxyalkyl," as used herein, refers to the group -R'-alkoxy where R' is an alkyl group as previously defined and alkoxy is an alkoxy group as previously defined.

[0056] The term "arylalkyl," as used herein, refers to the group -R'-aryl where aryl is an aryl group as previously defined, and R' is an alkyl group as previously defined.

[0057] The term "heteroarylalkyl," as used herein, refers to the group -R'-heteroaryl where heteroaryl is a heteroaryl group as previously defined, and R' is an alkyl group as previously defined.

[0058] The term "arylalkenyl," as used herein, refers to the group -alkenyl-aryl where aryl is an aryl group as previously defined, and alkenyl is an alkenyl group as previously defined.

[0059] The term "arylalkynyl," as used herein, refers to the group -alkynyl-aryl where aryl is an aryl group as previously defined, and alkynyl is an alkynyl group as previously defined.

[0060] The term "arylalkoxy," as used herein, refers to the group -alkoxy-aryl where aryl is an aryl group as previously defined and alkoxy is an alkoxy group as previously defined. The term "benzoxy" refers to the group -O-CH ₂ -phenyl.

[0061] The term "aminocarbonylalkoxy," as used herein, refers to the group -alkoxy- C(O)NH ₂ where alkoxy is an alkoxy group as previously defined.

[0062] The term "alkoxycarbonylalokxy," as used herein, refers to the group -alkoxy- C(O)-alkoxy where alkoxy is an alkoxy group as previously defined.

[0063] The term "carboxyalkoxy," as used herein, refers to the group -alkoxy-C(O)OH where alkoxy is an alkoxy group as previously defined.

[0064] The term "arylalkylcarbonyl," as used herein, refers to the group -alkylcarbonyl- aryl wherein alkylcarbonyl is an alkylcarbonyl group as previously defined and aryl is an aryl group as previously defined.

[0065] The term "arylcarbonyl," as used herein, refers to the group -C(O)-aryl, where aryl is an aryl group of 6 to 10 carbon atoms as previously defined.

[0066] The term "dialkylaminoarylcarbonyl," as used herein, refers to the group -arylcarbonyl-N(R')(R') where arylcarbonyl is an arylcarbonyl group as previously defined.

[0067] The term "arylthio," as used herein, refers to the group -S-aryl where aryl is an aryl group as previously defined.

[0068] The term "arylthiol," as used herein, refers to the group HS-aryl where aryl is an aryl group as previously defined.

[0069] The term "arylsulfonyl," as used herein, refers to the group -S(O)2-aryl where aryl is an aryl group as previously defined.

[0070] The term "arylsulfonylarylsulfonyl," as used herein, refers to the group -S(O) ₂ -aryl-S(O) ₂ -aryl where aryl is an aryl group as previously defined.

[0071] The term "carboxyarylsulfonyl," as used herein, refers to the group -S(O) ₂ -aryl-C(O)OH where aryl is an aryl group as previously defined.

[0072] The term "aminosulfonyl," as used herein, refers to the group -S(O) ₂ -NH ₂ .

[0073] The term "heteroarylsulfonyl," as used herein, refers to the group -S(O) ₂ -heteroaryl where heteroaryl is a heteroaryl group as previously defined.

[0074] The term "arylester," as used herein, refers to the group -C(O)O-aryl where aryl , is an aryl group as previously defined.

[0075] The term "alkylcarbonyl," as used herein, refers to the group -C(O)R' where R' is an alkyl group as previously defined.

[0076] The term "alkylthiocarbonyl," as used herein, refers to the group -C(S)R' where R' is an alkyl group as previously defined.

[0077] The term "alkylaminoalkylcarbonyl," as used herein, refers to the group -C(O)R ⁵ NH(R') where R' is an alkyl group as previously defined.

[0078] The term "dialkylaminoalkylcarbonyl," as used herein, refers to the group -C(O)R'N(R')(R') where R' is an alkyl group as previously defined.

[0079] The term "perfluoroalkylcarbonyl," as used herein, refers to the group -C(O)R" where R" is a perfluoroalkyl group as previously defined.

[0080] The term "carboxyalkylcarbonyl," as used herein, refers to the group -C(O)R ⁵ C(O)OH where R' is an alkyl group as previously defined.

[0081] The term "alkoxycarbonyl," as used herein, refers to the group -C(O)OR ⁵ where R ⁵ is an alkyl group as previously defined.

[0082] The term "alkoxythiocarbonyl," as used herein, refers to the group -C(S)OR ⁵ where R ⁵ is an alkyl group as previously defined.

[0083] The term "alkoxycarbonylalkyl," as used herein, refers to the group -R ⁵ C(O)OR ⁵ where R ⁵ is an alkyl group as previously defined.

[0084] The term "arylcarbonyl, ⁵⁵ as used herein, refers to the group -C(O)-aryl where aryl is an aryl group as previously defined.

[0085] The term "heteroarylcarbonyl, ⁵⁵ as used herein, refers to the group -C(O)-heteroaryl where heteroaryl is a heteroaryl group as previously defined.

[0086] The term "heteroarylalkylcarbonyl, ⁵⁵ as used herein, refers to the group -C(O)-R ⁵ -heteroaryl where heteroaryl is a heteroaryl group as previously defined and R ⁵ is an alkyl group as previously defined.

[0087] The term "heterocycloalkylalkylcarbonyl, ⁵⁵ as used herein, refers to the group -C(O)-R'-heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined and R ⁵ is an alkyl group as previously defined.

[0088] The term "heterocycloalkylalkylaminothiocarbonyl," as used herein, refers to the group -C(O)-S-NH-R' -heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined and R ⁵ is an alkyl group as previously defined.

[0089] The term "aryloxycarbonyl," as used herein, refers to the group -C(O)-O-aryl where aryl is an aryl group as previously defined.

[0090] The term "aryloxythiocarbonyl," as used herein, refers to the group -C(S)-O-aryl where aryl is an aryl group as previously defined.

[0091] The term "cyanoarylcarbonyl, ⁵⁵ as used herein, refers to the group

-C(O)-aryl-CN where aryl is an aryl group as previously defined.

[0092] The term "arylalkylcarbonyl," as used herein, refers to the group -C(O)-R'-aryl where R' is an alkyl group as previously defined and aryl is an aryl group as previously defined.

[0093] The term "cycloalkylcarbonyl," as used herein, refers to the group -C(O)-cycloalkyl where cycloalkyl is a cycloalkyl group as previously defined.

[0094] The term "heterocycloalkylcarbonyl," as used herein, refers to the group -C(O)-heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined.

[0095] The term "heterocycloalkylthiocarbonyl," as used herein, refers to the group -C(S)-heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined.

[0096] The term "aminoalkylcarbonyl," as used herein, refers to the group -C(O)-R' -NH ₂ where R' is an alkyl group as previously defined.

[0097] The term "alkoxycarbonylaminothiocarbonyl," as used herein, refers to the group -C(O)-S-NH-C(O)-O-R' where R' is an alkyl group as previously defined.

[0098] The term "alkoxycarbonylalkylaminothiocarbonyl," as used herein, refers to the group -C(O)-S-NH-R'-C(O)-O-R' where R' is an alkyl group as previously defined.

[0099] The term "alkylthiocarbonylalkylcarbonyl," as used herein, refers to the group -C(O)-R' -C(O)-S-R' where R' is an alkyl group as previously defined.

[0100] The term "cyanoalkoxycarbonyl," as used herein, refers to the group -C(O)-alkoxy-CN where alkoxy refers to an alkoxy group as previously defined.

[0101] The term "alkylaryl," as used herein, refers to the group -aryl-R' where R' is an alkyl group as previously defined, and aryl is an aryl group as previously defined.

[0102] The term "alkylester," as used herein, refers to the group -C(O)OR' wherein R' is an alkyl group as previously defined.

[0103] The term "aminocarbonyl," as used herein, refers to the group -C(O)NH ₂ .

[0104] The terms "alkylaminocarbonyl," and "dialkylaminocarbonyl," as used herein, refer to the groups -C(O)NHR' and -C(0)N(R') ₂ , respectively, where each R' is, independently, an alkyl group as previously defined.

[0105] The term "heterocycloalkylaminocarbonyl," as used herein, refers to the group -C(O)NH-heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined.

[0106] The term "carboxyalkylcarbonylheterocycloalkylaminocarbonyl," as used herein, refers to the group -heterocycloalkylaminocarbonyl-C(O)-R'-C(O)OH where heterocycloalkylaminocarbonyl is a heterocycloalkylaminocarbonyl group as previously defined and R' is an alkyl group as previously defined.

[0107] The term "carboxyalkylaminocarbonyl," as used herein, refers to the group -alkylaminocarbonyl-carboxy where carboxy is a carboxy group as previously defined and alkylaminocarbonyl is an alkylaminocarbonyl group as previously defined.

[0108] The term "alkoxycarbonylalkylaminocarbonyl," as used herein, refers to the group -alkylaminocarbonyl -carbonyl-alkoxy where alkoxy is an alkoxy group as previously defined, carbonyl is a carbonyl group as previously defined, and alkylaminocarbonyl is an alkylaminocarbonyl group as previously defined.

[0109] The term "aminocarbonylalkyl," as used herein, refers to the group -R ⁵ C(O)NH ₂ where R' is an alkyl group as previously defined.

[0110] The terms "alkylaminocarbonylalkyl," and "dialkylaminocarbonylalkyl," as used herein, refer to the groups -R ³ C(O)NHR' and -R' C(O)N(R' ) ₂ , respectively, where each R' is, independently, an alkyl group as previously defined.

[0111] The terms "alkylaminothiocarbonyl," and "dialkylaminothiocarbonyl," as used herein, refer to the groups -C(S)NHR' and -C(S)N(R')2, respectively, where each R' is, independently, an alkyl group as previously defined.

[0112] The term "heterocycloalkylcarbonylalkyl," as used herein, refers to the group -R'C(O)heterocycloalkyl where R' is an alkyl group as previously defined and heterocycloalkyl is a heterocycloalkyl group as previously defined.

[0113] The term "arylaminocarbonyl," as used herein, refers to the group - C(O)NH(aryl), where aryl is an aryl group as previously defined.

[0114] The term "heteroarylaminocarbonyl," as used herein, refers to the group -C(O)NH(heteroaryl), where heteroaryl is a heteroaryl group as previously defined.

[0115] The term "heteroarylaminothiocarbonyl," as used herein, refers to the group -C(S)NH(heteroaryl), where heteroaryl is a heteroaryl group as previously defined.

[0116] The term "arylaminothiocarbonyl," as used herein, refers to the group -C(S)NH(aryl), where aryl is an aryl group as previously defined.

[0117] The term "cycloalkylaminocarbonyl," as used herein, refers to an alkylaminocarbonyl or dialkylaminocarbonyl group as previously defined in which at least one alkyl group is replaced by a cycloalkyl group.

[0118] The term "alkylsulfonyl," as used herein, refers to the group -S(O) ₂ -R' where R' is an alkyl group as previously defined.

[0119] The term "alkylsulfmyl," as used herein, refers to the group -S(O)-R' where R' is an alkyl group as previously defined.

[0120] The term "alkylthio," as used herein, refers to the group -S-R' where R' is an alkyl group as previously defined.

[0121] The term "perfluoroalkylthio," as used herein, refers to the group -S-R" where R" is a perfluoroalkyl group as previously defined.

[0122] The term "tertiary alkylcarbinol," as used herein, refers to the group -C(R') ₂ OH where R' is an alkyl group as previously defined.

[0123] The term "tertiary cycloalkylcarbinol," as used herein, refers to the group -C(cycloalkyl) ₂ OH where cycloalkyl refers to a cycloalkyl group as previously defined.

[0124] The term "tertiary alkylcycloalkylcarbinol," as used herein, refers to the group -C(R')(cycloalkyl)OH where R' refers to an alkyl group as previously defined, and cycloalkyl refers to a cycloalkyl group as previously defined.

[0125] The term "tertiary arylcarbinol," as used herein, refers to the group -C(aryl)2θH where each "aryl" independently refers to an aryl group as previously defined.

[0126] The term "tertiary arylalkylcarbinol," as used herein, refers to the group -C(R')(aryl)OH where R' is an alkyl group as previously defined, and aryl is an aryl group as previously defined.

[0127] The term "phosphonic acid alkyl," as used herein, refers to the group -R'-P(O)(OH) ₂ where R' is an alkyl group as previously defined.

[0128] The term "dimethylphosphonatealkyl," as used herein, refers to the group -R'-P(O)(OCH ₃ )2 where R' is an alkyl group as previously defined.

[0129] The term "partially saturated," as used herein, refers to a nonaromatic cycloalkyl or heterocycloalkyl group containing at least one double bond and preferably one or two double bonds.

[0130] The term "therapeutically effective amount," as used herein, refers to the amount of a compound of formula 1 that, when administered to a patient, is effective to at least

partially treat a condition from which the patient is suffering or is suspected to suffer. Such conditions include, but are not limited to, osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, and leiomyoma.

[0131] The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable salt" includes acid addition salts, namely salts derived from treating a compound of formula 1 with an organic or inorganic acids or bases. Where the compound having formula I has an acidic function, for instance where R ₃ is carboxyalkyl or R ₈ is carboxy or phenolic hydroxyl, the term "pharmaceutically acceptable salts" or "pharmaceutically acceptable salt" includes salts derived from bases, for instance, sodium salts.

[0132] The term "patient," as used herein, refers to a mammal.

[0133] The terms "administer," "administering," or "administration," as used herein, refer to either directly administering a compound or composition to a patient, or administering a prodrug derivative or analog of the compound to the patient, which will form an equivalent amount of the active compound or substance within the patient's body.

[0134] The terms "treat" and "treating," as used herein, refer to partially or completely alleviating, inhibiting, preventing, ameliorating and/or relieving a condition from which a patient is suspected to suffer.

[0135] The terms "suffer" and "suffering," as used herein, refer to one or more conditions with which a patient has been diagnosed, or is suspected to have.

[0136] Certain embodiments of the invention relate to compounds of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein

R ₁ is

and each R ₁ group is optionally substituted with up to three R ₈ groups;

Y is O, S, or NR ₉ ;

R ₈ is alkyl, arylalkyl, perfluoroalkyl, alkenyl, arylalkenyl, alkynyl, arylallcynyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, aryl, alkylaryl, heteroaryl, alkoxy, perfluoroalkoxy, arylalkoxy, alkylcarbonyl, arylcarbonyl, halogen, cyano, azido, hydroxyl, carboxy, alkoxycarbonyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkylcarbonylalkylamino, hydroxyalkylamino, nitro, alkylcarbonyloxime, alkylsulfonyl, alkylsulfinyl, alkylthio, perfluoroalkylthio, arylthio, tertiary alkylcarbinol, tertiary alkylcycloalkylcarbinol, or tertiary arylalkylcarbinol;

R ₉ is hydrogen, alkyl, aryl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, or spirocycloalkyl;

X is oxygen or an electron pair;

R ₂ is hydrogen, alkyl, alkoxy, cycloalkyl, perfluoroalkyl, perfluoroalkylalkyl, perfluoroalkoxy, dialkylamino, or halogen;

R ₄ is hydrogen, halogen, alkyl, cycloalkyl, alkoxy, perfluoroalkyl, or perfluoroalkoxy; or R ₂ and R ₄ , together with the carbon atoms to which they are attached, form a cycloalkyl ring of 5 to 7 carbon atoms that is optionally substituted with 1 to 3 R groups; each R is, independently, hydrogen, alkyl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, spirocycloalkyl, aryl, arylalkyl, or alkoxyalkyl;

R ₅ , and R ₆ are, independently, hydrogen, alkyl, aryl, alkoxy, halogen, or perfluoroalkyl;

R ₃ and R ₇ are each, independently, hydrogen or an optionally substituted alkyl, cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, heteroarylalkyl, alkylaryl, alkylheteroaryl, alkenyl, alkynyl, fused cycloalkylaryl, fused heterocycloalkylaryl, cycloalkylcarbonyl, or heterocycloalkylcarbonyl group;

or R ₃ and R ₇ , together with the nitrogen atom to which they are attached, form a five or six membered heterocycloalkyl ring optionally substituted with 1 to 5 substituents selected from alkyl, aryl, heterocycloalkyl, heterocycloalkylalkyl, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, allcylaminocarbonylalkyl, and heterocycloalkylcarbonylalkyl; provided that the compound is not

2-methyl-N-(2-phenylethyl)-5-(phenylsulfonyl)-benzenesulf onamide;

2-methyl-N-(2-phenylmethyl)-5-(phenylsulfonyl)-benzenesul fonamide;

5-[(4-chlorophenyl)sulfonyl]-N-cyclohexyl-2-methylbenzene sulfonamide;

N-benzyl-5-[(4-chlorophenyl)sulfonyl]-2-methylbenzenesulf onamide;

5-[(4-chlorophenyl)sulfonyl]-N-(2-furylmethyl)-2-methylbe nzenesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-2-methylbenzenesulfonamide;

2-methyl-5-(phenylsulfonyl)-benzenesulfonamide;

5 - [(4-bromopheny l)sulfonyl] -2-methylbenzenesulfonamide ;

2-methyl-5-[(4-nitrophenyl)sulfonyl]-benzenesulfonamide;

5-[(2,4-dinitrophenyl)sulfonyl]-2-methyl-benzenesulfonami de; or

5-[(4-chlorophenyl)sulfonyl]-2-methyl-N-(3-pyridinylmethy l)-benzenesulfonamide.

[0137] Any carbon or nitrogen atom in R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ , as defined herein, may be optionally substituted with one or more substituents understood by those skilled in the art to be suitable substituents. The following lists provide exemples of such substituents.

[0138] The alkyl, cycloalkyl, alkylheterocycloalkyl, heteroarylalkyl, alkylaryl, alkylheteroaryl, alkenyl, alkynyl, fused cycloalkylaryl, fused heterocycloalkylaryl, cycloalkylcarbonyl, and heterocycloalkylcarbonyl groups of R ₃ and R ₇ may each be, independently, optionally substituted with 1 to 5 substituents selected from alkyl, perfluoroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused cycloalkylaryl, alkoxy, aminocarbonylalkoxy, alkoxycarbonylalkoxy, carboxyalkoxy, cycloalkyloxy, aryloxy, amino, alkylamino, dialkylamino, alkoxycarbonylamino, carboxy, cyano, halogen, oxo, hydroxyl, alkylcarbonyl, carboxyalkylcarbonyl, arylaminocarbonyl, heterocycloalkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, fused cycloalkylarylaminocarbonyl, and fused heterocycloalkylarylcarbonyl.

[0139] The cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the alkyl groups ofR ₃ and R ₇ may be, independently, optionally substituted with 1 to 5 substituents selected from alkyl, cycloalkyl, heterocycloalkyl, spirocycloalkyl, perfluoroalkyl, haloalkyl,

cyanoalkyl, carboxyalkyl, dimethylphosphonatealkyl, phosphonic acid alkyl, arylalkyl, cycloalkylallcyl, alkoxy, perfluoroalkoxy, arylalkoxy, benzoxy, aryl, heteroaryl, carboxyaryl, arylcarbonyl, alkylcarbonyl, perfluoroalkylcarbonyl, alkoxycarbonyl, carboxyalkylcarbonyl, aryloxycarbonyl, alkoxythiocarbonyl, aryloxythiocarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkylthiocarbonyl, arylthiocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, dialkylaminoarylcarbonyl, dialkylaminoalkylcarbonyl, alkylthiocarbonyl, arylaminocarbonyl, heteroarylcarbonyl, heteroarylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfonylarylsulfonyl, carboxyarylsulfonyl, nitro, amino, dialkylamino, alkylcarbonylamino, alkylsulfonylamino, carboxyarylsulfonylamino, hydroxy, carboxy, sulfonamide, alkylthio, halogen, cyano, guanidine, and oxo, and the nitrogen atoms in the heteroaryl substituents may be optionally substituted with an oxygen atom.

[0140] The heterocycloalkyl groups of R ₃ and R ₇ may be independently, optionally substituted with 1 to 5 substituents selected from alkyl, hydroxyalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylcarbonylalkyl, arylalkyl, heteroarylalkyl, arylcarbonylalkyl, alkylcarbonyl, cyano, alkylester, alkylamide, cycloalkylamide, aryl, arylester, alkylcarbonyl, perfluoroalkylcarbonyl, aminocarbonyl, arylaminocarbonyl, arylaminothiocarbonyl, cyanoalkoxycarbonyl, cycloalkylcarbonyl, arylcarbonyl, arylthiocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, cyanoarylcarbonyl, arylalkylcarbonyl, alkoxycarbonyl, alkoxyalkylcarbonyl, alkylthioalkylcarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocycloalkylalkylcarbonyl, heterocycloalkylalkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heteroarylalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylaminothiocarbonyl, alkoxycarbonylalkylaminothiocarbonyl, alkylthiocarbonylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylaminoarylsulfonyl, and heteroarylsulfonyl.

[0141] The cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the heterocycloalkyl groups of R ₃ and R ₇ may be independently, optionally substituted with 1 to 5 substituents selected from alkyl, cycloalkyl, heterocycloalkyl, spirocycloalkyl, perfluoroalkyl, haloalkyl, cyanoalkyl, carboxyalkyl, dimethylphosphonatealkyl, phosphonic acid alkyl,

arylalkyl, cycloalkylalkyl, alkoxy, perfluoroalkoxy, arylalkoxy, benzoxy, aryl, heteroaryl, carboxyaryl, arylcarbonyl, alkylcarbonyl, perfluoroalkylcarbonyl, alkoxycarbonyl, carboxyalkylcarbonyl, aryloxycarbonyl, alkoxythiocarbonyl, aryloxythiocarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkylthiocarbonyl, arylthiocarbonyl, alkylaminocarbonyl, diallcylaminocarbonyl, dialkylaminoarylcarbonyl, dialkylaminoalkylcarbonyl, alkylthiocarbonyl, arylaminocarbonyl, heteroarylcarbonyl, heteroarylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfonylarylsulfonyl, carboxyarylsulfonyl, nitro, amino, dialkylamino, alkylcarbonylamino, alkylsulfonylamino, carboxyarylsulfonylamino, hydroxy, carboxy, sulfonamide, alkylthio, halogen, cyano, guanidine, and oxo, and the nitrogen atoms in the heteroaryl substituents may be optionally substituted with an oxygen atom.

[0142] The amino substituents on the alkyl groups of R ₃ and R ₇ may be, independently, optionally substituted with 1 or 2 substituents selected from alkyl, hydroxyalkyl, carboxyalkyl, cycloalkyl, alkoxycarbonylalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylcarbonyl, cycloalkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkoxy carbonylalkylaminocarbonyl, carboxyalkylcarbonyl, carboxyalkylaminocarbonyl, carboxyalkylcarbonylheterocycloalkylaminocarbonyl, arylaminocarbonyl, arylcarbonyl, heteroarylaminocarbonyl, heterocycloalkylcarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocycloalkylaminocarbonyl, heterocycloalkylthiocarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkoxythiocarbonyl, and aryloxythiocarbonyl.

[0143] The cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the amino substituents on the alkyl groups of R ₃ and R ₇ may be, independently, optionally substituted with 1 to 5 substituents selected from alkyl, cycloalkyl, heterocycloalkyl, spirocycloalkyl, perfluoroalkyl, haloalkyl, cyanoalkyl, carboxyalkyl, dimethylphosphonatealkyl, phosphonic acid alkyl, arylalkyl, cycloalkylalkyl, alkoxy, perfluoroalkoxy, arylalkoxy, benzoxy, aryl, heteroaryl, carboxyaryl, arylcarbonyl, alkylcarbonyl, perfluoroalkylcarbonyl, alkoxycarbonyl, carboxyalkylcarbonyl, aryloxycarbonyl, alkoxythiocarbonyl, aryloxythiocarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkylthiocarbonyl, arylthiocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, dialkylaminoarylcarbonyl,

dialkylaminoalkylcarbonyl, alkylthiocarbonyl, arylaminocarbonyl, heteroarylcarbonyl, heteroarylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfonylarylsulfonyl, carboxyarylsulfonyl, nitro, amino, dialkylamino, alkylcarbonylamino, alkylsulfonylamino, carboxyarylsulfonylamino, hydroxy, carboxy, sulfonamide, alkylthio, halogen, cyano, guanidine, and oxo, and the nitrogen atoms in the heteroaryl substituents may be optionally substituted with an oxygen atom.

[0144] The alkyl group substituents on the heterocycloalkyl ring formed from R ₃ and R ₇ , together with the nitrogen atom to which they are attached may each be, independently, optionally substituted with 1 to 5 substituents selected from aryl, heteroaryl optionally substituted with one to three alkyl groups, aminoalkyl, heterocycloalkyl, fused heterocycloalkylaryl, and heterocycloalkylcarbonyl.

[0145] In preferred embodiments of the invention R ₁ of Formula 1 is aryl.

[0146] In other embodiments of the invention, R ₁ of Formula 1 is

[0147] Certain aspects of the invention relate to compounds of Formula 1 wherein each R ₈ is, independently, alkyl, alkylaryl, alkylheteroaryl, alkylamino, dialkylamino, carboxy, alkylcarbonyl, alkoxy, perfluoroalkoxy, halogen, or cyano.

[0148] Other aspects of the invention are directed to compounds of Formula 1 in which X is oxygen.

[0149] Additional embodiments of the invention relate to compounds of Formula 1 in which R ₄ , R ₅ , and R ₆ are each hydrogen. Alternative embodiments of the invention relate to compounds of Formula 1 in which R ₄ is methyl and R ₅ and R ₆ are each hydrogen, or R ₅ is methyl and R ₄ and R ₆ are each hydrogen, or R ₆ is methyl and R ₄ and R ₅ are each hydrogen.

[0150] Further embodiments of the invention are directed to compounds of Formula I in which R ₄ is halogen, alkyl, cycloalkyl, alkoxy, perfluoroalkyl, or perfluoroalkoxy.

[0151] Other aspects of the invention are directed to compounds of Formula I in which R ₅ , and R ₆ are, independently, alkyl, alkoxy, halogen, or perfluoroalkyl.

[0152] Certain embodiments of the invention are directed to compounds of Formula 1 in which R ₂ is methyl, ethyl, isopropyl, propyl, Cl, methoxy, trifluoromethyl, or trifluoromethoxy. In preferred embodiments, R ₂ is methyl, isopropyl, trifluoromethyl, or trifluoromethoxy. In particularly preferred embodiments, R ₂ is isopropyl or trifluoromethyl.

[0153] Still further embodiments of the invention relate to compounds of Formula I in which R ₂ is hydrogen, alkoxy, cycloalkyl, perfluoroalkyl, perfluoroalkylalkyl , perfluoroalkoxy, dialkylamino, or halogen.

[0154] Other aspects of the invention relate to compounds of Formula 1 in which R ₃ and R ₇ , together with the nitrogen atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocycloalkyl group. In preferred aspects, R ₃ and R ₇ , together with the nitrogen atoms to which they are attached, form an optionally substituted piperazinyl group.

[0155] Additional embodiments of the invention relate to compounds of Formula I in which R ₃ and R ₇ are each, independently, alkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylheterocycloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, fused cycloalkylaryl, fused heterocycloalkylaryl, cycloalkylcarbonyl, alkoxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, aminoalkyl, dialkylaminocarbonylalkyl, or alkylalkylaminocarbonylalkyl.

[0156] Further embodiments of the invention are directed to compounds of Formula 1 in which R ₇ is hydrogen and R ₃ is alkyl, cycloalkyl,

wherein the carbon atoms of each alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group are optionally substituted with up to four R ₁₃ groups;

R ₁₃ is hydrogen, F, Cl, Br, alkyl, alkoxy, aryl, nitro, aminosulfonyl, arylalkoxy, perfluoroalkyl, perfluoroalkoxy, amino, alkylamino, dialkylamino, hydroxy, carboxy, cycloalkyl, carboxyalkyl, carboxyalkoxy, alkoxycarbonyl, aminocarbonylalkyl, alkoxycarbonylalkoxy,ammocarbonylalkoxy, alkylaminocarbonylallcyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocycloalkylcarbonyl, heterocycloalkylaminocarbonyl, alkylaminocarbonylalkoxy, dialkylaminocarbonylalkyl, dialkylaminocarbonylalkoxy, heterocycloalkylcarbonylalkyl, heterocycloalkylaminocarbonylalkoxy, heterocycloalkylcarbonylalkoxy, cycloalkylaminoalkyl, heterocycloalkylaminoalkyl, aminoalkylaminoalkylarylamionalkyl, heteroarylaminoalkylarylalkylaminoallcyl, heteroarylalkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylaminoarylamino, heteroarylaminoarylalkylamino, heteroarylalkylamino, or cyano;

each R ₁₂ is alkyl, aryl, alkylamino, dialkylamino, alkoxy, hydroxyl, amino, arylamino, diarylamino, aryl(alkyl)amino, or aryloxy; each R ₁₄ is hydrogen, alkyl, aryl, cycloalkyl, alkylcarbonyl, arylcarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, heterocycloalkylcarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocycloalkylthiocarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkoxythiocarbonyl, alkoxycarbonylaminothiocarbonyl, cycloalkylcarbonyl, aminocarbonyl, alkoxycarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, heteroarylsulfonyl, or aryloxythiocarbonyl;

R ₁₅ is hydrogen, alkyl, aryl, cycloalkyl, alley lcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, heterocycloalkylcarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocycloalkylthiocarbonyl, heterocycloalkylalkylaminothiocarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, arylthiocarbonyl, alkoxythiocarbonyl, or aryloxythiocarbonyl;

R ₁₆ , R ₁₇ and R ₁₈ are each, independently, hydrogen, alkyl, aryl or cycloalkyl; m is 0, I, or 2; p is 0, 1, or 2; q is 1 or 2; s is 1 or 2; and

W is NR ₉ , O, or S.

[0157] The alkyl, aryl and cycloalkyl groups of R ₁₃ , R ₁₄ and R ₁₅ may each be, independently, optionally substituted with 1 to 5 substituents selected from alkyl, cycloalkyl, heterocycloalkyl, perfluoroalkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyloxy, amino, alkylamino, dialkylamino, carboxy, cyano, oxo, hydroxyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, alkoxycarbonylamino, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthio, alkyloxothio, and alkoxycarbonylalkylamino.

[0158] The arylsulfonyl, arylcarbonyl and heteroarylcarbonyl groups of R ₁₃ , R ₁₄ and R ₁₅ may be each, independently, optionally substituted with 1 to 5 substituents selected from hydrogen, halogen, hydroxyl, alkyl, cycloalkyl, perfluoroalkyl, aryl, alkoxy, heterocycloalkyl,

heteroaryl, cycloalkyloxy, aryloxy, amino, alkylamino, dialkylamino, alkylthio, alkyloxothio, carboxy, cyano, oxo, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl.

[0159] The heterocycloalkyl groups OfR ₁₃ , R ₁₄ and R ₁₅ may each be, independently, optionally substituted with 1 to 5 substituents selected from hydrogen, hydroxyl, alkyl, cycloalkyl, perfluoroalkyl, aryl, heterocycloalkyl, heteroaryl, heteroarylcarbonyl, heteroarylalkylcarbonyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, heterocycloalkylcarbonylalkyl, carboxyalkylcarbonyl, and arylaminocarbony 1.

[0160] In addition, the alkylcarbonyl groups of R ₁₃ , R ₁₄ and R ₁₅ may each be, independently, optionally substituted with 1 to 5 substituents selected from amino, alkylamino, dialkylamino, cycloalkyl, heterocycloalkyl, perfluoroalkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyloxy, carboxy, cyano, oxo, hydroxyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, and alkoxy carbony lamino .

[0161] The amino groups of the alkylamino and hetercycloalkylamino groups OfR ₁₃ , R ₁₄ and R ₁₅ may each be, independently, optionally substituted with a substituent selected from hydrogen, alkyl, cycloalkyl, and aryl.

[0162] Particular embodiments of the invention relate to compounds of Formula 1 in which R ₇ is hydrogen and R ₃ is heteroarylethyl, heteroarylpropyl, arylethyl, heterocycloalkyl, heterocycloalkylethyl, heterocycloalkylpropyl, heterocycloalkylmethyl, heterocyclalkylamino, cycloalkyl, fused cycloalkylaryl, aminoalkyl, or alkoxyalkyl. In preferred embodiments R ₇ is hydrogen and R ₃ is heteroarylethyl, heteroarylpropyl, heterocyclalkylamino, fused cycloalkylaryl, or phenylethyl. In particularly preferred embodiments R ₇ is hydrogen and R ₃ is pyridinylethyl, imidazolylethyl, imidazolylpropyl, heterocyclalkylamino, fused cycloalkylaryl, or phenylethyl.

[0163] Specific, representative compounds of Formula 1 include: λ/-(2-phenylethyl)-3-(phenylsulfonyl)benzenesulfonamide; iV-[2-(2-chlorophenyl)ethyl]-3-(phenylsulfonyl)benzenesulfon amide; N-[2-(2-methoxyphenyl)ethyl]-3-(phenylsulfonyl)benzenesulfon amide; N- [2-(3 -methoxypheny l)ethy 1] -3 -(phenylsulfony l)benzenesulfonamide ;

λ/-[2-(3,4-dimethoxyphenyl)ethyl]-3-(phenylsulfonyl)benz enesulfonamide; jV-[2-(4-bromophenyl)ethyl]-3-(phenylsulfonyl)benzenesulfona mide; iV-[2-(4-fluorophenyl)ethyl]-3-(phenylsulfonyl)benzenesulfon amide;

N-[2-(4-chlorophenyl)ethyl]-3-(phenylsulfonyl)benzenesulf onaniide;

λ/-[2-(4-methoxyphenyl)ethyl]-3-(phenylsulfonyl)benzenes ulfonamide;

JV- [2-(4-methy lpheny l)ethyl] -3 -(pheny lsulfony l)benzenesulfonamide ;

N-{2-[4-(aminosulfonyl)phenyl]ethyl}-3-(phenylsulfonyl)be nzenesulfonamide;

JV- { 2- [3 ,4-bis(benzyloxy )pheny 1] ethyl } -3 -(pheny lsulfony l)benzenesulfonamide;

7V-[2-(4-nitrophenyl)ethyl]-3-(phenylsulfonyl)benzenesulf onamide;

JV- [2-( 1 ,3 -benzodioxol-5 -y l)ethy 1] -3 -(pheny lsulfony l)benzenesulfonamide ;

3 -(pheny lsulfony Y)-N- { 2- [3 -(trifluoromethyl)pheny 1] ethyl } benzenesulfonamide;

JV-[2-(3-chlorophenyl)ethyl]-3-(phenylsulfonyl)benzenesul fonamide;

JV- [2-(2,4-dichloropheny l)ethy 1] -3 -(phenylsulfony l)benzenesulfonamide ;

JV-[2-(2,6-dichlorophenyl)ethyl]-3-(phenylsulfonyl)benzen esulfonamide;

JV-[2-(2,5-dimethoxyphenyl)ethyl]-3-(phenylsulfonyl)benze nesulfonamide;

JV-[2-(3,4-dichlorophenyl)ethyl]-3-(phenylsulfonyl)benzen esulfonamide; iV-[2-(3,5-dimethoxyphenyl)ethyl]-3-(phenylsulfonyl)benzenes ulfonaniide;

JV- [2-(4-ethoxypheny l)ethy l]-3 -(phenylsulfony l)benzenesulfonamide ;

JV-[2-(3-fluorophenyl)ethyl]-3-(phenylsulfonyl)benzenesul fonamide;

N-[2-(2-fluorophenyl)ethyl]-3-(phenylsulfonyl)benzenesulf onamide;

JV-[2-(3-ethoxy-4-methoxyphenyl)ethyl]-3-(phenylsulfonyl) benzenesulfonamide;

JV- [2-(4-ethoxy-3 -methoxyphenyl)ethyl] -3 -(pheny lsulfony l)benzenesulfonamide;

JV-(4-methoxybenzyl)-3-(phenylsulfonyl)benzenesulfonamide ;

JV-[2-(2-bromo-4,5-dimethoxyphenyl)ethyl]-3-(phenylsulfon yl)benzenesulfonamide;

JV-[2-(5-bromo-2-methoxyphenyl)ethyl]-3-(phenylsulfonyl)b enzenesulfonamide;

JV ³ -{[3-(phenylsulfonyl)phenyl]sulfonyl}-beta-alaninamide; methyl JV- { [3-(phenylsulfonyl)phenyl]sulfonyl} -beta-alaninate;

JV-(2-cyanoethyl)-3-(phenylsulfonyl)benzenesulfonamide;

3-(phenylsulfonyl)-JV-(2-pyridin-2-ylethyl)benzenesulfona mide;

JV-(3 -morpholin-4-y lpropyl)-3 -(pheny lsulfony l)benzenesulfonamide ;

JV- [2-( 1 -methy lpyrrolidin-2-y l)ethyl] -3 -(phenylsulfony l)benzenesulfonamide ;

3 -(pheny lsulfony l)-JV-(2-pyridin-4-ylethyl)benzenesulfonamide ;

AlYJLJLU JLOO3 - 26 -

3-(phenylsulfonyl)-iV-(2-piperidin-l-ylethyl)benzenesulfo namide;

N-[2-(lH-imidazol-4-yl)ethyl]-3-(phenylsulfonyl)benzenesu lfonamide;

N-[2-({[3-(phenylsulfon.yl)phenyl]sulfonyl}amino)ethyl]ac etatnide; iV-(2-morpholin-4-ylethyl)-3-(phenylsulfonyl)benzenesulfonam ide; iV-[3-(2-oxopyrrolidin-l-yl)propyl]-3-(phenylsulfonyl)benzen esulfonamide;

N-[2-(diethylamino)ethyl]-3-(phenylsulfonyl)benzenesulfon amide; iV-[2-(diinethylamino)ethyl]-3-(pb-enylsulfoiiyl)benzenesulf onamide;

JV-(3 -methoxypropy l)-3 -(pheny lsulfony l)benzenesulfonamide ;

N-[3-(dimeth.ylamino)propyl]-3-(pb.enylsulfonyl)benzenesu lfonamide;

N-(2-methoxy ethyl)-3 -(pheny lsulfony l)benzenesulfonamide ;

N-[3-(diethylamino)propyl]-3-(phenylsulfonyl)benzenesulfo namide;

N-[3-(lH-imidazol-l-yl)propyl]-3-(phenylsulfonyl)benzenes ulfonamide;

3-(phenylsulfonyl)-N-(3-pyrrolidin-l-ylpropyl)benzenesulf onamide;

N-[3-(4-methylpiperazin-l-yl)propyl]-3-(phenylsulfonyl)be nzenesulfonamide;

N- { [3 -(pheny lsulfony l)pheny 1] sulf ony 1} -beta-alanine ;

N-2,3-dihydro-lH-inden-2-yl-3-(phenylsulfonyl)benzenesulf onamide;

^[(lS^^^-phenylcyclopropylj-S-φhenylsulfony^benzenesulfo namide;

N-[(2i?)-2-phenylpropyl]-3-(phenylsulfonyl)benzenesulfona mide;

N-[(25)-2-phenylpropyl]-3-(phenylsulfonyl)benzenesulfonam ide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-iV-(2-phenylethyl)b enzenesulfonamide;

N-[2-(2-chlorophenyl)ethyl]-5-[(4-fluorophenyl)sulfonyl]- 2-methylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-λT-[2-(2-methoxyphenyl)ethy l]-2-methylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-iV-[2-(3-methoxyphenyl)ethyl ]-2-methylbenzenesulfonamide;

N-[2-(3,4-dimethoxyphenyl)ethyl]-5-[(4-fluorophenyl)sulfo nyl]-2-methylbenzenesulfonamide; iV-[2-(4-broniophenyl)ethyl]-5-[(4-fluoroρhenyl)sulfonyl]-2 -niethylbenzenesulfonamide;

JV-[2-(4-fiuorophenyl)ethyl]-5-[(4-fluorophenyl)sulfonyl] -2-methylbenzenesulfonamide;

λ ^r -[2-(4-chlorophenyl)ethyl]-5-[(4-fluoroρhenyl)sulfonyl]-2-m ethylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-N-[2-(4-methoxyphenyl)ethyl] -2-methylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-N-[2-(4-methylpheny l)ethyl]benzenesulfonamide;

7V-{2-[4-(aminosulfonyl)phenyl]ethyl}-5-[(4-fluorophenyl) sulfonyl]-2- methylbenzenesulfonamide;

iV-{2-[3,4-bis(benzyloxy)phenyl]ethyl}-5-[(4-fluorophenyl )sulfonyl]-2- methylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-iV-[2-(4-nitropheny l)ethyl]benzenesulfonamide;

N-[2-(l,3-benzodioxol-5-yl)ethyl]-5-[(4-fluorophenyl)sulf onyl]-2-methylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-N-{2-[3-

(trifluoromethy l)pheny 1] ethyl} benzenesulfonamide ;

λ/-[2-(3-chlorophenyl)ethyl]-5-[(4-fluoropb.enyl)sulfony l]-2-methylbenzenesulfonamide;

N-[2-(2,4-dichlorophenyl)ethyl]-5-[(4-fluorophenyl)sulfon yl]-2-methylbenzenesulfonamide;

N-[2-(2,6-dichlorophenyl)ethyl]-5-[(4-fluorophenyl)sulfon yl]-2-methylbenzenesulfonamide; iV-[2-(2,5-dimethoxyphenyl)ethyl]-5-[(4-fluoroplienyl)sulfon yl]-2-methylbenzenesulfonamide;

N-[2-(3,4-dichlorophenyl)ethyl]-5-[(4-fluorophenyl)sulfon yl]-2-methylbenzenesulfonamide;

N-[2-(3,5-dimethoxyphenyl)ethyl]-5-[(4-fluorophenyl)sulfo nyl]-2-methylbenzenesulfonamide;

N- [2-(4-ethoxyphenyl)ethy 1] -5- [(4-fluoropheny l)sulfony 1] -2-methy lbenzenesulfonamide ;

N-[2-(3-fluorophenyl)ethyl]-5-[(4-fluorophenyl)sulfonyl]- 2-methylbenzenesulfonamide;

_J /V-[2-(2-fluorophenyl)ethyl]-5-[(4-fluorophenyl)sulfonyl]-2- methylbenzenesulfonamide;

N- [2-(3 -ethoxy-4-methoxypheny l)etliy 1] -5 - [(4-fluoropheny l)sulfonyl] -2- methylbenzenesulfonamide; iV-[2-(4-ethoxy-3-methoxyphenyl)ethyl]-5-[(4-fluorophenyl)su lfonyl]-2- methylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-iV-(4-methoxybenzyl)-2-methy lbenzenesulfonaniide;

λ/-[2-(2-bromo-4,5-dimethoxyphenyl)ethyl]-5-[(4-fluoroph enyl)sulfonyl]-2- methylbenzenesulfonamide;

7V-[2-(5-bromo-2-methoxyphenyl)ethyl]-5-[(4-fluorophenyl) sulfonyl]-2- methylbenzenesulfonamide;

2-Methyl-N- (2-phenylethyl)-5-(phenylsulfonyl) benzene sulfonamide; iV-[2-(2-chlorophenyl)ethyl]-2-methyl-5-(phenylsulfonyl)benz enesulfonamide;

N-[2-(2-methoxyphenyl)ethyl]-2-methyl-5-(phenylsulfonyl)b enzenesulfonamide;

λ/-[2-(3-methoxyphenyl)ethyl]-2-raethyl-5-(phenylsulfony l)benzenesulfonamide;

N-[2-(3,4-dimethoxyphenyl)ethyl]-2-methyl-5-(phenylsulfon yl)benzenesulfonamide;

N-[2-(4-bromophenyl)ethyl]-2-methyl-5-(phenylsulfonyl)ben zenesulfonamide;

λ/-[2-(4-fluorophenyl)ethyl]-2-methyl-5-(phenylsulfonyl) benzenesulfonamide;

N-[2-(4-chlorophenyl)ethyl]-2-methyl-5-(phenylsulfonyl)be nzenesulfonamide;

iV-[2-(4-methoxyphenyl)ethyl]-2-metliyl-5-(phenylsulfonyl )benzenesulfonamide;

2-methyl-N-[2-(4-methylphenyl)ethyl]-5-(phenylsulfonyl)be nzenesulfonamide;

N-{2-[4-(aminosulfonyl)phenyl]ethyl}-2-methyl-5-(phenylsu lfonyl)benzenesulfonamide;

N-{2-[3,4-bis(benzyloxy)phenyl]ethyl}-2-methyl-5-(phenyls ulfonyl)benzenesulfonamide;

2-methyl-N-[2-(4-nitrophenyl)ethyl]-5-(phenylsulfonyl)ben zenesulfonamide;

N-[2-(l,3-benzodioxol-5-yl)ethyl]-2-methyl-5-(phenylsulfo nyl)benzenesulfonamide;

2-methyl-5-(phenylsulfonyl)-N-{2-[3-(trifluoromethyl)phen yl]ethyl}benzenesulfonamide; iV-[2-(3-chloropb.enyl)ethyl]-2-metb.yl-5-(phenylsulfonyl)be nzenesulfonamide; iV-[2-(2,4-dichlorophenyl)etliyl]-2-methyl-5-(phenylsulfonyl )benzenesulfonamide;

N-[2-(2,6-dichlorophenyl)ethyl]-2-methyl-5-(phenylsulfony l)benzenesulfonamide;

N-[2-(2,5-dimethoxyplienyl)ethyl]-2-methyl-5-(phenylsulfo nyl)benzenesulfonamide;

N-[2-(3,4-dichlorophenyl)ethyl]-2-methyl-5-(phenylsulfony l)benzenesulfonamide;

N-[2-(3,5-dimethoxyphenyl)ethyl]-2-methyl-5-(phenylsulfon yl)benzenesulfonamide;

N-[2-(4-ethoxyphenyl)ethyl]-2-methyl-5-(phenylsulfonyl)be nzenesulfonamide;

N-[2-(3-fluorophenyl)ethyl]-2-methyl-5-(phen.ylsulfonyl)b enzenesulfonamide;

N-[2-(2-fluorophenyl)ethyl]-2-methyl-5-(phenylsulfonyl)be nzenesulfonamide;

N-[2-(3-ethoxy-4-methoxyphenyl)ethyl]-2-methyl-5-(phenyls ulfonyl)benzenesulfonamide;

N-[2-(4-ethoxy-3-methoxyphenyl)ethyl]-2-methyl-5-(phenyls ulfonyl)benzenesulfonamide;

N-(4-methoxybenzyl)-2-methyl-5-(phenylsulfonyl)benzenesul fonamide;

N-[2-(2-bromo-4,5-dimethoxyphenyl)ethyl]-2-methyl-5-(phen ylsulfonyl)benzenesulfonamide;

N-[2-(5-bromo-2-methoxyphenyl)ethyl]-2-methyl-5-φhenylsu lfonyl)beiizenesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-2-methyl-iV-(2-phenylethyl)b enzenesulfonamide;

N-[2-(2-chlorophenyl)ethyl]-5-[(4-chlorophenyl)sulfonyl]- 2-methylbenzenesulfonamide;

5 - [(4-chloropheny l)sulfony I]-N- [2-(2-methoxypheny l)ethy 1] -2-methy lbenzenesulfonamide ;

5-[(4-chlorophenyl)sulfonyl]-N-[2-(3-methoxyphenyl)ethyl] -2-methylberizenesulfonamide;

5-[(4-cMorophenyl)sulfonyl]-N-[2-(3,4-dimethoxyphenyl)eth yl]-2-methylbenzenesulfonamide;

N-[2-(4-bromophenyl)ethyl]-5-[(4-chlorophenyl)sulfonyl]-2 -methylbenzenesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-N-[2-(4-fluorophenyl)ethyl]- 2-methylbenzenesulfonamide;

N-[2-(4-cliloropb.enyl)ethyl]-5-[(4-chlorophenyl)sulfonyl ]-2-methylbenzenesulfonamide;

5- [(4-chloropheny l)sulfonyl] -N- [2-(4-methoxypheny l)ethy 1] -2-methy lbenzenesulfonamide ;

5-[(4-chlorophenyl)sulfonyl]-2-methyl-N-[2-(4-methylpheny l)ethyl]benzenesulfonamide;

N-{2-[4-(aminosulfonyl)phenyl]ethyl}-5-[(4-chlorophenyl)s ulfonyl]-2- methylbenzenesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-2-methyl-N-[2-(4-nitrophenyl )ethyl]benzenesulfonamide;

N-[2-(l,3-benzodioxol-5-yl)ethyl]-5-[(4-chlorophenyl)sulf onyl]-2-methylbenzenesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-2-methyl-JV-{2-[3-

(trifluoromethyl)pheny 1] ethyl} benzenesulfonamide ;

N- [2-(3 -chloropheny l)ethy 1] -5 - [(4-chlorophenyl)sulfony 1] -2-methylbenzenesulfonamide ;

5-[(4-chlorophenyl)sulfonyl]-iV-[2-(2,4-dichlorophenyl)et hyl]-2-niethylbenzenesulfonamide;

5 - [(4-chloropheny l)sulfony 1] -N- [2-(2,6-dichlorophenyl)ethy 1] -2-methylbenzenesulfonamide ;

5-[(4-chlorophenyl)sulfonyl]-N-[2-(2,5-dimethoxyphenyl)et hyl]-2-methylbenzenesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-iV-[2-(3 ₅ 4-dichlorophenyl)ethyl]-2-methylbenzenesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-iV-[2-(3,5-dimethoxyphenyl)e thyl]-2-methylbenzenesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-N-[2-(4-ethoxyphenyl)etliyl] -2-methylbenzenesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-N-[2-(3-fluorophenyl)ethyl]- 2-methylbenzenesulfonamide;

5- [(4-chloropheny l)sulfonyl] -JV- [2-(2-fluoropheny l)ethyl] -2-methylbenzenesulfonamide ;

5-[(4-chlorophenyl)sulfonyl]-JV-[2-(3-ethoxy-4-methoxyphe nyl)ethyl]-2- methylbenzenesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-JV-[2-(4-ethoxy-3-methoxyphe nyl)ethyl]-2- methylbenzenesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-JV-(4-methoxybenzyl)-2-methy lbenzenesulfonamide;

JV-[2-(2-bromo-4,5-dimethoxyphenyl)ethyl]-5-[(4-chlorophe nyl)sulfonyl]-2- methylbenzenesulfonamide;

JV-[2-(5-bromo-2-methoxyphenyl)ethyl]-5-[(4-chlorophenyl) sulfonyl]-2- methylbenzenesulfonamide;

2-methyl-5-[(4-methylphenyl)sulfonyl]-N-(2-phenylethyl)be nzenesulfonamide;

N-[2-(2-chlorophenyl)ethyl]-2-methyl-5-[(4-methylphenyl)s ulfonyl]benzenesulfonamide;

JV-[2-(2-methoxyphenyl)ethyl]-2-methyl-5-[(4-methylphenyl )sulfonyl]benzenesulfonamide;

JV-[2-(3-methoxyphenyl)ethyl]-2-methyl-5-[(4-methylphenyl )sulfonyl]benzenesulfonamide;

7V-[2-(3,4-dimethoxyphenyl)ethyl]-2-methyl-5-[(4-methylph enyl)sulfonyl]benzenesulfonamide;

JV-[2-(4-bromophenyl)ethyl]-2-methyl-5-[(4-methylphenyl)s ulfonyl]benzenesulfonamide;

JV-[2-(4-fluorophenyl)ethyl]-2-methyl-5-[(4-methylphenyl) sulfonyl]benzenesulfonamide;

N-[2-(4-chlorophenyl)ethyl]-2-methyl-5-[(4-methylphenyl)s ulfonyl]beixzenesulfonamide;

N-[2-(4-methoxyphenyl)ethyl]-2-methyl-5-[(4-methylphenyl) sulfonyl]benzenesulfonamide;

2-methyl-N-[2-(4-methylphenyl)ethyl]-5-[(4-methylphenyl)s ulfonyl]benzenesulfonamide;

N-{2-[4-(aminosulfonyl)phenyl]ethyl}-2-methyl-5-[(4- methylphenyl)sulfonyl]beiizenesulfonamide;

2-methyl-5-[(4-methylphenyl)sulfonyl]-N-[2-(4-nitrophenyl )ethyl]benzenesulfonamide;

N-[2-(l,3-benzodioxol-5-yl)ethyl]-2-methyl-5-[(4-methylph enyl)sulfonyl]benzenesulfonamide;

2-methyl-5-[(4-methylphenyl)sulfonyl]-N-{2-[3-

(trifluoromethyl)phenyl]ethyl}benzenesulfonamide; iV-[2-(3-chlorophenyl)ethyl]-2-methyl-5-[(4-methylphenyl)sul fonyl]benzenesulfonamide;

N-[2-(2,4-dichlorophenyl)ethyl]-2-methyl-5-[(4-methylphen yl)sulfonyl]benzenesulfonamide;

N-[2-(2,6-dichlorophenyl)ethyl]-2-methyl-5-[(4-methylphen yl)sulfonyl]benzenesulfonamide;

N-[2-(2,5-dimethoxyphenyl)ethyl]-2-methyl-5-[(4-methylphe nyl)sulfonyl]benzenesulfonamide; iV-[2-(3,4-dichlorophenyl)ethyl]-2-methyl-5-[(4-methylpb.eny l)sulfonyl]benzenesulfonaniide;

N-[2-(3,5-dimethoxyphenyl)ethyl]-2-methyl-5-[(4-methylphe nyl)sulfonyl]benzenesulfonamide;

N-[2-(4-ethoxyphenyl)ethyl]-2-methyl-5-[(4-methylphenyl)s ulfonyl]benzenesulfonamide;

N-[2-(3-fluorophenyl)ethyl]-2-meώyl-5-[(4-methylphenyl)s ulfonyl]benzenesulfonamide;

N-[2-(2-fluorophenyl)etb.yl]-2-methyl-5-[(4-methylphenyl) sulfonyl]benzenesulfonamide;

N-[2-(2-bromo-4,5-dimethoxyphenyl)ethyl]-2-methyl-5-[(4- methylphenyl)sulfonyl]benzenesulfonamide;

N-[2-(5-bromo-2-methoxyphenyl)ethyl]-2-methyl-5-[(4- methylphenyl)sulfonyl]benzenesulfonamide;

2-ethyl-N-(2-phenylethyl)-5-(phenylsulfonyl)benzenesulfon amide;

2-ethyl-7V-[2-(2-methoxyphenyl)ethyl]-5-(phenylsulfonyl)b enzenesulfonamide;

2-ethyl-iV-[2-(3-methoxyphenyl)ethyl]-5-(phenylsulfonyl)b enzenesulfonamide; iV-[2-(3,4-dimethoxyphenyl)ethyl]-2-etb.yl-5-(phenylsulfonyl )benzenesulfonamide;

N-{2-[4-(aminosulfonyl)phenyl]ethyl}-2-etb.yl-5-(phenylsu lfonyl)benzenesulfonamide;

2-etb.yl-N-[2-(3-fluorophenyl)ethyl]-5-(phenylsulfonyl)be nzenesulfonamide;

2-ethyl-iV-[2-(2-fluoiOphenyl)ethyl]-5-(phenylsulfonyl)be nzenesulfonamide; iV-[2-(3-ethoxy-4-metb.oxyphenyl)ethyl]-2-ethyl-5-(phenylsul fonyl)benzenesulfonamide;

N-[2-(4-ethoxy-3-methoxyphenyl)ethyl]-2-ethyl-5-(phenylsu lfonyl)benzenesulfonamide;

2-methoxy-N-(2-phenylethyl)-5-(phenylsulfonyl)benzenesulf onamide;

2-methoxy-N-[2-(2-methoxyphenyl)ethyl]-5-(phenylsulfonyl) benzenesulfonamide;

2-methoxy-N-[2-(3-methoxyphenyl)ethyl]-5-(phenylsulfonyl) benzenesulfonamide;

N-[2-(3,4-dimethoxyphenyl)ethyl]-2-methoxy-5-(phenylsulfo nyl)benzenesulfonaniide;

N-{2-[4-(aminosulfonyl)phenyl]ethyl}-2-methoxy-5-(phenyls ulfonyl)benzenesulfonamide;

N-[2-(3-fluorophenyl)ethyl]-2-methoxy-5-(phenylsulfonyl)b enzenesulfonamide; iV-[2-(2-fluoroplienyl)ethyl]-2-methoxy-5-(pb.enylsulfonyl)b enzenesulfonamide;

N-[2-(3-ethoxy-4-metb.oxyphenyl)ethyl]-2-methoxy-5-(pheny lsulfonyl)benzenesulfoiiamide;

N-[2-(4-ethoxy-3-methoxypb.enyl)etb.yl]-2-metb.oxy-5-(phe nylsulfonyl)benzenesulfonamide;

2-methyl-N-(3-phenylpropyl)-5-(phenylsulfonyl)benzenesulf onamide;

2-ethyl-iV-(3-phenylpropyl)-5-(phenylsulfonyl)benzenesulf onaniide;

N-2,3-dihydro-lH-inden-2-yl-2-methyl-5-(phenylsulfonyl)be nzenesulfonamide;

2-methyl-iV-[(15',2i?)-2-phenylcyclopropyl]-5-(phenylsulf onyl)benzenesulfonamide;

2-methyl-iV-[(2i?)-2-phenylpropyl]-5-(phenylsulfonyl)benz enesulfonamide;

N-2,3-dihydro-li7-inden-2-yl-5-[(4-fluorophenyl)sulfonyl] -2-methylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-metb.yl-N-[(15',2i?)-2-phe nylcyclopropyl]benzenesulfonaniide;

5 - [(4-fluoropheny l)sulfonyl] -2-methy 1-N- [(2i?)-2-pheny lpropy l]benzenesulfonamide ;

N-2,3-dihydro-lH-inden-2-yl-2-methyl-5-[(4-methylphenyl)s ulfonyl]benzenesulfonamide;

2-methyl-5-[(4-methylphenyl)sulfonyl]-N-[(15',2i?)-2-phen ylcyclopropyl]benzenesulfonamide;

2-methyl-5-[(4-methylphenyl)sulfonyl]-N-[(2i?)-2-phenylpr opyl]benzenesulfonamide;

5-[(4-cUorophenyl)sulfonyl]-N-2,3-dihydro-lH-inden-2-yl-2 -methylbenzenesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-2-methyl-iV-[(l)S',2 _J R)-2-phenylcyclopropyl]benzenesulfonamide;

5 - [(4-chloropheny l)sulfony 1] -2-methy 1-N- [(2i?)-2-pheny lpropy l]benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-N-[(2)S)-2-phenylpr opyl]benzenesulfonamide;

2-methyl-N-[(2iS)-2-phenylpropyl]-5-(phenylsulfonyl)benze nesulfonamide;

2-methyl-5-[(4-methylphenyl)sulfonyl]-iV-[(25)-2-phenylpr opyl]ben2;enesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-2-methyl-N-[(2)S)-2-phenylpr opyl]benzenesulfonamide;

N-2,3-dihydro-lH-inden-2-yl-2-ethyl-5-(phenylsulfonyl)ben zenesulfonamide;

2-ethyl-N-[(liS',2i?)-2-phenylcyclopropyl]-5-(phenylsulfo nyl)benzenesulfonamide;

2-ethyl-N-[(2i?)-2-phenylpropyl]-5-(phenylsulfonyl)benzen esulfonamide;

N-2,3-dihydro-lif-inden-2-yl-2-methoxy-5-(pb.enylsulfonyl )benzenesulfonamide;

2-methoxy-N-[(15',2i?)-2-phenylcyclopropyl]-5-(phenylsulf onyl)benzenesulfonamide;

2-methoxy-N-[(2i?)-2-phenylpropyl]-5-(phenylsulfonyl)benz enesulfonamide;

2-isopropyl-iV-(2-pb.enylethyl)-5-(phenylsulfonyl)benzene sulfonamide;

2-methyl-A/-(2-phenylethyl)-3-(phenylsulfonyl)benzenesulf onamide;

2-chloro-iV-(2-phenylethyl)-5-(phenylsulfonyl)benzenesulf onamide;

2-(2-hydroxy-2-methylpropyl)-N-(2-phenylethyl)-5- (phenylsulfonyl)benzenesulfonamide;

N- { [2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl} -L-phenylalaninamide; methyl N-{[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}-D-phenylalan inate;

N-(2,3 -dihydro- 1 H-inden- 1 -yl)-2-methyl-5-(phenylsulfonyl)benzenesulfonamide;

N-[2-(2-fluorophenyl)ethyl]-3-[(4-metb.ylphenyl)sulfonyl]-5 ₃ 6 ₅ 7,8-tetrahydronaphthalene-l- sulfonamide;

5-[(4-fluoropb.enyl)sulfonyl]-2-isopropyl-iV-[(2i?)-2-phe nylpropyl]benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-[(25)-2-phenyl propyl]benzenesulfonamide;

N-(2-phenylethyl)-5-(phenylsulfonyl)-2-propylbenzenesulfo namide;

5-(phenylsulfonyl)-2-propylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-iV-(2-phenyletb.yl)-2-propyl benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-propylbenzenesulfonamide;

N-(2-phenylethyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)- benzenesulfonamide;

2,4-diisopropyl-7V-(2-phenylethyl)-5-(phenylsulfonyl)benz enesulfonamide; iV-(2,3-dihydro-lH-inden-2-yl)-2,4-diisopropyl-5-(phenylsulf onyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2,4-diisopropyl-λ/-(2-pheny leth.yl)benzenesulfonamide; iV-(2,3-dihydro-lH-inden-2-yl)-5-[(4-fluorophenyl)sulfonyl]- 2,4- diisopropy lbenzenesulfonamide ;

N-(2-hydroxy-2-phenylethyl)-2-methyl-5-(phenylsulfonyl)be nzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-phenylethyl)- 2-methylbenzenesulfonamide;

2-ethyl-5-[(4-fluorophenyl)sulfonyl]-7V-(2-hydroxy-2-phen ylethyl)benzenesulfonamide;

N-(2-hydroxy-2-phenylethyl)-2,4-dimethyl-5-(phenylsulfony l)benzenesulfonamide; trans-iV-(2-hydroxy-l-methyl-2-plienylethyl)-2-methyl-5-(phe nylsulfonyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-iV-[trans-2-hydroxy-l-metliy l-2-phenylethyl]-2- methylbenzenesulfonamide;

2-ethyl-5-[(4-fluorophenyl)sulfonyl]-N-[(trans)-2-hydroxy -l-methyl-2- phenylethyl]benzenesulfonamide; iV-[(trans)-2-hydroxy-l-methyl-2-pb.enylethyl]-2,4-dimethyl- 5-

(phenylsulfonyl)benzenesulfonamide;

N-[(1S*,2S* )-2-hy droxycy clohexyl] -2-methy 1-5 -(pheny lsulfony l)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-N-(2-hydroxyethyl)-2-isoprop ylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-N-(2-pyridin-2-ylet hyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-N-(3-moφholin-4-yl propyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-N-(2-pyridin-4-ylet hyl)benzenesulfonamide;

2-methyl-5-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)benzen esulfonamide;

2-methyl-5-(phenylsulfonyl)-iV-(2-pyridin-4-ylethyl)benze nesulfonamide;

2-ethyl-5-(phenylsulfonyl)-iV-(2-pyridin-2-ylethyl)benzen esulfonamide;

2-methoxy-5-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)benze nesulfonamide;

2-methoxy-5-(phenylsulfonyl)-λ/ ^' -(2-pyridin-4-ylet]iyl)benzenesulfonamide;

5-[(4-chloropb.enyl)sulfonyl]-2-methyl-N-(2-pyridin-2-yle tb.yl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(2-pyridin-2-y lethyl)benzenesulfonamide;

2,4-dimethyl-5-(pb.enylsulfonyl)-N-(2-pyridin-2-ylethyl)b enzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2,4-dimethyl-N-(2-pyridin-2- ylethyl)benzenesulfonamide;

2-chloro-5-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)benzen esulfonamide;

2,3-dimethyl-5-(phenylsulfonyl)-iV-(2-pyridin-2-ylethyl)b enzenesulfonaniide;

2-me1iιyl-5-{[4-(methylamino)phenyl]sulfonyl}-iV-(2-pyri din-2-yletb.yl)benzenesulfonamide;

2-isopropyl-5-{[4-(methylamino)phenyl]sulfonyl}-iV-(2-pyr idin-2-ylethyl)benzenesulfonaniide;

5- { [4-( 1 -cyclohexy 1- 1 -hydroxy ethy l)phenyl] sulfony 1 } -2-methy l-N-(2-pyridin-2- ylethyl)benzenesulfonamide;

5 - { [4-( 1 -hydroxy- 1 -pheny lethyl)pheny 1] sulfony 1} -2-methy l-N-(2-pyridin-2- ylethyl)benzenesulfonamide;

5- { [4-( 1 -hydroxy- 1 -methyl-2-phenylethyl)phenyl] sulfonyl} -2-methyl-iV-(2-pyridin-2- ylethyl)benzenesulfonamide;

5 - [(3 -cyanopheny l)sulfonyl] -2-methy l-N-(2-pyridin-2-y lethy l)benzenesulfonamide ;

2-methyl-5-(l-naphthylsulfonyl)-N-(2-pyridin-2-ylethyl)be nzenesulfonamide;

5-[(3-hydroxyphenyl)sulfonyl]-2-methyl-iV-(2-pyridm-2-yle thyl)benzenesulfonamide;

5-[(3,5-difluorophenyl)sulfonyl]-2-methyl-iV-(2-pyridin-2 -ylethyl)benzenesulfonamide;

5-[(4-ethylphenyl)sulfonyl]-2-methyl-7V-(2-pyridin-2-ylet hyl)benzenesulfonamide;

5-[(3-acetylphenyl)sulfonyl]-2-methyl-iV-(2-pyridin-2-yle thyl)benzenesulfonamide;

5-[(2-ethoxyphenyl)sulfonyl]-2-methyl-iV-(2-pyridin-2-yle thyl)benzenesulfonamide;

5-[(2,5-dimethoxyphenyl)sulfonyl]-2-methyl-iV-(2-pyridin- 2-ylethyl)benzenesulfonamide;

5-[(2,3-dimethoxyphenyl)sulfonyl]-2-methyl-iV-(2-pyridin- 2-ylethyl)benzenesulfonamide;

5-[(2,4-dimethoxyphenyl)sulfonyl]-2-methyl-7V-(2-pyridin- 2-ylethyl)benzenesulfonamide;

2-methyl-N-(2-pyridin-2-ylethyl)-5-(pyridin-3-ylsulfonyl) benzenesulfonamide;

5-(lH-indol-5-ylsulfonyl)-2-methyl-λ/ ^' -(2-pyridin-2-ylethyl)benzenesulfonamide;

5-[(4-cyanophenyl)sulfonyl]-2-methyl-N-(2-pyridin-2-yleth yl)benzenesulfonamide;

5-{[3-(etb.ylsulfonyl)phenyl]sulfonyl}-2-methyl-λ/-(2-py ridin-2-ylethyl)beiizenesulfonamide;

2-methy 1-5 - [(2-methy lpheny l)sulfony 1] -/V-(2-pyridin-2-y lethy l)benzenesulfonamide ;

5-[(2-ethylphenyl)sulfonyl]-2-metb.yl-N-(2-pyridin-2-ylet hyl)benzenesulfonamide;

5-(biphenyl-2-ylsulfonyl)-2-metb.yl-N-(2-pyridin-2-ylethy l)benzenesulfonamide;

5-(biphenyl-4-ylsulfonyl)-2-methyl-N-(2-pyridin-2-ylethyl )benzenesulfonamide;

5-(biphenyl-3-ylsulfonyl)-2-methyl-iV-(2-pyridm-2-ylethyl )benzenesulfonamide;

5-[(4-tert-butylphenyl)sulfonyl]-2-isopropyl-ν-(2-pyridi n-2- ylethyl)benzenesulfonamide;

5-[(4-tert-butylphenyl)sulfonyl]-2-methyl-N-(2-pyridin-2- ylethyl)benzenesulfonamide;

5-[(3,5-dimethylphenyl)sulfonyl]-2-isopropyl-N-(2-pyridin -2-ylethyl)benzenesulfonamide;

5-[(3-chlorophenyl)sulfonyl]-2-isopropyl-iV-(2-pyridin-2- yletliyl)benzenesulfonamide;

2-isopropyl-5-[(3-methoxyphenyl)sulfonyl]-N-(2-pyridin-2- ylethyl)benzenesulfonamide;

2-isopropyl-5-[(2-methoxyphenyl)sulfonyl]-λ/-(2-pyridin- 2-ylethyl)benzenesulfonamide;

5-[(3,5-difluorophenyl)sulfonyl]-2-isopropyl-iV-(2-pyridi n-2-ylethyl)benzenesulfonamide;

2-cyclohexyl-5-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)be nzenesulfonamide;

2-cyclohexyl-5-[(4-fluorophenyl)sulfonyl]-N-(2-pyridin-2- ylethyl)benzenesulfonamide;

2-tert-butyl-5-(phenylsulfonyl)-iV-(2-pyridin-2-ylethyl)b enzenesulfonamide;

2,6-dimethyl-3-(phenylsulfonyl)-λ/-(2-pyridin-2-ylethyl) benzenesulfonamide;

5- { [5-(dimethylamino)- 1 -naphthyljsulfonyl} -2-isopropyl-N-(2-pyridin-2- ylethyl)benzenesulfonamide;

5-[(3-chloro-5-cyanopb.enyl)sulfonyl]-2-methyl-N-(2-pyrid in-2-ylethyl)benzenesulfonamide

2-methyl-3-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)benzen esulfonamide;

5-[(3,5-dichlorophenyl)sulfonyl]-2-isopropyl-N-(2-pyridin -2-ylethyl)benzenesulfonamide;

2-isopropyl-iV-(2-pyridin-2-ylethyl)-5-{[3-

(trifluoromethoxy)phenyl]sulfonyl}benzenesulfonamide;

5-{[4-(dimethylamino)phenyl]sulfonyl}-2-isopropyl-iV-(2-p yridin-2- ylethyl)benzenesulfonamide;

2-isopropyl-iV-(2-pyridin-2-ylethyl)-5-{[3-

(trifluoromethy l)pheny 1] sulfony 1} benzenesulfonamide ;

5-[(5-chloro-2-methoxyphenyl)sulfonyl]-2-isopropyl-N-(2-p yridin-2- ylethyl)benzenesulfonamide;

2-isopropyl-N-(2-pyridin-2-ylethyl)-5-(quinolin-8-ylsulfo nyl)benzenesulfonamide;

5-[(2,5-dichloro-3-thienyl)sulfonyl]-2-isopropyl-iV-(2-py ridin-2-ylethyl)benzenesulfonamide;

5-[(5-chloro-l,3-dimethyl-lH-pyrazol-4-yl)sulfonyl]-2-iso propyl-N-(2-pyridin-2- ylethy l)benzenesulfonamide ;

2-isopropyl-5-[(l-methyl-lH-imidazol-4-yl)sulfonyl]-N-(2- pyridin-2- y lethy l)benzenesulfonamide ;

5-[(3-chloro-2-metb.ylphenyl)sulfonyl]-2-isopropyl-N-(2-p yridin-2-ylethyl)benzenesulfonamide;

5-[(4,4-dimethyl-2-oxo-l,4-dihydro-2H-3,l-benzoxazin-6-yl )sulfonyl]-2-isopropyl-N-(2-pyridin-

2-ylethyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(2-pyridin-4- ylethyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(2-pyridin-3- ylethyl)benzenesulfonamide;

5-[(3-cyanophenyl)sulfonyl]-2-isopropyl-N-(2-pyridin-2-yl ethyl)benzenesulfonamide;

5-(lH-indol-5-ylsulfonyl)-2-isopropyl-iV ^: -(2-pyridin-2-yleth.yl)beiizenesulfonamide;

5-(phenylsulfonyl)-2-propyl-iV-(2-pyridin-2-ylethyl)benze nesulfonaniide;

5-[(4-fluorophenyl)sulfonyl]-2-propyl-N-(2-pyridin-2-ylet hyl)benzenesulfonamide;

5-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-2-(trifluorome thyl)benzenesulfonamide;

2-isopropyl-5-(phenylsulfinyl)-N-(2-pyridin-2-ylethyl)ben zenesulfonamide;

5-[(3-bromo-2-methylphenyl)sulfonyl]-2-isopropyl-iV ^" -(2-pyridin-2-ylethyl)benzenesulfonamide;

5-[(2-chloro-6-methylphenyl)sulfonyl]-2-isopropyl-iV ^r -(2-pyridin-2-ylethyl)benzenesulfonamide;

2-isopropyl-5-[(3-methylphenyl)sulfonyl]-N-(2-pyridin-2-y lethyl)benzenesulfonamide;

2-isopropyl-5-[(i?)-phenylsulfinyl]-N-(2-pyridin-2-ylethy l)benzenesulfonamide;

2-isopropyl-5-[(5)-phenylsulfinyl]-N-(2-pyridin-2-ylethyl )benzenesulfonamide;

2-bromo-5-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)benzene sulfonamide;

5-[(3-cyano-2-methylphenyl)sulfonyl]-2-isopropyl-N-(2-pyr idin-2-ylethyl)benzenesulfonamide;

5-[(3-acetyl-2-methylphenyl)sulfonyl]-2-isopropyl-iV-(2-p yridin-2-ylethyl)benzenesulfonamide;

5-[(3-chloro-4-fluorophenyl)sulfonyl]-2-isopropyl-iV-(2-p yridin-2-ylethyl)benzenesulfonamide;

5-[(4-fluoro-2-methylphenyl)sulfonyl]-2-isopropyl-iV-(2-p yridin-2-yletb.yl)benzenesulfonamide;

2-isopropyl-5-[(l-methyl-lH-indol-5-yl)sulfonyl]-iV-(2-py ridm-2-yletliyl)benzenesulfonamide;

2-isopropyl-5-{[2-methyl-4-(methylamino)phenyl]sulfonyl}- iV-(2-pyridin-2- ylethyl)benzenesulfonamide;

5-{[3-chloro-4-(methylamino)phenyl]sulfonyl}-2-isopropyl- iV-(2-pyridin-2- ylethyl)benzenesulfonamide;

2,4-diisopropyl-5-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl )benzenesulfonamide;

2,4-diisopropyl-5-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl )benzenesulfonamide;

2,4-diisopropyl-5-(phenylsulfonyl)-λ ^/' -(2-pyridin-4-ylethyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2,4-diisopropyl-iV-(2-pyridm -2-ylethyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2,4-diisopropyl-iV-(2-pyridi n-3-ylethyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2,4-diisopropyl-iV-(2-pyridi n-4-ylethyl)benzenesulfonamide;

2-chloro-5-(phenylsulfonyl)-iV-(2-pyridin-3-ylethyl)benze nesulfonamide;

2-chloro-5-(phenylsulfonyl)-iV-(2-pyridin-4-ylethyl)benze nesulfonamide;

5 - [(4-fluorophenyl)sulfony 1] -2-isopropy 1-N- [2-( 1 -oxidopyridin-3 - yl)ethy l]benzenesulfonamide ;

5-[(4-fluorophenyl)sulfonyl]-N-[2-(lH ^" -imidazol-4-yl)ethyl]-2-methylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-iV-[3-(lH ^" -imidazol-l-yl)propyl]-2-methylbenzenesulfonamide;

N- [2-( 1 H-imidazol-4-y l)ethy 1] -2-methy l-5-(phenylsulfony l)benzenesulfonamide ;

N-[3-(lH-imidazol-l-yl)propyl]-2-methyl-5-(phenylsulfonyl )benzenesulfonamide;

2-ethyl-N-[2-(lH-imidazol-4-yl)ethyl]-5-(phenylsulfonyl)b enzenesulfonamide;

2-ethyl-N-[3-(lH-imidazol-l-yl)propyl]-5-(phenylsulfonyl) benzenesulfonamide;

N-[2-(l/f-imidazol-4-yl)ethyl]-2-methoxy-5-(phenylsulfony l)benzenesulfonamide;

N- [3-( 1 H-imidazol- 1 -yl)propyl]-2-methoxy-5-(phenylsulfony l)benzenesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-N-[3-(lH-imidazol-l-yl)propy l]-2-methylbenzenesulfonamide;

5-[(4-azidophenyl)sulfonyl]-N-[3-(lH-imidazol-l-yl)propyl ]-2-metb.ylbenzenesulfonamide;

ν-[2-(lη-indol-3-yl)ethyl]-2-methyl-5-(phenylsulfonyl)b enzenesulfonamide;

N-[3-(lH ^" -imidazol-l-yl)propyl]-2-isopropyl-5-(phenylsulfonyl)benzene sulfonamide;

2-ethyl-5-[(4-fluorophenyl)sulfonyl]-N-[2-(lH ^" -irnidazol-l-yl)ethyl]benzenesulfonamide;

2-ethyl-5-[(4-fluorophenyl)sulfonyl]-N-[3-(lH-imidazol-l- yl)propyl]benzenesulfonamide;

5-({4-[ethyl(methyl)amino]phenyl}sulfonyl)-N-[3-(l/f-imid azol-l-yl)propyl]-2- methylbenzenesulfonamide;

N-[3-(l/f-imidazol-l-yl)propyl]-2-methyl-5-[(4-pyrrolidin -l- ylphenyl)sulfonyl]benzenesulfonamide;

N-[3-(li/-imidazol-l-yl)propyl]-4-methyl-3-(phenylsulfiny l)benzenesulfonamide;

5 - [(4-fluorophenyl)sulfony 1] -N- [2-( 1 H-imidazol- 1 -y l)ethy 1] -2-methy lbenzenesulfonamide;

N-[3-(lH-imidazol-l-yl)propyl]-2-methyl-5-{[4-

(methylamino)phenyl]sulfonyl}benzenesulfonamide;

5- { [4-(ethylamino)phenyl]sulfonyl} -N- [3 -( lH-imidazol- 1 -yl)propyl] -2- methylbenzenesulfonamide;

N- [3 -( 1 H-imidazol- 1 -y l)propy 1] -2-methy 1-5 - [(4-piperidin- 1 - ylphenyl)sulfonyl]benzenesulfonamide;

N-[3-(lH-imidazol-l-yl)propyl]-2-methyl-5-[(4-moφholin-4 - ylphenyl)sulfonyl]benzenesulfonamide;

N-[2-(lH-imidazol-l-yl)ethyl]-2-methyl-5-(phenylsulfonyl) benzenesulfonamide;

N-[3-(lH-imidazol-l-yl)propyl]-5-[(4-methoxyphenyl)sulfon yl]-2-methylbenzenesulfonamide;

N-[3-(lH-imidazol-l-yl)propyl]-5-[(2-methoxyphenyl)sulfon yl]-2-methylbenzenesulfonamide;

N- [3 -( 1 H-imidazol- 1 -yl)propy 1] -4-methy 1-3 -(phenylsulfony l)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-N-[2-(lH-imidazol-l-yl)ethyl ]-2-isopropylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-N-[3-(li/-imidazol-l-yl)prop yl]-2-isopropylbenzenesulfonamide;

N- [3 -( 1 H-imidazol- 1 -yl)propy 1] -5- [(3 -methoxypheny l)sulfony 1] -2-methy lbenzenesulfonamide;

N-[2-(lH-imidazol-l-yl)ethyl]-2,4-dimethyl-5-(phenylsulfo nyl)benzenesulfonamide;

N- [3 -( 1 H-imidazol- 1 -y l)propy 1] -2,4-dimethyl-5-(phenylsulfony l)benzenesulfonamide ;

5-[(4-fluorophenyl)sulfonyl]-N-[2-(lH-imidazol-l-yl)ethyl ]-2,4-dimethylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-N-[3-(lH-imidazol-l-yl)propy l]-2,4-dimethylbenzenesulfonamide;

2-chloro-iV-[3-(lH-imidazol-l-yl)propyl]-5-(phenylsulfony l)benzenesulfonamide;

N-[3-(lH-imidazol-l-yl)propyl]-5-[(4-isopropylphenyl)sulf onyl]-2-methylbenzenesulfonamide;

N-[3-(lH-imidazol-l-yl)propyl]-2-methyl-5-(2-naphthylsulf onyl)benzenesulfonamide;

5- [(3 ,4-dichloropheny l)sulfony 1] -N- [3 -( 1 H-imidazol- 1 -y l)propyl] -2-methy lbenzenesulfonamide ;

5- [(3 -chloropheny l)sulfony 1] -N- [3 -( 1 H-imidazol- 1 -y l)propyl] -2-methy lbenzenesulfonamide;

5-[(3,5-dimethylphenyl)sulfonyl]-N-[3-(lH-imidazol-l-yl)p ropyl]-2-methylbenzenesulfonamide;

5- [(3 ,5 -dichloropheny l)sulfony 1] -N- [3 -( 1 H-imidazol- 1 -y l)propy 1] -2-methy lbenzenesulfonamide;

5- [(2,5 -dichloropheny l)sulfonyl] -N- [3 -( lH-imidazol- 1 -y l)propy 1] -2-methy lbenzenesulfonamide ;

N-[3-(lH-imidazol-l-yl)propyl]-2-methyl-5-(phenylsulfinyl )benzenesulfonamide;

N- [2-( 1 H-imidazol- 1 -y l)ethy 1] -2,3 -dimethy 1-5 -(phenylsulfony l)benzenesulfonamide ;

N- [3 -( 1 H-imidazol- 1 -y l)propy 1] -2,3 -dimethy l-5-(pheny lsulfony l)benzenesulfonamide ;

5- { [4-(cyclohexy lamino)pheny 1] sulfony 1 } -N- [3 -( 1 H-imidazol- 1 -yl)propy 1] -2- methy lbenzenesulfonamide ;

5-({4-[(2-cyanoethyl)amino]phenyl}sulfonyl)-N-[3-(lH-imid azol-l-yl)propyl]-2- methylbenzenesulfonamide ;

5-[(4-{[(lS,2S)-l-(hydroxymethyl)-2-methylbutyl]amino}ρh enyl)sulfonyl]-N-[3-(lH-imidazol- l-yl)propyl]-2-methylbenzenesulfonamide;

7V-[3-(l/f-imidazol-l-yl)propyl]-2-methyl-5-({4-[(l- phenylethy l)amino]pheny 1 } sulfony l)benzenesulfonamide ;

5 - [(2,3 -dichloropheny l)sulfony 1] -N- [3 -( 1 H-imidazol- 1 -y l)propy 1] -2-methy lbenzenesulfonamide ;

λ/-[3-(l/f-imidazol-l-yl)propyl]-2-methyl-5-(2-tb.ienyls ulfonyl)benzenesulfonamide;

N-[3-(lH-imidazol-l-yl)propyl]-2-nαethyl-5-[(2-methyl-3- furyl)sulfonyl]benzenesulfonamide; iV-[3-(lH-imidazol-l-yl)propyl]-2-methyl-5-{[4-(tetrahydro-2 H-pyran-4- ylamino)phenyl]sulfonyl}benzenesulfonamide;

N- [3 -( 1 H-imidazol- 1 -yl)propy 1] -5 -( {4- [(3 -isopropoxypropyl)amino]pheny 1 } sulfony l)-2- methylbenzenesulfonamide;

5-( {4- [(cy clopropylmethy l)amino]pheny 1 } sulfony I)-N- [3 -( 1 H-imidazol- 1 -yl)propy 1] -2- methylbenzenesulfonamide;

5-({4-[(li?,2i?,45)-bicyclo[2.2.1]hept-2-ylamino]phenyl}s ulfonyl)-N-[3-(l/f-imidazol-l- yl)propyl]-2-methylbenzenesulfonamide;

5-{[4-(benzylamino)phenyl]sulfonyl}-N-[3-(lH ^" -imidazol-l-yl)propyl]-2- methylbenzenesulfonamide;

5-[(4-{[(15)-l-cyclohexylethyl]amino}phenyl)sulfonyl]-N-[3-( lH ^' -imidazol-l-yl)propyl]-2- methy lbenzenesulfonamide ;

5- [(4- { [( 1 R)- 1 -cy clohexy lethyl] amino} pheny l)sulfony I]-N- [3 -( 1 H-imidazol- 1 -y l)propyl] -2- methylbenzenesulfonamide;

5 -( {4- [(2-hy droxybuty l)amino]phenyl } sulfony I)-N- [3 -( 1 H-imidazol- 1 -y l)propyl] -2- methylbenzenesulfonamide;

N-[3-(lH ^" -imidazol-l-yl)propyl]-2-methyl-5-[(4-{[4-

(trifluoromethy l)benzy 1] amino } pheny l)sulfonyl]benzenesulfonamide;

5-[(2-chlorophenyl)sulfonyl]-N-[3-(lH-imidazol-l-yl)propy l]-2-methylbenzenesulfonamide;

ν-(tert-butyl)-2-methyl-5-(phenylsulfonyl)benzenesulfona mide;

5-[(4-tert-butylphenyl)sulfonyl]-N-[3-(lη-imidazol-l-yl) propyl]-2- isopropylbenzenesulfonamide;

5-[(4-tert-butylphenyl)sulfonyl]-N-[3-(lH-imidazol-l-yl)p ropyl]-2- methylbenzenesulfonamide;

5- [(4-fluoropheny l)sulfony 1] -N- [2-( 1 H-imidazol-4-yl)ethy 1] -2-isopropy lbenzenesulfonamide;

5-({4-[(2-cyanoethyl)amino]phenyl}sulfonyl)-iV-[2-(lH-imi dazol-l-yl)ethyl]-2- isopropylbenzenesulfonamide; iV-[2-(lH-imidazol-l-yl)ethyl]-2-isopropyl-5-{[4-

(methylamino)phenyl]sulfonyl}benzenesulfonamide;

5-({4-[(2-hydroxybutyl)amino]phenyl}sulfonyl)-iV ^' -[2-(lH ^" -imidazol-l-yl)ethyl]-2- isopropylbenzenesulfonamide;

5-[(4-{[(25)-l-(hydroxymethyl)-2-methylbu1yl]amino}phenyl )sulfonyl]-N-[2-(lH-imidazol-l- yl)ethyl]-2-isopropylbenzenesulfonamide;

N-[S-(I H-imidazol- 1 -y l)propyl] -2-methy 1-3 -(pheny lsulfony l)benzenesulfonamide ;

N-[3-(lH-Imidazol-l-yl)propyl]-5-(phenylsulfonyl)-2-propy lbenzenesulfonamide;

5-[(4-Fluorophenyl)sulfonyl]-N-[3-(lH-imidazol-l-yl)propy l]-2-propylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-[2-(2-methyl-l H-imidazol-l- yl)ethyl]benzenesulfonamide;

N-[2-(2-ethyl-l/i-imidazol-l-yl)ethyl]-5-[(4-fluorophenyl )sulfonyl]-2- isopropylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-iV-[2-(2-isoprop yl-lH-iniidazol-l- yl)ethyl]benzenesulfonamide;

N-[3-(lH-Imidazol-l-yl)propyl]-2,4-diisopropyl-5-(plienyl sulfonyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-N-[2-(l-methylpyrro lidin-2-yl)ethyl]benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-iV-(2-piperidin-l-y lethyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-me1iiyl-iV-(2-morpholin-4- ylethyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-metb.yl-N-[3-(2-oxopyrroli din-l-yl)propyl]benzenesulfonamide;

N-[3-(dimetb.ylamino)propyl]-5-[(4-fluorophenyl)sulfonyl] -2-metliylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-N-(2-methoxyethyl)-2-methylb enzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-iV-(3-pyrrolidin-l- ylpropyl)benzenesulfonamide;

5- [(4-fluorophenyl)sulfony l]-2-methyl-N- [3 -(4-methy lpiperazin- 1 - yl)propyl]benzenesulfonamide;

2-methyl-iV-(3-morpholin-4-ylpropyl)-5-(phenylsulfonyl)be nzenesulfonamide;

2-methyl-iV-[2-(l-methylpyrrolidin-2-yl)ethyl]-5-(phenyls ulfonyl)benzenesulfonamide;

2-methyl-5-(phenylsulfonyl)-λ'-(2-piperidin-l-ylethyl)be nzenesulfonaniide;

2-methyl-iV-(2-morpholin-4-ylethyl)-5-(phenylsulfonyl)ben zenesulfonamide;

2-methyl-N-[3-(2-oxopyrrolidin-l-yl)propyl]-5-(phenylsulf onyl)benzenesulfonamide;

2-methyl-5-(phenylsulfonyl)-iV-(3-pyrrolidin-l-ylpropyl)b enzenesulfonamide;

2-methy l-N-[3 -(4-methy lpiperazin- 1 -y l)propy 1] -5 -(pheny lsulfony l)benzenesulfonamide ;

2-ethyl-N-(2-morpholin-4-ylethyl)-5-(phenylsulfonyl)benze nesulfonamide;

2-ethyl-5-(phenylsulfonyl)-A/ ^" -(3-pyrrolidin-l-ylpropyl)benzenesulfonamide;

2-methoxy-N-(2-morpholin-4-ylethyl)-5-(phenylsulfonyl)ben zenesulfonamide;

2-methoxy-5-(plienylsulfonyl)-iV-(3-pyrrolidin-l-ylpropyl )benzenesulfonamide;

5-[(4-chlorophenyl)sulfonyl]-2-methyl-N-(2-moφb.olin-4-y lethyl)beiizenesulfonamide;

2-methyl-5-(phenylsulfonyl)-N-tetrahydro-2i7-pyran-4-ylbe nzenesulfonamide;

2-methyl-5-(phenylsulfonyl)-N-(2-tetrahydro-2H ^" -pyran-4-ylethyl)benzenesulfonamide;

2-ethyl-5-(phenylsulfonyl)-iV-tetrahydro-2H-pyran-4-ylben zenesulfonaniide;

2-ethyl-5-(phenylsulfonyl)-N-(2-tetrahydro-2/i-pyran-4-yl ethyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-iV-tetraliydro-2H-p yran-4-ylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-N-(2-tetrahydro-2H- pyran-4-ylethyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-tetrahydro-2/i ^' -pyran-4-ylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(2-tetrahydro- 2/f-pyran-4- ylethyl)benzenesulfonamide;

2,4-dimethyl-5-(phenylsulfonyl)-N-tetrahydro-2/f-pyran-4- ylbenzenesulfonamide;

2,4-dimethyl-5-(phenylsulfonyl)-N-(2-tetrahydro-2H-pyran- 4-ylethyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2,4-dimethyl-iV-(tetrahydro- 2H-pyran-4-yl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2,4-dimethyl-iV ^" -[2-(tetrahydro-2H-pyran-4- yl)ethyl]benzenesulfonamide;

2-chloro-iV-(2-morpholin-4-yleth.yl)-5-(phenylsulfonyl)be nzenesulfonamide;

2,3-dimethyl-5-(phenylsulfonyl)-N-(tetrahydro-2i ^: f-pyran-4-yl)benzenesulfonamide;

2,3-dimethyl-5-(phenylsulfonyl)-N-[2-(tetrahydro-2H-pyran -4-yl)ethyl]benzenesulfonatnide;

2-isopropyl-5-{[4-(methylamino)phenyl]sulfonyl}-λ/-(tetr ahydro-2H-pyran-4- yl)benzenesulfonamide;

2-isopropyl-5-{[4-(methylamino)phenyl]sulfonyl}-N-[2-(tet rahydro-2H-pyran-4- yl)ethyl]benzenesulfonamide;

2-chloro-5-(phenylsulfonyl)-N-(tetrahydro-2iϊ-pyran-4-yl )benzenesulfonamide;

5-[(4-bromophenyl)sulfonyl]-2-methyl-N-(tetrahydro-2i/-py ran-4-yl)benzenesulfonamide;

5-[(4-cyanophenyl)sulfonyl]-2-methyl-7V-(tetrahydro-2H-py ran-4-yl)benzenesulfonamide;

N-[3-(lH ^" -imidazol-l-yl)propyl]-2-methyl-5-(pyridin-2-ylsulfonyl)benz enesulfonamide;

5 - [(2,4-dichloropheny l)sulfony 1] -N- [3 -( 1 H-imidazol- 1 -y l)propy 1] -2-methy lbenzenesulfonamide ;

5-[(4-acetylphenyl)sulfonyl]-2-methyl-N-(tetrahydro-2H-py ran-4-yl)benzenesulfonamide;

5-[(4-bromophenyl)sulfonyl]-2-methyl-N-(2-pyridin-2-yleth yl)benzenesulfonamide;

2-methyl-5-(phenylsulfonyl)-N-(te1xahydro-2H-pyran-4-ylme thyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-N-(tetrahydro-2H-py ran-4-ylmethyl)benzenesulfonamide;

2-ethyl-5-[(4-fluorophenyl)sulfonyl]-N-(tetrahydro-2H-pyr an-4-ylmethyl)benzenesulfonamide;

2,4-dimethyl-5-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4- ylmethyl)benzenesulfonamide;

ν-(2,2-dimethylpropyl)-2-methyl-5-(phenylsulfonyl)benzen esulfonamide;

5-({4-[(lE)-N-hydroxyethanimidoyl]phenyl}sulfonyl)-2-meth yl-N-(tetrahydro-2H-pyran-4- y l)benzenesulfonamide ;

5-[(4-acetylphenyl)sulfonyl]-2-methyl-iV-(2-pyridin-2-yle thyl)benzenesulfonamide;

5- { [4-( 1 -hydroxy- 1 -methylethyl)phenyl] sulfony 1 } -2-methy l-iV-(2-pyridm-2- ylethyl)benzenesulfonamide;

2-methyl-5-(phenylsulfonyl)-N-(2,2,6,6-tetramethylpiperid in-4-yl)benzenesulfonamide;

N-(l-benzylpiperidin-4-yl)-2-methyl-5-(phenylsulfonyl)ben zenesulfonamide;

N-(l-benzylpyrrolidin-3-yl)-2-methyl-5-(phenylsulfonyl)be nzenesulfonamide; ethyl 4-({[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)piperi dine-l-carboxylate;

5-[(4-tert-butylphenyl)sulfonyl]-2-isopropyl-N-(tetrahydr o-2H-pyran-4- yl)benzenesulfonamide;

5-[(4-tert-butylphenyl)sulfonyl]-2-methyl-N-(tetrahydro-2 H-pyran-4- yl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(tetrahydro-2H -pyran-4- ylmethyl)benzenesulfonamide; tert-butyl 4-({[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)piperi dine-l- carboxylate;

2-methy 1-5 -(pheny lsulfony l)-N-piperidin-4-y lbenzenesulfonamide ;

2-methyl-5-(phenylsulfonyl)-N-[l-(phenylsulfonyl)piperidi n-4- yl]benzenesulfonamide;

N- [ 1 -(2-furoy l)piperidin-4-y 1] -2-methy l-5-(pheny lsulfony l)benzenesulfonamide ;

N-[l-(2-methoxybenzoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide;

N- [ 1 -(3 -methoxybenzoy l)piperidin-4-yl] -2-methy 1-5 - (phenylsulfony l)benzenesulfonamide;

N-[l-(3,4-dimethoxybenzoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide;

2-methyl-5-(phenylsulfonyl)-N-{l-[3-(trifluoromethyl)benz oyl]piperidin-4- yl}benzenesulfonamide;

N-[l-(4-chlorobenzoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide;

N-[l-(4-methoxybenzoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide;

2-methyl-N-[l-(4-methylbenzoyl)piperidin-4-yl]-5- (phenylsulfonyl)benzenesulfonamide;

N-[l-(methoxyacetyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide;

2-methyl-N-[l-(phenylacetyl)piperidin-4-yl]-5-(phenylsulf onyl)benzenesulfonamide;

N-[l-(cyclohexylcarbonyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide;

2,6-dimethyl-3-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4- yl)benzenesulfonamide;

N-[l-(cyclopropylcarbonyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide;

N-[l-(4-cyanobenzoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide;

N-[l-(3-cyanobenzoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide;

2-methyl-N-[l-(methylsulfonyl)piperidin-4-yl]-5- (phenylsulfonyl)benzenesulfonamide;;

N-(l-acetylpiperidin-4-yl)-2-methyl-5-(phenylsulfonyl)ben zenesulfonamide

N-(4- { [4-( { [2-methyl-5-(phenylsulfonyl)phenyl] sulfonyl} amino)piperidin- 1 - y 1] carbony 1 } pheny l)acetamide;

2-methyl-N- { 1 -[( 1 -methyl- 1 H-imidazol-4-yl)sulfonyl]piperidin-4-yl} -5-

(phenylsulfonyl)benzenesulfonamide;

2-methyl-5-(phenylsulfonyl)-N-[l-(2-thienylsulfonyl)piper idin-4- yl]benzenesulfonamide;

N-( 1 - { [5 -(dimethylamino)- 1 -naphthy 1] sulfonyl } piperidin-4-y l)-2-methyl-5 -

(phenylsulfonyl)benzenesulfonamide;

N-[I-(1 ,3-benzodioxol-5-ylcarbonyl)piperidin-4-yl]-2-methyl-5-

(phenylsulfonyl)benzenesulfonamide;

N-[l-(isoxazol-5-ylcarbonyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide;

N-[l-(N,N-dimethylglycyl)piperidm-4-yl]-2-methyl-5- (phenylsulfonyl)beiizenesulfonamide; prop-2-yn-l-yl 4-({[2-metb.yl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)piper idine- 1- carboxylate; methyl 4-( { [2-methyl-5-(phenylsulfonyl)phenyl] sulfonyl } amino)piperidme- 1 - carboxylate;

2-methoxyphenyl 4-({ [2-methyl-5- (phenylsulfonyl)phenyl] sulfonyl} amino)piperidine- 1 - carboxylate;

N-(tert-buty l)-4-( { [2-methy 1-5 -(pheny lsulfony l)pheny 1] sulfonyl } amino)piperidine- 1 - carboxamide;

N-cyclohexyl-4-({[2-methyl-5-(phenylsulfonyl)phenyl]sulfo nyl}amino)piperidine-l- carboxamide;

2-methyl-iV-(2-morpholin-4-ylethyl)-3-(phenylsulfonyl)ben zenesulfonamide;

2-methyl-N-[l-(2-naphthoyl)piperidin-4-yl]-5-(phenylsulfo nyl)benzenesulfonamide;

2-methyl-5-(phenylsulfonyl)-N-[l-(2-thienylcarbonyl)piper idin-4- yl]benzenesulfonamide; isobutyl 4-({[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)piperi dine-l- carboxylate;

N- { 1 -[4-(dimethylamino)benzoyl]piperidin-4-yl}-2-methyl-5-

(pheny lsulfony l)benzenesulfonamide ; ;

4-fluorophenyl 4-({ [2-methyl-5-(pb.enylsulfonyl)phenyl]sulfonyl}amino)piperidin e- 1 - carboxylate

N-ethyl-4-({[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}a mino)piperidine-l- carboxamide;

2-methyl-N-[l-(morpholin-4-ylcarbonyl)piperidin-4-yl]-5- (phenylsulfonyl)benzenesulfonamide;

N,N-dimethy l-4-( { [2-methy 1-5 -(pheny lsulfony l)pheny 1] sulfony 1 } amino)piperidine- 1 - carboxamide;

N-[l-(3,3-dimethylbutanoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide;

2-methyl-5-(phenylsulfonyl)-N-[l-(pyridin-3-ylcarbonyl)pi peridm-4- yl]benzenesulfonamide; tert-butyl 4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidine-l- carboxylate;

N-(l-{[5-(dimethylamino)-l-naphthyl]sulfonyl}piperidin-4- yl)-5-[(4- fluorophenyl)sulfonyl]-2- isopropylbenzenesulfonamide;

5- [(4-fluoropheny l)sulfonyl] -2-isopropy 1-N- [ 1 -(methoxyacety l)piperidin-4- yljbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-piperidin-4-yl benzenesulfonamide;

N-(l-benzylpiperidin-4-yl)-5-[(4-fluorophenyl)sulfonyl]-2 - isopropylbenzenesulfonamide; ethyl 4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl} sulfony l)amino]piperidine-l- carboxylate;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(2-piperidin-l - ylethyl)benzenesulfonamide; tert-butyl 4-{[(2-isopropyl-5-{[4-

(methylamino)phenyl]sulfonyl}phenyl)sulfonyl]amino}piperi dine-l-carboxylate;

N-(l-acetylpiperidin-4-yl)-5-[(4-fluorophenyl)sulfonyl]-2 - isopropylbenzenesulfonamide;

N-[l-(cyclopropylcarbonyl)piperidin-4-yl]-5-[(4-fluorophe nyl)sulfonyl]-2- isopropylbenzenesulfonamide;

N-[I -(4-cyanobenzoy l)piperidin-4-y 1] -5 - [(4-fluoropheny l)sulfony 1] -2- isopropylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(tetrahydrofur an-2- yhnethyl)benzenesulfonamide;

5-({4-[(2-cyanoethyl)amino]phenyl}sulfonyl)-2-isopropyl-N-(t etrahydro-2H ^' -pyran-4- yl)benzenesulfbnamide;

5-({4-[(2-cyanoethyl)amino]phenyl}sulfonyl)-2-isopropyl-N-(t etrahydro-2H ^" -pyran-4- ylmethyl)benzenesulfonamide;

5-({4-[(2-cyanoethyl)amino]phenyl}sulfonyl)-2-isopropyl-iV-[ 2-(tetrahydro-2H ^' -pyran-4- yl)ethyl]benzenesulfonamide;

N-(3',6'-dihydroxy-3-oxo-3H-spiro[2-benzofuran-l ₅ 9'-xanthen]-5-yl)-4-[({5-[(4- fluorophenyl)sulfonyl]-2-isopropylphenyl}sulfonyl)amino]pipe ridine-l- carbothioamide;

2-isopropyl-5-[(2-methylphenyl)sulfonyl]-N-(tetraliydro-2H ^' -pyran-4-yl)benzenesulfonamide;

5-[(3-chloro-2-methylphenyl)sulfonyl]-2-isopropyl-iV-(tet rahydro-2i/-pyran-4- yl)benzenesulfonamide;

2-isopropyl-5-{[4-(methylamino)phenyl]sulfonyl}-N-(tetrah ydro-2/i-pyran-4- ylmethyl)benzenesulfonamide;

5-{[4-(dimethylamino)phenyl]sulfonyl}-2-isopropyl-λ/-(te trahydro-2i7-pyran-4- yl)benzenesulfonamide;

5- { [4-(dimethylamino)phenyl]sulfonyl} -2-isopropyl-N-(tetrahydro-2i7-pyran-4- ylmethyl)benzenesulfonamide;

5-{[4-(dimethylamino)phenyl]sulfonyl}-2-isopropyl-N-[2-(t etrahydro-2H-pyran-4- yl)ethyl]benzenesulfonamide;

2-isopropyl-5- { [4-(4-methylpiperazin- 1 -yl)phenyl] sulfonyl} -iV-(tetrahydro-2H-pyran-4- yl)benzenesulfonamide;

2-isopropyl-5- { [4-(4-methylpiperazin- 1 -yl)phenyl] sulfonyl} -iV-(tetrahy dro-2H-pyran-4- ylmethyl)benzenesulfonamide ;

2-isopropyl-5- { [4-(4-methylpiperazin- 1 -y l)pheny 1] sulfonyl } -N-[2-(tetrahydro-2H-pyran-4- yl)ethyl]benzenesulfonamide;

5-(phenylsulfonyl)-2-propyl-N-(tetrahydro-2H-pyran-4-yl)b enzenesulfonamide;

5-(phenylsulfonyl)-2-propyl-N-(tetrahydro-2H-pyran-4-ylme thyl)benzenesulfonamide;

5-(phenylsulfonyl)-2-propyl-N-[2-(tetrahydro-2/i ^' -pyran-4-yl)ethyl]benzenesulfonaniide; tert-butyl 4-({[5-(phenylsulfonyl)-2-propylphenyl]sulfonyl}amino)piperi dine-l-carboxylate;

5 - [(4-fluoropheny l)sulfony 1] -2-propyl-λ/-(tetrahy dro-2H-pyran-4-y l)benzenesulfonamide ;

5-[(4-fluorophenyl)sulfonyl]-2-propyl-N-(tetrahydro-2H-py ran-4-ylmethyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-propyl-N-[2-(tetrahydro-2u f-pyran-4- yl)ethyl]benzenesulfonamide; tert-Butyl 4-[({5-[(4-fluorophenyl)sulfonyl]-2-propylphenyl}sulfonyl)am ino]piperidine-l- carboxylate;

2-isopropyl-5-{[4-(methylamino)phenyl]sulfonyl}-ν-piperi din-4- ylbenzenesulfonamide;

5-[(5-chloro-l,3-dimethyl-lH-pyrazol-4-yl)sulfonyl]-2-iso propyl-N-(tetrahydro-2/i-pyran-4- yl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-[l-(morpholin- 4-ylcarbonyl)piperidin- 4- yl]benzenesulfonamide;

4- [( { 5- [(4-fluoropheny l)sulfonyl] -2-isopropy lpheny 1 } sulfony l)amino] -N,N- dimethy lpiperidine-

1-carboxamide;

N-(l-benzylpiperidin-4-yl)-5-[(4-fluorophenyl)sulfonyl]-2 - methylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-methyl-N-piperidin-4-ylben zenesulfonamide;

5 -( { 4- [(2-cy anoethy l)(methy l)amino]pheny 1 } sulfony l)-2-isopropyl-iV-(tetrahydro-27f-pyran-4- yl)benzenesulfonamide;

5-({4-[(2-cyanoethyl)(methyl)amino]phenyl}sulfonyl)-2-iso propyl-iV-(tetrahydro-2H-pyran-4- ylmethyl)benzenesulfonamide;

N-(l-acetylpiperidin-4-yl)-5-[(4-fluorophenyl)sulfonyl]-2 - methylbenzenesulfonamide;

N-[I -(4-cy anobenzoy l)piperidin-4-y 1] -5 - [(4-fluoropheny l)sulfony 1] -2- methylbenzenesulfonamide;

4-[({5-[(4-fluorophenyl)sulfonyl]-2-methylphenyl}sulfonyl )amino]-N,N- dimethylpiperidine-l- carboxaniide;

5-[(4-fluorophenyl)sulfonyl]-N-[l-(methoxyacetyl)piperidi n-4-yl]-2- methylbenzenesulfonamide;

2-isopropyl-5-[(3-methoxyphenyl)sulfonyl]-N-(tetrahydro-2 //-pyran-4-yl)benzenesulfonamide;

5- { [4-(dimethy lamino)-2-methy lpheny 1] sulfony 1} -2-isopropyl-N-(2-pyridin-2- ylethyl)benzenesulfonamide;

2-(dimethylamino)-5-(phenylsulfonyl)-N-(2-pyridin-2-yleth yl)benzenesulfonamide;

5- [(4-fluoropheny l)sulfonyl] -2-methy 1-ν- [ 1 -(morpholin-4-y lcarbonyl)piperidin-4- yljbenzenesulfonamide;

2-chloro-5-[(3-methylphenyl)sulfonyl]-iV-(tetrahydro-2H-p yran-4-yl)benzenesulfonamide;

2-chloro-5-[(3-methoxyphenyl)sulfonyl]-λ/-(tetrahydro-2H -pyran-4-yl)benzenesulfonamide;

2-chloro-5-[(l-methyl-lH-indol-5-yl)sulfonyl]-iV-(tetrahydro -2i- ⁷ -pyran-4- yl)benzenesulfonamide;

5-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-(triflu oromethyl)benzenesulfonamide;

2,4-diisopropyl-5-(phenylsulfonyl)-N-(tetrahydro-2i7-pyra n-4-yl)benzenesulfonaniide;

2,4-diisopropyl-5-(phenylsulfonyl)-N-(tetrahydro-2H-pyran -4-ylmethyl)benzenesulfonamide;

2,4-diisopropyl-5-(phenylsulfonyl)-N-[2-(tetrahydro-2//-p yran-4-yl)ethyl]benzenesulfonamide;

5-[(4-Fluorophenyl)sulfonyl]-2,4-diisopropyl-N-(te1xahydr o-2H-pyran-4-yl)benzenesulfonamide;

2-chloro-5-[(4-fluorophenyl)sulfonyl]-N-(tetrahydro-2/f-p yran-4-yl)benzenesulfonamide; tert-butyl 4-({[2-chloro-5-(phenylsulfonyl)phenyl]sulfonyl}amino)piperi dine-l-carboxylate

2-chloro-5-(phenylsulfonyl)-N-piperidin-4-ylbenzenesulfon amide;; tert-butyl 4-[4-({4-isopropyl-3-[(tetrahydro-2/i-pyran-4- ylamino)sulfonyl]phenyl} sulfonyl)phenyl]piperazine- 1 -carboxylate

5-({4-cw-3,5-dimethylpiperazin-l-ylphenyl}sulfonyl)-2-iso propyl-iV-(tetrahydro-2H-pyran-4- yl)benzenesulfonamide;

5-({4-trα«j ⁱ -2,5-dimethylpiperazin-l-ylphenyl}sulfonyl)-2-isopropyl-N-(t etrahydro-2i ^: /-pyran-4- yl)benzenesulfonamide;

2-isopropyl-5-[(4-piperazin-l-ylphenyl)sulfonyl]-N-(tetra hydro-2H-pyran-4- yl)benzenesulfonamide;

5-[(4-Fluorophenyl)sulfonyl]-2,4-diisopropyl-iV-(tetrahyd ro-2H-pyran-4- ylmethyl)benzenesulfonamide ;

5-[(4-Fluorophenyl)sulfonyl]-2,4-diisopropyl-N-[2-(tetrah ydro-2H-pyran-4- y l)ethy l]benzenesulfonamide ;

2-chloro-iV-[3-(4-metliylpiperazm-l-yl)propyl]-5-(phenyls ulfonyl)benzenesulfonamide; l-{[2-chloro-5-(phenylsulfonyl)plienyl]sulfonyl}-iV,N-diethy lpyrrolidin-3-amine; ethyl l-{[2-chloro-5-(phenylsulfonyl)phenyl]sulfonyl}piperidine-3- carboxylate;

2-chloro-5-(phenylsulfonyl)-λ/-[l-(trifluoroacetyl)piper idm-4-yl]benzenesulfonamide;

2-chloro-iV ^r -[l-(2,2-dimethylpropanoyl)piperidin-4-yl]-5-(phenylsulfonyl )benzenesulfonamide;

N-(tert-butyl)-4-({[2-chloro-5-(phenylsulfonyl)phenyl]sul fonyl}amino)piperidine-l- carboxamide;

2-chloro-N-[l-(morpholin-4-ylcarbonyl)piperidin-4-yl]-5-( phenylsulfonyl)benzenesulfonamide;

2-chloro-iV-(l-cyanopiperidin-4-yl)-5-(phenylsulfonyl)ben zenesulfonamide;

N ³ -({5-[(4-fluorophenyl)sulfonyl]-2-methylphenyl}sulfonyl)-bet a-alaninamide;

methyl N-( { 5- [(4-fluoropheny l)sulfony 1] -2-methylpheny 1 } sulfony l)-beta-alaninate;

N-(2-cyanoethyl)-5-[(4-fluorophenyl)sulfonyl]-2-methylben zenesulfonamide; iV-{2-[({5-[(4-fluorophenyl)sulfonyl]-2-methylphenyl}sulfony l)amino]ethyl}acetamide;

N-[2-(diethylamino)ethyl]-5-[(4-fluorophenyl)sulfonyl]-2- methylbenzenesulfonamide;

N-[2-(dimethylamino)ethyl]-5-[(4-fluorophenyl)sulfonyl]-2 -methylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-N-(3-methoxypropyl)-2-methyl benzenesulfonamide;

N- [3 -(diethy lamino)propyl] -5 - [(4-fluoropheny l)sulfony 1] -2-methy lbenzenesulfonamide ;

N- ({5-[(4-fluorophenyl) sulfony 1] -2-methy lphenyl} sulfonyl)-beta-alanine; iV ³ -{[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}-beta-alaninam ide; methyl N- { [2-methyl-5-(phenylsulfonyl)phenyl] sulfonyl} -beta-alaninate;

N-[2-(diethylamino)ethyl]-2-methyl-5-(phenylsulfonyl)benz enesulfonamide;

N-[2-(dimethylamino)ethyl]-2-methyl-5-(phenylsulfonyl)ben zenesulfonamide; iV-(3-methoxypropyl)-2-methyl-5-(phenylsulfonyl)benzenesulfo namide;

N- [3 -(dimethy lamino)propy 1] -2-methy 1-5 -(pheny lsulfony l)benzenesulfonamide;

N-(2-methoxyethyl)-2-methyl-5-(phenylsulfonyl)benzenesulf onamide;

N-[3-(diethylamino)propyl]-2-methyl-5-(phenylsulfonyl)ben zenesulfonamide; methyl N- { [2-ethyl-5-(phenylsulfonyl)phenyl]sulfonyl} -beta-alaninate;

2-ethyl-N-(3-methoxypropyl)-5-(phenylsulfonyl)benzenesulf onamide;

N-[3-(dimethylamino)propyl]-2-ethyl-5-(phenylsulfonyl)ben zenesulfonamide;

2-ethyl-N-(2-methoxyethyl)-5-(phenylsulfonyl)benzenesulfo namide;

ν- [3 -(diethy lamino) propyl]-2-ethyl-5- (phenylsulfonyl) benzene sulfonamide; methyl N-{[2-methoxy-5-(phenylsulfonyl)phenyl]sulfonyl}-beta-alanin ate;

2-methoxy-N-(3-methoxypropyl)-5-(phenylsulfonyl)benzenesu lfonamide;

N-[3-(dimethylamino)propyl]-2-methoxy-5-(phenylsulfonyl)b enzenesulfonamide;

2-methoxy-N-(2-methoxyethyl)-5-(phenylsulfonyl)benzenesul fonamide;

N-[3-(diethylamino)propyl]-2-methoxy-5-(phenylsulfonyl)be nzenesulfonamide;

2-methyl-5-(phenylsulfonyl)-ν-propylbenzenesulfonamide;

N-(l-ethylpropyl)-2-methyl-5-(phenylsulfonyl)benzenesulfo namide;

N-cyclobutyl-2-methyl-5-(phenylsulfonyl)benzenesulfonamid e;

N-cyclopentyl-2-methy 1-5 -(pheny lsulfony l)benzenesulfonamide ;

N-cyclohexyl-2-methyl-5-(phenylsulfonyl)benzenesulfonamid e;

2-methyl-5-(phenylsulfonyl)-N-(2,2,2-trifluoroethyl)benze nesulfonamide;

N-(2-hydroxy- 1 , 1 -dimethy lethyl)-2-methyl-5-(phenylsulfonyl)benzenesulfonamide;

N-cyclopropyl-2-methyl-5-(phenylsulfonyl)benzenesulfonami de;

N-cyclopropyl-5-[(4-fluorophenyl)sulfonyl]-2-isopropylben zenesulfonamide;

N-cyclobutyl-5-[(4-fluorophenyl)sulfonyl]-2-isopropylbenz enesulfonamide;

N-cy clopentyl-5 - [(4-fluoropheny l)sulfony 1] -2-isopropylbenzenesulfonamide ;

N-cyclohexyl-5-[(4-fluorophenyl)sulfonyl]-2-isopropylbenz enesulfonamide;

N-cyclopentyl-5-(phenylsulfonyl)-2-propylbenzenesulfonami de;

N-cyclopentyl-5-[(4-fluorophenyl)sulfonyl]-2-propylbenzen esulfonamide;

N-cyclopentyl-2,4-diisopropyl-5-(phenylsulfonyl)benzenesu lfonamide;

N-cyclopentyl-5-[(4-fluorophenyl)sulfonyl]-2,4-diisopropy lbenzenesulfonamide;

2-chloro-N-(2-cyanoethyl)-5-(phenylsulfonyl)berizenesulfo namide; methyl N-{[2-chloro-5-(phenylsulfonyl)phenyl]sulfonyl}-2-methylalan inate;

N-[2-(3,4-dimethoxyphenyl)ethyl]-N,2-dimethyl-5-(phenylsu lfonyl)benzenesulfonamide;

N-allyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-methyl-5-(phen ylsulfonyl)benzenesulfonamide;

N- [2-(3 ,4-dimethoxyphenyl)ethyl] -2-methyl-5-(phenylsulfonyl)-N-prop-2- ynylbenzenesulfonamide;

N-[2-(2-fluorophenyl)ethyl]-N,2-dimethyl-5-[(4-methylphen yl)sulfonyl]benzenesulfonamide;

ν-allyl-ν- [2-(2 -fluorophenyl) ethyl] -2-methy 1-5- [(4-methylphenyl) sulfonyl] benzene sulfonamide;

N-[2-(2-fluorophenyl)ethyl]-2-methyl-5-[(4-methylphenyl)s ulfonyl]-N-prop-2- ynylbenzenesulfonamide;

N,2-dimethyl-N-(2-phenylethyl)-5-(phenylsulfonyl)benzenes ulfonamide;

1 -{ [2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}-4-(2-oxo-2-pyrr olidin-l -ylethyl)piperazine;

N,N-diethyl-N-[2-(4-{[2-methyl-5-(phenylsulfonyl)phenyl]s ulfonyl}piperazin-l-yl)ethyl]amine;

4-[2-(4-{[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}pipe razin-l-yl)ethyl]morpholine;

1 - { [2-methy l-5-(phenylsulfonyl)phenyl] sulfonyl} -4-(2-pyrrolidin- 1 -ylethy l)piperazine;

4-[3-(4-{[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}pipe razin-l-yl)propyl]morpholine;

2-ethyl-N-methyl-N-(2-phenylethyl)-5-(phenylsulfonyl)benz enesulfonamide;

1 - { [2-ethyl-5-(phenylsulfonyl)phenyl] sulfonyl} -4-(2-oxo-2-pyrrolidin- 1 -ylethyl)piperazine;

N,N-diethyl-N-[2-(4-{[2-ethyl-5-(phenylsulfonyl)phenyl]su lfonyl}piperazin-l-yl)ethyl]amine;

4-[2-(4-{[2-ethyl-5-(phenylsulfonyl)phenyl]sulfonyl}piper azin-l-yl)ethyl]morpholine;

1 - { [2-ethyl-5-(phenylsulfonyl)phenyl]sulfonyl} -4-(2-pyrrolidin-l -ylethyl)piperazine;

4-[3-(4-{[2-ethyl-5-(phenylsulfonyl)phenyl]sulfonyl}piper azin-l-yl)propyl]morpholine; N-[I -(cy clopropylcarbony l)piperidin-4-y 1] -N~( { 5 -[(4-fluoropheny l)sulfony 1] -2- methylphenyljsulfonytycyclopropanecarboxamide;

1 - { [2-chloro-5-(phenylsulfonyl)phenyl]sulfonyl} -4-pyrrolidin-l -ylpiperidine; 4-[2-(4-{[2-chloro-5-(phenylsulfonyl)phenyl]sulfonyl}piperaz in-l-yl)ethyl]morpholine; 1 -(1 ,3-benzodioxol-5-ylmethyl)-4-{ [2-chloro-5-(phenylsulfonyl)phenyl]sulfonyl}piperazine; tert-buty^l-IP-chloro-S-φhenylsulfony^phenyysulfony^pyrroli din-S-y^carbamate; tert-butyl (l-{[2-chloro-5-(phenylsulfonyl)phenyl]sulfonyl}piperidin-4- yl)carbamate; 2-chloro-iV-methyl-5-(phenylsulfonyl)-iV-(2-pyridin-2-ylethy l)benzenesulfonamide; 1 - { [2-chloro-5-(phenylsulfonyl)phenyl]sulfonyl} -4-[(2,5-dimethyl-lH-pyrrol- 1 - y l)methy l]piperidine ;

2-chloro-N-(2-hydroxy-l,l-dimethylethyl)-5-(phenylsulfonyl)b enzenesulfonamide; 2-chloro-iV-(cyanomethyl)-5-(phenylsulfonyl)benzenesulfonami de; iV-(2-cyanoethyl)-5-[(4-fluorophenyl)sulfonyl]-2-isopropylbe nzenesulfonamide; 2-methyl-N-(3-oxo-3-pyrτolidin-l-ylpropyl)-5-(phenylsulfony l)benzenesulfonamide; N-(ter^butyl)-λ^-{[2-methyl-5-(phenylsulfonyl)phenyl]sulfon yl}-β-alaninamide; N ³ - { [2-methy l-5-(ρheny lsulfonyl)pheny 1] sulfony 1 } -N-( 1,2,3 ,4-tetrahy dronaphthalen- 1 -y I)- β - alaninamide;

N-methyl-λ^-{[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl }-N-phenyl-β-alaninamide; 2-methyl-N-[3-(6-methyl-3,4-dihydroquinolin-l(2H)-yl)-3-oxop ropyl]-5- (phenylsulfonyl)benzenesulfonamide;

2-chloro-N-(2-hydroxyethyl)-5-(phenylsulfonyl)benzenesulf onamide; 2-chloro-N-(2-hydroxy-l-methylethyl)-5-(phenylsulfonyl)benze nesulfonamide; 2-chloro-iV- [2-hydroxy- 1 -(hy droxymethy l)ethy 1] -5 -(pheny lsulfony l)benzenesulfonamide ; iV-(2-cyanoethyl)-5-(pb.enylsulfonyl)-2-(trifluoromethyl)ben zenesulfonamide; N-(2-hydroxyethyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)ben zenesulfonamide; N-(2-hydroxy-l-methylethyl)-5-(phenylsulfonyl)-2-(trifluorom ethyl)benzenesulfonamide; N-[(l-S)-2-hydroxy-l-methylethyl]-5-(phenylsulfonyl)-2-(trif luoromethyl)benzenesulfonamide; N-[(li?)-2-hydroxy-l-methylethyl]-5-φhenylsulfonyl)-2-(trif luoromethyl)benzenesulfonamide; 5-[(4-fluorophenyl)sulfonyl]-iV-(2-hydroxy-l-methylethyl)-2- isopropylbenzenesulfonamide; 5- [(4-fluoropheny l)sulfonyl] -N- [ 1 -(hy droxymethy l)-2-methy lpropy 1] -2- isopropylbenzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-N-(2-hydroxybutyl)-2-isoprop ylbenzenesulfonamide;

N-(2-cyanoethyl)-5-[(3-methoxyphenyl)sulfonyl]-2-(trifluo romethyl)benzenesulfonamide;

5-[(3-chlorophenyl)sulfonyl]-iV-(2-cyanoethyl)-2-(trifluo romethyl)benzenesulfonamide;

5-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-ylmetliyl)-2- (trifluoromethyl)benzenesulfonamide;

N-(2-morpholin-4-ylethyl)-5-(phenylsulfonyl)-2-(trifluoro methyl)benzenesulfonamide;

N-(3-morpholin-4-ylpropyl)-5-(plienylsulfonyl)-2-(trifluo romethyl)benzenesulfonamide;

N-(3-methoxypropyl)-5-(phenylsulfonyl)-2-(trifluoromethyl )benzenesulfonamide;

N-[l-(hydroxymethyl)-2-methylpropyl]-5-(phenylsulfonyl)-2 -

(trifluoromethyl)benzenesulfonamide;

N-[(lR)-l-(hydroxymethyl)propyl]-5-(plienylsulfonyl)-2-(t rifluoromethyl)benzenesulfonamide;

N-(2-hydroxy ethyl)-5 - [(3 -methoxypheny l)sulfony 1] -2-(trifluoromethy l)benzenesulfonamide ;

N-(2-cyanoethyl)-5-[(4-methoxyphenyl)sulfonyl]-2-(trifluo romethyl)benzenesulfonamide;

N-(2-cyanoethyl)-5-[(4-hydroxyphenyl)sulfonyl]-2-(trifluo romethyl)benzenesulfonamide;

N-[(l-hydroxycyclohexyl)methyl]-5-(phenylsulfonyl)-2-(tri fluoromethyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(2-piperidin-3 - ylethyl)benzenesulfonamide;

N-{[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl }-β-alanine;

4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfony l}amino)butanoic acid; tert-bu1yl 4-[({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl} amino)methyl]piperidine-

1-carboxylate;

5-(phenylsulfonyl)-N-(piperidin-4-ylmethyl)-2-(trifluorom ethyl)benzenesulfonamide; tert-butyl [trans-A-{{ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)cyclohexyl]carbama te;

4-oxo-4-{4-[({[5-(phenylsulfonyl)-2-(trifluoromethyl)phen yl]sulfonyl}aniino)methyl]piperidin- l-yl}butanoic acid;

5-oxo-5-{4-[({[5-(phenylsulfonyl)-2-(trifluoromethyl)phen yl]sulfonyl}amino)methyl]piperidin- l-yl}pentanoic acid;

3-({4-[({[5-(pb.enylsulfonyl)-2-(trifluoromethyl)phenyl]s ulfonyl}amino)methyl]piperidin-l- yl}sulfonyl)benzoic acid; tert-butyl 2-[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]pyrrolidine- l-carboxylate;

5-(phenylsulfonyl)-iV-(2-pyrrolidin-2-ylethyl)-2-(trifluo romethyl)benzenesulfonamide;

{2-[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sul fonyl}ammo)ethyl]pyrrolidin-l-

yl} acetic acid;

4-oxo-4-{2-[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)ph enyl]sulfonyl}amino)ethyl]pyrrolidin- l-yl}butanoic acid;

3-({2-[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl}amino)ethyl]pyrrolidin-l- yl}sulfonyl)benzoic acid; ter^utyl 4-[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfony l}ammo)ethyl]piperidine-

1-carboxylate; methyl 3 -( { [2-isopropyl-5-(phenylsulfonyl)phenyl] sulfony 1} amino)cyclohexanecarboxylate; methyl 4-({[2-isopropyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)cyc lohexanecarboxylate; methyl trans-A-[{{ [2-isopropyl-5-

(phenylsulfony^pheny^sulfonyljamino^ethyycyclohexanecarbo xylate;

5-(phenylsulfonyl)-N-(2-piperidin-4-ylethyl)-2-(trifluoro methyl)benzenesulfonamide;

{4-[({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfo nyl}amino)methyl]piperidin-l- yl} acetic acid;

{4-[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sul fonyl}amino)ethyl]piperidin-l- yl} acetic acid; methyl 3-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)cyclohexanecarboxy late; methyl 4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfonyl } amino)cyclohexanecarboxy late; methyl trans A-[({ [5-(phenylsulfonyl)-2-

(trifluoromethy^phenyljsulfonyljamino^ethyljcyclohexaneca rboxylate;

3-({[2-isopropyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino) cyclohexanecarboxylic acid;

4-( { [2-isopropyl-5-(phenylsulfonyl)phenyl] sulfonyl} amino)cyclohexanecarboxylic acid; trans-4-[({ [2-isopropyl-5-

(pheny lsulfonyl)phenyl] sulfonyl } amino)methy 1] cyclohexanecarboxy lie acid;

3-{4-[({[5 -(pheny lsulfony l)-2-(trifluoromethy l)pheny 1] sulfonyl} amino)methy l]piperidin- 1 - yl} benzoic acid;

3-{4-[2-({ [5-(pheny lsulfony l)-2-(trifluoromethyl)phenyl] sulfonyl } amino)ethy ljpiperidin- 1 - yl}benzoic acid;

N-(trαrø-4-aminocyclohexyl)-5-(phenylsulfonyl)-2-(trifl uoromethyl)benzenesulfonamide;

3-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfony l}amino)cyclohexanecarboxylic acid;

4-( { [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl} amino)cyclohexanecarboxylic acid; rra;w-4-[({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)methyl]cyclohexane carboxy lie acid;

N-(trβ77j'-4-hydroxycyclohexyl)-5-(phenylsulfonyl)-2-(tr ifluoromethyl)benzenesulfonamide; tert-butyl 4-[({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)carbonyl]piperidin e-l-carboxylate;

N- { [5 -(phenylsulfony l)-2-(trifluoromethy l)pheny 1] sulfonyl } piperidine-4-carboxaniide ;

5-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2-(triflu oromethoxy)benzenesulfonamide;

2-isopropyl-5-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-y l)benzenesulfonamide;

5-(phenylsulfonyl)-iV-piperidin-4-yl-2-(trifluoromethyl)b enzenesulfonamide;

2-Methoxy-5-(phenylsulfonyl)-iV-(tetrahydro-2H-pyran-4-yl )benzenesulfonamide;

5-[(3-metlioxyphenyl)sulfonyl]-λ/ ^' -(tetraliydro-2H ^' -pyran-4-yl)-2-

(trifluoromethyl)benzenesulfonamide;

5-[(3-hydroxyphenyl)sulfonyl]-iV-(tetrahydro-2H-pyran-4-y l)-2-

(trifluoromethyl)benzenesulfonamide;

5- [(3 -chloropheny l)sulfony 1] -iV-(tetrahy dro-2H-pyran-4-y l)-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-iV-[(3S)-piperidin-3-yl]-2-(trifluorom ethyl)benzenesulfonamide;

5-(phenylsulfonyl)-iV-[(3i?)-piperidin-3-yl]-2-(trifluoro metliyl)benzenesulfonamide;

5-[(l,2-dimethyl-lH-indol-5-yl)sulfonyl]-λ/-piperidin-4- yl-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-iV-[(35)-pyrrolidin-3-yl]-2-(trifluoro methyl)benzenesulfonamide;

5-(phenylsulfonyl)-iV-[(3i?)-pyrrolidin-3-yl]-2-(trifluor omethyl)benzenesulfonamide;

2-methyl-5-(phenylsulfonyl)-N-(tetrahydro-2η-thiopyran-4 -yl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(tetrahydro-2H -thiopyran-4- yl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-N-(tetrahydro-2H-pyran-4-yl) -2-

(trifluoromethyl)benzenesulfonamide;

5-[(2-fluorophenyl)sulfonyl]-N-(tetrahydro-2H-pyran-4-yl) -2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-iV-pyrrolidin-3-yl-2-(trifluoromethyl) benzenesulfonamide;

N-[(2R*,4S*,6S*)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-5- [(4- fluorophenyl)sulfonyl]-2- methylbenzenesulfonamide ;

5- { [4-(methylamino)pheny 1] sulfonyl} -N-piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide;

5-{[4-(dimethylamino)phenyl]sulfonyl}-N-ρiρeridin-4-yl- 2-

(trifluoromethyl)benzenesulfonamide;

5-({4-[(2-hydroxyethyl)amino]phenyl}sulfonyl)-iV-piperidm -4-yl-2-

(trifluoromethyl)benzenesulfonamide;

N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-5-[(4-fluorop henyl)sulfonyl]-2- isopropylbenzenesulfonamide ;

5 - { [2-(methy lamino)pheny 1] sulfonyl } -N-piperidin-4-yl-2-(trifluoromethy l)benzenesulfonamide ;

5-{[2-(dimethylamino)phenyl]sulfonyl}-iV-piperidm-4-yl-2-

(trifluoromethyl)benzenesulfonamide;

5-({2-[(2-h.ydroxyethyl)amino]phenyl}sulfonyl)-λ/-piperi din-4-yl-2-

(trifluoromethyl)benzenesulfonamide;

2-ethyl-5-(phenylsulfonyl)-7V-piperidin-4-ylbenzenesulfon amide;

2,3-dimethyl-5-(phenylsulfonyl)-iV-piperidin-4-ylbenzenes ulfonamide;

2,4-dimethyl-5-(phenylsulfonyl)-N-piperidin-4-ylbenzenesu lfonamide;

2-isopropyl-5-(phenylsulfonyl)-λ/ ^' -piperidin-4-ylbenzenesulfonamide;

5-(phenylsulfonyl)-N-piperidin-4-yl-2-propylbenzenesulfon amide;

2-isopropyl-5-(phenylsulfonyl)-N-(2,2,6,6-tetramethylpipe ridin-4-yl)benzenesulfonamide;

5-(phenylsulfonyl)-iV-(2,2,6,6-tetramethylpiperidin-4-yl) -2-

(trifluoromethyl)benzenesulfonamide;

5-[(4-methoxyphenyl)sulfonyl]-N-piperidin-4-yl-2-(trifluo rometh.yl)benzenesulfonamide;

5-[(3-bromophenyl)sulfonyl]-N-piperidin-4-yl-2-(trifluoro methyl)benzenesulfonamide;

2-chloro-iV- [ 1 -(4-fluorobenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)benzenes ulfonamide;

2-chloro-iV-[l-(4-cyanobenzoyl)piperidin-4-yl]-5-(phenyls ulfonyl)benzenesulfonamide;

2-chloro-5-(phenylsulfonyl)-iV-{l-[4-(trifluoromethyl)ben zoyl]piperidin-4- y 1 } benzenesulfonamide ;

5-(phenylsulfonyl)-2-(trifluoromethyl)-iV-{l-[4-(trifluor omethyl)benzoyl]piperidin-4- y 1 } benzenesulfonamide; iV-[l-(2-chlorobenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-[l-(2-niethoxybenzoyl)piperidin-4-yl]-5-(phenylsulfonyl )-2-

(trifluoromethyl)benzenesulfonamide;

TV-[I -(3-chloroben2;oyl)piperidin-4-yl]-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

TV-[I -(3 ,4-difluorobenzoyl)piperidin-4-yl] -5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

TV-[I -(3 ,5-difluorobenzoyl)piperidin-4-yl] -5-(pheny lsulfony l)-2-

(trifluoromethyl)beiizenesulfonamide;

7V-[l-(2,6-dimethoxybenzoyl)piperidin-4-yl]-5-(phenylsulf onyl)-2-

(trifluoromethyl)benzenesulfonamide;

/V-[l-(2,4-dimethoxybenzoyl)piperidin-4-yl]-5-(phenylsulf onyl)-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-N-{l-[4-(trifluoromethoxy)benzoyl]pipe ridin-4-yl}-2-

(trifluoromethyl)benzenesulfonamide;

7V-{l-[2-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl }-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

7V-{l-[3-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl }-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

TV- [ 1 -(3 ,4-dichlorobenzoy l)piperidin-4-yl] -5 -(pheny lsulfony l)-2-

(trifluoromethyl)benzenesulfonamide;

TV-[l-(4-chlorobenzoyl)piperidin-4-yl]-5-(phenylsulfonyl) -2-

(trifluoromethyl)benzenesulfonamide;

TV-(l-isonicotinoylpiperidin-4-yl)-5-(phenylsulfonyl)-2-( trifluoromethyl)benzenesulfonamide;

TV-[l-(2-chloro-6-methoxyisonicotinoyl)piperidin-4-yl]-5- (phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

TV-[l-(2-chloro-4-fluorobenzoyl)piperidin-4-yl]-5-(phenyl sulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-TV-[l-(2,4,6-trifluorobenzoyl)piperidi n-4-yl]-2-

(trifluoromethyl)benzenesulfonamide;

TV-[I -(4-tert-butylbenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

TV-(4-{[4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl ]sulfonyl}amino)piperidin-l- y 1] carbony 1 } pheny l)acetamide;

5-(pheny lsulfony l)-2-(trifluoromethy I)-TV-(I -{ [4-

(trifluoromethyl)phenyl]carbonothioyl}piperidin-4-yl)benz enesulfonamide; iV-[l-(4-te7Y-butylbenzoyl)piperidin-4-yl]-5-[(3-methoxyphen yl)sulfonyl]-2-

(trifluoromethyl)benzenesulfonamide; iV-[l-(4-tert-butylbenzoyl)piperidin-4-yl]-5-[(3-chloropheny l)sulfonyl]-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-N-{l-[2-(trifluoromethoxy)benzoyl]pipe ridin-4-yl}-2-

(trifluoromethyl)benzenesulfonamide; iV-(l-benzoylpiperidin-4-yl)-5-(phenylsulfonyl)-2-(trifluoro methyl)benzenesulfonamide;

N- [ 1 -(4-tert-buty lbenzoy l)pyrrolidin-3 -y 1] -5-(pheny lsulfony l)-2-

(trifluoromethyl)benzenesulfonamide;

N-[I -(4-tert-buty lbenzoy l)piperidin-4-y 1] -5 - [(3 -hydroxypheny l)sulfony 1] -2-

(trifluoromethyl)benzenesulfonamide;

N- [ 1 -(4-benzoy lbenzoy l)piperidin-4-yl]-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide; iV-[l-(3-benzoylbenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)-2 -

(trifluoromethyl)benzenesulfonamide; l-Isopropyl-4-(phenylsulfonyl)benzene;

2-Isopropyl-λ/-[l-(2-methoxybenzoyl)piperidin-4-yl]-5-(p henylsulfonyl)benzenesulfonamide;

N-[l-(3-Fluorobenzoyl)piperidin-4-yl]-2-isopropyl-5-(phen ylsulfonyl)benzenesulfonamide; iV-[l-(4-Fluorobenzoyl)piperidin-4-yl]-2-isopropyl-5-(plieny lsulfonyl)benzenesulfonamide;

7V-[l-(2-Fluorobenzoyl)piperidin-4-yl]-2-isopropyl-5-(phe nylsulfonyl)benzenesulfonamide;

2-Isopropyl-5-(phenylsulfonyl)-7V-{l-[4-(trifluoromethyl) benzoyl]piperidin-4- y 1 } benzenesulfonamide ;

2-Isopropyl-7V-[l-(l-naphthoyl)piperidin-4-yl]-5-(phenyls ulfonyl)benzenesulfonamide;

2-Isopropyl-N-[l-(2-naphthoyl)piperidin-4-yl]-5-(phenylsu lfonyl)benzenesulfonamide;

N-[l-(3-Cyanobenzoyl)piperidin-4-yl]-2-isopropyl-5-(pheny lsulfonyl)benzenesulfonamide;

N-[l-(4-Cyanobenzoyl)piperidin-4-yl]-2-isopropyl-5-(pheny lsulfonyl)benzenesulfonamide; jV-[l-(4-tert-Butylbenzoyl)piperidin-4-yl]-2-isopropyl-5-(ph enylsulfonyl)benzenesulfonamide;

N-[l-(2-Ethoxy-l-naphthoyl)piperidin-4-yl]-2-isopropyl-5- (phenylsulfonyl)benzenesulfonamide;

N-[l-(2-chloro-6-methylisonicotinoyl)piperidin-4-yl]-5-(p henylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-[l-(2,6-dichloroisonicotinoyl)piperidin-4-yl]-5-(phenyl sulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-{l-[4-(dimethylamino)benzoyl]piperidin-4-yl}-5-(phenyls ulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-{l-[(6-chloropyridin-3-yl)carbonyl]piperidin-4-yl}-5-(p henylsulfonyl)-2-

(trifluoromethyl)benzenesulfonaniide;

N-(I -[(2,5-dichloropyridin-3-yl)carbonyl]piperidin-4-yl} -5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-[l-(2-chloroisonicotinoyl)piperidin-4-yl]-5-(phenylsulf onyl)-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfony I)-N- { 1 -[(6-pyrrolidin- 1 -ylpyridin-3 -yl)carbony l]piperidin-4-yl } -2-

(trifluoromethyl)benzenesulfonamide;

N-(l-{[6-(dimethylamino)pyridin-3-yl]carbonyl}piperidin-4 -yl)-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-{1- [(6-oxo- 1 - { [5-(pheny lsulfony l)-2-(trifluoromethy l)pheny 1] sulfony 1 } - 1 ,6-dihy dropyridin-3 - yl)carbonyl]piperidin-4-yl}-5-(phenylsulfonyl)-2-(trifluorom ethyl)benzenesulfonamide;

N-{l-[(6-phenylpyridin-3-yl)carbonyl]piperidin-4-yl}-5-(p henylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-{l-[(6-morpholin-4-ylpyridin-3-yl)carbonyl]piperidin-4- yl}-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-N-[l-(2-pyrrolidin-l-ylisonicotinoyl)p iperidin-4-yl]-2-

(trifluorometb.yl)benzenesulfonamide;

N-{1- [(6-oxo- 1 ,6-dihy dropyridin-3 -yl)carbony l]piperidin-4-y 1} -5 -(pheny lsulfony l)-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-N-[l-(pyridin-3-ylcarbonyl)piperidin-4 -yl]-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-N-[l-(pyridin-2-ylcarbonyl)piperidm-4- yl]-2-

(trifluoromethyl)benzenesulfonamide;

N-{l-[4-(methylthio)benzoyl]piperidin-4-yl}-5-(phenylsulf onyl)-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-2-(trifluoromethyl)-N-(l-{[6-(trifluor oniethyl)pyridin-3- yl]carbonyl}piperidin-4-yl)benzenesulfonamide;

N- {1 -[4-(methylsulfinyl)benzoyl]piperidin-4-yl} -5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-iV-[l-(l,3-thiazol-4-ylcarbonyl)piperi din-4-yl]-2-

(trifluoromethyl)benzenesulfonamide; tert-butyl 4-({ [5-(phenylsulfonyl)-2-(trifluorometliyl)phenyl]sulfonyl}amin o)piperidine-l - carboxylate; tert-butyl (3S)-3-( { [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl} amino)piperidine- 1 - carboxylate; tert-butyl (3i?)-3-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulf onyl}amino)piperidine-l- carboxylate; tert-butyl 4-[({5-[(4-fluorophenyl)sulfonyl]-2- methylphenyl}sulfonyl)amino]piperidine-l- carboxylate; tert-butyl (3<S)-3 -( { [5-(phenylsulfony l)-2-(trifluoromethy l)pheny 1] sulfonyl } amino)pyrrolidine- 1 - carboxylate; tert-butyl (3i?)-3 -( { [5-(phenylsulfony l)-2-(trifluoromethy l)pheny 1] sulfonyl } amino)pyrrolidine- 1 - carboxylate; tert-butyl 4-({ [5-[(4-fluoroρhenyl)sulfonyl]-2-

(trifluoromethy l)phenyl] sulfonyl } amino)piperidine- 1 -carboxylate; tert-butyl 4-( { [2-ethyl-5-(phenylsulfonyl)phenyl] sulfonyl} amino)piperidine- 1 -carboxylate; tert-butyl 4-({[2,3-dimethyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)pi peridine-l-carboxylate; tert-butyl 4-({[2,4-dimethyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)pi peridine-l-carboxylate; tert-butyl 4-( { [2-isopropy 1-5 -(pheny lsulfonyl)pheny 1] sulfonyl } ammo)piperidine- 1 -carboxylate;

4- { [3 -( { [ 1 -(tert-butoxy carbony l)piperidin-4-yl] amino } sulfony l)-4-

(trifluoromethyl)phenyl] sulfonyl } benzoic acid;

4-oxo-4-[4-({[5-(pb.enylsulfonyl)-2-(trifluoromethyl)phen yl]sulfonyl}amino)piperidin-l- yljbutanoic acid;

4-oxo-4-[3-({[5-(phenylsulfonyl)-2-(trifluoromethyl)pheny l]sulfonyl}amino)pyrrolidin-l- yl]butanoic acid;

5-oxo-5-[4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)pheny l]sulfonyl}amino)piperidin-l- yljpentanoic acid;

5-oxo-5-[3-({[5-(phenylsulfonyl)-2-(trifluoromethyl)pheny l]sulfonyl}amino)pyrrolidin-l- yl]pentanoic acid;

N-[I -(N,N-dimethy lgly cy l)piperidin-4-y 1] -5 -(phenylsulfony l)-2-

(trifluoromethyl)benzenesulfonamide; tert-butyl 4-{2-oxo-2-[4-({[5-(ρhenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl} amino)piperidin- 1 -yl] ethyl }piperidine- 1 -carboxylate;

5-(phenylsulfonyl)-N-[l-(piperidin-4-ylacetyl)piperidin-4 -yl]-2-

(trifluoromethyl)benzenesulfonamide;

N-[l-(N-methylglycyl)piperidin-4-yl]-5-(phenylsulfonyl)-2 -

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-N-[l-(pyrrolidin-l-ylacetyl)piperidin- 4-yl]-2-

(trifluoromethyl)benzenesulfonamide;

N-[l-(morpholin-4-ylacetyl)piperidin-4-yl]-5-(phenylsulfo nyl)-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-N-[l-(piperazin-l-ylacetyl)piperidin-4 -yl]-2-

(trifluoromethyl)benzenesulfonamide;

N-{l-[3-(methylthio)propanoyl]piperidin-4-yl}-5-(phenylsu lfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-{l-[3-(methylsulfϊnyl)propanoyl]piperidin-4-yl}-5-(phe nylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-[I-(I H-imidazol- 1 -y lacetyl)piperidin-4-yl]-5 -(phenylsulfony l)-2-

(trifluoromethyl)benzenesulfonamide;

4- [( { 5- [(4-fluoropheny l)sulfonyl] -2-isopropy lphenyl } sulfony l)amino] -ν- 1 - naphthy lpiperidine-

1 -carbothioamide;

ν-(2-fluorophenyl)-4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropy lphenyl} sulfonyl)amino]piperidine- 1 -carbothioamide;

4- [( { 5 - [(4-fluoropheny l)sulfonyl] -2-isopropy lphenyl} sulfony l)amino] -N-(2- methylphenyl)piperidine-l-carbothioamide; ethyl ({4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidin-l- y 1 } carbonothioy l)carbamate ;

N-butyl-4- [( { 5- [(4-fluoropheny l)sulfony 1] -2- isopropy lphenyl } sulfony l)amino]piperidine- 1 - carbothioamide;

4- [( { 5- [(4-fluoropheny l)sulfonyl] -2-isopropy lphenyl } sulfony l)amino] -N-(4- methoxypheny l)piperidine- 1 -carbothioamide ;

methyl 4-[({4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidin-l- yl} carbonothioyl)amino]benzoate; methyl N-({4-[({ 5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl} sulfonyl)amino]piperidin- 1 - yl} carbonothioyl)glycinate;

4-[({5-[(4-fluorophenyl)sulfonyl]-2-isopropylphenyl}sulfo nyl)amino]-N-(2- morpholin-4- ylethyl)piperidine- 1 -carbothioamide;

4-[({5-[(4-fluorophenyl)sulfonyl]-2-isopropylphenyl}sulfo nyl)amino]-N-(3- nitrophenyl)piperidine- 1 -carbothioamide;

3- [({4- [({5- [(4-fluoropheny l)sulfony 1] -2- isopropylphenyl } sulfony l)amino]piperidin- 1 - yl} carbonothioyl)amino]benzoic acid;

4-[({5-[(4-fluorophenyl)sulfonyl]-2 -isopropylphenyl} sulfony l)ammo]-N-pyridin-3- ylpiperidine-

1 -carbothioamide;

4- [( { 5- [(4-fluoropheny l)sulfonyl] -2 -isopropylphenyl } sulfony l)amino] -N- [4-

(trifluoromethy l)pheny l]piperidine- 1 -carbothioamide ; iV-(4-tert-butylphenyl)-4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carbo xamide;

3 -( { [4-( { [5-(pheny lsulfonyl)-2-(trifluoromethy l)pheny 1] sulfony 1} amino)piperidin- 1 - yl]carbonothioyl}amino)benzoic acid; tert-butyl 4-{ [4-({ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino )piperidin-l - yl] carbony 1 } piperidine- 1 -carboxy late ;

5-(phenylsulfonyl)-N-[l-(piperidin-4-ylcarbonyl)piperidin -4-yl]-2-

(trifluoromethyl)benzenesulfonamide; tert-butyl (2S)-2-{ [4-({ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino )piperidin-

1 -yl] carbonyl}pyrrolidine- 1 -carboxylate;

5-(phenylsulfonyl)-iV-(l-L-prolylpiperidin-4-yl)-2-(trifl uoromethyl)benzenesulfonamide; tert-butyl (2i?)-2-{[4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl}amino)piperidin-

1 -yl] carbonyl}pyrrolidine- 1 -carboxylate;

5-(phenylsulfonyl)-N-(l-D-prolylpiperidin-4-yl)-2-(triflu oromethyl)benzenesulfonamide;

N-[I -(I -acetyl-L-prolyl)piperidin-4-yl]-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide; tert-butyl (55)-2-oxo-5-{[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]car bonyl}pyrrolidine-l -carboxylate;

N-[l-(5-oxo-L-prolyl)piperidin-4-yl]-5-(plienylsulfonyl)- 2-(trifluoromethyl)benzenesulfonamide;

N-[I -(I -methyl-L-prolyl)piperidin-4-yl]-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide; fe^butyl (4i?)-4-{[4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl}amino)piperidin-

1 -y 1] carbony 1 } - 1 ,3 -thiazolidine-3 -carboxy late ;

5-(phenylsulfonyl)-N-{l-[(4i?)-l,3-thiazolidin-4-ylcarbon yl]piperidin-4-yl}-2-

(trifluoromethyl)benzenesulfonamide; tert-butyl (3i?)-3-{[4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl}amino)piperidin-

1 -yl]carbonyl} pyrrolidine- 1 -carboxylate; tert-butyl (35)-3-{[4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]s ulfonyl}amino)piperidin-

1 -yl]carbonyl} pyrrolidine- 1 -carboxylate;

5-(phenylsulfonyl)-N-{l-[(3i?)-pyrrolidin-3-ylcarbonyl]pi peridin-4-yl}-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-N-{l-[(35)-pyrrolidin-3-ylcarbonyl]pip eridin-4-yl}-2-

(trifluoromethy l)benzenesulfonamide ; tert-butyl (4i?)-4-{ [4-({ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino )piperidin-

1 -y 1] carbony 1 } - 1 ,3 -thiazolidine-3 -carboxylate 1 -oxide;

N-( 1 - { [(3R)- 1 -acety lpyrrolidin-3 -yl] carbonyl } piperidin-4-y l)-5-(pheny lsulfony l)-2-

(trifluoromethyl)benzenesulfonamide;

N-(I -{ [(3S)-I -acetylpyrrolidin-3-yl]carbonyl}piperidin-4-yl)-5-(phenylsul fonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-[l-(l-isobutyryl-L-prolyl)piperidin-4-yl]-5-(phenylsulf onyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-(I-[I -(2,2-dimethylpropanoyl)-L-prolyl]piperidin-4-yl} -5-(pheny lsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-{l-[l-(3,3-dimethylbutanoyl)-L-prolyl]piperidin-4-yl}-5 -(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-{l-[l-(cyclohexylcarbonyl)-L-prolyl]piperidin-4-yl}-5-( phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-(I-[I -(morpholin-4-ylcarbonyl)-L-proly l]piperidin-4-y 1 } -5-(pheny lsulfony l)-2-

(trifluoromethyl)benzenesulfonamide;

(2S)-N-(tert-butyl)-2-([4-(([5-(phenylsulfonyl)-2-

(Mfluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]carbo nyl}pyrrolidine-l-carboxamide;

(25)-N-phenyl-2-{[4-({[5-(phenylsulfonyl)-2-(trifluoromet liyl)phenyl]sulfonyl}amino)piperidin- l-yl]carbonyl}pyrrolidine-l-carboxamide; iV-{l-[l-(methylsulfonyl)-L-prolyl]piperidin-4-yl}-5-(pb.eny lsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-[l-(l-benzoyl-L-prolyl)piperidin-4-yl]-5-(phenylsulfony l)-2-

(trifluoromethyl)benzenesulfonamide;

N-(I -{ 1 -[4-(dimethylamino)benzoyl]-L-prolyl}piperidin-4-yl)-5-(phen ylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-[I-(I -isonicotinoy 1-L-proly l)piperidin-4-yl] -5 -(pheny lsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-(I-(I- [(6-chloropyridin-3 -y l)carbony 1] -L-proly 1 } piperidin-4-y l)~5-(pheny lsulfony l)-2-

(trifluoromethyl)benzenesulfonamide;

4- [((2S)-2- { [4-( { [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl} amino)piperidin- 1 - yl]carbonyl}pyrrolidin-l -yl)sulfonyl]benzoic acid;

N-[l-(N,N-dimethylglycyl-L-prolyl)piperidin-4-yl]-5-(phen ylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-[I-(I -benzyl-L-prolyl)piperidin-4-yl]-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-{l-[l-(cyclohexylmethyl)-L-prolyl]piperidin-4-yl}-5-(ph enylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-{1 -[I -(3,3-dimethylbutyl)-L-prolyl]piperidin-4-yl}-5-(phenylsulfo nyl)-2-

(trifluoromethyl)benzenesulfonamide;

(25)-N-ethyl-2-{[4-(([5-(phenylsulfonyl)-2-(trifluorometb .yl)phenyl]sulfonyl}amino)piperidin-l- y^carbonyllpyrrolidine-l-carboxamide;

(25)-Nλ-dimethyl-2-( [4-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]car bonyl}pyrrolidine-l-carboxamide; tert-butyl (25)-2- { [4-( ( [5-[(3-cyanoρhenyl)sulfonyl]-2-

(1xifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]car bonyl}pyrrolidine-l-carboxylate;

N-[l-(2-hydroxy-2-methylpropyl)piperidin-4-yl]-5-(phenyls ulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-2-(trifluoromethyl)-N- ( 1 - [4-(trifluoromethyl)benzyl]piperidin-4-

yl}benzenesulfonamide;

N-[l-(cyanomethyl)piperidin-4-yl]-5-φhenylsulfonyl)-2-(t rifluoromethyl)benzenesulfonamide;

λ/-[l-(2-oxo-2-phenylethyl)piperidin-4-yl]-5-(phenylsulf onyl)-2-

(trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-2-(trifluoromethyl)-N-{l-[4-(trifluoro niethyl)phenyl]piperidin-4- yl}benzenesulfonamide;

λ/-[l-(2-hydroxyethyl)piperidin-4-yl]-5-(phenylsulfonyl) -2-

(trifluoromethyl)benzenesulfonamide;

2-Isopropyl-N-[(li?*,55'*)-8-methyl-8-azabicyclo[3.2.1]oc t-3-yl]-5-

(phenylsulfonyl)benzenesulfonamide monohydrochloride;

[4-( { [5 -(pheny lsulfony l)-2-(trifluorometliy l)pheny 1] sulfony 1} amino)piperidin- 1 -y 1] acetic acid;

2-[4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulf onyl}amino)piperidin-l-yl]acetamide;

5-(phenylsulfonyl)-iV-[l-(2H-tetrazol-5-ylmeth.yl)piperid in-4-yl]-2-

(trifluoromethyl)benzenesulfonamide;

3-[4-({[5 -(pheny lsulfony l)-2-(trifluoromethy l)pheny 1] sulfony 1} amino)piperidin- 1 -yl]propanoic acid;

3 - [4-( { [5 -(pheny lsulfony l)-2-(trifluoromethy l)pheny 1] sulfony 1} amino)piperidin- 1 -y ljbenzoic acid;

4- [4-( { [5-(pheny lsulfonyl)-2-(trifluoromethy l)pheny 1] sulfony 1 } amino)piperidin- 1 -yljbenzoic acid;

-Y-[l-(3-cyanophenyl)piperidin-4-yl]-5-(phenylsulfonyl)-2 -(trifluoromethyl)benzenesulfonamide;

2- [4-( { [5 -(pheny lsulfony l)-2-(trifluoromethyl)pheny 1] sulfony 1} amino)piperidin- 1 - yljpropanamide;

N-[l-(2-morpholin-4-ylethyl)piperidin-4-yl]-5-(phenylsulf onyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-[(1R*, SS^-δ-Methyl-δ-azabicycloP^.lJoctO-ylJ-S^henylsulfonyl)^-

(trifluoromethyl)benzenesulfonamide;

(2i?)-2-[4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)pheny l]sulfonyl}amino)piperidin-l- yljpropanamide;

(2jS)-2-[4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)pheny l]sulfonyl}amino)piperidin-l- yl]propanamide ; methyl [4-( { [5-(pheny lsulfony l)-2-(trifluoromethyl)phenyl]sulfonyl} amino)piperidin- 1 -

yl]acetate;

N-methy 1-2- [4-( { [5-(pheny lsulfony l)-2-(trifluoromethy l)pheny 1] sulfony 1 } amino)piperidin- 1 - yl]acetamide;

λζN-dimethy 1-2- [4-( { [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl} amino)piperidin- 1 - yljacetamide; iV-isopropyl-2-[4-( { [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl} amino)piperidin- 1 - yl]acetamide;

N-[l-(2-morpholin-4-yl-2-oxoethyl)piperidin-4-yl]-5-(phen ylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide;

7V-{l-[(4-tert-butylphenyl)sulfonyl]piperidin-4-yl}-5-(ph enylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-N-[l-(phenylsulfonyl)piperidin-4-yl]-2 -(trifluoromethyl)benzenesulfonamide; 3-{[4-({[5 -(pheny lsulfony l)-2-(trifluoromethy l)pheny 1] sulfonyl } amino)piperidin- 1 - yl]sulfonyl}benzoic acid;

4- { [4-( { [5 -(pheny lsulfony l)-2-(trifluoromethy l)pheny 1] sulfonyl} amino)piperidin- 1 - yl] sulfonyl} benzoic acid;

N- { 1 - [(4-hydroxypheny l)sulfonyl]piperidin-4-y 1 } -5 -(pheny lsulfony l)-2- (trifluoromethyl)benzenesulfonamide; methyl 3-{ [4-({ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino )piperidin-l - y 1] sulfonyl } benzoate;

N-{l-[(3-cyanophenyl)sulfonyl]piperidin-4-yl}-5-(phenylsu lfonyl)-2- (trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-iV-(l-{[3-(2H ^" -tetrazol-5-yl)phenyl]sulfonyl}piperidin-4-yl)-2- (trifluoromethyl)benzenesulfonamide;

5-(phenylsulfonyl)-iV-(2-pyridin-3-ylethyl)-2-(trifluorom ethoxy)benzenesulfonamide; 2-isopropyl-5-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)benzen esulfonainide; 2-isopropyl-5-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)benzen esulfonamide; 5-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-2-(trifluoromethy l)benzenesulfonamide; l-Methoxy-4-(phenylsulfonyl)benzene;

λ/ ^" -[2-(l-oxidopyridin-3-yl)ethyl]-5-(phenylsulfonyl)-2-(triflu oromethyl)benzenesulfonamide; 5-[(4-fluorophenyl)sulfonyl]-iV-(2-hydroxy-2-pyridin-2-yleth yl)-2- isopropylbenzenesulfonamide;

N-(2-hydroxy-2-pyridin-2-ylethyl)-2-isopropyl-5-(phenylsu lfonyl)benzene-sulfonamide;

N-(2-hydroxy-2-pyridin-2-ylethyl)-2,4-dimethyl-5-(phenyls ulfonyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-iV-(2-hydroxy-2-pyridin-3-yl ethyl)-2- isopropylbenzenesulfonamide;

N-(2-hydroxy-2-pyridin-3-ylethyl)-2-isopropyl-5-(phenylsu lfonyl)benzenesulfonamide;

N-(2-hydroxy-2-pyridin-3-yleth.yl)-2,4-dimetliyl-5-(pheny lsulfonyl)benzenesulfonamide;

N-[2-(l/f-Imidazol-l-yl)ethyl]-5-(phenylsulfonyl)-2-(trif luoromethyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-pyridin-3-yle thyl)-2-methylbenzenesulfonaniide;

N-(2-hydroxy-2-pyridin-3-ylethyl)-5-(phenylsulfonyl)-2-(t rifluoromethyl)benzenesulfonamide;

5-[(3-methoxyphenyl)sulfonyl]-iV-(2-pyridin-3-ylethyl)-2- (trifluoromethyl)benzenesulfonamide;

5-[(3-chlorophenyl)sulfonyl]-N-(2-pyridin-3-ylethyl)-2-(1 xifluorometb.yl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-pyridin-2-yle th.yl)-2-methylbenzenesulfonamide;

N-(2-hydroxy-2-pyridin-2-ylethyl)-5-(phenylsulfonyl)-2-(t rifluorometb.yl)benzenesulfonamide;

5-(phenylsulfonyl)-ν-(2-pyridin-4-ylethyl)-2-(trifluorom etliyl)benzenesulfonaniide;

5-[(4-hydroxyphenyl)sulfonyl]-N-(2-pyridm-3-ylethyl)-2-(t rifluorometliyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-N-[2-(lH-imidazol-l-yl)ethyl ]-2-

(trifluoromethyl)benzenesulfonamide;

5-[(2-fluorophenyl)sulfonyl]-N-[2-(lH-imidazol-l-yl)ethyl ]-2-

(trifluoromethyl)benzenesulfonamide ;

5-(Phenylsulfonyl)-2-propyl-iV-(2-pyridin-4-ylethyl)benze nesulfonaniide;

5-(phenylsulfonyl)-N-[2-(2H-tetrazol-5-yl)ethyl]-2-(trifl uoromethyl)benzenesulfonamide;

5-[(4-Fluorophenyl)sulfonyl]-2-propyl-iV-(2-pyridin-3-yle thyl)benzenesulfonamide;

5-[(4-Fluorophenyl)sulfonyl]-2-propyl-iV-(2-pyridin-4-yle thyl)benzenesulfonamide;

5-(Phenylsulfonyl)-2-propyl-iV-(2-pyridin-3-ylethyl)benze nesulfonaniide;

2-isopropyl-5-(phenylsulfonyl)-iV-(pyridin-4-ylmethyl)ben zenesulfonamide;

5-(phenylsulfonyl)-N-(pyridin-4-ylmethyl)-2-(trifluoromet hyl)benzenesulfonamide;

N-[(6-chloropyridin-3-yl)methyl]-5-(phenylsulfonyl)-2-(tr ifluoroniethyl)benzenesulfonamide;

5-(phenylsulfonyl)-A/-[(6-pyrrolidin-l-ylpyridin-3-yl)met hyl]-2-

(trifluoromethyl)benzenesulfonamide;

N-[(6-morpholin-4-ylpyridin-3-yl)methyl]-5-(phenylsulfony l)-2-

(trifluoromethyl)benzenesulfonamide;

2-chloro-iV-[(li? ^:1: ,2i?*)-2-hydroxy-l-methyl-2-phenylethyl]-5-

(phenylsulfonyl)benzenesulfonamide;

N-(2-hydroxy-2-phenyletiiyl)-5-(phenylsulfonyl)-2-(trifluoro methyl)benzenesulfonamide; iV-[(li? ^:i: ,2i2 ^:1: )-2-hydroxy-l-methyl-2-phenylethyl]-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N- [( 15',2i?)-2-hydroxy- 1 -methyl-2-phenylethyl] -5-(phenylsulfony l)-2-

(trifluoromethyl)benzenesulfonamide;

N-[(li? ₅ 25)-2-hydroxy-l-methyl-2-phenylethyl]-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-[(l(S)-l-benzyl-2-hydroxyethyl]-5-(phenylsulfonyl)-2-(t rifluoromethyl)benzenesulfonamide;

N-[(15)-2-hydroxy-l-(l/f-indol-3-ylmethyl)etb.yl]-5-(phen ylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

5-[(4-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-phenylethyl)- 2-isopropylbenzenesulfonamide;

JV-(2-hydroxy-2-phenylethyl)-2-isopropyl-5-(phenylsulfony l)benzenesulfonamide;

N-[(2R)-2-hydroxy-2-phenylethyl]-5-(phenylsulfonyl)-2-(tr ifluoromethyl)benzenesulfonamide;

N-[(2S)-2-hydroxy-2-phenylethyl]-5-(phenylsulfonyl)-2-(tr ifluoromethyl)benzenesulfonamide;

4- [2-( { [5 -(pheny lsulfony l)-2-(trifluoromethy l)pheny 1] sulfony 1} amino)ethy l]benzoic acid;

N-[2-(4-aminophenyl)ethyl]-5-(phenylsulfonyl)-2-(trifluor omethyl)benzenesulfonamide;

N-[2-(4-methoxyphenyl)etih.yl]-5-(phenylsulfonyl)-2-(trif luoromethyl)benzenesulfonamide;

N-(4-aminobenzyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)b enzenesulfonaniide;

N-[2-(4-hydroxyphenyl)ethyl]-5-(phenylsulfonyl)-2-(triflu oroniethyl)benzenesulfonamide; methyl 4-[({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl} amino)methyl]benzoate; methyl 4-[({[2-isopropyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)me thyl]benzoate; iV-[2-(4-bromophenyl)ethyl]-5-(phenylsulfonyl)-2-(trifluorom ethyl)benzenesulfonamide;

3-[({4-[({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)methyl]phenyl}amin o)sulfonyl]benzoic acid;

N-(4-bromobenzyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)b enzenesulfonamide;

N-[2-(4-cyanophenyl)ethyl]-5-(phenylsulfonyl)-2-(trifluor omethyl)benzenesulfonamide; methyl 4-[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfony l}amino)ethyl]benzoate;

4'-[({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfo nyl}amino)methyl]biphenyl-3- carboxylic acid;

4'-[({[5-(phenylsulfonyl)-2-(trifluorome1iiyl)phenyl]sulf onyl}amino)methyl]biphenyl-4- carboxylic acid;

5-(phenylsulfonyl)-N-{2-[4-(2H ^' -tetrazol-5-yl)phenyl]ethyl}-2-

(trifluoromethyl)benzenesulfonamide;

λ/-(2-{4-[(methylsulfonyl)amino]phenyl}ethyl)-5-(phenyls ulfonyl)-2-

(trifluoromethyl)benzenesulfonamide; iV-(3-bromobenzyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)ben zenesulfonamide;

3 '- [( { [5-(pheny lsulfony l)-2-(trifluoromethy l)pheny 1] sulfony 1 } amino)methy l]bipheny 1-3 - carboxylic acid;

3'-[({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfo nyl}amino)methyl]biphenyl-4- carboxylic acid;

N- [2-(4- { [amino(imino)methy 1] amino } pheny l)ethy 1] -5-(pheny lsulfony l)-2-

(trifluoromethyl)benzenesulfonamide; iV-[4-(dimethylamino)benzyl]-5-(phenylsulfonyl)-2-(trifluoro methyl)benzenesulfonamide; iV-(2,4-dimethoxybenzyl)-5-(phenylsulfonyl)-2-(trifluorometh yl)benzenesulfonamide; tert-Butyl [2-({[5-(phenylsulfonyl)-2-(1rifluoromethyl)phenyl]sulfonyl} amino)ethyl]carbamate;

N-(2-Aminoethyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)be nzenesulfonamide hydrochloride;

N-[2-({[5-(Phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulf onyl}amino)ethyl]benzamide;

4-Methyl-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide;

4-tert-Butyl-N- [2-( { [5-(pheny lsulfony l)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide;

4-Fluoro-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide;

4-Chloro-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide;

4-Bromo-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethy l)pheny 1] sulfony 1 } amino)ethyl]benzamide ;

4-Methoxy-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethy l)pheny 1] sulfony 1 } amino)ethy l]benzamide ;

N-[2-({[5-(Phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulf onyl}amino)ethyl]-4-

(trifluoromethy l)benzamide ;

N-[2-({[5-(Phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulf onyl}amino)ethyl]-4-

(trifluoromethoxy)benzamide ;

N-[2-({[5-(Phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulf onyl}amino)ethyl]isonicotinamide; tert-Butyl methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl] sulfonyl} amino)ethyl]carbamate;

N-[2-(Methylamino)ethyl]-5-(phenylsulfonyl)-2-(trifluorom ethyl)benzenesulfonamide hydrochloride;

N-Methyl-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethy l)pheny 1] sulfonyl} amino)ethyl]benzamide;

4-Methoxy-N-methyl-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfonyl} amino)ethyl]benzamide;

N-{2-[(anilinocarbonyl)(methyl)amino]ethyl}-5-(phenylsulf onyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-(2- {methyl [(pyridin-3 -ylamino)carbony 1] amino } ethyl)-5 -(pheny lsulfony l)-2-

(trifluoromethyl)benzenesulfonamide;

N- { 2- [ { [(2,4-dimethoxypheny l)amino]carbony 1 } (methy l)amino] ethyl} -5 -(pheny lsulfony l)-2-

(trifluoromethyl)benzenesulfonamide;

N-{2-[[(tert-butylamino)carbonyl](methyl)amino]ethyl}-5-( phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-{2-[{[(4-methoxyphenyl)amino]carbonyl}(methyl)amino]eth yl}-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;;

N- {2- [ [(butylamino)carbony 1] (methy l)amino] ethyl} -5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide

N-{2-[{[(2,4-difluorophenyl)amino]carbonyl}(methyl)amino] ethyl}-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-methyl-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]pyrrolidine- l-carboxamide;

N-{2-[[(diethylamino)carbonyl](methyl)amino]ethyl}-5-(phe nylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-methyl-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]moφholine-4 -carboxamide;

N- [2-(methy 1 { [methyl(pheny l)amino] carbony 1 } amino)ethy 1] -5 -(pheny lsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-Methyl-N- [2-( { [5 -(pheny lsulfony l)-2-(trifluoromethy l)phenyl] sulfony 1 } amino)ethy 1] -2- furamide;

4-tert-Butyl-N-methyl-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide;

N-Methyl-N-[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)ph enyl]sulfonyl}amino)ethyl]-2-

(trifluoromethoxy)benzamide;

N-methyl-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethy l)pheny 1] sulfonyl } amino)ethy 1] cy clohexanecarboxamide ;

3-Fluoro-N-methyl-N-[2-( { [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-4-(trifluor omethyl)benzamide;

Methyl 4-({methyl[2-( { [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbon yl)benzoate;

N-Methyl-N-[2-({[5-(phenylsulfonyl)-2-

(txifluoromethyl)phenyl]sulfonyl}amino)ethyl]nicotinamide ;

N-Methyl-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfonyl } amino)ethyl] isonicotinamide ;

2-Chloro-N-methyl-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]nicotinamide ;

N,2,2-trimethyl-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethy l)pheny 1] sulfonyl } amino)ethyl]propanamide;

2-ethyl-N-methyl-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]butanamide; butyl methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate; tert-butyl 4-[({methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}aniino)ethyl]amino}carbo nyl)amino]piperidine-l-carboxylate;

2,2-dimethylpropyl methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate; isobutyl methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethy l)pheny 1] sulfonyl } amino)ethyl] carbamate ;

3-(trifluoromethyl)phenyl methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethy l)pheny 1] sulfony 1} amino)ethy 1] carbamate ;

4-fluorophenyl methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate;

4-bromophenyl methyl [2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate;

λ/ ^" -(2-{methyl[(piperidin-4-ylamino)carbonyl]amino}ethyl)-5-(ph enylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide; ethyl N-({methyl[2-( { [5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfonyl } amino)ethy 1] amino } carbonyl)gly cinate;

3-({methyl[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfonyl } amino)ethy 1] amino } sulfony l)benzoic acid; tert-butyl 4-({methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbon yl)piperazine-l-carboxylate;

N-({methyl[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbon yl)glycine;

4-{methyl[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phen yl]sulfonyl}amino)ethyl]amino}-4- oxobutanoic acid;

N-methyl-iV-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]piperazine-l -carboxamide; iV-{2-[(2-hydroxyethyl)(methyl)amino]ethyl}-5-(phenylsulfony l)-2-

(trifluoromethyl)benzenesulfonamide; methyl N-methyl-N-[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]glycinate; ethyl iV-methyl-iV- [2-( { [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl } amino)ethyl]- D - alaninate; tert-butyl (35)-3-[({methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl] sulfonyl} amino)ethyl]amino} carbonyl)amino]pyrrolidine- 1 -carboxylate; tert-butyl methyl[3-( { [5-(phenylsulfonyl)-2-

(trifluoromethy l)pheny 1] sulfonyl} amino)propyl] carbamate ;

N-[3-(methylamino)propyl]-5-(phenylsulfonyl)-2-(trifluoro methyl)benzenesulfonamide;

N-[2-(methyl{[(35)-pyrrolidin-3-ylamino]carbonyl}amino)et hyl]-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide; tert-butyl 4-[({methyl[3-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)propyl]amino}carbo nyl)amino]piperidine-l- carboxylate; tert-butyl N-methyl-N-[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethy l)pheny 1] sulfony 1 } amino)ethy 1] - β -alaninate ; tert-butyl N-methyl-JV-[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]glycinate;

N-(3-{methyl[(piperidm-4-ylamino)carbonyl]amino}propyl)-5 -(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide; tert-butyl 4-({methyl[3-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl] sulfony 1} amino)propyl]amino} carbonyl)piperazine- 1 -carboxylate;

N-methyl-N-[3-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl] sulfony 1 } amino)propyl]piperazine- 1 -carboxamide;

4-{4-[({methyl[2-({[5-(phenylsulfonyl)-2-

(trifluoromethy l)pheny 1] sulfonyl } amino)ethy 1] amino } carbonyl)amino]piperidin- 1 -y 1 } -A- oxobutanoic acid;

N-methyl-N-[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)ph enyl]sulfonyl}amino)ethyl]glycine;

N-methyl-iV-[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)p henyl]sulfonyl}amino)ethyl]-β- alanine;

4-(bromomethyl)-iV-metb.yl-iV-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfonyl } amino)ethyl]benzamide ; tert-butyl [3-({[5-(phenylsulfonyl)-2-(trifluorometb.yl)pb.enyl]sulfony l}amino)propyl]carbamate; tert-butyl 4-[methyl({methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl] sulfonyl } amino)ethyl] amino } carbonyl)amino]piperidine- 1 -carboxylate; tert-butyl (3i?)-3-[({methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfonyl } amino)ethy 1] amino } carbony l)amino]pyrrolidine- 1 -carboxylate;

4-{methyl[3-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phen yl]sulfonyl}amino)propyl]amino}-4- oxobutanoic acid;

N-(3-aminopropyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)b enzenesulfonamide;

dimethyl [4-({methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]aniino}carbo nyl)benzyl]phosphonate;

N-[2-(methyl{[methylφiperidin-4-yl)amino]carbonyl}amino) ethyl]-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-[2-(methyl{[(3i-)-pyπ.Olidin-3-ylamino]carbonyl}amino) ethyl]-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide; tert-butyl (3i?)-3-[({methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethy l)pheny 1] sulfony 1 } amino)ethy 1] amino } carbony l)amino]piperidine- 1 -carboxy late; tert-butyl (3^-3-[({methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfony 1} amino)ethy 1] amino } carbony l)amino]piperidine- 1 -carboxy late ;

N-[2-(methyl{[(3i?)-piperidin-3-ylamino]carbonyl}amino)et hyl]-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-[2-(methyl{[(35)-piperidin-3-ylaniino]carbonyl}amino)et hyl]-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide ;

[4-({methyl[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfony 1 } amino)ethy 1] amino } carbony l)benzyl]phosphonic acid; tert-butyl 4-[methyl({ [2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbon yl)amino]piperidine-l-carboxylate; tert-butyl 4-[({[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfonyl } amino)ethyl] amino } carbony l)amino]piperidine- 1 -carboxy late ;

N-(2,3-dihydro-lH-inden-2-yl)-5-(phenylsulfonyl)-2-(trifl uoromethyl)benzenesulfonamide;

N-(2-hydroxy-2,3-dihydro- 1 H-inden- 1 -yl)-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-(l-hydroxy-2,3-dihydro-lH-inden-2-yl)-5-(phenylsulfonyl )-2-

(trifluoromethyl)benzenesulfonamide;

N-(5-methoxy-2,3 -dihydro- 1 H-inden-2-yl)-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

N-(5-hydroxy-2,3-dihydro-lH-inden-2-yl)-5-(phenylsulfonyl )-2-

(trifluoromethyl)benzenesulfonamide; methyl {[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl }amino)-2,3-dihydro-lH- inden-5-yl]oxy}acetate;

{[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfo nyl}amino)-2,3-dihydro-lH-inden-5- yl]oxy}acetic acid; methyl 2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}a mino)indane-5-carboxylate;

N-(l-hydroxy-6-methoxy-2,3-dihydro-lH-inden-2-yl)-5-(phen ylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide;

2-{[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sul fonyl}amino)-2,3-dihydro-lH-inden-

5-yl]oxy } acetamide;

2-({ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino )indane-5-carboxylic acid; or

N-(5-bromo-2,3-dihydro-lH-inden-2-yl)-5-(phenylsulfonyl)- 2-

(trifluoromethyl)benzenesulfonamide.

[0164] In certain embodiments of the invention, when R ₁ of Formula I is phenyl; X of Formula I is O; R ₂ of Formula I is CH ₃ ; and R ₄ , R ₅ , R ₆ , and R ₇ of Formula I are each H; then R ₃ of Formula I is not methylphenyl, ethylphenyl, or hydrogen. In other embodiments, when R ₁ of Formula I is phenyl; X of Formula I is O; R ₂ of Formula I is CH ₃ ; and R ₄ , R ₅ , R ₆ , and R ₇ of Formula I are each H; then R ₃ of Formula I is not alkylphenyl or hydrogen. In still further embodiments, when R ₁ of Formula I is phenyl; X of Formula I is O; R ₂ of Formula I is CH ₃ ; and R ₄ , R ₅ , R ₆ , and R ₇ of Formula I are each H; then R ₃ of Formula I is not alkylaryl or hydrogen.

[0165] In further embodiments of the invention, when R ₁ of Formula I is chlorophenyl; X of Formula I is O; R ₂ of Formula I is CH ₃ ; and R ₄ , R ₅ , R ₆ , and R ₇ of Formula I are each H; then R ₃ of Formula I is not cyclohexyl, methylphenyl, methylfuranyl, methylpyridyl, or hydrogen. In other embodiments, when R ₁ of Formula I is chlorophenyl; X of Formula I is O; R ₂ of Formula I is CH ₃ ; and R ₄ , R ₅ , R ₆ , and R ₇ of Formula I are each H; then R ₃ of Formula I is not cycloalkyl, alkylphenyl, alkylfuranyl, alkylpyridyl, or hydrogen. In additional embodiments, when R ₁ of Formula I is chlorophenyl; X of Formula I is O; R ₂ of Formula I is CH ₃ ; and R ₄ , R ₅ , R ₆ , and R ₇ of Formula I are each H; then R ₃ of Formula I is not cycloalkyl, alkylaryl, alkylheteroaryl, or hydrogen.

[0166] In certain embodiments of the invention, when R ₁ of Formula I is bromophenyl; X of Formula I is O; R ₂ of Formula I is CH ₃ ; and R ₄ , R ₅ , R ₆ , and R ₇ of Formula I are each H; then R ₃ of Formula I is not hydrogen.

[0167] In certain other embodiments of the invention, when Ri of Formula I is nitrophenyl or dinitrophenyl; X of Formula I is O; R ₂ of Formula I is CH ₃ ; and R ₄ , R ₅ , R ₆ , and R ₇ of Formula I are each H; then R ₃ of Formula I is not hydrogen.

[0168] Compounds of Formula 1 may be used to modulate the activity of secreted frizzled related protein- 1. Such compounds are of interest for the treatment of bone fractures as well as bone disorders, including osteoporosis, and for the treatment of arthritis, chronic obstructive pulmonary disease, cartilage defects, prostate cancer and leiomyoma.

[0169] In certain embodiments, the present invention therefore provides methods of treating, preventing, inhibiting, or alleviating each of the maladies listed above in a mammal, preferably in a human, comprising administering a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof to a patient suspected to suffer from such a malady.

[0170] In other embodiments, the invention relates to compositions comprising at least one compound of Formula 1, or a steroisomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. Such compositions include pharmaceutical compositions for treating or controlling disease states or conditions of the bone. In certain embodiments, the compositions comprise mixtures of one or more compounds of Formula 1.

[0171] Certain of the compounds of Formula 1 contain stereogenic carbon atoms or other chiral elements and thus give rise to stereoisomers, including enantiomers and diastereomers. The invention generally relates to all stereoisomers of the compounds of Formula 1, as well as to mixtures of the stereoisomers. Throughout this application, the name of a compound without indication as to the absolute configuration of an asymmetric center is intended to embrace the individual stereoisomers as well as mixtures of stereoisomers. Reference to optical rotation [(+), (-) and (±)] is utilized to distinguish the enantiomers from one another and from the racemate. Furthermore, throughout this application, the designations R* and S* are used to indicate relative stereochemistry, employing the Chemical Abstracts convention which automatically assigns R* to the lowest numbered asymmetric center.

[0172] An enantiomer can, in some embodiments of the invention, be provided substantially free of the corresponding enantiomer. Thus, reference to an enantiomer as being substantially free of the corresponding enantiomer indicates that it is isolated or separated via separation techniques or prepared so as to be substantially free of the corresponding enantiomer. "Substantially free," as used herein, means that a significantly lesser proportion of the corresponding enantiomer is present. In preferred embodiments, less than about 90 % by weight of the corresponding enantiomer is present relative to desired enantiomer, more preferably less

than about 1% by weight. Preferred enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC), and the formation and crystallization of chiral salts, or preferred enantiomers, can be prepared by methods described herein. Methods for the preparation of enantiomers are described, for example, in Jacques, et ah, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al, Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972), each of which is hereby incorporated by reference in its entirety.

[0173] The following synthetic schemes are designed to illustrate, but not limit, general procedures for the preparation of compounds of Formula 1. The reagents used can be either commercially obtained or can be prepared by standard procedures described in the literature.

Scheme 1:

2b (X = O) 1 i. AICI ₃ , aryl; ii. Chlorosulfonic acid, heat; iii. Amine, TEA, DCM or Amine, Na ₂ CO ₃ , ACN/water

[0174] In Scheme 1, step i, a suitably substituted aryl sulfonyl chloride (5), either commercially available, known in the literature, or prepared according to methods known and established for the preparation of sulfonyl chlorides, including procedures exemplified in the experimental section of this document, wherein, R ₂ , R ₄ , R ₅ , R ₆ and R ₁ are as previously defined, is reacted with an unsubstituted or suitably substituted aryl group, either commercially available, known in the literature, or prepared according to methods known and established for the preparation of substituted benzenes, with or without a Lewis acid catalyst such as aluminum chloride, either using the substituted aryl in excess as the solvent, or using another suitably acceptable solvent. The diaryl sulfone product is then treated with chlorosulfonic acid with or without solvent, step ii, at room temperature or with heating for several hours or longer where appropriate to provide a sulfonyl chloride (2b), which is used directly or purified according to established procedures. The sulfonyl chloride (T) is reacted in step iii with an amine (R ₇ R ₃ NH),

either commercially available, known in the literature, or prepared according to methods known and established for the preparation of primary and secondary amines, in a suitable solvent, such as dichloromethane or acetonitrile, in the presence of an acid scavenger, such as triethylamine, at room temperature to afford the desired product (1).

Scheme 2:

9a (X = LP) or

9b (X = O) iv. arylthiol, K ₂ CO ₃ , DMF; v. m-CPBA or oxone, DCM; vi. SnCl ₂ , or H ₂ /Pd; vii. NaNO ₂ , HCl, AcOH; viii. SO ₂ (g), CuCl ₂ ;

[0175] In Scheme 2, step iv, a suitably substituted 3-fluoro nitrobenzene derivative, either commercially available, known in the literature, or prepared according to methods known and established for the preparation of such nitrobenzenes, is reacted with an appropriately substituted arylthiol, either commercially available, known in the literature, or prepared according to methods known and established for the preparation of such arylthiols, in the presence of an acid scavenger, such as potassium carbonate, in a suitable solvent, such as dimethylformamide or dimethylacetamide, at an elevated temperature for several hours to provide diaryl sulfide (7). The diaryl sulfide (7) is oxidized, step v, using established procedures, or as known in the literature, in an acceptable solvent such as dichloromethane, with a suitable oxidant, such as meta-chloroperoxybenzoic acid or oxone, to afford either the sulfoxide (8a) or sulfone (8b). The sulfoxide or sulfone is subjected to reducing conditions, such as stannous chloride, step vi, or reagents that are commonly used to effect the reduction of a nitro group, known in the literature, to afford aniline (9a or 9b). Diazotization, step vii, of the anilinium hydrochloride salt under acidic conditions with sodium nitrite, followed by sulfonylation, step viii, with sulfur dioxide and hydrogen chloride in the presence of an organic

metal catalyst, such as copper (II) chloride, according to procedures described in the literature, results in the formation of sulfonyl chloride (2), which may be transformed into the sulfonamide (1) as previously described, step iii.

Scheme 3

LP or O)

12 ix. BuLi, -78 ⁰ C, THF; x. SO ₂ (g); xi. NCS, DCM; xii. NBS, H ₂ SO ₄ ; xiii. thiophenol, NiBr ₂ , Zn, Dppf, K ₂ CO ₃ , NMP, microwave, 160 ⁰ C, 10 min

[0176] In Scheme 3, an appropriately substituted sulfonyl chloride (11), wherein R ₂ is as previously defined for alkyl, either commercially available, known in the literature, or prepared according to methods known and established for the preparation of such sulfonyl chlorides, including procedures exemplified in the experimental section, such as from aryl bromide (10), either commercially available, known in the literature, or prepared according to methods known and established for the preparation of such aryl bromides, is transmetalated, step ix, at reduced temperature and in a suitable solvent such as tetrahydrofuran, using an acceptable organometallic reagent that is known to effect such transformations, such as n-butyl lithium, and the resulting metalated species is treated with sulfur dioxide, step x, to afford a sulfinic acid intermediate that is isolated or immediately oxidized, step xi, to a sulfonyl chloride (11). The sulfonyl chloride (11) is then transformed into a sulfonamide, step iii, and brominated, step xii, using N-bromosuccinimide in concentrated sulfuric acid, or other brominating conditions that are commonly used to brominate aryl sulfonamides, to afford an aryl bromosulfonamide (3). The aryl bromosulfonamide (3) is then reacted with an arylthiol, either commercially available, known in the literature, or prepared according to methods known and established for the preparation of thiophenols, using a catalytic system comprised of nickel (II) bromide and zinc metal, with a suitable ligand such as Dppf, step xiii, in the presence of an inorganic base, such as

potassium carbonate, and a polar aprotic solvent, such as l-methyl-2-pyrrolidinone, at elevated temperatures to afford a sulfide (12), which is oxidized, step v, using a suitable oxidant such as meta-chloroperoxybenzoic acid or oxone, or by established procedures, as known in the literature, in an acceptable solvent, such as dichloromethane, for the oxidation of sulfides, including procedures exemplified in the experimental section, to afford a diarylsulfone sulfonamide (1).

Scheme 4

(where X = O) xiv. MeMgBr, -78 to 0 ⁰ C, THF; xv. K ₂ CO ₃ , Cu(OAc) ₂ , DMSO, arylboronic acid

[0177] Alternatively, as depicted in Scheme 4, intermediate 3 is exposed to methyl magnesium bromide, step xiv, followed by a metal halogen exchange reagent, such as butyl lithium, step ix, at reduced temperature and in a suitable solvent, such as tetrahydrofuran, to afford a lithiated species that is quenched with sulfur dioxide, step x, to afford a sulfϊnic acid that is isolated as the sodium salt (4), as exemplified in the experimental section. The sodium sulfinate (4) is then reacted with an appropriately substituted aryl boronic acid, step xv, either commercially available, known in the literature, or prepared according to methods known and established for the preparation of aryl boronic acids, in a cross coupling reaction that is promoted by a copper salt, such as copper (II) acetate, in an appropriate polar aprotic solvent, such as dimethylsulfoxide or dimethylforamide, in the presence of an acid scavenger, such as triethylamine or potassium carbonate, and a desiccant, such as molecular sieves, at ambient or elevated temperatures, or as exemplified in the experimental section, to provide compounds of Formula 1.

Scheme 5 xiv, ix, xvi 3 — — — *- 1 xvi. arylsulfonyl fluoride

[0178] Alternatively, as depicted in Scheme 5, the lithiated intermediate from 3, Scheme 4, is quenched with an appropriately substituted aryl sulfonyl fluoride, step xvi, either commercially available, known in the literature, or prepared according to methods known and established for the preparation of aryl sulfonyl fluorides, as exemplified in the experimental section, to provide compounds of Formula 1.

Scheme 6

R ₆

[0179] In Scheme 6, an appropriately substituted aryl sulfonyl chloride, either commercially available, known in the literature, or prepared according to methods known and established for the preparation of aryl sulfonyl chlorides, is elaborated as described in Scheme 1, step i, to provide 8, and then, according to Scheme 2, steps vi, vii and viii, to provide sulfonyl chloride (T), which is transformed to compounds of Formula 1 as previously described.

Scheme 7

14 15

[0180] Alternatively, as depicted in Scheme 7, intermediate 3 is prepared from an appropriately substituted bromoaniline (14), either commercially available, known in the literature, or prepared according to methods known and established for the preparation of bromoanilines, according to the protocol followed in Scheme 2, steps vii and viii, to afford a sulfonyl chloride (15), which is converted into a sulfonamide (3), step iii, as outlined in the previous schemes. Intermediate 3 is elaborated to compounds of Formula 1 using methods previously described in Schemes 3, 4 or 5, as appropriate.

^' .1SBiEiMEi

AM101865 - 79 -

Scheme 8

16 xvii. Amine, DMA, K ₂ CO ₃ , microwave, 180 ⁰ C;

[0181] In Scheme 8, an aryl fluoride (16), either prepared according to procedures previously described, exemplified in the experimental section, commercially available, or known in the literature, is reacted with an appropriately substituted primary or secondary amine, either commercially available or known in the literature, using a suitable polar solvent, such as dimethylacetamide, in the presence of an acid scavenger, such as potassium carbonate, at elevated temperatures to afford the desired product.

Scheme 9

17

xviii. Electrophile, base, DCM

[0182] The piperidinyl sulfonamide (17), shown in Scheme 9, either prepared according to procedures exemplified in the experimental section, commercially available, or known in the literature, is reacted with an appropriately substituted electrophile such as, but not limited to, an acid chloride, sulfonyl chloride, alkyl halide, isothiocyanate, isocyanate, or epoxide, in the presence of an acid scavenger, such as morpholinomethyl-polystyrene or triethylamine where appropriate, in a suitable solvent, such as dichloromethane, to provide the desired product of Formula 1.

3. /X 888 B

AM101865 - 80 -

Scheme 10

xix. NaH, DMF, propynylchloride

[0183] Compounds of Formula 1, in which R ₇ is H and R3 is as previously described, are further alkylated by deprotonating using an alkali base, such as sodium hydride, in an appropriate solvent, such as dimethylformamide, and subsequently treating with an alkylating agent, such as propynyl chloride, to yield a tertiary sulfonamide.

Scheme 11

xx. Cu powder, CF ₂ Br ₂ , activated carbon, DMF, 100 ⁰ C

[0184] In Scheme 11 , an aryl sulfonyl chloride (5), either prepared according to procedures previously described, commercially available, or known in the literature, is reacted as described in Scheme 1, step i, to afford an intermediate diarylsulfone (18). Reaction of 18 with an in situ derived copper trifluoromethylating agent, step xx, also known in the literature as Burton's reagent, which is generated by the reaction of copper metal and dibromodifluoromethane in a polar aprotic solvent such as dimethylformamide, and heating for several hours, provides the trifluoromethyl intermediate 19. The conversion of 19 to aniline 20 and then to the subsequent sulfonyl chloride proceeds as previously described using steps vi - vm.

Scheme 12

Vl VIl, VIII III

19 20 2b 1 xxi. sodium arylsulfmate, DMA, 100 ⁰ C

[0185] Alternatively, in Scheme 12, the nitro benzene (21) can be converted to the trifluoromethyl intermediate (22) in an analogous manner used to prepared 19, employing step xx. Further elaboration of 22 to a diaryl sulfide (7), step iv, in an analogous fashion as outlined in Scheme 2. The sulfide can than be oxidized to the diaryl sulfone (19) using procedures that were previously discussed in Scheme 2, step v. Diaryl sulfone (19) can also be directly prepared by reacting 22 with an aryl sulfinate, step xxi, either commercially available, or known in the literature, in a polar aprotic solvent such as dimethylacetamide with heating for several hours. Intermediate 19 can be further transformed to aniline 20, step vi, using previously estabilished procedures. The aniline (20) can then be converted into the sulfonyl chloride, step vii - viii, using previously established procedures, and subsequently reacted with an amine, step iii, to afford compounds of formula 1.

[0186] In certain embodiments, the invention relates to compositions comprising at least one compound of Formula 1, or a stereoisomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. Such compositions are prepared in accordance with general pharmaceutical formulation procedures, such as, for example, those described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), which is incorporated herein by reference in its entirety. Pharmaceutically acceptable carriers are those carriers that are compatible with the other ingredients in the formulation and are biologically acceptable.

[0187] The compounds of Formula 1 can be administered orally or parenterally, neat, or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances that can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, or encapsulating

materials. In powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99 % of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

[0188] Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier can contain other suitable pharmaceutical additives such as, for example, solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0189] Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

[0190] The compounds of Formula 1 can be administered rectally or vaginally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of Formula 1 can be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of Formula 1 can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the sldn, and allows delivery of the agent for systemic absorption into the blood stream via the

skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient can also be suitable. A variety of occlusive devices can be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.

[0191] Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefϊlled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

[0192] The amount provided to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, and the state of the patient, the manner of administration, and the like. In therapeutic applications, compounds of Formula 1 are provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as a "therapeutically effective amount." The dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician. The variables involved include the specific condition and the size, age, and response pattern of the patient. The compounds can be administered orally, rectally, parenterally, or topically to the skin and mucosa. The usual daily dose depends on the specific compound, method of treatment and condition treated. The usual daily dose is 0.01 - 1000 mg/kg for oral application, preferably 0.5 - 500 mg/kg, and 0.1 - 100 mg/kg for parenteral application, preferably 0.5 - 50 mg/kg.

[0193] In certain embodiments, the present invention is directed to prodrugs of compounds of Formula 1. The term "prodrug," as used herein, means a compound that is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula 1. Various forms of prodrugs are known in the art such as those discussed in, for example,

Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et ah, Journal of Drug Delivery Reviews, 8:1-38(1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), each of which is hereby incorporated by reference in its entirety.

[0194] The following examples are illustrative of certain embodiments of the invention and should not be considered to limit the scope of the invention. ACD NamePro software was employed to generate IUPAC names for the following examples. The IUPAC names of the following examples are indicative of the neutral or free base forms. Compounds were either isolated as a free base or the corresponding hydrochloride salt as indicated in the experimental procedure.

_E , _ampl e _{1 : 2} -Me

[0195] Step 1 : To phenyl-4-tolyl sulfone (2.32 g, 10.0 mmol) was added chloro sulfonic acid (6.7 mL, 100 mmol) and the reaction mixture was stirred at 50 ⁰ C for 5 hours and then cooled to room temperature. The reaction mixture was slowly poured into ice (200 g) and a white solid precipitated. The resulting suspension was extracted with ethyl acetate (150 mL x 3) and the organic layers were combined and washed with brine (200 mL) and collected. The collected organic layer was dried over sodium sulfate and concentrated to give 5- Benzenesulfonyl-2-methyl-benzenesulfonyl chloride (3.30 g, 100 % yield). The product was used without further purification.

[0196] Step 2: The mixture of 5-Benzenesulfonyl-2-methyl-benzenesulfonyl chloride (66 mg, 0.20 mmol), phenethylamine (36 mg, 0.30 mmol) and triethyl amine (30 mg, 0.30 mmol) in methylene chloride (2 mL) was stirred at 37 ⁰ C for 12 hours. Then the reaction mixture was

concentrated and purified by reverse phase chromatography to give 2-Methyl-N- (2- phenylethyl)-5-(phenylsulfonyl) benzene sulfonamide (68 mg, 82% yield).

[0197] LC/MS conditions: Aquasil C18; Mobile Phase A: 100% (0.1% Formic Acid) in water (by volume), B: 100% (0.1% Formic Acid) in CAN; Flow Rate: 0.800 mL/min.

[0198] Column Temperature: 40 ⁰ C; Injection Volume: 5 μL, UV: monitor 215, 230, 254, 280, and 300 run; Purity is reported at 254 run unless otherwise noted.

[0199] Gradient Table:

Time (min) %B

0 0

2.5 100

4.0 100

4.1 0

5.5 0

MS Conditions (Same for both LC conditions)

Instrument: Agilent MSD

Ionization Mode: API-ES

Gas Temperature: 350 ⁰ C

Drying Gas : 13.0 L/min.

Nebulizer Pressure: 55 psig

Polarity: 50% positive, 50% negative

VCap: 3000V (positive), 2500V (negative)

Fragmentor: 120 (positive), 120 (negative)

Mass Range: 100 - 1000 m/z

Threshold: 150

Step size: 0.15

Gain: 1

Peak width: 0.15 min

HPLC: Rt = 3.1 min; MS 416 (M+H).

[0200] ¹ HNMR (CDCl ₃ ) δ 8.48 (IH, d), 7.97 (IH, dd), 7.94 (2H, dd), 7.58 (dd, IH), 7.51 (2H, dd), 7.39 (IH, dd), 7.30 (2H, dd), 7.05 (2H, dd), 4.44 (IH, t), 3.27 (2H, m), 2.78 (2H, t), 2.46 (3H, s).

Examples 2 to 30

[0201] The compounds of Examples 2 to 30 were prepared generally according to the procedures described in Example 1.

.•" -B- «..! ^■ IUi 'U ¹ IU!

- 87 -

Examples 31 to 179

[0202] The compounds of Examples 31 to 179 were prepared generally according to the procedures described in Example 1.

-Jb, ιu.« IU' ImIt

-90-

Example 180: N- ({5-[(4-fluorophenyl) sulfonyl]-2-methylphenyl} sulfonyl)-beta-alanine

[0203] To methyl N- ({5-[(4-fluorophenyl) sulfonyl]-2-methylphenyl} sulfonyl)-beta- alaninate (Example 160) (30 mg, 0.07 mmol) in methanol (1 mL) was added 2.0 M of lithium

hydroxide aqueous solution (1 niL, 2 mmol). The reaction mixture was stirred at room temperature for 5 hours and purified by reverse phase column to yield N- ({5-[(4-fluoro- phenyl) sulfonyl]-2-methylphenyl} sulfonyl)-beta-alanine (25 mg, 86 % yield). [0204] HPLC (Method 1): Rt = 2.56 min; MS 402.04 [M+H]

Examples 181-202

[0205] The compounds of Examples 181 to 201 were prepared generally according to the procedures described in Example 1.

Example 202: iV-{[3-(phenylsulfonyl)phenyl]sulfonyl}-beta-alanine

[0206] The compound of Example 202 was prepared generally according to the procedures described in Example 180.

Examples 203-221

[0207] The compounds of Examples 203 to 221 were prepared generally according to the procedures described in Example 1.

Examples 222, 223, and 225 to 229

[0208] The compounds of Examples 222, 223, and 225 to 229 were prepared generally according to the procedures described in Example 230.

Example 230: N- [3-(diethylamino) propyl] -2-ethyl-5- (phenylsulfonyl) benzene sulfonamide

[0209] Step 1 : To 4-Ethyl-benzenesulfonyl chloride (4.12 g, 20.0 mmol) and aluminum chloride (3.20 g, 24.0 mmol) was added benzene (10 niL). The reaction mixture was stirred at room temperature over night and then poured into water. The resulting solution was diluted with ethyl acetate (200 niL) and the organic layer was washed with IM aqueous sodium hydroxide solution (100 mL) and brine (100 niL). The organic layer was dried over sodium sulfate, filtered and concentrated to give l-Benzenesulfonyl-4-ethyl-benzene (4.58 g, 92.1% yield) as a white solid.

[0210] ¹ HNMR (CDCl ₃ ) δ 8.09 (2H, dd), 7.89 (2H, dd), 7.94 (2H, dd), 7.51 (m, 2H), 7.29 (IH, m), 7.00 (2H, dd), 2.86 (2H ₃ qt), 1.22 (3H, t).

[0211] Step 2: Following the same procedure described in Example 1 (step 1), 5- Benzenesulfonyl-2-ethyl-benzenesulfonyl chloride was made quanitively.

[0212] Step 3: Following the same procedure described in Example 1 (step 2), a 0.1 mmol scale reaction was set up and N- [3-(diethylamino) propyl]-2-ethyl-5- (phenylsulfonyl) benzene sulfonamide (38 mg, 86% yield) was synthesized.

[0213] HPLC (Method 2): Rt = 2.8 min; MS 439.2 [M+H]

Examples 231-243

[0214] The compounds of Examples 231 to 243 were prepared generally according to the procedures described in Example 230.

Examples 244-265

[0215] The compounds of Examples 244 to 265 were prepared generally according to the procedures described in Example 1.

Examples 266-271

[0216] The compounds of Examples 266 to 271 were prepared generally according to the procedures described in Example 230.

Examples 272-275

[0217] The compounds of Examples 272 to 275 were prepared generally according to the procedures described in Example 276.

Example 276: N-allyl-N- [2-(2-fluorophenyl) ethyl]-2-methyl-5- [(4-methylphenyI) sulfonyl] benzene sulfonamide

[0218] To N- [2-(2-fluoroρhenyl) ethyl]-2-methyl-5- [(4-methylphenyl) sulfonyl] benzene sulfonamide (Example 138) (22 mg, 0.05 mmol) in DMF (1 mL) was added sodium hydride (4 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 20 minutes, and then allyl bromide (12 mg, 0.1 mmol) was added. The reaction mixture was stirred at room temperature for another 2 hours and purified by a reverse phase column to yield N-allyl-N- [2-(2- fluorophenyl) ethyl]-2-methyl-5- [(4-methylphenyl) sulfonyl] benzene sulfonamide (8.2 mg, 34% yield).

Examples 277: λ ^/ -[2-(2-fluorophenyl)ethyl]-2-methyl-5-[(4-metliylphenyl)sulf onyl]-λ ^/ -prop- 2-ynylbenzenesuIfonamide

[0219] The compound of Example 277 was prepared generally according to the procedures described in Example 276.

Examples 278-283

[0220] The compounds of Examples 278 to 283 were prepared generally according to the procedures described in Example 1.

Examples 284-289

[0221] The compounds of Examples 284 to 289 were prepared generally according to the procedures described in Example 230.

[0222] The following table provides the HPLC retention time and mass spec data for the compounds of Examples 1 to 289.

V/ :!L ElBSiB

-102-

/ ^' 1,SBlBiEi ₁

AIVUUlOOS -105-

1.8!3SiB

AM101865 -106-

Example 290 : 5- [(4-chlorophenyl)sulfonyl] -2-methyl-iV-(2-morpholin-4- ylethyl)benzenesulfonamide

[0223] The title compound was prepared in a manner similar to that described in Example 1.

[0224] Step 1 : 4-chlorophenyl-4-tolyl sulfone and clilorosulfonic acid were used to prepare 5-(4-chlorophenyl)sulfonyl-2-methylbenzenesulfonyl chloride.

[0225] Step 2: 5-(4-chlorophenyl)sulfonyl-2-methylbenzenesulfonyl chloride and 4-(2- aminoethyl)-morpholine were used to prepare 5-[(4-chlorophenyl)sulfonyl]-2-methyl-N-(2- moφholin-4-ylethyl)benzenesulfonamide. MS (ES-) m/z 456.8; HRMS: calcd for C ₁₉ H ₂₃ ClN ₂ O ₅ S ₂ + H+, 459.08097; found (ESI, [M+H] ⁺ ), 459.0798.

Example 291 : 5- [(4-chlorophenyI)suIfonyl] -2-methyl-iV-(2-py ridin-2- ylethyl)benzenesulfonamide

[0226] In an analogous manner to Example 290, 2-(2-aminoethyl)-pyridine was used to prepare 5-[(4-chlorophenyl)sulfonyl]-2-methyl-N-(2-pyridin-2-ylethyl )benzenesulfonamide. MS (ES-) m/z 448.8; HRMS: calcd for C ₂₀ H ₁₉ ClN ₂ O ₄ S ₂ + H+, 451.05475; found (ESI, [M+H] ⁺ ), 451.0546.

Example 292: 5-[(4-chlorophenyl)sulfonyl]-A ^L [3-(l _J H-imidazol-l-yl)propyl]-2- methylbenzenesulfonamide

[0227] In an analogous manner to Example 290, l-(3-aminopropyl)-imidazole was used to prepare 5-[(4-chlorophenyl)sulfonyll-N-[3-(lH-imidazol-l-vDpropyl]-2 - methylbenzenesulfonamide. MS (ES-) m/z 451.8;HRMS: calcd for C ₁₉ H ₂₀ ClN ₃ O ₄ S ₂ + H+, 454.06565; found (ESI, [M+H] ⁺ ),

454.0644.

Example 293: 5-[(4-azidophenyI)suIfonyl]-λ43-(lif-imidazol-l-yl)propyl]- 2- methylbenzenesulfonamide

[0228] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-N-[3- (lH-imidazol-l-yl)propyl]-2-methylbenzenesulfonamide and sodium azide in DMF were used to prepare 5- r(4-azidophenyl)sulfonyl ^~ |-./V ^' - [ ^" 3 -( 1 H-imidazol- 1 -yl)propyl]-2- methylbenzenesulfonamide. MS (ES-) m/z 458.8; HRMS: calcd for C ₁₉ H ₂₀ N ₆ O ₄ S ₂ + H+, 461.10602; found (ESI, [M+H] ⁺ ), 461.1066.

Example 294: N-[2-(lH-indol-3-yl)ethyl]-2-methyl-5-(phenylsulfonyI)benzen esuIfonamide

[0229] To a solution of 5-benzenesulfonyl-2-methyl-benzenesulfonyl chloride (0.36 g, 1.1 mmol) in DMF (10 mL) was added pyridine (0.13 mL, 1.6 mmol) and tryptamine (0.21 g, 1.3 mmol). The reaction was stirred at room temperature overnight and then diluted with ethyl acetate and washed with saturated ammonium chloride, saturated sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified using automated flash chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of N- \2-( 1 H-indol- S-yDethyli^-methyl-S-CphenylsulfonvDbenzenesulfonamide. MS (ES-) m/z 452.8.

Example 295: 2-isopropyl-λ ^r -(2-phenylethyl)-5-(phenylsulfonyl)benzenesulfonamide

[0230] The title compound was prepared in a manner similar to that described in Example 230.

[0231] Step 1 : 4-isopropylbenzene sulfonyl chloride and benzene were used to prepare l-benzenesulfonyl-4-isopropylbenzene, which was purified via Biotage Horizon™ (FLASH 40 M, silica, gradient from 100% hexane to 20% EtOAc/hexane).

[0232] Step 2: l-Benzenesulfonyl-4-isopropylbenzene and chlorosulfonic acid were used to prepare 5-benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride, which was purified via Biotage Horizon (FLASH 40 M, silica, gradient from 100% hexane to 20% EtOAc/hexane).

[0233] Step 3: 5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and phenethyl amine were used to prepare 2-isopropyl-iV-(2-phenylethyl)-5-

(phenylsulfonyl)benzenesulfonamide, which was purified using a via Biotage Horizon™ (FLASH 25 M, silica, gradient from 10% hexane to 50% EtOAc/hexane gradient). MS (ES-) m/z 441.9; HRMS: calcd for C ₂₃ H ₂₅ NO ₄ S ₂ + H+, 444.12978; found (ESI, [M+H] ⁺ ), 444.1297.

Example 296: λ'-[3-(l _J H ^r -imidazol-l-yl)propyl]-2-isopr()pyl-5- (phenyϊsulfonyl)benzenesulfonamide

[0234] In an analogous manner to Example 295:

[0235] Step 3: 5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and 3-(1Ji ^" - imidazol-l-yl)propylamine were used to prepare N-[3-(lH ^~ -imidazol-l-yl)propyl]-2-isopropyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES-) m/z 445.9; HRMS: calcd for C ₂₁ H ₂₅ N ₃ O ₄ S ₂ + H+, 448.13592; found (ESI, [M+H] ⁺ ), 448.1364.

Example 297: 2-ethyl-5-[(4-fluorophenyl)suIfonyI]-λ^-[2-(lH-imidazol-l- yl)ethyl] benzenesulfonamide

[0236] In an analogous manner to Example 295:

[0237] Step 1 : 4-ethylbenzene sulfonyl chloride and fluorobenzene were used to prepare 1 -ethyl-4-[(4-fluorophenyl)sulfonyl]benzene.

[0238] Step 2: l-Ethyl-4-[(4-fluorophenyl)sulfonyl]benzene and chlorosulfonic acid were used to prepare 2-ethyl-5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride.

[0239] Step 3: 2-Ethyl-5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2- (liT-imidazol-l-yl)ethylamine were used to prepare 2-ethyl-5-[(4-fluorophenyDsulfonyl1-JV-[2- (lH-imidazol-l-yl)ethyl]benzenesulfonamide. MS (ES-) m/z 435.9; HRMS: calcd for C ₁₉ H ₂₀ FN ₃ O ₄ S ₂ + H+, 438.09520; found (ESI, [M+H] ⁺ ), 438.0945.

Example 298: 2-methyI-5-(phenyIsulfonyl)-iV-tetrahydro-2jEr-pyran-4- ylbenzenesulfonamide

[0240] In an analogous manner to Example 1 :

- Ill -

[0241] Step 2: 5-Benzenesulfonyl-2-methyl-benzenesulfonyl chloride and tetrahydro- pyran-4-ylamine were used to prepare 2-methyl-5-fphenylsulfonylVN-tetrahvdro-2iy-pyran-4- ylbenzenesulfonamide, which was purified using a via Biotage Horizon™ (FLASH 25 M, silica, gradient from 10% EtOAc/hexane to 50% EtOAc/hexane gradient. MS (ESI+) m/z 396; MS (ESI-) m/z 394; HRMS: calcd for C ₁₈ H ₂₁ NO ₅ S ₂ + H+, 396.09339; found (ESI, [M+H] ⁺ ), 396.0932.

Example 299: 2-methyI-5-(phenylsulfonyl)-iV-(2-tetrahydro-2iy-pyraii-4- ylethyl)benzenesulfonamide

[0242] In an analogous manner to Example 298:

[0243] Step 2: 5-Benzenesulfonyl-2-methyl-benzenesulfonyl chloride and 2- (tetrahydro-pyran-4-yl)-ethylamine were used to prepare 2-methyl-5-(phenylsulfonyl)-N-(2- tetrahydro-2H-pyran-4-ylethyl)benzenesulfonamide. MS (ESI+) m/z 424; MS (ESI-) m/z All; HRMS: calcd for C ₂₀ H ₂₅ NO ₅ S ₂ + H+, 424.12469; found (ESI, [M+H] ⁺ ), 424.1237.

Example 300 : 2-ethyl-5-(phenylsulfonyl)-λ'-tetrahydro-2Jϊ-pyran-4-ylben zenesulfonamide

[0244] In an analogous manner to Example 295 :

[0245] Step 3: 5-benzenesulfonyl-2-ethyl-benzenesulfonyl chloride and tetrahydro- pyran-4-ylamine were used to prepare 2-ethyl-5-(phenylsulfonyl ^' )-./V-tetrahvdro-2i ^: 7-pyran-4- ylbenzenesulfonamide. MS (ESI+) rø/z 410; MS (ESI-) m/z 408; HRMS: calcd for C ₁₉ H ₂₃ NO ₅ S ₂ + H+, 410.10904; found (ESI, [M+H] ⁺ ), 410.11.

Example 301 : 2-ethyI-5-(phenylsulfonyl)-iV-(2-tetrahydro-2jH ^r -pyran-4- ylethyl)benzenesulfonamide

[0246] In an analogous manner to Example 295:

[0247] Step 3: 5-benzenesulfonyl-2-ethyl-benzenesulfonyl chloride and 2-(tetrahydro- pyran-4-yl)-ethylamine were used to prepare 2-ethyl-5-fphenylsulfonyl)-N-(2-tetrahvdro-2//- pyran-4-ylethyl)benzenesulfonamide. MS (ESI+) m/z 438; MS (ESI-) m/z 436; HRMS: calcd for C ₂ IH ₂₇ NO ₅ S ₂ + H+, 438.14034; found (ESI, [M+H] ⁺ ), 438.1385.

Example 302: 2-methyI-λ ^r -(2-phenyIethyl)-3-(phenylsulfonyl)benzenesulfonamide

[0248] To a stirred solution of 2-fluoro-6-riitrotoluene (5.O g, 32.2 mmol) in DMF (80 mL) was added benzenethiol (4.0 niL, 38.8 mmol) and potassium carbonate (8.9 g, 64.4 mmol). The resulting solution was heated to 100 °C overnight and concentrated. The residue was taken up in ethyl acetate and washed with ammonium chloride solution (sat) and brine. The organic phase was dried over magnesium sulfate, concentrated and flash column separated using 3% ethyl acetate/ hexane. The recovered material was dissolved in methylene chloride (70 mL) and m-chloroperbenzoic acid (8.0 g, 46.3 mmol) was added portionwise over 1 hour. The mixture was stirred an additional 30 minutes, washed with sodium bicarbonate solution (sat), dried over magnesium sulfate and concentrated. The residue was flash column separated using 20 % ethyl acetate/ hexane. The resulting material was added to methanol (30 mL), chilled to 0 °C and 10 % palladium on carbon (120 mg) was added. Sodium borohydride (0.84 g, 22.2 mmol) was then added portionwise and stirred for 1 hour. The reaction was quenched with ammonium chloride solution (sat) and extracted several times with ethyl acetate. The organic layer was filtered through celite, washed with brine, dried over magnesium sulfate, and concentrated. The resulting material was dissolved in acetonitrile (16 mL), chilled to 0 °C and concentrated acetic acid (1.6 mL) and concentrated hydrochloric acid (1.6 mL) were added. Sodium nitrite (0.17 g, 2.42 mmol) dissolved in D.I. water (0.5 mL) was added dropwise and the solution was stirred 20 minutes. Sulfur dioxide was then bubbled into the solution over 20 minutes. Copper chloride dihydrate (0.34 g, 2.02 mmol) dissolved in D.I. water (0.5 mL) was added to the solution, the ice bath was removed and the solution was stirred at room temperature for 3.5 hours. The mixture was concentrated, taken up in ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, and concentrated. The resulting material was dissolved in THF (4 mL), triethylamine (0.4 mL, 2.86 mmol) and phenethylamine (0.1 mL, 0.79 mmol) were added and the mixture was stirred at room temperature for 30 minutes. The solution was treated with sodium

bicarbonate solution (sat) and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated to give 2-methyl-N-f2-phenylethylV

3-(phenylsulfonyl)benzenesulfonamide (0.05 g, 5%).

MS (ES-) m/z 413.9;

HRMS: calcd for C ₂₁ H ₂ iNO ₄ S ₂ + H+, 416.09848; found (ESI ₅ [M+H] ⁺ ), 416.0975.

Example 303: 2-ethyl-5-[(4-fluorophenyl)sulfonyl]-iV-[3-(lfl ^r -imidazol-l- yl)propyl]benzenesulfonamide

[0249] In an analogous manner to Example 295 :

[0250] Step 3: 2-Ethyl-5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 3- (Ii7-imidazol-l-yl)propylamine were used to prepare 2-ethyl-5 - [(4-fluorophenyl)sulfonyl1 -N- ]2- ( 1 H-imidazol- 1 -y Dpropy 1] benzenesulfonamide .

Example 304: 5-({4-[ethyl(methyl)amino]phenyl}sulfonyl)-λ'-[3-(l _J H-imidazol-l-yl)propyl]- 2-methylbenzenesulfonamide

[0251] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-iV-[3- (lH-imidazol-l-yl)propyl]-2-methylbenzenesulfonamide and N-ethylmethylamine were used to prepare 5-((4-[ethyl( ^' methyl ^' )amino1phenvUsulfonylVA/-[ ^' 3-riH-imidazol-l-yl)propyl1-2- methy lbenzenesulfonamide . MS (ES-) m/z 474.9; HRMS: calcd for C ₂₂ H ₂₈ N ₄ O ₄ S ₂ + H+, 477.16247; found (ESI, [M+H] ⁺ ), 477.1625.

Example 305: iV-[3-(l _J H ^r -imidazol-l-yl)propyl]-2-methyl-5-[(4-pyrrolidin-l- ylphenyl)sulfonyl]benzenesulfonamide

[0252] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-iV-[3- (lH-imidazol-l-yl)propyl]-2-methy lbenzenesulfonamide and pyrrolidine were used to prepare Nz [3-d/i ^" -imidazol-l-yl)propyl1-2-methyl-5-r(4-pyrrolidin-l- ylphenyDsulfonyllbenzenesulfonamide. MS (ES-) m/z 486.9; HRMS: calcd for C ₂₃ H ₂₈ N ₄ O ₄ S ₂ + H+, 489.16247; found (ESI, [M+H] ⁺ ), 489.1643.

Example 306: JV-[3-(l#-imidazol-l-yl)propyl]-4-methyl-3- (phenylsulfinyl)benzenesulfonamide

[0253] In an analogous manner to Example 302, 2-fluoro-4-nitrotoluene and 1 equivalent of m-chloroperbenzoic acid were used to prepare N- \3 -( 1 i7-imidazol- 1 -vDpropyl] -4- methyl-3-fphenylsulfinyl)benzenesulfonamide. MS (ESI+) m/z 404; HRMS: calcd for C ₁₉ H ₂₁ N ₃ O ₃ S ₂ + H+, 404.10971; found (ESI, [M+H] ⁺ ), 404.1116.

Example 307: 5-[(4-fluorophenyl)sulfonyl]-^-[2-(lH-imidazol-l-yl)ethyl]-2 - methylbenzenesulfonamide

[0254] In an analogous manner to Example 298:

[0255] Step 2: 2-Methyl-5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2- (lH-imidazol-l-yl)ethylamine were used to prepare 5-[f4-fluorophenyl)sulfonyll-iV-[2-( ^' lH ^' - imidazol- 1 -yl)ethyll-2-methylbenzenesulfonamide. MS (ES+) w/z 424; MS (ES-) m/z 422; HRMS: calcd for C ₁₈ H ₁₈ FN ₃ O ₄ S ₂ + H+, 424.07955; found (ESI, [M+H] ⁺ ), 424.0798.

Example 308: 5-[(4-fluorophenyl)sulfonyl]-2-methyl-λf-tetrahydro-2#-pyra n-4- ylbenzenesulfonamide

[0256] In an analogous manner to Example 298:

[0257] Step 2: 2-Methyl-5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and tetrahydro-pyran-4-ylamine were used to prepare 5-[ ^" (4-fluorophenyl)sulfonyl1-2-methyl-iV- tetrahydro-2H-pyran-4-ylbenzenesulfonamide. MS (ES+) w/z 414; MS (ES-) m/z AU; HRMS: calcd for C ₁₈ H ₂₀ FNO ₅ S ₂ + H+, 414.08397; found (ESI, [M+H] ⁺ ), 414.0843.

Example 309: 5-[(4-fluorophenyl)sulfonyl]-2-methyl-λ'-(2-tetrahydro-2iϊ -pyran-4- ylethyl)benzenesulfonamide

[0258] In an analogous manner to Example 298:

[0259] Step 2: 2-Methyl-5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2- (tetrahydro-pyran-4-yl)-ethylamine were used to prepare 5-[(4-fluorophenyl)sulfonyl]-2-methyl- N-(2-tetrahydro-2H-pyran-4-ylethyl)benzenesulfonamide. MS (ES+) m/z 442; MS (ES-) m/z 440; HRMS: calcd for C ₂₀ H ₂₄ FNO ₅ S ₂ + H+, 442.11527; found (ESI, [M+H] ⁺ ), 442.1167.

Example 310: iV-[3-(lH-imidazol-l-yl)propyl]-2-methyl-5-{[4- (methylamino)phenyl]sulfonyl}benzenesulfonamide

[0260] In an analogous manner to Example 356, 5-[(4-fluorophenyl)sulfonyi]-N-[3- (li7-imidazol-l-yl)propyl]-2-methylbenzenesulfonamide and methylamine were used to prepare N-r3-qH-imidazol-l -vnpropyll-2-methyl-5-f f4- (methylamino)phenyl]sulfonyUbenzenesulfonamide. MS (ES-) m/z 446.9; HRMS: calcd for C ₂₀ H ₂₄ N ₄ O ₄ S ₂ + H+, 449.13117; found (ESI, [M+H] ⁺ ), 449.1319.

Example 311: 5- { [4-(ethy lamino)phenyl] sulf onyl} -N- [3-(ljH ^r -imidazol-l -yl)propy 1] -2- methylbenzenesulfonamide

[0261] In an analogous manner to Example 356, 5-[(4-fluorophenyl)sulfonyl]-N-[3- (lH-imidazol-l-yl)propyl]-2-methylbenzenesulfonamide and ethylamine (70% aqueous solution) were used to prepare 5- { [4-f ethylamino ^* )phenyl]sulfonyl| -N- f 3 -( 1 H-imidazol- 1 -yDpropyl] -2- methylbenzenesulfonamide. MS (ES-) m/z 460.9; HRMS: calcd for C ₂₁ H ₂₆ N ₄ O ₄ S ₂ + H+, 463.14682; found (ESI, [M+H] ⁺ ), 463.1487.

Example 312: JV-[3-(l#-imidazol-l-yl)propyl]-2-methyl-5-[(4-piperidin-l- ylphenyl)sulfonyl]benzenesulfonamide

[0262] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-N-[3- (lH-imidazol-l-yl)propyl]-2-methylbenzenesulfonamide and piperidine were used to prepare N- [3 -( 1 i/-imidazol- 1 -yDpropy 1] -2-methyl-5- [ ^" (4-piperidin- 1 - ylphenyDsulfonynbenzenesulfonamide.

MS (ES+) m/z 503; MS (ES-) m/z 501; HRMS: calcd for C ₂₄ H ₃₀ N ₄ O ₄ S ₂ + H+, 503.17812; found (ESI, [M+H] ⁺ ), 503.1782.

Example 313: iV-[3-(liϊ-imid[azol-l-yl)propyl]-2-methyl-5-[(4-morpholin- 4- ylphenyl)sulfonyl]benzenesulfonamide

[0263] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-JV-[3- (lH ^" -imidazol-l-yl)propyl]-2-methylbenzenesulfonamide and morpholine were used to prepare iV-|[3-(l/i-imidazol-l-yl)propyl]-2-methyl-5-r(4-morpholm-4- ylphenyl)sulfonyl ^" |benzenesulfonamide. MS (ES+) m/z 505; MS (ES-) m/z 503; HRMS: calcd for C ₂₃ H ₂₈ N ₄ O ₅ S ₂ + H+, 505.15739; found (ESI, [M+H] ⁺ ), 505.1587.

Example 314: λ42-(llϊ-imidazoI-l-yl)ethyl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0264] In an analogous manner to Example 298:

[0265] Step 2: 5-Benzenesulfonyl-2-methyl-benzenesulfonyl chloride and 2-(IH- imidazol-l-yl)ethylamine were used to prepare N- \2-( 1 H-imidazol- 1 -y Dethy 1] -2-methy 1-5 - (phenylsulfonyDbenzenesulfonamide. MS (ES-) m/z 403.8; HRMS: calcd for C ₁₈ H ₁₉ N ₃ O ₄ S ₂ + H+, 406.08897; found (ESI, [M+H] ⁺ ), 406.0878.

Example 315: iV-[3-(lH-imidazol-l-yl)propyl]-5-[(4-methoxyphenyl)sulfonyl ]-2- methylbenzenesulfonamide

[0266] Step 1: To a stirred solution of 5-bromo-2-methylaniline (1.49 g, 8.01 mmol) in acetonitrile (65 mL) at O ⁰ C was added glacial acetic acid (6.5 mL) and concentrated HCl (6.5 mL). A solution of sodium nitrite (0.66 g, 9.61 mmol) dissolved in D.I water (2 mL) was added dropwise. The resulting solution was stirred 20 minutes. Sulfur dioxide was then bubbled into the solution for 20 minutes. A solution of copper (II) chloride dihydrate (1.37 g, 8.01 mmol) dissolved in D.I. water (2 mL) was added, the ice bath was removed and the solution was allowed to stir overnight at room temperature. The reaction volume was concentrated to one

third and extracted several times with ethyl acetate. The organic layers were combined, washed with water and sat. sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The crude was dissolved in THF (22 mL) and triethylamine (1.8 mL, 12.91 mmol) was added. l-(3-aminopropyl)-imidazole (1.0 mL, 8.38 mmol) was added dropwise and the resulting solution was stirred 30 minutes at room temperature. The solution was partitioned between an aqueous ammonium chloride solution and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give 5-bromo-N- [3 -( 1 i/-imidazol- 1 -y Dpropy 1] -2- methylbenzenesulfonamide (1.41 g, 49%). MS (ES) m/z 355.8; HRMS: calcd for C ₁₃ H ₁₆ BrN ₃ O ₂ S + H+, 358.02193; found (ESI, [M+H] ⁺ ), 358.0211.

[0267] Step 2: A solution of nickel (II) bromide (0.03 g, 0.11 mmol), zinc powder (0.03 g, 0.45 mmol), l,r-bis(diphenylphosphino)-ferrocene (0.12 g, 0.22 mmol), and potassium carbonate (0.31 g, 2.24 mmol) in NMP (10 mL) was stirred at room temperature for 1 hour. 5- bromo-N-[3-(li7-imidazol-l-yl)propyl]-2-methylbenzenesulfona mide (0.70 g, 1.95 mmol) and 4- methoxybenzenethiol (0.2 mL, 1.61 mmol) were added and the resulting solution was heated overnight at 80°C. The solution was partitioned between an aqueous ammonium chloride solution and ethyl acetate. The organic layer was concentrated and HPLC separated. The resulting solid was dissolved in methylene chloride (5 mL). M-chloroperbenzoic acid (0.29 g, 77%, 1.29 mmol) was added and the solution was stirred 1 hour at room temperature, concentrated and HPLC separated to give N-[ ^" 3-(lH-imidazol-l-yl)propyl]-5-[(4- methoxyphenyDsulfonyll-2-methylbenzenesulfonamide (0.11 g, 13%). MS (ES-) m/z 447.9; ηRMS: calcd for C ₂₀ H ₂₃ N ₃ O ₅ S ₂ + H+, 450.11519; found (ESI, [M+H] ⁺ ), 450.1148.

Example 316: N- [3-(lϋT-imidazol-l -y l)propy 1] -5- [(2-methoxypheny l)sulf ony 1] -2- methylbenzenesulfonamide

[0268] In an analogous manner to Example 315:

[0269] Step 2: 2-methoxybenzenethiol was used to prepare JV-P-dϋf-imidazol- 1 - yl)propyl1-5-[ ^" (2-methoxyphenyl)sulfonvn-2-methylbenzenesulfonamide. MS (ES+) m/z 450; MS (ES-) m/z 448; HRMS: calcd for C ₂₀ H ₂₃ N ₃ O ₅ S ₂ + H+, 450.11519; found (ESI, [M+H] ⁺ ), 450.1148.

Example 317: iV-[3-(li?-imidazol-l-yl)propyl]-4-methyl-3- (phenylsulfonyl)benzenesulfonamide

[0270] To a stirred solution of N-[3-(lH-imidazol-l-yl)propyl]-4-methyl-3- (phenylsulfinyl)benzenesulfonamide (0.13 g, 0.32 mmol) in methylene chloride (7 mL) was added m-chloroperbenzoic acid (0.05 g, 0.32 mmol). The solution was then concentrated and HPLC separated to give N- \3 -( 1 H-imidazol- 1 -y Dpropy 1] -4-methy 1-3 - (phenylsulfonyl)benzenesulfonamide. (0.004 g, 3%). MS (ES+) w/_: 420;

Example 318: 5-[(4-fluorophenyl)sulfonyl]-λ'-[2-(liϊ-imidazol-l-yI)ethy l]-2- isopropylbenzenesulfonamide

[0271] In an analogous manner to Example 295 :

[0272] Step 1 : 4-isopropylbenzene sulfonyl chloride and fluorobenzene were used to prepare l-isopropyl-4-[(4-fluorophenyl)sulfonyl]benzene, which was purified via Biotage Horizon™ (FLASH 40 M, silica, gradient from 100% hexane to 20% EtOAc/hexane).

[0273] Step 2: l-Isopropyl-4-[(4-fluorophenyl)sulfonyl]benzene and chlorosulfonic acid were used to prepare 2- isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride, which was purified via Biotage Horizon™ (FLASH 40 M, silica, gradient from 100% hexane to 20% EtOAc/hexane).

[0274] Step 3: 2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2-(li7-imidazol-l-yl)ethylamine were used to prepare 5- [(4-fluorophenyr)sulfony 1] -N- \2-( 1 H- imidazol- 1 -y Dethy 1] -2-isopropylbenzenesulfonamide . MS (ES-) m/z 449.8; HRMS: calcd for C ₂₀ H ₂₂ FN ₃ O ₄ S ₂ + H+, 452.11085; found (ESI, [M+H] ⁺ ), 452.1094.

Example 319: 5-[(4-fluorophenyl)sulfonyl]-7V-[3-(li7-imidazol-l-yl)propyI ]-2- isopropylbenzenesulfonamide

[0275] In an analogous manner to Example 295:

[0276] Step 3: 2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 3-(l/f-imidazol-l-yl)propylamine were used to prepare 5- [(4-fluorophenvDsulfonyl]-iV- [ ^" 3 \-( 1 H- imidazol- 1 -yl)τ>ropyll-2-isopropylbenzenesulfonamide.

MS (ES-) m/z 463.8;

HRMS: calcd for C _2I H ₂₄ FN ₃ O ₄ S ₂ + H+, 466.12650; found (ESI, [M+H] ⁺ ), 466.1253.

Example 320 ; 5-[(4-fluorophenyl)suIfonyl]-2-isopropyl-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0277] In an analogous manner to Example 295 :

[0278] Step 3: 2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2-pyridin-2-yl-ethylamine were used to prepare 5-[f4-fluorophenyl)sulfonyl]-2-isopropyl-iV-f2- pyridin-2-ylethyl)benzenesulfonamide. MS (ES-) m/z 460.8; HRMS: calcd for C ₂₂ H ₂₃ FN ₂ O ₄ S ₂ + H+, 463.11560; found (ESI ₅ [M+H] ⁺ ) ₅ 463.115.

Example 321 : 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-iV-tetrahydro-2/7-p yran-4- ylbenzenesulfonamide

[0279] In an analogous manner to Example 295 :

[0280] Step 3: 2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and tetrahydro-pyran-4-ylamine were used to prepare 5-[(4-fluorophenyl ^' )sulfonyl1-2-isopropyl-JV- tetrahydro-2H-pyran-4-ylbenzenesulfonamide. MS (ES-) m/z 439.9; HRMS: calcd for C ₂₀ H ₂₄ FNO ₅ S ₂ + H+, 442.11527; found (ESI, [M+H] ⁺ ), 442.1174.

Example 322: 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-7V-(2-tetrahydro-2 _J fiT-pyran-4- ylethyl)benzenesulfonamide

[0281 ] In an analogous manner to Example 295 :

[0282] Step 3: 2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2-(tetrahydro-pyran-4-yl)-ethylamine were used to prepare 5 - t ^" (4-fluorophenyl)sulfony 1] -2- isopropyl-7V-(2-tetrahydro-2H-pyran-4-ylethyl)benzenesulfona mide. MS (ES-) m/z 467.9; HRMS: calcd for C ₂₂ H ₂₈ FNO ₅ S ₂ + H+, 470.14657; found (ESI ₃ [M+H] ⁺ ), 470.1471;

Example 323: λ ^r -[3-(l _J H ^r -imidazol-l-yl)propyl]-5-[(3-methoxyphenyl)sulfonyl]-2- methylbenzenesulfonamide

[0283] In an analogous manner to Example 315:

[0284] Step2: 3-methoxybenzenethiol was used to prepare TV- [3 -( 1 H-imidazol- 1 - vDpropyll -5- \(3 -methoxyphenvDsulfonyfl -2-methylbenzenesulfonamide . MS (ES-) m/z 447.9; HRMS: calcd for C ₂₀ H ₂₃ N ₃ O ₅ S ₂ + H+, 450.11519; found (ESI, [M+H] ⁺ ), 450.1154.

Example 324: JV-[2-(liy-imidazol-l~yl)ethyl]-2,4-dimethyl-5- (phenylsulfonyl)benzenesulfonamide

[0285] In an analogous manner to Example 295 :

[0286] Step 1 : Benzene sulfonyl chloride and meta xylene were used to prepare 1- benzenesulfonyl-2,4-dimethyl-benzene, which was purified via Biotage Horizon™ (FLASH 40 M ₅ silica, gradient from 100% hexane to 20% EtOAc/hexane).

[0287] Step 2: l-Benzenesulfonyl-2,4-dimethyl-benzene and chlorosulfonic acid were used to prepare 5-benzenesulfonyl-2,4-dimethyl-benzenesulfonyl chloride, which was purified via Biotage Horizon™ (FLASH 40 M, silica, gradient from 100% hexane to 20% EtO Ac/hexane) .

[0288] Step 3: 5-Benzenesulfonyl-2,4-dimethyl-benzenesulfonyl chloride and 2-(IH- imidazol-l-yl)ethylamine were used to prepare N-[2-(lH-imidazol-l-yl)ethyll-2,4-dimethyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ESI+) m/z 420; MS (ESI-) m/z 418; HRMS: calcd for C ₁₉ H ₂₁ N ₃ O ₄ S ₂ + H+, 420.10462; found (ESI, [M+H] ⁺ ), 420.1051.

Example 325: JV-[3-(l#-imidazol-l-yl)pr(>pyl]-2,4-dimethyl-5- (phenylsulfbnyl)benzenesulfonamide

[0289] In an analogous manner to Example 298:

[0290] Step 2: 5-Benzenesulfonyl-2,4-dimethyl-benzenesulfonyl chloride and 3-(17f- imidazol-l-yl)propylamine were used to prepare JV- [3-( 1 H-imidazol- 1 -yl)propyl]-2,4-dimethyl- 5-(phenylsulfonyl)benzenesulfonamide. MS (ESI+) m/z 434; MS (ESI-) m/z 432;

HRMS: calcd for C ₂₀ H ₂₃ N ₃ O ₄ S ₂ + H+, 434.12027; found (ESI, [M+H] ⁺ ), 434.1186.

Example 326: 2,4-dimethyl-5-(phenylsulfonyl)-iV-(2-pyridin-2-ylethyl)benz enesulfonamide

[0291] In an analogous manner to Example 298:

[0292] Step 2: 5-Benzenesulfonyl-2,4-dimethyl-benzenesulfonyl chloride and 2- pyridin-2-yl-ethylamine were used to prepare 2,4-dimethyl-5-(plienylsulfonyl)-iV-(2-pyridin-2- ylethyDbenzenesulfonamide. MS (ES-) m/z 428.9; HRMS: calcd for C ₂₁ H ₂₂ N ₂ O ₄ S ₂ + H+, 431.10937; found (ESI, [M+H] ⁺ ), 431.1079.

Example 327: 2,4-dimethyl-5-(phenylsuIfonyl)-λ ^L tetrahydro-2 _J ff-pyran-4- ylbenzenesulfonamide

[0293] In an analogous manner to Example 298:

[0294] Step 2: 5-Benzenesulfonyl-2,4-dimethyl-benzenesulfonyl chloride and tetrahydro-pyran-4-ylamine were used to prepare 2,4-dimethyl-5-(phenylsulfonyl)-iV-tetrahydro- 2/i-pyran-4-ylbenzenesulfonamide. MS (ES-) m/z 407.9; HRMS: calcd for C ₁₉ H ₂₃ NO ₅ S ₂ + H+, 410.10904; found (ESI, [M+H] ⁺ ), 410.1096.

Example 328: 2,4-dimethyl-5-(phenylsulfonyl)-λ'-(2-tetrahydro-2 _J H ^r -pyran-4- ylethyl)benzenesulfbnamide

[0295] In an analogous manner to Example 298:

[0296] Step 2: 5-Benzenesulfonyl-2,4-dimethyl-benzenesulfonyl chloride and 2- (tetrahydro-pyran-4-yl)-ethylamine were used to prepare 2,4-dimethyl-5-(phenylsulfonyl)-A/-(2- tetrahydro-2i ^: f-pyran-4-ylethyl)benzenesulfonamide. MS (ES-) m/z 435.9; HRMS: calcd for C ₂₁ H ₂₇ NO ₅ S ₂ + H+, 438.14034; found (ESI, [M+H] ⁺ ), 438.141.

Example 329: 5-[(4-fluorophenyl)suIfonyl]-iV-[2-(l^-imidazol-l-yl)ethyl]- 2,4- dimethylbenzenesulfonamide

[0297] In an analogous manner to Example 295:

[0298] Step 1 : 4-Fluorobenzene sulfonyl chloride and meta xylene were used to prepare l-(4-fluoro-benzenesulfonyl)-2,4-dimethyl-benzene, which was purified via Biotage Horizon™ (FLASH 40 M, silica, gradient from 100% hexane to 20% EtOAc/hexane).

[0299] Step 2: l-(4-Fluoro-benzenesulfonyl)-2,4-dimethyl-benzene and chlorosulfonic acid were used to prepare 5-(4-fluoro-benzenesulfonyl)-2,4-dimethyl-benzenesulfonyl chloride, which was purified via Biotage Horizon™ (FLASH 40 M, silica, gradient from 100% hexane to 20% EtOAc/hexane).

[0300] Step 3: 5-(4-Fluoro-benzenesulfonyl)-2,4-dimethyl-benzenesulfonyl chloride and 2-(lH-imidazol-l-yl)ethylamine were used to prepare 5-[(4-fluorophenvπsulfonyl]-N-[2- ( 1 H ^~ -imidazol- 1 -y Dethy 1] -2 ,4-dimethylbenzenesulfonamide . MS (ESI+) m/z 438; MS (ESI-) m/z 436; ηRMS: calcd for C ₁₉ H ₂₀ FN ₃ O ₄ S ₂ + H+, 438.09520; found (ESI ₅ [M+H] ⁺ ), 438.0945.

Example 330: S-IC^fluorophenyOsulfonylJ-iV-tS-Clfl-imidazol-l-y^propyl]^^ - dimethylbenzenesulfonamide

[0301] In an analogous manner to Example 298 :

[0302] Step 2: 5-(4-Fluoro-benzenesulfonyl)-2,4-dimethyl-benzenesulfonyl chloride and 3-(l/f-imidazol-l-yl)propylamine were used to prepare 5-[(4-fluorophenyl)sulfonyl]-N-f3- ( 1 H ^~ -imidazol- 1 -vDpropy 1] -2,4-dimethylbenzenesulfonamide . MS (ESI-) m/z 450; HRMS: calcd for C ₂₀ H ₂₂ FN ₃ O ₄ S ₂ + H+, 452.11085; found (ESI ₅ [M+H] ⁺ ), 452.1115.

Example 331 : 5-[(4-fluorophenyI)suIfonyl]-2,4-dimethyl-JV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0303] In an analogous manner to Example 298:

[0304] Step 2: 5-(4-Fluoro-benzenesulfonyl)-2,4-dimethyl-benzenesulfonyl chloride and 2-pyridin-2-yl-ethylamine were used to prepare 5 - [(4-fluoropheny Dsulfony 11 -2,4-dimethy 1- iV-(2-pyridin-2-ylethyl)benzenesulfonamide. MS (ESI+) w/z 449; MS (ESI-) m/z AAl;

HRMS: calcd for C ₂₁ H ₂₁ FN ₂ O ₄ S ₂ + H+, 449.09995; found (ESI, [MH-H] ⁺ ), 449.0979.

Example 332: 5-[(4-fluorophenyl)sulfonyl]-2,4-dimethyI-λ'-(tetrahydro-2 _J fi?-pyran-4- yl)benzenesulfonamide

[0305] In an analogous manner to Example 298:

[0306] Step 2: 5-(4-Fluoro-benzenesulfonyl)-2,4-dimethyl-benzenesulfonyl chloride and tetrahydro-pyran-4-ylamine were used to prepare 5-[(4-fluorophenyl)sulfonyl1-2,4-dimethyl- A/ ^" -ftetrahydro-2H ^' -pyran-4-yl)benzenesulfonamide. MS (ESI+) m/z 428; MS (ESI-) m/z 426; HRMS: calcd for C ₁₉ H ₂₂ FNO ₅ S ₂ + H+, 428.09962; found (ESI, [M+H] ⁺ ), 428.0981.

Example 333: 5-[(4-jπuorophenyl)sulfonyl]-2,4-dimethyl-λ ^r -[2-(tetrahydro-2H ^r -pyran-4- yl)ethyl] benzenesulfonamide

[0307] In an analogous manner to Example 298:

[0308] Step 2: 5-(4-Fluoro-benzenesulfonyl)-2,4-dimethyl-benzenesulfonyl chloride and 2-(tetrahydro-pyran-4-yl)-ethylamine were used to prepare 5-[(4-fluorophenyl)sulfonyl]-2,4- dimethyl-iV-r2-rtetrahvdro-2H ^' -pyran-4-yDethyl]benzenesulfonamide. MS (ESI+) w/z456; MS (ESI-) m/z 454; HRMS: calcd for C ₂₁ H ₂₆ FNO ₅ S ₂ + H+, 456.13092; found (ESI, [M+H] ⁺ ), 456.1321.

Example 334: 2-chloro-iV-(2-phenylethyl)-5-(phenylsulfonyl)benzenesulfona mide

[0309] Step 1: 3-nitro-4-chlorobenzenesulfonylchloride (5.0 g, 19.5 mmol) was added portionwise to a stirred solution of aluminum chloride (3.12 g, 23.4 mmol) in benzene (10 mL) and stirred overnight at room temperature. The solution was poured over ice and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. The crude solid was dissolved in methanol (100 mL) and water (3 mL). Tin (II) chloride (11.0 g, 58.0 mmol) was added and the resulting solution was heated to 70 °C overnight The solution was concentrated and partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated to give [2-chloro-5-fphenylsulfonyl)phenyl ^' |amine (2.59 g, 36%).

MS (ESI+) rø/z 268;

HRMS: calcd for C ₁₂ H ₁₀ ClNO ₂ S + H+, 268.01935; found (ESI, [M+H] ⁺ ), 268.0202;

[0310] Step 2: To a stirred solution of [2-chloro-5-(phenylsulfonyl)phenyl]amine (2.5 g, 9.34 mmol) in acetonitrile (75 niL) at 0 °C was added glacial acetic acid (7.5 mL) and concentrated HCl (7.5 mL). A solution of sodium nitrite (0.77 g, 11.21 mmol) dissolved in D.I water (3 mL) was added dropwise. The resulting solution was stirred 20 minutes. Sulfur dioxide was then bubbled into the solution for 20 minutes. A solution of copper (II) chloride dihydrate (1.59 g, 9.34 mmol) dissolved in D.I. water (3 mL) was added, the ice bath was removed and the solution was allowed to stir overnight at room temperature. The reaction volume was concentrated to one third and extracted several times with ethyl acetate. The organic layers were combined, washed with water and sat. sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The crude material was carried on without further purification.

[0311] Step 3: Following the same procedure described in Example 1 (step 2), 5- benzenesulfonyl-2-chlorobenzenesulfonyl chloride and phenethylamine were used to prepare 2z chloro-N-(2-phenylethyl)-5-(phenylsulfonyl)benzenesulfonamid e. MS (ES-) m/z 433.8; HRMS: calcd for C ₂₀ H ₁₈ ClNO ₄ S ₂ + H+, 436.04385; found (ESI, [M+H] ⁺ ), 436.0475.

Example 335: 2-chloro-iV-(2-morpholin-4-ylethyl)-5-(phenylsulfonyl)benzen esulfonamide

[0312] In an analogous manner to Example 334:

[0313] Step 3 : 4-(2-aminoethyl)-morpholine was used to prepare 2-chloro-7V-r2- morpholin-4-ylethyl)-5-(phenylsulfonyl)benzenesulfonamide. MS (ES-) m/z 442.8; HRMS: calcd for C ₁₈ H ₂₁ ClN ₂ O ₅ S ₂ + H+, 445.06532; found (ESI ₃ [M+H] ⁺ ) ₅ 445.0679.

Example 336: 2-chloro-JV-[3-(l//-imidazol-l-yI)propyl]-5- (phenylsulfonyl)benzenesulfonamide

[0314] In an analogous manner to Example 334:

[0315] Step 3: l-(3-aminopropyl)-imidazole was used to prepare 2-chloro-iV- \3-(lH- imidazol-l-yl)propyl]-5-fphenylsulfonyl)benzenesulfonamide. MS (ES-) m/z 437.8;

HRMS: calcd for C ₁₈ H ₁₈ ClN ₃ O ₄ S ₂ + H+, 440.05000; found (ESI, [M+H] ⁺ ), 440.0482.

Example 337: 2-chloro-5-(phenylsulfonyl)-iV-(2-pyridin-2-ylethyl)benzenes uIfonamide

[0316] In an analogous manner to Example 334:

[0317] Step 3: 2-(2-aminoethyl)-pyridine was used to prepare 2-chloro-5- (phenylsulfonyl ^* )-N-(2-pyridin-2-ylethyl)benzenesulfonamide. MS (ES-) m/z 434.8; HRMS: calcd for C ₁₉ H ₁₇ ClN ₂ O ₄ S ₂ + H+, 437.03910; found (ESI, [M+H] ⁺ ), 437.042.

Example 338: iV-[3-(ljH-imidazol-l-yl)propyl]-5-[(4-isopropylphenyI)su!fo nyl]-2- methylbenzenesulfonamide

[0318] In an analogous manner to Example 315:

[0319] Step 2: 4-isopropylbenzenethiol was used to prepare

A/-r3-dH-imidazol-l-yl ^' )propyl]-5-r(4-isopropylphenyl)sulfonyl]-2- methylbenzenesulfonamide .

MS (ES-) m/z 460.0;

HRMS: calcd for C ₂₂ H ₂₇ N ₃ O ₄ S ₂ + H+, 462.15157; found (ESI, [M+H] ⁺ ), 462.1525.

Example 339: iV-[3-(liϊ~imidazol-l-yl)propyl]-2-methyl-5-(2- naphthylsulfonyl)benzenesulfonamide

[0320] In an analogous manner to Example 315:

[0321] Step 2: 2-naphthlyene was used to prepare TV- [3 -( 1 H-imidazol- 1 -vDpropyl] -2- methyl-5-(2-naphthylsulfonyl)benzenesulfonamide. MS (ES-) m/z 467.9; HRMS: calcd for C ₂₃ H ₂₃ N ₃ O ₄ S ₂ + H+, 470.12027; found (ESI, [M+H] ⁺ ), 470.1189.

Example 340: 5-[(3,4-dichlorophenyl)sulfonyl]-iV-[3-(l _J fir-imidazol-l-yl)propyl]-2- methylbenzenesulfonamide

[0322] Step 1 : In an analogous manner to Example 315, step 1.

[0323] Step 2: A solution of nickel (II) bromide (0.03 g, 0.11 mmol), zinc powder (0.03 g, 0.45 mmol), 1,1 '-bis(diphenylphosphino)-ferrocene (0.12 g, 0.22 mmol), and potassium carbonate (0.31 g, 2.24 mmol) in NMP (8 mL) was stirred at room temperature for 1 hour. 5-

bromo-iV-[3-(lH ^: -imidazol-l-yl)propyl]-2-methylbenzenesulfonamide (0.70 g, 1.95 mmol) and 3,4-dichlorobenzenethiol (0.2 mL,1.57 mmol) were added and the resulting solution was heated in the microwave at 160 °C for 10 minutes. The solution was partitioned between a saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was concentrated and HPLC separated. The resulting solid was dissolved in methylene chloride (5 niL). M- chloroperbenzoic acid (0.22 g, 77%, 0.99 mmol) was added and the solution was stirred 1 hour at room temperature, washed with a saturated aqueous sodium dithionite solution, a saturated aqueous sodium bicarbonate solution, concentrated and HPLC separated to give 5-[(3,4- dichlorophenyl)sulfonyll-N-[3-(lH-imidazol-l-yl)propyl1-2-me thylbenzenesulfonamide (0.08 g,

'%>.

MS (ES-) m/z 485.8;

HRMS: calcd for C ₁₉ H ₁₉ Cl ₂ N ₃ O ₄ S ₂ + H+, 488.02668; found (ESI ₅ [M+H] ⁺ ), 488.03.

Example 341: 2-(2-hydroxy-2-methylpropyl)-N-(2-phenylethyl)-5- (phenylsulfonyl)benzenesulfonamide

[0324] To a solution of 2-methyl-N-(2-phenylethyl)-5-

(phenylsulfonyl)benzenesulfonamide(l .0 g 2.4 mmol) in tetrahydrofuran (20 mL) was added butyllithiurn (6.0 mL of 2.5 M in hexanes) dropwise at -78 ⁰ C. The solution was allowed to stir at —78 ⁰ C for twenty minutes and then acetone (0.18 mL, 2.4 mmol) was added dropwise. The reaction was stirred at —78 ⁰ C for one hour and then poured onto ice/water and extracted with ethyl acetate (3 x 75 mL). The combined organics were dried with magnesium sulfate and concentrated down. The crude residue was purified using automated flash chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of 2-(2- hydroxy-2-memylpropyl)-N-(2-phenylethyr)-5- (phenylsulfonyl)benzenesulfonamide (0.12 g, 11%).

MS (ES+) m/z AlA; MS (ES-) m/z All; HRMS: calcd. for C ₂₄ H ₂₇ NO ₅ S ₂ + H ⁺ , 474.1409: found (ESI, [m+H] ⁺ ), 474.1397.

Example 342: 5-[(3-chlorophenyl)sulfonyl]-iV-[3-(lJϊ-imidazol-l-yl)propy l]-2- methylbenzenesulfonamide

[0325] In an analogous manner to Example 340:

[0326] Step 2: 3-chlorobenzenethiol was used to prepare 5 - [(3 -chlorophenyl) sulfony 1] - JV-f3-(l /f-imidazol- 1 -y Dpropyl] -2-methylbenzenesulfonamide . HRMS: calcd for C ₁₉ H ₂₀ ClN ₃ O ₄ S ₂ + H+, 454.06565; found (ESI, [M+H] ⁺ ), 454.0649.

Example 343: 5-[(3,5-dimethylphenyl)suIfonyl]-iV-[3-(l _J fr-imidazol-l-yl)propyl]-2- methylbenzenesulfonamide

[0327] In an analogous manner to Example 340:

[0328] Step 2: 3,5-dimethylbenzenethiol was used to prepare 5-[Y3,5- dimethylpheny Dsulfony 1] -JV- [3 -( 1 /f-imidazol- 1 -vDpropyH -2-methylbenzenesulfonamide.

MS (ESI+) m/z 448;

HRMS: calcd for C ₂₁ H ₂₅ N ₃ O ₄ S ₂ + H+, 448.13592; found (ESI, [M+H] ⁺ ), 448.1387.

Example 344: 5-[(3,5-dichlorophenyI)sulfonyl]-JV-[3-(lJy-imidazol-l-yI)pr opyl]-2- methylbenzenesulfonamide

[0329] In an analogous manner to Example 340:

[0330] Step2: 3,5-dichlorobenzenethiol was used to prepare 5-[(3,5- dichlorophenypsulfonyll -JV- [3 -( 1 /f-imidazol- 1 -yDpropyl] -2-methylbenzenesulfonamide .

HRMS: calcd for C ₁₉ H ₁₉ Cl ₂ N ₃ O ₄ S ₂ + H+, 488.02668; found (ESI, [M+H] ⁺ ), 488.0278.

Example 345: 5-[(2,5-dichlorophenyl)sulfonyl]-JV-[3-(lH-imidazol-l-yl)pro pyl]-2- methylbenzenesulfonamide

[0331] In an analogous manner to Example 377:

[0332] Step 2: 2,5-dichlorobenzenethiol was used to prepare 5-[(2,5- dichloropheny Psulfonyl] -JV- [3 -( 1 /f-imidazol- 1 -yDpropyl] -2-methylbenzenesulfonamide.

MS (ES-) m/z 485.8;

HRMS: calcd for C ₁₉ H ₁₉ Cl ₂ N ₃ O ₄ S ₂ + H+, 488.02668; found (ESI, [M+H] ⁺ ), 488.0279.

Example 346: JV-[3-(liϊ-imidazol-l-yl)propyl]-2-methyl-5- (phenylsulfinyl)benzenesulfonamide

[0333] In an analogous manner to Example 340:

[0334] Step 2: benzenethiol and 1 equivalent of m-chloroperbenzoic acid were used to prepare JV-[3-(li/-imidazol-l-yl)propyl]-2-methyl-5-(phenylsulfinyl) benzenesulfonamide.

MS (ES-) m/z 402.0;

HRMS: calcd for C ₁₉ H ₂₁ N ₃ O ₃ S ₂ + H+, 404.10971; found (ESI, [M+H] ⁺ ), 404.1118.

Example 347: λφ-(l#-imidazol-l-yl)ethyl]-2,3-dimethyl-5- (phenylsulfonyl)benzenesulfonamide

[0335] In an analogous manner to Example 295 :

[0336] Step 1 : Benzene sulfonyl chloride and ortho xylene were used to prepare A- Benzenesulfonyl-l,2-dimethyl-benzene, which was purified via Biotage Horizon™ (FLASH 40 M, silica, gradient from 100% hexane to 20% EtOAc/hexane).

[0337] Step 2: 4-Benzenesulfonyl-l,2-dimethyl-benzene and chlorosulfonic acid were used to prepare 5-benzenesulfonyl-2,3-dimethyl-benzenesulfonyl chloride, which was purified via Biotage Horizon™ (FLASH 40 M, silica, gradient from 100% hexane to 20% EtO Ac/hexane) .

[0338] Step 3: 5-Benzenesulfonyl-2,3-dimethyl-benzenesulfonyl chloride and 2-(1H- imidazol-l-yl)ethylamine were used to prepare N-[2-πH-imidazol-l-yl)ethyl]-2,3-dimethyl-5- (phenylsulfonyl)benzenesulfonamide. ηRMS: calcd for C ₁₉ H ₂₁ N ₃ O ₄ S ₂ + H+, 420.10462; found (ESI, [M+H] ⁺ ), 420.1036.

Example 348: A^-[3-(li?-imidazol-l-yl)propyl]-2,3-dimethyl-5- (phenylsulfonyl)benzenesulfonamide

[0339] In an analogous manner to Example 298:

[0340] Step 2: 5-Benzenesulfonyl-2,3-dimethyl-benzenesulfonyl chloride and 3-(1H- imidazol-l-yl)propylamine were used to prepare N-[3-(lH-imidazol-l-yl)propyl1-2,3-dirnethyl- 5-fphenylsulfonyl)benzenesulfonamide. ηRMS: calcd for C ₂₀ H ₂₃ N ₃ O ₄ S ₂ + H+, 434.12027; found (ESI, [M+H] ⁺ ), 434.1187.

Example 349 : 2,3-dimethyl-5-(phenylsulfonyl)-iV-(2-py ridin-2-ylethyl)benzenesulfonamide

[0341] In an analogous manner to Example 298:

[0342] Step 2: 5-Benzenesulfonyl-2,3-dimethyl-benzenesulfonyl chloride and 2- pyridin-2-yl-ethylamine were used to prepare 2,3-dimethyl-5-(phenylsulfonyl)-A/ ^' -(2-pyridin-2- ylethvDbenzenesulfonamide .

HRMS: calcd for C ₂₁ H ₂₂ N ₂ O ₄ S ₂ + H+, 431.10937; found (ESI, [M+H] ⁺ ), 431.1085.

Example 350: 2,3-dimethyl-5-(phenylsulfonyl)-iV-(tetrahydro-2iϊ-pyran-4- yl)benzenesulfonamide

[0343] In an analogous manner to Example 298 :

[0344] Step 2: 5-Benzenesulfonyl-2,3-dimethyl-benzenesulfonyl chloride and tetrahydro-pyran-4-ylamine were used to prepare 2,3-dimethyl-5-(phenylsulfonyl)-iV-(tetrahvdro- 2H-pyran-4-yDbenzenesulfonamide. HRMS: calcd for C ₁₉ H ₂₃ NO ₅ S ₂ + H+, 410.1096; found (ESI, [M+H] ⁺ ), 410.1114.

Example 351 : 2,3-dimethyl-5-(phenylsulfonyl)-λ'-[2-(tetrahydro-2jH ^r -pyran-4- yl)ethyl] benzenesulfonamide

[0345] In an analogous manner to Example 298:

[0346] Step 2: 5-Benzenesulfonyl-2,3-dimethyl-benzenesulfonyl chloride and 2- (tetrahydro-pyran-4-yl)-ethylamine were used to prepare 2,3-dimethyl-5-(phenylsulfonyl)-A/-[2- (tetrahydro-2H-pyran-4-yDemyl]benzenesulfonamide.

[0347] HRMS: calcd for C ₂₁ H ₂₇ NO ₅ S ₂ + H+, 438.14034; found (ESI, [M+H] ⁺ ), 438.1413.

Example 352: 5-{[4-(cyclohexylamino)phenyl]sulfonyl}-iV-[3-(liϊ-imidazol -l-yl)propyl]-2- methylbenzenesulfonamide

[0348] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-iV-[3- (lH-imidazol-l-yl)propyl]-2-methylbenzenesulfonamide and cyclohexylamine were used to prepare 5- { [4-(cy clohexy lamino^pheny 1] sulfonyl } -N- [3 -( 1 H-imidazol- 1 -yPpropy 1] -2- methylbenzenesulfonamide. MS (ES-) m/z 515.0; HRMS: calcd for C ₂₅ H ₃₂ N ₄ O ₄ S ₂ + H+, 517.19377; found (ESI, [M+H] ⁺ ), 517.1782.

Example 353: 5-({4-[(2-cyanoethyl)amino]phenyl}sulfonyl)-N-[3-(lH-imidazo l-l- yl)propyl]-2-methylbenzenesulfonamide

[0349] To a solution of 5-[(4-fluorophenyl)sulfonyl]-N-[3-(lH-imidazol-l-yl)propyl]- 2-methylbenzenesulfonamide (75 mg, 0.17 mmol) in N,N-dimethylacetamide (0.5 mL) was

added 3-aminopropionitrile (67 mg, 0.96 mmol). The solution was heated with stirring using microwave irradiation (180 ⁰ C) for 65 minutes. Upon cooling, the reaction mixture was diluted with water (10 niL) and the aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were concentrated and the resulting crude residue was purified using automated flash column chromatography with a graduated mobile phase consisting of dichloromethane and methanol resulting in the isolation of 5-({4-[(2- cyanoethyl)ammo1phenyUsulfonyl)-N-[3-(lH-imidazol-l-yl)propy r|-2- methylbenzenesulfonamide (38 mg, 45%).

MS (ES+) m/z 488.0

MS (ES-) m/z 485.9

HRMS: calcd for C ₂₂ H ₂₅ N ₅ O ₄ S ₂ + H+, 488.1426; found (ESI, [M+HJ+), 488.1440.

Example 354: 5-[(4-{[(lS,2S)-l-(hydroxymethyl)-2-methylbutyl]amino}phenyI )sulfonyl]-λ'- [3-(l/f-imidazoI-l-yI)propyl]-2-methylbenzenesulfonamide

[0350] In an analogous manner to Example 353, 5-[(4~fluorophenyl)sulfonyl]-iV-[3- ( 1 H-imidazol- 1 -y l)propyl] -2-methy lbenzenesulfonamide and ( 1 S, 2S)- 1 -(hy droxymethyl)-2- methylbutyl] amine were used to prepare 5- |Y4- { [( 1 SJ.S)- 1 -(hy droxymethy P)-2- methy lbutyl] amino } phenyDsulfonyl] -N- [3 -( lif-imidazol- 1 -yDpropyll -2- methy lbenzenesulfonamide . MS (ES-) m/z 533.0; HRMS: calcd for C ₂₅ H ₃₄ N ₄ O ₅ S ₂ + H+, 535.20434; found (ESI, PSdH-H] ⁺ ), 535.2024.

Example 355: λ^3-(lif-imidazol-l-yl)propyl]-2-methyl-5-({4-[(l- phenylethyl)amino]phenyl}sulfonyl)benzenesulfonamide

[0351] In an analogous manner to Example 353, 5-[(4-fmorophenyl)sulfonyl]-N-[3- (lH ^" -imidazol-l-yl)propyl]-2-methylbenzenesulfonamide and 2-phenylethylamine were used to prepare N- [3 -( 1 H-imidazol- 1 -y Dpropy 1] -2-methyl-5-( { 4- F( 1 - phenylethvDaminolphenyUsulfonyDbenzenesulfonamide. MS (ES-) m/z 536.9; HRMS: calcd for C ₂₇ H ₃₀ N ₄ O ₄ S ₂ + H+, 539.17812; found (ESI, [M+H] ⁺ ), 539.1788.

Example 356: 2-methyl-5-{[4-(methylamino)phenyl]sulfonyl}-iV~(2-pyridin-2 - ylethyl)benzenesulfonamide

[0352] To a solution of 5-[(4-fluorophenyl)sulfonyl]-2-methyl-N-(2-pyridin-2- ylethyl)benzene-sulfonamide (75 mg, 0.17 mmol) in N,N-dimethylacetamide (0.5 mL) was added an ethanolic solution containing methyl amine (33%, 0.5 mL). The solution was heated with stirring using microwave irradiation (180 ⁰ C) for 20 minutes. Upon cooling, the reaction mixture was diluted with water (10 mL) and the aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were concentrated and the resulting crude residue was purified using automated flash column chromatography with a graduated mobile phase consisting of dichloromethane and methanol resulting in the isolation of 2-methyl-5-{ [4- (methylamino)phenyl1sulfonyl}-N-(2-pyridin-2-ylethyl)-benzen esulfonamide (92 mg, 81%). MS (ES-) m/z 446; HRMS: calcd for C ₂₁ H ₂₃ N ₃ O ₄ S ₂ + H+, 446.12027; found (ESI, [M+H] ⁺ ), 446.1209.

Example 357: 2-isopropyl-5-{[4-(methylamino)phenyl]sulfonyl}-iV-(2-pyridm -2- ylethyl)benzenesulfonamide

[0353] In an analogous manner to Example 356, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide and methylamine were used to prepare JV^ ϊ3 -( lH-imidazol- 1 -yl ^" )propyn-2-methyl-5-f T4- (methylamino)phenyllsulfonyllbenzenesulfonamide. MS (ES+) w/z 474; MS (ES-) m/z 472; HRMS: calcd for C ₂₃ H ₂₇ N ₃ O ₄ S ₂ + H+, 474.15157; found (ESI, [M+H] ⁺ ), 474.1511.

Example 358: 2-isopropyl-5-{[4-(methylamino)phenyl]suIfonyl}-iV-(tetrahyd ro-2iϊ-pyran- 4-yl)benzenesulfonamide

[0354] In an analogous manner to Example 356, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-tetrahydro-2H ^" -pyran-4-ylbenzenesulfonamide and methylamine were used to prepare 2-isopropyl-5- { [4-(methylamino)phenyl] sulfonyl } -N-ftetrahydro-2H ^" -pyran-4- yDbenzenesulfonamide.

MS (ES-) m/z 451;

HRMS: calcd for C ₂₁ H ₂₈ N ₂ O ₅ S ₂ + H+, 453.15124; found (ESI ₅ [M+H] ⁺ ), 453.1505.

Example 359: 2-isopropyl-5-{[4-(methylamino)phenyI]sulfonyl}-A ^L [2-(tetrahydro-2 _J H ^r - pyran-4-yl)ethyI]benzenesulfonamide

[0355] In an analogous manner to Example 356, 5-[ ^" (4-fluorophenyl)sulfonyl]-2- isopropyl-N-(2-tetrahydro-2H-pyran-4-ylethyl)benzenesulfonam ide and methylamine were used to prepare 2-isopropyl-5-{r4-(methylamino)phenvπsulfonyl>-JV-r2-( ^' tetrahvdro-2/j ^' -pyran-4- yl)ethyl]benzenesulfonamide. MS (ES+) w/z 481; MS (ES-) m/z 479; HRMS: calcd for C ₂₃ H ₃₂ N ₂ O ₅ S ₂ + H+, 481.18254; found (ESI, [M+H] ⁺ ), 481.1837.

Example 360: 5-[(2,3-dichlorophenyl)sulfonyI]-iV-[3-(lJϊ-imidazol-l-yl)p ropyI]-2- methylbenzenesulfonamide

[0356] In an analogous manner to Example 340:

[0357] Step 2: 2,3-dichlorobenzenethiol was used to prepare 5-| ^" (2,3- dichlorophenyl)sulfonyl]-A/-[3-(lH-imidazol-l-yl)propyl]-2-m ethylbenzenesulfonamide.

MS (ESI+) m/z 488;

MS (ESI-) m/z 486;

HRMS: calcd for C ₁₉ H ₁₉ Cl ₂ N ₃ O ₄ S ₂ + H+, 488.02668; found (ESI, [M+H] ⁺ ), 488.0269.

Example 361 : 2-chloro-5-(phenylsulfonyl)-iV-(tetrahy dro-2Jϊ-py ran-4- yl)benzenesulfonamide

[0358] In an analogous manner to Example 334:

[0359] Step 3: tetrahydropyran-4-ylamine was used to prepare 2-chloro-5- (phenylsulfonylVA/ ^" -(tetrahydro-2/f-pyran-4-yl)benzenesulfonamide. MS (ESI-) m/z 414; HRMS: calcd for C ₁₇ H ₁₈ ClNO ₅ S ₂ + H+, 416.03877; found (ESI, [M+H] ⁺ ), 416.0392.

Example 362: iV-[3-(ljy-imidazol-l-yl)propyl]-2-methyl-5-(2- thienylsulfonyl)benzenesulfonamide

[0360] In an analogous manner to Example 340:

[0361] Step 2: thiopliene-2-thiol was used to prepare N- [3 -(I H-imidazol- 1 -yDpropy 1] - 2-methyl-5-f2-thienylsulfonyl ^* )benzenesulfonamide. MS (ESI+) m/z 426; HRMS: calcd for C ₁₇ H ₁₉ N ₃ O ₄ S ₃ + H+, 426.06104; found (ESI, [M+H] ⁺ ) ₃ 426.062.

Example 363: A'-[3-(lH ^r -imidazoH-yl)propyI]-2-methyl-5-[(2-inethyl-3- furyl)sulfonyl]benzenesulfonamide

[0362] In an analogous manner to Example 340:

[0363] Step 2: 2-methylfuran-3 -thiol was used to prepare A/-[3-ri//-imidazol-l- yl')propyl]-2-methyl-5-r(2-methyl-3-furvDsulfonyl]benzenesul fonamide. MS (ESI+) m/z 424; MS (ESI-) m/z 422; HRMS: calcd for C ₁₈ H ₂ IN ₃ O ₅ S ₂ + H+, 424.09954; found (ESI, [M+H] ⁺ ) ₅ 424.0983.

Example 364 : N- { [2-methy l-5-(phenylsulfonyl)phenyl] sulf onyl} -L-pheny lalaninamide

[0364] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, diisopropylethylamine, and L-phenylalaninamide in dichloromethane were used to prepare N-f[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl>-L-phenyla laninamide. MS (ESI+) m/z 459 MS (ESI-) m/z 457.

Example 365: methyl N-{[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}-D-phenylalan inate

[0365] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, diisopropylethylamine, and D-phenylalanine methyl ester in dichloromethane were used to prepare methyl N-{[2-methyl-5- (phenylsulfonyDphenyl]sulfonyl}-D-phenylalaninate. MS (ESI+) m/z 474; MS (ESI-) m/z 472.

Example 366: iV-[3-(l/- ^r -imidazol-l-yI)propyl]-2-methyI-5-{[4-(tetrahydro-2iϊ-pyran -4- ylamino)phenyl]sulfonyl}benzenesulfonamide

[0366] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-iV-[3- (lH-imidazol-l-yl)propyl]-2-methylbenzenesulfonamide and 4-aminotetrahydropyran were used to prepare N-[ ^" 3-(l/j ^r -imidazol-l-vπpropyll-2-methyl-5-{[4-ftetrahvdro-2H-pyran-4 - ylaminotphenyl] sulfony 1 } benzenesulfonamide . MS (ESI+) rø/z 519; MS (ESI-) m/z 517; HRMS: calcd for C ₂₄ H ₃₀ N ₄ O ₅ S ₂ + H+, 519.17304; found (ESI, [M+H] ⁺ ), 519.1755.

Example 367: iV-[3-(liϊ-imidazol-l-yl)propyl]-5-({4-[(3- isopropoxypropyl)amino]phenyl}suIfonyl)-2-methyIbenzenesulfo namide

[0367] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-iV-[3- (lH ^" -imidazol-l-yl)propyl]-2-methylbenzenesulfonamide and 3-isopropoxypropyl)amine were used to prepare N- \3 -( 1 H-imidazol- 1 -y Dpropy 1] -5 -( { 4- [(3 - isopropoxypropy l)amino]pheny 1 } sulfonyl V2-methylbenzenesulfonamide . MS (ESI+) m/z 535; MS (ESI-) m/z 533; HRMS: calcd for C ₂₅ H ₃₄ N ₄ O ₅ S ₂ + H+, 535.20434; found (ESI, [M+H] ⁺ ), 535.2054.

Example 368: 5-({4-[(cycIopropylmethyl)amino]phenyl}sulfonyI)-iV-[3-(liϊ -imidazol-l- yl)propyl]-2-methyIbenzenesulfonamide

[0368] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-iV-[3- (lH-imidazol-l-yl)propyl]-2-methylbenzenesulfonamide and cyclopropylmethylamine were used to prepare 5-( {4- [(cyclopropy lmethvDaminolphenyl } sulfonvD-N- F3 -( 1 H-imidazol- 1 -yDpropyl] - 2-methylbenzenesulfonamide. MS (ESI+) m/z 489; MS (ESI-) m/z 487; ηRMS: calcd for C ₂₃ H ₂₈ N ₄ O ₄ S ₂ + H+, 489.16247; found (ESI, [M+H] ⁺ ), 489.1653.

Example 369: 5-({4-[(lR,2if,45)-bicyclo[2.2.1]hept-2-ylamino]phenyl}sulfo nyl)-iV-[3-(lJϊ- imidazol-l-yl)propyl]-2-methylbenzenesulfonamide

[0369] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-N-[3- ( 1 H-imidazol- 1 -y l)propyl] -2-methy lbenzenesulfonamide and ( 1 i?,2i?,45)-bicyclo [2.2.1 ]hept~2- ylamine were used to prepare 5-({4-r(li?,2i?,4 _l S ^r )-bicvclo[2.2.1]hept-2-ylamino1phenyl|sulfonyl)- N-r3-(lH ^" -imidazol-l-yl)propyl1-2-methylbenzenesulfonamide. MS (ESI+) m/z 529; MS (ESI-) m/z 527; HRMS: calcd for C ₂₆ H ₃₂ N ₄ O ₄ S ₂ + H+, 529.19377; found (ESI, [M+H] ⁺ ), 529.1946.

Example 370: 5-{[4-(benzylamino)phenyl]sulfonyl}-iV-[3-(lJϊ-imidazoI-l-y l)propyl]-2- methylbenzenesulfonamide

[0370] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-N-[3- (lH-imidazol-l-yl)propyl]-2-methylberizenesulfonamide and benzylamine were used to prepare 5-{ [ ^~ 4-(benzylamino)pheny 1] sulfony 1 > -N- [3-d H-imidazol- 1 -y Dpropyl] -2- methylbenzenesulfonamide. MS (ESI+) m/z 525; MS (ESI-) m/z 523.

Example 371 : 5-[(4-{[(lS)-l-cyclohexylethyl]amino}phenyl)sulfonyl]-iV-[3- (lH ^r -iinidazol-l- yl)propyl]-2-methylbenzenesulfonamide

[0371] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-N-[3- (lH-imidazol-l-yl)propyl]-2-methylbenzenesulfonamide and (15)-l-cyclohexylethylamine were used to prepare 5-1 ^" (4-1 [YIISVI -cyclohexylethyl] amino } pheny Dsulfonyl] -N- [ ^" 3-(I H-imidazol- 1 - yl)propyl]-2-methylbenzenesulfonamide. MS (ESI+) m/z 545; ηRMS: calcd for C ₂₇ H ₃₆ N ₄ O ₄ S ₂ + H+, 545.22507; found (ESI, [M+H] ⁺ ), 545.2244.

Example 372: 5-[(4-{[(lR)-l-cyclohexylethyl]amino}phenyl)sulfonyl]-iV-[3- (lH-imidazol-l- yl)propyl]-2-methylbenzenesulfonamide

[0372] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-N-[3- (lH-imidazol-l-yl)propyl]-2-methylbenzenesulfonamide and (li?)-l-cyclohexylethylamine were used to prepare 5 - [(4- { [( 1 R)- 1 -cyclohexy lethyl] amino 1 pheny Dsulfonyl] -N- [3 -( 1 H-imidazol- 1 - vDpropyll -2-methy lbenzenesulfonamide .

MS (ESI+) m/z 545; MS (ESI-) m/z 543; HRMS: calcd for C ₂₇ H ₃₆ N ₄ O ₄ S ₂ + H+, 545.22507; found (ESI, [M+H] ⁺ ), 545.2255.

Example 373: 5-({4-[(2-hydroxybutyl)amino]phenyl}sulfonyl)-iV-[3-(l _J H ^r -imidazol-l- yl)propyl]-2-methylbenzenesulfonamide

[0373] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-JV-[3- (lH-imidazol-l-yl)propyl]-2-methylbenzenesulfonamide and 2-hydroxybutylamine were used to prepare 5-( (4- r(2-hydroxybutyl)amino1phenyl j sulfonylViV- f3-(l H-imidazol- 1 -yl)propyl]-2- methylbenzenesulfonamide. MS (ESI+) m/z 507; MS (ESI-) m/z 505; HRMS: calcd for C ₂₃ H ₃₀ N ₄ O ₅ S ₂ + H+, 507.17304; found (ESI, [M+H] ⁺ ), 507.1738.

Example 374: iV-[3-(lZT-imidazol-l-yl)propyl]-2-methyl-5-[(4-{[4- (trifluoromethyl)benzyl]amino}phenyl)sulfonyl]benzenesulfona mide

[0374] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-N-[3- ( 1 i/-imidazol- 1 -yl)propy 1] -2-methylbenzenesulfonamide and 4-(trifluoromethyl)benzylamine were used to prepare N-\3-(l H-imidazol- 1 -y Dpropyl] -2-methyl-5- | ^~ f 4- { [4- (trifluoromethvDbenzyllaminolphenylisulfonylibenzenesulfonam ide. MS (ESI+) m/z 593; HRMS: calcd for C ₂₇ H ₂₇ F ₃ N ₄ O ₄ S ₂ + H+, 593.14986; found (ESI, [M+H] ⁺ ), 593.1508.

Example 375: 5-[(4-bromophenyl)sulfonyl]-2-methyl-λ'-(tetrahydro-2 _J H ^r -pyraii-4- yl)benzenesulfonamide

[0375] In an analogous manner to Example 230:

[0376] Step 1: p-toluene sulfonyl chloride and bromobenzene were used to prepare 1- bromo-4-[(4-methylphenyl)sulfonyl]benzene.

[0377] Step 2: Following the same procedure described in Example 1 (step 1), 1- bromo-4-[(4-methylphenyl)sulfonyl]benzene and chlorosulfonic acid was used to prepare 5-(4- bromobenzenesulfonyl)-2-rnethylbenzenesulfonyl chloride.

[0378] Step 3: Following the same procedure described in Example 1 (step 2), 5-(4- bromobenzenesulfonyl)-2-methylbenzenesulfonyl chloride and tetrahydropyran-4-ylamine were used to prepare 5-[(4-bromophenγl)sulfonvn-2-methyl-iV-( ^' tetrahvdro-2/j ^' -pyran-4- vDbenzenesulfonamide. MS (ESI-) m/z 472;

Example 376: 5-[(4-cyanophenyl)sulfonyl]-2~methyl-iV-(tetrahydro-217-pyra n-4- yl)benzenesulfonamide

[0379] To a stirred solution of 5-[(4-bromophenyl)sulfonyl]-2-methyl-A^tetrahydro- 2H-pyran-4-yl)benzenesulfonamide (0.30 g, 0.63 mmol) in DMF (3 mL) was added zinc cyanide (0.05 g, 0.38 mmol), tris(dibenzylideneacetone) dipalladium(O) (0.03 g, 0.03 mmol), and 1,1'- bis(diphenylphosphino)-ferrocene (0.04 g, 0.06 mmol). The resulting solution was heated to reflux for 1 hour. The solution was concentrated. Flash column separation with 10%-60% ethyl acetate/ hexane followed by trituration gave 5-[(4-cyanophenyDsulfonyl]-2-methyl-iV- (tetrahvdro-2H ^" -pyran-4-yπbenzenesulfonamide (0.11 g, 42%). MS (ESI-) m/z 419.

Example 377: 5-[(2-chlorophenyl)sulfonyl]-iV-[3-(l _J H ^r -imidazol-l-yl)propyl]-2- methylbenzenesulfonamide

[0380] Step 1 : In an analogous manner to Example 315, step 1.

[0381] Step 2: A solution of nickel (II) bromide (0.03 g, 0.11 mmol), zinc powder (0.03 g, 0.45 mmol), l,l'-bis(diphenylphosphino)-ferrocene (0.12 g, 0.22 mmol), and potassium carbonate (0.31 g, 2.24 mmol) in NMP (8 mL) was stirred at room temperature for 1 hour. 5- bromo-iV-[3-(lH-imidazol-l-yl)propyl]-2-methylbenzenesulfona mide (0.70 g, 1.95 mmol) and 2- chlorobenzenethiol (0.18 niL,1.57 mmol) were added and the resulting solution was heated in the microwave at 160 °C for 10 minutes. The solution was partitioned between a saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was concentrated and FfPLC separated. The resulting solid was dissolved in methylene chloride (5 mL). Oxone (0.68 g, 1.10 mmol) was added and the solution was stirred 2 days at room temperature, washed with a saturated aqueous ammonium chloride solution, dried over magnesium sulfate and concentrated to give 5-[f2-chlorophenyl)sulfonyl]-N-[3-(lH-imidazol-l-yl)propyl]- 2- methylbenzenesulfonamide (0.04 g, 4%).

MS (ESI+) m/z 454;

MS (ESI-) m/z 452;

HRMS: calcd for C ₁₉ H ₂₀ ClN ₃ O ₄ S ₂ + H+, 454.06565; found (ESI, [M+H] ⁺ ), 454.0683.

Example 378: λ43-(l#-imidazol-l~yI)propyl]-2-methyI-5-(pyridin-2- ylsulfonyl)benzenesulfonamide

[0382] In an analogous manner to Example 340:

[0383] Step 2: 2-mercaptopyridine was used to prepare N-[3-( Ii7-imidazol- 1 - yl)propyl]-2-methyl-5-(pyridin-2-ylsulfonyl)benzenesulfonami de. MS (ESI+) rø/z 421; HRMS: calcd for C ₁₈ H ₂₀ N ₄ O ₄ S ₂ + H+, 421.09987; found (ESI, [M+H] ⁺ ), 421.0989.

Example 379: 5-[(2,4-dichlorophenyl)sulfonyl]-iV-[3-(lH-imidazol-l-yl)pro pyl]-2- methylbenzenesulfonamide

[0384] In an analogous manner to Example 377:

[0385] Step 2: 2,4-dichlorobenzenethiol was used to prepare 5-|Y2,4- dichlorophenvDsulfony 11 -N- [3 -( 1 ff-imidazol- 1 -vDpropyl] -2-methy lbenzenesulfonamide .

MS (ESI+) m/z 488;

MS (ESI-) m/z 486;

HRMS: calcd for C ₁₉ H ₁₉ Cl ₂ N ₃ O ₄ S ₂ + H+, 488.02668; found (ESI, [M+H] ⁺ ), 488.0299.

Example 380: 5-[(4-acetylphenyl)sulfonyl]-2-methyl-iV-(tetrahydro-2Jϊ-py ran-4- yl)benzenesulfonamide

[0386] To a stirred mixture of 5-[(4-bromophenyl)sulfonyl]-2-methyl-N-(tetrahydro- 2H-pyran-4-yi)benzenesulfonamide (0.70 g, 1.46 mmol) in toluene (10 niL) was added tetrakis(triphenylphosphine) palladium(O) (0.01 g, 0.07 mmol), and tributyl(l-ethoxyvinyl)tin (0.5 mL, 1.48 mmol). The resulting solution was heated at 100 ⁰ C overnight and partitioned between a saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was concentrated, taken up in THF (10 mL) and 2ν HCl (5 mL) was added. The resulting solution was stirred at room temperature for 2 hours and extracted several times with ethyl acetate. The combined organic layers were filtered through celite and concentrated. Trituration with ether gave 5-[f4-acetylphenyl)sulfonyl1-2-methyl-N-( ^' tetrahvdro-2H-pyran-4-

vDbenzenesulfonamide (0.54 g, 85%).

MS (ESI+) rø/z 438;

MS (ESI-) m/z 436;

HRMS: calcd for C ₂₀ H ₂₃ NO ₆ S ₂ + H+, 438.10396; found (ESI, [M+H] ⁺ ), 438.1023.

Example 381 : 5-[(4-bromophenyl)sulfonyl]-2-methyl-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0387] In an analogous manner to Example 375 :

[0388] Step 3: 2-(2-aminoethyl)-pyridine was used to prepare 5-[(4- bromophenyl ^' )sulfonyl]-2-methyl-iV-(2-pyridm-2-ylethyl)benzenesulfonamid e.

MS (ESI+) m/z 495;

HRMS: calcd for C ₂₀ Hi ₉ BrN ₂ O ₄ S ₂ + H+, 495.00424; found (ESI, [M+H] ⁺ ), 495.0048.

Example 382 : 2-methyl-5-(phenylsulfonyl)-iV-(tetrahy dro-2/7-py ran-4- ylmethyl)benzenesulfonamide

[0389] In an analogous manner to Example 298:

[0390] Step 2: 5-Benzenesulfonyl-2-methyl-benzenesulfonyl chloride and 2- (tetrahydro-pyran-4-yl)-methylamine were used to prepare 2-methyl-5 -( ^" phenylsulfonyD-iV- (tetrahydro-2H-pyran-4-ylmethyDbenzenesulfonamide. MS (ESI+) rø/z 410; MS (ESI-) m/z 408; HRMS: calcd for C ₁₉ H ₂₃ NO ₅ S ₂ + H+, 410.10904; found (ESI, [M+H] ⁺ ), 410.111.

Example 383 : 5- [(4-fluorophenyl)sulfony 1] -2-methyl-λ ^r -(tetrahy dro-2/Z-py ran-4- ylmethyl)benzenesulfonamide

[0391] In an analogous manner to Example 298:

[0392] Step 2: 2-Methyl-5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and tetrahydro-pyran-4-yl-methylamine were used to prepare 5-[(4-fluorophenyl)sulfonyl1-2-methyl- N-(tetrahydro-2//-pyran-4-ylmethyl)benzenesulfonamide. MS (ESI+) m/z 428; MS (ESI-) m/z 426; HRMS: calcd for C ₁₉ H ₂₂ FNO ₅ S ₂ + H+, 428.09962; found (ESI, [M+H] ⁴ ), 428.1015.

Example 384: 2-ethyl-5-[(4-fluorophenyl)sulfonyl]-A ^r -(tetrahydro-2H-pyran-4- ylmethyl)benzenesulfonamide

[0393] In an analogous manner to Example 298:

[0394] Step 2: 2-Ethyl-5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and tetrahydro-pyran-4-yl-metliylamine were used to prepare 2-ethyl-5-[f4-fluorophenyl)sulfonyri-iV- (tetrahvdro-2H ^" -pyran-4-ylmethyl)benzenesulfonamide. MS (ESI+) m/z 442; MS (ESI-) m/z 440; HRMS: calcd for C ₂₀ H ₂₄ FNO ₅ S ₂ + H+, 442.11527; found (ESI, [MH-H] ⁺ ), 442.1144.

Example 385: 2,4-dimethyl-5-(phenyIsulfonyl)-λ ^r -(tetrahydro-2 _J fiT-pyran-4- ylmethyl)benzenesulfonamide

[0395] In an analogous manner to Example 298 :

[0396] Step 2: 5-Benzenesulfonyl-2,4-dimethyl-benzenesulfonyl chloride and tetrahydro-pyran-4-yl-mthylamine were used to prepare 2,4-dimethyl-5-fphenylsulfonyiyN- (tetrahydro-2H-pyran-4-ylmethvDbenzenesulfonamide. MS (ESI+) m/z 424; MS (ESI-) m/z 422; HRMS: calcd for C ₂₀ H ₂₅ NO ₅ S ₂ + H+, 424.12469; found (ESI, [M+H] ⁺ ), 424.124.

Example 386: JV-(2-hydroxy-2-phenylethyl)-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0397] In an analogous manner to Example 298:

[0398] Step 2: 5-Benzenesulfonyl-2-methyl-benzenesulfonyl chloride and 2-amino-l- phenyl-ethanol were used to prepare N-(2-hvdroxy-2-phenylethylV2-methyl-5- (phenylsulfonyDbenzenesulfonamide. MS (ESI-) m/z 430; HRMS: calcd for C ₂₁ H ₂₁ NO ₅ S ₂ + NH ₄ ⁺ , 449.11994; found (ESI, [M+NH4] ⁺ ), 449.119.

Example 387: 5-[(4-fluorophenyl)suIfonyl]-iV-(2-hydroxy-2-phenylethyl)-2- methylbenzenesulfonamide

[0399] In an analogous manner to Example 298:

[0400] Step 2: 2-Methyl-5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2- amino-1-phenyl-ethanol were used to prepare 5-[(4-fluorophenyl)sulfonyl1-N-(2-hydroxy-2- phenylethyl)-2-methylbenzenesulfonamide. MS (ESI-) m/z 448; HRMS: calcd for C ₂₁ H ₂₀ FNO ₅ S ₂ + NH ₄ ⁺ , 467.11052; found (ESI, [M+NH4] ⁺ ), 467.1105.

Example 388: 2-ethyl-5-[(4-fluorophenyl)sulfonyl]-iV-(2-hydroxy-2- phenylethyl)benzenesulfonamide

[0401] In an analogous manner to Example 298:

[0402] Step 2: 2-Ethyl-5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2- amino-1-phenyl-ethanol were used to prepare 2-ethyl-5-[(4-fluorophenyl)sulfonyll-N-(2- hydroxy-2-phenylethyl)benzenesulfonamide. MS (ESI-) m/z 462.

Example 389: λ ^r -(2-hydroxy-2-phenylethyl)-2,4-dimethyl-5- (phenylsulfonyl)benzenesulfonamide

[0403] In an analogous manner to Example 298:

[0404] Step 2: 5-Benzenesulfonyl-2,4-dimethyl-benzenesulfonyl chloride and 2-amino- 1-phenyl-ethanol were used to prepare N-( ^' 2-hvdroxy-2-phenylethyl ^' )-2,4-dimethyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ESI-) m/z 444; HRMS: calcd for C ₂₂ H ₂₃ NO ₅ S ₂ + NH ₄ ⁺ , 463.13559; found (ESI, [M+NH4] ⁺ ), 463.1356.

Example 390: trans-iV-(2-hydroxy-l-methyl-2-phenylethyl)-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0405] In an analogous manner to Example 298:

[0406] Step 2: 5-Benzenesulfonyl-2-methyl-benzenesulfonyl chloride and norephedrine hydrochloride were used to prepare trans-A/ ^' -(2-hydroxy- 1 -methyl-2-phenylethyl V2-methyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ESI-) m/z 444; HRMS: calcd for C ₂₂ H ₂₃ NO ₅ S ₂ + NH ₄ ⁺ , 463.13559; found (ESI, [M+NH4] ⁺ ), 463.1376.

Example 391 : 5-[(4-fluorophenyl)sulfonyI]-λ ^r -[trans-2-hydroxy-l-methyl-2-phenylethyl]-2- methylbenzenesulfonamide

[0407] In an analogous manner to Example 298:

[0408] Step 2: 2-Methyl-5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and norephedrine hydrochloride were used to prepare 5 - [f4-fluorophenyl)sulfbnyl] -N- [trans-2- hydroxy- 1 -methy 1-2-pheny lethy 1] -2-methy lbenzenesulfonamide . MS (ESI-) m/z 462; HRMS: calcd for C ₂₂ H ₂₂ FNO ₅ S ₂ + NH ₄ ⁺ , 481.12617; found (ESI, [M+NH4] ⁺ ), 481.1258.

Example 392: 2-ethyI-5-[(4-fluorophenyl)sulfonyl]-λ ^r -[(trans)-2-hydroxy-l-methyI-2- phenylethyl]benzenesulfonamide

[0409] In an analogous manner to Example 298:

[0410] Step 2: 2-Ethyl-5-(4-fiuoro-benzenesulfonyl)-benzenesulfonyl chloride and norephedrine hydrochloride were used to prepare 2-ethyl-5-[(4-fluorophenyl)sulfonyl]-iV- [(trans)-2-hydroxy-l-methyl-2-phenylethyl]benzenesulfonamide . MS (ESI-) m/z Al 6; HRMS: calcd for C ₂₃ H ₂₄ FNO ₅ S ₂ + NH ₄ ⁺ , 495.14182; found (ESI, [M+NH4] ^"1" ), 495.1408.

Example 393: iV-[(trans)-2-hydroxy-l-methyl-2-phenylethyl]-2,4-dimethyl-5 - (phenylsulfonyl)benzenesulfonamide

[0411] In an analogous manner to Example 298:

[0412] Step 2: 5-Benzenesulfonyl-2,4-dimethyl-benzenesulfonyl chloride and norephedrine hydrochloride were used to prepare N-[ftrans)-2-hydroxy-l-methyl-2-phenylethyl ^~ |- 2,4-dimethyl-5-fphenylsulfonyl)benzenesulfonamide. HRMS: calcd for C ₂₃ H ₂₅ NO ₅ S ₂ + NH ₄ ⁺ , 477.15124; found (ESI, [M+NH4] ⁺ ), 477.1517.

Example 394: 2-methyl-5-(phenylsulfonyl)-N-propylbenzenesulfonamide

[0413] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and propylamine hydrochloride in dichloromethane were used to prepare 2-methyl-5-(phenylsulfonylVN-propylbenzenesulfonamide. MS (ES-) m/z 352.0.

Example 395: N-(tert-butyl)-2-methyl-5-(phenylsulfonyl)benzenesulfonamide

[0414] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and tert-butylamine in dichloromethane were used to prepare N-ftert-butyl)-2-methyl-5-(phenylsulfonyl ^' )benzenesulfonamide. MS (ESI-) m/z 366.

Example 396: N-(2,2-dimethylpropyl)-2-methyl-5-(phenylsulfonyl)benzenesul fonamide

[0415] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and røeø-pentylamine in dichloromethane were used to prepare N-(2,2-dimethylpropyl)-2-methyl-5-(phenylsulfonvDbenzenesulf onamide. MS (ES-) m/z 380.0.

Example 397: N-(l-ethylpropyl)-2-methyl-5-(phenylsulfonyl)benzenesulfonam ide [0416] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and 3-aminopentane in dichloromethane were used to prepare N-(l-ethylpropyl)-2-methyl-5-(phenylsulfonyl)benzenesulfonam ide. MS (ES-) m/z 380.0.

Example 398: N-cyclobutyl-2-methyl-5-(phenylsulfonyl)benzenesulfonamide

[0417] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and cyclobutylamine in dichloromethane were used to prepare N-cyclobutyl-2-methyl-5-fphenylsulfonyl)benzenesulfonamide. MS (ESI-) m/z 364.

Example 399: N-cyclopentyl-2-methyl-5-(phenylsulfonyl)benzenesulfonamide

[0418] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and cyclopentylamine in dichloromethane were used to prepare N-cyclopentyl^-methyl-S-fphenylsulfonyDbenzenesulfonamide. MS (ESI-) m/z 378.

Example 400: N-cyclohexyl-2-methyl-5-(phenylsulfonyl)benzenesulfonamide

[0419] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and cyclohexylamine in dichloromethane were used to prepare N-cvclohexyl-2-methyl-5-(phenylsulfonyl)benzenesulfonamide. MS (ESI-) m/z 392.

Example 401 : 2-methyl-5-(phenylsulfonyl)-N-(2,2,2-trifluoroethyl)benzenes ulfonamide

[0420] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and 2,2,2 -trifluoroethylamine in dichloromethane were used to prepare 2-methyl-5-(phenylsulfonyl)-N-(2,2,2-trifluoroethyl ^' )benzenesulfonamide. MS (ES-) m/z 391.9.

Example 402: 5-({4-[(l£)-iV-hydroxyethanimidoyl]phenyl}sulfonyl)-2-methy l-iV- (tetrahydro-2i?-pyran-4-yl)benzenesulfonamide

[0421] To a stirred mixture of 5-[(4-acetylphenyl)sulfonyl]-2-methyl-iV-(tetrahydro-2H ^' - pyran-4-yl)benzenesulfonamide (0.2Og, 0.46mmol) in ethanol (2mL) and D.I. water (0.5mL) was> added sodium acetate (0.05g, 0.55mmol) and hydroxylamine hydrochloride (0.04g, 0.50mmol). The resulting mixture was heated to reflux for 2.5 hours. The solution was concentrated and filtered to give 5-({4-[(l E)-N-hy droxyethanimidoy rjphenyl ) sulfony IV 2-methy l-JV ^" -(tetrahvdro- 2H-pyran-4-yDbenzenesulfonamide (0.11 g, 55%). MS (ES1+) tn/z 453; HRMS: calcd for C ₂₀ H ₂₄ N ₂ O ₆ S ₂ , 452.10758; found (ESI, [H+M] ⁺ ), 453.1131.

Example 403: 5-[(4-acetylphenyl)sulfonyl]-2-methyl-JV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0422] In an analogous manner to Example 380, 5-[(4-bromophenyl)sulfonyl]-2- methyl-λ/ ^" -(2-pyridin-2-ylethyl)benzenesulfonamide was used to prepare 5-[(4- acetylphenyl ^' )sulfonyl]-2-methyl-JV-(2-pyridin-2-ylethyl ^' )benzenesulfonamide. MS (ESI+) rø/z 459; HRMS: calcd for C ₂₂ H ₂₂ N ₂ O ₅ S ₂ + H+, 459.10429; found (ESI, [M+H] ⁺ ), 459.1054.

Example 404: N-(2-hydroxy-l,l-dimethylethyl)-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0423] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and 2-amino-2 -methyl- 1-propanol in dichloromethane were used to prepare N-f2 -hydroxy- 1 , 1 -dimethylethyl)-2-methyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ESI-) m/z 382.

Example 405: 5-{[4-(l-hydroxy-l-methylethyl)phenyl]sulfonyl}-2-methyl-iV- (2-pyridin-2- ylethyl)benzenesulfonamide

[0424] To a stirred mixture of 5-[(4-acetylphenyl)sulfonyl]-2-methyl-iV-(2-pyridin-2- ylethyl)benzenesulfonamide (0.15 g, 0.33 mmol) in THF (3 mL) was added methyl magnesium bromide 1.4M in 75% toluene/THF (0.75 mL, 1.0 mmol) at 0 °C. The resulting mixture was stirred 2 hours, quenched with a saturated aqueous ammonium chloride solution, and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. HPLC separation gave 5- {[4-d -hydroxy- 1- methylethyDphenyl]sulfonyl>-2-methyl-A/-( ^' 2-pyridin-2-ylethyl)benzenesulfonamide (0.02 g,

%).

MS (ES+) m/z 475;

HRMS: calcd for C ₂₃ H ₂₆ N ₂ O ₅ S ₂ , 474.12831; found (ESI, [H+M] ⁺ ), 475.1382.

Example 406 : 5-{ [4-(l -cy clohexyl-1 -hydroxy ethyl)phenyl] sulfonyl} -2-methyl-iV-(2-py ridin- 2-ylethyl)benzenesulfonamid

[0425] In an analogous manner to Example 405, cyclohexyl magnesium chloride was used to prepare 5 - { \4-( 1 -cyclohexyl- 1 -hy droxy ethy Pphenyl] sulfonyl } -2-methyl-JV ^" -(2-pyridin-2- ylethyPbenzenesulfonamide. MS (ES-) m/z 541.0; HRMS: calcd for C ₂₈ H ₃₄ N ₂ O ₅ S ₂ + H+, 543.19819; found (ESI, [M+H] ⁺ ), 543.1959.

Example 407: 5-{[4-(l-hydroxy-l-phenylethyl)phenyl]sulfonyl}-2-methyl-λ' -(2-pyridin-2- ylethyl)benzenesulfonamide

[0426] In an analogous manner to Example 405, phenyl magnesium bromide was used to prepare 5-{[4-(l-hydroxy-l-phenylethyl)phenyl1sulfonyl}-2-methyl-N-r 2-pyridin-2- ylethyDbenzenesulfonamide.

MS (ES-) m/z 535.0;

HRMS: calcd for C ₂₈ H ₂₈ N ₂ O ₅ S ₂ + H+, 537.15124; found (ESI, [M+H] ⁺ ), 537.1492.

Example 408: 5-{[4-(l-hydroxy-l-methyI-2-phenylethyI)phenyl]sulfonyl}-2-m ethyl-iV-(2- pyridin-2-yIethyI)benzenesulfonamide

[0427] In an analogous manner to Example 405, benzyl magnesium chloride was used to prepare 5-{r4-(l-hvdroxy-l-methyl-2-phenylethyl)plienyllsulfonyl}-2- methyl-A/ ^' -(2-pyridin-2- ylethvDbenzenesulfonamide . MS (ES-) m/z 549.0; HRMS: calcd for C ₂₉ H ₃₀ N ₂ O ₅ S ₂ + H+, 551.16689; found (ESI, [M+H] ⁺ ), 551.1655.

Example 409: 5-[(3-cyanophenyl)sulfonyl]-2-methyl-λ'-(2-pyridin-2- ylethyl)benzenesulfonamide

[0428] Step 1 : Following the same procedure described in Example 315 (step 1), 2-(2- aminoethyl)-pyridine was used to prepare 5-bromo-2-methyl-JV-(2-pyridin-2- ylethyl)benzenesulfonamide . MS (ES) m/z 352.9;

[0429] Step 2: To a stirred solution of 5-bromo-2-methyl-iV-(2-pyridin-2- ylethyl)benzenesulfonamide (10.0 g, 28.15 mmol) in THF (200 niL) at -78°C was added methyl magnesium bromide 1.4M in 75% toluene/THF (24.0 mL, 33.6 mmol). The reaction was stirred 10 minutes and n-butyl lithium 2.5M in hexane (14.0 mL, 35.0 mmol) was added dropwise. The reaction was stirred an additional 10 minutes. Sulfur dioxide was bubbled into the reaction for 20 minutes and was then allowed to warm to room temperature over a period of 2 hours. The reaction was quenched with D.I. water (200 mL) and extracted with ethyl acetate. Sodium hydroxide 2.5M was added to the aqueous layer to a pH of 11 and extracted again with ethyl acetate. The aqueous layer was concentrated and the resulting solid was triturated with methanol to give 4-methyl-3-{[(2-pyridin-2-ylethyl)amino]sulfonyl}benzenesulf inic acid (10.6 g, 103% contains undetermined quantity of inorganic salts.) MS (ESI) m/z 341;

[0430] Step 3 : To a stirred solution of 4-methyl-3- { [(2-pyridin-

2ylethyl)amino]sulfonyl}benzenesulfϊnic acid (0.30 g, 0.83 mmol) in DMSO (4 mL) was added 3-cyanophenylboronic acid (0.12 g, 0.83 mmol), potassium carbonate (0.46 g, 3.31 mmol), and

copper (II) acetate (0.16 g, 0.91 mmol). The resulting solution was stirred overnight at room temperature under a drying tube. The reaction was partitioned between ammonium chloride solution (sat) and ethyl acetate. The organic layer was concentrated. HPLC separation gave 5^ r(3-cyanophenyl)sulfoiiyl]-2-methyl-iV-(2-pyridin-2-ylethyl) benzenesulfonamide (0.0 2g, 5%). MS (ES+) m/z 442.0; MS (ES-) m/z 440.0.

Example 410: 2-methyl-5-(l-naphthyIsulfonyl)-λ'-(2-pyridin-2-ylethyl)ben zenesuIfonamide

[0431] In an analogous manner to Example 409,

[0432] Step 3: 1-naphthylene boronic acid was used to prepare 2-methyl-5-(l- naphthylsulfonylVN-(2-pyridin-2-ylethyl)benzenesulfonamide. MS (ES-) m/z 465.0; HRMS: calcd for C ₂₄ H ₂₂ N ₂ O ₄ S ₂ + H+, 467.10937; found (ESI, [M+H] ⁺ ), 467.1113.

Example 411: 2-methyl-5-(phenylsulfonyl)-N-(2,2,6,6-tetramethylpiperidin- 4- yl)benzenesulfonamide

[0433] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and 4-amino-2,2,4,4-tetramethylpiperidine in dichloromethane were used to prepare 2-methyl-5-(phenylsulfonyl)-N-(2,2,6,6- tetramethylpiperidin-4-yl)benzenesulfonamide. MS (ESI+) m/z 451; MS (ESI-) m/z 449.

Example 412: N-[(lS%2S*)-2-hydroxycyclohexyl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0434] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and frαw-2-aminocyclohexanol hydrochloride in dichloromethane were used to prepare N- \( 1 S * ,2S * )-2-hydroxy cyclohexyl] -2-methyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ESI+) m/z 410; MS (ESI-) m/z 408.

Example 413: N-(l-benzylpiperidin-4-yI)-2-methyI-5-(phenylsulfonyl)benzen esulfonamide

[0435] In an analogous manner to Example 294, 5-benzenesulfonyl-2~methyl- benzenesulfonyl chloride, triethylamine, and 4-amino-l-benzylpiperidine in dichloromethane were used to prepare N-d-benzylpiperidin-4-yl)-2-methyl-5- (phenylsulfonyDbenzenesulfonamide. MS (ESI+) m/z 485; MS (ESI-) m/z 483.

Example 414: N-(l-benzylpyrrolidin-3-yl)-2-methyl-5-(phenylsulfonyl)benze nesulfonamide

[0436] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and l-benzyl-3-aminopyrrolidine in dichloromethane were used to prepare N-(l-benzylpyrrolidin-3-yl>2-methyl-5- (phenylsulfonvDbenzenesulfonamide. MS (ESI+) m/z 471; MS (ESI-) m/z 469.

Example 415: N-(2,3-dihydro-lH-inden-l-yl)-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0437] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and 1-aminoindane in dichloromethane were used to prepare N-(2,3-dihvdro-lH-inden-l-yl)-2-methyl-5-(phenylsulfonyDbenz enesulfonamide. MS (ESI-) m/z 426.

Example 416: 5- [(3-hy droxyphenyl)sulfonyl] -2-methy l-iV-(2-py ridin-2- ylethyl)benzenesulfonamide

[0438] In an analogous manner to Example 409,

[0439] Step 3 :3-hydroxyphenyl boronic acid was used to prepare 5-[(3- hydroxyphenyl)sulfonyl]-2-methyl-7V-f2-pyridin-2-ylethyl)ben zenesulfonamide.

HRMS: calcd for C ₂₀ H ₂₀ N ₂ O ₅ S ₂ + H+, 433.08864; found (ESI, [M+H] ⁺ ), 433.0912.

Example 417: 5-[(3,5-difluorophenyI)suIfonyl]-2-methyl-N-(2-pyridin-2- ylethyl)benzenesulfonamide

[0440] In an analogous manner to Example 409,

[0441] Step 3: 3,5-difluorophenyl boronic acid was used to prepare 5-r(3,5- difluorophenyl)sulfonyll-2-methyl-iV-(2-pyridin-2-yleth.yl)b enzenesulfonamide. MS (ES-) m/z 451.0; HRMS: calcd for C ₂₀ H ₁₈ F ₂ N ₂ O ₄ S ₂ + H+, 453.07488; found (ESI, [M+H] ⁺ ) ₅ 453.0736.

Example 418: 5-[(4-ethylphenyI)sulfonyl]-2-methyI-JV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0442] In an analogous manner to Example 409,

[0443] Step 3: 4-ethylphenyl boronic acid was used to prepare 5-[(4- ethylphenyl)sulfonyll-2-methyl-A/ ^' -(2-pyridin-2-ylethyl)benzenesulfonamide.

MS (ES-) m/z 443.0;

HRMS: calcd for C ₂₂ H ₂₄ N ₂ O ₄ S ₂ + H+, 445.12502; found (ESI, [M+H] ⁺ ), 445.1262.

Example 419: 5- [(3-acetylphenyl)sulf ony 1] -2-methyl-iV-(2-py ridin-2- ylethyl)benzenesulfonamide

[0444] In an analogous manner to Example 409,

[0445] Step 3: 2-acetylphenyl boronic acid was used to prepare 5-[(3- acetylphenvDsulfonvn-2-meth.yl-iV-(2-pyridin-2-ylethyl)benze nesulfonamide.

MS (ES-) m/z 457.0;

HRMS: calcd for C ₂₂ H ₂₂ N ₂ O ₅ S ₂ + H+, 459.10429; found (ESI, [M+H] ⁺ ), 459.1059.

Example 420: 5-[(2-ethoxyphenyl)sulfonyl]-2-methyl-JV~(2~pyridin-2- ylethyl)benzenesulfonamide

[0446] In an analogous manner to Example 409,

[0447] Step 3: 2-ethyoxyphenyl boronic acid was used to prepare 5-[(2- ethoxyphenvDsulfonvn-σ-methyl-N-C∑-pyridin-σ-ylethYDbenz enesulfonamide. MS (ES-) m/z 459.0; HRMS: calcd for C ₂₂ H ₂₄ N ₂ O ₅ S ₂ + H+, 461.11994; found (ESI, [M+H] ⁺ ), 461.1215.

Example 421 : 5-[(2,5-dimethoxyphenyl)sulfonyI]-2-methyl-iV-(2-pyridm-2- ylethyl)benzenesulfonamide

[0448] In an analogous manner to Example 409,

[0449] Step 3: 2,5-dimethoxyphenyl boronic acid was used to prepare 5-[(2,5- dimethoxyphenyl)sulfonyl]-2-methyl-iV-(2-pyridin-2-ylethyl)b enzenesulfonamide. MS (ES-) m/z 475.0; HRMS: calcd for C ₂₂ H ₂₄ N ₂ O ₆ S ₂ + H+, 477.11485; found (ESI, [M+H] ⁺ ), 477.1174.

Example 422: 5-[(2,3-dimethoxyphenyl)sulfonyI]-2-methyl--V-(2-pyridm-2- ylethyl)benzenesulfonamide

[0450] In an analogous manner to Example 409,

[0451] Step 3: 2,3-dimethoxyphenyl boronic acid was used to prepare 5-[(2,3- dimetlioxyphenyl)sulfonyl1-2-methyl-iV-( ^' 2-pyridin-2-yletlivπbenzenesulfonamide. MS (ES-) m/z 475.0; HRMS: calcd for C ₂₂ H ₂₄ N ₂ O ₆ S ₂ + H+, 477.11485; found (ESI, [M+H] ⁺ ), 477.1169.

Example 423: 5-[(2,4-dimethoxyphenyl)sulfonyI]-2-methyI-λ ^L (2-pyridin-2- ylethyl)benzenesulfonamide

[0452] In an analogous manner to Example 409,

[0453] Step 3 : 2,4-dimethoxyphenyl boronic acid was used to prepare 5-| ^" (2,4- dimethoxyphenyl)sulfonyll-2-methyl-iV-(2-pyridin-2-ylethvπb enzenesulfonamide. MS (ES-) m/z 475.0; HRMS: calcd for C ₂₂ H ₂₄ N ₂ O ₆ S ₂ + H+, 477.11485; found (ESI, [M+H] ⁺ ), 477.1144.

Example 424: N-cyclopropyl-2-methyl-5-(phenylsulfonyl)benzenesulfonamide

[0454] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and cyclopropylamine in dichloromethane were used to prepare N-cyclopropyl-2-metriyl-5-(phenylsulfonyDbenzenesulfonamide. MS (ES-) m/z 350.0.

Example 425: ethyl 4-({[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)piperi dine-l- carboxylate

[0455] In an analogous manner to Example 294, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride, triethylamine, and ethyl 4-amino-l-piperidine carboxylate in

dichloromethane were used to prepare ethyl 4-({| ^~ 2-methyl-5- (phenylsulfonyl)phenyllsulfonyl}amino)piperidine-l-carboxyla te. MS (ES-) m/z 465.0.

Example 426: 2-methyl-iV-(2-pyridin~2-ylethyl)-5-(pyridin-3- ylsulfonyl)benzenesulfonamide

[0456] In an analogous manner to Example 409,

[0457] Step 3: pyridine-3-boronic acid was used to prepare 2-methyl-JV-(2-pyridin-2- ylethyl)-5-(pyridm-3-ylsulfonvDbenzenesulfonamide. MS (ESI+) m/z 418.

Example 427: 5-(lH-indol-5-yIsulfonyl)-2-methyl-JV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0458] In an analogous manner to Example 409,

[0459] Step 3: 5-indole boronic acid was used to prepare 5-( 1 ϋ/-indol-5-ylsulfonylV2- methyl-iy-(2-pyridin-2-ylethyl)benzenesulfonamide. MS (ES+) m/z 456.1.

Example 428: 5-[(4-cyanophenyl)sulfonyl]-2-methyl-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0460] In an analogous manner to Example 409,

[0461] Step 3: 4-cyanophenyl boronic acid was used to prepare 5-[(4- cvanophenyl)sulfonyll-2-methyl-N-(2-pyridin-2-ylethyl)benzen esulfonamide.

MS (ESI+) m/z 442.

Example 429: 5-{[3-(ethyIsulfonyl)phenyl]sulfonyl}-2-methyl-iV-(2-pyridii i-2- ylethyl)benzenesulfonamide

[0462] In an analogous manner to Example 409,

[0463] Step 3: 3-(ethylsulfonyl)phenyl boronic acid was used to prepare 5-{| ^~ 3- ( ^' ethylsulfonyl)phenyl]sulfonyl}-2-metb.yl-iV-(2-pyridin-2-yle thyl ^' )benzenesulfonamide. MS (ES+) m/z 509.0.

Example 430: 2-methyl-5-[(2-methylphenyl)sulfonyI]-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0464] In an analogous manner to Example 409,

[0465] Step 3: 2-methylphenyl boronic acid was used to prepare 2-methyl-5-rf2- methylphenyl ^' )sulfonyll-./V-( ^' 2-pyridin-2-ylethyl ^> )benzenesulfonamide. MS (ESl+) m/z 431.

Example 431 : 5-[(2-ethylphenyl)sulfonyl]-2-methyl-iV-(2-pyridm-2- ylethyl)benzenesulfonamide

[0466] In an analogous manner to Example 409,

[0467] Step 3: 2-ethylphenyl boronic acid was used to prepare 5-| ^" (2- ethylphenyl ^" )sulfonyl1-2-metliyl-N-(2-pyridin-2-ylethyl)benzenesulfonami de.

MS (ESI+) w/z 445.

Example 432: 5-(biphenyl-2-ylsulfonyl)-2-methyI-7V-(2-pyridin-2- ylethyl)benzenesulfonamide

[0468] In an analogous manner to Example 409,

[0469] Step 3: 2-biphenyl boronic acid was used to prepare 5 -(biphenyl-2-y lsulfony I)- 2-methyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide. MS (ESI+) m/z 493.

Example 433: 5-(biphenyl-4-ylsulfonyl)-2-methyI-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0470] In an analogous manner to Example 409,

[0471] Step 3: 4-biphenyl boronic acid was used to prepare 5-(biphenyl-4-ylsulfonyl)- 2-methyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide. MS (ESI+) m/z 493.

Example 434: 5-(biphenyl-3-ylsulfonyl)-2-methyl-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0472] In an analogous manner to Example 409,

[0473 J Step 3 : 3-biphenyl boronic acid was used to prepare 5-(biphenyl-3 -ylsulfonyl)- 2-methyl-N-f2-pyridin-2-ylethyl)benzenesulfonamide. MS (ESI+) rø/z 493.

Example 435: 5-[(4-tert-butylphenyl)sulfonyl]-2-isopropyI-N-(2-pyridin-2- ylethyl)benzenesulfonamide

[0474] In an analogous manner to Example 230,

[0475] Step 1 : 4-Isopropylbenzenesulfonyl chloride and tert-butylbenzene were used to prepare 1 -tert-butyl-4-[(4-isopropylphenyl)sulfonyl]benzene.

[0476] Step 2: l-tert-Butyl-4-[(4-isopropylphenyl)sulfonyl]benzene and chlorosulfonic acid were used to prepare 5-(4-tert-butyl-benzenesulfonyl)-2-isopropyl-benzenesulfonyl chloride.

[0477] Step 3: To a solution of 5-(4-tert-Butyl-benzenesulfonyl)-2-isopropyl- benzenesulfonyl chloride (150 mg, 0.36 mmol) in dichloromethane (4.0 mL) was added pyridine (73 mg, 0.72 mmol) and 2-(2-aminoethyl)pyridine (44 mg, 0.36 mmol). The reaction was stirred at room temperature overnight and then extracted with saturated sodium bicarbonate (2 x 10 mL), followed by saturated ammonium chloride (2 x 10 mL). The organic layer was dried with magnesium sulfate and concentrated down under vacuum. The crude residue was purified using automated flash chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of 5-[(4-tert-butylphenyl)sulfonyl]-2-isopropyl-N-(2- pyridin-2-ylethyl)benzenesulfonamide (178 mg, 98%).

Example 436: 5-[(4-tert-butylphenyl)sulfonyl]-N-[3-(lH-imidazoI-l-yl)prop yl]-2- isopropylbenzenesulfonamide

[0478] In an analogous manner to Example 435, 5-(4-tert-Butyl-benzenesulfonyl)-2- isopropyl-benzenesulfonyl chloride and l-(3-aminopropyl)imidazole were used to prepare 5-[(4- tert-butylphenyl)sulfonyl]-N-[3-(lH-imida2ol-l-yl)propyl]-2- isopropylbenzenesulfonamide. MS (ES+) m/z 504; HRMS: calcd. for C ₂₅ H ₃₃ N ₃ O ₄ S ₂ + H ⁺ , 504.1991 : found (ESI, [m+H]*), 504.2007.

Example 437: 5-[(4-tert-butylphenyI)sulfonyl]-2-isopropyl-N-(tetrahydro-2 H-pyran-4- yl)benzenesulfonamide

[0479] In an analogous manner to Example 435, 5-(4-tert-Butyl-benzenesulfonyl)-2- isopropyl-benzenesulfonyl chloride and 4-aminotetrahydropyran were used to prepare 5-[( ^" 4-tert- butylphenyl)sulfonyl]-2-isopropyl-N-( ^' tetrahvdro-2H-pyran-4- vDbenzenesulfonamide. MS (ES+) m/z 480.

Example 438: 5-[(4-tert-butyIphenyl)sulfonyl]-2-methyl-N-(2-pyridin-2- ylethyl)benzenesulfonamide

[0480] In an analogous manner to Example 230,

[0481] Step 1 : p-Toluenesulfonyl chloride and tert-butylbenzene were used to prepare l-tert-butyl-4-[(4-methylphenyl)sulfonyl]benzene.

[0482] Step 2: l-tert-Butyl-4-[(4-methylphenyl)sulfonyl]benzene and chlorosulfonic acid were used to prepare 5-(4-tert-butyl-benzenesulfonyl)-2-methyl-benzenesulfonyl chloride.

[0483] Step 3 : In an analogous manner to Example 435, 5-(4-tert-Butyl- benzenesulfonyl)-2-methyl-benzenesulfonyl chloride and 2-(2-aminoethyl)pyridine were used to prepare 5-[(4-tert-butylphenyl)sulfonyl]-2-methyl-N-(2-pyridin-2- ylethyl)benzenesulfonamide. MS (ES+) m/z 473; HRMS: calcd. for C ₂₄ H ₂₈ N ₂ O ₄ S ₂ + H ⁺ , 473.1569; found (ESI ₃ [m+H] ⁺ ), 473.1551.

Example 439: 5-[(4-tert-butylphenyl)sulfonyl]-N-[3-(lH-imidazol-l-yl)prop yl]-2- methylbenzenesulfonamide

[0484] In an analogous manner to Example 435, 5-(4-tert-Butyl-benzenesulfonyl)-2- methyl-benzenesulfonyl chloride and l-(3-aminopropyl)imidazole were used to prepare 5-[(4- tert-butylpheny Dsulfony H -N- [3 -( 1 H-imidazol- 1 -vDpropy 11 -2- methy lbenzenesulfonamide . MS (ES+) m/z 476; HRMS: calcd. for C ₂₃ H ₂₉ N ₃ O ₄ S ₂ + H ⁺ , 476.1678; found (ESI, [m+H] ⁺ ), 476.1662.

Example 440: 5-[(4-tert-butylphenyl)sulfonyI]-2-methyI-N-(tetrahydro-2H-p yran-4- yl)benzenesulfonamide

[0485] In an analogous manner to Example 435, 5-(4-tert-Butyl~benzenesulfonyl)-2- methyl-benzenesulfonyl chloride and 4-aminotetrahydropyran were used to prepare 5-[(4-tert- butylphenyl)sulfonyl]-2-methyl-N-(tetrahydro-2H-pyran-4- vDbenzenesulfonamide. MS (ES+) m/z 452.

Example 441 : iV-[2-(2-Fluorophenyl)ethyl]-3-[(4-methylphenyI)sulfonyl]-5, 6,7,8- tetrahydronaphthalene-l-sulfonamide

[0486] Step a: A stirred solution of 1 ,2,3,4-tetrahydronaphthalene (10.0 niL, 74 mmol) and p-toluenesulfonyl chloride (3.81 g, 20 mmol) was cooled to 0 ⁰ C and treated slowly under nitrogen with solid anhydrous aluminum chloride (3.20 g, 24 mmol). After stirring neat for 4 hours at room temperature, the mixture was slowly poured into ice water and extracted with ethyl acetate (2x). The organic phase was washed with a saturated, aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered through a short column of silica gel. The filtrate was evaporated in vacuo to yield a crude oil containing a mixture of isomers in approximately a 6:1 ratio. The crude oil was recrystallized twice from diethyl ether-hexane to yield 4-methylphenyl 5,6,7,8-tetrahvdronaphthalen-2-yl sulfone (3.04 g, 53%) as a homogeneous, colorless, crystalline solid, m.p. 130-132 °C; MS(EI) m/z 286; HRMS: calcd for C ₁₇ H ₁₈ O ₂ S, 286.10275; found (EI, M+.), 286.1022.

[0487] Step b: 4-Methylphenyl 5,6,7,8-tetrahydronaphthalen-2-yl sulfone (0.29 g, 1.0 mmol) was heated with stirring at 60 °C for one hour under nitrogen with chlorosulfonic acid (0.67mL, 1.17 g, 10.0 mmol). The mixture was cooled to room temperature, poured slowly into a cold solution of IN hydrochloric acid, and extracted with ethyl acetate (2x.). The organic phase was washed with a saturated, aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent concentrated in vacuo to an oil. The oil was dissolved in dichloromethane and treated dropwise under nitrogen with a solution of 2-fluorophenethylamine (0.28 g, 2.0 mmol) in dichloromethane. After stirring for one hour at room temperature, the reaction mixture was concentrated in vacuo and diluted with ethyl acetate. The organic phase was washed sequentially with IN hydrochloric acid and a saturated, aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and the filtrate concentrated to a crude oil. The crude oil was purified by preparative liquid chromatography on a Biotage ^® 40 Mi column of pre-packed silica gel (90 g) eluting with a gradient of 25% - 50% methyl fert-butyl ether in hexane at a flow rate of 50 niL/min to afford,

after evaporation of the solvent under vacuum, N- [2-(2-fluorophenyl)ethy 11 -3 - [ ^" (4- methylphenyl)sulfonvn-5,6.,7,8-tetralivdronaphthalene-l-sulf onamide (0.12 g, 25%) as a colorless, homogeneous, amorphous foam, m.p. 55-60 °C; MS (ES-) m/z 486.1; MS (ES+) m/z 488.1.

Example 442: 5-[(4-fluorophenyl)sulfonyl]-λ'-[2-(l _J H ^r -imidazol-4-yl)ethyI]-2- isopropylbenzenesulfonamide

[0488] In an analogous manner to Example 298 :

[0489] Step 3: 2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2-(lH-imidazol-4-yl)-ethylarnine were used to prepare 5- [(4-fluoropheny Dsulfonyll -N- \2-( 1 H- imidazol-4-yl)ethyl]-2-isopropylbenzenesulfonamide. MS (ES+) m/z 452.0; MS (ES-) m/z 450.0.

Example 443: 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-iV-[(2R)-2- phenylpropyl] benzenesulfonamide

[0490] In an analogous manner to Example 298:

[0491] Step 3: 2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2-(R)-phenylpropyl-l -amine were used to prepare 5 - r(4-fluorophenv0sulfonyl1 -2-isopropyl-N- r(2J?V2-phenylpropyllbenzenesulfonamide. MS (ES+) m/z 476.1; MS (ES-) m/z 474.1.

Example 444: 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-iV-[(2S)-2- phenylpropyl] benzenesulfonamide

[0492] In an analogous manner to Example 298:

[0493] Step 3: 2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2-(S)-phenylpropyl-l -amine were used to prepare 5-[f4-fluorophenyl)sulfonyl ^~ |-2-isopropyl-N- r(2iSV2-phenylpropyπberizenesulfonamide. MS (ES-) m/z Al AA.

Example 445: 5-[(4-fluorophenyl)suIfonyl]-2-isopropyl-λ ^r -(tetrahydro-2iϊ-pyran-4- ylmethyl)benzenesulfonamide

[0494] In an analogous manner to Example 298:

[0495] Step 3: 2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and tetrahydro-pyran-4-yl-methylamine were used to prepare 5 - Ff 4-fluorophenyl)sulfbnyl] -2- isopropyl-A/-(tetrahydro-2H ^' -pyran-4-ylmethyl ^' )benzenesulfonamide. MS (ES+) m/z 456.1; MS (ES-) m/z 454.1.

Example 446: tert-butyl 4-({[2-methyl-5- (phenylsulfonyl)phenyl]sulfonyl}amino)piperidine-l- carboxylate

[0496] In an analogous manner to Example 435, 5-benzenesulfonyl-2-methyl- benzenesulfonyl chloride and 4-amino-l-Boc-piperidine were used to prepare tert-butyl 4-({[2- methyl-5-(phenylsulfony Dphenyll sulfonylj aminolpiperidine- 1 - carboxylate. MS (ES-) m/z 493.

Example 447: 2-methyl-5-(phenylsulfonyl)-N-piperidin-4-ylbenzenesulfonami de

[0497] To a solution of 25% trifluoroacetic acid/dichloromethane was added tert-butyl 4-({[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)piperi dine-l- carboxylate (2.0 g, 4.04 mmol) and the solution was stirred at room temperature for two hours. The reaction was then extracted with saturated sodium bicarbonate, dried with magnesium sulfate, and concentrated down under vacuum to give 2-methyl-5-(phenylsulfonylVN-piperidin-4-ylbenzenesulfonamid e (1.5g, 94%). MS (ES+) m/z 495 MS (ES-) m/z 493.

Example 448: 2-methyl-5-(phenylsulfonyl)-N-[l-(phenylsulfonyl)piperidin-4 - yljbenzenesulfonamide

[0498] To a solution of 2-methyl-5-(phenylsulfonyl)-N-piperidin-4- ylbenzenesulfonamide (125 mg, 0.32 mmol) and pyridine (48 mg, 0.48 mmol) in dichloromethane (4 mL) was added benzenesulfonyl chloride (59 mg, 0.33 mmol). The reaction was stirred at room temperature for three hours and then extracted with saturate sodium

bicarbonate. The aqueous phase was washed with dichloromethane (2 x 10 mL). The combined organic phases were dried with magnesium sulfate and concentrated down under vacuum. The crude residue was purified using automated flash chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of 2-methyl-5-(phenylsulfonyl)- N-[I -fphenylsulfonyP)piperidin-4- ylibenzenesulfonamide (95 mg, 56%). MS (ES+) m/z 535 MS (ES-) m/z 533.

Example 449: N-[l-(2-furoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0499] To a slurry of 2-methyl-5-(phenylsulfonyl)-N-piperidin-4-ylbenzenesulfonami de (75 mg, 0.19 mmol), morphlinomethyl-polystyrene (170 mg, 62 mmol), and dimethylaminopyridine-polystyrene (70 mg, 0.14 mmol) in dichloromethane (8 mL) was added 2-furoyl chloride (50 mg, 0.38 mmol). The reaction was rotated on an orbital shaker for four hours. Then aminomethylated-polystyrene (150 mg, 0.33 mmol) was added to the reaction and it was rotated for an addition two and one-half hours. The reaction was then filtered and the resin was washed alternately with dichloromethane (3 x 5 mL) and methanol (3 x 5 mL) and concentrated down under vacuum. The crude residue was purified using automated flash chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation ofN-[l-r2-furoyl)piperidin-4-yl]-2-methyl-5-(phenylsulfonyπ benzenesulfonamide (68 mg, 73 %). MS (ES+) m/z 489.

Example 450: 5-({4-[(2-cyanoethyl)amino]phenyl}sulfonyl)-iV-[2-(lH-imidaz ol-l-yl)ethyl]- 2-isopropylbenzenesulfonamide

[0500] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-N-[2- (lH-imidazol-l-yl)ethyl]-2-isopropylbenzenesulfonamide and 3-aminopropionitrile were used to prepare 5-( { 4- [(2-cyanoethy Daminojpheny 1 ) sulfony IViV- \2-( 1 H-imidazol- 1 -vDethyll -2- isopropylbenzenesulfonamide. MS (ESI+) m/z 502; MS (ESI-) m/z 500.

Example 451: iV-[2-(lJϊ-imidazol-l-yl)ethyl]-2-isopropyI-5-{[4- (methylamino)phenyl]sulfonyl}benzenesulfonamide

[0501] In an analogous manner to Example 356, 5-[(4-fluorophenyl)sulfonyl]-iV-[2- (lH ^" -imidazol-l-yl)ethyl]-2-isopropylbenzenesulfonamide and methylamine were used to prepare JV-r2-flH ^" -imidazol-l-yl^ethvn-2-isopropyl-5-(r4- (methy laminolpheny 1] sulfony 1 } benzenesulfonamide . MS (ESI+) m/z 463; MS (ESI-) m/z 461.

Example 452: 5-({4-[(2-hydroxybutyl)amino]phenyl}sulfonyl)-iV-[2-(lH ^r -imidazol-l- yl)ethyl]-2-isopropylbenzenesuIfonamide

[0502] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfbnyl]-JV-[2- (l/f-imidazol-l-yl)ethyl]-2-isopropylbenzenesulfonamide and 2-hydroxybutylamine were used to prepare 5 -( {4- [(2-hydroxybutyl)ammo]pheny 1 } sulfony \)-N-\2-( 1 if-imidazol- 1 -vDethyl] -2- isopropylbenzenesulfonamide . MS (ESI+) rø/z 521; MS (ESI-) m/z 519.

Example 453: 5-[(4-{[(2S)-l-(hydroxymethyl)-2-methylbutyl]amino}phenyl)su lfonyl]-λ'-[2- (lJϊ-imidazol-l-y^etliyll^-isopropylbenzenesulfonamide

[0503] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-iV-[2- (lH-imidazol-l-yl)ethyl]-2-isopropylbenzenesulfonamide and L-isoleucinol were used to prepare 5-r(4-(r(2^-l-(hvdroxymethylV2-methylbutyllamino)phenyl)sulf onyll-N-r2-αH-imidazol-l- yl1ethyl]-2-isopropylbenzenesulfonamide. MS (ESI+) m/z 549; MS (ESI-) m/z 547.

Example 454: 5-[(3,5-dimethylphenyl)sulfonyl]-2-isopropyl-λ ^L (2-pyridin-2- ylethyl)benzenesulfonamide

[0504] Step 1 : Following the procedure described in Example 409 (Step 2), 5-bromo-2- isopropyl-7V-(2-pyridin-2-ylethyl)benzenesulfonamide (Example 474 Steps 1 and 2) was used to prepare 4-isopropyl-3-{r(2-pyridin-2-ylethyl)aminolsulfonyl)benzenes ulfinic acid.

[0505] Step 2: Following the procedure described in Example 409 (Step 3), 4- isopropyl-3-{[(2-pyridin-2-ylethyl)amino]sulfonyl}benzenesul finic acid and 3,5-dimethylphenyl boronic acid were used to prepare 5-[f3,5-dimethylphenyl)sulfonyll-2-isopropyl-N-(2-pyridin-2- ylethy Dbenzenesulfonamide . MS (ESI+) rø/z 473; MS (ESI-) m/z 471.

Example 455: 5-[(3-chlorophenyl)suIfonyl]-2-isopropyl-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0506] In an analogous manner to Example 454,

[0507] Step 2: 3-chlorophenyl boronic acid was used to prepare 5-[(3- chlorophenyπsulfonvn-2-isopropyl-iV-f2-pyridin-2-ylethyl)be nzenesulfonamide.

MS (ESI+) rø/z 479;

MS (ESI-) m/z 477.

Example 456: 2-isopropyl-5-[(3-methoxyphenyl)sulfonyl]-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0508] In an analogous manner to Example 454,

[0509] Step 2: 3 -methyoxy phenyl boronic acid was used to prepare 2-isopropyl-5-[(3- methoxyphenyl ^' )sulfonyl]-iV-(2-pyridin-2-ylethyl ^' )benzenesulfonamide. MS (ESI+) m/z 475; MS (ESI-) m/z 473.

Example 457: 2-isopropyl-5-[(2-methoxyphenyI)sulfonyl]-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0510] In an analogous manner to Example 454,

[0511] Step 2: 2-methoxyphenyl boronic acid was used to prepare 2-isopropyl-5-IY2- methoxyphenyl)sulfonyll-A/-(2-pyridin-2-ylethyl)benzenesulfo namide. MS (ESI+) m/z ; MS (ESI-) m/z.

Example 458: 5-[(3,5-difluorophenyl)sulfonyl]-2-isopropyI-JV-(2-pyridin-2 - ylethyl)benzenesulfonamide

[0512] In an analogous manner to Example 454,

[0513] Step 2: 3,5-difluorophenyl boronic acid was used to prepare 5-| ^" (3,5- difluoroplienyl)sulfonyl]-2-isopropyl-iV ^: -(2-pyridin-2-ylethyl')benzenesulfonamide. MS (ESI+) m/z 481; MS (ESI-) m/z 479.

Example 459 : 2-cyclohexyl-5-(phenylsulfonyl)-iV-(2-pyridin-2-ylethyl)benz enesulfonamide

[0514] Step 1 : Following the same procedure described in Example 474 (Step 1), 2- cyclohexylbromobenzene was used to prepare 2-cyclohexyl-N-(2-pyridin-2- ylethyDbenzenesulfonamide.

MS (ESI+) m/z 345; MS (ESI-) m/z 343.

[0515] Step 2: Following the same procedure described in Example 474 (Step 2), 2- cyclohexyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide was used to prepare 5-bromo-2- cyclohexyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide. MS (ESI+) m/z 423; MS (ESI-) m/z 421.

[0516] Step 3: Following the same procedure described in Example 409 (Step 2), 5- bromo-2-cyclohexyl-iV-(2-pyridin-2-ylethyl)benzenesulfonamid e was used to prepare 4^ cyclohexyl-3 - { |Y2-pyridin-2-y lethy Dammo] sulfonyl } benzenesulfinic acid.

[0517] Step 4: Following the same procedure in Example 409 (Step 3), 4-cyclohexyl-3- {[(2-pyridin-2-ylethyl)amino]sulfonyl}benzenesulfinic acid and phenyl boronic acid was used to prepare 2-cyclohexyl-5-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)benze nesulfonamide. MS (ESI+) m/z 485; MS (ESI-) m/z 483.

Example 460: 2-cyclohexyl-5-[(4-fluorophenyl)sulfonyl]-λ ^/ -(2-pyridin-2- ylethyl)benzenesulfonamide

[0518] In an analogous manner to Example 459,

[0519] Step 4: 4-fluorophenyl boronic acid was used to prepare 2-cyclohexyl-5-[(4- fluorophenyl)sulfonyl1-A/-(2-pyridin-2-ylethyl)benzenesulfon amide. MS (ESI+) m/z 503; MS (ESI-) m/z 501.

Example 461 : 2-fer/-butyl-5-(phenylsulfonyI)-iV-(2-py ridin-2-ylethyl)benzenesuIfonamide

[0520] Step 1 : To a stirred solution of 2-tertbutylbenzenethiol (4.72 g, 28.4 mmol) in concentrated sulfuric acid (90 niL) at 0 °C was added 6% sodium hypochlorite solution (426 niL) dropwise. The resulting mixture was extracted with methylene chloride. Triethylamine (10.0 mL, 71.7 mmol) and 2-(2-aminoethyl)pyridine (4.0 mL, 33.4 mmol) were added and the mixture was stirred 30 minutes, washed with a saturated aqueous ammonium chloride solution and concentrated. Flash column separation with 50% ethyl acetate/ hexane gave 2-fert-butyl-iV- (2-pyridin-2-ylethvDbenzenesulfonamide (3.29 g, 36%). MS (ESI+) m/z 319; MS (ESI-) m/z 317.

[0521] Step 2: Following the same procedure described in Example 474 (Step T), 2- tert-butyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide was used to prepare 5-bromo-2-fert-butyl- N-(2-pyridin-2-ylethyl)benzenesulfonamide.

[0522] Step 3: Following the same procedure described in Example 474 (Step 4), 5- bromo-2-tert-butyl-iV-(2-pyridin-2-ylethyl)benzenesulfonamid e and phenyl sulfonyl fluoride were used to prepare 2-fert-butyl-5-(phenylsulfonyl)-.A/-( ^' 2-pyridin-2- ylethvDbenzenesulfonamide. MS (ESI+) m/z 459.

Example 462: N-[l-(2-methoxybenzoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0523] To a slurry of 2-methyl-5-(phenylsulfonyl)-N-piperidin-4-ylbenzenesulfonami de (50 mg, 0.13 mmol) and moφhlinomethyl-polystyrene (170 mg, 62 mmol) in dichloromethane (8 mL) was added 2-anisolyl chloride (65 mg, 0.38 mmol). The reaction was rotated on an orbital shaker overnight. Then aminomethylated-polystyrene (150 mg, 0.33 mmol) was added to the reaction and it was rotated for addition four hours. The reaction was then filtered and the resin was washed alternately with 10% dichloromethane/methanol (3 x 6 mL). The crude residue

was purified using automated flash chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of N- F 1 -(2-methoxybenzoyl)piperidin-4-yH-2- methyl-5- (phenylsulfonyl)benzenesulfonamide (52 mg, 78 %). MS (ES+) m/z 529.

Example 463: N-[l-(3-methoxybenzoyl)piperidin-4-yl]-2-methyI-5- (phenylsulfonyl)benzenesulfonamide

[0524] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 3- anisolyl chloride were used to prepare N-[I -(3- methoxybenzoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES+) m/z 529.

Example 464: N-[l-(3,4-dimethoxybenzoyl)piperidin-4-yI]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0525] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 3,4-dimethoxybenzene-l-carbonyl chloride were used to prepare N-[l-(3,4-dimethoxybenzoyl)piperidm-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES+) m/z 559.

Example 465: 2-methyl-5-(phenylsulfonyI)-N-{l-[3-(trifluoromethyl)benzo^l ]piperidin-4- yl}benzenesulfonamide

[0526] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidm-4-ylbenzenesulfonamide and 3-(trifluoromethyl)benzoyl chloride were used to prepare 2-methyl-5-(phenylsulfonyl)-N-π-r3-( ^' trifluoromethyl)benzoyllpiperidm-4- yl} benzenesulfonamide. MS (ES+) m/z 567.

Example 466: N-[l-(4-chlorobenzoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0527] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 4-chlorobenzoic acid chloride were used to prepare N-[I- (4-chlorobenzoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES+) m/z 533.

Example 467: N-[l-(4-methoxybenzoyl)piperidin-4-yI]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0528] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 4-anisoyl chloride were used to prepare N-Fl -(4- methoxybenzoyl ^' )piperidin-4-vn-2-methyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES+) m/z 529.

Example 468: 2-methyl-N-[l-(4-methylbenzoyI)piperidin-4-yl]-5- (phenylsulfonyl)benzenesulfonamide

[0529] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 4-methylbenzoyl chloride were used to prepare 2-methyl- N-[ ^" l-(4-methylbenzovDpiperidin-4-yll-5- (phenylsulfonyDbenzenesulfonamide. MS (ES+) m/z 513.

Example 469: N-[l-(methoxyacetyl)piperidm-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0530] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and methoxyacetic acid chloride were used to prepare N-[I- (methoxyacetyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl ^* )benzenesulfonamide. MS (ES+) m/z 467.

Example 470: 2-methyl-N-[l-(phenylacetyl)piperidin-4-yl]-5- (phenylsulfonyl)benzenesulfonamide

[0531] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and α-toluyl chloride were used to prepare 2-methyl-N-[l- (phenylacetyl)piperidin-4-yl]-5-(phenylsulfonyl)benzenesulfo namide. MS (ES+) m/z 513.

Example 471 : N-[l-(cyclohexyIcarbonyl)piperidin-4-yI]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0532] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and cyclohexanecarbonyl chloride were used to prepare N-[I- rcvclohexylcarbonyl)piperidin-4-vn-2-methyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES+) m/z 505.

Example 472: 2,6-dimethyl-3-(phenylsulfonyI)-N-(2-pyridin-2-ylethyl)benze nesuIfonamide [0533] Step 1 : Following the same procedure described in Example 1 (Step 1), 2- bromo- 1,3 -dimethyl benzene was used to prepare 3-bromo-2,4-dimethylbenzenesulfonyl chloride.

[0534] Step 2: Following the same procedure described in Example 230 (Step 1), 3- bromo-2,4-dimethylbenzenesulfonyl chloride was used to prepare 2-bromo- 1 ,3-dimethyl-4-

(phenylsulfonvDbenzene.

[0535] Step 3: Following the same procedure described in Example 474 (Step 1), 2- bromo-l,3-dimethyl-4-(phenylsulfonyl)benzene was used to prepare 2,6-dimethyl-3-

(phenylsulfonyD-A/-(2-pyridin-2-ylethyDbenzenesulfonamide .

MS (ESI+) m/z 431;

MS (ESI-) m/z 429.

Example 473: 2,6-dimethyl-3-(phenylsulfonyl)-iV-(tetrahydro-2i/-pyraii-4- yl)benzenesulfbnamide

[0536] In an analogous manner to Example 472,

[0537] Step 3: tetrahydropyran-4-ylamine was used to prepare 2,6-dimethyl-3- (phenylsulfonyl)-iV-(tetrahydro-2H-pyran-4-yl)benzenesulfona mide. MS (ESI+) w/z 410; MS (ESI-) m/z 408.

Example 474: 5-{[5-(dimethylamino)-l-naphthyl]sulfonyl}-2-isopropyl-λ'-( 2-pyridin-2- ylethyl)benzenesulfonamide

[0538] Step 1 : To a stirred solution of 2-bromoisopropylbenzene (10.0 g, 50.2 mmol) in THF (350 mL) at -78°C was added n-butyl lithium 2.5 M in hexane (14.0 niL, 35.0 mmol)

dropwise. After 10 minutes, sulfur dioxide was bubbled in over a period of 30 minutes. The solution was allowed to warm to room temperature and stirred for 2 hours. The solution was concentrated and taken up in methylene chloride (300 mL). N-chlorosuccinimide (8.1 g, 60.6 mmol) was added and the solution was stirred 1.5 hours at room temperature. 2-(2- aminoethyl)pyridine (7.2 mL, 60.2 mmol) was added and the solution was stirred an additional 45 minutes at room temperature, washed with a saturated aqueous ammonium chloride solution. The organic layer was dried over magnesium sulfate and concentrated. Trituration with ether gave 2-isopropyl-iV-(2-pyridm-2-ylethyl)benzenesulfonamide (8.67 g, 56%). MS (ESI) m/z 305.

[0539] Step 2: To a stirred solution of 2-isopropyl-iV-(2-pyridin-2- ylethyl)benzenesulfonamide (10.0g, 32.8mmol) in 90% concentrated sulfuric acid (110 mL) was added N-bromosuccinimide (5.85 g, 32.8 mmol) at room temperature and the solution was stirred 15 minutes. The solution was chilled in an ice bath and 25% sodium hydroxide was slowly added to pH 9. The solution was extracted several times with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and concentrated. Trituration with ether gave 5^ bromo-2-isopropyl-N-(2-pyridin-2-ylethvDbenzenesulfonamide (6.0 g, 48%). MS (ESI+) m/z 383; MS (ESI-) m/z 381.

[0540] Step 3: To a stirred solution of dansyl chloride (1.0 g, 3.70 mmol) in acetonitrile (3 mL), was added potassium fluoride (0.86 g, 14.8 mmol) and 18-crown-6 (0.05 g, 0.19 mmol). The resulting solution was stirred overnight at room temperature. The solution was diluted with D.I. water and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated to give dansyl fluoride (0.50 g, 53%).

[0541] Step 4: To a stirred solution of 5-bromo-2-isopropyl-iV-(2-pyridin-2- ylethyl)benzenesulfonamide (0.30 g, 0.78 mmol) in THF (3 mL) at 0 °C was added methyl magnesium bromide 1.4 M in 75% toluene/THF (0.6 mL, 0.84 mmol). The reaction was stirred 10 minutes, then cooled to -78 °C and n-butyl lithium 2.5 M in hexane (0.35 mL, 0.87 mmol) was added dropwise. The reaction was stirred an additional 10 minutes. The reaction was warmed to 0 °C and dansyl fluoride (0.20 g, 0.79 mmol) was added. The reaction was stirred overnight at room temperature, partitioned between ammonium chloride solution and ethyl acetate. The organic layer was concentrated and HPLC separated to give 5-{[5- ( dimethylamino)- 1 -naphthyll sulfony 1 > -2-isopropyl-N-f 2-pyridin-2-ylethvDbenzenesulfonamide

(0.05 g, 12%).

MS (ESI+) m/z 538;

MS (ESI-) m/z 536.

Example 475: N-[l-(cyclopropylcarbonyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0542] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and cyclopropanecarbonyl chloride were used to prepare N- [l-fcyclopropylcarbonyl)piperidin-4-yll-2-methyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES+) m/z 463.

Example 476: N-[l-(4-cyanobenzoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0543] In an analogous manner to Example 462, 2-methy 1-5 -(phenylsulfony I)-N- piperidin-4-ylbenzenesulfonamide and 4-(chlorocarbonyl)benzonitrile were used to prepare N- [l-(4-cyanoben2oyDpiperidin-4-yl]-2-methyl-5- (phenylsulfonvDben2enesulfonamide. MS (ES+) m/z 524.

Example 477: N-[l-(3-cyanobenzoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0544] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 3-cyanobenzoyl chloride were used to prepare N-[I -(3- cyanobenzoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES+) m/z 524.

Example 478: 2-methyl-N-[l-(methylsulfonyl)piperidin-4-yl]-5- (phenylsulfonyl)benzenesulfonamide

[0545] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and methanesulfonyl chloride were used to prepare 2-methyl- N-[l-(methylsulfonyl)piperidin-4-yll-5- (phenylsulfonyl)benzenesulfonamide. MS (ES+) rø/z 473.

Example 479: N-(l-acetylpiperidin-4-yl)-2-methyI-5-(phenylsulfonyl)benzen esulfonamide

[0546] In an analogous manner to Example 462, 2-methy 1-5 -(phenylsulfony I)-N- piperidin-4-ylbenzenesulfonamide and acetyl chloride were used to prepare N-(I -acetylpiperidin- 4-yl)-2-methyl-5-(phenylsulfonyDbenzenesulfonamide. MS (ES+) m/z ASl.

Example 480: N-(4-{[4-({[2-methyI-5-(phenylsulfonyl)phenyl]sulfonyl}amino )piperidin-l- yl]carbonyl}phenyl)acetamide

[0547] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 4-acetamidobenzoyl chloride were used to prepare N-(4- { \4-( { r2-methyl-5-(phenylsulfonvDphenyl] sulfonyl } amino)piperidm- 1 - yl ^" ) carbonyl } phenvDacetamide . MS (ES+) m/z 556.

Example 481 : 2-methyI-N-{l-[(l-methyl-lH-imidazoI-4-yI)sulfonyl]piperidin -4-yl}-5- (phenylsulfonyl)benzenesulfonamide

[0548] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and l-methylimidazole-4-sulfonyl chloride were used to prepare 2-methy 1-N- { 1 - [( 1 -methyl- 1 H-imidazol-4-vDsulfony llpiperidin-4-yl > -5- CphenylsulfonyDbenzenesulfonamide. MS (ES+) m/z 539.

Example 482 : 2-methyl-5-(phenylsulfonyl)-N- [l-(2-thienylsulfonyl)piperidin-4- yl]benzenesulfonamide

[0549] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 2-thiophenesulfonyl chloride were used to prepare 2z methyl-5-(phenylsulfonyl ^' )-N-[ ^' l-( ^' 2-thienylsulfonyl)piperidin-4- yllbenzenesulfonamide.

MS (ES+) m/z 541.

Example 483: N-(l-{[5-(dimethyIamino)-l-naphthyl]sulfonyl}piperidin-4-yl) -2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0550] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and dansyl chloride were used to prepare N-(I-I [5- (dimethylaminoVl-naphthyl1sulfonyl)piperidin-4-yl)-2-methyl- 5- (phenylsulfonyl)benzenesulfonamide.

MS (ES+) m/z 628.

Example 484: N-[l-(l,3-benzodioxoI-5-ylcarbonyl)piperidin-4-yl]-2-methyl- 5- (phenylsulfonyl)benzenesulfonamide

[0551] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 1 ,3-benzodioxole-5-carbonyl chloride were used to prepare N-[I -(1 ,3-benzodioxol-5-ylcarbonyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyDbenzenesulfonamide. MS (ES+) m/z 543 MS (ES-) m/z 541.

Example 485: N-[l-(isoxazol-5-ylcarbonyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0552] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 5-isoxazolecarbonyl chloride were used to prepare N-[I- (isoxazol-5-ylcarbonvDpiperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES+) m/z 490.

Example 486: N-[l-(N,N-dimethylglycyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0553] In an analogous manner to Example 462, 2-methy 1-5 -(phenylsulfony I)-N- piperidin-4-ylbenzenesulfonamide and dimethylaminoacetyl chloride hydrochloride were used to prepare N-[I -(TSf ,N-dimethylgly cy l)piperidin-4-yl1 -2-methyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES+) m/z 480.

Example 487: prop-2-yn-l-yl 4-({[2-methyl-5- (phenylsulfonyl)phenyl]sulfonyl}amino)piperidine- 1-carboxylate

[0554] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and propargylchloroformate were used to prepare prop-2-yn- 1 -y 1 4-( { r2-methy 1-5 -(phenylsulfonvDphenyl] sulfony 11 amino)piperidine- 1 -carboxy late . MS (ES+) m/z All MS (ES-) m/z 475.

Example 488: methyl 4-({[2-methyl-5-(phenylsuIfonyl)phenyl]sulfonyl}amino)piperi dine-l- carboxylate

[0555] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfbnyl)-N- piperidin-4-ylbenzenesulfonamide and methylchloroforrnate were used to prepare methyl 4-(([2- methyl-5-(phenylsulfonyl)plienyl1sulfonyl}ammo)piperidine-l- carboxylate. MS (ES+) m/z 453 MS (ES-) m/z 451.

Example 489: 2-methoxyphenyl 4-({[2-methyl-5- (phenylsulfonyl)phenyl]sulfonyl}amino)piperidine-l-carboxyla te

[0556] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 2-methoxyphenylchloroformate were used to prepare 2z methoxyphenyl 4-f { [2-methy 1-5 - (pheny lsulfonyDpheny 1] sulfonyl > amino)piperidine- 1 - carboxylate. MS (ES+) m/z 545 MS (ES-) m/z 543.

Example 490: N-(tert-butyl)-4-({[2-methyl-5- (phenylsulfonyl)phenyl]sulfonyl}amino)piperidine- 1-carboxamide

[0557] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and t-butylisocyanate were used to prepare N-(tert-butyl>4- ({ β-methyl-S-fphenylsulfonyDphenv^sulfonyllamino^piperidine- 1 -carboxamide. MS (ES+) m/z 494 MS (ES-) m/z 492.

Example 491: N-cyclohexyl-4-({[2-methyI-5- (phenylsulfonyl)phenyl]sulfonyl}amino)piperidine-l-carboxami de

[0558] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and cyclohexylisocyanate were used to prepare N-cyclohexyl- 4-( { [2-methyl-5 -(phenylsulfony Dpheny 1] sulfonyl } amino)piperidine- 1 - carboxamide . MS (ES+) m/z 520; MS (ES-) m/z 518.

Example 492: 5-[(3-chloro-5-cyanophenyl)sulfonyl]-2-methyI-JV-(2-pyridin- 2- ylethyl)benzenesulfonamide

[0559] In an analogous manner to Example 409,

[0560] Step 3: 3-chloro-5-cyanophenyl boronic acid was used to prepare 5-r(3-chloro- 5-cyanopb.enyl)sulfonyl1-2-methyl-N-(2-pyridin-2-ylethyl)ben zenesulfonamide. MS (ES-) m/z 474.0.

Example 493: JV-[3-(l#-imidazol-l-yl)propyl]-2-methyl-3- (phenylsulfonyl)benzenesulfonamide

[0561] In an analogous manner to Example 302, l-(3-aminopropyl)-imidazole was used to prepare N- [3 -( 1 H-imidazol- 1 -yDpropyll -2-methyl-3 -(phenylsulfonyl)benzenesulfonamide. MS (ES-) m/z All.9; HRMS: calcd for C ₁₉ H ₂₁ N ₃ O ₄ S ₂ + H+, 420.10462; found (ESI, [M+H] ⁺ ), 420.1049.

Example 494: 2-methyl-3-(phenylsulfonyl)-iV-(2-pyridm-2-ylethyl)benzenesu lfonamide

[0562] In an analogous manner to Example 302, 2-(2-aminoethyl)-pyridine was used to prepare 2-methyl-3-(phenylsulfonyl)-N-(2-pyridin-2-ylethyl)benzenesu lfonamide. MS (ES-) m/z 414.9; HRMS: calcd for C ₂₀ H ₂₀ N ₂ O ₄ S ₂ + H+, 417.09372; found (ESI, [M+H] ⁺ ), 417.0934.

Example 495: 2-methyl-λ ^L (2-morpholin-4-yIethyl)-3-(phenylsulfonyl)benzenesulfonamide

[0563] In an analogous manner to Example 302, 1-ethylaminomorpholine was used to prepare 2-methyl-N-(2-moφholin-4-ylethyl)-3-(phenylsulfonyl)benzene sulfonamide (0.28g,

>%).

MS (ES-) m/z 422.9;

HRMS: calcd for C ₁₉ H ₂₄ N ₂ O ₅ S ₂ + H+, 425.11994; found (ESI, [M+H] ⁺ ), 425.1211.

Example 496: 2-methyl-N-[l-(2-naphthoyl)piperidin-4-yl]-5- (phenylsulfonyl)benzenesulfonamide

[0564] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 2-naphthalenecarbonyl chloride were used to prepare 2; methyl-N-[l-(2-naphthoyl)piperidin-4-yll-5-(phenylsulfonyl)b enzenesulfonamide. MS (ES+) m/z 549 MS (ES-) m/z 547 HRMS: calcd. for C ₂₉ H ₂₈ N ₂ O ₅ S ₂ + H ⁺ , 549.15124: found (ESI, [m+H]*), 549.15026.

Example 497: 2-methyl-5-(phenylsulfonyl)-N-[l-(2-thienylcarbonyl)piperidi n-4- yl] benzenes ulfonamide

[0565] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 2-thenoyl chloride were used to prepare 2-methyl-5- (phenylsulfonyl)-N-[l-(2-thienylcarbonyl)piperidin-4- yl1benzenesulfonamide. MS (ES+) m/z 505 MS (ES-) m/z 503 HRMS: calcd. for C ₂₃ H ₂₄ N ₂ O ₅ S ₃ + H ⁺ , 505.092564: found (ESI, [m+H] ⁺ ), 505.0947.

Example 498: isobutyl 4-({[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)piperi dine- 1- carboxylate

[0566] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and isobutyl chloroformate were used to prepare isobutyl 4- d[2-methyl-5-(phenylsulfonyl)phenvnsulfonyl}amino)piperidine -l- carboxylate. MS (ES+) m/z 495 MS (ES-) m/z 493 HRMS: calcd. for C ₂₃ H ₃₀ N ₂ O ₆ S ₂ + H ⁺ , 495.16181: found (ESI, [m+H] ⁺ ), 495.16266.

Example 499 : N- {1 - [4-(dimethy lamino)benzoyl] piperidin-4-y 1} -2-methy 1-5- (phenylsulfonyl)benzenesulfonamide

[0567] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N~ piperidin-4-ylbenzenesulfonamide and 4-dimethylaminobenzoyl chloride were used to prepare N-(I -[4-f dimethylamino)benzoyHpiperidin-4-yU -2-methyl-5- (phenylsulfonypbenzenesulfonamide. MS (ES+) m/z 542 MS (ES-) m/z 540 HRMS: calcd. for C ₂₇ H ₃₁ N ₃ O ₅ S ₂ + H ⁺ , 542.17779: found (ESI, [m+H] ⁺ ), 542.17725.

Example 500: 4-fluorophenyl 4-({[2-methyl-5- (phenylsulfonyl)phenyl]sulfonyl}amino)piperidine- l-carboxylate

[0568] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 4-fluorophenylchloroformate were used to prepare 4; fluorophenyl 4-(([2-methyl-5-(phenylsulfonyl)phenyl1sulfonyl}amino)piperi dine- l-carboxylate. MS (ES+) m/z 533 MS (ES-) m/z 531 HRMS: calcd. for C ₂₅ H ₂₅ FN ₂ O ₆ S ₂ + H ⁺ , 533.12109: found (ESI, [m+H] ⁺ ), 533.12157.

Example 501: N-ethyl-4-({[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}amin o)piperidine- 1- carboxamide

[0569] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and ethylisocyanate were used to prepare N-ethyl-4-C-f| ^~ 2- methyl-5-f phenylsulfonyDphenyll sulfony 1 } amino)piperidine- 1 - carboxamide . MS (ES+) m/z 466 MS (ES-) m/z 464 HRMS: calcd. for C ₂₁ H ₂₇ N ₃ O ₅ S ₂ + H ⁺ , 466.14649: found (ESI, [m+H] ⁺ ), 466.14684.

Example 502: 2-methyl-N-[l-(morpholin-4-yIcarbonyl)piperidin-4-yI]-5- (plienylsulfonyl)benzenesulfonamide

[0570] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 4-morpholinecarbonyl chloride were used to prepare 2a methyl-N-[l-(moφholin-4-ylcarbonyl ^' )piperidin-4-yll-5- ( ^' phenylsulfonyl)benzenesulfonamide. MS (ES+) m/z 508

MS (ES-) m/z 506

HRMS: calcd. for C ₂₃ H ₂₉ N ₃ O ₆ S ₂ + H ⁺ , 508.15706: found (ESI, [m+H] ⁺ ) ₅ 508.15678.

Example 503: N,N-dimethyl-4-({[2-methyl-5- (phenylsulfonyl)phenyl]sulfonyl}amino)piperidine-l- carboxamide

[0571] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-n- piperidin-4-ylbenzenesulfonamide and dimethylcarbamyl chloride were used to prepare N,N- dimethyl-4-r{r2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}ami no)piperidine-l- carboxamide. MS (ES+) m/z 466 MS (ES-) m/z 464 HRMS: calcd. for C ₂₁ H ₂₇ N ₃ O ₅ S ₂ + H ⁺ , 466.14649: found (ESI, [m+H] ⁺ ), 466.14672.

Example 504: N-[l-(3,3-dimethylbutanoyl)piperidin-4-yl]-2-methyl-5- (phenylsulfonyl)benzenesulfonamide

[0572] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-n- piperidin-4-ylbenzenesulfonamide and t-butylacetyl chloride were used to prepare N-[I -(3,3- dimethylbutanoyl)piperidin-4-yl]-2-methyl-5- fphenylsulfonvDbenzenesulfonamide. MS (ES+) rø/z 493 MS (ES-) m/z 491 HRMS: calcd. for C ₂₄ H ₃₂ N ₂ O ₅ S ₂ + H ⁺ , 493.183092: found (ESI, [m+H] ⁺ ), 493.1813.

Example 505: 5-[(3,5-dichlorophenyl)sulfonyl]-2-isopropyl-iV-(2-pyridin-2 - ylethyl)benzenesulfonamide

[0573] Step 1 : Following the same procedure described in Example 474 (Step 3), 3,5- dichlorobenzene sulfonyl chloride was used to prepare 3,5-dichlorobenzene sulfonyl fluoride.

[0574] Step 2: Following the same procedure described in Example 474 (Step 4), 5- bromo-2-isopropyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide and 3,5-dichlorobenzene sulfonyl fluoride were used to prepare 5 - [Y3 , 5-dichlorophenyl)sulfonyl] -2-isopropyl-./V-(2- pyridin-2-ylethyDbenzenesulfonamide. MS (ESI) m/z 513; MS (ESI) m/z 511; HRMS: calcd for C ₂₂ H ₂₂ Cl ₂ N ₂ O ₄ S ₂ + H+, 513.04708; found (ESI-FTMS, [M+H] ¹⁺ ), 513.04709.

Example 506: 2-isopropyI-iV-(2-pyridin-2-yIethyl)-5-{[3- (trifluo romethoxy)pheny 1] sulf ony 1} benzenesulf onamide

[0575] In an analogous manner to Example 454,

[0576] Step 2: 3 -trifluoromethoxy phenyl boronic acid was used to prepare 2-isopropyl- N-(2-pyridin-2-ylethylV5-(r3-(trifluoromethoxy)phenyl]sulfon yl ^' }benzenesulfonamide. MS (ESI) m/z 529; MS (ESI) m/z 527; HRMS: calcd for C ₂₃ H ₂₃ F ₃ N ₂ O ₅ S ₂ + H+, 529.10732; found (ESI-FTMS, [M+H] ¹⁺ ), 529.10719.

Example 507: 5-{[4-(dimethylamino)phenyl]sulfonyl}-2-isopropyl-iV-(2-pyri din-2- ylethyl)benzenesulfonamide

[0577] In an analogous manner to Example 454,

[0578] Step 2: 4-dimethylaminophenyl boronic acid was used to prepare 5-{[4- (dimethylamino)phenyl1sulfonyl}-2-isopropyl-N-(2-pyridin-2-y lethyDbenzenesulfonamide. MS (ESI) m/z 488; MS (ESI) m/z 486; HRMS: calcd for C ₂₄ H ₂₉ N ₃ O ₄ S ₂ + H+, 488.16722; found (ESI-FTMS, [M+H] ¹⁺ ), 488.16721.

Example 508: 2~isopropyl-iV-(2-pyridin-2-ylethyl)-5-{[3- (trifluoromethyl)phenyl]sulfonyl}benzenesulfbnamide

[0579] Step 1 : Following the same procedure described in Example 474 (Step 3), 3- trifluoromethylbenzene sulfonyl chloride was used to prepare 3-trifluoromethylbenzene sulfonyl fluoride.

[0580] Step 2: Following the same procedure described in Example 474 (Step 4), 5- bromo-2-isopropyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide and 3-trifluoromethylbenzene sulfonyl fluoride were used to prepare 2-isopropyl-iV-(2-pyridin-2-ylethyl ^' )-5- { [3 - (trifluoromethyl)phenyl] sulfonyl} benzenesulfonamide. MS (ESI) m/z 513; MS (ESI) m/z 511; HRMS: calcd for C ₂₃ H ₂₃ F ₃ N ₂ O ₄ S ₂ + H+, 513.11241; found (ESI-FTMS, [M+H] ¹⁺ ), 513.11169.

Examle 509: 5-[(5-chIoro-2-methoxyphenyl)suIfonyI]-2-isopropyl-iV-(2-pyr idin-2- ylethyl)benzenesulfonamide

[0581] Step 1 : Following the same procedure described in Example 474, (Step 3), 5- chloro-2-methoxybenzene sulfonyl chloride was used to prepare 5-chloro-2-methoxybenzene sulfonyl fluoride.

[0582] Step 2: Following the same procedure described in Example 474 (Step 4), 5- bromo-2-isopropyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide and 5-chloro-2-methoxybenzene sulfonyl fluoride were used to prepare 5-[f5-chloro-2-methoxyphenyl)sulfonyl1-2-isopropyl-iV- (2-pyridin-2-ylethyl)benzenesulfbnamide. MS (ESI) m/z 509; MS (ESI) m/z 507; HRMS: calcd for C ₂₃ H ₂₅ ClN ₂ O ₅ S ₂ + H+, 509.09662; found (ESI-FTMS, [M+H] ¹⁺ ), 509.0966.

Example 510: 2-isopropyI-λ ^? -(2-pyridiii-2-ylethyI)-5-(quinolra-8- ylsulfonyl)benzenesulfonamide

[0583] Step 1 : Following the same procedure described in Example 474, (Step 3), quinolin-8 -sulfonyl chloride was used to prepare quinolin-8-sulfonyl fluoride.

[0584] Step 2: Following the same procedure described in Example 474, (Step 4), 5- bromo-2-isopropyl-iV-(2-pyridin-2-ylethyl)benzenesulfonamide and quinolin-8-sulfonyl fluoride were used to prepare 2-isopropyl-iV-(2-pyridin-2-ylethylV5-( ^' quinolin-8- ylsulfonvDbenzenesulfonamide. MS (ESI) m/z 496; MS (ESI) m/z 494; HRMS: calcd for C ₂₅ H ₂₅ N ₃ O ₄ S ₂ + H+, 496.13592; found (ESI-FTMS, [M+H] ¹⁺ ), 496.13588.

Example 511: 5-[(2,5-dichloro-3-thienyl)sulfonyl]-2-isopropyl~iV-(2-pyrid in-2- ylethyl)benzenesulfonamide

[0585] Step 1 : Following the same procedure described in Example 474, (Step 3), 2,5- dichlorothiophene-3 -sulfonyl chloride was used to prepare 2,5-dichlorothiophene-3-sulfonyl fluoride.

[0586] Step 2: Following the same procedure described in Example 474, (Step 4), 5- bromo-2-isopropyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide and 2,5-dichlorothiophene-3-

sulfonyl fluoride were used to prepare 5-[(2,5-dichloro-3-thienvDsulfonyl ^" |-2-isopropyl-iV ^' -( ^' 2- pyridin-2-ylethyl)benzenesulfonamide.

MS (ESI) m/z 519;

MS (ESI) m/z 517;

HRMS: calcd for C ₂₀ H ₂₀ Cl ₂ N ₂ O ₄ S ₃ + H+, 519.00350; found (ESI-FTMS, [M+H] ¹⁺ ), 519.00298.

Example 512: 5-[(5-chloro-l,3-dimethyl-lJϊ ^r -pyrazoI-4-yl)suIfonyl]-2-isopropyl-λ' ^: -(2- pyridin-2-yIethyl)benzenesulfonamide

[0587] Step 1 : Following the same procedure described in Example 474, (Step 3), 5- chloro-l,3-dimethyl-lH-pyrazole-4-sulfonyl chloride was used to prepare 5-chloro-l ,3-dimethyl- lH-pyrazole-4-sulfonyl fluoride.

[0588] Step 2: Following the same procedure described in Example 474, (Step 4), 5- bromo-2-isopropyl-N-(2-pyridm-2-ylethyl)benzenesulfonamide and 5-chloro-l ,3-dimethyl-lH- pyrazole-4-sulfonyl fluoride were used to prepare 5 - [Y5-chloro- 1 ,3 -dimethyl- 1 H-pyrazol-4- yDsulfonyl]-2-isopropyl-N-f2-pyridin-2-ylethyl)benzenesulfon amide. MS (ESI) m/z 497; MS (ESI) m/z 495; HRMS: calcd for C ₂₁ H ₂₅ ClN ₄ O ₄ S ₂ + H+, 497.10785; found (ESI, [M+H] ⁺ ), 497.1062.

Example 513: 2-isopropyl-5-[(l-methyl-ljH ^r -imidazol-4-yl)suIfonyl]-λ'-(2-pyridin-2- ylethyl)benzenesulfonamide

[0589] Step 1 : Following the same procedure described in Example 474, (Step 3), 1- methyl-lH-imidazole-4-sulfonyl chloride was used to prepare 1 -methyl- 1 H-imidazole-4-sulfony 1 fluoride.

[0590] Step 2: Following the same procedure described in Example 474, (Step 4), 5- bromo-2-isopropy l-iV-(2-pyridin-2-y lethy l)benzenesulfonamide and 1 -methyl- 1 H-imidazole-4- sulfonyl fluoride were used to prepare 2-isopropyl-5-r(l-methyl-lH-imidazol-4-yl)sulfonyl1-iV- (2-pyridin-2-ylethyDbenzenesulfonamide. MS (ESI) m/z 449; MS (ESI) m/z 441; HRMS: calcd for C ₂₀ H ₂₄ N ₄ O ₄ S ₂ + H+, 449.13117; found (ESI, [M+H] ⁺ ), 449.133.

Exaraple 514: 5-[(3-chloro~2-methyIphenyl)suIfonyl]-2-isopropyl-iV-(2-pyri din-2- ylethyl)benzenesulfonamide

[0591] Step 1 : Following the same procedure described in Example 474, (Step 3), 3- chloro-2-methylbenzene sulfonyl chloride was used to prepare 3 -chloro-2-methylbenzene sulfonyl fluoride.

[0592] Step 2: Following the same procedure described in Example 474, (Step 4), 5- bromo-2-isopropy l-iV-(2-pyridin-2-ylethy l)benzenesulfonamide and 3 -chloro-2-methylbenzene sulfonyl fluoride were used to prepare 5-[(3-chloro-2-methylphenyl)sulfonyl]-2-isopropyl-N-(2- pyridin-2-ylethyl)benzenesulfonamide. MS (ESI) m/z 493; MS (ESI) m/z 491; HRMS: calcd for C ₂₃ H ₂₅ ClN ₂ O ₄ S ₂ + H+, 493.10170; found (ESI, [M+H] ⁺ ), 493.1028.

Example 515: 5-[(4,4-dimethyl-2-oxo-l,4-dihydro-2H ^r -3,l-benzoxazin-6-yI)sulfonyl]-2- isopropyl-iV-(2-pyridin-2-yIethyl)benzenesulfonainide

[0593] In an analogous manner to Example 454,

[0594] Step 2: 4,4-dimethyl-2-oxo-l,4-dihydro-2/J-3,l-berizoxazin-6-boronic acid was used to prepare 5-[(4,4-dimethyl-2-oxo-l,4-dihydro-2H-3,l-benzoxazin-6-yl ^' )sulfonyll-2- isopropyl-N-(2-pyridm-2-ylethyl)benzenesulfonamide. MS (ES) m/z 542.0; HRMS: calcd for C ₂₆ H ₂₉ N ₃ O ₆ S ₂ + H+, 544.15705; found (ESI-FT/MS, [M+H] ¹⁺ ), 544.1574;

Example 516: 2-metb.yl-5-(phenylsulfonyl)-N-[l-(pyridin-3-ylcarbonyl)pipe ridin-4- yl] benzenesulfonamide

[0595] In an analogous manner to Example 462, 2-methyl-5-(phenylsulfonyl)-n- piperidin-4-ylbenzenesulfonamide and 3-pyridinecarbonyl chloride were used to prepare 2z methyl-5-( ^" phenylsulfonyl)-N-ri-(pyridm-3-ylcarbonyl)piperidin-4- yl]benzenesulfonamide. MS (ES+) m/z 500 MS (ES-) m/z 498 HRMS: calcd. for C ₂₄ H ₂₅ N ₃ O ₅ S ₂ + H ⁺ , 500.131391: found (ESI, [m+H]^, 500.1339.

Example 517: tert-butyl 4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidine-l-carboxylate

[0596] In an analogous manner to Example 435, 5-(4-fluoro-benzenesulfonyl)-2- isopropyl-benzenesulfonyl chloride and 4-amino-l-boc-piperidine were used to prepare tert-butyl 4- IY ( 5- | ^" (4-fluorophenyl)sulfonyl]-2- isopropy lphenyl 1 sulfonyl)amino ^" jpiperidine- 1 -carboxy late. MS (ES-) m/z 539.

Example 518: N-(l-{[5-(dimethylamino)-l-naphthyI]sulfonyl}piperidin-4-yl) -5-[(4- fluorophenyl)suIfonyl]-2-isopropylbenzenesulfonamide

[0597] In an analogous manner to Example 462, 2-isopropyl-5-(phenylsulfonyl)-n- piperidin-4-ylbenzenesulfonamide and dansyl chloride were used to prepare N-(I -{[ ^" 5- (dimethylaminoVl-naphtliyllsulfonyl}piperidin-4-yl)-5-r(4- fluorophenyl)sulfonyl]-2- isopropylbenzenesulfonamide. MS (ES+) m/z 61 A MS (ES-) m/z 672.

Example 519: 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-[l-(methoxyacetyl )piperidin-4- yl] benzenesulfonamide

[0598] In an analogous manner to Example 462, 2-isopropyl-5-(phenylsulfonyl)-n- piperidin-4-ylbenzenesulfonamide and methoxyacetic chloride were used to prepare 5-[(4- fluorophenvDsulfonyll -2-isopropy 1-N- [ ^" 1 -(methoxy acetyDpiperidin-4- yl]benzenesulfonamide . MS (ES+) w/z 513 MS (ES-) m/z 511 HRMS: calcd. for C ₂₃ H ₂₉ FN ₂ O ₆ S ₂ + H ⁺ , 513.1524: found (ESI, [m+H] ⁺ ), 513.1525.

Example 520: 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-piperidin-4- ylbenzenesulfonamide

[0599] tert-Butyl 4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidine-l -carboxy late (0.5 mg, 0.92 mmol) was added to 3 mL of 4 M hydrochloric acid in dioxane and the precipitate was filtered giving the desired 5-[(4- fluorophenyl)sulfonyl]-2-isopropyl-N-piperidin-4-ylbenzenesu lfonamide. MS (ES-) m/z 539

HRMS: calcd. for C ₂₅ H ₃₃ FN ₂ O ₆ S ₂ + H ⁺ , 558.2102: found (ESI, [m+H] ⁺ ), 558.211.

Example 521 : N-cyclopropyI-5-[(4-fluorophenyI)sulfonyl]-2-isopropylbenzen esulfonamide

[0600] In an analogous manner to Example 435, 5-(4-fluoro-benzenesulfonyl)-2- isopropyl-benzenesulfonyl chloride and cyclopropylamine were used to prepare N-cyclopropyl- 5-[(4-fluorophenyl)sulfonyll-2-isopropylbenzenesulfonamide. MS (ES+) rø/_r 398 MS (ES-) m/z 396 HRMS: calcd. for C ₁₈ H ₂₀ FNO ₄ S ₂ + H ⁺ , 398.0891: found (ESI, [m+H] ⁺ ), 398.091.

Example 522: N-cyclobutyl-5-[(4-fluorophenyl)sulfonyl]-2-isopropylbenzene sulfonamide

[0601] In an analogous manner to Example 435, 5-(4-fluoro-benzenesulfonyl)-2- isopropyl-benzenesulfonyl chloride and cyclobutylamine were used to prepare N-cyclobutyl-5- [(4-fluorophenyl)sulfonyll-2-isopropylbenzenesulfonamide.

MS (ES+) m/z 412 MS (ES-) m/z 410 HRMS: calcd. for C ₁₉ H ₂₂ FNO ₄ S ₂ + H ⁺ , 412.1047: found (ESI, [m+H] ⁺ ), 412.1059.

Example 523 : N-cyclopentyl-5- [(4-fluorophenyl)sulfonyl]-2-isopropylbenzenesulfonamide

[0602] In an analogous manner to Example 435, 5-(4-fluoro-benzenesulfonyl)-2- isopropyl-benzenesulfonyl chloride and cyclopentylamine were used to prepare N-cyclopentyl-5- r(4-fluorophenvDsulfonyll-2-isopropylbenzenesulfonamide. MS (ES+) m/z 426 MS (ES-) m/z 424 HRMS: calcd. for C ₂₀ H ₂₄ FNO ₄ S ₂ + H ⁺ , 426.1204: found (ESI, [m+H] ⁺ ), 426.1211.

Example 524 : N-cy clohexyl-5- [(4-fluorophenyl)sulf onyl] -2-is opropylbenzenesulf onamide

[0603] In an analogous manner to Example 435, 5-(4-fluoro-benzenesulfonyl)-2- isopropyl-benzenesulfonyl chloride and cyclohexylamine were used to prepare N-cyclohexyl-5- [(4-fluorophenyl)sulfonyl]-2-isopropylbenzenesulfonamide. MS (ES+) m/z 440 MS (ES-) rø/z 438

HRMS: calcd. for C ₂₁ H ₂₆ FNO ₄ S ₂ + H ⁺ , 440.136: found (ESI ₅ [m+H] ⁺ ), 440.1373.

Example 525: N-(l-benzylpiperidin-4-yl)-5-[(4-fluorophenyl)suIfonyl]-2- isopropylbenzenesulfonamide

[0604] In an analogous manner to Example 435, 5-(4-fluoro-benzenesulfonyl)-2- isopropyl-benzenesulfonyl chloride and 4-amino-l-benzylpiperidine were used to prepare N-(I- benzylpiperidin-4-yl)-5-[(4-fluorophenyl)sulfonyl ^" j-2- isopropylbenzenesulfonamide. MS (ES+) m/z 531 MS (ES-) m/z 529 HRMS: calcd. for C ₂₇ H ₃₁ FN ₂ O ₄ S ₂ + H ⁺ , 531.1782: found (ESI, [m+H] ⁺ ), 531.1785.

Example 526: ethyl 4-[({5-[(4-fluorophenyl)suIfonyl]~2- isopropylphenyl}sulfonyl)amino]piperidine-l-carboxylate

[0605] In an analogous manner to Example 435, 5-(4-fluoro-benzenesulfonyl)-2- isopropyl-benzenesulfonyl chloride and ethyl 4-amino-l-piperidine carboxylate were used to prepare ethyl 4-[({5-[ ^' ( ^' 4-fluorophenyl)sulfonyl]-2- isopropylphenyl|sulfonyl)aminolpiperidine-l- carboxylate. MS (ES+) m/z 513 MS (ES-) m/z 511 HRMS: calcd. for C ₂₃ H ₂₉ FN ₂ O ₆ S ₂ + H ⁺ , 513.1524: found (ESI, [m+H] ⁺ ), 513.1536.

Example 527: 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(2-piperidin-l- ylethyl)benzenesulfonamide

[0606] In an analogous manner to Example 435, 5-(4-fluoro-benzenesulfonyl)-2- isopropyl-benzenesulfonyl chloride and l-(2-aminoethyl)piperidine were used to prepare 5-IY4- fluorophenyl)sulfonyrj-2-isopropyl-N-f 2-piperidin- 1 - ylethvDbenzenesulfonamide. MS (ES+) m/z 469 MS (ES-) m/z 467 HRMS: calcd. for C ₂₂ H ₂₉ FN ₂ O ₄ S ₂ + H ⁺ , 469.1626: found (ESI, [m+H] ⁺ ), 469.1632.

Example 528: tert-bufyl 4-{[(2-isopropyl-5-{[4- (methylamino)phenyl]sulfonyl}phenyl)sulfonyl]amino}piperidin e-l-carboxylate

[0607] To a solution of methylamine in ethanol (2.0 mL, 2.0 M) was added tert-butyl 4- [({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidine-l-carboxylate (350 mg, 0.64 mmol) and the reaction was heated to 130 ⁰ C for 30 minutes in the microwave. The reaction mixture was concentrated and purified by automated flash chromatography using a gradient of 20% to 100% ethyl acetate/hexane resulting in the isolation of 353 mg of tert-butyl 4- { [(2-isopropyl-5-{ [4- (methylamino)phenyl]sulfonyl}phenyl)sulfonyl]amino}piperidin e-l - carboxylate. MS (ES-) m/z 550.

Example 529: N-(l-acetylpiperidin-4-yl)-5-[(4-fluorophenyl)sulfonyI]-2- isopropylbenzenesulfonamide

[0608] In an analogous manner to Example 462, 2-isopropyl-5-(phenylsulfonyl)-n- piperidin-4-ylbenzenesulfonamide and acetyl chloride were used to prepare N-(I -acetylpiperidin- 4-yl)-5-[(4-fluorophenyDsulfonyl]-2- isopropylbenzenesulfonamide. MS (ES+) m/z 483 MS (ES-) m/z 481 HRMS: calcd. for C ₂₂ H ₂₇ FN ₂ O ₅ S ₂ + H ⁺ , 483.142370: found (ESI, [m+H] ⁺ ), 483.143.

Example 530: N-[l-(cyclopropylcarbonyl)piperidin-4-yl]-5-[(4-fluorophenyl )sulfonyl]-2- isopropylbenzenesulfonamide

[0609] In an analogous manner to Example 462, 2-isopropyl-5-(phenylsulfonyl)-n- piperidin-4-ylbenzenesulfonamide and cyclopropylcarbonyl chloride were used to prepare N-[I- (cyclopropylcarbonyl')piperidin-4-yl]-5-[(4-fluorophenyl')su lfonyl]-2- isopropylbenzenesulfonamide. MS (ES+) m/z 509 MS (ES-) m/z 507 HRMS: calcd. for C ₂₄ H ₂₉ FN ₂ O ₅ S ₂ + H ⁺ , 509.158019: found (ESI, [m+H] ⁺ ), 509.1589.

Example 531 : N-[l-(4-cyanobenzoyl)piperidin-4-yl]-5-[(4-fluorophenyl)sulf onyl]-2- isopropylbenzenesulfonamide

[0610] In an analogous manner to Example 462, 2-isopropyl-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 4-cyanobenzoyl chloride were used to prepare N- [1 -(4- cvanobenzovπpiperidin-4-yl1-5-[r4-fluorophenyl)sulfonyl1-2- isopropylbenzenesulfonamide. MS (ES+) m/z 570 MS (ES-) m/z 568.

Example 532: 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(tetrahydrofuran- 2- ylmethyl)benzenesulfonamide

[0611] In an analogous manner to Example 435, 5-(4-fluoro-benzenesulfonyl)-2- isopropyl-benzenesulfonyl chloride and tetrahydrofurfurylamine were used to prepare 5-[C4- fluorophenvDsulfonyll^-isopropyl-N-Ctetrahydrofuran^- ylmethvDbenzenesulfonamide. MS (ES+) m/z 442 MS (ES-) m/z 440.

Example 533: 5-[(4-fluorophenyI)sulfonyl]-2-isopropyl-N-(2-pyridin-4- ylethyl)benzenesulfonamide

[0612] In an analogous manner to Example 435, 5-(4-fluoro-benzenesulfonyl)-2- isopropyl-benzenesulfonyl chloride and 4-(2-aminoethyl)pyridine were used to prepare 5-[(4- fluorophenyl)sulfonyl ^' |-2-isopropyl-N-r2-pyridm-4- ylethyDbenzenesulfonamide. MS (ES+) w/z 463

Example 534: 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(2-pyridin-3- ylethyl)benzenesulfonamide

[0613] In an analogous manner to Example 435, 5-(4-fluoro-benzenesulfonyl)-2- isopropyl-benzenesulfonyl chloride and 3-(2-aminoethyl)pyridine were used to prepare 5-| ^" (4- fluorophenyl ^' )sulfonyll-2-isopropyl-N-(2-pyridin-3- ylethyl)benzenesulfonamide. MS (ES+) m/z 463 MS (ES-) m/z 461 HRMS: calcd. for C ₂₂ H ₂₃ FN ₂ O ₄ S ₂ + H ⁺ , 463.116155: found (ESI, [m+H] ⁺ ), 463.1174.

Example 535: 5-({4-[(2-cyanoethyI)amino]phenyI}sulfonyl)-2-isopropyl-iV-( tetrahydro-2 _J H ^r - pyran-4-yI)benzenesulfonamide

[0614] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-iV-tetrahydro-2H-pyran-4-ylbenzenesulfonamide and 3-aminopropionitrile in DMA were used to prepare 5-({4-rf2-cvanoethyl)amino]phenyllsulfonyl ^' )-2-isopropyl-N-rtetrahydro- 2ij ^r -pyran-4-yl)benzenesulfonamide. MS (ES) m/z 490.1;

HPLC purity 96.7% at 210-370 urn, 8.3 min.; 96.9% at 304 ran, 8.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₉ N ₃ O ₅ S ₂ + H+, 492.16214; found (ESI, [M+H] ⁺ ), 492.1638.

Example 536: 5-({4-[(2-cyanoethyI)amino]phenyl}sulfonyl)-2-isopropyl-iV-( tetrahydro-2 _J H ^r - pyran-4-yImethyl)benzenesulfonamide

[0615] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-tetrahydro-2/i-pyran-4-ylmethyl)benzenesulfonami de and 3-aminopropionitrile in DMA were used to prepare 5-({4-[(2-cyanoethyl)amino1phenyUsulfonyl)-2-isopropyl-N- (tetrahydro-2iir-pyran-4-ylmethyl ^' )benzenesulfonamide. MS (ES) m/z 504.1;

HPLC purity 96.7% at 210-370 ran, 8.5 min.; 97.0% at 304 nm, 8.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₃₁ N ₃ O ₅ S ₂ + H+, 506.17779; found (ESI, [M+H] ⁺ ), 506.1786.

Example 537: 5-({4-[(2-cyanoethyl)amino]phenyl}sulfonyl)-2-isopropyl-iV-[ 2-(tetrahydro- 2/f-pyran-4-yl)ethyl]benzenesulfonamide

[0616] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-iV-tetrahydro-2H-pyran-4-ylethyl)benzenesulfonamid e and 3-aminopropionitrile in DMA were used to prepare 5-( {4- [(2-cyanoethyDaminolphenyl} sulfonyl)-2-isopropyl-N- [2- ftetrahydro-2H-pyran-4-yl)ethyl1benzenesulfonamide. MS (ES) m/z 518.2; ηPLC purity 97.4% at 210-370 nm, 8.7 min.; 97.6% at 304 nm, 8.7 min.; Xterra RP18, 3.5u, 150

x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₅ H ₃₃ N ₃ O ₅ S ₂ + H+, 520.19344; found (ESI, [M+H] ⁺ ), 520.1949.

Example 538: N-(3',6'-dihydroxy-3-oxo-3H-spiro[2-benzofuran-l,9'-xanthen] -5-yl)-4-[({5- [(4-fluorophenyl)sulfonyl]-2-isopropylphenyl}sulfonyl)amino] piperidine-l- carbothioamide

[0617] In an analogous manner to Example 462, 2-isopropyl-5-(phenylsulfonyl)-n- piperidin-4-ylbenzenesulfonamide and fluorescein isothiocyanate were used to prepare N-(3',6'- dihydroxy-3-oxo-3H-spiro[2-benzofuran-l,9'-xanthenl-5-yl)-4- r({5-r(4-fluorophenyl)sulfonyll- 2-isopropylphenyl} sulfonyl)ammo]piperidine- 1 - carbothioamide. MS (ES+) m/z 830.

Example 539: 5-[(3-cyanophenyl)sulfonyl]-2-isopropyl-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0618] In an analogous manner to Example 454,

[0619] Step 2: 3-cyanophenylboronic acid was used to prepare 5-[(3- cyanophenyl)sulfonyl1-2-isopropyl-N-(2-pyridin-2-ylethvDbenz enesulfonamide.

MS (ES) m/z 468.1;

HRMS: calcd for C ₂₃ H ₂₃ N ₃ O ₄ S ₂ + H+, 470.12027; found (ESI, [M+H] ⁺ ) ₅ 470.1223.

Example 540: 5-(l/Z-indoI-5-ylsulfonyI)-2-isopropyl-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0620] In an analogous manner to Example 454,

[0621] Step 2: indole-5-boronic acid was used to prepare 5-riϋ/-indol-5-ylsulfonyl)-2- isopropyl-iV-(2-pyridm-2-ylethyl)benzenesulfonamide. MS (ES) m/z 482.1; HRMS: calcd for C ₂₄ H ₂₅ N ₃ O ₄ S ₂ + H+, 484.13592; found (ESI, [M+H] ⁺ ), 484.1382.

Example 541 : 2-isopropyl-5-[(2-methylphenyl)sulfonyl]-λ ^r -(tetrahydro-2Jϊ-pyran-4- yl)benzenesulfonamide

[0622] In an analogous manner to Example 474,

[0623] Step 1 : 4-amino tetrahydropyran was used to prepare 2-isopropyl-N-(tetrahvdro- 2H-pyran-4-yl)benzenesulfonamide.

[0624] Step 2: 2-isopropyl-N-(tetrahydro-2H ^" -pyran-4-yl)benzenesulfonamide was used to prepare 5-bromo-2-isopropyl-N-(tetrahvdro-2H-pyran-4-yl)ben2enesulfo namide.

[0625] Step 3: 2-methylphenyl sulfonyl fluoride and 5-bromo-2-isopropyl-iV- (tetrahydro-2/f-pyran-4-yl)benzenesulfonamide were used to prepare 2-isopropyl-5-| ^" f2- methylphenyl)sulfonyl1-N-(tetrahydro-2H-pyran-4-yl)benzenesu lfonamide. MS (ES) m/z 436.1; HRMS: calcd for C ₂₁ H ₂₇ NO ₅ S ₂ + H+, 438.14034; found (ESI, [M+H] ⁺ ), 438.1409.

Example 542: 5-[(3-chloro-2-methylphenyl)suIfonyl]-2-isopropyl-iV-(tetrah ydro-2/?-pyran- 4-yl)benzenesuIfonamide

[0626] In an analogous manner to Example 541 ,

[0627] Step 3: 5-bromo-2-isopropyl-iV-(tetraliydro-2H-pyran-4-yl)benzenesul fonamide and 3-chloro-2-methylphenyl sulfonyl fluoride were used to prepare 5-[(3-chloro-2- methylphenyl)sulfonyll-2-isopropyl-iV-rtetrahydro-2H-pyran-4 -yl)benzenesulfonamide. MS (ES) m/z 470.1; HRMS: calcd for C ₂₁ H ₂₆ ClNO ₅ S ₂ + H+, 472.10137; found (ESI-FTMS, [MH-H] ¹⁺ ), 472.1024.

Example 543: 2-isopropyl-5-{[4-(methylamino)phenyl]suIfonyI}-iV-(tetrahyd ro-2i3 ^r -pyran- 4-ylmethyl)benzenesulfonamide

[0628] In an analogous manner to Example 356, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-iV-(2-tetrahydro-2H-pyran-4-ylmethyl)benzenesulfon amide and methylamine were used to prepare 2-isopropyl-5- { [4-(methylamino)phenyl] sulfonyl} -N-(tetrahydro-2H-pyran-4- ylmethyl)benzenesulfonamide. MS (ES) m/z 465.2;

HPLC purity 96.6% at 210-370 nm, 9.0 min.; 98.2% at 310 nni, 9.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₃₀ N ₂ O ₅ S ₂ + H+, 467.16689; found (ESI, [M+H] ⁺ ), 467.1691.

.. H! IH fell ifcii

AM101865 - 187 -

Example 544: 5-{[4-(dimethylamino)phenyl]sulfonyl}-2-isopropyl-λ ^r -(tetrahydro-2fl ^r - pyran-4-yl)benzenesulfonamide

[0629] In an analogous manner to Example 356, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N~tetrahydro-2H-pyran-4-ylbenzenesulfonamide and a dimethylamine solution in THF were used to prepare 5-{[4-(dimethylammo)phenyllsulfonyl>-2-isoproρyl-7V-(tet rahydro-2H ^" - py ran-4-yDbenzenesulfonamide . MS (ES) m/z 465.1;

HPLC purity 96.2% at 210-370 nm, 9.2 min.; 96.2% at 318 nm, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₃₀ N ₂ O ₅ S ₂ + H+, 467.16689; found (ESI, [M+H] ⁺ ), 467.1694.

Example 545: 5-{[4-(dimethylamino)phenyl]sulfonyl}-2-isopropyl-iV-(tetrah ydro-2JEr- pyran-4-ylmethyl)benzenesulfonamide

[0630J In an analogous manner to Example 356, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-λ/-(2-tetrahydro-2ϋ/-pyran-4-ylmethyl)benzenesul fonamide and a dimethylamine solution in THF were used to prepare 5 - { [4-(dimethylamino)pheny 1] sulfony 1} -2-isopropyl-JV- (tetrahydro-2/f-pyran-4-ylmethyl)benzenesulfonamide. MS (ES) m/z 479.2;

HPLC purity 96.3% at 210-370 nm, 9.4 min.; 96.6% at 318 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₃₂ N ₂ O ₅ S ₂ + H+, 481.18254; found (ESI, (M+H] ⁺ ), 481.1829.

Example 546: 5-{[4-(dimethylamino)phenyl]sulfonyl}-2-isopropyl-iV-[2-(tet rahydro-2iϊ- pyran-4-yl)ethyl]benzenesulfonamide

[0631] In an analogous manner to Example 356, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-iV-(2-tetrahydro-2H-pyran-4-ylethyl)benzenesulfona mide and a dimethylamine solution in THF were used to prepare 5-{[4-(dimethylammo)phenyl]sulfonyl|-2-isopropyl-iV-[2- (tetrahydro-2H-pyran-4-yl)ethyl]benzenesulfonamide. MS (ES) m/z 493.2; HPLC purity 100% at 210-370 nm, 9.6 min.; 99.2% at 318 nm, 9.6 min.; Xterra RPl 8, 3.5u, 150

x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₄ H ₃₄ N ₂ O ₅ S ₂ + H+, 495.19819; found (ESI, [M+H] ⁺ ), 495.1986.

Example 547: 2-isopropyl-5-{[4-(4-methyIpiperazin-l-yl)phenyl]sulfonyl}-i V-(tetrahydro- 2iϊ-pyran-4-yI)benzenesulf6namide

[0632] To a solution of 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-tetrahydro-2H ^" - pyran-4-ylbenzenesulfonamide (88 mg, 0.2 mmol) in acetonitrile (0.5 mL) was added N- methylpiperazine (101 mg, 0.99 mmol). The solution was heated with stirring using microwave irradiation (150 ⁰ C) for 60 minutes. Upon cooling, the reaction mixture was diluted with water (10 mL) and the aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were concentrated and the resulting crude residue was purified using automated flash column chromatography with a graduated mobile phase consisting of dichloromethane and methanol resulting in the isolation of 2-isopropyl-5-f [4-(4-methylpiperazin- 1 - yl)phenyl1sulfonvU-N-(tetrahydro-2H-pyran-4-yl)benzenesulfon amide (100 mg, 97%). MS (ES) m/z 520.2;

HPLC purity 93.9% at 210-370 nm, 6.7 min.; 95.8% at 300 mn, 6.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₃₅ N ₃ O ₅ S ₂ + H+, 522.20909; found (ESI, [MH-H] ⁺ ), 522.2094.

Example 548: 2-isopropyl-5-{[4-(4-methylpiperazin-l-yl)phenyl]sulfonyl}-i V-(tetrahydro- 2/2 ^r -pyran-4-ylmethyl)benzenesulfonamide

[0633] In an analogous manner to Example 547, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-tetrahydro-2/f-pyran-4-ylmethyl)benzenesulfonami de and N-methylpiperazine were used to prepare 2-isopropyl-5-{[4-r4-methylpiperazin-l-yl)phenyl]sulfonyU-N- (tetrahydro-2H- pyran-4-ylmethyl)benzenesulfonamide. MS (ES) m/z 534.2;

HPLC purity 94.8% at 210-370 nm, 7.0 min.; 95.2% at 300 nm, 7.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₆ H ₃₇ N ₃ O ₅ S ₂ + H+, 536.22474; found (ESI, [MH-H] ⁺ ), 536.2244.

Example 549: 2-isopropyl-5-{[4-(4-methyIpiperazin-l-yl)phenyl]sulfonyl}-i V-[2- (tetrahydro-2 _J fiT-pyran-4-yl)ethyl]benzenesulfonamide

[0634] In an analogous manner to Example 547, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-tetrahydro-2H-pyran-4-ylethyl)berizenesulfonamid e and N-methylpiperazine were used to prepare 2-isopropyl-5-{[4-(4-methylpiperazin-l-vDphenyl]sulfonyl|-N- [ ^' 2-( ^' tetrahydro- 2H-pyran-4-yl)ethyl1benzenesulfonamide. MS (ES) m/z 548.2;

HPLC purity 96.1% at 210-370 nm, 7.3 min.; 96.2% at 300 nm, 7.3 min.; Xten-a RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10min ₃ hold 4min. HRMS: calcd for C ₂₇ H ₃₉ N ₃ O ₅ S ₂ + H+, 550.24039; found (ESI, [M+H] ⁺ ), 550.2411.

Example 550: iV-(2-phenyIethyl)-5-(phenylsulfonyl)-2-propylbenzenesuIfona mide

[0635] Step a) l-(Phenylsulfonyl)-4-propylbenzene

[0636] A stirred solution of n-propylbenzene (2.40 g, 20 mmol) and benzenesulfonyl chloride (3.52 g, 20 mmol) was cooled to -40 °C and treated slowly under nitrogen with solid anhydrous aluminum chloride (3.20 g, 24 mmol). After stirring neat for 4 hours at room temperature, the mixture was slowly poured into ice water and extracted with ethyl acetate (2x). The organic phase was washed with a saturated, aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered through a short column of silica gel. The filtrate was evaporated in vacuo to yield a crude oil, which was crystallized from diethyl ether-hexane to yield 1 -(phenylsulfonyl) 4-propylbenzene (4.57 g, 88%) as a homogeneous, colorless, crystalline solid, m.p. 83-85 °C; MS (+ESI), m/z: 261 [M+H] ⁺ ; MS (-ESI), m/z: 259 [M-H] ^" ;

HRMS: calcd for C ₁₅ H ₁₆ O ₂ S, 260.08710; found (EI, M+.), 260.0876; HPLC purity 100% at 210-370 nm, 9.8 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

[0637] Step b) 5-Benzenesulfonyl-2-propyl-benzenesulfonyl chloride

[0638] 1 -(Phenylsulfonyl) 4-propylbenzene (2.60 g, 10 mmol) was heated with stirring at 60 °C for one hour under nitrogen with chlorosulfonic acid (6.7 mL, 11.7 g, 100 mmol). The mixture was cooled to room temperature, poured slowly into a cold solution of IN hydrochloric

acid, and extracted with ethyl acetate (2x.). The organic phase was washed with a saturated, aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent concentrated in vacuo to a crude oil. The crude oil was crystallized from diethyl ether-hexane to afford 5-benzenesulfonyl-2-propyl-benzenesulfonyl chloride (3.51 g, 98%) as a homogeneous, colorless, crystalline solid, which was utilized in subsequent reactions.

[0639] Step c) N-(2-Phenylethyl)-5-(phenylsulfonyl)-2-propylbenzenesulfonam ide [0640] A stirred solution of 5-benzenesulfonyl-2-propyl-benzenesulfonyl chloride (0.18 g, 0.5 mmol) in dichloromethane (10 niL) was treated dropwise under nitrogen with a solution of phenethylamine (0.12 g, 1.0 mmol) in dichloromethane. After stirring for one hour at room temperature, or until the reaction was complete, the mixture was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-25% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min. After evaporation of the solvent under vacuum, the title compound, N-(2-phenylethyl)-5- (phenylsulfonyl>2-propylbenzenesulfonamide (0.17 g, 77%), was obtained as a homogeneous, clear oil;

MS (-ESI), m/z: 442.1 [M-H] ^" ;

HRMS: calcd for C ₂₃ H ₂₅ NO ₄ S ₂ + H+, 444.12978; found (ESI, [M+H] ⁺ ), 444.1323; HPLC purity 100% at 210-370 rnn, 10.3 min; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 551 : 5-(PhenyIsuIfonyl)-2-propyl-iV-(tetrahydro-2iϊ-pyran-4- yl)benzenesulfonamide

[0641] The title compound was prepared from 5-benzenesulfonyl-2-propyl- benzenesulfonyl chloride (0.18 g, 0.5 mmol) and tetrahydro-pyran-4-ylamine (0.10 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 550, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 30%-70% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford 5-(phenylsulfonyl)-2-propyl-iV-( ^' tetrahydro-2H ^' - pyran-4-yl)benzenesulfonamide (0.15 g, 71%), as a homogeneous, colorless, crystalline solid, m.p. 131-133 °C; MS (-ESI), m/z: 422.1 [M-H] ^" ; HRMS: calcd for C ₂₀ H ₂₅ NO ₅ S ₂ + H+, 424.12469; found (ESI, [M+H] ⁺ ), 424.1262;

HPLC purity 100% at 210-370 nm, 9.0 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 552 : 5-(Phenylsulfonyl)-2-propyl-iV-(tetrahy dro-2i/-py ran-4- ylmethyl)benzenesulfonamide

[0642] The title compound was prepared from 5-benzenesulfonyl-2-propyl- benzenesulfonyl chloride (0.18 g, 0.5 mmol) and (tetrahydro-pyran-4-yl)methylamine (0.12 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 550, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 30%-70% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford S-fphenylsulfonyD-σ-propyl-iV- ftetrahydro-2H-pyran-4-ylmethyl)benzenesulfonaim ^' de (0.21 g, 98%), as a homogeneous, clear oil;

MS (-ESI), m/z: 436.1 [M-H] ^" ;

HRMS: calcd for C ₂₁ H ₂₇ NO ₅ S ₂ + H+, 438.14034; found (ESI, [M+H] ⁺ ), 438.1419; HPLC purity 100% at 210-370 nm, 9.2 min; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 553: 5-(PhenyIsulfonyl)-2-propyl-λ ^r -[2-(tetrahydro-2iϊ-pyran-4- yl)ethyl]benzenesulfonamide

[0643] The title compound was prepared from 5-benzenesulfonyl-2-propyl- benzenesulfonyl chloride (0.18 g, 0.5 mmol) and 2-(tetrahydro-pyran-4-yl)ethylamine (0.13 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 550, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 30%-70% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford 5-(ρhenylsulfonyl)-2-propyl-iV-[2- ftetrahydro-2i/-pyran-4-yl)emyl]benzenesulfonamide (0.16 g, 72%), as a glass; MS (-ESI), m/z: 450.1 [M-H] ^" ;

HRMS: calcd for C ₂₂ H ₂₉ NO ₅ S ₂ + H+, 452.15599; found (ESI, [M+H] ⁺ ), 452.1551; HPLC purity 100% at 210-370 nm, 9.4 min; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 554: iV-Cyclopentyl-5-(phenylsulfonyI)-2-propylbenzenesulfonamide

[0644] The title compound was prepared from 5-benzenesulfonyl-2-propyl- benzenesulfonyl chloride (0.18 g, 0.5 mmol) and cyclopentylamine (0.09 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 550, step c. The crude product was purified by preparative liquid chromatography on a Biotage" 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-25% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford A/-cyclopentyl-5-(phenylsulfonyl)-2-propylbenzenesulfonamide (0.14 g, 67%), as a glass; MS (-ESI), m/z: 406.1 [M-H] ^" ;

HRMS: calcd for C ₂₀ H ₂₅ NO ₄ S ₂ + H+, 408.12978; found (ESI, [M+H] ⁺ ), 408.1322; HPLC purity 100% at 210-370 nm, 10.1 min; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 555: 5-(Phenylsulfonyl)-2-propyI-iV-(2-pyridin-2-ylethyl)benzenes ulfonamide

[0645] The title compound was prepared from 5-benzenesulfonyl-2-propyl- benzenesulfonyl chloride (0.18 g, 0.5 mmol) and 2-pyridin-2-yl-ethylamine (0.12 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 550, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 50%-100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford 5-(phenylsulfonyl>2-propyl-N-(2-pyridin-2- ylethvDbenzenesulfonamide (0.17 g, 75%), as a homogeneous, colorless, crystalline solid, m.p. 100-102 °C;

MS (+ESI), m/z: 445 [M+H] ⁺ ; MS (-ESI), m/z: 443 [M-H] ^" ;

HRMS: calcd for C ₂₂ H ₂₄ N ₂ O ₄ S ₂ + H+, 445.12502; found (ESI, [M+H] ⁺ ), 445.1255; HPLC purity 100% at 210-370 nm, 9.0 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 556: _J /V-[3-(liϊ-Imidazol-l-yl)propyl]-5-(phenylsulfonyl)-2- propylbenzenesulfonamide

[0646] The title compound was prepared from 5-benzenesulfonyl-2-propyl- benzenesulfonyl chloride (0.18 g, 0.5 mmol) and 3-imidazol-l-yl-propylamine (0.13 g, 1.0

mmol) according to the procedure and in the same manner as described in Example 550, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-4% methanol in dichloromethane at a flow rate of 50 mL/min, to afford N-[3-flH-imidazol-l-yl)propyr|-5- (phenylsulfonyl)-2-propylbenzenesulfonamide (0.03 g, 14%), as a homogeneous, off-white, amorphous solid, m.p. 143-146 ⁰ C; MS (-ESI), m/z: 443 [M-H] ^" ;

HRMS: calcd for C ₂₁ H ₂₅ N ₃ O ₄ S ₂ + H+, 448.13592; found (ESI, [M+H] ⁺ ), 448.1381; HPLC purity 100% at 210-370 nm, 7.3 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 557: 5-(PhenylsuIfonyl)-2-propylbenzenesuIfonamide

[0647] The title compound was prepared from 5-benzenesulfonyl-2-propyl- benzenesulfonyl chloride (0.18 g, 0.5 mmol) and 3-miidazol-l-yl-propylamine (0.13 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 550, step c. The crude product was purified by preparative liquid chromatography on a Biotage 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-4% methanol in dichloromethane at a flow rate of 50 mL/min, to afford 5-(phenylsulfonyl)-2- propylbenzenesulfonamide (0.06 g, 34%), as a clear, tan oil; MS (-ESI), m/z: 338.1 [M-H] ^" ;

HRMS: calcd for C ₁₅ H ₁₇ NO ₄ S ₂ + NH ₄ ⁺ , 357.09372; found (ESI, [M+NH4] ^"1" ), 357.0938; HPLC purity 89.5% at 210-370 nm; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 558: tert-Bntyl 4-({[5-(phenylsulfonyl)-2- propylphenyl]sulfonyl}amino)piperidine-l-carboxylate

[0648] The title compound was prepared from 5-benzenesulfonyl-2-propyl- benzenesulfonyl chloride (0.36 g, 1.0 mmol) and 4-amino-piperidine-l-carboxylic acid, tert- butyl ester (0.40 g, 2.0 mmol) according to the procedure and in the same manner as described in Example 550, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 15%-50% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford tert-butyl 4-(fr5-

fphenylsulfonvD^-propyrphenyl] sulfonyl} amino)piperidine- 1 -carboxylate (0.40 g, 77%), as homogeneous, colorless, crystalline solid, m.p. 128-130 °C;

MS (-ESI), m/z: 521.1 [M-H]-;

HRMS: calcd for C ₂₅ H ₃₄ N ₂ O ₆ S ₂ + NH ₄ ⁺ , 540.21965; found (ESI, [M+NH4] ⁺ ), 540.2227;

HPLC purity 100% at 210-370 nm, 10.3 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 559: 5-[(4-fluorophenyl)sulfonyl]-iV-(2-phenylethyl)-2-propyIbenz enesulfonamide [0649] Step a) l-Fluoro-4-[(4-propylphenyl)sulfonyl]benzene [0650] A stirred solution of n-propylbenzene (2.40 g, 20 mmol) and 4- fluorobenzenesulfonyl chloride (3.88 g, 20 mmol) was cooled to -40 °C and treated slowly under nitrogen with solid anhydrous aluminum chloride (3.20 g, 24 mmol). After stirring neat for 4 hours at room temperature, the mixture was poured slowly into ice water and extracted with ethyl acetate (2x). The organic phase was washed with a saturated, aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered through a short column of silica gel. The filtrate was evaporated in vacuo to yield an oil, l-fluoro-4-r(4-propylphenyl)sulfonyl]benzene (5.56 g, 100%) as a homogeneous, clear, pale, yellow oil; MS (+ESI), m/z: 279.1 [M+H] ⁺ ;

HRMS: calcd for C ₁₅ H ₁₅ FO ₂ S, 278.07768; found (EI, M+.), 278.0774;

HPLC purity 98.8% at 242 nm, 9.9 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

[0651] Step b) 5-[(4-Fluorophenyl)sulfonyl]-2-propylbenzenesulfonyl chloride [0652] l-Fluoro-4-[(4-propylphenyl)sulfonyl]benzene (2.78 g, 10 mmol) was heated with stirring at 60 ⁰ C for one hour under nitrogen with chlorosulfonic acid (6.7mL, 11.7 g, 100 mmol). The mixture was cooled to room temperature, poured slowly into a cold solution of IN hydrochloric acid, and extracted with ethyl acetate (2x.). The organic phase was washed with a saturated, aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent concentrated in vacuo to a homogeneous, clear, tan oil, 5-[(4-fluorophenyl)sulfonyl1- 2-propylbenzenesulfonyl chloride (3.74 g, 99%), which solidified on standing and was utilized in subsequent reactions.

[0653] Step c) 5-[(4-Fluorophenyl)sulfonyl]-N-(2-phenylethyl)-2- propylbenzenesulfonamide

SB E B AM101865 - 195 -

[0654] A stirred solution of 5-[(4-fluorophenyl)sulfonyl]-2-propylbenzenesulfonyl chloride (0.19 g, 0.5 mmol) in dichloromethane (10 mL) was treated dropwise under nitrogen with a solution of phenethylamine (0.12 g, 1.0 mmol) in dichloromethane. After stirring for one hour at room temperature or until the reaction was complete, the mixture was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-25% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min. After evaporation of the solvent under vacuum, the title compound, 5-r(4-fluorophenyl)sulfonyl1- A/-(2-phenylethylV2-propylbenzenesulfonamide (0.22 g, 93%), was obtained as a homogeneous, clear, colorless oil; MS (-ESI), m/z: 460.1 [M-H] ^" ;

HRMS: calcd for C ₂₃ H ₂₄ FNO ₄ S ₂ + H+, 462.12035; found (ESI, [M+H] ⁺ ), 462.1214; HPLC purity 100% at 210-370 nm, 10.4 min.; 100% at 242 nm, 10.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 560: 5-[(4-Fluorophenyl)sulfonyl]-2-propyl-iV-(tetrahydro-2iϊ-py ran-4- yl)benzenesulfonamide

[0655] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2- propylbenzenesulfonyl chloride (0.19 g, 0.5 mmol) and tetrahydro-pyran-4-ylamine (0.10 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 559, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 30%-70% methyl tert-hυtyl ether in hexane at a flow rate of 50 mL/min, to afford 5-[f4-fluorophenyl)sulfonyl]-2-propyl-N- (tetrahvdro-2H-pyran-4-yl)benzenesulfonamide (0.18 g, 80%), as a homogeneous, colorless, crystalline solid, m.p. 131-133 °C; MS (-ESI), m/z: 440.1 [M-H] ^" ;

HRMS: calcd for C ₂₀ H ₂₄ FNO ₅ S ₂ + H+, 442.11527; found (ESI, [M+H] ⁺ ), 442.1644; HPLC purity 100% at 210-370 nm, 9.2 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 561 : 5-[(4-Fluorophenyl)sulf onyl]-2-propyl-λ'-(tetrahydro-2jH ^r -pyran-4- ylmethyl)benzenesulfonamide

[0656] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2- propylbenzenesulfonyl chloride (0.19 g, 0.5 mmol) and (tetrahydro-pyran-4-yl)methylamine (0.12 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 559, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 30%-70% methyl tert- butyl ether in hexane at a flow rate of 50 rnL/min, to afford 5-| ^' (4-fluorophenyl ^' )sulfonyl]-2- propyl-N-(tetrahvdro-2/f-pyran-4-γlmethyl)benzenesulfonamid e (0.20 g, 87%), as a glass; MS (-ESI), m/z: 454.1 [M-H] ^" ;

HRMS: calcd for C ₂₁ H ₂₆ FNO ₅ S ₂ + H+, 456.13092; found (ESI, [M+H] ^"1" ), 299.19; HPLC purity 100% at 210-370 ran, 9.4 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 562: 5-[(4-Fluorophenyl)sulfonyl]-2-propyl-λ'-[2-(tetrahydro-2 _J £r-pyran-4- yl)ethyl] benzenesulf onamide

[0657] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2- propylbenzenesulfonyl chloride (0.19 g, 0.5 mmol) and 2-(tetrahydro-pyran-4-yl)ethylamine (0.13 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 559, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 30%-70% methyl tert- butyl ether in hexane at a flow rate of 50 mL/min, to afford 5-| ^" (4-fluorophenyDsulfonyll-2- propyl-N-r2-rtetrahydro-2H-pyran-4-yl)ethyllbenzenesulfonami de (0.14 g, 58%), as a glass; MS (-ESI), m/z: 468.1 [M-Hp;

HRMS: calcd for C ₂₂ H ₂₈ FNO ₅ S ₂ + H+, 470.14657; found (ESI, [M+H] ⁺ ), 470.1467; HPLC purity 100% at 210-370 nm, 9.6 min; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 563: λ ^L Cyclopentyl-5-[(4-fluorophenyl)sulfonyl]-2-propyIbenzenesulf onamide

[0658] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2- propylbenzenesulfonyl chloride (0.19 g, 0.5 mmol) and cyclopentylamine (0.09 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 559, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-25% methyl tert-butyl ether in hexane

at a flow rate of 50 mL/min, to afford N-cvclopentλd-5-r( ^" 4-fluorophenyl)sulfbnyl]-2- propylbenzenesulfonamide (0.15 g, 71%), as a glass;

MS (-ESI) ₃ m/z: 424.1 [M-H] ^" ;

HRMS: calcd for C ₂₀ H ₂₄ FNO ₄ S ₂ + H+, 426.12035; found (ESI, [M+H] ⁺ ), 426.1199;

HPLC purity 99.1% at 210-370 nm, 10.2 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 564: 5~[(4-Fluorophenyl)sulfonyl]-2-propyl-JV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0659] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2- propylbenzenesulfonyl chloride (0.19 g, 0.5 mmol) and 2-(pyridin-2-yl)ethylamine (0.12 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 559, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 50%- 100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford 5-[(4-fluorophenyl)sulfonyl]-2-propyl-iV- (2-pyridin-2-ylethyl)benzenesulfonamide (0.18 g, 78%), as a homogeneous, colorless, crystalline solid, m.p. 113-115 °C; MS (+ESI) ₅ m/z: 463 [M+H] ⁺ ; MS (-ESI), m/z: 461 [M-H]-;

HRMS: calcd for C ₂₂ H ₂₃ FN ₂ O ₄ S ₂ + H+, 463.11560; found (ESI, [M+H] ⁺ ), 463.1176; HPLC purity 100% at 210-370 nm, 9.2 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 565: 5-[(4-Fluorophenyl)sulfonyl]-iV-[3-(l _J fir-imidazol-l-yl)propyl]-2- propylbenzenesulfonamide

[0660] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2- propylbenzenesulfonyl chloride (0.38 g, 1.0 mmol) and 3-(lH-imidazol-lyl)propylamine (0.25 g, 2.0 mmol) according to the procedure and in the same manner as described in Example 559, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-4% methanol in dichloromethane at a flow rate of 50 mL/min, to afford 5 - [(4-fluoropheny Dsulf onyl] - JV- [3 - ( 1 H- imidazol- 1 -yl)propyl]-2-propylbenzenesulfonamide (0.12 g, 25%), as a foam;

MS (-ESI), m/z: 464.1 [M-H] ^" ;

HRMS: calcd for C ₂₁ H ₂₄ FN ₃ O ₄ S ₂ + H+, 466.12650; found (ESI, [M+H] ⁺ ), 466.125; HPLC purity 100% at 210-370 nm, 7.6 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 566: 5-[(4-FIuorophenyl)sulfonyI]-2-propylbenzenesuIfonamide

[0661] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2- propylbenzenesulfonyl chloride (0.38 g, 1.0 mmol) and 3-(l/f-imidazol-lyl)propylamine (0.25 g, 2.0 mmol) according to the procedure and in the same manner as described in Example 559, step c. The crude product was purified by preparative liquid chromatography on a Biotage ' 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-4% methanol in dichloromethane at a flow rate of 50 mL/min, to afford 5 - [f 4-fluorophenyl)sulfonyl] -2- propylbenzenesulfonamide (0.23 g, 50%), as a tan foam; MS (-ESI), m/z: 356.1 [M-H] ^" ;

HRMS: calcd for C ₁₅ H ₁₆ FNO ₄ S ₂ + H+, 358.05775; found (ESI, [M+H] ⁺ ), 409.0887; HPLC purity 79.8% at 210-370 nm, 8.5 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 567: fert-Butyl 4-[({5-[(4-fluorophenyl)sulfonyl]-2- propylphenyl}sulfonyl)amino]piperidine~l-carboxylate

[0662] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2- propylbenzenesulfonyl chloride (0.38 g, 1.0 mmol) and 4-amino-piperidine-l-carboxylic acid, fert-butyl ester (0.40 g, 2.0 mmol) according to the procedure and in the same manner as described in Example 559, step c. The crude product was purified by preparative liquid chromatography on a Biotage 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 15%-50% methyl fert-butyl ether in hexane at a flow rate of 50 mL/min, to afford fert-butyl 4- [( { 5 -[^-fluorophenylisulfonyl] -2-propylphenyl > sulfonvDaminolpiperidine- 1 - carboxylate (0.46 g, 85%), as a homogeneous, colorless, crystalline solid, m.p. 151-153 ⁰ C; MS (-ESI), m/z: 539.1 [M-H] ^" ;

HRMS: calcd for C ₂₅ H ₃₃ FN ₂ O ₆ S ₂ + NH ₄ ⁺ , 558.21023; found (ESI, [M+NH4] ⁺ ), 558.208; HPLC purity 100% at 210-370 nm, 10.4 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 568: 2-isopropyl-5-{[4-(methylamino)phenyI]sulfonyl}-N-piperidin- 4- ylbenzenesulfonamide

[0663] 100 mg of tert-butyl 4-{[(2-isopropyl-5-{[4-

(methylamino)phenyl]sulfonyl}phenyl)sulfonyl]aniino}piperidi ne-l-carboxylate was added to 2 niL of 4M hydrochloric acid in dioxane and the precipitate was filtered giving the desired 2^ isopropyl-5- { [4-( ^" methylamino)phenyl]sulfonyl| -N-piperidin-4- ylbenzenesulfonamide. MS (ES+) m/z 452 MS (ES-) m/z 450 HRMS: calcd. for C ₂₁ H ₂₉ N ₃ O ₄ S ₂ + H ⁺ , 452.167776: found (ESI ₃ [m+H] ⁺ ), 452.166.

Example 569: 5-[(5-chIoro-l,3-dimethyl-lH ^r -pyrazol-4-yl)sulfonyl]-2-isopropyl-λ'- (tetrahydro-2 _J fiT-pyran-4-yl)benzenesulfonamide

[0664] In an analogous manner to Example 541,

[0665] Step 3: 5-bromo-2-isopropyl-iV-(tetrahydro-2H ^" -pyran-4-yl)benzenesulfonamide and 5-chloro-l,3-dimethyl-lH ^' -pyrazole-4-sulfonyl fluoride were used to prepare 5-[(5-chloro- l,3-dimethyl-li7-pyrazol-4-yl ^' )sulfonyl1-2-isopropγl-N-(tetrahvdro-2H ^" -pyran-4- vDbenzenesulfbnamide. MS (ES) m/z Al AA; ηRMS: calcd for C ₁₉ H ₂₆ ClN ₃ O ₅ S ₂ + H+, 476.10752; found (ESI, [M+H] ⁺ ), 476.1059.

Example 570: N-Cl-Phenylethy^-S-φhenylsulfony^^-Ctrifluoromethyl)- benzenesulfonamide

[0666] Step 1: l-Benzenesulfonyl-2-nitro-4-trifluomethyl-benzene: A mixture of 4- bromo-3-nitrobenzotriflluoride (10 mL, 65 mmol) and benzenesulfinic acid, sodium salt (10.77 g, 66 mmol) in 100 mL of DMF was stirred under nitrogen overnight at 80 ⁰ C. After cooling to room temperature the reaction was partitioned with water and methylene chloride. The organic layer was separated and the aqueous layer was extracted three times with methylene chloride. The combined extracts were dried (anhydrous MgSO ₄ ), filtered and the solvent was removed under reduced pressure to give l-benzenesulfonyl-2-nitro-4-trifluomethyl-benzene (21.52 g, 99%) as a white solid, mp 148-150°C.

[0667] Step 2: 2-Benzenesulfonyl-5-trifluoromethyl-phenylamine. A mixture of 1- benzenesulfonyl-2-nitro-4-trifluomethyl-benzene (10.21 g, 31 mmol), prepared in the previous

step and Tin(II) chloride (29.22 g, 160 mol) in 100 niL of methanol and 5 mL of water was stirred at reflux under nitrogen for three days. The methanol was removed under reduced pressure and then the residue was partitioned between methylene chloride and 2 N HCl. The organic layer was separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were dried (anhydrous MgSO ₄ ), filtered and the solvent removed under reduced pressure to give 2-benzenesulfonyl-5-trifluoromethyl-phenylamine (8.87g, 95%) as a white solid, mp 142-143 °C.

[0668] Step 3: [4-bromo-2-(phenylsulfonyl)-5-(trifluoromethyl)phenyl] amine. A mixture of 2-benzenesulfonyl-5-trifluoromethyl-phenylamine (3.87 g, 13 mmol), prepared in the previous step, benzyltrimethylammonium tribromide (5.02g, 13 mmol), and calcium carbonate (3.86 g, 40 mmol) in 100 mL methylene chloride and 50 mL of methanol was stirred under nitrogen overnight at room temperature. The solvent was removed under reduced pressure and then the residue was partitioned between methylene chloride and 2 N HCl. The organic layer was separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were dried (anhydrous MgSO ₄ ), filtered and the solvent removed under reduced pressure to produce 4.97 g of a yellow solid. The solid was taken up in methylene chloride and purified on a Horizon™ Flash Collector (Column: Biotage Si 40+M) using a linear gradient of 5% ethyl acetate-hexane to 100% ethyl acetate as the eluent. Isolation of the main component [4-bromo- 2-(phenylsulfonyl)-5-(trifluoromethyl)phenyl]amine (4.87g, 94%) as a light yellow solid, mp 169-171 ⁰ C; MS (ESI) m/z 380; MS (ESI) m/z 378;

[0669] Step 4: 4-Benzenesulfonyl-2-bromo-l-trifluoromethyl-benzene. A solution of Sodium Nitrite (918.9 mg, 13.3 mmol) in 20 mL of water was added under nitrogen at ice bath temperature drop wise over 15 minutes to a solution of [4-bromo-2-(phenylsulfonyl)-5- (trifluoromethyl)phenyl] amine (4.22 g, 11.1 mmol) prepared in the previous step in 200 mL of acetonitrile and 20 mL of concentrated sulfuric acid. After the addition the reaction was stirred at ice bath temperature for thirty minutes. 50% Hypophosphorous acid- water (11.5 mL, 110 mmol) was then added under nitrogen at ice bath temperature drop wise over 20 minutes to the stirring reaction and then was immediately capped and placed into the refrigerator overnight. The reaction was then partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed four times with water, dried (anhydrous MgSO ₄ ) and the solvent removed under reduced pressure to give 4-benzenesulfonyl-2-bromo-l-trifluoromethyl-benzene (3.20 g, 79%) as a yellow solid.

[0670] Step 5: S-Benzenesulfonyl^-trifluoromethyl-benzenesulfinic acid. Butyllithium (2.5 M solution in hexanes; 1.6 niL, 4.0 mmol) was added under nitrogen over approximately two minutes to a solution of 4-benzenesulfonyl-2-bromo-l-trifluoromethyl-benzene (1.0 g, 2.7 mmol) in 10 mL of anhydrous tetrahydrofuran at dry ice-acetone temperature. After the addition the reaction was stirred at dry ice-acetone temperature for one hour. After that time SO ₂ gas was bubbled into the reaction flask for approximately five minutes at dry ice-acetone bath temperature. After warming to room temperature the solvent and the excess SO ₂ were removed under reduced pressure and then the residue was partitioned between methylene chloride and 2 N HCl. The organic layer was separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were dried (anhydrous MgSO ₄ ), filtered and the solvent removed under reduced pressure to produce 0.77 g of brown solid.

[0671] Step 6: N-(2-phenylethyl)-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide. A mixture of 5-benzenesulfonyl-2-trifluoromethyl- benzenesulfϊnic acid (0.58 g, 1.6 mmol), prepared in the previous step, N-Chlorosuccinimide (0.26 g, 1.98 mmol), and triethylamine (0.7 mL, 5 mmol) in 30 mL methylene chloride was stirred under nitrogen for thirty minutes at room temperature. Phenethylamine (0.25 mL, 2 mmol) was slowly syringed into the flask and the reaction was stirred under nitrogen overnight at room temperature. The solvent was removed under reduced pressure and then the residue was partitioned between methylene chloride and 2 N HCl. The organic layer was separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were dried (anhydrous MgSO ₄ ), filtered and the solvent removed under reduced pressure to produce 0.82 g of brown solid. The solid was taken up in methylene chloride and purified on a Horizon™ Flash Collector (Column: Biotage Si 25+M) using a linear gradient of 5% methylene chloride-hexane to 100% methylene chloride as the eluent. Additional purification was done on 0.20 g of product with a Luna Cl 8 (50 x 250 mm) reverse phase column on a Varian HPLC system using 70% methanol / water mobile phase isocraticly at 100 ml/min. Isolation of the main component gave the title compound N-(2-phenylethyl)-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide (0.23 g, 35.4%), as a white solid mp 151-153 °C. MS (ES) m/z 468.1.

Example 571: 5-(Phenylsulfonyl)-N-(2-pyridin-2-ylethyl)-2- (trifluoromethyl)benzenesulfonamide

[0672] A mixture of 5-benzenesulfonyl-2-trifluoromethyl-benzenesulfinic acid (0.59 g, 1.7 mmol), prepared in the same manner as described in step 5 of Example 570, N- Chlorosuccinimide (0.27 g, 2.0 mmol), and triethylamine (0.7 mL, 5 mmol) in 30 ml methylene chloride was stirred under nitrogen for thirty minutes at room temperature. 2-(2- pyridyl)ethylamine (0.24 mL, 2 mmol) was slowly syringed into the flask and the reaction was stirred under nitrogen overnight at room temperature. The solvent was removed under reduced pressure and then the residue was partitioned between methylene chloride and 2 N HCl. The organic layer was separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were dried (anhydrous MgSO ₄ ), filtered and the solvent was removed under reduced pressure to produce 0.67 g of a dark brown solid. The solid was taken up in methylene chloride and purified on a Horizon™ Flash Collector (Column: Biotage Si 25+M) using a linear gradient of 5% methylene chloride-hexane to 100% methylene chloride as the eluent. Isolation of the main component gave the title compound 5-(phenylsulfonyl)-N-(2- pyridin-2-ylethyl)-2-(trifluoromethyl)benzenesulfonamide (75.5 mg, 9.6%) as a white solid, mp 149-151 °C; MS (ES) m/z 469.0.

Example 572: 5-[(4-fluorophenyI)suIfonyl]-2-isopropyl-N-[l-(morpholin-4- ylcarbonyl)piperidin- 4-yI]benzenesulfonamide

[0673] In an analogous manner to Example 462, 2-isopropyl-5-(phenylsulfonyl)-n- piperidin-4-ylbenzenesulfonamide and 4-morpholinecarbonyl chloride were used to prepare 5^ [(4-fluorophenyDsulfonyll-2-isopropyl-N-[l-rmorpholin-4-ylca rbonyπpiperidin- 4- ylibenzenesulfonamide. MS (ES+) m/z 554 MS (ES-) m/z 552 HRMS: calcd. for C ₂₅ H ₃₂ FN ₃ O ₆ S ₂ + H ⁺ , 554.179484: found (ESI, [m+H] ⁺ ), 554.1799.

Example 573 : 4- [({5- [(4-fluorophenyl)sulfonyl] -2-isopropy lphenyl} sulfony l)amino] -N,N- dimethylpiperidine-1-carboxamide

[0674] In an analogous manner to Example 462, 2-isopropyl-5-(phenylsulfonyl)-n- piperidin-4-ylbenzenesulfonamide and dimethylcarbamyl chloride were used to prepare 4- [({5-

r(4-fluorophenyl)sulfonyll-2-isopropylphenyl>sulfonyl) amino]-N,N- dimethylpiperidine-l- carboxamide.

MS (ES+) w/z 512

MS (ES-) m/z 510

HRMS: calcd. for C ₂₃ H ₃₀ FN ₃ O ₅ S ₂ + H ⁺ , 512.168919: found (ESI, [m+H] ⁺ ), 512.1692.

Example 574: N-(l~benzylpiperidin-4-yI)-5-[(4-fluorophenyl)suIfonyl]-2- methylbenzenesulfonamide

[0675] In an analogous manner to Example 435, 5-(4-fluoro-benzenesulfonyl)-2- methyl-benzenesulfonyl chloride and 4-amino-l-benzylpiperidine were used to prepare N-(I- benzylpiperidm-4-yl)-5-| ^" (4-fluorophenγl)sulfonyll-2- methylbenzenesulfonamide. MS (ES+) m/z 503 MS (ES-) m/z 501 HRMS: calcd. for C ₂₅ H ₂₇ FN ₂ O ₄ S ₂ + H ⁺ , 503.147455: found (ESI, [m+H] ⁺ ), 503.1489.

Example 575: 2-isopropyl-5-(phenylsulfinyl)-iV-(2-pyridiii-2-ylethyl)benz enesulfonamide

[0676] Step 1 : Following the same procedure as described in Example 474 (Stepl), 2- bromoisopropylbenzene was used to prepare 2-isopropyl-iV-(2-pyridin-2- ylethyPbenzenesulfonamide .

[0677] Step 2: Following the same procedure as described in Example 474 (Step2), 2- isopropyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide was used to prepare 5-bromo-2-isopropyl- N-(2-pyridin-2-ylethyl)benzenesulfonamide.

[0678] Step 3: Following the same procedure as described in Example 346, 5-bromo-2- isopropyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide, and benzenethiol were used to prepare 2^ isopropyl-5-(phenylsulfinyl)-JV-f2-pyridin-2-ylethyl)benzene sulfonamide. MS (ES) m/z 427.1; HRMS: calcd for C ₂₂ H ₂₄ N ₂ O ₃ S ₂ + H+ ₅ 429.13011; found (ESI, [M+H] ⁺ ), 429.1309.

Example 576: 5-[(4-fluorophenyl)sulfonyl]-2-methyl-N-piperidin-4-yIbenzen esulfonamide [0679] 200 mg of palladium on carbon were wetted with 30 mL of ethanol and 1.5 g of N-(l-benzylpiperidin-4-yl)-5-[(4-fluorophenyl)sulfonyl]-2- methylbenzenesulfonamide hydrochloride was added. The reaction was mixed on a Parr shaker at 45 psi overnight. The

reaction mixture was filtered through Celite ^® and the filtrate was concentrated down giving the desired 5-[(4-fluorophenyl)sulfonyl]-2-methyl-N-piperidin-4-ylbenzen esulfonamide.

MS (ES+) rø/z 413

MS (ES-) m/z 411

HRMS: calcd. for C ₁₈ H ₂₁ FN ₂ O ₄ S ₂ + H ⁺ , 413.100505: found (ESI, [m+H] ⁺ ), 413.0997.

Example 577: 5-[(3-bromo-2-methyIphenyl)suIfonyl]-2-isopropyI-A ^L (2-pyridin-2- ylethyl)benzenesulfonamide

[0680] Step 1 : Following the same procedure described in Example 334, 2-methyl-3- bromoaniline was used to prepare 2-methyl-3-bromobenzenesulfonyl chloride.

[0681] Step 2: Following the same procedure described in Example 474, 2-methyl-3- bromobenzenesulfonyl chloride was used to prepare 2-methyl-3-bromobenzenesulfonyl fluoride.

[0682] Step 4: Following the same procedure described in Example 474, 5-bromo-2- isopropyl-iV-(2-pyridin-2-ylethyl)benzenesulfonamide and 3-bromo-2-methylbenzene sulfonyl fluoride were used to prepare 5-[(3-bromo-2-methylphenyl)sulfonyll-2-isopropyl-A/-( ^' 2-pyridm- 2-ylethyl)benzenesulfonamide. MS (ESI) m/z 537; HRMS: calcd for C ₂₃ H ₂₅ BrN ₂ O ₄ S ₂ + H+, 537.05119; found (ESI, M+H), 537.0517.

Example 578: 5-[(2-chloro-6-methylphenyl)sulfonyl]-2-isopropyl-iV-(2-pyri din-2- ylethyl)benzenesulfonamide

[0683] Step 1 : Following the same procedure described in Example 474 (Step 3), 2- chloro-6-methylbenzene sulfonyl chloride was used to prepare 2-chloro-6-methylbenzene sulfonyl fluoride.

[0684] Step 2: Following the same procedure described in Example 474 (Step 4), 5- bromo-2-isopropyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide and 2-chloro-6-methylbenzene sulfonyl fluoride were used to prepare 5 - [(2-chloro-6-methylphenyl)sulfonyl1 -2-isopropyl-iV-(2- pyridin-2-ylethyl)benzenesulfonamide. MS (ESI) m/z 493; HRMS: calcd for C ₂₃ H ₂₅ ClN ₂ O ₄ S ₂ + H+, 493.10170; found (ESI, M+H), 493.1023.

Example 579: 2-isopropyl-5~[(3-methylphenyl)sulfonyl]-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0685] Step 1 : Following the same procedure described in Example 474 (Step 3), 3- methylbenzene sulfonyl chloride was used to prepare 3-methylbenzene sulfonyl fluoride.

[0686] Step 2: Following the same procedure described in Example 474 (Step 4), 5- bromo-2-isopropyl-N-(2~pyridin-2-ylethyl)benzenesulfonamide and 3-methylbenzene sulfonyl fluoride were used to prepare 2-isopropyl-5-r(3-memylphenyl)sulfonyl ^" |-N-(2-pyridin-2- ylethyl)benzenesulfonamide . MS (ESI) m/z 459; FIRMS: calcd for C ₂₃ H ₂₆ N ₂ O ₄ S ₂ + H+, 459.14067; found (ESI, M+H), 459.1412.

Example 580: 5-({4-[(2-cyanoethyl)(methyl)amino]phenyI}sulfonyI)-2-isopro pyI-iV- (tetrahydro-2Jϊ-pyran-4-yI)benzenesulfonamide

[0687] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-tetrahydro-2H-pyran-4-ylbenzenesulfonamide and 3-(methylamino)propionitrile in DMA were used to prepare 5 -( { 4- [(2-cyanoethy l)(methyDamino]pheny 1 } sulfony l)-2-isopropyl- ν-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide. MS (ESI) m/z 506;

HPLC purity 96.0% at 210-370 nm, 8.6 min.; 95.8% at 312 nm, 8.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₃₁ N ₃ O ₅ S ₂ + H+, 506.17779; found (ESI, [M+H]+), 506.1783.

Example 581: 5-({4-[(2-cyanoethyl)(methyl)amino]phenyl}sulfonyl)-2-isopro pyl-λ'- (tetrahydro-2jH ^r -pyran-4-ylmethyl)benzenesuIfonamide

[0688] In an analogous manner to Example 353, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-tetrahydro-2H-pyran-4-ylmethyl)benzenesulfonamid e and 3- (methylamino)propionitrile in DMA were used to prepare 5-({4-[(2- cvanoethyl)(methyl)amino]phenyl}sulfonyl)-2-isopropyl-ν-(te trahydro-2H-pyran-4- ylmethvDbenzenesulfonamide. MS (ESI) m/z 520; HPLC purity 96.3% at 210-370 nm, 8.8 min.; 96.0% at 312 nm, 8.8 min.; Xterra RP18, 3.5u, 150

x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₅ H ₃₃ N ₃ O ₅ S ₂ + H+, 520.19344; found (ESI, [M+H]+), 520.194.

Example 582: 5-[(4-fluorophenyl)sulfonyl]-iV-(2-hydroxyethyl)-2- isopropylbenzenesulfonamide

[0689] In an analogous manner to Example 230:

[0690] Step 3: 2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2-aminoethanol were used to prepare 5-r(4-fluorophenyl)sulfonyl]-N-(2-hydroxyethyl)-2- isopropylbenzenesulfonamide. MS (ESI +) m/z 402; MS (ESI -) m/z 400;

HPLC purity 100% at 210-370 nm, 8.3 min.; 100% at 242 nm, 8.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₇ H ₂₀ FNO ₅ S ₂ + H+, 402.08397; found (ESI, [M+H]+), 402.0845.

Example 583: 5-[(4-fluorophenyI)suIfonyl]-2-isopropyl-iV-[2-(2-methyI-li� �-imidazol-l- yl)ethyl]benzenesulfonamide

[0691] Step 1 : To a stirred solution of 5-[(4-fluorophenyl)sulfonyl]-N-(2- hydroxyethyl)-2-isopropylbenzenesulfonamide (0.6 mg, 1.5 mmol), triethylamine (2.2 mmol) and a catalytic amount of N,Ndimethylaminopyridine in dichloromethane was added 4- methylbenzenesulfonyl chloride (1.8 mmol) and after 4 hours an additional 1.8 mmol of 4- methylbenzene sulfonyl chloride was added. The reaction was concentrated and then purified by flash column chromatography using an ethyl acetate-hexane gradient affording predominately the N,O-bistosyl intermediate.

[0692] Step 2: 2-Methylimidazole (164 mg, 2 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL) and sodium hydride (60% mineral oil dispersion, 24 mg, 1 mmol) was added. After 30 minutes, a solution of the intermediate bistosylate (stepl, 0.14 mmol) in tetrahydrofuran was added and the reaction was allowed to stir at room temperature for 30 additional minutes. The mixture was quenched upon the addition of water. The mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic phases were concentrated and the

resulting crude residue was purified by automated flash column chromatography resulting in the recovery of 56 mg (85%) of 5-[(4-fluorophenyl)sulfonvn-2-isopropyl-N-[2-( ^' 2-methyl-lH- imidazol- 1 -yl)ethyl]benzenesulfonamide.

MS (ESI +) m/z 466;

MS (ESI -) w/z 464;

HPLC purity 100% at 210-370 nm, 7.5 min.; 100% at 244 nm, 7.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₁ H ₂₄ FN ₃ O ₄ S ₂ + H+, 466.12650; found (ESI, [M+H]+), 466.1271.

Example 584: 7V-[2-(2-ethyl-lH ^r -imidazol-l-yl)ethyI]-5-[(4-fluorophenyl)sulfonyl]-2- isopropylbenzenesulfonamide

[0693] In an analogous manner to Example 583 :

[0694] Step 2: 2- The bistosylate and 2-ethylimidazole were used to prepare N-[ ^" 2-(2- ethy 1- 1 H-imidazol- 1 -y Dethyl] -5 - [f 4-fluoropheny Dsulfonyl] -2-isopropy lbenzenesulfonamide. MS (ESI +) m/z 480; MS (ESI -) m/z 478;

HPLC purity 100% at 210-370 nm, 7.7 min.; 100% at 244 nm, 7.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₆ FN ₃ O ₄ S ₂ + H+, 480.14215; found (ESI, [M+H]+), 480.1427.

Example 585: N-(l-acetylpiperidm-4-yl)-5-[(4-fluorophenyl)sulfbnyl]-2- methylbenzenesulfonamide

[0695] In an analogous manner to Example 462, 5-[(4-fluorophenyl)sulfonyl]-2- methyl-N-piperidin-4-ylbenzenesulfonamide and acetic anhydride were used to prepare N-Cl- acetylpiperidin-4-yl)-5-[ ^" (4-fluorophenyl)sulfonyl]-2- methylbenzenesulfonamide. MS (ES+) rø/z 455 MS (ES-) m/z 453.

Example 586: N-[l-(4-cyanobenzoyl)piperidin-4-yl]-5-[(4-fluorophenyl)sulf onyl]-2- methylbenzenesulfonamide

[0696] In an analogous manner to Example 462, 5-[(4-fluorophenyl)sulfonyl]-2- methyl-N-piperidin-4-ylbenzenesulfonamide and 4-cyanobenzoyl chloride were used to prepare N- r 1 -f 4-cyanobenzoyl)piperidm-4-y 1] -5 - | ^" (4-fluorophenyl)sulfony 1] -2- methylbenzenesulfonamide. MS (ES+) m/z 542 MS (ES-) m/z 540.

Example 587: 4-[({5-[(4-fluorophenyl)sulfonyl]-2-methylphenyI}sulfonyI)am ino]-N,N- dimethylpiperidine-1-carboxamide

[0697] In an analogous manner to Example 462, 5-[(4-fluorophenyl)sulfonyl]-2- methyl-N-piperidin-4-ylbenzenesulfonamide and dimethylcarbamyl chloride were used to prepare 4-[({5-r(4-fluorophenyl)sulfonyll-2-methylphenyl>sulfonyl ^' )amino]-N,N- dimethy lpiperidine- 1 -carboxamide . MS (ES+) m/z 484 MS (ES-) m/z 482.

Example 588: 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-7V-[2-(2-isopropyl- ljH-imidazol-l- yl)ethyl]benzenesulfonamide

[0698] In an analogous manner to Example 583 :

[0699] Step 2: 2- The bistosylate and 2-isopropylimidazole were used to prepare 5-[(4- fluorophenylisulfonyll-σ-isopropyl-N-β-^-isopropyl-lH-imid azol-l- yDethyl]benzenesulfonamide . MS (ESI +) m/z 494; MS (ESI -) m/z 492;

HPLC purity 91.6% at 210-370 ran, 8.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₈ FN ₃ O ₄ S ₂ + H+, 494.15780; found (ESI, M+H), 494.1584.

Example 589: 5-[(4-fluorophenyl)sulfonyl]-N-[l-(methoxyacetyl)piperidin-4 -yl]-2- methylbenzenesulfonamide

[0700] In an analogous manner to Example 462, 5-[(4-fluorophenyl)sulfonyl]-2- methyl-N-piperidin-4-ylbenzenesulfonamide and methoxyacetyl chloride were used to prepare 5^ r(4-fluorophenyl)sulfonyl1-N-[l-(methoxyacetyl)piperidin-4-y l]-2- methylbenzenesulfonamide. MS (ES+) m/z 4S5 MS (ES-) m/z 483 HRMS: calcd. for C ₂₁ H ₂₅ FN ₂ O ₆ S ₂ + H ⁺ , 485.121634: found (ESI, [m+H] ⁺ ), 485.1216.

Example 590: 2-isopropyl-5-[(i?)-phenylsulfϊnyl]-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0701] Chiral separation of 2-isopropyl-5-(phenylsulfinyl)-iV-(2-pyridin-2- ylethyl)benzenesulfonamide using a prep chiral SFC column AD-H 35%methanol/65% CO ₂ at 50mL/min yielded ylethvDbenzenesulfonamide. MS (ES) m/z 426.9.

Example 591: 2-isopropyl-5-[(S)-phenylsulfinyl]-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0702] Chiral separation of 2-isopropy l-5-(phenylsulfmyl)-λ/-(2-pyridin-2- ylethyl)benzenesulfonamide using a prep chiral SFC column AD-H 35%methanol/65% CO ₂ at 50mL/min yielded 2-isopropyl-5-[6SVphenylsulfinyl]-N-(2-pyridin-2- ylethyPbenzenesulfonamide. MS (ES) m/z 426.9.

Example 592: 2-bromo-5-(phenylsulfonyl)-iV-(2-pyridiii-2-ylethyl)benzenes ulfonamide

[0703] Step 1: Following the same procedure described in Example 1 (Step 1), 4- nitrobromobenzene and chlorosulfonic acid were used to prepare 2-bromo-5- nitrobenzenesulfonyl chloride.

[0704] Step 2: Following the same procedure described in Example 1 (Step 2), 2-(2- ethylamino)pyridine and 2-bromo-5-nitrobenzenesulfonyl chloride were used to prepare 2c bromo-5-nitro-N-(2-pyridin-2-ylethyl)benzenesulfonamide.

[0705] Step 3: 2-bromo-5-nitro-N-(2-pyridin-2-ylethyl)benzenesulfonamide (1.5 g, 3.88 mmol) was dissolved in methanol (25 mL) and water (1 mL). Tin (II) chloride (3.68 g, 19.4

mmol) was added and the resulting solution was heated to 70 °C overnight. The solution was concentrated and partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated to give 2- bromo-5-amino-N-(2-pyridin-2-ylethyl)benzenesulfonamide (1.2 g, 87%).

[0706] Step 4: Following the same procedure described in Example 334 (Step 2), 2- bromo-5-amino-iV-(2-pyridin-2-ylethyl)benzenesulfonamide was used to prepare 4-bromo-3-(2- pyridin-2-yl-ethylsulfamoyl)-benzenesulfonyl chloride.

[0707] Step 5: To a stirred solution of aluminum chloride (1.82 g, 13.64 mmol) in nitrobenzene (40 mL), was added benzene (3 mL), and 4-bromo-3-(2-pyridin-2-yl- ethylsulfamoyl)-benzenesulfonyl chloride (1.0 g, 2.27 mmol) at 80 ⁰ C. The resulting mixture was stirred 4 days at 80 ⁰ C with daily addition of benzene (2 mL). The reaction was then cooled to room temperature, poured over ice and extracted with dichloromethane. The organic phase was concentrated and flash column separated with 50% ethyl acetate/ hexane to give 2-bromo-5- ( ^' phenylsulfonyl)-7V-( ^' 2-pyridin-2-ylethyDbenzenesulfonamide (0.23 g, 21%). MS (ES) m/z 478.8; HRMS: calcd for C ₁₉ H ₁₇ BrN ₂ O ₄ S ₂ + H+, 480.98859; found (ESI, M+H), 480.9891.

Example 593: 5-[(3-cyano-2-methylphenyI)sulfonyl]-2-isopropyl-λ'-(2-pyri din-2- ylethyl)benzenesulfonamide

[0708] In an analogous manner to Example 376, 5-[(3-bromo-2- methylphenyl)sulfonyl]-2-isopropyl-iV-(2-pyridin-2-ylethyl)b enzenesulfonamide was used to prepare 5-r(3-cyano-2-methylphenyl)sulfonyl]-2-isopropyl-iV-( ^' 2-pyridin-2- ylethypbenzenesulfonamide. MS (ES) m/z 481.9.

Example 594: 5-[(3-acetyl-2-methylphenyl)sulfonyl]-2-isopropyl-iV-(2-pyri din-2- ylethyl)benzenesulfonamide

[0709] In an analogous manner to Example 380, 5-[(3-bromo-2- methylphenyl)sulfonyl]-2-isopropyl-iV-(2-pyridin-2-ylethyl)b enzenesulfonamide was used to prepare 5-r( ^" 3-acetyl-2-methylphenyDsulfonyl]-2-isopropyl-iV-(2-pyridin-2 - ylethvDbenzenesulfonamide. MS (ES) m/z 499.0;

HRMS: calcd for C ₂₅ H ₂₈ N ₂ O ₅ S ₂ + H+, 501.15124; found (ESI ₅ M+H), 501.1518.

Example 595: 5-[(3-chloro-4-fluorophenyI)sulfonyI]-2-isopropyl-iV-(2~pyri din-2- ylethyl)benzenesulfonamide

[0710] Step 1 : Following the same procedure described in Example 474 (Step 3), 3- chloro-4-fluorobenzene sulfonyl fluoride was used to prepare 3-chloro-4-fluorobenzene sulfonyl fluoride.

[0711] Step 2: Following the same procedure described in Example 474 (Step 4), 5- bromo-2-isopropyl-iV-(2-pyridin-2-ylethyl)benzenesulfonamide and 3-chloro-4-fiuorobenzene sulfonyl fluoride were used to prepare 5 - \(3 -chloro-4-fluorophenyl)sulfony 1] -2-isopropy l-iV-(2- pyridin-2-ylethyDbenzenesulfonamide. MS (ESI) m/z 497; MS (ESI) m/z 495.

Example 596: 5-[(4-fluoro-2-methylphenyl)suIfonyl]-2-isopropyl-JV-(2-pyri din-2- ylethyl)benzenesulfonamide

[0712] Step 1 : Following the same procedure described in Example 474 (Step 3), 2- methyl-4-fluorobenzene sulfonyl chloride was used to prepare 2-methyl-4-fluorobenzene sulfonyl fluoride.

[0713] Step 2: Following the same procedure described in Example 474 (Step 4), 5- bromo-2-isopropyl-iV-(2-pyridin-2-ylethyl)benzenesulfonamide and 2-methyl-4-fluorobenzene sulfonyl fluoride were used to prepare 5-[f4-fluoro-2-methylphenyDsulfonyl]-2-isopropyl-N-(2- pyridin-2-ylethyl)benzenesulfonamide. MS (ES) m/z 474.9; HRMS: calcd for C ₂₃ H ₂₅ FN ₂ O ₄ S ₂ + H+, 477.13125; found (ESI, M+H), 477.1318.

Example 597: 2-isopropyl-5-[(l-methyl-lH ^r -indol-5-yl)sulfonyl]-λ^-(2-pyridin-2- ylethyl)benzenesulfonamide

[0714] Step 1 : To a stirred solution of 5-bromoindole (2.0 g, 10.2 mmol) in DMF (25 mL) at 0 °C was added sodium hydride (0.45 g, 60%, 11.22 mmol) and the resulting solution was stirred for 5 minutes. Methyl iodide (1.3 mL, 20.8 mmol) was added and the reaction was allowed to warm to room temperature. After 1 hr the reaction was quenched with a saturated

aqueous ammonium chloride solution and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to give crude l-methyl-5-bromoindole. This material was dissolved in THF (20 niL) and chilled to -78 ⁰ C. n-Butyl lithium 2.5 M in hexane (3.8 mL, 9.5 mmol) was added dropwise. After 10 minutes sulfur dioxide was bubbled into the reaction mixture for 5 minutes. The mixture was allowed to warm to room temperature and concentrated. The crude mixture was taken up in methylene chloride (20 mL) and N-bromosuccinimide (1.25 g, 9.36 mmol) was added and the resulting solution was stirred for 1 hr. The solution was washed with a saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The mixture was flash column separated using 20% ethyl acetate/ hexane to give 1 -methylindole-5 - sulfonyl chloride (0.64 g, 27%).

[0715] Step 2: Following the same procedure described in Example 474 (Step 3), 1- methylindole-5-sulfonyl chloride was used to prepare 1 -methylindole-5-sulfonyl fluoride.

[0716] Step 3: Following the same procedure described in Example 474 (Step 4), 5- bromo-2-isopropyl-iV-(2-pyridin-2-ylethyl)benzenesulfonamide and 1 -methylindole-5-sulfonyl fluoride were used to prepare 5-[r4-fluoro-2-methylphenyl)sulfonyl]-2-isopropyl-N-(2-pyrid in-2- ylethypbenzenesulfonamide . MS (ESI) m/z 498; MS (ESI) m/z 496.

Example 598: 2-isopropyl-5-[(3-methoxyphenyl)sulfonyl]-iV-(tetrahydro-2J� �-pyran-4- yl)benzenesulfonamide

[0717] Step 1 : Following the same procedure described in Example 474 (Step 3), 3- methoxybenzene sulfonyl chloride was used to prepare 3-methoxybenzenesulfonyl fluoride.

[0718] Step 2: 3-methoxybenzenesulfonyl fluoride and 5-bromo-2-isopropyl-N- (tetrahydro-2H ^" -pyran-4-yl)benzenesulfonamide were used to prepare 2-isopropyl-5-[(3- methoxyphenyl)sulfonyl1-7V-rtetrahydro-2H-pyran-4-yl)benzene sulfonamide. MS (ESI) m/z 454; MS (ESI) m/z 452.

Example 599: 2-isopropyl-5-{[2-methyl-4-(methylamino)phenyl]sulfonyI}-7V- (2-pyridin-2- ylethyl)benzenesulfonamide

[0719] In an analogous manner to Example 356, 5-[(4-fluoro-2- methylphenyl)sulfonyl]-2-isopropyl-N-(2-pyridin-2-ylethyl)be nzenesulfonamide was used to prepare 2-isopropyl-5-{[2-methyl-4-( ^' methylamino)phenyl1sulfonyl}-iV-r2-pyridin-2- ylethvDbenzenesulfonamide . MS (ESI) m/z 488; MS (ESI) m/z 486.

Example 600: 5-{[4-(dimethylamino)-2-methyIphenyl]sulfonyl}-2-isopropyl-i V-(2-pyridin- 2-ylethyl)benzenesulfonamide

[0720] In an analogous manner to Example 353, 5-[(4-fluoro-2- methylphenyl)sulfonyl]-2-isopropyl-N-(2-pyridin-2-ylethyl)be nzenesulfonamide was used to prepare 5-{[4-(dimethylammoV2-methylphenyllsulfonyl|-2-isopropyl-N-( 2-pyridin-2- ylethyDbenzenesulfonamide. MS (ES) m/z 500.1; HRMS: calcd for C ₂₅ H ₃₁ N ₃ O ₄ S ₂ + H+, 502.18287; found (ESI-FTMS, [M+H] ¹⁺ ), 502.18264.

Example 601 : 2-(dimethylamino)-5-(phenylsulfonyI)-iV-(2-pyridm-2- ylethyl)benzenesulfonamide

[0721] Step 1 : Following the same procedure described in Example 1 (Step 1), A- nitrobromobenzene and chlorosulfonic acid were used to prepare 2-bromo-5- nitrobenzenesulfonyl chloride.

[0722] Step 2: Following the same procedure described in Example 1 (Step T), 2-(2- ethylamino)pyridine and 2-bromo-5-nitrobenzenesulfonyl chloride were used to prepare 2^ bromo-5-nitro-iV-(2-pyridin-2-ylethyl)benzenesulfonamide.

[0723] Step 3 : 2-bromo-5-nitro-N-(2-pyridin-2-ylethyl)benzenesulfonamide ( 1.5 g, 3.88 mmol) was dissolved in dimethylamine 2.0 M in THF (10 mL) and the resulting solution was microwave heated for 10 mintues at 160 °C. The solution was diluted with ethyl acetate and washed with a saturated aquous ammonium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 2-dimethylamino-5-m ^' tro-iV-f2-pyridin-2- ylethvDbenzenesulfonamide (1.3 g, 95%).

[0724] Step 4: Following the same procedure described in Example 592 (Step 3), 2- dimethylamino-5-nitro-N-(2-pyridin-2-ylethyl)benzenesulfonam ide was used to prepare 2_r dimethylamino-5-ammo-7V-(2-pyridin-2-ylethyl)benzenesulfonam ide.

[0725] Step 5: To a stirred solution of 2-dimethylamino-5-amino-N-(2-pyridin-2- ylethyl)benzenesulfonamide (0.60 g, 1.87 mmol) in acetonitrile (15 mL) and hydrobromic acid 48% (1.5 mL) at 0 ⁰ C was added sodium nitrite (0.16 g, 2.2 mmol) dissolved in a minimum amount of water dropwise. The resulting solution was stirred 20 minutes and copper I bromide (0.36 g, 2.5 mmol) was added and stirred 1 hr. The solution was diluted with water, neutralized with sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 2-dimethylamino-5-bromo-N-(2-pyridin-2- ylethvDbenzenesulfonamide (0.49 g, 81%).

[0726] Step 6: Following the same procedure described in Example 474 (Step 4), 2- dimethylamino-5-bromo-iV-(2-pyridin-2-ylethyl)benzenesulfona mide and benzene sulfonyl fluoride were used to prepare 2-(dimethylamino)-5-Cphenylsulfonyl)-N-(2-pyridin-2- ylethyDbenzenesulfonamide. MS (ES) m/z 444.1; HRMS: calcd for C ₂₁ H ₂₃ N ₃ O ₄ S ₂ + H+, 446.12027; found (ESI-FTMS, [M+H] ¹⁺ ), 446.1205

Example 602: N-[l-(cycIopropyIcarbonyl)piperidin-4-yl]-N-({5-[(4-fluoroph enyl)sulfonyl]- 2- methylphenyl}sulfonyl)cyclopropanecarboxamide

[0727] In an analogous manner to Example 462, 5-[(4-fluorophenyl)sulfonyl]-2- methyl-N-piperidin-4-ylbenzenesulfonamide and cyclopropylcarbonyl chloride were used to prepare N-[l-(cvclopropylcarbonyl)piperidin-4-yl1-N-({5-|T4-fluoroph enyl ^' )sulfonyl]-2- methylphenyllsulfonvDcyclopropanecarboxamide. MS (ES+) m/z 549.

Example 603: 5-[(4-fluorophenyl)sulfonyl]-2-methyI-N-[l-(morpholin-4- ylcarbonyl)piperidin-4- yl] benzenesulfonamide

[0728] In an analogous manner to Example 462, 5-[(4-fluorophenyl)sulfonyl]-2- methyl-N-piperidin-4-ylbenzenesulfonamide and 4-morpholinecarbonyl chloride were used to prepare 5-r(4-fluorophenyl)sulfonyl]-2-methyl-N-[l-( ^' morpholin-4-ylcarbonyl ^' )piperidin-4- yllbenzenesulfonamide.

MS (ES+) m/z 526 MS (ES-) m/z 524.

Example 604: 2-chIoro-5-[(3-methylphenyl)sulfonyl]-iV-(tetrahydro-2i- ^r -pyran-4- yl)benzenesulfonamide

[0729] Step 1 : Following the same procedure described in Example 1 (Step 2), 4- aminotetrahydropyran and 2-chloro-5-nitiObenzenesulfonyl chloride were used to prepare 5^ nitro-2-chloro-iV-(tetrahydro-2/j ^' -pyran-4-yl)benzenesulfonamide.

[0730] Step 2: Following the same procedure described in Example 592 (Step 3), 5- nitro-2-chloro-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamid e was used to prepare 5-amino-2- chloro-N-rtetrahvdro-2H-pyran-4-yl)benzenesulfonamide.

[0731] Step 3: Following the same procedure described in Example 601 (Step 5), 5- amino-2-chloro-iV-(tetrahydro-2H-pyran-4-yl)benzenesulfonami de was used to prepare 5-bromo- 2-chloro-iV-(tetrahydro-2H ^' -pyran-4-yDbenzenesulfonamide.

[0732] Step 4: Following the same procedure described in Example 474 (Step 3), 3- methylbenzene sulfonyl chloride was used to prepare 3 -methylbenzenesulfony 1 fluoride.

[0733] Step 5: Following the same procedure described in Example 474 (Step 4), 5- bromo-2-chloro-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamid e and 3-methylbenzene sulfonyl fluoride were used to prepare 2-chloro-5-[(3-methylphenvπsulfonyl1-7V ^" -(tetrahydro-2H- pyran-4-vDbenzenesulfonamide. MS (ES) m/z 428.0.

Example 605 : 5- { [3-chloro-4-(methylamino)phenyl] sulfonyl} -2-isopropyl-iV-(2-py ridin-2- ylethyl)benzenesulfonamide

[0734] In an analogous manner to Example 356, 5-[(3-chloro-4-fluorophenyl)sulfonyl]- 2-isopropyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide was used to prepare 5-{| ^" 3-chloro-4- (methylamino)phenyllsulfonyl}-2-isopropyl-N-(2-pyridin-2-yle thyl)benzenesulfonamide. MS (ES) m/z 506.1.

Example 606: 2-chloro-5-[(3-methoxyphenyl)sulfonyl]-λ'-(tetraliydro-2i?- pyran-4- yl)benzenesulfonamide

[0735] Step 1 : Following the same procedure described in Example 474 (Step 3), 3- methoxybenzene sulfonyl chloride was used to prepare 3 -methoxybenzenesulfony 1 fluoride.

[0736] Step 2: Following the same procedure described in Example 474 (Step 4), 5- bromo-2-chloro-iV-(tetrahydro-2/i ^' -pyran-4-yl)benzenesulfonamide and 3-methoxybenzene sulfonyl fluoride were used to prepare 2-chloro-5 - [(3 -methoxypheny Dsulfony 1] -iV-ftetrahy dro- 2H ^~ -pyran-4-yl)benzenesulfonamide. MS (ES) m/z 444.0.

Example 607: 2-chIoro-5- [(l-methyl-LH-indol-5-yl)sulfonyl] -iV-(tetrahy dro-2H-pyran-4- yl)benzenesulfonamide

[0737] In an analogous manner to Example 597,

[0738] Step 3: 5-bromo-2-chloro-iV-(tetrahydro-2H-pyran-4-yl)benzenesulfona mide was used to prepare 2-chloro-5-[(l-methyl-liJ ^r -indol-5-yl ^' )sulfonyl]-N-(tetrahydro-2iJ ^r -pyran-4- yDbenzenesulfonamide. MS (ES) m/z 467.0.

Example 608: 5-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)-2- (trifluoromethyl)benzenesulfonamide

[0739] A mixture of 5-Berizenesulfonyl-2~trifluoromethyl-benzenesulfinic acid (0.47 g, 1.35 mmol), prepared in the same manner as described in step 5 of Example 570, N- Chlorosuccinimide (0.18 g, 1.36 mmol), and triethylamine (0.38 mL, 2.7 mmol) in 20 mL methylene chloride was stirred under nitrogen for thirty minutes at room temperature. Tetrahydro-2H-pyran-4-amine (0.14 g, 1.35 mmol) was slowly syringed into the flask and the reaction was stirred under nitrogen overnight at room temperature. The solvent was removed under reduced pressure and then the residue was partitioned between methylene chloride and 2 N HCl. The organic layer was separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were dried (anhydrous MgSO ₄ ), filtered and the solvent removed under reduced pressure to produce 0.51 g of a dark brown solid. The solid was taken up in methylene chloride and purified on a Horizon™ Flash Collector (Column: Biotage Si 25+M) using a linear gradient of 5% methylene chloride-hexane to 100% methylene chloride as the eluent. Isolation of the main component gave the title compound 5-(phenylsulfonyl)-N-

(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)benzenesulf onamide (55.1 mg, 10%) as a white solid, mp 155-158 °C.

MS (ES) m/z 448.0;

Anal. Calcd for C ₁₈ H ₁₈ F ₃ NO ₅ S ₂ : C, 48.10; H, 4.04; N, 3.12. Found: C, 48.12; H, 3.81; N, 2.88.

Example 609: 2,4-Diisopropyl-iV-(2-phenylethyl)-5-(phenylsulfonyl)benzene sulfonamide [0740] Step a) 2,4-Diisopropyl-l-(phenylsulfonyl)benzene

[0741] A stirred solution of 1,3-diisopropylbenzene (16.25 g, 100 mmol) and benzenesulfonyl chloride (8.8 g, 50 mmol) was cooled to -20 ⁰ C and treated slowly under nitrogen with solid anhydrous aluminum chloride (8.O g, 60 mmol). After stirring neat for 4 hours at room temperature, the mixture was poured slowly into ice water and extracted with ethyl acetate (2x). The organic phase was washed with a saturated, aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered through a short column of silica gel. The filtrate was evaporated in vacuo to yield a crude oil. The crude oil was purified by preparative liquid chromatography on a Biotage ^® 40 Mi column of pre-packed silica gel (90 g) (multiple runs), eluting with a gradient of 0%-25% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford 2,4-diisopropyl- 1 -(phenylsulfonvPbenzene (5.07 g, 33%), as a clear oil which crystallized on standing to a homogeneous, amorphous solid, m.p. 105-107 °C; MS (-ESI), m/z: 301 [M-FfT;

HRMS: calcd for C ₁₈ H ₂₂ O ₂ S, 302.13405; found (EI, M+.), 302.1332; HPLC purity 100% at 210-370 ran, 10.5 min.; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. [0742] Step b) 2,4-Diisopropyl-5-(phenylsulfonyl)benzenesulfonyl chloride [0743] 2,4-Diisopropyl-l-(phenylsulfonyl)benzene (3.01 g, 10 mmol) was heated with stirring at 60 °C for 30 minutes under nitrogen with chlorosulfonic acid (6.7 mL, 11.7 g, 100 mmol). The mixture was cooled to room temperature, poured slowly into a cold solution of IN hydrochloric acid, and extracted with ethyl acetate (2x.). The organic phase was washed with a saturated, aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent concentrated in vacuo to a crude oil. The crude oil was crystallized from diethyl ether-hexane to afford 2,4-diisopropyl-5-(phenylsulfonvDbenzenesulfonyl chloride (2.92 g, 73%) as a colorless, crystalline solid, which was utilized in subsequent reactions.

[0744] Step c) 2,4-Diisoρroρyl-N-(2-phenylethyl)-5- (phenylsulfonyl)benzenesulfonamide

[0745] A stirred solution of 2,4-diisopropyl-5-(phenylsulfonyl)benzenesulfonyl chloride (0.20 g, 0.5 mmol) in dichloromethane (10 mL) was treated dropwise under nitrogen with a solution of phenethylamine (0.12 g, 1.0 mmol) in dichloromethane. After stirring for one hour at room temperature or until the reaction was complete, the mixture was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-25% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min. After evaporation of the solvent under vacuum, the title compound, 2,4-diisopropyl-iV-(2- phenylethyiy5-(phenylsulfonyl)benzenesulfonamide (0.22 g, 90%), was obtained as a homogeneous, colorless, crystalline solid, m.p. 156-158 °C; MS (-ESI), m/z: 483.9.1 [M-H] ^" ;

HRMS: calcd for C ₂₆ H ₃₁ NO ₄ S ₂ + H+, 486.17673; found (ESI, [M+H] ⁺ ), 486.1773; HPLC purity 100% at 210-370 nm, 10.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 610: 2,4-Diisopropyl-5-(phenylsulfonyl)-iV-(tetrahydro-2jH ^r -pyran-4- yl)benzenesulfonamide

[0746] The title compound was prepared from 2,4-diisopropyl-5-

(phenylsulfonyl)benzenesulfonyl chloride (0.20 g, 0.5 mmol) and tetrahydro-pyran-4-ylamine (0.10 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 609, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 30%-70% methyl tert- butyl ether in hexane at a flow rate of 50 mL/min, to afford 2,4-diisopropyl-5-(phenylsulfonyl> iV-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide (0.20 g, 87%), as a homogeneous, colorless, crystalline solid, m.p. 159-160 °C; MS (εSI), m/z: 464.0 [M-H] ^" ;

HRMS: calcd for C ₂₃ H ₃₁ NO ₅ S ₂ + H+, 466.17164; found (ESI, M+H), 466.1722; HPLC purity 100% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 611: 2,4~Diisopropyl~5-(phenyIsulfonyl)-iV-(tetrahydro-2/Z-pyran- 4- ylmethyl)benzenesulfonamide

[0747] The title compound was prepared from 2,4-diisopropyl-5- (phenylsulfonyl)benzenesulfonyl chloride (0.20 g, 0.5 mmol) and (tetrahydro-pyran-4- yl)methylamine (0.12 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 609, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 30%-70% methyl fert-butyl ether in hexane at a flow rate of 50 rnL/min, to afford 2,4-diisopropyl-5-(phenylsulfonyl)-A/-(tetrahvdro-2iJ ^' -pyran-4-ylmethyl)benzenesulfonamide (0.22 g, 93%), as a homogeneous, colorless, crystalline solid, m.p. 148-150 °C; MS (+ESI), m/z: 480 [M+H] ⁺ ; MS (-ESI), m/z: 478 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 612: 2,4-Diisopropyl-5-(phenylsulfonyl)-iV-[2-(tetrahydro-2iϊ-py ran-4- y l)ethyl] benzenesulf onamide

[0748] The title compound was prepared from 2,4-diisopropyl-5- (phenylsulfonyl)benzenesulfonyl chloride (0.20 g, 0.5 mmol) and 2-(tetrahydro-pyran-4- yl)ethylamine (0.12 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 609, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 30%-70% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford 2,4-diisopropyl-5-fphenylsulfonylVN-[2-(tetrahydro-27i-pyran -4-yDethyl1benzenesulfonamide (0.23 g, 91%), as a homogeneous, colorless, crystalline solid, m.p. 90-92 °C; MS (+ESI), m/z: 494 [M+H] ⁺ ; MS (-ESI), m/z: 492 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 10.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 613: λ ^f -CyclopentyI-2,4-diisopropyl-5-(phenylsulfonyl)benzenesulfon amide

[0749] The title compound was prepared from 2,4-diisopropyl-5-

(phenylsulfonyl)benzenesulfonyl chloride (0.20 g, 0.5 mmol) and cyclopentylamine (0.09 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 609, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-25% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford N-cy clopentyl-2 ,4-diisopropy 1-5 - (phenylsulfonyl)benzenesulfonamide (0.17 g, 76%), as a homogeneous, colorless, crystalline solid, m.p. 179-181 ⁰ C; MS (+ESI), m/z: 450 [M+H] ⁺ ; MS (-ESI), m/z: 448 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min.

Example 614: 2,4-Diisopropyl-5-(phenylsulfonyl)-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0750] The title compound was prepared from 2,4-diisopropyl-5-

(phenylsulfonyl)benzenesulfonyl chloride (0.20 g, 0.5 mmol) and 2-(pyridin-2-yl)ethylamine (0.12 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 609, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 50%-100% methyl tert- butyl ether in hexane at a flow rate of 50 mL/min, to afford 2,4-diisopropyl-5-(phenylsulfonyl)- A/-(2-pyridin-2-ylethyDbenzenesulfonamide (0.21 g, 84%), as a homogeneous, colorless, crystalline solid, m.p. 189-191 ⁰ C; MS (+ESI), m/z: 487 [M+H] ⁺ ; MS (-ESI), m/z: 485 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=θ.5/ACN+MeOH) for lOmin, hold 4min.

Example 615: λ^-[3-(liϊ-Imidazol-l-yl)propyl]-2,4-diisopropyl-5- (phenylsulfonyl)benzenesulfonamide

[0751] The title compound was prepared from 2,4-diisopropyl-5- (phenylsulfonyl)benzenesulfonyl chloride (0.20 g, 0.5 mmol) and 3-(lH-imidazol-l-

yl)propylamine (0.13 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 609, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-4% methanol in dichloromethane at a flow rate of 50 mL/min, to afford N- [3- (lH ^' -imidazol-l-yl ^' )propyl1-2,4-diisopiOpyl-5-( ^' phenylsulfonyl)ben2enesulfonamide (0.07 g, 27%), as a homogeneous, colorless, crystalline solid, m.p. 203-205 °C; MS (-ESI), m/z: 488.2 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 8.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 616: 2,4-Diisopropyl-5-(phenylsulfonyl)-iV-(2-pyridin-3- ylethyl)benzenesulfonamide

[0752] The title compound was prepared from 2,4-diisopropyl-5-

(phenylsulfonyl)benzenesulfonyl chloride (0.20 g, 0.5 mmol) and 2-(pyridin-3-yl)ethylamine (0.12 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 609, step c. The crude product was purified by preparative liquid chromatography on a Biotage " 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 50%- 100% methyl tert- butyl ether in hexane at a flow rate of 50 mL/min, to afford 2,4-diisopropyl-5-( ^' phenylsulfonylV iV-(2-pyridin-3-ylethyl)benzenesulfonamide (0.15 g, 60%), as a homogeneous, colorless, crystalline solid, m.p. 163-165 ⁰ C; MS (-ESI), m/z: 485.2 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 617: 2,4-Diisopropyl-5-(phenylsulfonyl)-iV-(2-pyridin-4- ylethyl)benzenesulfonamide

[0753] The title compound was prepared from 2,4-diisopropyl-5-

(phenylsulfonyl)benzenesulfonyl chloride (0.20 g, 0.5 mmol) and 2-(pyridin-4-yl)ethylamine (0.12 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 609, step c. The crude product was purified by preparative liquid chromatography on a Biotage ¹¹ 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 50%- 100% methyl tert- butyl ether in hexane at a flow rate of 50 mL/min, to afford 2,4-diisopropyl-5-(phenylsulfonyl>

iV-( ^' 2-pyridin-4-ylethyl)benzenesulfonamide ( ^" 0.12 g, 49%), as a homogeneous, colorless, crystalline solid, m.p. 178-180 °C;

MS (-ESI), m/z: 485.1 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 618: A'-(2,3-Dihydro-l _J fir-inden-2-yl)-2,4-diisopropyl-5- (phenylsulfonyl)benzenesulfonamide

[0754] The title compound was prepared from 2,4-diisopropyl-5-

(phenylsulfonyl)benzenesulfonyl chloride (0.20 g, 0.5 mmol) and indan-2-ylamine (0.13 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 609, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-25% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford N-(2,3-dihvdro-lH ^~ -inden-2-yl)-2,4-diisopropyl- 5-fphenylsulfonyl ^* )benzenesulfonamide (0.22 g, 90%), as a homogeneous, colorless, crystalline solid, m.p. 215-217 ⁰ C; MS (-ESI), m/z: 496.1 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 11.0 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min.

Example 619: 5-[(4-FIuorophenyl)sulfonyl]-2,4-diisopropyl-iV-(2- phenylethyl)benzenesulfonamide

[0755] Step a) l-[(4-Fluorophenyl)sulfonyl]-2,4-diisopropylbenzene [0756] A stirred solution of 1,3-diisopropylbenzene (16.25 g, 100 mmol) and 4- fluorobenzenesulfonyl chloride (9.73 g, 50 mmol) was cooled to -20 °C and treated slowly under nitrogen with solid anhydrous aluminum chloride (8.0 g, 60 mmol). After stirring neat for 4 hours at room temperature, the mixture was poured slowly into ice water and extracted with ethyl acetate (2x). The organic phase was washed with a saturated, aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered through a short column of silica gel. The filtrate was evaporated in vacuo to yield a crude oil. The crude oil was purified by preparative liquid chromatography on a Biotage ^® 40 Mi column of pre-packed silica gel (90 g) (multiple runs), eluting with a gradient of 0%-25% methyl tert-butyl ether in hexane at a flow rate of 50

■ mL/min, to afford l-[ ^" (4-fluorophenyl)sulfonyl1-2,4-diisopropylbenzene (9.71 g, 60%), as a clear oil which crystallized on standing to a homogeneous, amorphous solid, m.p. 75-80 °C; MS (EI), m/z: 320 [M] ⁺ ;

HRMS: calcd for C ₁₈ H ₂₁ FO ₂ S, 320.12463; found (ESI, M+.), 320.1237; HPLC purity 100% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

[0757] Step b) 5-[(4-Fluorophenyl)sulfonyl]-2,4-diisopropylbenzenesulfonyl chloride

[0758] l-[(4-Fluorophenyl)sulfonyl]-2,4-diisopropylbenzene (3.20 g, 10 mmol) was heated with stirring at 60 ⁰ C for 30 minutes under nitrogen with chlorosulfonic acid (6.7 mL, 11.7 g, 100 mmol). The mixture was cooled to room temperature, poured slowly into a cold solution of IN hydrochloric acid, and extracted with ethyl acetate (2x). The organic phase was washed with a saturated, aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent concentrated in vacuo to a crude oil. The crude oil was crystallized from diethyl ether-hexane to afford 5-[(4-fluorophenyDsulfonyl]-2,4-diisopropylbenzenesulfonyl chloride (3.11 g, 74%) as a colorless, crystalline solid, which was utilized in subsequent reactions.

[0759] Step c) 5-[(4-Fluorophenyl)sulfonyl]-2,4-diisopropyl-N-(2- phenylethyl)benzenesulfonamide

[0760] A stirred solution of 5-[(4-fluorophenyl)sulfonyl]-2,4- diisopropylbenzenesulfonyl chloride (0.21 g, 0.5 mmol) in dichloromethane (10 mL) was treated dropwise under nitrogen with a solution of phenethylamine (0.12 g, 1.0 mmol) in dichloromethane. After stirring for one hour at room temperature or until the reaction was complete, the mixture was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-25% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min. After evaporation of the solvent under vacuum, the title compound, 5-r(4-fluorophenyl ^' )sulfonyl]-2,4-diisopropyl-N-f2-phenylethyl)benzenesulfonami de (0.24 g, 95%), was obtained as a homogeneous, colorless, crystalline solid, m.p. 154-156 °C; MS (-ESI), m/z: 502 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 10.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

ExampIe 620: 5-[(4-Fluorophenyl)sulfonyl]-2,4-diisopropyl-iV-(tetrahydro- 2Jϊ-pyran-4- yl)benzenesulfonamide

[0761] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyi]-2,4- diisopropylbenzenesulfonyl chloride (0.32 g, 0.75 mmol) and tetrahydro-pyran-4-ylamine (0.15 g, 1.5 mmol) according to the procedure and in the same manner as described in Example 619, step c. The crude product was purified by preparative liquid chromatography on a Biotage ' 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 30%-70% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford 5- [(4-fluoropheny Dsulfonyll -2,4- diisopropyl-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide (0.31 g, 86%), as a homogeneous, colorless, crystalline solid, m.p. 183-186 ⁰ C; MS (-ESI), m/z: 481.8 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 621: iV-CyclopentyI-5-[(4-fluorophenyl)sulfonyl]-2,4- diisopropylbenzenesulfonamide

[0762] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2,4- diisopropylbenzenesulfonyl chloride (0.21 g, 0.5 mmol) and cyclopentylamine (0.09 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 619, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-25% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford N-cyclopen1yl-5-[(4-fluorophenvDsulfonyl]-2,4- diisopropylbenzenesulfonamide (0.20 g, 85%), as a homogeneous, colorless, crystalline solid, m.p. 202-205 °C; MS (-ESI), m/z: 465.7 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 10.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 622: 2-chIoro-5-[(4-fluorophenyl)sulfonyl]-λ ^r -(tetrahydro-2fi-pyran-4- yl)benzenesulfonamide

[0763] Step 1 : Following the same procedure described in Example 474 (Step 3), 4- fluorobenzene sulfonyl chloride was used to prepare 4-fluorobenzenesulfonyl fluoride.

[0764] Step 2: Following the same procedure described in Example 474 (Step 4), 5- bromo-2-chloro-iV-(tetrahydro-2H ^" -pyran-4-yl)benzenesulfonamide and 4-fluorobenzene sulfonyl fluoride were used to prepare 2-chloro-5-r(4-fluorophenyDsulfonvn-iV-( ^' tetrahvdro-2i ^: /-pyran-4- yDbenzenesulfonamide. MS (ES) m/z 432.0.

Example 623: tert-hntyl 4-({[2-chloro-5-(phenylsulfonyl)phenyl] sulfonyl} amino)piperidine- 1-carboxylate

[0765] In an analogous manner to Example 334,

[0766] Step 3: 4-aminopiperidine-l- carboxylic acid tert-butyl ester was used to prepare tert-butyM-dβ-chloro-S-rphenylsulfonvDphenyllsulfonyljamino ^' jpiperidine-l-carboxylate. MS (ES) m/z 513.1.

Example 624: 2-chloro-5-(phenylsulfonyl)-iV-piperidin-4-ylbenzenesulfonam ide

[0767] tert-butyl 4-({ [2-chloro-5-(phenylsulfonyl)phenyl]sulfonyl} amino)piperidine-l - carboxylate (0.65 g, 1.26 mmol) was stirred in HCl 4 M in dioxane (5 rnL) for 1 hr. The mixture was neutralized with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 2-chloro-5-( ^' phenylsulfonyl ^' )-A/ ^' -piperidin-4-ylbenzenesulfonamide (0.37 g, 70%). MS (ES) m/z 412.9.

Example 625: tert-butyl 4-[4-({4-isopropyl-3-[(tetrahydro-2/2 ^r -pyran-4- ylamino)sulfonyl]phenyl}sulfonyl)phenyl]piperazine-l-carboxy late

[0768] In an analogous manner to Example 547, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-tetrahydro-2H-pyran-4-ylbenzenesulfonamide, piperazine-1 -carboxylic acid tert- butyl ester, and dimethylacetamide as solvent were used to prepare tert-butyl 4-[4-f {4-isopropyl- 3-[ ^" (tetrahvdro-2H-pyran-4-ylamino)sulfonyl]phenyllsulfonyl) phenyllpiperazine-l-carboxylate. MS (ESI +) m/z 608;

HPLC purity 97.2% at 210-370 nm, 10.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph-3.5/ACN+MeOH) for lOmin, hold 4min.

Example 626: 5-({4-c/s-3,5-dimethyIpiperazin-l-ylphenyl}sulfonyl)-2-isopr opyI-λ ^r - (tetrahydro-2 _J H ^r -pyran-4-yl)benzenesulfonamide

[0769] In an analogous manner to Example 547, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-iV-tetrahydro-2H-pyran-4-ylbenzenesulfonamide, cw-2,6-dimethylpiperazine, and dimethylacetamide as solvent were used to prepare 5 -( (4-cis-3 , 5 -dimethy lpiperazin- 1 - ylphenyUsulfonyl)-2-isopropyl-N-(tetrahvdro-2H-pyran-4-yl)be nzenesulfonamide. MS (ESI +) m/z 536;

HPLC purity 100% at 210-370 ran, 7.2 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 627: 5-({4-/rαM5-2,5-dimethylpiperazin-l-ylphenyl}sulfonyl)-2-is opropyl-A'- (tetrahydro-2H-pyran-4~yl)benzenesulfonamide

[0770] In an analogous manner to Example 547, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-tetrahydro-2iϊ-pyran-4-ylbenzenesulfonamide, c/>s-2,6-dimethylpiperazine _:> and dimethylacetamide as solvent were used to prepare 5-({4-trans-2,5-dimethylpiperazin-l- ylphenyUsulfonylV2-isopropyl-N-( ^' tetrahvdro-2H-pyran-4-yl)benzenesulfonamide. MS (ESI +) m/z 536;

HPLC purity 100% at 210-370 nm, 7.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 628: 2-isopropyl-5-[(4-piperazin-l-ylphenyl)sulfonyl]-iV-(tetrahy dro-2Jϊ-pyraii-4- yl)benzenesulfonamide

[0771] To a stirred slurry of tert-butyl 4-[4-({4-isopropyl-3-[(tetrahydro-2H-pyran-4- ylamino)sulfonyl]phenyl}sulfonyl) phenyl]piperazine-l-carboxylate (50 mg, 0.08 mmol) in anhydrous tetrahydrofuran (1 mL) was added a 2.0 M HCl solution in tetrahydrofuran (0.5 mL). After 16 hours the starting material was still present and an additional 0.5 mL of the HCl solution was added and the slurry was stirred at room temperature for an additional 12 h where upon a predominately single product was observed. An aqueous solution of 2 M HCl was added and the aqueous phase was extracted with ethyl acetate (2 x 1 mL). The aqueous phase was then neutralized with a saturated aqueous solution of sodium bicarbonate until it was basic as determined by pH strip. The aqueous phase was then extracted with ethyl acetate (3 x 1 mL) and the combined organic phases were dried (MgSO ₄ ), filtered and concentrated to afford 2c

isopropy 1-5 - [ ^" (4-piperazin- 1 -ylpheny Psulfonyl] -N-(tetrahydro-2H-pyran-4- yPbenzenesulfonamide (31 mg, 75 %).

MS (ES -) m/z 506.1;

HPLC purity 100% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 629: 5-[(4-Fluorophenyl)sulfonyl]-2,4-diisopropyI-λ'-(tetrahydro -2i3 ^r -pyran-4- ylmethyl)benzenesulfonamide

[0772] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2,4- diisopropylbenzenesulfonyl chloride (0.21 g, 0.5 mmol) and (tetrahydro-pyran-4-yl)methylamine (0.12 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 619, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 30%-70% methyl tert- butyl ether in hexane at a flow rate of 50 mL/min, to afford 5-[(4-fluorophenyl)sulfonyll-2,4- diisopropyl-N-(tetrahydro-2iJ ^r -pyran-4-ylmethyπbenzenesulfonamide (0.22 g, 87%), as a homogeneous, colorless, crystalline solid, m.p. 200-202 ⁰ C; MS (-ESI), m/z: 496.1 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 10.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 630 : 5- [(4-Fluorophenyl)sulf onyl] -2,4-diisopropyl-TV- [2-(tetrahy dro~2/ϊ-py ran-4- yl)ethyl]benzenesulfonamide

[0773] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2,4- diisopropylbenzenesulfonyl chloride (0.21 g, 0.5 mmol) and 2-(tetrahydro-pyran-4-yl)ethylamine (0.13 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 619, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 30%-70% methyl tert- butyl ether in hexane at a flow rate of 50 mL/min, to afford 5-r(4-fluorophenyl)sulfonyll-2,4- diisopropyl-N-[ ^" 2-(tetrahvdro-2H-pyran-4-yl)ethyl]benzenesulfonamide (0.18 g, 69%), as a homogeneous, colorless, crystalline solid, m.p. 141-143 ⁰ C; MS (-ESI), m/z: 510.2 [M-H] ^' ;

HPLC purity 100% at 210-370 nm, 10.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 631: 5-[(4-FIuorophenyl)sulfonyI]-2,4-diisopropyl-λ ^L (2-pyridin-2- ylethyl)benzenesulfonamide

[0774] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2,4- diisopropylbenzenesulfonyl chloride (0.21 g, 0.5 mmol) and 2-(pyridin-2-yl)ethylamine (0.12 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 619, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 50%-100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford 5-[(4-fluorophenyl)sulfonyl]-2,4- diisopropyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide (0.22 g, 86%), as a homogeneous, colorless, crystalline solid, m.p. 159-161 ⁰ C; MS (-ESI), m/z: 503.1 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 632: 5-[(4-Fluorophenyl)sulfonyl]-2,4-diisopropyl-iV-(2-pyridin-3 - ylethyl)benzenesulfonamide

[0775] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2,4- diisopropylbenzenesulfonyl chloride (0.21 g, 0.5 mmol) and 2-(pyridin-3-yl)ethylamine (0.12 g, 1.0 mmol) according to the procedure and in the same manner described in Example 619, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 50%-100% methyl tert-hutyl ether in hexane at a flow rate of 50 mL/min, to afford 5-[(4-fluorophenyl ^* )sulfonyl]-2,4- diisopropyl-A/-(2-pyridin-3-ylethvDben2enesulfonamide (0.18 g, 71%), as a homogeneous, colorless, crystalline solid, m.p. 148-150 °C; MS (-ESI), m/z: 503.1 [M-H] ^' ;

HPLC purity 100% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 633: 5-[(4-Fluorophenyl)sulfonyl]-2,4-diisopropyl-iV-(2-pyridin-4 - ylethyl)benzenesulfonamide

[0776] The title compound was prepared from 5-[(4-fluorophenyi)sulfonyl]-2,4- diisopropylbenzenesulfonyl chloride (0.21 g, 0.5 mmol) and 2-(pyridin-4-yl)ethylamine (0.12 g, 1.0 mmol) according to the procedure and in the same manner described in Example 619, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 50%- 100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford 5-[(4-fluorophenyl)sulfonyl ^' l-2,4- diisopropyl-N-(2-pyridin-4-ylethyl)benzenesulfonamide (0.14 g, 55%), as a homogeneous, colorless, crystalline solid, m.p. 210-211 ⁰ C; MS (-ESI), m/z: 503.1 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 634: λ ^r -(2,3-Dihydro-ljH ^r -inden-2-yl)-5-[(4-fluorophenyl)sulfonyI]-2,4- diisopropylbenzenesulfonamide

[0777] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2,4- diisopropylbenzenesulfonyl chloride (0.21 g, 0.5 mmol) and indan-2-ylamine (0.13 g, 1.0 mmol) according to the procedure and in the same manner as described in Example 619, step c. The crude product was purified by preparative liquid chromatography on a Biotage 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 0%-25% methyl fert-butyl ether in hexane at a flow rate of 50 mL/min, to afford N-(2.3-dihvdro-lH-inden-2-ylV5-| ^" ( ^' 4- fluorophenyl)sulfonyll-2,4-diisopropylbenzenesulfonamide (0.23 g, 89%), as a homogeneous, colorless, crystalline solid, m.p. 202-204 °C; MS (-ESI), m/z: 514.1 [M-H] ^" ;

HPLC purity 100% at 210-370 nm, 11.1 min.; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 635 : 1 -{ [2-chloro-5-(pheny lsulfony l)phenyl] sulf onyl} -4-py rrolidin-1 -ylpiperidine

[0778] In an analogous manner to Example 334,

[0779] Step 3: 4-pyrrolidin-l-yl-piperidine was used to prepare l-{[2-chloro-5- (phenylsulfonγl)phenvnsulfonyl} -4-pyrrolidin- 1 -ylpiperidine.

MS (ESI) m/z 469.

Example 636: 4-[2-(4-{[2-chIoro-5-(phenylsulfonyl)phenyl]sulfonyI}piperaz in~l- yl)ethy 1] morpholine

[0780] In an analogous manner to Example 334,

[0781] Step 3: 4-(2-piperazin-l-ylethyl)-morpholine was used to prepare 4-[2-(4-{[2- chloro-5-(phenylsulfonyl)phenyl1sulfonyl}piperazin-l-yl)ethy llmorpholine. MS (ESI) m/z 514.

Example 637: l-(l,3-benzodioxol-5-y!methyl)-4-{[2-chloro-5- (phenylsulfonyl)phenyl]sulfonyl}piperazine

[0782] In an analogous manner to Example 334,

[0783] Step 3: l-benzo[l,3]dioxol-5-ylmethyl-piperazine was used to prepare 1-(1,3- benzodioxol-5-ylmethyl ^' )-4-{r2-chloro-5-(phenylsulfonyl)phenyl1sulfonyUpiperazine. MS (ESI) m/z 535.

Example 638: fert-butyl (l-{[2-chloro-5-(phenylsulfonyl)phenyl]sulfonyl}pyrrolidin-3 - yl)carbamate

[0784] In an analogous manner to Example 334,

[0785] Step 3: pyrrolidin-3-yl-carbamic acid tert-butyl ester was used to prepare tert- butyl ( 1 - { [2-chloro-5-(phenylsulfony Dphenyl] sulfonyl } pyrrolidin-3 -vDcarbamate . MS (ESI) m/z 501.

Example 639: tert-butyl (l-{[2-chloro-5-(phenylsulfonyl)phenyl]sulfonyl}piperidin-4- yl)carbamate

[0786] In an analogous manner to Example 334,

[0787] Step 3 : piperidin-4-yl-carbamic acid tert-butyl ester was used to prepare tert- butyl ri-{r2-chloro-5-(phenylsulfonyl)phenyl]sulfonyljpiperidin-4- yDcarbamate. MS (ESI) m/z 515.

Example 640: 2-chloro-5-(phenylsulfonyl)-iV-(2-pyridin-3-ylethyl)benzenes uIfonamide

[0788] In an analogous manner to Example 334,

[0789] Step 3: 2~pyridin-3-yl-ethylarnine was used to prepare 2-chloro-5- (phenylsulfonyl)-N-(2-pyridin-3-ylethyl)benzenesulfonamide. MS (ESI) m/z 437.

Example 641 : 2-chloro-5-(phenyIsulfonyl)-iV-(2-pyridin-4-ylethyl)benzenes ulfonamide

[0790] In an analogous manner to Example 334,

[0791] Step 3: 2-pyridin-4-yl-ethylamine was used to prepare 2-chloro-5- (phenylsulfonylVA/ ^' -(2-pyridin-4-yletliyl ^> )benzenesulfonamide. MS (ESI) m/z 437.

Example 642: 2-chloro-iV-[3-(4-methylpiperazin-l-yl)propyl]-5- (phenylsulfonyl)benzenesulfonamide

[0792] In an analogous manner to Example 334,

[0793] Step 3: 3-(4-methylpiperazin-l-yl)-propylamine was used to prepare 2-chloro- N-[3-(4-methylpiperazin-l-yl)propyll-5-(phenylsulfonyl)benze nesulfonamide. MS (ESI) m/z 472.

Example 643: 2-chloro-iV-(2-cyanoethyl)-5-(phenylsulfonyl)benzenesulfonam ide

[0794] In an analogous manner to Example 334,

[0795] Step 3 : 3-aminopropionitrile was used to prepare 2-chloro-A/ ^" -(2-cvanoethyiy5- (phenylsulfonyDbenzenesulfonamide. MS (ESI) m/z 385.

Example 644: l-{[2-chloro-5-(phenylsulfonyl)phenyl]sulfonyl}-λVV-diethyl pyrrolidin-3- amine

[0796] In an analogous manner to Example 334,

[0797] Step 3: diethylpyrrolidin-3-yl-amine was used to prepare l-{r2-chloro-5- (phenylsulfonyl)pb.enyllsulfonyl}-N,A/-diethylpyrrolidin-3-a mine. MS (ESI) m/z 457.

Example 645: ethyl l-{[2-chloro-5-(phenylsulfonyl)phenyl]sulfonyl}piperidine-3- carboxylate

[0798] In an analogous manner to Example 334,

[0799] Step 3: piperidine-3-carboxylic acid ethyl ester was used to prepare ethyl 1-{| ^" 2- chloro-5-(phenylsulfonyl)phenyllsulfonyl)piperidine-3-carbox ylate. MS (ESI) m/z All.

Example 646: 2-chloro-iV-methyI-5-(phenylsulfonyl)-iV-(2-pyridin-2- ylethyl)benzenesulfonamide

[0800] In an analogous manner to Example 334,

[0801] Step 3 : methyl-(2-pyridin-2-yl-ethyl)-amine was used to prepare 2-chloro-JV- methyl-5-(phenylsulfonyD-iV-(2-pyridin-2-ylethyl)benzenesulf onamide. MS (ESI) m/z 451.

Example 647: 2-chloro-5-(phenylsulfonyl)-JV-[l-(trifluoroacetyl)piperidin -4- yl]benzenesulfonamide

[0802] To a stirred solution of 2-chloro-5-(phenylsulfonyl)-N-piperidin-4- ylbenzenesulfonamide (0.09 g, 0.22 mmol) in dichloromethane (2 mL) was added triethylamine (0.1 mL, 0.72 mmol) and trifluoroacetic anhydride (0.09 g, 0.42 mmol). The resulting solution was stirred for 1 hr and concentrated. The crude mixture was flash column separated using 10- 50% ethyl acetate/ hexane to give 2-chloro-5-( ^" phenylsulfonyl)-N-[ ^" l-(trifluoroacetyl)piperidin-4- yl ^~ |benzenesulfonamide (0.04 g, 36%). MS (ESI) m/z 511.

Example 648: 2-chIoro-λ ^L [l-(2,2-dimethyIpropanoyI)piperidin-4-yI]-5- (phenylsulfonyl)benzenesulfonamide

[0803] In an analogous manner to Example 647, trimethylacetyl chloride was used to prepare 2-chloro-N-ri-(2,2-dimethylpropanoyl)piperidin-4-yl1-5- ( ^" phenylsulfonvDbenzenesulfonamide. MS (ESI) m/z 499.

Example 649: 7V-(tert-butyl)-4-({[2-chloro-5- (phenylsulfonyl)phenyl]sulfonyl}amino)piperidine-l-carboxami de

[0804] In an analogous manner to Example 647, tert-butyl isocyanate was used to prepare N-(tert-butylV4-({r2-chloro-5-(phenylsulfonyl)phenyl]sulfony l}amino)piperidine-l- carboxamide. MS (ESI) m/z 512.

Example 650: 2-chloro-λ ^r -[l-(morphoIin-4-ylcarbonyl)piperidin-4-yl]-5- (phenylsulfonyl)benzenesulfonamide

[0805] In an analogous manner to Example 647, morpholine-4-carbonyl chloride was used to prepare 2-chloro-iV- [ 1 -(morpholin-4-y lcarbony l)piperidin-4-vn -5 - (phenylsulfonvDbenzenesulfonamide. MS (ESI) m/z 528.

Example 651 : 2-chloro-λ'-(l-cyanopiperidm-4-yl)-5-(phenylsulfonyl)benzen esulfonamide

[0806] In an analogous manner to Example 647, cyanogens bromide was used to prepare 2-chloro-JV-( 1 -cyanopiperidin-4-yl V 5 -(pheny lsulfonyDbenzenesulfonamide . MS (ESI) m/z 440.

Example 652: 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-[2-(l-oxidopyridi n-3- yl)ethyl]benzenesulfonamide

[0807] 100 mg of 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(2-pyridin-3- ylethyl)benzenesulfonamide was added to 4 mL of 50% hydrogen peroxide/acetic acid and the reaction was heated at 100 ⁰ C for four hours. The reaction was poured onto saturated bicarbonate solution and extracted with dichloromethane. The organic layer was washed with sodium dithionite solution. The organic layer was dried with magnesium sulfate and concentrated. Crude material was purified by flash chromatography using 10% methanol/dichloromethane to give 5- [Y 4-fluorophenyl)sulfony 1] -2-isopropy 1-N- \2-( 1 - oxidopyridin-3- yl)ethyl]benzenesulfonamide. MS (ES+) m/z 479 MS (ES-) m/z All.

Example 653: l-{[2-chloro-5-(phenylsulfonyl)phenyl]sulfonyl}-4-[(2,5-dime thyl-l _J H-pyrrol- l-yl)methyl]piperidine

[0808] In an analogous manner to Example 647, 4-(2,5-dimethylpyrrol-l -ylmethyl)- piperidine was used to prepare l-{| ^" 2-chloro-5-(phenylsulfonyl)phenyllsulfonyl|-4-[(2,5- dimethy 1- 1 i7-pyrrol- 1 -vDmethyllpiperidine . MS (ES) m/z 507.0.

Example 654: methyl λ ^r -{[2-chloro-5-(phenylsuIfonyl)phenyl]sulfonyl}-2-methylalani nate

[0809] To a stirred solution of methyl alpha-aminoisobutyrate hydrochloride (1.3 g, 8.53 mmol) in a saturated aqueous sodium bicarbonate solution was added 5-benzenesulfonyl-2- chlorobenzenesulfonyl chloride (1.5 g, 4.27 mmol) dissolved in acetonitrile (10 mL). The resulting solution was stirred vigorously 1 hr and extracted several times with ethyl acetate. The combined organic layers were washed with ammonium chloride solution and concentrated. Flash column separation using 10-50% ethyl acetate /hexane gave methyl iV-{[2-chloro-5- (pheny lsulfony Dphenyl] sulfonyl } -2-methylalaninate (0.96 g, 52%) MS (ESI) m/z 432.

Example 655: 2-chloro-λ^2-hydroxy-l,l-dimethylethyl)-5- (phenylsulfonyl)benzenesulfonamide

[0810] To a stirred solution of methyl N- { [2-chloro-5-

(phenylsulfonyl)phenyl]sulfonyl}-2-methylalaninate (1.20 g, 2.78 mmol) in THF (16 mL) at -78 °C was added diisobutylaluminum hydride 1.0 M in toluene (16.0 mL, 16.0 mmol) dropwise over 10 minutes. The resulting solution was stirred for 6 hours at -78°C, quenched with 0.5 M HCl solution and extracted several times with ethyl acetate. The combined organic layer was dried over magnesium sulfate, and concentrated to give 2-chloro-iV-(2-hydroxy-l,l- dimethylethyl)-5-(phenylsulfonyl)benzenesulfonamide (0.64 g, 57%). MS (ES-) m/z 402.0;

HPLC purity 100% at 210-370 nm, 8.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₆ H ₁₈ ClNO ₅ S ₂ + H+, 404.03877; found (ESI, [M+H] ⁺ ), 404.0384.

Example 656: 2-chloro-A'-[l-(4-fluorobenzoyl)piperidin-4-yl]-5- (phenylsulfonyl)benzenesulfonamide

[0811] In an analogous manner to example 462, 2-chloro-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 4-fluorobenzoyl chloride were used to prepare 2-chloro- iV-[l-(4-fluorobenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)ben zenesulfonamide. MS (ES-) m/z 534.9;

HPLC purity 100% at 210-370 nm, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₂₂ ClFN ₂ O ₅ S ₂ + H+, 537.07154; found (ESI, [M+H] ⁺ ), 537.0699.

Example 657: 2-chloro-iV-[l-(4-cyanobenzoyl)piperidin-4-yl]-5- (phenylsulfonyl)benzenesulfonamide

[0812] In an analogous manner to example 462, 2-chloro-5-(phenylsulfonyl)-N- piperidin-4-ylbenzenesulfonamide and 4-cyanobenzoyl chloride were used to prepare 2-chloro- iV-[l-(4-cyanobenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)benz enesulfonamide. MS (ES-) m/z 541.9;

HPLC purity 100% at 210-370 nm, 8.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₂₂ ClN ₃ O ₅ S ₂ + H+, 544.07622; found (ESI, [M+H] ⁺ ), 544.075.

Example 658: 2-chloro-5-(phenylsulfonyl)-λ'-{l-[4-(trifluoromethyl)benzo yl]piperidin-4- yl}benzenesulfonamide

[0813] In an analogous manner to example 462, 2-chloro-5-(phenylsulfony I)-N- piperidin-4-ylbenzenesulfonamide and 4-trifluoromethylbenzoyl chloride were used to prepare 2- chloro-5-(phenylsulfonyl)-N-{l-[4-(trifluoromethyl)benzoyl]p iperidin-4-yl}benzenesulfonamide. MS (ES-) m/z 584.9;

HPLC purity 94.5% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min.

Example 660: 5-(phenyIsulfonyl)-iV-(2-pyridiii-3-ylethyl)-2- (trifluoromethoxy)benzenesulfonamide

[0814] Step 1 : l-bromo-4-trifluoromethoxybenzene (0.50 g, 2.07 mmol) was added to chlorosulfonic acid (2 mL, 29.0 mmol) at room temperature. The resulting mixture was stirred 2 hours, poured over ice, and extracted several times with ethyl acetate. The combined organic

layer was washed with water, dried over magnesium sulfate and concentrated to give 5-bromo-2- trifluoromethoxybenzene sulfonyl chloride (0.45 g, 64%)

[0815] Step 2: In an analogous manner to example 435, 5-bromo-2- trifluoromethoxybenzene sulfonyl chloride and 3-(2-aminoethyl)pyridine were used to prepare 5- bromo-N-(2-pyridin-3-ylethyl)-2-(trifluoromethoxy)benzenesul fonamide.

[0816] Step 3: Following the same procedure described on example 474 (Step 4), 5- bromo-N-(2-pyridin-3-ylethyl)-2-(tiifluoromethoxy)benzenesul fonamide and benzene sulfonyl fluoride were used to prepare 5-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-2- (trifluoromethoxy)benzenesulfonamide. MS (ES-) m/z 485.0;

HPLC purity 92.5% at 210-370 nm, 8.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₁₇ F ₃ N ₂ O ₅ S ₂ + H+, 487.06037; found (ESI, [M+H] ⁺ ), 487.0615.

Example 662: 5-(phenylsulfonyl)-JV~(tetrahydro-2iϊ-pyraii-4-yl)-2- (trifluoromethoxy)benzenesulfonamide

[0817] In an analogous manner to Example 660,

Step 2: 5-bromo-2-trifluoromethoxybenzene sulfonyl chloride and tetrahydro-pyran-4- ylamine was used to prepare 5-bromo-N-(tetrahydro-2/f-pyran-4-yl)-2- (trifluoromethoxy)benzenesulfonamide

[0818] Step 3: 5-bromo-N-(tetrahydro-2H-pyran-4-yl)-2-

(trifluoromethoxy)benzenesulfonamide and benzene sulfonyl fluoride were used to prepare 5- (phenylsulfonyl)-N-(tetrahydro-2/i ^' -pyran-4-yl)-2-(trifluoromethoxy)benzenesulfonamide. MS (ES-) m/z 464.0;

HPLC purity 95.2% at 210-370 nm, 8.8 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₈ Hi ₈ F ₃ NO ₆ S ₂ + H+, 466.06004; found (ESI, [M+H] ⁺ ), 466.0606.

Example 663: 2-chloro-iV-(cyanomethyl)-5-(phenylsuIfonyl)benzenesulfonami de

[0819] In an analogous manner to example 654, 2-chloro-5~(phenylsulfonyl)- benzenesulfonyl chloride and aminoacetonitrile HCl were used to prepare 2-chloro-vV- (cyanomethyl)-5-(phenylsulfonyl)benzenesulfonamide.

MS (ES-) m/z 369.0;

HPLC purity 88.5% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 664: λ^-(2-cyanoethyl)-5-[(4-fluorophenyl)suIfonyl]-2- isopropylbenzenesulfonamide

[0820] In an analogous manner to example 435, 5-(4-fluoro-benzenesulfonyl)-2- isopropyl-benzenesulfonyl chloride and aminopropionitrile were used to prepare N-(2- cyanoethyl)-5-[(4-fluorophenyl)sulfonyl]-2-isopropylbenzenes ulfonamide. MS (ES-) m/z 409.1;

HPLC purity 99.0% at 210-370 nm, 8.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₈ H ₁₉ FN ₂ O ₄ S ₂ + H+, 411.08430; found (ESI, [M+H] ⁺ ), 411.0841.

Example 665: 2-methyI-iV-(3-oxo-3-pyrrolidm-l-ylpropyl)-5- (phenylsulfonyl)benzenesulfonamide

[0821] To a solution of methyl N- { [2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}-beta- alaninate (1.3 g, 3.3 mmol) in water (10 mL) and tetrahydrofuran (10 mL) was added lithium hydroxide monohydrate (0.67 g, 16 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was then washed with ether and the organic phase was discarded. The aqueous phase was treated with 4 N HCl to pH 1 and then extracted with ethyl acetate. The ethyl acetate extract was dried (MgSO ₄ ), filtered, and concentrated to provide the desired 3-(5- benzenesulfonyl-2-methyl-benzenesulfonylamino)-propionic acid (1.2 g, 3.1 mmol). The 3-(5- benzenesulfonyl-2-methyl-benzenesulfonylamino)-propionic acid (1.2 g, 3.1 mmol) was dissolved in dichloromethane (40 mL) containing dimethylformamide (3 drops) and then treated with oxalyl chloride (1.0 mL, 11 mmol). The resulting solution was stirred at room temperature for 2 h and then concentrated to dryness. The crude 3-(5-benzenesulfonyl-2-methyl- benzenesulfonylamino)-propionyl chloride was dissolved in dichloromethane and used without further purification. To a solution of crude 3-(5-benzenesulfonyl-2-methyl- benzenesulfonylamino)-propionyl chloride (0.10 g, 0.25 mmol) in dichloromethane (1 mL) was added pyrrolidine (22 mg, 0.31 mmol) and triethylamine (55 μL, 0.39 mmol). The resulting solution was stirred overnight at ambient temperature, and then diluted with ethyl acetate and

washed with saturated aqueous ammonium chloride, sodium bicarbonate, and brine. The organic phase was dried (MgSO ₄ ), concentrated, and purified by flash column chromatography to provide 2-methyl-iV-(3-oxo-3-pyrrolidin-l -ylpropyl)-5-(phenylsulfonyl)benzenesulfonamide (48 mg).

MS (ES+) m/z 437.1;

HPLC purity 91.3% at 210-370 nm, 8.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 666: λ^-(tert-butyl)-iV ³ -{[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}-β- alaninamide

[0822] In an analogous manner to Example 665, crude 3-(5-benzenesulfonyl-2-methyl- benzenesulfonylamino)-propionyl chloride (0.10 g, 0.25 mmol), t-butylamine (23 mg, 0.31 mmol) and triethylamine (55 μL, 0.39 mmol) in dichloromethane (1 mL) were used to prepare N- (tert-butyl)-N ³ -{[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}-β-alaninamid e (21 mg). MS (ES+) m/z 439.1;

HPLC purity 86.3% at 210-370 nm, 8.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min.

Example 667: iV ³ -{[2-methyl-5-(phenylsulfonyl)phenyl]suIfonyl}-iV-(l,2,3,4- tetrahydronaphthalen-l-yl)-β-alaninamide

[0823] In an analogous manner to Example 665, crude 3-(5-benzenesulfonyl-2-methyl- benzenesulfonylamino)-propionyl chloride (0.10 g, 0.25 mmol), 1,2,3,4-tetrahydro-l- naphthylamine (46 mg, 0.31 mmol) and triethylamine (55 μL, 0.39 mmol) in dichloromethane (1 mL) were used to prepare N ³ -{[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}-N-(l,2,3,4- tetrahydronaphthalen-l-yl)-β-alaninamide (63 mg). MS (ES-) m/z 511.0;

HPLC purity 87.0% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min.

Example 668: iV-methyl-λ' ³ -{[2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}-iV-phenyl-β- alaninamide

[0824] In an analogous manner to Example 665, crude 3-(5-benzenesulfonyl-2-methyl- benzenesulfonylamino)-propionyl chloride (0.10 g, 0.25 mmol), iV-methylaniline (34 mg, 0.31 mmol) and triethylamine (55 μL, 0.39 mmol) in dichloromethane (1 mL) were used to prepare iV- methyl-N ³ "! [2-methyl-5-(phenylsulfonyl)phenyl]sulfonyl}-λ/-phenyl-β-a laninamide (34 mg). MS (ES+) m/z 473.1;

HPLC purity 82.7% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 669: 2-methyI-λ'-[3-(6-methyl-3,4-dihydroquinoIin-l(2ir)-yl)-3-o xopropyl]-5- (phenylsulfonyl)benzenesulfonamide

[0825] In an analogous manner to Example 665, crude 3-(5~benzenesulfonyl-2-methyl- benzenesulfonylamino)-propionyl chloride (0.10 g, 0.25 mmol), 6-methy 1-1, 2,3,4- tetrahydroquinoline (46 mg, 0.31 mmol) and triethylamine (55 μL, 0.39 mmol) in dichloromethane (1 mL) were used to prepare 2-methyl-iV-[3-(6-methyl-3,4-dihydroquinolin- 1 (2/i)-yl)-3-oxopropyl]-5-(phenylsulfonyl)benzenesulfonamide (29 mg). MS (ES+) m/z 513.1;

HPLC purity 91.0% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 670: 2-isopropyl-5-(phenylsulfonyI)-JV-(tetrahydro-2/f-pyran-4- yl)benzenesulfonamide

[0826] In an analogous manner to Step 3, Example 295:

5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and tetrahydro-pyran-4-ylamine were used to prepare 2-isopropyl-5-(phenylsulfonyl)-N-(te1xahydro-2H-pyran-4- yl)benzenesulfonamide MS (ES-) m/z 422.1;

HPLC purity 99.5% at 210-370 nm, 8.9 min.; Xterra RPl 8, 3.5u, 15O x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₅ NO ₅ S ₂ + H+, 424.12469; found (ESI, [M+H] ⁺ ), 424.127.

Example 671 : 2-isopropyl-5-(phenylsulfonyl)-iV-(2-pyridin-2-ylethyl)benze nesulfonamide

[0827] In an analogous manner to Step 3, Example 295:

5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and 2-pyridin-2-yl-ethylamine were used to prepare 2-isopropyl-5-(phenylsulfonyl)-N-(2-pyridin-2- y lethy l)benzenesulfonamide . MS (ES+) m/z 445.0;

HPLC purity 99.5% at 210-370 nm, 9.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₄ N ₂ O ₄ S ₂ + H+, 445.12502; found (ESI, [M+H] ⁺ ) ₅ 445.1251.

Example 672: 2-isopropyl-5-(phenylsulfonyl)-iV-(2-pyridin-3-ylethyl)benze nesulfonamide

[0828] In an analogous manner to Step 3, Example 295:

5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and 2-pyridin-3-yl-ethylamine were used to prepare 2-isopropyl-5-(phenylsulfonyl)-N-(2-pyridin-3- y lethy l)benzenesulfonamide . MS (ES+) m/z 445.0;

HPLC purity 99.6% at 210-370 nm, 8.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 673: 2-chloro-iV-(2-hydroxyethyl)-5-(phenylsulfonyl)benzenesulfon amide [0829] In an analogous manner to example 654, 2-chloro-5-(phenylsulfonyl)- benzenesulfonyl chloride and ethanolamine were used to prepare 2-chloro-N-(2-hydroxyethyl)-5- (phenylsulfonyl)benzenesulfonamide. MS (ES-) m/z 373.9;

HPLC purity 99.6% at 210-370 nm, 7.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₄ H ₁₄ ClNO ₅ S ₂ + H+, 376.00747; found (ESI, [M+H] ⁺ ), 376.0079.

Example 674: 2-chloro-JV-(2-hydroxy-l-methylethyl)-5- (phenylsulfonyl)benzenesulfonamide

[0830] In an analogous manner to example 654, 2-chloro-5-(phenylsulfonyl)- benzenesulfonyl chloride and alanol were used to prepare 2-chloro-7V-(2-hydroxy-l- methylethyl)-5-(phenylsulfonyl)benzenesulfonamide.

MS (ES-) m/z 388.0;

HPLC purity 96.9% at 210-370 nm, 7.6 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₅ H ₁₆ ClNO ₅ S ₂ + H+, 390.02312; found (ESI-FTMS, [M+H] ¹⁺ ), 390.02353.

Example 675: 2-chloro-iV-[2-hydroxy-l-(hydroxymethyl)ethyl]-5- (phenylsulfonyl)benzenesulfonamide

[0831] In an analogous manner to example 654, 2-chloro-5-(phenylsulfonyl)- benzenesulfonyl chloride and serinol were used to prepare 2-chloro-iV-[2~hydroxy-l- (hydroxymethyl)ethyl]-5-(phenylsulfonyl)benzenesulfonamide.

MS (ES-) m/z 403.9;

HPLC purity 95.9% at 210-370 nm, 6.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₅ H ₁₆ ClNO ₆ S ₂ + H+, 406.01803; found (ESI-FTMS, [M+H] ¹⁺ ), 406.01897.

Example 676: 2-chloro-iV-[(lR*,2R*)-2-hydroxy-l-methyl-2-phenylethyl]-5- (phenylsulfonyl)benzenesulfonamide

[0832] In an analogous manner to example 654, 2-chloro-5-(phenylsulfonyl)- benzenesulfonyl chloride and norephedrine were used to prepare 2-chloro-N-[(li?*,2i?*)-2- hydroxy-l-methyl-2-phenylethyl]-5-(phenylsulfonyl)benzenesul fonamide. MS (ES-) m/z 463.9;

HPLC purity 100% at 210-370 nm, 9.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₂₀ ClNO ₅ S ₂ + Na+, 488.03636; found (ESI-FTMS, [M+Na] ¹⁺ ), 488.0366.

Example 677: 5-(phenylsuIfonyl)-N-(2-pyridin-3-ylethyl)-2- (trifluoromethyl)benzenesulfbnamide

[0833] Step 1: To a stirred solution of aluminum chloride (9.56 g, 71.7 mmol) in benzene (30 mL) was added 4-chloro-3-nitrobenzenesulfonyl chloride (15.3 g, 59.75 mmol). The resulting mixture was stirred overnight at room temperature, poured over ice, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give 5-(phenylsulfonyl)-2-chloro-nitrobenzene. (14.9 g, 84%).

[0834] Step 2: To a stirred solution of 5-(phenylsulfonyl)-2-chloro-nitrobenzene (13.8g, 41.66 mmol) in dimethylacetamide (85 mL) was added copper powder (15.9 g, 250 mmol), activated charcoal (6.9 g), and difluorodibromomethane (7.6 mL, 83.32 mmol). The resulting solution was stirred at 100°C for 3 hours. The mixture was allowed to cool to room temperature and filtered through celite with ethyl acetate. The filtrate was partitioned between ammonium chloride solution (sat) and ethyl acetate. The aqueous layer was extracted a second time with ethyl acetate. The combined organic layers were washed with water several times, washed with brine, dried over magnesium sulfate and concentrated. Flash column separation using 0%-20% ethyl acetate/hexane gradient gave 5-(phenylsulfonyl)-2-trifluoromethyl-nitrobenzene (5.6 g, 41%).

[0835] Step 3 : To a stirred solution of 5-(phenylsulfonyl)-2-trifluoromethyl- nitrobenzene (4.14 g, 12.5 mmol) in methanol (90 mL) was added water (4 mL) and Tin (II) Chloride (11.85 g, 62.85 mmol). The resulting solution was heated to 70 ⁰ C for 3 days. The solution was allowed to cool to room temperature and quenched with sodium bicarbonate solution (sat) and extracted several times with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 5-(phenylsulfonyl)-2- trifluoromethylaniline (3.6 g, 95%).

[0836] Step 4: To a stirred solution of 5-(phenylsulfonyl)-2-trifluoromethylaniline (3.6 g, 11.95 mmol) in acetonitrile (85 mL) at 0°C was added concentrated acetic acid (8.5 mL) and concentrated hydrochloric acid (8.5 mL). To this solution was added sodium nitrite (0.99 g, 14.34 mmol) dissolved in water (1.5 mL) in a dropwise fashion. The resulting solution was stirred for 20 minutes, followed by bubbling in sulfur dioxide over 10 minutes. Immediately upon completion of sulfur dioxide addition, copper (II) chloride dihydride (2.0 g, 12.0 mmol) dissolved in water (2 mL) was added all at once. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was diluted with water and extracted with ethyl acetate several times. The combined organic layer was washed with ammonium chloride solution (sat.), water, and brine. The organic phase was dried over magnesium sulfate, and concentrated. Flash column separation using 10%-30% ethyl acetate/hexane gradient gave 2- trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride (1.7 g, 37%).

[0837] Step 5: Following the same procedure described on example 435, 2- trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 3-(2-aminoethyl)pyridine were

used to prepare 5-(phenylsulfonyl)-iV-(2-pyridin-3-ylethyl)-2-

(trifluoromethyl)benzenesulfonamide.

MS (ES-) m/z 468.9;

HPLC purity 100% at 210-370 ran, 8.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₀ H ₁₇ F ₃ N ₂ O ₄ S ₂ + H+, 471.06546; found (ESI-FTMS, [M+H] ¹⁺ ), 471.06448.

Example 678: l-Methoxy-4-(phenylsulfonyI)benzene

[0838] Step a

A stirred solution of benzene (10 mL, 100 mmol) and 4-methoxybenzenesulfonyl chloride (4.12 g, 20 mmol) was cooled to -40 °C and treated slowly under nitrogen with solid anhydrous aluminum chloride (3.2 g, 24 mmol). After stirring neat for 4 hours at room temperature, the mixture was slowly poured into cold IN hydrochloric acid and extracted with ethyl acetate (2x). The organic phase was washed with a saturated, aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered through a short column of silica gel. The filtrate was evaporated in vacuo to yield l-methoxy-4-(phenylsulfonyl)benzene (4.96 g, 100%) as a homogeneous oil which solidified on standing.

[0839] Step b

2-Methoxy-5-(phenylsulfonyl)benzenesulfonyl chloride l-methoxy-4-(phenylsulfonyl)benzene (4.96 g, 20 mmol) was stirred for 30 minutes under nitrogen with chlorosulfonic acid (13.2 mL, 23.2 g, 200 mmol). The mixture was cooled to room temperature, poured slowly into a cold solution of IN hydrochloric acid, and extracted with ethyl acetate (2x). The organic phase was washed with a saturated, aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent concentrated in vacuo to a crude oil. The crude oil was crystallized from diethyl ether-hexane to afford 2- methoxy-5-(phenylsulfonyl)benzenesulfonyl chloride (5.12 g, 74%) as a colorless solid, which was utilized in subsequent reactions.

[0840] Step c

2-Methoxy-5-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)benze nesulfonamide

A stirred solution of 2-methoxy-5-(phenylsulfonyl)benzenesulfonyl chloride (0.35 g, 1.0 mmol) in dichloromethane (10 mL) was treated dropwise under nitrogen with a solution of 2- (pyridin-3-yl)ethanamine (0.24 g, 2.0 mmol) in dichloromethane. The reaction was stirred for 18

hours at room temperature. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (90 g), eluting with a gradient of 50%-100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford, after crystallization from ethyl acetate-diethyl ether-hexane, 2-methoxy-5-(phenylsulfonyl)-N-(2- pyridin-3-ylethyl)benzenesulfonamide (0.26 g, 60%), as a homogeneous, colorless, crystalline solid, m.p. 181-183 ⁰ C;

MS (+ESI), m/z: 433.1 [M+H] ⁺ ;

HRMS: calcd for C ₂₀ H ₂₀ N ₂ O ₅ S ₂ + H+, 433.08864; found (ESI, [M+H] ⁺ ), 433.0907;

HPLC purity 100% at 210-370 run, 6.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 679: iV-(2-cyanoethyl)-5-(phenyIsulfonyl)-2-(trifluoromethyl)benz enesulfonamide [0841] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and aminopropionitrile were used to prepare JV-(2-cyanoethyl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide. MS (ES-) m/z 417.0;

HPLC purity 95.3% at 210-370 nm, 8.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₆ H ₁₃ F ₃ N ₂ O ₄ S ₂ + H+, 419.03416; found (ESI, [M+H]*), 419.0344.

Example 680: 5-(phenylsulfonyl)-2-(trifluoromethyl)-iV-{l-[4- (trifluoromethyl)benzoyl]piperidin-4-yI}benzenesulfonamide

[0842] Step 1 : In an analogous manner to example 462, piperidin-4-yl-carbamic acid tert-butyl ester and 4-trifluoromethylbenzoyl chloride were used to prepare [l-(4- trifluoromethyl-benzoyl)-piperidin-4-yl]-carbamic acid tert-butyl ester.

[0843] Step 2: [l-(4-trifluoromethyl-benzoyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (1.50 g, 4.0 mmol) was dissolved in HCl in 1,4-dioxane 4M solution (6 mL, 24 mmol). The resulting solution was stirred 2 hours and concentrated. The crude was partitioned between sodium bicarbonate solution (sat) and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give l-(trifluoromethyl)benzoyl-4- aminopiperidine.

[0844] Step 3: In an analogous manner to example 435, 2-trifluoromethyl-5- (phenylsulfonyl)- benzenesulfonyl chloride and l-(trifluoromethyl)benzoyl-4-aminopiperidine were used to prepare 5-(phenylsulfonyl)-2-(trifluoromethyl)-N-{l-[4- (trifluoromethyl)benzoyl]piperidin-4-yl}benzenesulfonamide. MS (ES+) m/z 621.1;

HPLC purity 100% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₆ H ₂₂ F ₆ N ₂ O ₅ S ₂ + H+, 621.09471; found (ESI, [M+H] ⁺ ), 621.0933.

Example 681: iV-(2-hydroxyethyl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0845] In an analogous manner to example 654, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and ethanolamine were used to prepare iV-(2-h.ydroxyethyi)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide. MS (ES-) m/z 410.1;

HPLC purity 100% at 210-370 nm, 7.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₅ Hi ₄ F ₃ NO ₅ S ₂ + H+, 410.03382; found (ESI, [M+H] ⁺ ), 410.0352.

Example 682: iV-(2-hydroxy-2-phenylethyl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0846] In an analogous manner to example 654, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 2-phenylethanolamine were used to prepare N-(2-hydroxy-2- phenylethyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)benzenesu lfonamide. MS (ES-) m/z 484.0;

HPLC purity 100% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 683: iV-(2-hydroxy-l-methylethyl)-5-(phenylsuIfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0847] In an analogous manner to example 654, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and alanol were used to prepare N-(2-hydroxy-l-methylethyl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide. MS (ES-) m/z 422.0;

HPLC purity 97.9% at 210-370 ran, 8.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₆ H ₁₆ F ₃ NO ₅ S ₂ + H+, 424.04947; found (ESI, [MfH] ⁺ ), 424.0484.

Example 684: iV-[(li?*,2i? ^A )-2-hydroxy-l-methyl-2-phenyIethyl]-5-(phenyIsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0848] In an analogous manner to example 654, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and norephedrine were used to prepare N-[(li-*,2i?*)-2-hydroxy-l- methyl-2-phenylethyl]-5-(phenylsulfonyl)-2-(trifluoromethyl) benzenesulfonamide. MS (ES-) m/z 498.0;

HPLC purity 98.0% at 210-370 ran, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 685: iV-[(lS,2R)-2-hydroxy-l-methyl-2-phenylethyl]-5-(phenylsulfo nyl)-2- (trifluoromethyl)benzenesulfbnamide

[0849] In an analogous manner to example 654, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and (15',2i?)-2-hydroxy-2-phenyl-l -methyl- 1-aminoethane were used to prepare N-[(lS',2i?)-2-hydroxy-l -methyl-2-phenylethyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES-) m/z 498.0;

HPLC purity 96.6% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 686: iV-[(ljR,25)-2-hydroxy-l-methyl-2-phenylethyl]-5-(phenylsulf onyl)-2- (trifluoromethyl)benzenesulfonamide

[0850] In an analogous manner to example 654, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and (li?,25)-2-hydroxy-2-phenyl-l-methyl-l-aminoethane were used to

prepare N-[(li?,25)-2-hydroxy-l-methyl-2-phenylethyl]-5-(p]ienylsulf onyl)-2-

(trifluoromethyl)benzenesulfonamide.

MS (ES-) m/z 498.0;

HPLC purity 97.6% at 210-370 nm, 9.4 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 687: fert-butyl 4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carboxyl ate

[0851] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 4-ammopiperidine-l- carboxylic acid tert-butyl ester were used to prepare tert-butyl 4-({ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl} amino)piperidine- 1-carboxylate. MS (ES-) m/z 547.0;

HPLC purity 97.4% at 210-370 nm, 10.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 688: 5-(phenylsuIfonyl)-iV-piperidin-4-yl-2-(trifluoromethyI)benz enesulfonamide

[0852] tert-butyl 4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carbo xylate (1.57 g, 2.86 mmol) was dissolved in HCl in 1,4-dioxane 4M solution (8 mL, 32 mmol). The resulting solution was stirred overnight and concentrated. The crude was partitioned between sodium bicarbonate solution (sat) and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide (1.1 g, 85%). MS (ES+) m/z 449.1;

HPLC purity 98.0% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₈ H ₁₉ F ₃ N ₂ O ₄ S ₂ + H+, 449.08111; found (ESI, [M+H] ⁺ ), 449.083.

Example 689: 2-Methoxy-5-(phenyIsuIfonyl)-λ ^r -(tetrahydro-2/jT-pyran-4- yl)benzenesulfonamide

[0853] A stirred solution of 2-methoxy-5-(phenylsulfonyl)benzenesulfonyl chloride (0.35 g, 1.0 mmol) in dichloromethane (10 mL) was treated under nitrogen with tetrahydro-2/J- pyran-4-amine hydrochloride (0.27 g, 2.0 mmol) and a solution of diisopropylethylamine (0.39 g, 3.0 mmol) in dichloromethane. The reaction was stirred for 18 hours at room temperature. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (90 g), eluting with a gradient of 30%-70% methyl tert-bntyl ether in hexane at a flow rate of 50 niL/min, to afford, after crystallization from ethyl acetate- diethyl ether-hexane, 2-methoxy-5-(phenylsulfonyl)-iV-(tetrahydro-2// ^' -pyran-4- yl)benzenesulfonaniide (0.29 g, 70%), as a homogeneous, colorless, crystalline solid, m.p. 176- 178 ⁰ C;

MS (+ESI), m/z: 412.1 [M+H] ⁺ ;

HRMS: calcd for C ₁₈ H ₂₁ NO ₆ S ₂ + H+, 412.08830; found (ESI, [M+H] ⁺ ), 412.0899; HPLC purity 100% at 210-370 nm, 7.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 rnL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 690: 4-[({5-[(4-fluorophenyl)suIfonyI]-2-isopropylphenyl}sulfonyl )ammo]-N-l- naphthylpiperidine-1-carbothioamide

[0854] To a solution of 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-piperidin-4- ylbenzenesulfonamide (example 520) (75 mg, 0.17 mmol) in dichloromethane (4.0 mL) was added triethylamine (36 μL, 0.25 mmol) followed by 1-naphthyl isothiocyanate (37 mg, 0.2 mmol). The reaction was mixed on an orbital shaker overnight at room temperature. The following day the reaction was concentrated down onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of 4- [( { 5 - [(4-fluoropheny l)sulfonyl]-2-isopropy lphenyl } sulfonyl)amino] -N- 1 - naphthylpiperidine-1-carbothioamide (42 mg, 40%). MS (ES+) m/z 626; HRMS: calcd. for C ₃₁ H ₃₂ FN ₃ O ₄ S ₃ + H ⁺ , 626.1617: found (ESI, [m+H] ⁺ ), 626.1589.

Example 691: N-(2-fluorophenyl)-4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidine-l-carbothioamide

[0855] In an analogous manner to example 690, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-piperidin-4-ylbenzenesulfonamide and 2-fluorophenyl isothiocyanate were used to

prepare N-(2-fluorophenyl)-4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidine-l-carbothioamide.

MS (ES+) m/z 594.1;

HRMS: calcd. for C ₂₇ H ₂₉ F ₂ N ₃ O ₄ S ₃ + H ⁺ , 594.1366: found (ESI, [m+H] ^4" ), 594.137.

Example 692: 4-[({5-[(4-fluorophenyl)sulfonyl]-2-isopropylphenyl}sulfonyl )amino]-N-(2- methylphenyl)piperidine-l-carbothioamide

[0856] In an analogous manner to example 690, 5-[(4-fluorophenyl)sulfonyl]~2- isopropyl-N-piperidin-4-ylbenzenesulfonamide and o-toluyl isothiocyanate were used to prepare 4- [( { 5- [(4-fluoroplieny l)sulfony 1] -2-isopropy lpheny 1 } sulfony l)amino] -N-(2- methy lpheny l)piperidine- 1 -carbothioamide . MS (ES+) m/z 590; HRMS: calcd. for C ₂₈ H ₃₂ FN ₃ O ₄ S ₃ + H ⁺ , 590.1617: found (ESI ₃ [m+H] ⁺ ), 590.1628.

Example 693: ethyl ({4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidin-l-yl}carbonothioyl) carbamate

[0857] In an analogous manner to example 690, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-piperidin-4-ylbenzenesulfonamide and ethyl isothiocyanatoformate were used to prepare ethyl ({4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropy lpheny 1} sulfony l)amino]piperidin- 1 -yl} carbonothioyl)carbamate. MS (ES+) m/z 572; HRMS: calcd. for C ₂₄ H ₃₀ FN ₃ O ₆ S ₃ + H ⁺ , 572.1359: found (ESI, [m+H] ⁺ ) ₃ 572.1353.

Example 694: N-butyl-4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidine-l-carbothioamide

[0858] In an analogous manner to example 690, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-piperidin-4-ylbenzenesulfonamide and 1 -butyl isothiocyanate were used to prepare N-butyl-4- [( { 5- [(4-fluoropheny l)sulfony 1] -2- isopropy lpheny 1 } sulfony l)amino]piperidine- 1 - carbothioamide. MS (ES+) m/z 556.2; HRMS: calcd. for C ₂₅ H ₃₄ FN ₃ O ₄ S ₃ + H ⁺ , 556.1773: found (ESI, [m+H] ⁺ ), 556.1765.

Example 695: 4-[({5-[(4-fluorophenyl)sulfonyl]-2-isopropylphenyl}sulfonyl )amino]-N-(4- methoxyphenyl)piperidine-l-carbothioamide

[0859] In an analogous manner to example 690, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-piperidin-4-ylbenzenesulfonamide and 4-isothiocyanatoanisole were used to prepare 4- [( { 5 - [(4-fluoropheny l)sulfony 1] -2-isopropylpheny 1} sulfony l)amino] -N-(4- methoxypheny l)piperidine- 1 -carbothioamide . MS (ES+) m/z 606.1; HRMS: calcd. for C ₂₈ H ₃₂ FN ₃ O ₅ S ₃ + H ⁺ , 606.1566: found (ESI, [m+H] ⁺ ), 606.1456.

Example 696: methyl 4-[({4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidin-l-yl}carbonothioyl) amino]benzoate

[0860] In an analogous manner to example 690, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-piperidin-4-ylbenzenesulfonamide and 4-isothiocyanato-benzoic acid methyl ester were used to prepare methyl 4-[({4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidin-l-yl}carbonothioyl) amino]benzoate. MS (ES-) m/z 632.1; HRMS: calcd. for C ₂₉ H ₃₂ FN ₃ O ₆ S ₃ + H ⁺ , 634.1516: found (ESI, [m+H] ⁺ ), 634.1478.

Example 697: methyl N-({4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidin-l-yl}carbonothioyl) glycinate

[0861] In an analogous manner to example 690, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-piperidin-4-ylbenzenesulfonamide and 2-isothiocyanatoacetic methyl ester were used to prepare methyl N-({4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidin-l-yl}carbonothioyl) glycinate. MS (ES-) m/z 570; HRMS: calcd. for C ₂₄ H ₃₀ FN ₃ O ₆ S ₃ + H ⁺ , 572.1359: found (ESI, [m+H] ⁺ ), 572.1348.

Example 698 : 4- [({5- [(4-fluorophenyl)sulfony 1] -2-isopropylphenyl} sulf onyl)amino] -N-(2~ morpholin-4-ylethyl)piperidine-l-carbothioamide

[0862] In an analogous manner to example 690, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-piperidin-4-ylbenzenesulfonamide and 2-(4-morpholino)ethyl isothiocyanate were

used to prepare methyl N-({4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl } sulfonyl)amino]piperidin- 1 -yl} carbonothioyl)glycinate. MS (ES-) m/z 611.

Example 699: 4-[({5-[(4-fluorophenyl)sulfonyl]-2-isopropylphenyl}sulfonyl )amino]-N-(3- nitrophenyl)piperidine-l-carbothioamide

[0863] In an analogous manner to example 690, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-piperidin-4-ylbenzenesulfonamide and 3-nitrophenyl isothiocyanate were used to prepare 4- [( { 5- [(4-fluorophenyl)sulfony 1] -2-isopropy lpheny 1 } sulfony l)amino] -N-(3 - nitrophenyl)piperidine- 1 -carbothioamide. MS (ES-) m/z 619; HRMS: calcd. for C ₂₇ H ₂₉ FN ₄ O ₆ S ₃ + H ⁺ , 621.1312: found (ESI, [m+H] ⁺ ), 621.1219.

Example 700: 3-[({4-[({5-[(4-fluorophenyl)sulfonyl]-2- isopropylphenyl}sulfonyl)amino]piperidin-l-yl}carbonothioyl) amino]benzoic acid

[0864] In an analogous manner to example 690, 5- [(4-fluoropheny tysulfonyl] -2- isopropyl-N-piperidin-4-ylbenzenesulfonamide and 3-carboxyphenyl isothiocyanate were used to prepare 3 - [( {4- [( { 5- [(4-fluoropheny l)sulfony l]-2- isopropy lpheny 1 } sulfony l)amino]piperidin- 1 - yl}carbonothioyl)amino]benzoic acid. MS (ES-) m/z 618; HRMS: calcd. for C ₂₈ H ₃₀ FN ₃ O ₆ S ₃ + H ⁺ , 620.1359: found (ESI, [m+H] ⁺ ), 620.1364.

Example 701 : 4-[({5-[(4-fluorophenyl)sulfonyl]-2-isopropylphenyl}sulfonyl )amino]-N- pyridin-3- ylpiperidine-l-carbothioamide

[0865] In an analogous manner to example 690, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-piperidin-4-ylbenzenesulfonamide and 3-pyridyl isothiocyanate were used to prepare 4- [( { 5- [(4-fluoropheny l)sulfony 1] -2-isopropy lphenyl} sulfony l)amino] -N-pyridin-3 - y lpiperidine- 1 -carbothioamide . MS (ES+) m/z 577.1; HRMS: calcd. for C ₂₆ H ₂₉ FN ₄ O ₄ S ₃ + H ⁺ , 577.1413: found (ESI, [m+H] ⁺ ), 577.1396.

Example 702: N-[l-(2-chlorobenzoyl)piperidin-4-yl]-5-(phenyIsuIfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0866] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-chlorobenzoyl chloride were used to prepare N-[I- (2-chlorobenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)-2-(trifl uoromethyl)benzenesulfonamide. MS (ES+) m/z 587.0;

HPLC purity 93.6% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₂₂ ClF ₃ N ₂ O ₅ S ₂ + H+, 587.06835; found (ESI, [M+H] ⁺ ), 587.0666.

Example 703: iV-[l-(2-methoxybenzoyl)piperidin-4-yI]-5-(phenylsulfonyl)-2 - (trifluoromethyl)benzenesulfonamide

[0867] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-methoxybenzoyl chloride were used to prepare N-[I- (2-methoxybenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)-2-(trif luoromethyl)benzenesulfonamide. MS (ES+) m/z 583.1;

HPLC purity 96.8% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min.

Example 704: JV-[l-(3-chIorobeiizoyl)piperidin-4-yl] -5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0868] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 3-chlorobenzoyl chloride were used to prepare N-[I- (3-chlorobenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)-2-(trifl uoromethyl)benzenesulfonamide. MS (ES+) m/z 587.0;

HPLC purity 98.4% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₂₂ ClF ₃ N ₂ O ₅ S ₂ + H+, 587.06835; found (ESI, [M+H] ⁺ ), 587.0674.

Example 705: λ ^L [l-(3,4-difluorobenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)-2 - (trifluoromethyl)benzenesulfonamide

[0869] In an analogous manner to example 462, 5-(phenylsurfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 3,4-difluorobenzoyl chloride were used to prepare N- [ 1 -(3 ,4-difluorobenzoy l)piperidin-4-y 1] -5 -(phenylsulfony l)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 589.1;

HPLC purity 98.3% at 210-370 ran, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₂₁ F ₅ N ₂ O ₅ S ₂ + H+, 589.08848; found (ESI ₅ [M+H] ⁺ ), 589.0875.

Example 706: iV-[l-(3,5-difluorobenzoyl)piperidin-4-yl]-5-(phenylsulfonyl )-2- (trifluoromethyl)benzenesulfonamide

[0870] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 3,5-difluorobenzoyl chloride were used to prepare N- [l-(3,5-difluorobenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)-2 - (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 589.1;

HPLC purity 99.0% at 210-370 ran, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₂₁ F ₅ N ₂ O ₅ S ₂ + H+, 589.08848; found (ESI, [M+FfJ ⁺ ), 589.0884.

Example 707: iV-[l-(2,6-dimethoxybenzoyl)piperidin-4-yl]-5-(phenylsuIfony l)-2- (trifluoromethyl)benzenesιilfonamide

[0871] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2,6-dimethoxybenzoyl chloride were used to prepare N-[l-(2,6-dimethoxybenzoyl)piperidin-4-yl]-5-(phenylsulfonyl )-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 613.1;

HPLC purity 98.3% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₇ H ₂₇ F ₃ N ₂ O ₇ S ₂ + H+, 613.12845; found (ESI, [M+H] ⁺ ), 613.1266.

ExampIe 708: iV-[l-(2,4-dimethoxybenzoyl)piperidin-4-yl]-5-(phenylsulfony l)-2- (trifluoromethyl)benzenesulfonamide

[0872] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2,4-dimethoxybenzoyl chloride were used to prepare N-[l-(2,4-dimethoxybenzoyl)piperidin-4-yl]-5-(phenylsulfonyl )-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 613.1;

HPLC purity 95.9% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 rnL/min, 85/15-5/95 (Ammon. Form. Buff. Pb=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 709: 5-(phenylsulfonyl)-iV-{l-[4-(trifluoromethoxy)benzoyl]piperi din-4-yl}-2- (trifluoromethyl)benzenesulfonamide

[0873] In an analogous manner to example 462, 5-(phenylsulfonyl)-JV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 4-trifluoromethoxybenzoyl chloride were used to prepare 5-(phenylsulfonyl)-N-{l-[4-(trifluoromethoxy)benzoyl]piperid in-4-yl}-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 637.1;

HPLC purity 98.6% at 210-370 nm, 10.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₆ H ₂₂ F ₆ N ₂ O ₆ S ₂ + H+, 637.08962; found (ESI, [M+H] ⁺ ), 637.0912.

Example 710: N- {1- [2-fluoro-4-(trifluoromethy l)benzoy 1] piperidin-4-y 1} -5-(phenylsulfonyl)- 2-(trifluoromethyl)benzenesulfonamide

[0874] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-fluoro-4-trifluoromethylbenzoyl chloride were used to prepare N-{ l-[2-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}-5-(ph enylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide . MS (ES+) m/z 639.1;

HPLC purity 98.9% at 210-370 nm, 10.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₆ H _2J F ₇ N ₂ O ₅ S ₂ + H+, 639.08528; found (ESI, [M+H] ⁺ ), 639.0881.

Example 711: λ ^r -{l-[3-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}-5-( phenylsulfonyl)- 2-(trifluoromethyl)benzenesulfonamide

[0875] In an analogous manner to example 462, 5-(phenylsulfonyl)-/V~piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 3-fluoro-4-trifluoromethylbenzoyl chloride were used to prepare N- { l-[3-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}-5-(ph enylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 639.1;

HPLC purity 98.2% at 210-370 ran, 10.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₆ H ₂₁ F ₇ N ₂ O ₅ S ₂ + H+, 639.08528; found (ESI, [M+H] ⁺ ), 639.0863.

Example 712: λ^-[l-(3,4-dichlorobenzoyl)piperidin-4-yl]-5-(phenylsulfony l)-2- (trifluoromethyl)benzenesulfonamide

[0876] In an analogous manner to example 462, 5-(phenylsulfonyl)-JV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 3,4-dichlorobenzoyl chloride were used to prepare JV- [ 1 -(3 ,4-dichlorobenzoy l)piperidin-4-y 1] -5 -(phenylsulfony l)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 621.9;

HPLC purity 98.2% at 210-370 nm, 10.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₂₁ Cl ₂ F ₃ N ₂ O ₅ S ₂ + H+, 621.02938; found (ESI, [M+H] ⁺ ), 621.0306.

Example 713: JV-[l~(4-chlorobenzoyl)piperidm-4-yl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0877] In an analogous manner to example 462, 5-(phenylsulfonyi)-JV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 4-chlorobenzoyl chloride were used to prepare TV-[I- (4-chlorobenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)-2-(trifl uoromethyl)benzenesulfonamide. MS (ES+) m/z 587.0;

HPLC purity 98.2% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₂₂ ClF ₃ N ₂ O ₅ S ₂ + H+, 587.06835; found (ESI, [M+H] ⁺ ), 587.0698.

ExampIe 714: iV-(l-isonicotinoylpiperidin-4-yl)-5-(phenylsuIfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0878] In an analogous manner to example 462, 5-(phenylsulfonyi)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and pyridine-4-carbonyl chloride were used to prepare N- (l-isonicotinoylpiperidin-4-yl)-5-(phenylsulfonyl)-2-(triflu oromethyl)benzenesulfonamide. MS (ES+) m/z 554.1;

HPLC purity 99.4% at 210-370 nm, 8.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₂₂ F ₃ N ₃ O ₅ S ₂ + H+, 554.10257; found (ESI, [M+H] ⁺ ), 554.1038.

Example 715: iV-[l-(2-chloro-6-methoxyisonicotinoyI)piperidin-4-yl]-5-(ph enyIsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0879] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-chloro-6-methoxypyridine-4-carbonyl chloride were used to prepare N-[l-(2-chloro-6-methoxyisonicotinoyl)piperidin-4-yl]-5-(phe nylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 618.1;

HPLC purity 98.5% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₂₃ ClF ₃ N ₃ O ₆ S ₂ + H+, 618.07416; found (ESI, [M+H] ⁺ ), 618.0737.

Example 716: iV-[l-(2-chloro-4-fluorobenzoyl)piperidm-4-yl]-5-(phenylsulf onyl)-2- (trifluoromethyl)benzenesulfonamide

[0880] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-chloro-4-fluorobenzoyl chloride were used to prepare N-[l-(2-chloro-4-fluorobenzoyl)piperidin-4-yl]-5-(phenylsulf onyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 605.0;

HPLC purity 98.7% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₂₁ ClF ₄ N ₂ O ₅ S ₂ + H+, 605.05893; found (ESI, [M+H] ⁺ ), 605.0582.

Example 717: 5-(phenylsulfonyl)-λ ^r -[l-(2,4,6-trifluorobenzoyl)piperidin-4-yl]-2- (trifluoromethyl)benzenesulfonamide

[0881] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-piperidm-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2,4,6-trifluorobenzoyl chloride were used to prepare 5- (phenylsulfonyl)-iV-[l-(2,4,6-trifluorobenzoyl)piperidin-4-y l]-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 607.0;

HPLC purity 93.5% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₂₀ F ₆ N ₂ O ₅ S ₂ + H+, 607.07906; found (ESI, [M+H] ⁺ ), 607.0799.

Example 718: iV-[l-(4-tert-butylbenzoyl)piperidin-4-yI]-5-(phenylsulfonyl )-2- (trifluoromethyl)benzenesulfonamide

[0882] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 4-tert-butylbenzoyl chloride were used to prepare iV- [l-(4-tert-butylbenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)-2 - (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 609.1;

HPLC purity 98.0% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₉ H ₃₁ F ₃ N ₂ O ₅ S ₂ + H+, 609.16992; found (ESI, [M+H] ⁺ ), 609.1714.

Example 719: iV-(4-{[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]carbon yl}phenyl)acetamide

[0883] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 4-ν-acetamidebenzoyl chloride were used to prepare N-(4- { [4-( { [5 -(pheny lsulfony l)-2-(trifluoromethy l)pheny 1] sulfony 1} amino)piperidin- 1 - yl]carbonyl}phenyl)acetamide. MS (ES+) m/z 610.1;

HPLC purity 96.7% at 210-370 nm, 8.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₇ H ₂₆ F ₃ N ₃ O ₆ S ₂ + H+, 610.12879; found (ESI, [M+H] ⁺ ), 610.1293.

Example 720: iV-[(15)-l-benzyl-2-hydroxyethyl]-5-(phenylsuIfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0884] In an analogous manner to example 435, 2-trifluoromethyl~5-(phenylsulfonyl)- benzenesulfonyl chloride and L-phenylalaninol were used to prepare N-[(liS)-l-benzyl-2- hydroxyethyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)benzenes ulfonamide. MS (ES+) m/z 500.0;

HPLC purity 99.1% at 210-370 nm, 9.2 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₀ F ₃ NO ₅ S ₂ + H+, 500.08077; found (ESI, [M+H] ⁺ ), 500.0791.

Example 721 : iV-[(15)-2-hydroxy-l-(lJϊ-indol-3-ylmethyl)ethyl]-5-(phenyl sulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0885] In an analogous manner to example 654, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and L-tryptophanol were used to prepare iV-[(ljS)-2-hydroxy-l-(lH- indol-3-ylmethyl)ethyl]-5-(phenylsulfonyl)-2-(trifluoromethy l)benzenesulfonamide. MS (ES+) m/z 539.0;

HPLC purity 97.2% at 210-370 nm, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₂₁ F ₃ N ₂ O ₅ S ₂ + H+, 539.09167; found (ESI, [M+H] ⁺ ), 539.0943.

Example 722: iV-[l-(2-hydroxy-2-methylpropyl)piperidin-4-yl]-5-(phenylsuI fonyl)-2- (trifluoromethyl)benzenesulfonamide

[0886] To a stirred mixture of 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide (0.075 g, 0.167 mmol) in ethanol (2 mL) was added 2,2- Dimethyl-oxirane (0.05 g, 0.69mmol) and the resulting mixture was heated to reflux overnight. The crude mixture was concentrated and flash column separation using 50% to 100% ethyl acetate/hexane gradient gave N-[l-(2-hydroxy-2-methylpropyl)piperidin-4-yl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide (0.06 g, 70%). MS (ES-) m/z 519.0;

HPLC purity 96.8% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₂ H ₂₇ F ₃ N ₂ O ₅ S ₂ + H+, 521.13862; found (ESI, [M+H] ⁺ ), 521.1403.

Example 723: iV-[2-(l-oxidopyrid[in-3-yl)ethyl]-5-(phenyIsuIfonyI)-2- (trifluoromethyl)benzenesulfonamide

[0887] To a stirred solution of 5-(phenylsulfonyl)-N-(2-pyridin-3-ylethyl)-2- (trifluoromethyl)benzenesulfonamide (0.10 g, 0.21mmol) in concentrated acetic acid (2 mL) was added 30% hydrogen peroxide solution (2 mL) and the resulting solution was heated to reflux for three hours. The solution was allowed to cool, poured into sodium bicarbonate solution (sat), and extracted with ethyl acetate. The organic layer was washed with sodium dithionite solution (sat), and brine. The organic layer was concentrated and flash column separation using 0%-10% methanol/methylene chloride gradient gave iV-[2-(l-oxidopyridin-3-yl)ethyl]-5-(phenylsulfonyl)- 2-(trifluoromethyl)benzenesulfonamide (0.015 g, 15%). MS (ES-) m/z 485.0;

HPLC purity 98.8% at 210-370 nm, 7.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₁₇ F ₃ N ₂ O ₅ S ₂ + H+, 487.06037; found (ESI, [M+H] ⁺ ), 487.0619.

Example 724: 5-(phenylsulfonyl)-2-(trifluoromethyl)-iV-(l-{[4- (trifluoromethyl)phenyl]carbonothioyl}piperidin-4-yl)benzene sulfonamide

[0888] To a stirred solution of 5-(phenylsulfonyl)-2-(trifluoromethyl)-N-{l-[4- (trifluoromethyl)benzoyl]piperidin-4-yl}benzenesulfonamide (0.10 g, 0.16 mmol) in toluene (1 mL) was added Lawesson's reagent (0.06 g, 0.15 mmol) and the resulting solution was stirred overnight at reflux. The solution was allowed to cool, partitioned between ethyl acetate and ammonium chloride solution (sat.). The organic layer was concentrated and flash column separation using 0% to 20% ethyl acetate/hexane gradient gave 5-(phenylsulfonyl)-2- (trifluoromethy \)-N-{ 1 - { [4-(trifluoromethy l)pheny 1] carbonothioyl } piperidin-4- yl)benzenesulfonamide (0.053 g, 56%). MS (ES+) m/z 637.1;

HPLC purity 100% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₆ H ₂₂ F ₆ N ₂ O ₄ S ₃ + H+, 637.07186; found (ESI, [M+H] ⁺ ), 637.0749.

Example 725: iV-[(lS)-2-hydroxy-l-methylethyl]-5-(phenylsuIfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0889] In an analogous manner to example 654, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and S-2-amino-l-propanol were used to prepare JV-[(lS)-2-hydroxy-l- methylethyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)benzenesu lfonamide. MS (ES+) m/z 424.1;

HPLC purity 95.1% at 210-370 ran, 8.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₆ Hi ₆ F ₃ NO ₅ S ₂ + H+, 424.04947; found (ESI, [M+H] ⁺ ), 424.0497.

Example 726: iV-[(lR)-2-hydroxy-l-methylethyl]-5-(phenyIsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0890] In an analogous manner to example 654, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and R-2-amino-l-propanol were used to prepare 7V-[(li?)-2-hydroxy-l- methylethyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)benzenesu lfonamide. MS (ES+) m/z 424.0;

HPLC purity 98.2% at 210-370 ran, 8.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₆ H ₁₆ F ₃ NO ₅ S ₂ + H+, 424.04947; found (ESI, [M+H] ⁺ ), 424.0505.

Example 727: 5-[(4-fluorophenyl)sulfonyl]-iV-(2-hydroxy-2-pyridin-2-yleth yl)-2- isopropylbenzenesulfonamide

[0891] In an analogous manner to Step 3, Example 317:

2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2-amino-l- pyridin-2-yl-ethanol were used to prepare 5-[(4-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-pyridin- 2-ylethyl)-2-isopropylbenzenesulfonamide. MS (ES+) m/z 419 λ;

HPLC purity Checked by AN LC/MS. MW confirmed.; Luna C8(2), 5u, 4.6x250mm column, 0.5 mL/min, Water/MeOH 20 min gradient.

HPLC purity 96.1% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₃ FN ₂ O ₅ S ₂ + H+, 479.11052; found (ESI, [M+H] ⁺ ), 479.1099.

Example 728: λ ^L (2-hydroxy-2-pyridin-2-ylethyl)-2-isopropyl-5-(phenylsulfony I)benzene- sulfonamide

[0892] In an analogous manner to Step 3, Example 295:

5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and 2-amino-l-pyridin-2-yl- ethanol were used to prepare N-(2-hydroxy-2-pyridin-2-ylethyl)-2-isopropyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES+) m/z 461.2;

HPLC purity Checked by AN LC/MS. MW confirmed by MS.; Luna C8(2), 5u, 4.6x250mm column, 0.5 mL/min, prep conditions.

HPLC purity 100% at 210-370 nm, 8.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₄ N ₂ O ₅ S ₂ + H+, 461.11994; found (ESI ₅ [M+H] ⁺ ), 461.118.

Example 729: iV-(2-hydroxy-2-pyridin-2-ylethyI)-2,4-dimethyl-5- (phenylsulfonyl)benzenesulfonamide

[0893] In an analogous manner to Step 3, Example 295:

5-Benzenesulfonyl-2,4-dimethyl-benzenesulfonyl chloride and 2-amino-l-pyridin-2-yl- ethanol were used to prepare N-(2-hydroxy-2-pyridin-2-ylethyl)-2,4-dimethyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES+) m/z 447.1;

HPLC purity Checked by AN LC/MS. MW confirmed by MS.; Luna C8 (2), 5u, 4.6x250mni column, 0.5 mL/min, MeOH /water 20min gradient.

HPLC purity 100% at 210-370 nm, 8.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₂₂ N ₂ O ₅ S ₂ + H+, 447.10429; found (ESI, [M+H] ⁺ ), 447.1033.

Example 730: 4-[({5-[(4-fluorophenyl)sulfonyl]-2-isopropylphenyl}sulfonyl )amino]-N-[4- (trifluoromethyl)phenyl]piperidine-l-carbothioamide

[0894] In an analogous manner to example 690, 5-[(4-fluorophenyl)sulfonyl]-2- isopropyl-N-piperidin-4-ylbenzenesulfonamide and 4-(trifluoromethyl)phenyl isothiocyanate

were used to prepare 4-[({5-[(4-fluorophenyl)sulfonyl]-2-isopropylphenyl}sulfonyl )amino]-N-

[4- (trifluoromethyl)phenyl]piperidine- 1 -carbothioamide.

MS (ES+) m/z 644.1;

HRMS: calcd. for C ₂₈ H ₂₉ F ₄ N ₃ O ₄ S ₃ + H ⁺ , 644.1335: found (ESI, [m+H] ⁺ ), 644.1406.

Example 731 : 5-[(4-fluorophenyl)sulfonyl]-iV-(2-hydroxy-2-pyridin-3-yIeth yl)-2- isopropylbenzenesulfonamide

[0895] In an analogous manner to Step 3, Example 317:

2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2-amino-l- pyridin-3-yl-ethanol were used to prepare 5-[(4-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-pyridin- 3-ylethyl)-2-isopropylbenzenesulfonamide. MS (ES+) m/z 479.1;

HPLC purity 96.7% at 210-370 nm, 8.4 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₃ FN ₂ O ₅ S ₂ + H+, 479.11052; found (ESI, (M+H] ⁺ ), 479.1088.

Example 732: 5-[(4-fluoroplienyl)sulfonyl]-λ'-(2-hydroxy-2-phenylethyl)- 2- isopropylbenzenesulfonamide

[0896] In an analogous manner to Step 3, Example 317:

2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2-amino-l- phenyl-ethanol were used to prepare 5-[(4-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-phenylethyl)- 2-isopropylbenzenesulfonamide . MS (ES-) m/z 476.1;

HPLC purity 100% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₄ FNO ₅ S ₂ + NH ₄ ⁺ , 495.14182; found (ESI, [M+NH4] ^"1" ), 495.1433.

Example 733: 5-[(4-fluorophenyl)sulfonyl]-iV-(2-hydroxy-l-methylethyl)-2- isopropylbenzenesulfonamide

[0897] In an analogous manner to Step 3, Example 317:

2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2-amino-l- propanol were used to prepare 5-[(4-fluorophenyl)sulfonyl]-N-(2-hydroxy-l-methylethyl)-2- isopropy lbenzenesulfonamide . MS (ES-) m/z 414.0;

HPLC purity 98.1% at 210-370 ran, 8.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₈ H ₂₂ FNO ₅ S ₂ + H+, 416.09962; found (ESI ₅ [M+H] ⁺ ), 416.0975.

Example 734 : 5- [(4-fluoropheny l)sulf ony 1] -N- [1 -(hydroxy methy l)-2-methylp ropy 1] -2- isopropylbenzenesulfonamide

[0898] In an analogous manner to Step 3, Example 317:

2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2-amino-3- methyl-butan-1-ol were used to prepare 5-[(4-fluorophenyl)sulfonyl]-iV-[l-(hydroxymethyl)-2- methylpropyl]-2-isopropylbenzenesulfonamide. MS (ES+) m/z 444.1;

HPLC purity 96.4% at 210-370 ran, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₆ FNO ₅ S ₂ + H+, 444.13092; found (ESI, [M+H] ⁴ ), 444.1322.

Example 735: iV-(2-hydroxy-2-pyridin-3-ylethyl)-2-isopropyl-5- (phenylsulfonyl)benzenesulfonamide

[0899] In an analogous manner to Step 3, Example 295:

5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and 2-amino-l-pyridin-3-yl- ethanol were used to prepare λ/-(2-hydroxy-2-pyridin-3-ylethyl)-2-isopropyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES+) m/z 461.1;

HPLC purity 100% at 210-370 ran, 8.1 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₄ N ₂ O ₅ S ₂ + H+, 461.11994; found (ESI, [M+H] ⁺ ), 461.1203.

Example 736: iY-(2-hydroxy-2-phenylethyl)-2-isopropyl-5-

(phenylsulfonyl)benzenesulfonamide

[0900] In an analogous manner to Step 3, Example 295:

5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and 2-amino-l-phenyl-ethanol were used to prepare N-(2-hydroxy-2-phenylethyl)-2-isopropyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES-) m/z 458.1;

HPLC purity 97.2% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₅ NO ₅ S ₂ + NH ₄ ⁺ , 477.15124; found (ESI, [M+NH4] ⁺ ), 477.1512.

Example 737: iV-(2-hydroxy-2-pyridin-3-ylethyl)-2,4-dimethyl-5- (phenylsulfonyl)benzenesulfonamide

[0901] In an analogous manner to Step 3, Example 295:

5-Benzenesulfonyl-2,4-dimethyl-benzenesulfonyl chloride and 2-amino-l-pyridin-3-yl- ethanol were used to prepare N-(2-hydroxy-2-pyridin-3-ylethyl)-2,4-dimethyl-5- (phenylsulfonyl)benzenesulfonamide. MS (ES+) m/z 447.1;

HPLC purity 100% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₂₂ N ₂ O ₅ S ₂ + H+, 447.10429; found (ESI, [M+H] ⁺ ), 447.1032.

Example 738: 5-[(4-fluorophenyl)sulfonyI]-JV-(2-hydroxybutyl)-2- isopropylbenzenesulfonamide

[0902] In an analogous manner to Step 3, Example 317:

2- Isopropyl -5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 1-aminobutan- 2-ol were used to prepare 5-[(4-fluorophenyl)sulfonyl]-iV-(2-hydroxybutyl)-2- isopropylbenzenesulfonamide. MS (ES-) m/z 428.1;

HPLC purity 100% at 210-370 nm, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₁₉ H ₂₄ FNO ₅ S ₂ + H+, 430.11527; found (ESI, [M+H] ⁺ ), 430.1147.

Example 739: N-[2-(liy-Imidazol-l-yl)ethyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0903] [2-(lH-Imidazol-l-yl)ethyl]amine dihydrochloride (97.3 mg, 0.529 mmol) was dissolved in 1 mL of water containing 169.3 mg (1.6 mmol) of sodium carbonate. Acetonitrile (4 mL) was then added. To this mixture 5-(phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonyl chloride (201.8 mg, 0.524 mmol), prepared in Example 677, in 10 mL of acetonitrile was added dropwise over 1.5 h. After the addition the reaction was stirred at room temperature for 19 h (overnight). The reaction was filtered and the filtrate concentrated under reduced pressure to give 255.4 mg of a yellow oil. Purification of the oil on 50 g of silica gel (230-400 mesh) using 50% ethyl acetate-methylene chloride and then 5% methanol-methylene chloride as the eluents gave N-[2-(l/i-imidazol-l-yl)ethyl]-5-(phenylsulfonyl)-2-(trifluo romethyl)benzenesulfonamide (78.4 mg, 33%) as a white solid. MS (ES) m/z 460.0;

HRMS: calcd for C ₁₈ H ₁₆ F ₃ N ₃ O ₄ S ₂ + H ⁺ , 460.06071; found (ESI, [M+H] ⁺ ), 460.0605; Anal. Calcd for C ₁₈ H ₁₆ F ₃ N ₃ O ₄ S ₂ : C, 47.05; H, 3.51; N, 9.15. Found: C, 47.04; H, 3.14; N, 9.03.

Example 740: 5-[(4-fluorophenyl)sulfonyl]-7V-(2-hydroxy-2-pyridin-3-yleth yl)-2- methylbenzenesulfonamide

[0904] In an analogous manner to Step 3, Example 298:

2-Methyl-5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2-amino-l-pyridin- 3-yl-ethanol were used to prepare 5-[(4-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-pyridin-3- ylethyl)-2-methylbenzenesulfonamide. MS (ES+) m/z 451.1;

HPLC purity 100% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₁₉ FN ₂ O ₅ S ₂ + H+, 451.07922; found (ESI, [M+H] ⁺ ), 451.0803.

Example 741 : iV-(2-hydroxy-2-py ridin-3-ylethyl)-5-(phenylsuIfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0905] In an analogous manner to Step 3, Example 677:

5-Benzenesulfonyl-2-trifluoromethyl-benzenesulfonyl chloride and 2-amino-l-pyridin-3- yl-ethanol were used to prepare N-(2-hydroxy-2-pyridin-3-ylethyl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 487.1;

HPLC purity 98.0% at 210-370 ran, 7.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₁₇ F ₃ N ₂ O ₅ S ₂ + H+, 487.06037; found (ESI, [M+H] ⁺ ), 487.0612.

Example 742: tert-Butyl [2-({[5-(phenylsuIfonyl)-2- (trifluoromethyl)phenyl] sulfonyl} amino)ethyl] carbamate

[0906] 5-(Phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonyl chloride (2.1471 g, 5.58 mmol), prepared in Example 677, in 25 mL of methylene chloride was added under nitrogen dropwise over 15 minutes to a solution of N-(2-aminoethyl)carbamic acid tert-butyl ester (883 ML, 5.58 mmol) and triethylamine (2.33 mL, 16.7 mmol) in 50 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for 5.5 h. The reaction was extracted with 2 N HCl, dried (anhydrous magnesium sulfate) and the solvent removed under reduced pressure to give 2.71 g of a white solid. Purification of the solid on 300 g of silica gel (230-400 mesh) using 100% methylene chloride to 15% ethyl acetate-methylene chloride as the eluent gave tert-butyl [2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate (2.05 g, 72%) as a white solid. MS (ESI) m/z 507.

Example 743 : 5- [(3-methoxy phenyl)sulf ony 1] -/V-(tetrahy dro-2H-py ran-4-yl)-2- (trifluoroniethyl)benzenesulfonamide

[0907] Step 1 : : Following the same procedure described on example 677 (Step 2), 2- chloro-5-fluoronitrobenzene was used to prepare 2-nitro-4-fluorobenzotrifluoride.

[0908] Step 2: To a stirred solution of 2-nitro-4-fluorobenzotrifluoride (1.6 g, 7.65 mmol) in dimethylformamide (20 mL) was added 3-methoxybenzenethiol (1 mL, 8.0 mmol) and potassium carbonate (2.1 g, 15.3 mmol). The resulting mixture was stirred at room temperature 2 hours, diluted with water and extracted with ethyl acetate. The organic layer was washed several times with water, dried over magnesium sulfate and concentrated. The crude mixture was dissolved in methylene chloride (25 mL) and mCPBA (3.5 g 77%, 15.7 mmol) was added. The

resulting mixture was stirred at room temperature for 30 minutes, washed with sodium dithionite solution and with sodium bicarbonate solution (sat). The organic layer was dried over magnesium sulfate and concentrated. Flash column separation using 0%-20% ethyl acetate/hexane gradient gave 5-(3-methoxyphenylsulfonyl)-2-trifluoromethyl-nitrobenzene (1.84 g, 65%).

[0909] Step 3: Following the same procedure described on example 677 (Step 3), 5-(3- methoxyphenylsulfonyl)-2-trifluoromethyl-nitrobenzene was used to prepare 5-(3- methoxyphenylsulfonyl)-2-trifluoromethylaniline.

[0910] Step 4: Following the same procedure described on example 677 (Step 4), 5-(3- methoxyphenylsulfonyl)-2-trifluoromethylaniline, was used to prepare 2-trifluoromethyl-5-(3- methoxylphenylsulfonyl)- benzenesulfonyl chloride.

[0911] Step 5: In an analogous manner to example 435, 2-trifluoromethyl-5-(3- methoxylphenylsulfonyl)- benzenesulfonyl chloride and tetrahydrofurfurylamine were used to prepare 5-[(3-methoxyphenyl)sulfonyl]-iV-(tetrahydro-2H-pyran-4-yl)- 2- (trifluoromethyl)benzenesulfonamide. MS (ES-) m/z 478.0;

HPLC purity 97.2% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 744: 5-[(3-hydroxyphenyl)sulfonyl]-iV-(tetrahydro-2fl-pyran-4-yl) -2- (trifluoromethyl)benzenesulfonamide

[0912] To a stirred solution of 5-[(3-methoxyphenyl)sulfonyl]-iV-(tetrahydro-2H-pyran- 4-yl)-2-(trifluoromethyl)benzenesulfonamide (0.08g, 0.17 mmol) in methylene chloride (2 mL) was added cyclohexene (2 drops) and boron tribromide solution IM in methylene chloride (0.6 mL, 0.6 mmol) at O ⁰ C. The resulting solution was stirred 1 hour, quenched with methanol, and washed with sodium bicarbonate solution (sat). The organic layer was concentrated and the crude solid was triturated in methylene chloride to give 5-[(3-hydroxyphenyl)sulfonyl]-iV- (tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)benzenesulfona mide (0.04 g, 51%). MS (ES-) m/z 464.0;

HPLC purity 95.7% at 210-370 nm, 8.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₈ H ₁₈ F ₃ NO ₆ S ₂ + H+, 466.06004; found (ESI, [M+H] ⁺ ), 466.0625.

Example 745: iV-(2-cyanoethyl)-5-[(3-methoxyphenyl)sulfonyl]-2- (trifluoromethyl)benzenesulfonamide

[0913] In an analogous manner to example 435, 2-trifluoromethyl-5-(3- methoxylphenylsulfonyl)- benzenesulfonyl chloride and aminopropionitrile were used to prepare iV-(2-cyanoetriyl)-5-[(3-methoxyphenyl)sulfonyl]-2-(trifluor omethyl)benzenesulfonamide. MS (ES-) m/z 447.0;

HPLC purity 97.9% at 210-370 ran, 8.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₇ Hi ₅ F ₃ N ₂ O ₅ S ₂ + H+, 449.04472; found (ESI, [M+H] ⁺ ), 449.0448.

Example 746 : N- [ l-(4-tert-butylbenzoyl)piperidin-4-yI] -5- [(3-methoxypheny l)sulf ony 1] -2- (trifluoromethyl)benzenesulfonamide

[0914] Step 1 : Following the same procedure described on example 462, piperidin-4-yl- carbamic acid tert-butyl ester and 4-tertbutylbenzoyl chloride were used to prepare [l-(4-tert- butyl-benzoyl)-piperidin-4-yl]-carbamic acid tert-butyl ester.

[0915] Step 2: Following the same procedure described on example 688, [l-(4-tert- butyl-benzoyl)-piperidin-4-yl]-carbamic acid tert-butyl ester was used to prepare (4-amino- piperidin-l-yl)-(4-tert-butyl-phenyl)-methanone.

[0916] Step 3: Following the same procedure described on example 435, 2- trifluoromethyl-5-(3-methoxylphenylsulfonyl)- benzenesulfonyl chloride and (4-amino- piperidin-l-yl)-(4-tert-butyl-phenyl)-methanone were used to prepare iV-[l-(4-tert- buty lbenzoy l)piperidin-4-yl] -5 - [(3 -methoxypheny l)sulfony 1] -2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 639.2;

HPLC purity 96.2% at 210-370 nm, 10.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₃₀ H ₃₃ F ₃ N ₂ O ₆ S ₂ + H+, 639.18049; found (ESI, [M+H] ⁺ ), 639.1804.

Example 747: 5-[(3-methoxyphenyl)sulfonyl]-7V-(2-pyridin-3-ylethyl)-2- (trifluoromethyl)benzenesulfonamide

[0917] In an analogous manner to example 435, 2-trifluoromethyl-5-(3- methoxylphenylsulfonyl)- benzenesulfonyl chloride and 3~(2-aminoethyl)pyridine were used to prepare 5-[(3-methoxyphenyl)sulfonyl]-N-(2-pyridin-3-ylethyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 501.1;

HPLC purity 100% at 210-370 nm, 8.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₁₉ F ₃ N ₂ O ₅ S ₂ + H+, 501.07602; found (ESI, [M+H] ^"1" ), 501.0756.

Example 748: λ'-{l-[(4-terϊ ^! -butylphenyl)sulfonyl]piperidin-4-yl}-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0918] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 4-tert-butylbenzenesulfonyl chloride were used to prepare N-{l-[(4-tert-butylphenyl)sulfonyl]piperidin-4-yl}-5-(phenyl sulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 645.1;

HPLC purity 94.7% at 210-370 nm, 10.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₈ H ₃₁ F ₃ N ₂ O ₆ S ₃ + H+, 645.13691; found (ESI, [M+H] ⁺ ) ₅ 645.1376.

Example 749: 5-(phenylsulfonyl)-2-(trifluoromethyl)-JV-{l-[4- (trifluoromethyl)benzyl] piperidin-4-ylJbenzenesulfonamide

[0919] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 4-trifluoromethylben2yl bromide were used to prepare 5-(phenylsulfonyl)-2-(trifluoromethyl)-N-{l-[4-(trifluoromet hyl)benzyl]piperidin-4- y 1 } benzenesulfonamide . MS (ES+) m/z 607.1;

HPLC purity 96.8% at 210-370 nm, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₆ H ₂₄ F ₆ N ₂ O ₄ S ₂ + H+, 607.11544; found (ESI, [M+H] ⁺ ), 607.1147.

Example 750: λ ^r -[l-(cyanomethyl)piperidin-4-yl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfbnamide

[0920] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and bromoacetonitrile were used to prepare N-[I- (cyanomethyl)piperidin-4-yl]-5-(phenylsulfonyl)-2-(trifluoro methyl)benzenesulfonamide. MS (ES+) m/z 488.1;

HPLC purity 96.7% at 210-370 nm, 8.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 rnL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₀ F ₃ N ₃ O ₄ S ₂ + H+, 488.09201; found (ESI, [M+H] ⁺ ), 488.0933.

Example 751 : λ ^r -[l-(2-oxo-2-phenylethyl)piperidin-4-yl]-5-(phenyIsulfonyl)- 2- (trifluoromethyl)benzenesulfonamide

[0921] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2'-bromoacetophenone were used to prepare N-[I -(2- oxo-2-phenylethyl)piperidin-4-yl]-5-(phenylsulfonyl)-2-(trif luoromethyl)benzenesulfonamide. MS (ES+) m/z 567.1;

HPLC purity 92.6% at 210-370 nm, 8.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₆ H ₂₅ F ₃ N ₂ O ₅ S ₂ + H+, 567.12297; found (ESI, [M+H] ⁺ ), 567.1232.

Example 752: 5-[(3-chlorophenyl)sulfonyl]~iV-(2-cyanoethyl)-2- (trifluoromethyl)benzenesulfonamide

[0922] In an analogous manner to example 743

Step 2: 3-chlorobenzenethiol and 2-nitro-4-fluorobenzotrifluoride were used to prepare 5- (3 -chloropheny lsulfonyl)-2-trifluoromethy 1-nitrobenzene .

[0923] Step 3 : Following the same procedure described on example 677 (Step 3), 5-(3- chlorophenylsulfonyl)-2-trifluoromethyl-nitrobenzene was used to prepare 5-(3- chlorophenylsulfonyl)-2-trifluoromethylaniline.

[0924] Step 4: Following the same procedure described on example 677 (Step 4), 5-(3- chlorophenylsulfonyl)-2-trifluoromethylaniline, was used to prepare 2-trifluoromethyl-5-(3- chlorophenylsulfonyl)- benzenesulfonyl chloride.

[0925] Step 5: In an analogous manner to example 435, 2-trifluoromethyl-5-(3~ chlorophenylsulfonyl)- benzenesulfonyl chloride and propionitrile were used to prepare 5-[(3- chlorophenyl)sulfonyl]-N-(2-cyanoethyl)-2-(trifluoromethyl)b enzenesulfonamide. MS (ES-) m/z 450.9;

HPLC purity 100% at 210-370 nm, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 753: iV-[l-(4-te^-butylbenzoyl)piperidm-4-yl]-5-[(3-chIorophenyI) sulfonyl]-2- (trifluoromethyl)benzenesulfonamide

[0926] Step 1 : Following the same procedure described on example 462, piperidin-4-yl- carbamic acid tert-butyl ester and 4-tertbutylbenzoyl chloride were used to prepare [l-(4-tert- butyl-benzoyl)-piperidin-4-yl]-carbamic acid tert-butyl ester.

[0927] Step 2: Following the same procedure described on example 688, [l-(4-tert- butyl-benzoyl)-piperidin-4-yl]-carbamic acid tert-butyl ester was used to prepare (4-amino- piperidin- 1 -y l)-(4-tert-buty l-phenyl)-methanone .

[0928] Step 3: Following the same procedure described on example 435, 2- trifluoromethyl-5-(3-chlorophenylsulfonyl)- benzenesulfonyl chloride and (4-amino-piperidin-l- yl)-(4-tert-butyl-phenyl)-methanone were used to prepare iV-[l-(4-te/-t-butylbenzoyl)piperidin-4- yl]-5-[(3-chlorophenyl)sulfonyl]-2-(trifluoromethyl)benzenes ulfonamide. MS (ES+) m/z 643.2;

HPLC purity 99.3% at 210-370 nm, 11.0 min.; Xterra RP18, 3.5u, 15O x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₉ H ₃₀ ClF ₃ N ₂ O ₅ S ₂ + H+, 643.13095; found (ESI, [MfH] ⁺ ), 643.1304.

Example 754: 5-[(3-chlorophenyl)sulfonyl]-iV-(tetrahydro-2jH ^r -pyran-4-yl)-2- (trifluoromethyl)benzenesulfonamide

[0929] In an analogous manner to example 435, 2-trifluoromethyl-5-(3- chlorophenylsulfonyl)- benzenesulfonyl chloride and tetrahydrofurfurylamine were used to prepare 5-[(3-chlorophenyl)sulfonyl]-N-(tetrahydro-2H ^" -pyran-4-yl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES-) m/z 481.9; HPLC purity 100% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2

mL/min ₅ 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 755: 5-[(3-chlorophenyl)sulfonyI]-λ ^r -(2-pyridin-3-ylethyl)-2- (trifluoromethyl)benzenesulfonamide

[0930] In an analogous manner to example 435, 2-trifluoromethyl-5-(3- chlorophenylsulfonyl)- benzenesulfonyl chloride and 3-(2-aminoethyl)pyridine were used to prepare 5-[(3-chlorophenyl)sulfonyl]-iV-(2-pyridin-3-ylethyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 505.1;

HPLC purity 94.1% at 210-370 nm, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₁₆ ClF ₃ N ₂ O ₄ S ₂ + H+, 505.02649; found (ESI, [M+H] ⁺ ), 505.0247.

Example 756 : 5- [(4-fluorophenyl)sulf onyl] -JV-(2-hy droxy-2-py ridin-2-ylethyl)-2- methylbenzenesulfonamide

[0931] In an analogous manner to Step 3, Example 298:

2-Methyl-5-(4-fluoro-benzenesulfonyl)-benzenesulfonyl chloride and 2-amino-l-pyridin- 2-yl-ethanol were used to prepare 5-[(4-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-pyridin-2- ylethyl)-2-methylbenzenesulfonamide. MS (ES+) m/z 451.1;

HPLC purity 100% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₁₉ FN ₂ O ₅ S ₂ + H+, 451.07922; found (ESI, [M+H] ⁺ ), 451.0801.

Example 757: λ^2-hydroxy-2-pyridin~2-ylethyl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0932] In an analogous manner to Step 3, Example 677:

5-Benzenesulfonyl-2-trifluoromethyl-benzenesulfonyl chloride and 2-amino-l-pyridin-2- yl-ethanol were used to prepare N-(2-hydroxy-2-pyridin-2-ylethyl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 487.1; HPLC purity 100% at 210-370 nm, 8.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2

mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₁₇ F ₃ N ₂ O ₅ S ₂ + H+, 487.06037; found (ESI, [M+H] ⁺ ), 487.0581.

Example 758: 5-(phenylsulfonyl)-iV-{l-[2-(trifluoromethoxy)benzoyl]piperi din-4-yI}-2- (trifluoromethyl)benzenesulf<mamide

[0933] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-trifluoromethoxybenzoyl chloride were used to prepare 5-(phenylsulfonyl)-N-{l-[2-(trifluoromethoxy)benzoyl]piperid in-4-yl}-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 637.1;

HPLC purity 96.0% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₆ H ₂₂ F ₆ N ₂ O ₆ S ₂ + H+, 637.08962; found (ESI ₅ [M+H] ⁺ ), 637.0891.

Example 759: iV-(4-tert-butylphenyl)-4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carboxam ide

[0934] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 4-tertbutylphenylisocyanate were used to prepare N- (4-tert-butylphenyl)-4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl} amino)piperidine-l -carboxamide. MS (ES+) m/z 624.2;

HPLC purity 97.0% at 210-370 nm, 10.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₉ H ₃₂ F ₃ N ₃ O ₅ S ₂ + H+, 624.18082; found (ESI, [MfH] ⁺ ), 624.1806.

Example 760: iV-(l-benzoylpiperidin-4-yl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0935] Step 1 : In an analogous manner to example 462, piperidin-4-yl-carbamic acid tert-butyl ester and benzoyl chloride were used to prepare (l-benzoyl-piperidin-4-yl)-carbaniic acid tert-butyl ester.

[0936] Step 2: In an analogous manner to example 680, (l-benzoyl-piperidin-4-yl)- carbamic acid tert-butyl ester was used to give l-benzoyl-4-aminopiperidine.

[0937] Step 3: In an analogous manner to example 435, 2-trifluoromethyl-5- (phenylsulfonyl)- benzenesulfonyl chloride and l-benzoyl-4-aminopiperidine were used to prepare iV-(l-benzoylpiperidin-4-yl)-5-(phenylsulfonyl)-2-(trifluoro methyl)benzenesulfonamide. MS (ES+) m/z 553.1;

HPLC purity 98.6% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₂₃ F ₃ N ₂ O ₅ S ₂ + H+, 553.10732; found (ESI, [M+H] ⁺ ), 553.1075.

Example 761: iV-[l-(4-ter^-butylbenzoyI)pyrrolidin-3-yl]-5-(phenylsulfony I)-2- (trifluoromethyl)benzenesulfonamide

[0938] Step 1 : In an analogous manner to example 462, 3-aminopyrrolidine-l- carboxylic acid tert-butyl ester and 4-tertbutylbenzoyl chloride were used to prepare [l-(4-tert- butyl-benzoyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester.

[0939] Step 2: In an analogous manner to example 680, [l-(4-tert-butyl-benzoyl)- pyrrolidin-3-yl]-carbamic acid tert-butyl ester was used to give l-(4-tertbutylbenzoyl)-3- aminopyrrolidine.

[0940] Step 3: In an analogous manner to example 435, 2-trifluoromethyl-5- (phenylsulfonyl)- benzenesulfonyl chloride and l-(4-tertbutylbenzoyl)-3-aminopyrrolidine were used to prepare λ/-[l-(4-tert-butylbenzoyl)pyrrolidin-3-yl]-5-(phenylsulfon yl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 595.1;

HPLC purity 96.2% at 210-370 nm, 10.3 min.; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₈ H ₂₉ F ₃ N ₂ O ₅ S ₂ + H+, 595.15427; found (ESI, [M+H] ⁺ ), 595.1547.

Example 762: N-(2-Aminoethyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)benze nesulfonamide hydrochloride

[0941] Approximately 100 mL of a saturated solution of anhydrous hydrogen chloride in ethyl acetate was added under nitrogen to a solution of tert-butyl [2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate (2.00 g, 3.93 mmol), prepared in Example 742, in 100 mL of ethyl acetate at room temperature. After the addition the reaction was stirred for 5 h. The solid was collected by filtration, rinsed with ethyl acetate and dried

under reduced pressure to give N-(2-aminoethyl)-5~(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide hydrochloride (1.6270 g, 93%) as a white solid. MS (ES+) m/z 409.1; HRMS: calcd for C ₁₅ H ₁₅ F ₃ N ₂ O ₄ S ₂ + H ⁺ , 409.04981; found (ESI ₅ [M+H] ⁺ ) ₅ 409.049.

Example 763: 5-(phenylsulfonyl)-2-(trifluoromethyl)-iV-{l-[4- (trifluoromethyl)phenyl]piperidin-4-yl}benzenesulfonamide

[0942] To a stirred solution of 5-(phenylsulfonyl)-N-piperidin-4-yl-2~ (trifluoromethyl)benzenesulfonamide (0.09 g, 0.2 mmol) in dimethylformamide (1 niL) was added potassium carbonate (0.06 g, 0.43 mmol) and 4-fluorobenzotrifluoride (0.06 g, 0.37 mmol). The resulting solution was heated to 100°C for three days and concentrated. The crude mixture was dissolved in methylene chloride, washed with ammonium chloride solution (sat.) and concentrated. Flash column separation using 0%-30% ethyl acetate/hexane gradient gave 5- (phenylsulfonyl)-2-(trifluoromethyl)-iV-{l-[4-(trifluorometh yl)phenyl]piperidin-4- yljbenzenesulfonamide (0.032 g, 28%). MS (ES+) m/z 593.1;

HPLC purity 98.1% at 210-370 nm, 11.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₂₂ F ₆ N ₂ O ₄ S ₂ + H+, 593.09979; found (ESI, [M+H] ⁺ ), 593.1013.

Example 764: iV-[l-(4-te^-butylbenzoyl)piperidin-4-yl]-5-[(3-hydroxypheny l)sulfonyl]-2- (trifluoromethyl)benzenesulfonamide

[0943] In an analogous manner to example 744, N-[l-(4-tert-butylbenzoyl)piperidin-4- yl]-5-[(3-methoxyphenyl)sulfonyl]-2-(trifluoromethyl)benzene sulfonamide was used to prepare N-[I -(4-tert-buty lbenzoy l)piperidin-4-yl] -5 - [(3 -hydroxypheny l)sulfony 1] -2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 625.2;

HPLC purity 97.0% at 210-370 nm, 10.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₉ H ₃₁ F ₃ N ₂ O ₆ S ₂ + H+, 625.16484; found (ESI, [M+H] ⁺ ), 625.1625.

Example 765: 5-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-4-ylmethyI)-2- (trifluoromethyl)benzenesulfonamide

[0944] A stirred solution of 5-(phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonyl chloride (0.101 g, 0.26 mmol) prepared in same matter as example 677, was taken up in dichloromethane (2 ml). 1.2 eq of 4-Aminomethyltetrahydropyran and 1.5 eq. trietylamine was syringed into the reaction vial and was allowed to stir overnight at room temperature. The product was transferred onto a 4 g Isco RediSep® Normal Phase column and was purified by automated flash chromatography using a gradient of 20% to 100% hexane/ethyl acetate. Isolation of the main component gave the title compound of 5-(phenylsulfonyl)-N-(tetrahydro-2H-pyran- 4-ylmethyl)-2-(trifluoromethyl)benzenesulfonamide (29 mg, 23.8%) as a white solid. MS (ES+) m/z 464.0;

HPLC purity 98.9% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₉ H ₂₀ F ₃ NO ₅ S ₂ + H+, 464.08077; found (ESI, [M+H]+), 464.079.

Example 766: N-(2-morpholin-4-ylethyl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0945] In an analogous manner to example 765, 5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonyl chloride and 2-morpholinoethanamine was used to prepare the title compound of N-(2-morpholin-4-ylethyl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide (99 mg, 78.8%) as a white solid. MS (ES+) m/z 479.1;

HPLC purity 100% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₉ H ₂₁ F ₃ N ₂ O ₅ S ₂ + H+, 479.09167; found (ESI, [M+H]+), 479.0921.

Example 767: N-(3-morpholin-4-ylpropyl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0946] In an analogous manner to example 765, 5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonyl chloride and N-(3-Aminopropyl)-morpholine was used to prepare the title compound N-(3-moφholin-4-ylpropyl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide (72 mg, 55.7%) as a white solid.

MS (ES+) m/z 493.1;

HPLC purity 93.8% at 210-370 ran, 6.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min. HRMS: calcd for C ₂₀ H ₂₃ F ₃ N ₂ O ₅ S ₂ + H+, 493.10732; found (ESI, [M+H]+), 493.1053;

Example 768: N-(3-methoxypropyl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0947] In an analogous manner to example 765, 5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonyl chloride and 3-methoxypropylamine was used to prepare the title compound N-(3 -methoxypropy l)-5 -(pheny lsulfonyl)-2-(trifluoromethy l)benzenesulfonamide (75 mg, 65.3%) as a white solid. MS (ES+) m/z 438.1;

HPLC purity 100% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₇ H ₁₈ F ₃ NO ₅ S ₂ + H+, 438.06512; found (ESI, [M+H]+), 438.064.

Example 769: N-[l-(hydroxymethyl)-2-methylpropyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0948] In an analogous manner to example 765, 5-(phenylsulfonyl)~2-

(trifluoromethyl)benzenesulfonyl chloride and 2-amino-3-methylbutanol was used to prepare the title compound N-[I -(hydroxymethyl)-2-methylpropyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide (27.5 mg, 23%) as a white solid. MS (ES+) m/z 452;

HPLC purity 89.5% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for Ci ₈ H ₂₀ F ₃ NO ₅ S ₂ + H+, 452.08077; found (ESI, [M+H]+), 452.0813.

Example 770: N-[2-({[5-(Phenylsulfonyl)-2- (trifluoromethyl)phenyl] sulfonyl} amino)ethyl]benzamide

[0949] Benzoyl chloride (39 μL, 0.336 mmol) was added under nitrogen to a mixture of N-(2-aminoethyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)benze nesulfonamide hydrochloride (150.7 mg, 0.339 mmole), prepared in Example 762, and triethylamine (57 μL, 0.409 mmol) in

20 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for approximately 24 h. An additional 57 μL (0.409 mmol) of triethylamine and 20 μL (0.172 mmol) of benzoyl chloride were added and the reaction was stirred for 4 h at room temperature. The reaction was extracted with 2 N HCl. The organic layer was separated and the aqueous layer was extracted three times with 10 % methanol-methylene chloride. The combined organic extracts were dried (anhydrous magnesium sulfate) and the solvent removed under reduced pressure to give 183 mg of a solid. Purification of the solid on a 12 g Redi Sep Flash Column (silica gel) using a gradient of 100% methylene chloride to 20% ethyl acetate- methylene chloride as the eluent gave N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide (106.2 mg, 61%) as a white solid. MS (ESI+) m/z 513;

HRMS: calcd for C ₂₂ H ₁₉ F ₃ N ₂ O ₅ S ₂ + H ⁺ , 513.07602; found (ESI, [M+H] ⁺ ), 513.0763; Anal. Calcd for C ₂₂ H ₁₉ F ₃ N ₂ O ₅ S ₂ : C, 51.56; H, 3.74; N, 5.47. Found: C, 51.53; H, 3.58; N, 5.40.

Example 771: 5-(phenylsuIfonyl)-N-(2-pyridin-4-ylethyl)-2- (trifluoromethyl)benzenesulfonamide

[0950] In an analogous manner to example 765, 5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonyl chloride and 2-(pyridine-4-yl)ethanamine was used to prepare the title compound 5-(phenylsulfonyl)-N-(2-pyridin-4-ylethyl)-2- (trifluoromethyl)benzenesulfonamide (40.4 mg, 38%) as a white solid. MS (ES+) m/z 471.1;

HPLC purity 100% at 210-370 nm, 8.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₁₇ F ₃ N ₂ O ₄ S ₂ + H+, 471.06546; found (ESI, [MfH]+), 471.0663.

Example 772 : N-(2,3-dihydro-lH-inden-2-yl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzeuesulfonamide

[0951] In an analogous manner to example 765, 5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonyl chloride and 2-aminoindan was used to prepare the title compound N-(2,3-dihydro-lH-inden-2-yl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide (56.2 mg, 44%) as a white solid. MS (ES-) m/z 480.0;

HPLC purity 91.5% at 210-370 nm, 10.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 773: N-[(2R)-2-hydroxy-2-phenyIethyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0952] In an analogous manner to example 765, 5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonyl chloride and (R)-2-amino-l-phenylethanol was used to prepare the title compound N-[(2R)-2-hydroxy-2-phenylethyl]~5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide (24.6 mg, 19%) as a white solid. MS (ES-) m/z 484.0;

HPLC purity 100% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 774: N-[(2S)-2-hydroxy-2-phenylethyl]-5-(phenylsuIfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0953] In an analogous manner to example 765, 5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonyl chloride and (>S)-2-ammo-l-phenylethanol was used to prepare the title compound iV-[(25)-2-hydroxy-2-phenylethyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide (45.5 mg, 36%) as a white solid. MS (ES-) m/z 484.0;

HPLC purity 100% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 775: 4-Methyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide

[0954] In an analogous manner as described in Example 770, replacing benzoyl chloride with 4-methyl-benzoyl chloride and using a gradient of 100% methylene chloride to 50% ethyl acetate-methylene chloride as the eluent gave 4-methyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide (105.1 mg, 59%) as a white solid. MS (ES+) m/z 527.1;

HRMS: calcd for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ + H ⁺ , 527.09167; found (ESI, [M+H] ⁺ ), 527.0905; Anal. Calcd for C ₂₃ H _2J F ₃ N ₂ O ₅ S ₂ : C, 52.46; H, 4.02; N, 5.32. Found: C, 52.28; H, 4.05; N, 5.12.

Example 776: 4-tert-Butyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide

[0955] In an analogous manner as described in Example 775, and replacing 4-methyl- benzoyl chloride with 4-tert-butyl-benzoyl chloride, gave 4~tert-butyl-N-[2-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)et hyl]benzamide (134.2 mg, 70%) as a white solid. MS (ES+) m/z 569.2;

HRMS: calcd for C ₂₆ H ₂₇ F ₃ N ₂ O ₅ S ₂ + H ⁺ , 569.13862; found (ESI, [M+H] ⁺ ), 569.1392; Anal. Calcd for C ₂₆ H ₂₇ F ₃ N ₂ O ₅ S ₂ : C, 54.92; H, 4.79; N, 4.93. Found: C ₅ 54.89; H, 4.74; N, 4.77.

Example 777: 4-Fluoro-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide

[0956] In an analogous manner as described in Example 775, and replacing 4-methyl- benzoyl chloride with 4-fluoro-benzoyl chloride, gave 4-fluoro-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide (96.8 mg, 54%) as a white solid. MS (ES+) m/z 531.0;

HRMS: calcd for C ₂₂ H ₁₈ F ₄ N ₂ O ₅ S ₂ + H ⁺ , 531.06660; found (ESI, [M+H] ⁺ ), 531.0664; Anal. Calcd for C ₂₂ H ₁₈ F ₄ N ₂ O ₅ S ₂ : C, 49.81; H ₃ 3.42; N, 5.28. Found: C, 49.71; H, 3.42; N, 5.09.

Example 778: 4-Chloro-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide

[0957] In an analogous manner as described in Example 775, and replacing 4-methyl- benzoyl chloride with 4-chloro-benzoyl chloride, gave 4-chloro-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide (131.2 mg, 71%) as a white solid. MS (ES+) m/z 547.0;

HRMS: calcd for C ₂₂ H ₁₈ ClF ₃ N ₂ O ₅ S ₂ + H ⁺ , 547.03705; found (ESI, [M+H] ⁺ ), 547.0378; Anal. Calcd for C ₂₂ H ₁₈ ClF ₃ N ₂ O ₅ S ₂ : C, 48.31; H, 3.32; N, 5.12. Found: C, 48.15; H, 3.38; N, 4.95.

Example 779: 4-Bromo-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl] sulf onyl} amino)ethyl]benzamide

[0958] In an analogous manner as described in Example 775, and replacing 4-methyl- benzoyl chloride with 4-bromo-benzoyl chloride, gave 4-bromo-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide (149.3 mg, 74%) as a white solid. MS (ESI+) m/z 591;

HRMS: calcd for C ₂₂ H ₁₈ BrF ₃ N ₂ O ₅ S ₂ + H ⁺ , 590.98653; found (ESI, [MH-H] ⁺ ), 590.9851; Anal. Calcd for C ₂₂ H ₁₈ BrF ₃ N ₂ O ₅ S ₂ : C, 44.68; H, 3.07; N ₅ 4.74. Found: C, 44.57; H, 3.32; N, 4.55.

Example 780: 4-Methoxy-N-[2-({[5-(phenylsuIfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide

[0959] In an analogous manner as described in Example 775, and replacing 4-methyl- benzoyl chloride with 4-methoxy-benzoyl chloride, gave 4-methoxy-N-[2-({[5-(phenylsulfonyl)~ 2-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide (163.5 mg, 89%) as a white solid. MS (ES+) m/z 543.1;

HRMS: calcd for C ₂₃ H ₂₁ F ₃ N ₂ O ₆ S ₂ + H ⁺ , 543.08659; found (ESI, [M+H] ⁺ ), 543.0869; Anal. Calcd for C ₂₃ H ₂₁ F ₃ N ₂ O ₆ S ₂ : C, 50.92; H, 3.90; N, 5.16. Found: C, 51.11; H, 3.71; N, 4.94.

Example 781: N-[2-({[5-(Phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfony l}amino)ethyl]- 4-(trifluoromethyl)benzamide

[0960] In an analogous manner as described in Example 775, and replacing 4-methyl- benzoyl chloride with 4-trifluoromethyl-benzoyl chloride, gave N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-4-(trifluorome thyl)benzamide (118.8 mg, 60%) as a white solid. MS (ES+) m/z 581.0;

HRMS: calcd for C ₂₃ H ₁₈ F ₆ N ₂ O ₅ S ₂ + H ⁺ , 581.06341; found (ESI, [M+H] ⁺ ), 581.0607; Anal. Calcd for C ₂₃ H ₁₈ F ₆ N ₂ O ₅ S ₂ : C, 47.59; H, 3.13; N, 4.83. Found: C, 47.45; H, 2.84; N ₃ 4.63.

Example 782: N-[2-({[5-(Phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfony l}amino)ethyl]- 4-(trifluoromethoxy)benzamide

[0961] In an analogous manner as described in Example 775, and replacing 4-methyl- benzoyl chloride with 4-trifluoromethoxy-benzoyl chloride, gave N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-4-(trifluor omethoxy)benzamide (122.8 mg, 60%) as a white solid.

MS (ES+) m/z 597.0;

HRMS: calcd for C ₂₃ H ₁₈ F ₆ N ₂ O ₆ S ₂ + H ⁺ , 597.05832; found (ESI, [M+H] ⁺ ) ₅ 597.0574;

Anal. Calcd for C ₂₃ Hi ₈ F ₆ N ₂ O ₆ S ₂ : C, 46.31; H, 3.04; N, 4.70. Found: C, 46.24; H, 2.59; N, 4.49.

Example 783: N-[2-({[5-(Phenylsulfonyl)-2- (trifluoromethyl)phenyl] sulf onyl} amino)ethyl] isonicotinamide

[0962] Isonicotinoyl chloride (61.5 mg, 0.345 mmol) was added under nitrogen to a mixture of N-(2-aminoethyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)benze nesulfonamide hydrochloride (150.1 mg, 0.337 mmol), prepared in Example 762, and triethylamine (141 IEIL, 1.01 mmol) in 20 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for approximately 24 h. The reaction was partitioned with water. The organic layer was separated and the aqueous layer was extracted three times with methylene chloride. The combined extracts were dried (anhydrous magnesium sulfate) and the solvent removed under reduced pressure to give 186.8 mg of a solid. Purification of the solid on a 12 g Redi Sep Flash Column (silica gel) using a gradient of 100% methylene chloride to 20% methanol-methylene chloride as the eluent gave N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]isonicotinamide (153.5 mg, 89%) as a white solid. MS (ES+) m/z 514.1;

HRMS: calcd for C ₂₁ H ₁₈ F ₃ N ₃ O ₅ S ₂ + H ⁺ , 514.07127; found (ESI, [M+H] ^"1" ), 514.0713; Anal. Calcd for C ₂₁ H ₁₈ F ₃ N ₃ O ₅ S ₂ : C, 49.12; H ₃ 3.53; N, 8.18. Found: C, 48.98; H, 2.94; N, 8.04.

Example 784: N-[(lR)-l-(hydroxymethyl)propyI]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[0963] In an analogous manner to example 765, 5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonyl chloride and (S)-(+)-2-amino-l-butanol was used to prepare the title compound N-[(lR)-l-(hydroxymethyl)propyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide (74.6 mg, 65%) as a white solid. MS (ES+) m/z 438.0;

HPLC purity 100% at 210-370 nm, 8.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₁₇ H ₁₈ F ₃ NO ₅ S ₂ + H+, 438.06512; found (ESI, [M+H]+), 438.0621.

Example 785: λ ^r -(2-hydroxyethyI)-5-[(3-methoxyphenyl)sulfonyl]-2- (trifluoromethyl)benzenesulfonamide

[0964] In an analogous manner to example 654, 2-txifluoromethyl-5-(3- methoxylphenylsulfonyl)- benzenesulfonyl chloride and ethanolamine were used to prepare N- (2-hydroxyethyl)-5-[(3-methoxyphenyl)sulfonyl]-2-(trifluorom ethyl)benzenesulfonamide. MS (ES-) m/z 438.0;

HPLC purity 100% at 210-370 nm, 8.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 rnL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₆ H ₁₆ F ₃ NO ₆ S ₂ + H+, 440.04439; found (ESI, [M+H] ⁺ ), 440.0446.

Example 786: tert-butyl (35)-3-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carboxyl ate

[0965] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and S-3-aminopiperidine-l- carboxylic acid tert-butyl ester were used to prepare fert-butyl (3S)-3-({[5-(phenylsulfonyl)-2- (trifluoromethyl)pheny 1] sulfony 1 } amino)piperidine- 1 -carboxy late . MS (ES-) m/z 547.0;

HPLC purity 96.6% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₇ F ₃ N ₂ O ₆ S ₂ + H+, 549.13354; found (ESI, [M+H] ⁺ ), 549.1335.

Example 787: tert-butyl (3U)-3-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carboxyl ate

[0966] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and R-3-aminopiperidine-l- carboxylic acid fert-butyl ester were used to prepare tert-butyl (3i?)-3-({[5-(phenylsulfonyl)-2- (trifluoromethy l)pheny 1] sulfonyl } amino)piperidine- 1 -carboxy late . MS (ES-) m/z 547.0;

HPLC purity 97.3% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₃ H ₂₇ F ₃ N ₂ O ₆ S ₂ + H+, 549.13354; found (ESI, [M+H]*), 549.1335.

Example 788: iV-[l-(2-hydroxyethyl)piperidin-4-yl]-5-(phenyIsulfonyI)-2- (trifluoromethyl)benzenesulfonamide

[0967] To a stirred solution of 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide (0.09 g, 0.20 mmol) in 1,4-dioxane (1 mL) was added 2- bromoethanol (0.05, 0.40 mmol) and triethylamine (0.1 mL, 0.7 mmol). The resulting solution was heated 150 ⁰ C in a microwave for 10 minutes and concentrated. Flash column separation using 0%-5% methanol/methylene chloride gradient gave N-[l-(2-hydroxyethyl)piperidin-4-yl]- 5-(phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide. (0.03 g, 30%). MS (ES+) m/z 493.1;

HPLC purity 98.3% at 210-370 ran, 6.8 min.; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₃ F ₃ N ₂ O ₅ S ₂ + H+, 493.10732; found (ESI, [M+H] ⁺ ), 493.1083.

Example 789: tert-butyl 4-[({5-[(4-fluorophenyl)sulfonyl]-2- methylphenyl}sulfonyl)amino]piperidine-l-carboxylate

[0968] To a solution of 5-(4-fluoro-benzenesulfonyl)-2-methyl-benzenesulfonyl chloride (1.0 g, 2.87 mmol) in dichloromethane (20.0 mL) was added triethylamine (0.80 mL, 5.73 mmol) followed by 4-amino-l-Boc-piperidne (0.69 g, 3.44 mmol). The reaction was stirred overnight at room temperature under nitrogen. The following day the reaction was concentrated down onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of tert-butyl 4-[({5-[(4- fluorophenyl)sulfonyl]-2- methylphenyl}sulfonyl)amino]piperidine-l-carboxylate (1.42 g, 97%). MS (ES-) m/z 511.0.

Example 790: 5-(phenylsulfonyl)-iV-[(3S)-piperidin-3-yl]-2- (trifluoromethyl)benzenesulfonamide

[0969] In an analogous manner to example 688, tert-butyl (35)-3-({[5-(phenylsulfonyl)- 2-(trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carbox ylate was used to prepare 5- (pheny lsulfony I)-N- [(35)-piperidin-3 -y 1] -2-(trifluoromethy l)benzenesulfonamide .

MS (ES+) m/z 449.1;

HPLC purity 97.1% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₈ H ₁₉ F ₃ N ₂ O ₄ S ₂ + H+, 449.08111; found (ESI, [M+H] ^"1" ), 449.0825.

Example 791: 5-(phenylsulfonyl)-iV-[(3R)-piperidin-3-yl]-2- (trifluoromethyl)benzenesulfonamide

[0970] In an analogous manner to example 688, tert-huty\ (3i?)-3-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl} amino)piperidine-l -carboxylate was used to prepare 5-(pheny lsulfony I)-N- [(3i?)-piperidin-3 -y 1] -2-(trifluoromethy l)benzenesulfonamide . MS (ES+) m/z 449.1;

HPLC purity 96.9% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₈ H ₁₉ F ₃ N ₂ O ₄ S ₂ + H+, 449.08111 ; found (ESI, [M+H] ⁺ ), 449.0822.

Example 792: 5-[(l,2-dimethyl-lZT-indol-5-yl)sulfonyl]-iV-piperidin-4-yl- 2- (trifluoromethyl)benzenesulfonamide

[0971] Step 1 : To a stirred solution of 4-fluoro-2-bromobenzotrifluoride (2.0 g, 8.23 mmol) in THF (50 mL) at -78 °C was added nButyl lithium 2.5M in hexane (4.0 mL, 10.0 mmol) dropwise over 5 minutes. The resulting solution was stirred for 15minutes, then sulfur dioxide was bubbled in over 20 minutes, and the solution as concentrated. The crude mixture was taken up in methylene chloride (50 mL) and N-Chlorosuccinimide (1.1 g, 8.23 mmol) was added. The resulting solution was stirred room temperature for 1.5hrs, washed with ammonium chloride solution (sat.) and concentrated. Flash column separation using 0%-30% ethyl acetate/hexane gradient gave 5-fluoro-2-trifluoromethylbenzenesulfonyl chloride (0.55 g, 25%).

[0972] Step 2: In an analogous manner to example 435, 5-fluoro-2- trifluoromethylbenzenesulfonyl chloride and 4-aminopiperidine-l- carboxylic acid tert-butyl ester were used to prepare tert-butyl 4-({[5-fluoro-2- (trifluoromethy l)pheny 1] sulfony 1} amino)piperidine- 1 -carboxylate .

[0973] Step 3: To a stirred solution of 5-bromo-2-methyl-indole (5.0 g, 23.5 mmol) in DMF (50 mL) at 0 ⁰ C was added sodium hydride (1.13 g(60%), 28.05 mmol) and the resulting solution was stirred for 5 minutes. Methyl iodide (3.3mL, 52.8 mmol) was added and the

reaction was allowed to warm to room temperature. After lhr, the reaction was quenched with ammonium chloride solution (sat), and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Flash column separation using 0%-10% ethyl acetate/hexane gradient gave crude l,2-dimethyl-5- bromoindole. This material was dissolved in THF (30 mL) and chilled to -78 ⁰ C. nButyl lithium 2.5M in hexane (4.0 mL, 10.0 mmol) was added dropwise. After 10 minutes sulfur dioxide was bubbled into the reaction mixture for 15 minutes. The mixture was allowed to warm to room temperature and concentrated to give l,2-dimethylindole-5-sulfinic acid lithium salt. HRMS: calcd for C ₂₁ H ₂₅ F ₃ N ₂ O ₆ S ₂ + H+, 523.11789; found (ESI, [M+H-C ₄ H ₈ ] ⁺ ), 467.0601. C ₄ H ₈ .

[0974] Step 4: To a stirred solution of l,2-dimethylindole-5-sulfinic acid lithium salt (0.10 g, 0.54 mmol) in dimethylformamide (1 mL), fert-butyl 4-({[5-fluoro-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carboxyl ate (0.115 g, 0.27 mmol) was added and the resulting solution was heated to 80°C overnight and concentrated. The crude material was taken up in ethyl acetate, washed with sodium bicarbonate solution (sat) and concentrated. Flash column separation using 0%-40% ethyl acetate/hexane gradient gave tert- butyl 4-({[5-(l,2-dimethyl-lH-indol-5-yl)sulfonyl)-2- (trifluoromethy l)pheny 1] sulfony 1 } amino)piperidine- 1 -carboxy late .

[0975] Step 5: In an analogous manner to example 688, tert-butyl 4-({[5-(l,2-dimethyl- lH-indol-5-yl)sulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}a mino)piperidine-l-carboxylate was used to prepare 5-[(l,2-dimethyl-l/f-indol-5-yl)sulfonyl]-N-piperidin-4-yl-2 - (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 516.1;

HPLC purity 100% at 210-370 nm, 8.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₄ F ₃ N ₃ O ₄ S ₂ + H+, 516.12331; found (ESI, [M+H] ⁺ ), 516.1237.

Example 793: tert-Butyl methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate

[0976] 5-(Phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonyl chloride (2.6940 g, 7.00 mmol), prepared in Example 677, in 25 mL of methylene chloride was added under nitrogen dropwise over 30 minutes to a solution of N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl

ester (1.25 mL, 6.99 mmol) and triethylamine (2.93 mL, 21.0 mmol) in 50 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for 7 h. The reaction was extracted with 2 N HCl. The organic layer was separated and the aqueous layer was extracted three times with methylene chloride. The combined extracts were dried (anhydrous magnesium sulfate) and the solvent removed under reduced pressure to give 2.98 g of a yellow foam. Purification of the foam on 500 g of silica gel (230-400 mesh) using 10% ethyl acetate-methylene chloride to 20% ethyl acetate-methylene chloride as the eluent gave tert- butyl methyl[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sul fonyl}amino)ethyl]carbamate (862.1 mg, 24%) as a yellow foam. MS (ES) m/z 521.0.

Example 794: tert-butyl (3S)-3-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)pyrrolidine-l-carboxy late

[0977] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and S-3-aminopyrrolidine-l- carboxylic acid tert-butyl ester were used to prepare tert-butyl (3>S)-3-({[5-(phenylsulfonyl)-2- (trifluoromethy l)pheny 1] sulfony 1} amino)pyrrolidine- 1 -carboxy late . MS (ES-) m/z 533.0;

HPLC purity 97.3% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 795: tert-butyl (3R)-3-({[5-(phenylsuIfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)pyrrolidine-l-carboxy late

[0978] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and R-3-aminopyrrolidine-l- carboxylic acid tert-butyl ester were used to prepare tert-butyl (3i?)-3-({[5-(phenylsulfonyl)-2- (trifluoromethy l)pheny 1] sulfony 1 } amino)pyrrolidine- 1 -carboxy late.

HPLC purity 97.6% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. MS (ES-) m/z 533.0.

Exaraple 796: 5-(phenylsulfonyl)-iV-[(3S)-pyrroIidin-3-yl]-2- (trifluoromethyl)benzenesulfonamide

[0979] In an analogous manner to example 688, tert-butyl (35)-3-({[5-(phenylsulfonyl)- 2-(trifluoromethyl)phenyl]sulfonyl}amino)pyrrolidine-l-carbo xylate was used to prepare 5- (phenylsulfonyl)-N-[(3)S)-pyrrolidin-3-yl]-2-(trifluoromethy l)benzenesulfonamide. MS (ES+) m/z 434.7;

HPLC purity 97.2% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₇ H ₁₇ F ₃ N ₂ O ₄ S ₂ + H+, 435.06546; found (ESI, [M+H] ⁺ ), 435.0656.

Example 797: 5-(phenylsulfonyl)-iV-[(3R)-pyrrolidin-3-yl]-2- (trifluoromethyl)benzenesulfonamide

[0980] In an analogous manner to example 688, fert-butyl (3i?)-3-({[5- (phenylsulfonyl)-2-(trifluoromethyl)p]ienyl]sulfonyl}amino)p yrrolidine-l-carboxylate was used to prepare 5-(phenylsulfonyl)-iV-[(3i?)-pyrrolidin-3-yl]-2-(trifluorome tliyl)benzenesulfonamide. MS (ES+) m/z 434.7;

HPLC purity 96.9% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₇ H ₁₇ F ₃ N ₂ O ₄ S ₂ + H+, 435.06546; found (ESI ₅ [M+H] ⁺ ), 435.0658.

Example 798: 2-methyl-5-(phenyIsulfonyl)-N-(tetrahydro-2H-thiopyran-4- yl)benzenesulfonamide

[0981] Step 1 : To a solution of tetrahydrothiopyran-4-one (3.0 g, 25.82 mmol) and 2,4- dimethoxybenzylamine (4.3 g, 25.82 mmol) in dichloroethane was added sodium triacetoxyborohydride (7.7 g, 36.15 mmol). The reaction was stirred overnight at room temperature under nitrogen. The reaction was quenched with a saturated aqueous bicarbonate solution and extracted. Dried with magnesium sulfate and concentrated down to give (2,4- dimethoxy-benzyl)-(tetrahydro-thiopyran-4-yl)-amine (6.7 g, 97%).

[0982] Step 2: To a solution of 5-benzenesulfonyl-2-methyl-benzenesulfonyl chloride (0.30 g, 0.90 mmol) in dichloromethane (12 niL) was added triethylamine (0.38 μL, 2.72 mmol) followed by (2,4-dimethoxy-benzyl)-(tetrahydro-thiopyran-4-yl)-amine (0.49 g, 1.81 mmol). The reaction was stirred overnight at room temperature under nitrogen. The following day the

reaction was concentrated down onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of 5-benzenesulfonyl-N-(2 ₅ 4-dimethoxy-benzyl)-2-methyl-N-(tetrahydro-thiopyran-4-yl)- benzenesulfonamide .

[0983] Step 3: 5-Benzenesulfonyl-N-(2,4-dimethoxy-ben2yl)-2-methyl-N-(tetra hydro- thiopyran-4-yl)-benzenesulfonamide was taken up in 5 mL of 6% trifluoroacetic acid/dichloromethane and was stirred overnight at room temperature under nitrogen. The reaction was extracted with water. The organic layer was washed with saturated solution of sodium bicarbonate and dried with magnesium sulfate. The reaction was concentrated down onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of 2-methyl-5-(phenylsulfonyl)- N-(tetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (0.31 g, 84%). MS (ES+) m/z 411.7; HRMS: calcd. for C ₁₈ H ₂₁ NO ₄ S ₃ + H ⁺ , 412.0711: found (ESI, [M+H] ⁺ ), 412.0681.

Example 799: N-[2-(Methylamino)ethyl]-5-(phenylsuIfonyl)-2- (trifluoromethyl)benzenesulfonamide hydrochloride

[0984] Approximately 100 mL of a saturated solution of anhydrous hydrogen chloride in ethyl acetate was added to a solution of tert-butyl methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate (2.8555 g, 5.46 mmol), prepared in Example 793, in 100 mL of ethyl acetate at room temperature. After the addition the reaction was stirred for 6 h. The solid was collected by filtration, rinsed with ethyl acetate and dried under reduced pressure to give N-[2-(methylamino)ethyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide hydrochloride (2.2506 g, 90%) as a white solid. MS (ES-) m/z 420.6; HRMS: calcd for C ₁₆ H ₁₇ F ₃ N ₂ O ₄ S ₂ + H ⁺ , 423.06546; found (ESI, [M+H] ⁺ ), 423.0543.

Example 800: JV-[l-(4-benzoylbenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)-2 - (trifluoromethyl)benzenesulfonamide

[0985] A solution of 4-benzoyl-benzoyl chloride (34 mg, 0.14 mmol) in dichloromethane (1 mL) was added to a stirred dichloromethane solution of Example 688 (62 mg, 0.14 mmol) and triethylamine (0.28 mmol). The reaction was concentrated to dryness and

immediately purified by flash column chromatography using an ethyl acetate hexane gradient

(20-50%) resulting in the isolation of iV-[l-(4-benzoylbenzoyl)piperidin-4-yl]-5-

(phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide (72 mg, 79%).

MS (ES+) m/z 656.6;

HPLC purity 93.4% at 210-370 ran, 10.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₃₂ H ₂₇ F ₃ N ₂ O ₆ S ₂ + H+, 657.13354; found (ESI, [M+H] ^"1" ), 657.1337.

Example 801 : iV-[l-(3-benzoylbenzoyI)piperidin-4-yl]-5-(phenylsulfonyl)-2 - (trifluoromethyl)benzenesulfonamide

[0986] A solution of 3 -benzoyl-benzoyl chloride (34 mg, 0.14 mmol) in dichloromethane (1 mL) was added to a stirred dichloromethane solution of Example 688 (62 mg, 0.14 mmol) and triethylamine (0.28 mmol). The reaction was concentrated to dryness and immediately purified by flash column chromatography using an ethyl acetate hexane gradient (20-50%) resulting in the isolation of iV-[l-(3-benzoylbenzoyl)piperidin-4-yl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide (67 mg, 71%). MS (ES+) m/z 656.7;

HPLC purity 95.1% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₃₂ H ₂₇ F ₃ N ₂ O ₆ S ₂ + H+, 657.13354; found (ESI, [M+H] ⁺ ), 657.1326.

Example 802: l-Isopropyl-4-(phenylsulfonyl)benzene

[0987] Step a

The title compound was prepared from 4-isopropylbenzenesulfonyl chloride (8.75 g, 40.0 mmol), benzene (20.0 mL, 200 mmol), and aluminum chloride (6.4 g, 48.0 mmol) according to the procedure and in the same manner as described in Example 678, step a. l-Isopropyl-4- (phenylsulfonyl)benzene (10.32g, 99%) was obtained as a homogeneous oil which solidified on standing.

[0988] Step b

2-Isopropyl-5-(phenyIsulfonyl)benzenesulfonyl chloride l-Isopropyl-4-(phenylsulfonyl)benzene (10.4 g, 40.0 mmol) was heated with stirring at 60 ⁰ C for one hour under nitrogen with chlorosulfonic acid (26.5 mL, 400 mmol). The mixture

was cooled to room temperature, poured slowly into a cold solution of 2N hydrochloric acid, and extracted with ethyl acetate (2x.). The organic phase was washed with a saturated, aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent concentrated in vacuo to yield 2-isopropyl-5-(phenylsulfonyl)benzenesulfonyl chloride (3.3 g, 24%) as a homogeneous, colorless, crystalline solid. [0989] Step c

N-(l-Benzoylpiperidin-4-yl)-2-isopropyI-5-(phenylsulfonyI)be nzenesulfonamide A stirred solution of 2-isopropyl-5-(phenylsulfonyl)benzenesulfonyl chloride (0.18 g, 0.5 mmol) in dichloromethane (10 mL) was treated under nitrogen with (4-aminopiperidin-l- yl)(phenyl)methanone hydrochloride (0.18 g, 0.75 mmol) and a solution of diisopropylethylamine (0.26 g, 2.0 mmol) in dichloromethane. The reaction was stirred from 2- 18 hours at room temperature. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 50%- 100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford, after crystallization from diethyl ether-hexane, JV-(I -benzoylpiperidin-4-yi)-2-isopropyl-5- (phenylsulfonyl)benzenesulfonamide (0.26 g, 76%), as a homogeneous, colorless, crystalline solid, m.p. 225 °C; MS (+ESI), m/z: 526.7 [MH-H] ⁺ ;

HRMS: calcd for C ₂₇ H ₃₀ N ₂ O ₅ S ₂ + H+, 527.16689; found (ESI, [M+H] ⁺ ), 527.1677; HPLC purity 100% at 210-370 nm, 9.5 min.; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 803: 2-Isopropyl-iV-[l-(2-methoxybenzoyl)piperidin-4-yl]-5- (phenylsulfonyl)benzenesulfonamide

[0990] The title compound was prepared from 2-isopropyl-5-

(phenylsulfonyl)benzenesulfonyl chloride (0.18 g, 0.5 mmol), (4-aminopiperidin-l-yi)(2- methoxyphenyl)methanone hydrochloride (0.20 g, 0.75 mmol), and diisopropylethylamine (0.26 g, 2.0 mmol) according to the procedure and in the same manner as described in Example 802, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 75%-100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min to afford 2-isopropyl-iV-[l-(2-

methoxybenzoyl)piperidin-4-yl]-5-(phenylsulfonyl)benzenesulf onamide (0.21 g, 75%), as a homogeneous, amorphous solid, m.p. 160-162 ⁰ C;

MS (+ESI), m/z: 556.7 [M+H] ⁺ ;

HRMS: calcd for C ₂₈ H ₃₂ N ₂ O ₆ S ₂ + H+, 557.17745; found (ESI ₅ [M+H] ⁺ ), 557.1782;

HPLC purity 99.3% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 804: JV-[l-(3-Fluorobenzoyl)piperidin-4-yl]-2-isopropyI-5- (phenylsulfonyl)benzenesulfonamide

[0991] The title compound was prepared from 2-isopropyl-5-

(phenylsulfonyl)benzenesulfonyl chloride (0.18 g, 0.5 mmol), (4-aminopiperidin~l-yl)(3- fluorophenyl)methanone hydrochloride (0.19 g, 0.75 mmol), and diisopropylethylamine (0.26 g, 2.0 mmol) according to the procedure and in the same manner as described in Example 802, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 50%- 100% methyl terf-butyl ether in hexane at a flow rate of 50 mL/min to afford, after crystallization from diethyl ether- hexane, N-[I -(3-fluorobenzoyl)piperidin-4-yl]-2-isopropyl-5-

(phenylsulfonyl)benzenesulfonamide (0.16 g, 59%), as a homogeneous, colorless, crystalline solid, m.p. 215-218 °C; MS (+ESI), m/z: 544.7 [M+H] ⁺ ;

HRMS: calcd for C ₂₇ H ₂₉ FN ₂ O ₅ S ₂ + H+, 545.15747; found (ESI, [M+H] ⁺ ), 545.158; HPLC purity 100% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 805: JV-[l-(4-Fluorobenzoyl)piperidin-4-yl]-2-isopropyl-5- (phenylsulfonyl)benzenesulfonamide

[0992] The title compound was prepared from 2-isopropyl-5-

(phenylsulfonyl)benzenesulfonyl chloride (0.18 g, 0.5 mmol), (4-aminopiperidin-l-yl)(4- fluorophenyl)methanone hydrochloride (0.19 g, 0.75 mmol), and diisopropylethylamine (0.26 g, 2.0 mmol) according to the procedure and in the same manner as described in Example 802, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 50%- 100% methyl tert-butyl

ether in hexane at a flow rate of 50 mL/min to afford, after crystallization from diethyl ether- hexane, N-[I -(4-fTuorobenzoyi)piperidin-4-yi]-2-isopropyl-5-

(phenylsulfonyl)benzenesulfonamide (0.18 g, 64%), as a homogeneous, colorless, crystalline solid, m.p. 218-220 °C;

MS (+ESI), m/z: 544.7 [M+H] ⁺ ;

HRMS: calcd for C ₂₇ H ₂₉ FN ₂ O ₅ S ₂ + H+, 545.15747; found (ESI, [M+H] ⁺ ), 545.1559;

HPLC purity 100% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 806: iV-[l-(2-Fluorobenzoyl)piperidin-4-yl]-2-isopropyl-5- (phenylsulfonyl)benzenesulfonamide

[0993] The title compound was prepared from 2-isopropyl-5-

(phenylsulfonyl)benzenesulfonyl chloride (0.18 g, 0.5 mmol), (4-aminopiperidin-l-yl)(2- fluorophenyl)methanone hydrochloride (0.19 g, 0.75 mmol), and diisopropylethylamine (0.26 g, 2.0 mmol) according to the procedure and in the same manner as described in Example 802, step c. The crude product was purified by preparative liquid chromatography on a Biotage 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 50%- 100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min to afford, after crystallization from diethyl ether- hexane, N-[I -(2-fluorobenzoyl)piperidin-4-yl]-2-isopropyl-5-

(phenylsulfonyl)benzenesulfonamide (0.18 g, 68%), as a homogeneous, colorless, crystalline solid, m.p. 210-212 °C; MS (+ESI) ₅ m/z: 544.7 [M+H] ⁺ ;

HRMS: calcd for C ₂₇ H ₂₉ FN ₂ O ₅ S ₂ + H+, 545.15747; found (ESI, [M+H] ⁺ ), 545.1573; HPLC purity 100% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 807: 2-Isopropyl-5-(phenylsulfonyl)-iV-{l-[4-(trifluoromethyl)ben zoyl]piperidin-4- yl} benzenesulfonamide

[0994] The title compound was prepared from 2-isopropyl-5-

(phenylsulfonyl)benzenesulfonyl chloride (0.18 g, 0.5 mmol), (4-aminopiperidin-l-yl)(4- (trifiuoromethyl)phenyl)methanone hydrochloride (0.23 g, 0.75 mmol), and diisopropylethylamine (0.26 g, 2.0 mmol) according to the procedure and in the same manner as

described in Example 802, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 25%-100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min to afford 2- isopropyl-5-(phenylsulfonyl)-N-{l-[4-(trifluoromethyl)benzoy l]piperidin-4- yl}benzenesulfonamide (0.24 g, 79%), as a homogeneous, amorphous solid, m.p. 140-142 °C; MS (+ESI), m/z: 594.7 [M+H] ⁺ ;

HRMS: calcd for C ₂₈ H ₂₉ F ₃ N ₂ O ₅ S ₂ + H+, 595.15427; found (ESI, [M+H] ⁺ ), 595.1538; HPLC purity 99.3% at 210-370 nm, 10.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 808: 2-Isopropyl-iV-[l-(l-naphthoyl)piperidin-4-yl]-5- (phenylsulfonyl)benzenesulfonamide

[0995] The title compound was prepared from 2-isopropyl-5- (phenylsulfonyl)benzenesulfonyl chloride (0.18 g, 0.5 mmol), (4-aminopiperidin-l- yl)(naphthalen-l-yl)methanone hydrochloride (0.22 g, 0.75 mmol), and diisopropylethylamine (0.26 g, 2.0 mmol) according to the procedure and in the same manner as described in Example 802, step c. The crude product was purified by preparative liquid chromatography on a Biotage ³ 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 50%- 100% methyl tert- butyl ether in hexane at a flow rate of 50 mL/min to afford 2-isopropyl-iV-[l-(l- naphthoyl)piperidin-4-yl]-5-(phenylsulfonyl)benzenesulfonami de (0.27 g, 92%), as a homogeneous, amorphous solid, m.p. 163-165 °C; MS (+ESI), m/z: 576.7 [M+H] ⁺ ;

HRMS: calcd for C ₃₁ H ₃₂ N ₂ O ₅ S ₂ + H+, 577.18254; found (ESI, [M+H] ⁺ ), 577.1828; HPLC purity 99.0% at 210-370 nm, 10.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 809: 2-Isopropyl-λ ^L [l-(2-naphthoyl)piperidin-4-yl]-5- (phenylsulfonyl)benzenesulfonamide

[0996] The title compound was prepared from 2-isopropyl-5- (phenylsulfonyl)benzenesulfonyl chloride (0.18 g, 0.5 mmol), (4-aminopiperidin-l- yl)(naphthalen-2-yl)methanone hydrochloride (0.22 g, 0.75 mmol), and diisopropylethylamine (0.26 g, 2.0 mmol) according to the procedure and in the same manner as described in Example

802, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^®

40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 25%- 100% methyl tert- butyl ether in hexane at a flow rate of 50 mL/min to afford 2-isopropyl-N-[l-(2- naphthoyl)piperidin-4-yl]-5-(phenylsulfonyl)benzenesulfonami de (0.24 g, 84%), as a homogeneous, amorphous solid, m.p. 130-132 ⁰ C;

MS (+ESI), m/z: 576.7 [M+H] ⁺ ;

HRMS: calcd for C ₃₁ H ₃₂ N ₂ O ₅ S ₂ + H+, 577.18254; found (ESI, [M+H] ⁺ ), 577.183;

HPLC purity 99.7% at 210-370 nm, 10.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 810: iV-[l-(3-Cyanobenzoyl)piperidin-4-yl]-2-isopropyl~5- (phenylsulfonyl)benzenesulfonamide

[0997] The title compound was prepared from 2-isopropyl-5- (phenylsulfonyl)benzenesulfonyl chloride (0.18 g, 0.5 mmol), 3-(4-aminopiperidine-l- carbonyl)benzonitrile hydrochloride (0.20 g, 0.75 mmol), and diisopropylethylamine (0.26 g, 2.0 mmol) according to the procedure and in the same manner as described in Example 802, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 50%-100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min to afford JV-[I -(3-cyanobenzoyl)piperidin-4-yl]-2- isopropyl-5-(phenylsulfonyl)benzenesulfonamide (0.19 g, 69%), as a homogeneous, amorphous solid, m.p. 120-122 °C; MS (+ESI), m/z: 551.7 [M+H] ⁺ ;

HRMS: calcd for C ₂₈ H ₂₉ N ₃ O ₅ S ₂ + H+, 552.16214; found (ESI, [M+H] ⁺ ), 552.1634; HPLC purity 100% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 811: iV~[l-(4-Cyanobenzoyl)piperidm-4-yI]-2-isopropyI-5- (phenylsulfonyl)benzenesulfonamide

[0998] The title compound was prepared from 2-isopropyl-5- (phenylsulfonyl)benzenesulfonyl chloride (0.18 g, 0.5 mmol), 4-(4-aminopiperidine-l- carbonyl)benzonitrile hydrochloride (0.20 g, 0.75 mmol), and diisopropylethylamine (0.26 g, 2.0 mmol) according to the procedure and in the same manner as described in Example 802, step c.

The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 25%- 100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min to afford iV-[l-(4-cyanobenzoyl)piperidin-4-yl]-2- isopropyl-5-(phenylsulfonyl)benzenesulfonamide (0.21 g, 77%), as a homogeneous, amorphous solid, m.p. 136-138 ⁰ C;

MS (+ESI) ₅ m/z: 551.7 [M+H] ⁺ ;

HRMS: calcd for C ₂₈ H ₂₉ N ₃ O ₅ S ₂ + H+, 552.16214; found (ESI, [M+H] ⁺ ) ₅ 552.1635;

HPLC purity 100% at 210-370 ran, 9.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 812: iV-[l-(4-te^-Butylbenzoyl)piperidin-4-yl]-2-isopropyl-5- (phenylsulfonyl)benzenesulfonamide

[0999] The title compound was prepared from 2-isopropyl-5-

(phenylsulfonyl)benzenesulfonyl chloride (0.18 g, 0.5 mmol), (4-aminopiperidin-l-yl)(4-tert- butylphenyl)methanone hydrochloride (0.22 g, 0.75 mmol), and diisopropylethylamine (0.26 g, 2.0 mmol) according to the procedure and in the same manner as described in Example 802, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 10%- 100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min to afford, after crystallization from diethyl ether- hexane, N-[l-(4-tert-butylbenzoyl)piperidin-4-yl]-2-isopropyl-5-

(phenylsulfonyl)benzenesulfonamide (0.28 g, 95%), as a homogeneous, colorless, crystalline solid, m.p. 150-152 ⁰ C; MS (+ESI), m/z: 582.8 [M+H] ⁺ ;

HRMS: calcd for C ₃₁ H ₃₈ N ₂ O ₅ S ₂ + H+, 583.22949; found (ESI, [M+H] ⁺ ), 583.2277; HPLC purity 99.4% at 210-370 nm, 10.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 813: N-[l-(2-Ethoxy-l-naphthoyI)piperidin-4-yl]-2-isopropyl-5- (phenylsulfonyl)benzenesulfonamide

[1000] The title compound was prepared from 2-isopropyl-5-

(phenylsulfonyl)benzenesulfonyl chloride (0.18 g, 0.5 mmol), (4-aminopiperidin-l-yl)(2- ethoxynaphthalen-l-yl)methanone hydrochloride (0.25 g, 0.75 mmol), and

diisopropylethylamine (0.26 g, 2.0 mmol) according to the procedure and in the same manner as described in Example 802, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (45 g), eluting with a gradient of 10%-100% methyl terf-butyl ether in hexane at a flow rate of 50 mL/min to afford, after crystallization from diethyl ether-hexane, iV-[l-(2-ethoxy-l-naphthoyl)piperidin-4-yl]-2- isopropyl-5-(phenylsulfonyl)benzenesulfonamide (0.28 g, 89%), as a homogeneous, colorless, crystalline solid, m.p. 164-166 ⁰ C;

MS (+ESI), m/z: 620.8 [M+H] ⁺ ;

HRMS: calcd for C ₃₃ H ₃₆ N ₂ O ₆ S ₂ + H+, 621.20875; found (ESI, [M+H] ⁺ ), 621.2089;

HPLC purity 100% at 210-370 ran, 10.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 814: 5-[(4-hydroxyphenyl)sulfonyl]-iV-(2-pyridin-3-ylethyl)-2- (trifluoromethyl)benzenesulfonamide

[1001] Step 1 : Following the same procedure described on example 677 (Step 2), 2- chloro-5-fluoronitrobenzene was used to prepare 2-nitro-4-fluorobenzotrifluoride.

[1002] Step 2: In an analogous manner to example 743 (Step 2), 4- methoxybenzenethiol was used to prepare 5-(4-methoxyphenylsulfonyl)-2-trifluoromethyl- nitrobenzene.

[1003] Step 3: In an analogous manner to example 677 (Step 3), 5-(4- methoxyphenylsulfonyl)-2-trifluoromethyl-nitrobenzene was used to prepare 5-(4- methoxyphenylsulfonyl)-2-trifluoromethylaniline.

[1004] Step 4: In an analogous manner to example 677 (Step 4), 5-(4- methoxyphenylsulfonyl)-2-trifluoromethylaniline was used to prepare 2-trifluoromethyl-5-(4- methoxyphenylsulfonyl)-benzenesulfonyl chloride.

[1005] Step 5: In an analogous manner to example 435, 2-trifluoromethyl-5-(4- methoxyphenylsulfonyl)-benzenesulfonyl chloride and 3-(2-aminoethyl)pyridine were used to prepare 5-[(4-methoxyphenyl)sulfonyl]-λ/-(2-pyridin-3-ylethyl)-2- (trifluoromethyl)benzenesulfonamide.

[1006] Step 6: In an analogous manner to example 744, 5-[(4- methoxyphenyl)sulfonyl]-iV-(2-pyridin-3-ylethyl)-2-(trifluor omethyl)benzenesulfonamide, was

used to prepare 5-[(4-hydroxyphenyl)sulfonyl]-iV-(2-pyridin-3-yletliyl)-2-

(trifluoromethyl)benzenesulfonamide.

MS (ES+) m/z 486.6;

HPLC purity 95.7% at 210-370 run, 8.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₀ H ₁₇ F ₃ N ₂ O ₅ S ₂ + H+, 487.06037; found (ESI, [M+H] ⁺ ), 487.0609.

Example 815: 5-[(4-fluorophenyl)suIfonyl]-2-isopropyl-N-(tetrahydro-2H-th iopyran-4- yl)benzenesulfonamide

[1007] Step 1 : To a solution of tetrahydrothiopyran (3.0 g, 25.82 mmol) and 2,4- dimethoxyben∑ylamine (4.3 g, 25.82 mmol) in dicliloromethane (100 mL) was added sodium triacetoxyborohydride (7.7 g, 36.15 mmol). The reaction was stirred overnight at room temperature under nitrogen. The reaction was quenched with a saturated aqueous bicarbonate solution and extracted. Dried with magnesium sulfate and concentrated to give N-(2,4- dimethoxybenzyl)tetrahydro-2H-thiopyran-4-amine (6.7 g, 97%).

[1008] Step 2: To a solution of 5-(4-fluorophenylsulfonyl)-2-isopropylbenzene-l- sulfonyl chloride (350 mg, 0.93 mmol) in dichloromethane 10 mL) was added triethylamine (388 μL, 2.79 mmol) followed by N-(2,4-dimethoxybenzyl)tetrahydro-2H-thiopyran-4-amine (497 mg, 1.86 mmol). The reaction was stirred overnight at room temperature. The following day the reaction was concentrated down onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of N-(2,4-dimethoxybenzyl)-5-(4-fluorophenylsulfonyl)-2-isoprop yl-N-(tetrahydro-2H-thiopyran- 4-yl)benzenesulfonamide (504 mg, 89%).

[1009] Step 3: N-(2 ₅ 4-dimethoxybenzyl)-5-(4-fluorophenylsulfonyl)-2-isopropyl-N- (tetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (504 mg, 0.83 mmol) was dissolved in 6% trifluoroacetic acid/dichloromethane (6 mL) and stirred overnight at room temperature under nitrogen. Saturated bicarbonate solution was added and the reaction was extracted. Dried with magnesium sulfate and concentrated onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(tetrahydro-2H-th iopyran-4- yl)benzenesulfonamide (350 mg, 92%). MS (ES+) m/z 456.

Example 816: 5-[(4-fluorophenyl)sulfonyl]-N-[2-(lH-imidazol-l-yl)ethyl]-2 - (trifluoromethyl)benzenesulfonamide

[1010] Step 1 : l-chloro-4-(4-fluorophenylsulfonyl)-2-nitrobenzene (L31023-148). A mixture of 4-chloro-3-nitrobenzenesulfonyl chloride (25.13 g, 98.1 mmol), fluorobenzene (50 ml, 533 mmol) and aluminum chloride (15.71 g, 118 mmol) refluxed under nitrogen overnight. The next morning the reaction was allowed to cool to R.T. and then was transferred to a 1 L beaker where the reaction was mixed with ice for ten minutes. The contents of the beaker was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried (anhydrous MgSO ₄ ) and the solvent removed under reduced pressure to give l-chloro-4-(4- fluorophenylsulfonyl)-2 -nitrobenzene (29.12 g, 93.9%).

[1011] Step 2: 4-(4-fluorophenylsulfonyl)-2-nitro-l-(trifluoromethyl)benzen e (L31023- 152). To a flame dried flask the l-chloro-4-(4-fluorophenylsulfonyl)-2-nitrobenzene (29.12 g, 92.3 mmol) prepared in the previous step was taken up in 200 mL of anh. N,N- Dimethylformamide and was allowed stir under nitrogen at ice bath temperature. To the stirring reaction at ice bath temp., copper nanopowder (25.24 g , 0.4 mol) and activated carbon (13.67 g, 1.1 mol) was added to the reaction stirred for five minutes to which dibromodifluoromethane (19.8 ml, 0.2 mol) was slowly syringed into the reaction. After the complete addition of the dibromodifluoromethane, the reaction was heated to 100° C for five hours and then allowed to cool to R.T.. The contents of the flask was filtered though a plug of celite and the filtrate was then partitioned between ethyl acetate and ammonium chloride / water once. The organic layer was washed twice more with water. The ethyl acetate layer was separated, dried (anhydrous MgSO ₄ ) and the solvent removed under reduced pressure to give 4-(4-fluorophenylsulfonyl)-2- nitro-l-(trifluoromethyl)benzene (24.3 g, 75.3%).

[1012] Step 3 : 5-(4-fluorophenylsulfonyl)-2-(trifluoromethyl)aniline (L31023-153). A mixture of 4-(4-fluorophenylsulfonyl)-2-nitro-l-(trifluoromethyl)benzen e (24.3 g, 69.6 mmol) and tin(II) chloride (65.9 g , 0.4 mol) was taken up in 1 : 16 water / methanol was refluxed for three days. The reaction was concentrated and then was partitioned between ethyl acetate and 2N hydrochloric acid. The ethyl acetate layer was separated, dried (anhydrous MgSO ₄ ) and the solvent removed under reduced pressure to give 25.6 g of a brown solid. The solid was purified on the Isco using a 330 g column and a gradient of hexane/ methylene chloride to give 5-(4- fluorophenylsulfonyl)-2-(trifluoromethyl)aniline.

[1013] Step 4: 5-(4-fluorophenylsulfonyl)-2-(trifluoromethyl)benzene-l-sulf onyl chloride (L31023-160). 5-(4-fluoroρhenylsulfonyl)-2-(trifluoromethyl)aniline(3.79 g, 11.9 mmol) prepared in the previous step was taken up in 100 ml of acetonitrile and was cooled to ice bath temperature. To the chilled flask, 10 ml of acetic acid, 10 ml of hydrochloric acid and then sodium nitrite (0.98 g, 14.2 mmol) taken up in 2 ml of water were slowly syringed into the flask. The mixture was allowed to stir at ice bath temperature for one hour. Sulfur dioxide was then bubbled into the flask for fifteen minutes and then copper(II) chloride dihydrate taken up in 2 ml of water was syringed into the flask and was allowed to stir at ice bath temp, for three hours. The mixture was allowed to warm to room temp, and then was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried (anhydrous MgSO ₄ ) and the solvent removed under reduced pressure to provide an orange oil which was purified on the Isco using a 330 g column and a gradient of hexane/ methylene chloride to give 5-(4-fluorophenylsulfonyl)-2- (trifluoromethyl)benzene-l-sulfonyl chloride (2.2234 g, 46.5 %).

[1014] Step 5: 5-[(4-fluorophenyl)sulfbnyl]-N-[2-(lH-imidazol-l-yl)ethyl]-2 - (trifluoromethyl)benzenesulfonamide). A mixture of sodium carbonate (0.1601 g, 1.5 mmol) in 1 ml of water and 2-(lH-imidazol-l-yl) ethyl amine (0.092, 0.5 mmol) in 3 ml of acetonitrile was treated with the mixture of 5-(4-fluorophenylsulfonyl)-2-(trifluoromethyl)benzene-l-sulf onyl chloride and 5-(2-fluorophenylsulfonyl)-2-(trifluoromethyl)benzene-l-sulf onyl chloride (0.2514 g, 0.6 mmol) prepared in the previous step in 10 ml of acetonitrile. The reaction was allowed to stir overnight at R. T. and then was partitioned between ethyl acetate and 2N hydrochloric acid. The ethyl acetate layer was separated, dried (anhydrous MgSO ₄ ) and the solvent removed under reduced pressure to give approximately 50 mg of the isomeric mixture that was dissolved in 3 mL of methanol / acetonitrile. 200 DL of the resulting solution was repetitively injected onto the Supercritical Fluid Chromatography (SFC) instrument, and the baseline resolved isomers were separately collected using the conditions described below to give the title compound 5-[(4- fluorophenyl)sulfonyl]-N-[2-(lH-imidazol-l-yl)ethyl]-2-(trif luoromethyl)benzenesulfonamide (31.2 mg, 10%) as a white solid.

SFC Instrument: Berger MultiGram Prep SFC

Column: Ethylpyridine; IQDm; 250 mm L x 20 mm ID

Column temperature: 35°C

SFC Modifier: 15% MeOH with 0.2% DEA /85% CO2

Flow rate: 50 mL/min

Outlet Pressure: 100 bar

Detector: UV at 220 ran

MS (ES+) m/z 477.6;

HPLC purity analytical SFc purity check after prep SFC separation of regioisomers peak 1 = 97.5% peak 2 = 96.8% minor impurities are of unknown composition; Ethyl pyridine 4.6 x 250 mm column, 2 mL/min, 15% MeOH / 85% CO2. HPLC purity 100% at 210-370 ran, 7.1 min.; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₈ H ₁₅ F ₄ N ₃ O ₄ S ₂ + H+ ₅ 478.05129; found (ESI, [M+H]+), 478.0507.

Example 817: 5-[(4-fluorophenyl)sulfonyl]-N-(tetrahydro-2H-pyran-4-yl)-2- (trifluoromethyl)benzenesulfonamide

[1015] In an analogous manner to example 765, a mixture of 5-[(4- fluorophenyl)sulfonyl]-N-[2-(lH-imidazol-l-yl)ethyl]-2- (trifluoromethyl)benzenesulfonamide)and 5-(2-fluorophenylsulfonyl)-2-

(trifluoromethyl)benzene-l-sulfonyl chloride and 4-Aminotetrahydropyran to give approximately 85 mg of the isomeric mixture that was dissolved in 2.5 mL of methanol/acetonitrile. 250 μL of the resulting solution was repetitively injected onto the Supercritical Fluid Chromatography (SFC) instrument, and the baseline resolved isomers were separately collected using the conditions described below to give the title compound of 5-[(4-fluorophenyl)sulfonyl]-N~ (tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)benzenesulfona mide (22.2 mg, 8%) as a white solid.

SFC Instrument: Berger MultiGram Prep SFC

Column: Ethylpyridine; 10 μm; 250 mm L x 20 mm ID

Column temperature: 35°C

SFC Modifier: 15% MeOH /85% CO2

Flow rate: 50 mL/min

Outlet Pressure: 100 bar

Detector: UV at 220 nm

MS (ES-) m/z 465.6;

HPLC purity The peak purity is checked by analytical SFC: peak 1 - >99.9% peak 2 - >99.9%;

Ethyl Pyridine (4.6x250mm) column, 2mL/min, 15% MeOH /85%CO2.

HPLC purity 100% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 rnL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 818: tert-butyl 4-({[5-[(4-fluorophenyl)sulfonyl]-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carboxyl ate

[1016] In an analogous manner to example 765, a mixture of 5-[(4- fluorophenyl)sulfonyl]-N-[2-( lH-imidazol- 1 -yl)ethyl]-2-(trifluoromethyl)benzenesulfonamide) and 5-(2-fluorophenylsulfonyl)-2-(trifluoromethyl)benzene-l-sulf onyl chloride and 4-Amino- piperidine-1-carboxylic acid tert-butyl to give approximately 40 mg of the isomeric mixture that was dissolved in 2 mL of methanol/acetonitrile. 250 μL of the resulting solution was repetitively injected onto the Supercritical Fluid Chromatography (SFC) instrument, and the baseline resolved isomers were separately collected using the conditions described below to give the title compound tert-butyl 4-({[5-[(4-fluorophenyl)sulfonyl]-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carbo xylate (27.6 mg, 8%) as a white solid.

SFC Instrument: Berger MultiGram Prep SFC

Column: Ethylpyridine; 10 μm; 250 mm L x 20 mm ID

Column temperature: 35°C

SFC Modifier: 15% MeOH/85% CO2

Flow rate: 50 rnL/min

Outlet Pressure : 100 bar

Detector: UV at 220 nm

MS (ESI-) m/z 565;

HPLC purity The purity was checked by analytical SFC: peak 1 - >99.9% peak 2 - >99.9%; Ethyl Pyridine (4.6x250mm) column, 2mL/min, 15% MeOH / 85% CO ₂ . HPLC purity 100% at 210-370 nm, 10.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₆ F ₄ N ₂ O ₆ S ₂ + H+, 567.12412; found (ESI, [M+H-C4H8]+), 511.0644.

Example 819: N-Methyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl] sulfonyl} amino)ethyl]benzamide

[1017] Benzoyl chloride (38 μL, 0.327 mmol) was added under nitrogen to a solution ofN-[2-(methylamino)ethyl]-5-(phenylsulfonyl)-2-(1xifluorome thyl)benzenesulfonamide hydrochloride (150.8 mg, 0.329 mmol), prepared in Example 799, and triethylamine (229 μL, 1.64 mmol) in 20 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for 19 h. The reaction was extracted two times with 2 N HCl, dried (anhydrous magnesium sulfate) and the solvent removed under reduced pressure to give 184.1 mg of a solid. Purification of the solid on a 12 g Redi Sep Fash Column (silica gel) using a gradient of 100% methylene chloride to 40% ethyl acetate-methylene chloride as the eluent gave N-methyl-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl] sulfonyl} amino)ethyl]benzamide (156.3 mg, 91%) as a white solid. MS (ES+) m/z 526.6;

HRMS: calcd for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ + H ⁺ , 527.09167; found (ESI, [M+H] ⁺ ), 527.0908; Anal. Calcd for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ . 0.20 CH ₂ Cl ₂ : C, 51.27; H, 3.97; N, 5.15. Found: C, 52.54; H, 3.87; N, 5.17.

Example 820: iV-(2-cyanoethyl)-5-[(4-methoxyphenyl)sulfonyl]-2- (trifluoromethyl)benzenesulfonamide

[1018] Step 1 : Following the same procedure described on example 677 (Step 2), 2- chloro-5-fluoronitrobenzene was used to prepare 2-nitro-4-fluorobenzotrifluoride.

[1019] Step 2: In an analogous manner to example 743 (Step 2), 4- methoxybenzenethiol was used to prepare 5-(4-methoxyphenylsulfonyl)-2-trifluoromethyl- nitrobenzene.

[1020] Step 3: In an analogous manner to example 677 (Step 3), 5-(4- methoxyphenylsulfonyl)-2-trifluoromethyl-nitrobenzene was used to prepare 5-(4- methoxyphenylsulfonyl)-2-trifluoromethylaniline.

[1021] Step 4: In an analogous manner to example 677 (Step 4), 5-(4- methoxyphenylsulfonyl)-2-trifluoromethylaniline was used to prepare 2-trifluoromethyl-5-(4- methoxyphenylsulfony l)-benzenesulfonyl chloride .

[1022] Step 5: In an analogous manner to example 435, 2-trifluoromethyl-5-(4- methoxyphenylsulfonyl)-benzenesulfonyl chloride and aminopropionitrile were used to prepare iV-(2-cyanoethyl)-5-[(4-methoxyphenyl)sulfonyl]-2-(trifluoro methyl)benzenesulfonamide. MS (ES+) m/z 448.6;

HPLC purity 94.6% at 210-370 nm, 8.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HUMS: calcd for C ₁₇ H ₁₅ F ₃ N ₂ O ₅ S ₂ + H+, 449.04472; found (ESI, [M+H] ⁺ ), 449.0429.

Example 821: iV-(2-cyanoethyl)-5-[(4-hydroxyphenyI)sulfonyI]-2- (trifluoromethyl)benzenesulfonamide

[1023] In an analogous manner to example 744, iV-(2-cyanoethyl)-5-[(4- methoxyphenyl)sulfonyl]-2-(trifluoromethyl)benzenesulfonamid e was used to prepare N-(2- cyanoethyl)-5-[(4-liydroxyphenyl)sulfonyl]-2-(trifluoromethy l)benzenesulfonamide MS (ES-) m/z 432.5;

HPLC purity 85.6% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Prrf.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₆ H ₁₃ F ₃ N ₂ O ₅ S ₂ + H+, 435.02907; found (ESI, [M+H] ^"1" ), 435.0308.

Example 822: 4-Methoxy-N-methyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide

[1024] In an analogous manner as described in Example 819, and replacing benzoyl chloride with 4-methoxy-benzoyl chloride, gave 4-methoxy-N-methyl-N-[2-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)et hyl]benzamide (176.5 mg, 97%) as a white solid. MS (ES+) m/z 556.6;

HRMS: calcd for C ₂₄ H ₂₃ F ₃ N ₂ O ₆ S ₂ + H+, 557.10224; found (ESI, [M+H]+), 557.1029; Anal. Calcd for C ₂₄ H ₂₃ F ₃ N ₂ O ₆ S ₂ : C ₃ 51.79; H, 4.17; N, 5.03. Found: C, 52.03; H, 4.13; N, 4.74.

Example 823: N-(2-hydroxy-2,3-dihydro-lH-inden-l-yl)-5-(phenylsulfonyl)-2 - (trifluoromethyl)benzenesulfonamide

[1025] In an analogous manner to example 765, 5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonyl chloride and l-amino-2,3-dihydro-lH-inden-2-ol was used to

prepare the title compound N-(2-hydroxy-2,3-dihydro-lH-inden-l-yl)-5-(phenylsulfonyl)-2 -

(trifluoromethyl)benzenesulfonamide (150.2 mg, 57%) as a white solid.

MS (ES-) m/z 495.7;

HPLC purity 94.4% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph-3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₂ H ₁₈ F ₃ NO ₅ S ₂ + H+, 498.06512; found (ESI, [M+H]+), 498.0664.

Example 824: 5-[(2-fluorophenyl)sulfonyl]-N-(tetrahydro-2H-pyran-4-yl)-2- (trifluoromethyl)benzenesulfbnamide

[1026] In an analogous manner to example 765, 5-[(4-fluorophenyl)sulfonyl]-N-[2- (lH-imidazol-l-yl)ethyl]-2-(trifluoromethyl)benzenesulfonami de)and 5-(2- fluorophenylsulfonyl)-2-(trifluoromethyl)benzene-l-sulfonyl chloride and 4- aminotetrahydropyran to give approximately 85 mg of the isomeric mixture that was dissolved in 2.5 mL of methanol/acetonitrile. 250 μL of the resulting solution was repetitively injected onto the Supercritical Fluid Chromatography (SFC) instrument, and the baseline resolved isomers were separately collected using the conditions described below to give the title compound 5-[(4- fluorophenyl)sulfonyl]-N-(tetrahydro-2H-pyran-4-yl)-2-(trifl uoromethyl)benzenesulfonamide (22.2 mg, 8%) as a white solid.

SFC Instrument: Berger MultiGram Prep SFC

Column: Ethylpyridine; lOμm; 250 mm L x 20 mm ID

Column temperature: 35°C

SFC Modifier: 15% MeOH /85% CO2

Flow rate: 50 mL/min

Outlet Pressure: 100 bar

Detector: UV at 220 nm

MS (ES+) m/z 467.6;

HPLC purity 100% at 210-370 nm, 8.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 825: 5-(phenylsulfonyl)-iV-[l-(phenylsulfonyl)piperidin-4-yl]-2- (trifluoromethyl)benzenesulfonamide

[1027] In an analogous manner to Example 462, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and benzenesulfonyl chloride were used to prepare 5- (phenylsulfonyl)-N-[l-(phenylsulfonyl)piperidin-4-yl]-2-(tri fluoromethyl)benzenesulfonamide. MS (ES+) m/z 588.5;

HPLC purity 98.0% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₂₃ F ₃ N ₂ O ₆ S ₃ + H+, 589.07431; found (ESI, [M+H] ⁺ ), 589.0731.

Example 826: iV-{2-[(anilinocarbonyl)(methyl)amino]ethyl}-5-(phenylsulfon yl)-2- (trifluoromethyl)benzenesulfonamide

[1028] To a stirred suspension of iV-[2-(methylamino)ethyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide hydrochloride (0.16 g, 0.35 mmol) from Example 799 in a solution of phenyl isocyanate (42 mg, 0.35 mmol) in CH ₂ Cl ₂ (8 mL) under N ₂ at room temperature was added diisopropylethylamine (70 μL, 52 mg, 0.40 mmol). The mixture was stirred at room temperature for 18 hours. It was loaded directly onto a silica gel column and eluted with a gradient of hexane and ethyl acetate to give 0.18 g (95%) of N-{2- [(anilinocarbonyl)(methyl)amino]ethyl}-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 541.6; HRMS: calcd for C ₂₃ H ₂₂ F ₃ N ₃ O ₅ S ₂ + H+, 542.10257; found (ESI, [M+H] ⁺ ), 542.1027.

Example 827: iV-(2-{methyl[(pyridin-3-ylamino)carbonyl]amino}ethyI)-5-(ph enylsulfonyl)- 2-(trifluoromethyl)benzenesulfonamide

[1029] In an analogous manner to Example 826, N-[2-(methylamino)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 799 and pyridine-3 -isocyanate were used to prepare iV-(2-{methyl[(pyridin-3- ylamino)carbonyl]amino}ethyl)-5-(phenylsulfonyl)-2-(trifluor omethyl)benzenesulfonamide. MS (ES+) m/z 543.2; HRMS: calcd for C ₂₂ H ₂₁ F ₃ N ₄ O ₅ S ₂ + H+, 543.09782; found (ESI, [M+H] ⁺ ), 543.0983.

Example 828: 7V-{2-[{[(2,4-dimethoxyphenyl)amino]carbonyl}(methyl)amino]e thyl}-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide

[1030] In an analogous manner to example 826, N-[2-(methylamino)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 799 and 2,4-dimethoxyphenyl isocyanate were used to prepare' N-{2-[{ [(2,4- dimethoxyphenyl)amino]carbonyl}(methyl)amino]ethyl}-5-(pheny lsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 601.6; HRMS: calcd for C ₂₅ H ₂₆ F ₃ N ₃ O ₇ S ₂ + H+, 602.12370; found (ESI, DMH-H] ⁺ ), 602.1265.

Example 829: N-{2-[[(ter^-butylamino)carbonyl](methyl)amino]ethyI}-5-(phe nylsulfonyI)-2- (trifluoromethyl)benzenesulfonamide

[1031] In an analogous manner to Example 826, N-[2-(methylamino)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 799 and 4-(tert-butyl)phenyl isocyanate were used to prepare N-{2-[[(tert- butylamino)carbonyl](methyl)amino]ethyl}-5-(phenylsulfonyl)- 2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 521.7; HRMS: calcd for C ₂₁ H ₂₆ F ₃ N ₃ O ₅ S ₂ + H+, 522.13387; found (ESI, [M+H] ⁺ ), 522.1318.

Example 830: λ^-{2-[{[(4-methoxyphenyl)amino]carbonyl}(methyl)ainmo]ethy l}-5- (phenylsulfonyI)-2-(trifluoromethyl)benzenesuIfonamide

[1032] In an analogous manner to Example 826, iV-[2-(methylamino)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 799 and 4-methoxyphenyl isocyanate were used to prepare N- {2- [{[(4- methoxyphenyl)amino]carbonyl}(methyl)amino]ethyl}-5-(phenyls ulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 571.6; HRMS: calcd for C ₂₄ H ₂₄ F ₃ N ₃ O ₆ S ₂ + H+, 572.11314; found (ESI ₅ [M+H] ⁺ ), 572.1152.

Example 831: λ ^r -{2-[[(butyIamino)carbonyl](methyl)amino]ethyl}-5-(phenyIsuI fonyI)-2- (trifluoromethyl)benzenesulfonamide

[1033] In an analogous manner to Example 826, N-[2-(methylamino)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 799 and

butyl isocyanate were used to prepare 7V-{2-[[(butylammo)carbonyl](methyl)amino]ethyl}-5-

(phenylsulfonyl)-2-(trifluorometb.yl)benzenesulfonamide.

MS (ES+) m/z 521.7;

HRMS: calcd for C ₂₁ H ₂₆ F ₃ N ₃ O ₅ S ₂ + H+, 522.13387; found (ESI, [M+H] ^"1" ), 522.1337.

Example 832: iV-{2-[{[(2,4-difluorophenyl)amino]carbonyI}(methyl)amino]et hyl}-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide

[1034] In an analogous manner to Example 826, N-[2-(methylamino)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 799 and 2,4-difluorophenyl isocyanate were used to prepare N-{2-[{[(2,4- difluorophenyl)amino]carbonyl}(methyl)amino]ethyl}-5-(phenyl sulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 577.6; HRMS: calcd for C ₂₃ H ₂₀ F ₅ N ₃ O ₅ S ₂ + H+, 578.08373; found (ESI, [M+H] ⁺ ), 578.0847.

Example 833: iV-methyl-iV-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]pyrrolidine-l-c arboxamide

[1035] To a stirred suspension of iV-[2-(methylamino)ethyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide hydrochloride (0.16 g, 0.35 mmol) from Example 799 in a solution of 1-pyrrolidinecarbonyl chloride (39 μL, 47 mg, 0.35 mmol) in CH ₂ Cl ₂ (8 mL) under N ₂ at room temperature was added diisopropylethylamine (0.26 mL, 0.19 g, 1.5 mmol). The mixture was stirred at room temperature for 18 hours. It was loaded directly onto a silica gel column and eluted with a gradient of hexane and ethyl acetate to give 0.16 g (85%) of iV-methyl- N-[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfony l}amino)ethyl]pyrrolidine-l- carboxamide. MS (ES+) m/z 519.7.

Example 834: iV-{2-[[(diethylamino)carbonyl](methyl)amino]ethyl}-5-(plien ylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1036] In an analogous manner to Example 833, N-[2-(methylamino)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 799 and diethylcarbamoyl chloride were used to prepare N- {2-

[[(diethylamino)carbonyl](methyl)amino]ethyl}-5-(phenylsu lfonyl)-2-

(trifluoromethyl)benzenesulfonamide.

MS (ES+) m/z 521.8;

HRMS: calcd for C ₂₁ H ₂₆ F ₃ N ₃ O ₅ S ₂ + H+, 522.13387; found (ESI, [M+H] ⁺ ), 522.1322.

Example 835: iV-methyl-λ-[2-({[5-(phenylsulfonyI)-2- (trifluoromethyI)phenyl]sulfonyl}amino)ethyl]morpholine-4-ca rboxamide

[1037] In an analogous manner to Example 833, iV-[2-(methylamino)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 799 and 4-morpholinylcarbonyl chloride were used to prepare iV-methyl-λ/-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]morpholine-4-ca rboxamide. MS (ES+) m/z 535.7; HRMS: calcd for C ₂₁ H ₂₄ F ₃ N ₃ O ₆ S ₂ + H+, 536.11314; found (ESI, [M+Hf), 536.1124.

Example 836: iV-[2-(methyl{[methyl(phenyl)amino]carbonyl}amino)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide

[1038] In an analogous manner to Example 833, N-[2-(methylamino)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 799 and N-methyl-N-phenyl carbamoyl chloride were used to prepare N- [2- (methyl{[methyl(phenyl)amino]carbonyl}amino)ethyl]-5-(phenyl sulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 555.7; HRMS: calcd for C ₂₄ H ₂₄ F ₃ N ₃ O ₅ S ₂ + H+, 556.11822; found (ESI, [M+H]*), 556.1173.

Example 837: N-Methyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-2-furamide

[1039] In an analogous manner as described in Example 819, and replacing benzoyl chloride with furan-2-carbonyl chloride, gave N-methyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-2-furamide (156.3 mg, 93%) as a white solid. MS (ES+) m/z 516.6;

HRMS: calcd for C ₂₁ H ₁₉ F ₃ N ₂ O ₆ S ₂ + H ⁺ , 517.07094; found (ESI, [M+H] ⁺ ), 517.072; Anal. Calcd for C ₂₁ H ₁₉ F ₃ N ₂ O ₆ S ₂ : C, 48.83; H, 3.71; N, 5.42. Found: C, 49.02; H, 3.44; N, 5.31.

Example 838: 4-tert-Butyl-N-methyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide

[1040] In an analogous manner as described in Example 819, and replacing benzoyl chloride with 4-fert-butyl-benzoyl chloride, gave 4-tert-butyl-N-methyl-N-[2-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)et hyl]benzamide (184.0 mg, 97%) as a white solid. MS (ESI+) m/z 583;

HRMS: calcd for C ₂₇ H ₂₉ F ₃ N ₂ O ₅ S ₂ + H ⁺ , 583.15427; found (ESI, [M+H] ⁺ ), 583.1552; Anal. Calcd for C ₂₇ H ₂₉ F ₃ N ₂ O ₅ S ₂ : C, 55.66; H, 5.02; N, 4.81. Found: C, 55.63; H, 4.90; N, 4.54.

Example 839: N-Methyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyI]sulfonyl}amino)ethyl]-2-(trifluorome thoxy)benzainide

[1041] In an analogous manner as described in Example 819, and replacing benzoyl chloride with 2-trifluoromethoxy-benzoyl chloride, gave N-methyl-N-[2-({[5-(phenylsulfonyl)- 2-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-2-(trifluoro methoxy)benzamide (184.1 mg, 92%) as a white solid foam. MS (ESI+) m/z 611;

HRMS: calcd for C ₂₄ H ₂₀ F ₆ N ₂ O ₆ S ₂ + H ⁺ , 611.07397; found (ESI, [M+H] ⁺ ), 611.0728; Anal. Calcd for C ₂₄ H ₂₀ F ₆ N ₂ O ₆ S ₂ : C, 47.21; H, 3.30; N, 4.59. Found: C ₅ 47.51; H, 2.90; N ₃ 4.43.

Example 840: 5-(phenylsulfonyl)-λ'-pyrrolidiii-3-yl-2-(trifluoromethyl)b enzenesulfonamide

[1042] Step 1 : Following the same procedure described on example 435, 2- trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 3-aminopyrrolidine-l- carboxylic acid tert-butyl ester were used to prepare tert-butyl-3-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl] sulfonyl} amino)pyrrolidine- 1 -carboxylate.

[1043] Step 2: Following the same procedure described on example 688, tert-butyl-3- ( { [5-(pheny lsulfony l)-2-(trifluoromethy l)pheny 1] sulfonyl } amino)pyrrolidine- 1 -carboxylate was used to prepare 5-(phenylsulfonyl)-λ/-pyrrolidin-3-yl-2-(trifluoromethyl)be nzenesulfonamide. MS (ESI+) m/z 435;

HPLC purity 94.2% at 210-370 nm, 6.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₁₇ H ₁₇ F ₃ N ₂ O ₄ S ₂ + H+, 435.06546; found (ESI ₅ [M+H] ⁺ ), 435.0666.

Example 841: N-[(2R*,4S ^A ,6S*)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-5-[(4- fluorophenyl)sulfonyl]-2-methylbenzenesulfonamide

[1044] Step 1 : 2,6-Dimethyl-gamma-pyrone (5.0 g, 40.28 mmol) was hydrogenated with palladium on carbon (250 mg) in ethanol (50 mL) at 50 psi. The reaction was filtered through Celite ^® and washed with ethanol. The filtrate was concentrated to give (2R,6S)-2,6- dimethyldihydro-2H-pyran-4(3H)-one (5.1 g, 99%).

[1045] Step 2: To a solution of (2R,6S)-2,6-dimethyldihydro-2H-pyran-4(3H)-one (5.1 g, 39.79 mmol) in dichloromethane (50 mL) and 2,4-dimethoxybenzylamine (6.7 g, 39.79 mmol) was added sodium triacetoxyborohydride (11.8g, 55.70 mmol). The reaction was stirred overnight at room temperature under nitrogen. Added saturated bicarbonate solution and extracted. Dried with magnesium sulfate and concentrated to give (2R,4S,6S)-N-(2,4- dimethoxybenzyl)-2,6-dimethyltetrahydro-2H-pyran-4-amine (10.8 g, 97%).

[1046] Step 3: To a solution of 5-(4-fluorophenylsulfonyl)-2-methylbenzene-l- sulfonyl chloride (150 mg, 0.43 mmol) in dichloromethane (5.0 mL) was added triethylamine (137 uL, 0.25 mmol) followed by (2R,4S,6S)-N-(2,4-dimethoxyben2yl)-2,6-dimethyltetrahydro- 2H-pyran-4-amine (132 mg, 0.47 mmol). The reaction was stirred overnight at room temperature. The following day the reaction was concentrated down onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of N-(2,4-dimethoxybenzyl)-N-((2R,4s,6S)-2,6- dimethyltetrahydro-2H-pyran-4-yl)-5-(4-fluorophenylsulfonyl) -2-methylbenzenesulfonamide (96 mg, 38%).

[1047] Step 4: N-(2,4-dimethoxybenzyl)-N-((2R,4S,6S)-2,6-dimethyltetrahydro -2H- pyran-4-yl)-5-(4-fluorophenylsulfonyl)-2-methylbenzenesulfon amide (96 mg, 0.16 mmol) was dissolved in 6% trifluoroacetic acid/dichloromethane (6 mL) and stirred overnight at room temperature under nitrogen. Saturated bicarbonate solution was added and the reaction was extracted. Dried with magnesium sulfate and concentrated onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of N-[(2R*,4S*,6S*)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-5-[(4 - fluorophenyl)sulfonyl]-2-methylbenzenesulfonamide (33 mg, 46%).

MS (ES-) m/z 440;

HRMS: calcd for C ₂₀ H ₂₄ FNO ₅ S ₂ + H+, 442.115821; found (ESI ₃ [M+H] ⁺ ), 442.1147.

Example 842: 5-{[4-(methylamino)phenyl]sulfonyl}-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide

[1048] Step 1 : A stirred solution of tert-butyl 4-({ [5-[(4-fluorophenyl)sulfonyl]-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carboxyl ate (0.10 g, 0.18 mmol) in 33% methylamine in ethanol (0.5 mL) was microwave irradiated for 15 minutes at 160°C. The resulting solution was washed with ammonium chloride solution (sat.) and extracted with ethyl acetate. The organic layer was concentrated to give tert-butyl 4-({[5-[(4- methylaminophenyl)sulfonyl]-2-(trifluoromethyl)phenyl]sulfon yl}amino)piperidine-l- carboxylate.

[1049] Step 2: Following the same procedure described on example 688, tert-butyl 4- ({[5-[(4-methylaminophenyl)sulfonyl]-2-(trifluoromethyl)phen yl]sulfonyl}amino)piperidine-l- carboxylate was used to prepare 5-{[4-(methylamino)phenyl]sulfonyl}-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide. MS (ESI+) m/z 478;

HPLC purity 100% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₉ H ₂₂ F ₃ N ₃ O ₄ S ₂ + H+, 478.10766; found (ESI, [M+H] ⁺ ), 478.1064.

Example 843 : 5- { [4-(dimethylamino)phenyl] sulf ony l}-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide

[1050] Step 1 : Following the same procedure described on example 842, dimethylamine in THF and tert-butyl 4-({[5-[(4-fluorophenyl)sulfonyl]-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carboxyl ate was used to prepare tert-butyl 4-({[5-[(4-dimethylaminophenyl)sulfonyl]-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carboxyl ate.

[1051] Step 2: Following the same procedure described on example 688, tert-butyl 4- ({[5-[(4-dimethylaminophenyl)sulfonyl]-2-(trifluoromethyl)ph enyl]sulfonyl}amino)piperidine- 1 -carboxylate was used to prepare 5-{[4-(dimethylamino)phenyl]sulfonyl}-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide.

MS (ESI+) m/z 492;

HPLC purity 97.1% at 210-370 nm, 7.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₄ F ₃ N ₃ O ₄ S ₂ + H+, 492.12331; found (ESI, [M+H] ⁺ ), 492.1243.

Example 844: 5-({4-[(2-hydroxyethyl)amino]phenyl}sulfonyl)-JV-piperidin-4 -yl-2- (trifluoromethyl)benzenesulfonamide

[1052] Step 1: Following the same procedure described on example 842, ethanolamine in THF and tert-butyl 4-({[5-[(4-fluorophenyl)sulfonyl]-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carbo xylate was used to prepare 4-({[5- [(4-[(2-hydroxyethyl)amino]phenyl)sulfonyl]~2- (trifluoromethyl)phenyl]sulfonyl} amino)piperidine-l -carboxylate.

[1053] Step 2: Following the same procedure described on example 688, 4-({[5-[(4-[(2- hydroxyethyl)amino]phenyl)sulfonyl]-2-(trifluoromethyl)pheny l]sulfonyl}amino)piperidine-l- carboxylate was used to prepare 5-({4-[(2-hydroxyethyl)amino]phenyl}sulfonyl)-N-piperidin-4- yl-2-(trifluoromethyl)benzenesulfonamide. MS (ESI+) m/z 508;

HPLC purity 95.1% at 210-370 nm, 6.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₄ F ₃ N ₃ O ₅ S ₂ + H+, 508.11822; found (ESI, [M+H] ⁺ ), 508.1198.

Example 845: 5-[(2-fluorophenyl)sulfonyl]-N-[2-(lH-imidazol-l-yl)ethyl]-2 - (trifluoromethyl)benzenesulfonamide

[1054] To a mixture of sodium carbonate (0.1601 g, 1.5 mmol) in 1 ml of water and 2- (lH-imidazol-1-yl) ethyl amine (0.092, 0.5 mmol) in 3 ml of acetonitrile was stirred at R.T. as the mixture of 5-(4-fluorophenylsulfonyl)-2-(trifluoromethyl)benzene-l-sulf onyl chloride and 5- (2-fluorophenylsulfonyl)-2-(trifluoromethyl)benzene-l-sulfon yl chloride (0.2514 g, 0.6 mmol) prepared in Example 816 Step 4 was taken up in 10 ml of acetonitrile was slowly added to the reaction with an addition funnel. The reaction was allowed to stir overnight at room temperature, and then was partitioned between ethyl acetate and 2N hydrochloric acid. The ethyl acetate layer was separated, dried (anhydrous MgSO ₄ ) and the solvent removed under reduced pressure to give approximately 50 mg of the isomeric mixture that was dissolved in 3 mL of

methanol/acetonitrile. 200 μL of tlie resulting solution was repetitively injected onto the Supercritical Fluid Chromatography (SFC) instrument, and the baseline resolved isomers were separately collected using the conditions described below to give the title compound 5-[(2- fluorophenyl)sulfonyl]-N-[2-(lH-imidazol-l-yl)ethyl]-2-(trif luoromethyl)benzenesulfonamide (19.8 mg, 7%) as a white solid. MS (ESI+) m/z 478;

HPLC purity 97.8% at 210-370 nm, 6.8 min.; XterraRP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₈ H ₁₅ F ₄ N ₃ O ₄ S ₂ + H+, 478.05129; found (ESI ₅ [M+EQ+), 478.0506.

Example 846: N-methyl-N-[2-({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]cyclohexanecarb oxamide

[1055] A stirred mixture of tert-butyl methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate (0.1062 g, 0.25 mmol) prepared in the same manner as Example 799 in dichloromethane (2 ml). 1.1 eq of cyclohexanecarbonyl chloride (35 μL, 0.26 mmol) and 1.5 eq. N,N-Diisoprpylethylamine was syringed into the reaction vial and was allowed to stir overnight at room temperature. The product was transferred onto a 4 g Isco RediSep® Normal Phase column and was purified by automated flash chromatography using a gradient of 20% to 100% hexane/ethyl acetate. Isolation of the main component gave the title compound N-methyl-N-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]cyclohexanec arboxamide (58.3 mg, 44%) as a white solid. MS (ESI+) m/z 533;

HPLC purity 100% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₇ F ₃ N ₂ O ₅ S ₂ + H+, 533.13862; found (ESI, [M+H]+), 533.138.

Example 847: 3-Fluoro-N-methyl-N-[2-({[5-(phenylsuIfonyl)-2- (trifluoromethyl)phenyl]sulfonyI}amino)ethyl]-4-(trifluorome thyl)benzamide

[1056] In an analogous manner as described in Example 819, and replacing benzoyl chloride with 3-fluoro-4-trifluoromethyl-benzoyl chloride, gave 3-fluoro-N-methyl-N-[2-({[5-

(phenylsulfonyl)-2-(1rifluoromethyl)phenyl]sulfonyl}amino )ethyl]-4-(trifluoromethyl)ben^

(168.1 mg, 84%) as a white solid.

MS (ESI+) m/z 613;

HRMS: calcd for C ₂₄ H ₁₉ F ₇ N ₂ O ₅ S ₂ + H ⁺ , 613.06964; found (ESI, [M+H] ⁺ ), 613.0691;

Anal. Calcd for C ₂₄ H ₁₉ F ₇ N ₂ O ₅ S ₂ : C, 47.06; H, 3.13; N, 4.57. Found: C ₅ 46.83; H, 3.00; N, 4.34.

Example 848: Methyl 4-({methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) benzoate

[1057] In an analogous manner as described in Example 819, and replacing benzoyl chloride with 4-chlorocarbonyl-benzoic acid methyl ester, gave methyl 4-({methyl[2-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)et hyl]amino}carbonyl)benzoate (155.8 mg, 81%) as a white solid. MS (ESI+) m/z 585;

HRMS: calcd for C ₂₅ H ₂₃ F ₃ N ₂ O ₇ S ₂ + H ⁺ , 585.09715; found (ESI, [M+H] ⁺ ), 585.0983; Anal. Calcd for C ₂₅ H ₂₃ F ₃ N ₂ O ₇ S ₂ : C, 51.37; H, 3.97; N, 4.79. Found: C, 51.13; H, 3.74; N, 4.63.

Example 849: N-Methyl-N-[2-({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]nicotinamide

[1058] In an analogous manner as described in Example 819, and replacing benzoyl chloride with nicotinoyl chloride, extracting with water instead of 2 N HCl, and using 100% methylene chloride to 5% methanol-methylene chloride as the eluent, gave N-methyl-N-[2-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)et hyl]nicotinamide (166.6 mg, 97%) as a white solid foam. MS (ESI+) m/z 528;

HRMS: calcd for C ₂₂ H ₂₀ F ₃ N ₃ O ₅ S ₂ + H ⁺ , 528.08692; found (ESI, [M+H] ^"1" ), 528.0885; Anal. Calcd for C ₂₂ H ₂₀ F ₃ N ₃ O ₅ S ₂ : C, 50.09; H, 3.82; N, 7.97. Found: C, 49.99; H, 3.59; N, 7.72.

Example 850: N-Methyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethy l)phenyl] sulf onyl} amino)ethy 1] is onicotinamide

[1059] In an analogous manner as described in Example 849, and replacing nicotinoyl chloride with isonicotinoyl chloride gave N-methyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]isonicotinamide (151.1 mg, 88%) as a white solid.

MS (ESI+) m/z 528;

HRMS: calcd for C ₂₂ H ₂₀ F ₃ N ₃ O ₅ S ₂ + H ⁺ , 528.08692; found (ESI, [M+H] ⁺ ), 528.0889;

Anal. Calcd for C ₂₂ H ₂₀ F ₃ N ₃ O ₅ S ₂ . 0.70 CH ₂ Cl ₂ : C, 46.45; H, 3.67; N ₅ 7.16. Found: C, 46.71; H,

3.46; N, 7.18.

Example 851: 2-Chloro-N-methyl-N-[2-({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]nicotinamide

[1060] In an analogous manner as described in Example 849, and replacing nicotinoyl chloride with 2-chloro-nicotinoyl chloride gave 2-chloro-N-methyl-N-[2-({[5-(phenylsulfonyl)- 2-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]nicotinamide (168.4 mg, 91%) as a white solid foam.

MS (ESI+) m/z 562;

HRMS: calcd for C ₂₂ H ₁₉ ClF ₃ N ₃ O ₅ S ₂ + H ⁺ , 562.04795; found (ESI, [M+H] ⁺ ), 562.0471; Anal. Calcd for C ₂₂ H ₁₉ ClF ₃ N ₃ O ₅ S ₂ . 0.40 CH ₂ Cl ₂ : C, 45.15; H, 3.35; N, 7.05. Found: C, 46.48; H, 3.19; N, 7.32.

Example 852: N,2,2-trimethyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]propanamide

[1061] In an analogous manner to example 846, tert-butyl methyl[2-({ [5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl} amino)ethyl] carbamate and trimethylacetyl chloride was used to prepare the title compound N,2,2-trimethyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]propanamide (102 mg, 81%) as a white solid. MS (ES+) m/z 506.7;

HPLC purity 98.6% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₂₅ F ₃ N ₂ O ₅ S ₂ + H+, 507.12297; found (ESI, [M+H]+), 507.1238.

Example 853: 3-{[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]sulfon yl}benzoic acid

[1062] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 3-(chlorosulfonyl)benzoic acid were used to prepare 3-

{ [4-({ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}ammo) piperidin-l - yl]sulfonyl}benzoic acid.

HPLC purity 97.1% at 210-370 nm, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₂₃ F ₃ N ₂ O ₈ S ₃ + H+, 633.06414; found (ESI, [M+H] ⁺ ), 633.0627.

Example 854: 4-{[4-({[5-(phenyIsulfonyl)-2-

(trifluo romethy I)phenyl] sulf ony 1} amino)piperidin-l -y 1] sulf ony 1} benzoic acid

[1063] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 4-(chlorosulfonyl)benzoic acid were used to prepare 4- { [4-( { [5-(pheny lsulfony l)-2-(trifluoromethy l)pheny 1] sulf ony 1 } amino)piperidin- 1 - yl] sulf ony 1} benzoic acid. MS (ES+) m/z 632.5;

HPLC purity 100% at 210-370 nm, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 855: 3-({[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]carbon othioyl}amino)benzoic acid

[1064] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 3-carboxyphenyl isothiocyanate were used to prepare 3-({[4-({[5 -(pheny lsulfony l)-2-(trifluoromethy l)phenyl] sulfony 1 } amino)piperidin- 1 - yl]carbonothioyl}amino)benzoic acid. MS (ES+) m/z 627.5;

HPLC purity 98.4% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₆ H ₂₄ F ₃ N ₃ O ₆ S ₃ + H+, 628.08521; found (ESI, [M+H] ⁺ ), 628.0853.

Example 856: iV-[l-(2-chloro-6-methylisonicotinoyl)piperidin-4-yl]-5-(phe nylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1065] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-piperidm-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-chloro-6-methylpyridine-4-carbonyl chloride were

used to prepare N-[l-(2-chloro-6-methylisonicotinoyl)piperidin-4-yl]-5-(phen ylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide.

MS (ES-) m/z 599.5;

HPLC purity 95.5% at 210-370 ran, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₅ H ₂₃ ClF ₃ N ₃ O ₅ S ₂ + H+, 602.07925; found (ESI, [M+H] ⁺ ), 602.0812.

Example 857: A'-[l-(2,6-dichloroisonicotinoyI)piperidin-4-yI]-5-(phenyIsu lfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1066] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2,6-dichloropyridine-4-carbonyl chloride were used to prepare N-[l-(2,6-dichloroisonicotinoyl)piperidin-4-yl]-5-(phenylsul fonyl)-2- (tfifluoromethyl)benzenesulfonamide. MS (ES+) m/z 621.5;

HPLC purity 91.5% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₂₀ Cl ₂ F ₃ N ₃ O ₅ S ₂ + H+, 622.02463; found (ESI, [M+H] ⁺ ), 622.0237.

Example 858: N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-5-[(4-fluorophen yl)sulfonyl]-2- isopropylbenzenesulfonamide

[1067] Step 1 : To a solution of tetrahydrothiopyran (3.0 g, 25.82 mmol) and 2,4- dimethoxybenzylamine (4.3 g, 25.82 mmol) in dichloromethane (100 mL) was added sodium triacetoxyborohydride (7.7 g, 36.15 mmol). The reaction was stirred overnight at room temperature under nitrogen. Added saturated bicarbonate solution and extracted. Dried with magnesium sulfate and concentrated to give N-(2,4-dimethoxybenzyl)tetrahydro-2H-thiopyran- 4-amine (6.7 g, 97%).

[1068] Step 2: To a solution of 5-(4-fluorophenylsulfonyl)-2-isopropylbenzene-l- sulfonyl chloride (350 mg, 0.93 mmol) in dichloromethane 10 mL) was added triethylamine (388 μL, 2.79 mmol) followed by N-(2,4-dimethoxybenzyl)tetrahydro-2H-thiopyran-4-amine (497 mg, 1.86 mmol). The reaction was stirred overnight at room temperature. The following day the reaction was concentrated down onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of

N-(2,4-dimethoxybenzyl)-5-(4-fluorophenylsulfonyl)-2-isop ropyl-N-(tetrahydro-2H-thiopyran- 4-yl)benzenesulfonamide (504 mg, 89%).

[1069] Step 3: N-(2,4-dimethoxybenzyl)-5-(4-fluorophenylsulfonyl)-2-isoprop yl-N- (tetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (504 mg, 0.83 mmol) was dissolved in 6% trifluoroacetic acid/dichloromethane (6 mL) and stirred overnight at room temperature under nitrogen. Saturated bicarbonate solution was added and the reaction was extracted. Dried with magnesium sulfate and concentrated onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(tetrahydro-2H-th iopyran-4- yl)benzenesulfonamide (350 mg, 92%).

[1070] Step 4: 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(tetrahydro-2H-th iopyran- 4- yl)benzenesulfonamide (150 mg, 0.32 mmol) was dissolved in dichloromethane (8 mL) and 3- chloroperoxybenzoic acid (154 mg, 0.69 mmol) was added. The reaction was stirred overnight at room temperature and was then concentrated onto silica gel and purified using automated chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of N-( 1 , 1 -dioxidotetrahydro-2H-thiopyran-4-y l)-5 - [(4-fluorophenyl)sulfonyl] -2- isopropylbenzenesulfonamide (80 mg, 50%). MS (ES-) m/z 487.6.

Example 859: 5-(Phenylsulfonyl)-2-propyl-iV-(2-pyridin-4-ylethyl)benzenes ulfonamide

[1071] The title compound was prepared from 5-phenylsulfonyl-2-propyl- benzenesulfonyl chloride (0.36 g, 1.0 mmol) and 2-(pyridin-4-yl)ethanamine (0.25 g, .2.0 mmol) according to the procedure and in the same manner as described in Example 550, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (90 g), eluting with a gradient of 50%-100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford 5-(phenylsulfonyl)-2-propyl-N-[2-(tetrahydro-2i7- pyran-4-yl)ethyl]benzenesulfonamide (0.26 g, 58%), as a homogeneous, amorphous solid, m.p. 155-157 °C;

MS (+ESI), m/z: 444.1 [M+H] ⁺ ;

HRMS: calcd for C ₂₂ H ₂₄ N ₂ O ₄ S ₂ + H+, 445.12502; found (ESI, [M+H] ⁺ ), 445.1229; HPLC purity 100% at 210-370 nm, 8.5 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example δθO^-Isopropyl-iV-t^iϊ^jSS^-S-methyl-S-azabicyclop^.lloct -S-yll-S- (phenylsulfonyl)benzenesulfonamide monohydrochloride

[1072] A stirred solution of 2-isopropyl-5-(phenylsulfonyl)benzenesulfonyl chloride (0.36 g, 1.0 mmol) in 3:1 dichloromethane-acetonitrile (10 mL) was treated under nitrogen with enrfo-S-methyl-δ-azabicyclop^.lJoctan-S-amine dihydrochloride (0.42 g, 2.0 mmol) and diisopropylethylamine (0.52 g, 4.0 mmol). The reaction was stirred for 18 hours at room temperature. The crude product was purified by reverse phase preparative liquid chromatography on a Gilson ^® semi-prep column, eluting with a gradient of 10%- 100% water in acetonitrile at a flow rate of 2 niL/min, to afford, after concentration of the solvent and extraction with ethyl acetate (3x), an oil. The oil was dissolved in ethanol-dioxane and treated with a solution of IN hydrogen chloride in diethyl ether. Filtration of the solid afforded 2-isopropyl-N- [(Ii?*, 5S* )-8-methy 1-8-azabicyclo [3.2.1 ] oct-3 -y 1] -5 -(phenylsulfony l)benzenesulfonamide monohydrochloride (0.10 g, 20%), as a homogeneous, cream-colored, amorphous solid, m.p. 90

MS (+ESI), m/z: 462.8 [M+H] ⁺ ;

HRMS: calcd for C ₂₃ H ₃₀ N ₂ O ₄ S ₂ + H+, 463.17197; found (ESI, [M+H] ⁺ ), 463.171;

HPLC purity 98.7% at 210-370 ran, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Amman. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 861 : 5-{[2-(methylamino)phenyl]suIfonyI}-iV-piperidin-4-yI-2- (trifluoromethyl)benzenesulfonamide

[1073] Step 1 : Following the same procedure described on example 677 Step 1 , 4- chloro-3-nitrobenzenesulfonyl chloride and fluorobenzene was used to prepare 5-(2- fluorophenylsulfonyl)-2-chloro-nitrobenzene.

[1074] Step 2: Following the same procedure described on example 677 Step 2, 5-(2- fluorophenylsulfonyl)-2-chloro-nitrobenzene was used to prepare 5-(2-fluorophenylsulfonyl)-2- trifluoromethyl-nitrobenzene.

[1075] Step 3: Following the same procedure described on example 677 Step 3, 5-(2- fluorophenylsulfonyl)-2-trifluoromethyl-nitrobenzene was used to prepare 5-(2- fluorophenylsulfonyl)-2-trifluoromethylaniline.

[1076] Step 4: Following the same procedure described on example 677 Step 4, 5-(2- fluorophenylsulfonyl)-2-trifluoromethylaniline was used to prepare 2-trifluoromethyl-5~(2- fluorophenylsulfonyl)- benzenesulfonyl chloride.

[1077] Step 5: Following the same procedure described on example 435, 2- trifluoromethyl-5-(2-fluorophenylsulfonyl)- benzenesulfonyl chloride and 4-aminopiperidine-l- carboxylic acid tert-butyl ester were used to prepare tert-butyl 4-({[5-(2-fluorophenylsulfonyl)- 2-(trifluoromethyl)pheny 1] sulfony 1 } amino)piperidine- 1 -carboxy late .

[1078] Step 6: Following the same procedure described on example 842 Step 1, tert- butyl 4-({[5-(2-fluorophenylsulfonyl)-2-(trifluoromethyl)phenyl]su lfonyl}amino)piperidine-l- carboxylate was used to prepare tert-butyl 4-({[5-(2-methylaminophenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carboxyl ate.

[1079] Step 7: Following the same procedure described on example 842 Step 2: tert- butyl 4-({ [5-(2-methylaminophenylsulfonyi)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l -carboxylate was used to prepare 5-{[2- (methylamino)phenyl]sulfonyl}-iV-piperidin-4-yl-2-(trifluoro methyl)benzenesulfonamide. MS (ES+) m/z 477.7;

HPLC purity 100% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₉ H ₂₂ F ₃ N ₃ O ₄ S ₂ + H+, 478.10766; found (ESI ₅ [MH-H] ⁺ ), 478.1078.

Example 862: 5-{[2-(dimethylamino)phenyϊ]sulfonyl}-JV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide

[1080] Step 1 : Following the same procedure described on example 842 Step 1, tert- butyl 4-({ [5-(2-fluorophenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfon yl}amino)piperidine-l - carboxylate and dimethylamine were used to prepare tert-butyl 4-({[5-(2- dimethylaminophenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfo nyl}amino)piperidine-l- carboxylate.

[1081] Step 2: Following the same procedure described on example 842 Step 2, tert- butyl 4-({ [5-(2-dimethylaminophenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l -carboxylate was used to prepare 5-{[2- (dimethylamino)phenyl]sulfonyl}-λ/-piperidin-4-yl-2-(triflu oromethyl)benzenesulfonamide.

MS (ES+) m/z 491.7;

HPLC purity 95.8% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 863: 5-(phenylsulfonyl)-iV-[2-(2H-tetrazol-5-yl)ethyl]-2- (trifluoromethyl)benzenesulfonamide

[1082] To a stirred solution of trimethylaluminum 2M in toluene (0.13mL, 0.26 mmol) and trimethylsilylazide (0.03 g, 0.26 mmol) in toluene (1 mL) at 0°C was added N-(2- cyanoethyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)benzenesul fonamide (0.09 g, 0.22 mmol). The resulting solution was heated to 80°C overnight, cooled to 0°C, quenched with 6N HCl solution and extracted with ethyl acetate. The organic layer was concentrated and the resulting solid was triturated in ethyl acetate to give 5-(phenylsulfonyl)-N-[2-(2H-tetrazol-5-yl)ethyl]-2- (trifluoromethyl)benzenesulfonamide. (0.045 g, 45%). MS (ES+) m/z 461.6;

HPLC purity 100% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₆ H ₁₄ F ₃ N ₅ O ₄ S ₂ + H+, 462.05121; found (ESI, [M+H] ⁺ ), 462.049.

Example 864: 2-ethyl-N-methyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]butanamide

[1083] In an analogous manner to example 846, tert-butyl methyl [2-({ [5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)et hyl]carbamate and 2-Ethylbutyryl chloride was used to prepare the title compound 2-ethyl-N-methyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]butanamide (47.8 mg, 36.1%) as a white solid. MS (ES+) m/z 520.6;

HPLC purity 100% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=θ.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₇ F ₃ N ₂ O ₅ S ₂ + H+, 521.13862; found (ESI, [M+HJ+), 521.1391.

Example 865: butyl methyl[2-({[5-(phenylsulfonyI)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate

[1084] In an analogous manner to example 846, tert-butyl methyl[2-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl} amino)ethyl]carbamate and butyl chloroformate was used to prepare the title compound butyl methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate (39.7 mg, 32%) as a white solid. MS (ES+) m/z 522.6;

HPLC purity 100% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂ IH ₂₅ F ₃ N ₂ O ₆ S ₂ + H+, 523.11789; found (ESI, [M+H]+), 523.1178.

Example 866: tert-butyl 4-[({methyl[2-({[5-(phenyIsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbon yl)amino]piperidine-l- carboxylate

[1085] Step 1 : To a mixture of N,N'-carbonyldiimidazole (143.0 mg, 0.8819 mmol) and 4-amino-l-BOC-piperidine (160.6 mg, 0.80 mmol) was added dichloromethane (10 mL). The reaction was stirred at room temperature under N ₂ for 18 hours. The solution was washed with H ₂ O (3 x) and dried over MgSO ₄ . The solvent was evaporated to give 224.7 mg (95%) of intermediate tert-butyl 4-[(l/i-imidazol-l -ylcarbonyl)amino]piperidine-l -carboxylate.

[1086] Step 2: To a stirred suspension of iV-[2-(methylamino)ethyl]-5-(phenylsulfonyl)- 2-(trifluoromethyl)benzenesulfonamide hydrochloride (0.16 g, 0.35 mmol) from Example 799 in a solution of tert-butyl 4- [(lH-imidazol-l-ylcarbonyl)amino]piperidine-l -carboxylate (0.11 g, 0.37 mmol) in CH ₂ Cl ₂ (5 mL) under N ₂ at room temperature was added diisopropylethylamine (64 μL, 47 mg, 0.37 mmol). The mixture was stirred at room temperature for 3 days. The solution was washed 3 times with water. It was loaded directly onto a silica gel column and eluted with a gradient of hexane and ethyl acetate to give 0.18 g (80%) of tert-butyl 4- [({methyl[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfony 1 } amino)ethyl] amino } carbonyl)amino]piperidine- 1 -carboxylate. MS (ES-) m/z 646.7; HRMS: calcd for C ₂₇ H ₃₅ F ₃ N ₄ O ₇ S ₂ + H+, 649.19720; found (ESI, [M+H] ⁺ ), 649.1979.

Example 867: 2,2-dimethylpropyl methyl[2-({[5-(phenyϊsulfonyl)-2- (trifluoromethyl)phenyl] sulfonyl} ammo)ethyl] carbamate

[1087] In an analogous manner to example 846, tert-butyl methyl[2-({ [5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)et hyl]carbamate and neopentyl chloroformate was used to prepare the title compound 2,2-dimethylpropyl methyl[2-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)et hyl] carbamate (86.2 mg, 67%) as a white solid. MS (ES+) m/z 536.8;

HPLC purity 99.0% at 210-370 run, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amman. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₇ F ₃ N ₂ O ₆ S ₂ + H+, 537.13354; found (ESI, [M+H]+), 537.1332.

Example 868: JV-[(l-hydroxycyclohexyl)methyl]-5-(phenyIsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1088] In an analogous manner to example 654, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 1-aminomethyl-l-cyclohexanol hydrochloride were used to prepare N- [( 1 -hydroxycyclohexyl)methyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES) m/z 475.1;

HPLC purity 97.6% at 210-370 nm, 9.7 min.; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 869: 5-({2-[(2-hydroxyethyl)amino]phenyl}sulfonyl)-JV~piperidin-4 -yl-2~ (trifluoromethyl)benzenesulfonamide

[1089] Step 1 : Following the same procedure described on example 842 Step 1, tert- butyl 4-( { [5-(2-fluorophenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl} amino)piperidine- 1 - carboxylate and ethanolamine were used to prepare tert-butyl 4-({[5-([2- hydroxyethyl)amino]pheny lsulfonyl)-2-(trifluoromethy l)pheny 1] sulfonyl } amino)piperidine- 1 - carboxylate.

[1090] Step 2: Following the same procedure described on example 842 Step 2, tert- butyl 4-({ [5-([2-hydroxyethyl)amino]phenylsulfonyl)-2-

(trifluoromethyl)phenyl] sulfonyl} amino)piperidine-l -carboxylate was used to prepare 5-({2-[(2- hydroxyethyl)amino]phenyl}sulfonyl)-N-piperidin-4-yl-2-(trif luoromethyl)benzenesulfonamide.

MS (ES) m/z 507.8;

HPLC purity 94.9% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₄ F ₃ N ₃ O ₅ S ₂ + H+, 508.11822; found (ESI, [M+H] ⁺ ), 508.119.

Example 870: isobutyl methyl[2-({[5-(phenylsulfonyl)~2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate

[1091] In an analogous manner to example 846, tert-butyl methyl[2-({[5- (phenylsulfoiiyl)-2-(ti-ifluoromethyl)phenyl]sulfonyl}amino) ethyl]carbamate and isobutyl chloroformate was used to prepare the title compound isobutyl methyl[2-({[5-(phenylsulfonyl)- 2-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate (57.7 mg, 46%) as a white solid. MS (ES+) m/z 522.9;

HPLC purity 99.1% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Pfr=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₂₅ F ₃ N ₂ O ₆ S ₂ + H+, 523.11789; found (ESI, [M+FTJ+), 523.1175.

Example 871: 3-(trifluoromethyl)phenyl methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethy l)phenyl] sulfony 1} amino)ethyl] carbamate

[1092] In an analogous manner to example 846, tert-butyl methyl[2-({ [5- (pheny lsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl} amino)ethyl] carbamate and 3 - (Trifluoromethyl)phenyl chloroformate was used to prepare the title compound 3- (trifluoromethyl)phenyl methyl[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate (77.8 mg, 53%) as a white solid. MS (ES+) m/z 610.9;

HPLC purity 98.1% at 210-370 nm, 10.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₂₀ F ₆ N ₂ O ₆ S ₂ + H+, 611.07397; found (ESI, [M+H]+), 611.0731.

Example 872: 4-fluorophenyI methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamate

[1093] In an analogous manner to example 846, tert-butyl methyl[2-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)et hyl]carbamate and 4-Fluorophenyl

chloroformate was used to prepare the title compound 4-fluorophenyl methyl[2-({[5-

(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino )ethyl]carbamate (85.6 mg, 62.4%) as a white solid.

MS (ES+) m/z 560.7;

HPLC purity 98.1% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₃ H ₂₀ F ₄ N ₂ O ₆ S ₂ + H+, 561.07717; found (ESI, [M+H]+), 561.0757.

Example 873: 4-bromophenyl methyl [2-({ [5-(phenylsulf onyl)-2- (trifluoromethyl)phenyl] sulfonyl} amino)ethyl] carbamate

[1094] In an analogous manner to example 846, tert-butyl methyl[2-({ [5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl} amino)ethyl] carbamate and 4-Bromophenyl chloroformate was used to prepare the title compound 4-bromophenyl methyl[2-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl} amino)ethyl] carbamate (66.7mg, 39%) as a white solid. MS (ES+) m/z 620.6;

HPLC purity 97.0% at 210-370 nm, 10.4 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₀ BrF ₃ N ₂ O ₆ S ₂ + H+, 620.99710; found (ESI, [M+H]+), 620.9971.

Example 874: 5-[(4-Fluorophenyl)sulfonyl]-2-propyI-7V-(2-pyridin-3- ylethyl)benzenesulfonamide

[1095] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2- propylbenzenesulfonyl chloride (0.38 g, 1.0 mmol) and 2-(pyridin-3-yl)ethanamine (0.25 g, .2.0 mmol) according to the procedure and in the same manner as described in Example 559, step c. The crude product was purified by preparative liquid chromatography on a Biotage ^® 40 Si column of pre-packed silica gel (90 g), eluting with a gradient of 50%- 100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford, after crystallization from ethyl acetate- diethyl ether-hexane, 5-[(4-fluorophenyl)sulfonyl]-2-propyl-iV-(2-pyridin-3- ylethyl)benzenesulfonamide (0.27 g, 59%), as a homogeneous, colorless, crystalline solid, m.p. 111-113 ⁰ C; MS (+ESI), m/z: 462.8 [M+H] ⁺ ;

HRMS: calcd for C ₂₂ H ₂₃ FN ₂ O ₄ S ₂ + H ⁺ , 463.11560; found (ESI, [M+H] ⁺ ), 463.1161; HPLC purity 100% at 210-370 run, 8.9 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 875: 5-[(4-Fluorophenyl)sulfonyl]-2-propyl-JV-(2-pyridin-4- ylethyl)benzenesulfonamide

[1096] The title compound was prepared from 5-[(4-fluorophenyl)sulfonyl]-2- propylbenzenesulfonyl chloride (0.38 g, 1.0 mmol) and 2-(pyridin-4-yl)ethanamine (0.25 g, .2.0 mmol) according to the procedure and in the same manner as described in Example 559, step c. The crude product was purified by preparative liquid chromatography on a Biotage' 40 Si column of pre-packed silica gel (90 g), eluting with a gradient of 50%- 100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford, after crystallization from ethyl acetate- diethyl ether-hexane, 5-[(4-fluorophenyl)sulfonyl]-2-propyl-N-(2-pyridin-4- ylethyl)benzenesulfonamide (0.29 g, 63%), as a homogeneous, colorless, crystalline solid, m.p. 160-162 ⁰ C;

MS (+ESI), m/z: 462.8 [M+H] ⁺ ;

HRMS: calcd for C ₂₂ H ₂₃ FN ₂ O ₄ S ₂ + H ⁺ , 463.11560; found (ESI, [MfH] ⁺ ), 463.1139; HPLC purity 100% at 210-370 nm, 8.6 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 876: 5-(Phenylsulfonyl)-2-propyl-λ ⁷ -(2-pyridin-3-ylethyl)benzenesulfonamide

[1097] The title compound was prepared from 5-phenylsulfonyl-2-propyl- benzenesulfonyl chloride (0.36 g, 1.0 mmol) and 2-(pyridin-3-yl)ethanamine (0.25 g, .2.0 mmol) according to the procedure and in the same manner as described in Example 550, step c. The crude product was purified by preparative liquid chromatography on a Biotage 40 Si column of pre-packed silica gel (90 g), eluting with a gradient of 50%- 100% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min, to afford 5-(phenylsulfonyl)-2-propyl-N-(2-pyridin-3- ylethyl)benzenesulfonamide (0.30 g, 68%), as a white foam; MS (+ESI), m/z: 444.8 [M+H] ⁺ ;

HRMS: calcd for C ₂₂ H ₂₄ N ₂ O ₄ S ₂ + H+, 445.12502; found (ESI, [M+H] ⁺ ), 445.1261; HPLC purity 98.1% at 210-370 nm, 8.6 min; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 877: 4-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzoic acid

[1098] In an analogous manner to example 654, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 4-(2-aminoethyl)benzoic acid"were used to prepare 4-[2-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)et hyl]benzoic acid. MS (ESI-) m/z 512;

HPLC purity 100% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₁₈ F ₃ NO ₆ S ₂ + H+, 514.06004; found (ESI, [M+H] ⁺ ), 514.0597.

Example 878: 4-oxo-4-[4-({[5-(phenylsuIfonyI)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]butano ic acid

[1099] A stirred solution of 5-(phenylsulfonyl)-iV-piperidin-4-yl-2-

(trifluoromethyl)benzenesulfonamide (0.10 g, 0.22 mmol) and succinic anhydride (0.023 g, 0.23 mmol) in EtOH (1 mL) was microwave irradiated for 10 minutes at 150°C. The resulting solution was concentrated and flash column separation using 0-10% methanol/methylene chloride gradient gave 4-oxo-4-[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]but anoic acid. (0.04 g, 33%). MS (ESI+) m/z 549;

HPLC purity 100% at 210-370 nm, 8.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₃ F ₃ N ₂ O ₇ S ₂ + H+, 549.09715; found (ESI, [M+H] ⁺ ), 549.095.

Example 879: [4-({[5-(phenyIsuIfonyl)-2-(trifluoromethyl)phenyl]sulfonyl} amino)piperidin- l-yl] acetic acid

[1100] A stirred solution of 5-(phenylsulfonyl)-N-piperidin-4-yl-2-

(trifluoromethyl)benzenesulfonamide (0.14 g, 0.30 mmol) and tert-butylbromoacetate (0.06 g, 0.30 mmol) and triethylamine (0.1 mL, 0.7 mmol) in THF (1 mL) was microwave irradiated for 10 minutes at 120°C. The resulting solution was concentrated and flash column separation using 0-50% ethyl acetate/hexane gradient gave a crude solid. The solid was dissolved in 4N HCl in dioxane solution (1 mL) and stirred overnight. The solution was concentrated and trituration

with ethyl acetate gave [4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl] acetic acid. (0.09 g, 59%). HPLC purity 100% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₁ F ₃ N ₂ O ₆ S ₂ + H+, 507.08659; found (ESI, [M+H] ⁺ ), 507.0854.

Example 880: 2-[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]acetam ide

[1101] A stirred solution of 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide (0.10 g, 0.21mmol) and bromoacetamide (0.03 g, 0.20 mmol) and triethylamine (0.1 mL, 0.7 mmol) in THF (1 mL) was microwave irradiated for 10 minutes at 120 ⁰ C. The resulting solution was partitioned between sodium bicarbonate solution (sat.) and ethyl acetate. The organic layer was concentrated and flash column separation using 0- 10% methanol/methylene chloride gradient gave 2-[4-({[5-(phenylsulfonyl)~2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]acetam ide. (0.06 g, 57%). HPLC purity 98.6% at 210-370 nm, 6.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₂ F ₃ N ₃ O ₅ S ₂ + H+, 506.10257; found (ESI, [M+H]*), 506.103.

Example 881: iV-(2-{methyl[(piperidin-4-yIamino)carbonyl]amino}ethyl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide

[1102] To a solution of tert-butyl 4-[({methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) amino]piperidine-l-carboxylate (166.0 mg, 0.2559 mmol) from Example 866 in CH ₂ Cl ₂ ( 3 mL) was added EtOAc saturated with HCl (3 mL). This mixture stood at room temperature 18 hours but solid had not formed. It was concentrated to 1 mL. EtOH (1 mL) was added. The oil/gel almost completely dissolved. The solvent was evaporated from this mixture. The residue crystallized as it stood at room temperature overnight to give 140.6 mg (94%) of N-(2-{methyl[(piperidin-4- ylamino)carbonyl]amino}ethyl)-5-(phenylsulfonyl)-2-(trifluor omethyl)benzenesulfonamide. MS (ES+) m/z 548.8; HRMS: calcd for C ₂₂ H ₂₇ F ₃ N ₄ O ₅ S ₂ + H+, 549.14477; found (ESI, [M+H] ⁴ ), 549.1453.

Example 882: ethyl iV-({methyl[2-({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl] sulfonyl} amino)ethyl] amino} carbonyl)glycinate

[1103] In an analogous manner to Example 826, N-[2-(methylamino)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 799 and ethyl isocyanatoacetate were used to prepare ethyl N-({methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethy l)pheny 1] sulfonyl } amino)ethy 1] amino } carbonyl)gly cinate . MS (ES+) m/z 551.8; HRMS: calcd for C ₂₁ H ₂₄ F ₃ N ₃ O ₇ S ₂ + H+, 552.10805; found (ESI, [M+H] ⁺ ), 552.1089.

Example 883: 3-({methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}sulfonyl) benzoic acid

[1104] To a stirred suspension of iV-[2-(methylamino)ethyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide hydrochloride (111 mg, 0.242 mmol) from Example 799 in a solution of 3-(chlorosulfonyl)benzoic acid (53.3 mg, 0.242 mmol) in CH ₂ Cl ₂ (5 mL) under N ₂ at room temperature was added diisopropylethylamine (0.127 mL, 94.2 mg, 0.729 mmol). The mixture was stirred at room temperature for 3 days. It was washed twice with 2N HCl. The solution of crude was loaded directly onto a silica gel column and eluted with a gradient of hexane and ethyl acetate to give 109 mg (75%) of 3-({methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}sulfonyl) benzoic acid. MS (ES+) m/z 606.7; HRMS: calcd for C ₂₃ H ₂₁ F ₃ N ₂ O ₈ S ₃ + H+, 607.04849; found (ESI, [M+H] ⁺ ), 607.0455.

Example 884: 5-[(4-fluorophenyl)sulfonyl]-2-isopropyI-N-(2-piperidin-3- ylethyl)benzenesulfonamide

[1105] 5-[(4-fluorophenyl)sulfonyl]-2-isopropyl-N-(2-pyridin-3- ylethyl)benzenesulfonamide (Example 534) (0.20 g, 0.43 mmol) was hydrogenated with palladium on carbon (70 mg) in ethanol (30 mL) at 50 psi. The reaction was filtered through Celite ^® and washed with ethanol. The filtrate was concentrated to give 5-[(4- fluorophenyl)sulfonyl]-2-isopropyl-N-(2-piperidin-3- ylethyl)benzenesulfonamide (0.17 g, 84%). MS (ES+) m/z 468.8.

Example 885: 5-(phenylsulfonyl)-iV-[l-(2iϊ-tetrazol-5-yImethyI)piperidin -4-yl]-2- (trifluoromethyl)benzenesulfonamide

[1106] Step 1 : A solution of 5-(phenylsulfonyl)-iV-piperidm-4-yl-2-

(trifluoromethyl)benzenesulfonamide (0.15 g, 0.34 mmol) and bromoacetonitrile (0.04 g, 0.34 mmol) and triethylamine (0.1 mL, 0.7 mmol) in THP (1 mL) was stirred overnight at room temperature. The mixture was concentrated and flash column separation using 0-50% ethyl acetate/hexane gradient gave crude 2-[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]aceton itrile. (0.10 g, 62%).

[1107] Step 2: Following the same procedure described on example 863, 2-[4-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)pi peridin-l-yl]acetonitrile was used to prepare 5-(phenylsulfonyl)-iV-[l -(2H ^" -tetrazol-5-ylmethyl)piperidin-4-yl]-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 530.8;

ηPLC purity 90.7% at 210-370 rnn, 6.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOη) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₁ F ₃ N ₆ O ₄ S ₂ + H+, 531.10905; found (ESI, [M+H] ⁺ ), 531.1094.

Example 886: 4-oxo-4-[3-({[5-(phenylsulfonyl)-2~ (trifluoromethyl)phenyl]sulfonyl}amino)pyrrolidin-l-yl]butan oic acid

[1108] In an analogous manner to example 878, 5-(phenylsulfonyl)-iV-pyrrolidin-3-yl- 2-(trifluoromethyl)benzenesulfonamide and succinic anhydride were used to prepare 4-oxo-4-[3- ({ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino )pyrrolidin-l -yl]butanoic acid. MS (ES+) m/z 534.7;

HPLC purity 96.4% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 887: tert-butyl 4-({methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) piperazine-l-carboxylate

[1109] Step 1 : Li an analogous manner to Example 866, step 1, N ₅ N'- carbonyldiimidazole and 1-tert-butyl piperazinecarboxylate were used to prepare the intermediate tert-buty 14-( 1 H-imidazol- 1 -y lcarbony l)piperazine- 1 -carboxy late .

[1110] Step 2: To a solution of tert-butyl 4-(lH-imidazol-l-ylcarbonyl)piperazine-l- carboxylate (119 mg, 0.425 mmol) stirring in acetonitrile (0.79 mL) at room temperature under N ₂ was added iodomethane (0.10 mL, 0.23 g, 1.6 mmol). The solution stirred at room temperature 18 hours. The acetonitrile and excess iodomethane were evaporated at reduced pressure. N-[2- (methylamino)ethyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)be nzenesulfonamide hydrochloride (172 mg, 0.375 mmol) from Example 799, CH ₂ Cl ₂ (5.25 mL) and diisopropylethylamine (74 μL, 55 mg, 0.42 mmol) were added. The mixture was stirred at room temperature for 3 days. It was washed with dilute aqueous HCl (0.22 mL, 2N, 0.44 mmol diluted to < IM). An emulsion formed. The layers separated with the addition of 2N NaOH. The organic phase was loaded directly onto a silica gel column and eluted with a gradient of hexane and ethyl acetate to give 133 mg (56%) of tert-butyl 4-({methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) piperazine-l-carboxylate. MS (ES+) m/z 634.8; HRMS: calcd for C ₂₆ H ₃₃ F ₃ N ₄ O ₇ S ₂ + H+, 635.18155; found (ESI, [M+H] ⁺ ), 635.1817.

Example 888: N-{ {methyl [2-({[5-(pheny lsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) glycine

[1111] To a solution of ethyl N-({methyl[2-({ [5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}ammo)ethyl]amino}carbonyl)g lycinate (2.472 mg, 0.4481 mmol) from Example 882 in EtOH (6.5 mL) was added lithium hydroxide hydrate (94 mg, 2.24 mmol) in water (0.8 mL). The solution was stirred at room temperature for 2 h. The EtOH was evaporated. The residue was partitioned with EtOAc and 2N HCl. The EtOAc was washed once with water and dried over MgSO ₄ . Evaporation gave 236.7 mg (100%) of iV-({methyl[2-({[5- (pheny lsulfony l)-2-(trifluoromethy l)pheny 1] sulfony 1} amino)ethy 1] amino } carbony l)glycine . MS (ES+) m/z 523.7; HRMS: calcd for C ₁₉ H ₂₀ F ₃ N ₃ O ₇ S ₂ + H+, 524.07675; found (ESI, [M+H]*), 524.0753.

Example 889: iV-{[5-(phenylsulfonyI)-2-(trifluoromethyI)phenyl]sulfonyI}- D -alanine

[1112] Step 1 : Following the same procedure described on example 654, 2- trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and beta-alanine tertbutyl ester hydrochloride were used to prepare 3-(5-benzenesulfonyl-2-trifluoromethyl- benzenesulfonylamino)-propionic acid tert-butyl ester.

[1113] Step 2: Following the same procedure described on example 688, 3-(5- benzenesulfonyl-2-trifluoromethyl-benzenesulfonylamino)-prop ionic acid tert-butyl ester was used to prepare iV-{[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}- D-alanine. MS (ES-) m/z 435.7;

HPLC purity 100% at 210-370 nm, 8.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₆ H ₁₄ F ₃ NO ₆ S ₂ + H+, 438.02874; found (ESI ₅ [M+H] ⁺ ), 438.0272.

Example 890: 3-[4-({[5-(phenyIsulfonyI)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]propan oic acid

[1114] In an analogous manner to example 879, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and tert-butyl 3-bromopropionate were used to prepare 3- [4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl} amino)piperidin-l-yl]propanoic acid.

HPLC purity 97.6% at 210-370 nm, 6.8 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₂₃ F ₃ N ₂ O ₆ S ₂ + H+, 521.10224; found (ESI ₅ [M+H]+), 521.1035.

Example 891: 3-[4-({[5-(phenyIsuIfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]benzoi c acid

[1115] To a stirred solution of 5-(phenylsulfonyl)-N-piperidin-4-yl-2-

(trifluoromethyl)benzenesulfonamide (0.13 g, 0.29mmol) in methylene chloride (2 mL) under a drying tube was added 3-(tertbutoxycarbonyl)-phenylboronic acid (0.08g, 0.35 mmol), triethylamine (0.15 mL, 1.0 mmol) and copper II acetate (0.10 g, 0.58 mmol). The resulting solution was stirred room temperature for 2 days. The reaction mixture was washed with ammonium chloride solution (sat.), concentrated, and flash column separated using a 0-30% ethyl acetate/hexane gradient. The resulting material was dissolved in 4N HCl in dioxane solution (1 mL) and stirred overnight. The solution was concentrated and trituration with methylene chloride to give 3-[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]ben zoic acid. (0.026 g, 16%). HPLC purity 100% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HElMS: calcd for C ₂₅ H ₂₃ F ₃ N ₂ O ₆ S ₂ + H+, 569.10224; found (ESI, [M+H] ⁺ ), 569.1034.

Example 893: 4-({[5-(phenyIsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}a mino)butanoic acid

[1116] Step 1 : Following the same procedure described on example 654, 2- trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 4-amino-N-butyric acid tert- butyl ester hydrochloride were used to prepare 3-(5-Benzenesulfonyl-2-trifluoromethyl- benzenesulfonylamino)-butyric acid tert-butyl ester.

[1117] Step 2: Following the same procedure described on example 688, 3-(5- Benzenesulfonyl-2-trifluoromethyl-benzenesulfonylamino)-buty ric acid tert-butyl ester was used to prepare 4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}a mino)butanoic acid. HPLC purity 99.1% at 210-370 run, 8.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₇ H ₁₆ F ₃ NO ₆ S ₂ + H+, 452.04439; found (ESI, [M+H] ⁺ ), 452.0446.

Example 894: 5-oxo-5-[4-({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl] sulfonyl} amino)piperidin-l-yl]pentanoic acid

[1118] In an analogous manner to example 878, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and glutaric anhydride were used to prepare 5-oxo-5-[4- ({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}ami no)piperidin-l-yl]pentanoic acid. HPLC purity 100% at 210-370 nm, 8.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₅ F ₃ N ₂ O ₇ S ₂ + H+, 563.11280; found (ESI, [M+H]^), 563.1128.

Example 895: 5-oxo-5~[3-({[5-(phenylsulfonyI)-2- (trifluoromethyl)phenyl]sulfonyl}amino)pyrrolidin-l-yl]penta noic acid

[1119] In an analogous manner to example 878, 5-(phenylsulfonyl)-N-pyrrolidin-3-yl- 2-(trifluoromethyl)benzenesulfonamide and glutaric anhydride were used to prepare 5-oxo-5-[3- ({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}ami no)pyrrolidin-l-yl]pentanoic acid. HPLC purity 93.7% at 210-370 nm, 8.0 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₃ F ₃ N ₂ O ₇ S ₂ + H+, 549.09715; found (ESI, [M+H] ⁺ ), 549.0967.

Example 896: tert-butyl 4-[({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]piperidine-l-c arboxylate

[1120] In an analogous manner to example 435, 5-(phenylsulfonyl)-7V ^" -piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 4-aminomethyl-l -(tert-butoxycarbonyl)piperidine were used to prepare fert-butyl 4-[({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]piperidine-l-c arboxylate. MS (ES-) m/z 560.7;

HPLC purity 97.9% at 210-370 nm, 10.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₂₉ F ₃ N ₂ O ₆ S ₂ + H+, 563.14919; found (ESI, [M+H] ⁺ ), 563.1487.

Example 897: 4-{methyl[2-({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyI]sulfonyI}amino)ethyl]amino}-4-oxobut anoic acid

[1121] To a stirred suspension of N-[2-(methylamino)ethyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide hydrochloride (0.10 g, 0.22 mmol) from Example 799 in a solution of succinic anhydride (34 mg, 0.34 mmol) in toluene (3 mL) under N ₂ at room temperature was added diisopropylethylamine (0.076 mL, 56 mg, 0.44 mmol). The mixture was stirred at 105 ⁰ C for 3 hours. An oil had formed which after cooling didn't dissolve with the addition of EtOAc saturated with HCl. The solution was decanted from the oil and saved. The oil was dissolved in methanol. The organic solutions were combined and washed with 2N HCl and water. It was loaded directly onto a Isco silica gel column and eluted with a gradient of hexane and ethyl acetate to give 45 mg (40%) of

4-{methyl[2-({[5-(phenylsulfonyl)-2-

(trifluoromethy l)pheny 1] sulfonyl } amino)ethyl] amino } -4-oxobutanoic acid. MS (ES-) m/z 520.7; HRMS: calcd for C ₂₀ H ₂₁ F ₃ N ₂ O ₇ S ₂ + H+, 523.08150; found (ESI, [M+H] ⁺ ), 523.0803.

Example 898: 7V-methyWV-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]piperazine-l-ca rboxamide

[1122] To a solution of tert-butyl 4-({methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) piperazine-l-carboxylate (81 mg, 0.13 mmol) from Example 887 in EtOH (1 mL) was added EtOAc saturated with HCl (1 mL).

This mixture stood at room temperature 18 hours but solid had not formed. The solvent was evaporated after 4 days. The residue was dissolved in EtOH and transferred to another vial. No solid formed The solvent was evaporated and dried to give 48 mg (66%) of N-methyl-N-[2-({[5-

(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino )ethyl]piperazine-l-carboxamide.

MS (ES+) m/z 534.8;

HRMS: calcd for C ₂₁ H ₂₅ F ₃ N ₄ O ₅ S ₂ + H+, 535.12912; found (ESI, [M+H] ⁺ ), 535.1285.

Example 899: 5-(phenylsulfonyl)-λf-(piperidin-4-ylmethyl)-2- (trifluoromethyl)benzenesulfonamide

[1123] In an analogous manner to example 688, tert-butyl 4-[({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]piperidine-l-c arboxylate was used to prepare 5- (phenylsulfonyl)-N-(piperidin-4-ylmethyl)-2-(trifluoromethyl )benzenesulfonamide. MS (ES-) m/z 460.8;

HPLC purity 98.3% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. for lOmin, hold 4min. HRMS: calcd for C ₁₉ H _2I F ₃ N ₂ O ₄ S ₂ + H+, 463.09676; found (ESI, [M+H] ⁺ ), 463.0958.

Example 900: N-(l-hydroxy-2,3-dihydro-lH-inden-2-yl)-5-(phenyIsulfonyl)-2 - (trifluoromethyl)benzenesulfonamide

[1124] In an analogous manner to example 765, 5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonyl chloride and 2-amino-2,3-dihydro-lH-inden-l-ol was used to prepare the title compound N-(l-hydroxy-2,3-dihydro-lH-inden-2-yl)-5-(phenylsulfonyl)-2 - (trifluoromethyl)benzenesulfonamide (105.7 mg, 54.3%) as a white solid. MS (ES-) m/z 495.7;

HPLC purity 97.7% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₁₈ F ₃ NO ₅ S ₂ + H+ - H+, 497.05785; found (ESI, [M+H-H20]+), 480.0508.

Example 901: tert-butyl [frø«s-4-({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)cyclohexyl]carbamate

[1125] Step 1 : To a stirred solution of trans- 1,4-cyclohexanediamine (0.50 g, 4.4 mmol) in ethyl ether (25 mL) was added BOC anhydride (0.96 g, 4.4 mmol) and the resulting solution

was stirred room temperature overnight. The mixture was filtered to give (4-aminocyclohexyl)- carbamic acid tert-butyl ester. (0.90 g, 82%).

[1126] Step 2: Following the same procedure described on example 435, 2- trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and (4-aminocyclohexyl)-carbamic acid tert-butyl ester were used to prepare tert-butyl [7røra'-4-({[5-(phenylsulfonyl)-2- (trifluoromethy l)ρhenyl] sulfonyl } amino)cy clohexyl] carbamate . MS (ES-) m/z 560.7;

HPLC purity 94.5% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₂₉ F ₃ N ₂ O ₆ S ₂ + H+, 563.14919; found (ESI, [M+H] ^4" ), 563.1474.

Example 902: 4-oxo-4-{4-[({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]piperidin-l-yl }butanoic acid

[1127] In an analogous manner to example 878, 5-(jphenylsulfonyl)-iV-(piperidin-4- ylmethyl)-2-(trifluoromethyl)benzenesulfonamide and succinic anhydride were used to prepare 4-OXO-4- {4- [( { [5 -(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl } amino)methy l]piperidin- l-yl}butanoic acid. MS (ES-) m/z 560.7;

HPLC purity 90.6% at 210-370 nm, 8.2 min.; Xterra RPl 8, 3.5u, 15O x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Pb=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₅ F ₃ N ₂ O ₇ S ₂ + H+, 563.11280; found (ESI, [M+H] ⁺ ), 563.1136.

Example 903: 5-oxo-5-{4-[({[5-(phenylsuIfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]piperidin-l-yl }pentanoic acid

[1128] In an analogous manner to example 878, 5-(phenylsulfonyl)-N-(piperidin-4- ylmethyl)-2-(trifluoromethyl)benzenesulfonamide and glutaric anhydride were used to prepare 5- oxo-5-{4-[({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]su lfonyl}amino)methylJpiperidin-l- yl}pentanoic acid. MS (ES+) m/z 576.8;

HPLC purity 100% at 210-370 nm, 8.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₂₇ F ₃ N ₂ O ₇ S ₂ + H+, 577.12845; found (ESI, [M+H] ⁺ ), 577.1257.

86

/λ.J.VJLAUJ.OUO - 338 -

Example 904: 3-({4-[({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]piperidin-l-yl }sulfonyl)benzoic acid

[1129] In an analogous manner to example 462, 5-(phenylsulfonyl)~JV-(piperidin-4- ylmethyl)-2-(trifluoromethyl)benzenesulfonamide and 3-(chlorosulfonyl)benzoic acid were used to prepare 3-({4-[({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)methyl]piperidin-l -yl}sulfonyl)benzoic acid. MS (ES+) m/z 646.7;

HPLC purity 92.6% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₆ H ₂₅ F ₃ N ₂ O ₈ S ₃ + H+, 647.07979; found (ESI, [M+H] ⁺ ), 647.0802.

Example 905: iV-{2-[(2-hydroxyethyl)(methyl)ammo]ethyl}-5-(phenylsulfonyl )-2- (trifluoromethyl)benzenesulfonamide

[1130] To a stirred suspension of N-[2-(methylamino)ethyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide hydrochloride (65 mg, 0.14 mmol) from Example 799 in a solution of 2-bromoethanol (11 μL, 19 mg, 0.16 mmol) in CH ₃ CN (2 mL) under N ₂ at room temperature was added diisopropylethylamine (49 μL, 36 mg, 0.28 mmol). The mixture was stirred under N ₂ at 74 ⁰ C for 18 hours. The solvent was evaporated. The residue was partitioned with CH ₂ Cl ₂ and water and washed twice with water. It was loaded directly onto a silica gel column and eluted with a gradient of hexane and ethyl acetate to give 40 mg (61%) of 7V-{2-[(2- hydroxyethyl)(methyl)amino]ethyl}-5-(phenylsulfonyl)-2-(trif luoromethyl)benzenesulfonamide. MS (ES+) m/z 466.8; HRMS: calcd for C ₁₈ H ₂₁ F ₃ N ₂ O ₅ S ₂ + H+ ₅ 467.09167; found (ESI, [M+H] ⁺ ), 467.0922.

Example 906: methyl iV-methyl-iV-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl] sulf onyl} amino)ethyl] glycinate

[1131] To a stirred suspension of 7V-[2-(methylamino)ethyl]-5-(ρhenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide hydrochloride (12 mg, 0.26 mmol) from Example 799 in CH ₂ Cl ₂ (3.5 mL) under N ₂ at room temperature was added methyl bromoacetate (26 μL, 43 mg, 0.28 mmol) and diisopropylethylamine (83 μL, 62 mg, 0.48 mmol). The mixture was stirred at room temperatue for 2 days. . It was washed twice with water and loaded directly onto a silica

gel column and eluted with a gradient of hexane and ethyl acetate to give 0.11 g (85%) of methyl

N-methyl-N-[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)ph enyl]sulfonyl}amino)ethyl]glycinate.

MS (ES-) m/z 492.7;

HRMS: calcd for C ₁₉ H ₂₁ F ₃ N ₂ O ₆ S ₂ + H+, 495.08659; found (ESI ₃ [M+H] ⁺ ), 495.0846.

Example 907: ethyl iV-methyl-λ^[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-β-alaninate

[1132] To a stirred suspension of N-[2-(methylamino)ethyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide hydrochloride (0.15 g, 0.33 mmol) from Example 799 in CHCl ₃ (15 mL) under N ₂ at room temperature was added ethyl acrylate (48 μL, 44 mg, 0.44 mmol) and diisopropylethylamine (70 μL, 52 mg, 0.40 mmol). The mixture was stirred at 57 ⁰ C for 18 hours. Ethyl acrylate (46 μL, 42 mg, 0.42 mmol) and diisopropylethylamine (90 μL, 67 mg, 0.52 mmol) were added. The mixture was stirred at 57 ⁰ C for 2 days. It was washed with water and concentrated to 5 mL. This was loaded directly onto a Isco silica gel column and eluted with a gradient of hexane and ethyl acetate to give 0.15 g (88%) of ethyl N-methyl-N-[2- ({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}ami no)ethyl]-β-alaninate. MS (ES+) m/z 522.8; HRMS: calcd for C ₂₁ H ₂₅ F ₃ N ₂ O ₆ S ₂ + H+, 523.11789; found (ESI, [M+H] ⁺ ), 523.1188.

Example 908: tert-bntyl 2-[2-({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]pyrrolidine-l-c arboxylate

[1133] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 2-(aminoethyl)-l-N-BOC-pyrrolidine were used to prepare tert- butyl 2-[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfony l}amino)ethyl]pyrrolidine-l- carboxylate. MS (ES-) m/z 560.8;

HPLC purity 100% at 210-370 nm, 10.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 909: tert-butyl 4-({[2-ethyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)piperid ine-l- carboxylate

[1134] In an analogous manner to Example 300:

5-benzenesulfonyl-2-ethyl-benzenesulfonyl chloride and 4-amino-piperidine-l- carboxylic acid tert-butyl ester were used to prepare tert-butyl 4-({[2-ethyl-5- (phenylsulfonyl)phenyl]sulfonyl} amino)piperidine- 1 -carboxylate. MS (ES-) m/z 507.1;

HPLC purity 100% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₃₂ N ₂ O ₆ S ₂ + H+, 509.17745; found (ESI, [M+H] ⁺ ), 509.1793.

Example 910: tert-butyl 4-({[2,3-dimethyl-5- (phenylsulfonyl)phenyl]sulfonyl}amino)piperidine-l -carboxylate

[1135] In an analogous manner to Example 347:

5-Benzenesulfony 1-2,3 -dimethyl-benzenesulfonyl chloride and 4-amino-piperidine-l- carboxylic acid tert-butyl ester were used to prepare tert-butyl 4-({[2,3-dimethyl-5- (phenylsulfonyl)phenyl]sulfonyl}amino)piperidine-l-carboxyla te. MS (ES-) m/z 507.1;

HPLC purity 100% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₃₂ N ₂ O ₆ S ₂ + H+, 509.17745; found (ESI, [M+H] ⁺ ), 509.1761.

Example 911: tert-butyl 4-({[2,4-dimethyI-5- (phenylsulfonyl)phenyl]sulfonyl}amino)piperidine-l-carboxyla te

[1136] In an analogous manner to Step 3, Example 295:

5-Benzenesulfony 1-2,4-dimethyl-benzenesulfonyl chloride and 4-amino-piperidine-l- carboxylic acid tert-butyl ester were used to prepare tert-butyl 4-({[2,4-dimethyl-5- (phenylsulfonyl)phenyl]sulfonyl}amino)piperidine-l-carboxyla te. MS (ES-) m/z 507.1;

HPLC purity 100% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₃₂ N ₂ O ₆ S ₂ + H+, 509.17745; found (ESI, [M+H] ⁺ ), 509.1798.

Example 912: tert-butyl 4-({[2-isopropyl-5-

W 2

- 341 -

(phenylsulfonyl)phenyl]sulfonyl}amino)piperidine-l-carbox ylate

[1137] In an analogous manner to Step 3, Example 295:

5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and 4-amino-piperidine-l- carboxylic acid tert-butyl ester were used to prepare tør/-butyl 4-({[2-isopropyl-5- (phenylsulfonyl)phenyl]sulfonyl}amino)piperidine-l-carboxyla te. MS (ES-) m/z 521.1;

HPLC purity 100% at 210-370 ran, 10.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Pb=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₃₄ N ₂ O ₆ S ₂ + H+, 523.19310; found (ESI, [M+H] ⁺ ) ₃ 523.1921.

Example 913: 5-(phenyIsulfonyI)-iV-(2-pyrrolidin-2-ylethyI)-2- (trifluoromethyl)benzenesulfonamide

[1138] In an analogous manner to example 688, tert-butyl 2-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]pyrrolidine-l-c arboxylate was used to prepare 5- (phenylsulfonyl)-λ/-(2-pyrrolidin-2-ylethyl)-2-(trifluorome thyl)benzenesulfonamide. MS (ES+) m/z 462.8;

HPLC purity 100% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₉ H ₂₁ F ₃ N ₂ O ₄ S ₂ + H+, 463.09676; found (ESI, [M+H] ⁺ ), 463.0961.

Example 914: iV-{l-[(4-hydroxyphenyl)sulfonyl]piperidin-4-yl}-5-(phenyIsu lfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1139] Step 1 : Following the same procedure described on example 462, 5- (phenylsulfonyl)-N-piperidin-4-yl-2-(trifluoromethyl)benzene sulfonamide and 4- methoxybenzene sulfonyl chloride were used to prepare 7V-{l-[(4- methoxyphenyl)sulfonyl]piperidin-4-yl}-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide .

[1140] Step 2: Following the same procedure described on example 744, N-{l-[(4- methoxyphenyl)sulfonyl]piperidin-4-yl } -5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide was used to prepare 7V-{l-[(4- hydroxyphenyl)sulfonyl]piperidin-4-yl}-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide.

MS (ES+) m/z 604.7;

MS (ES) m/z 604.7;

HPLC purity 100% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₄ H ₂₃ F ₃ N ₂ O ₇ S ₃ + H+, 605.06922; found (ESI, [M+H] ⁴ ), 605.0696.

Example 915: tert-bntyl 4-{[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]car bonyl}piperidine-l-carboxylate [1141] To a stirred solution of 1 -BOC-piperidine-4-carboxylic acid (0.08g, 0.34 mmol) in methylene chloride (2 mL) was added triethylamine (0.1 mL, 0.7 mmol) and carbonyldiimidazole (0.06 g, 0.34 mmol). The resulting solution was stirred at room temperature for 20 minutes. To the mixture was added 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide (0.15 g, 0.34 mmol). The resulting solution was stirred lhr, washed with ammonium chloride solution (sat), and concentrated. Flash column separation using 0%-50% ethyl acetate/hexane gradient gave tert-butyl 4-{[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl} amino)piperidin- 1 -yl]carbonyl}piperidine- 1 -carboxylate. (0.13 g, 70%).

MS (ES-) m/z 657.8;

HPLC purity 100% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₉ H ₃₆ F ₃ N ₃ O ₇ S ₂ + H+, 660.20195; found (ESI, [M+H] ⁺ ), 660.2032.

Example 916: A'-[l-(λVV-dimethyIglycyI)piperidin-4-yl]-5-(phenyIsulfonyI )-2- (trifluoromethyl)benzenesulfonaniide

[1142] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and dimethylaminoaceyl chloride hydrochloride were used to prepare N-[l-(iV,N-dimethylglycyl)piperidin-4-yl]-5-(phenylsulfonyl) -2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 533.8;

HPLC purity 100% at 210-370 nm, 7.1 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₆ F ₃ N ₃ O ₅ S ₂ + H+, 534.13387; found (ESI, [M+H] ⁺ ), 534.1341.

Example 917: iV-{l-[4-(dimethylamino)benzoyl]piperidm-4-yl}-5-(phenylsuIf onyl)-2- (trifluoromethyl)benzenesulfonamide

[1143] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-pipeπdin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 4-(dimethylamino)beπzoyl chloride were used to prepare 7V-{1 -[4-(dimethylamino)benzoyl]piperidin-4-yl}-5-(phenylsulfonyl )-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 595.8;

HPLC purity 95.8% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₇ H ₂₈ F ₃ N ₃ O ₅ S ₂ + H+, 596.14952; found (ESI ₅ [M+Hj ⁺ ), 596.1509.

Example 918: {2-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]pyrrolidin-l-yl }acetic acid

[1144] In an analogous mariner to example 879, 5-(phenylsulfonyl)-/V-(2-pyrrolidin-2- ylethyl)-2-(trifluoromethyl)benzenesulfonamide and tert-butylbromoacetate were used to prepare {2- [2-( { [5 -(phenylsulfonyl)-2-(trifluoromethy l)pheny 1] sulfony 1} amino)ethy l]pyrrolidin- 1 - yl} acetic acid. MS (ES+) m/z 520.8;

HPLC purity 100% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₂₃ F ₃ N ₂ O ₆ S ₂ + H+, 521.10224; found (ESI, [M+H] ⁺ ), 521.1031.

Example 919: 4-oxo-4-{2-[2-({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]pyrrolidin-l-yl }butanoic acid

[1145] In an analogous manner to example 878, 5-(phenylsulfonyl)-iV-(2-pyrrolidin-2- ylethyl)-2-(trifluoromethyl)benzenesulfonamide and succinic anhydride were used to prepare 4- oxo-4-{2-[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl}amino)ethyl]pyrrolidin-l- yljbutanoic acid. MS (ES+) m/z 562.7;

HPLC purity 100% at 210-370 nm, 8.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₃ H ₂₅ F ₃ N ₂ O ₇ S ₂ + H+, 563.11280; found (ESI, [IVB-H] ⁺ ), 563.1114.

Example 920: 3-({2-[2-({[5-(phenylsulfonyI)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]pyrrolidin-l-yl }sulfonyl)benzoic acid

[1146] In an analogous manner to example 462, 5~(phenylsulfonyl)-iV-(2-pyrrolidm-2- ylethyl)-2-(trifluoromethyl)benzenesulfonamide and and 3-(chlorosulfonyl)benzoic acid were used to prepare 3-({2-[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfonyl} amino)ethy l]pyrrolidin- 1 -y 1 } sulfony l)benzoic acid. MS (ES+) m/z 646.7;

HPLC purity 95.2% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₆ H ₂₅ F ₃ N ₂ O ₈ S ₃ + H+, 647.07979; found (ESI, [M+H] ⁺ ), 647.0803.

Example 921 : 2-ethyl-5-(phenylsulfonyl)-λ ^r -piperidin-4-ylbenzenesulfonamide

[1147] Example 909 (550 mg, 1.1 mmol) was dissolved in dry dioxane and a 4M hydrogenechloride solution in dioxane (2 mL) was added and the reaction was stirred at room temperature until the starting material was consumed as evidence by LCMS analysis. The resulting white precipitate was isolated by suction filtration and then recrystalized in hot ethanol resulting in the isolation of 2-ethyl-5-(phenylsulfonyl)-iV-piperidrn-4-ylbenzenesulfonami de (270 mg, 55%)

MS (ES+) m/z 408.8;

HPLC purity 100% at 210-370 nm, 6.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₉ H ₂₄ N ₂ O ₄ S ₂ + H+, 409.12502; found (ESI, [M+H] ⁺ ), 409.1242.

Example 922: 2,3-dimethyl-5-(phenylsulfonyl)-λ ^r -piperidin-4-ylbenzenesulfonamide

[1148] In an analogous manner to Example 921:

Example 910 was treated with a solution of hydrogen chloride in dioxane to provide 2,3- dimethyl-5-(phenylsulfonyl)-iV-piperidin-4-ylbenzenesulfonam ide. MS (ES+) m/z 408.8;

HPLC purity 100% at 210-370 nm, 6.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph-3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for Ci ₉ H ₂₄ N ₂ O ₄ S ₂ + H+, 409.12502; found (ESI, [M+H] ⁺ ) ₅ 409.1246.

Example 923: 2,4-dimethyI-5-(phenylsulfonyI)-A'-piperidin-4-ylbenzenesulf onamide

[1149] In an analogous manner to Example 921 :

Example 911 was treated with a solution of hydrogen chloride in dioxane to provide 2,4- dimethyl-5-(phenylsulfonyl)-iV-piperidin-4-ylbenzenesulfonam ide. MS (ES+) m/z 408.8;

HPLC purity 100% at 210-370 nm, 6.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₉ H ₂₄ N ₂ O ₄ S ₂ + H+, 409.12502; found (ESI, [M+H] ⁺ ), 409.1241.

Example 924: 2-isopropyl-5-(phenylsuIfonyl)-iV-piperidin-4-ylbenzenesulfo namide

[1150] In an analogous manner to Example 921 :

Example 912 was treated with a solution of hydrogen chloride in dioxane to provide 2- isopropyl-5-(phenylsulfonyl)-iV-piperidin-4-ylbenzenesulfona mide. MS (ES+) m/z 422.9;

HPLC purity 100% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₆ N ₂ O ₄ S ₂ + H+, 423.14067; found (ESI, [M+Hf), 423.1404.

Example 925: 5-(phenylsulfonyl)-iV-piperidin-4-yl-2-propylbenzenesuIfonam ide

[1151] In an analogous manner as Example 909, 5-benzenesulfonyl-2-propyl- benzenesulfonyl chloride and 4-amino-piperidine-l-carboxylic acid tert-butyl ester were used to prepare tert-butyl 4-({[2-propyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)piperi dine-l- carboxylate.

[1152] In an analogous manner to Example 921 : tert-butyl 4-({[2-propyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)piperi dine-l- carboxylate was treated with a solution of hydrogen chloride in dioxane to provide 5-

(phenylsulfonyl)-N-piperidin-4-yl-2-propylbenzenesulfonam ide.

MS (ES+) m/z 422.9;

HPLC purity 100% at 210-370 nm, 7.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2

mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₆ N ₂ O ₄ S ₂ + H+, 423.14067; found (ESI, [M+H] ^"1 ), 423.1412.

Example 926: tert-butyl (3S)-3-[({methyl[2-({[5-(phenyIsuIfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbon yl)amino]pyrrolidine-l- carboxylate

[1153] Step 1 :In an analogous manner to Example 866, Step 1, N ₅ N'- carbonyldiimidazole and (S)-N-BOC-3-aminopyrrolidine were used to prepare the intermediate fert-butyl (3S)-3 - [( 1 H-imidazol- 1 -ylcarbonyl)amino]pyrrolidine- 1 -carboxylate .

Step 2: In an analogous manner to Example 866, Step 2, JV-[2-(methylamino)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 799 and tert-butyl (3S)-3- [(I H-imidazol- l-ylcarbonyl)amino]pyrrolidine-l -carboxylate were used to prepare tert-butyl (35)-3-[({methyl[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl} amino)ethyl]amino} carbonyl)amino]pyrrolidine- 1 -carboxylate. MS (ES-) m/∑ 632.8; ηRMS: calcd for C ₂₆ H ₃₃ F ₃ N ₄ O ₇ S ₂ + H+, 635.18155; found (ESI, [M+H] ⁺ ), 635.1805.

Example 927: tert-butyl methyI[3-({[5-(phenylsuIfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)propyl]carbamate

[1154] In an analogous manner to example 765, 5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonyl chloride and N-(3-Aminopropyl)-N-methylcarbamic acid tert- butyl was used to prepare the title compound tert-butyl methyl[3-({[5-(ρhenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)propyl]carbamate (1.827 g, 84%) as a white solid. MS (ES) m/z 536.8;

HPLC purity 97.1% at 210-370 nm, 9.9 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₇ F ₃ N ₂ O ₆ S ₂ + H+, 537.13354; found (ESI, [M+H-C4H8]+), 481.0687.

Example 928: λ^-[2-(4-aminophenyl)ethyl]-5-(phenyIsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1155] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 4-(2-aminoethyl)phenylamine were used to prepare 7V-[2-(4- aminophenyl)ethyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)ben zenesulfonamide. MS (ES+) m/z 484.8;

HPLC purity 98.7% at 210-370 nm, 8.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂ IH ₁₉ F ₃ N ₂ O ₄ S ₂ + H+, 485.08111; found (ESI, [M+H] ⁺ ), 485.0799.

Example 929: N-[3-(methyIamino)propyl]-5-(phenyI$uIfonyI)-2- (trifluoroniethyl)benzenesulfonamide

[1156] Tert-butyl methyl[3-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)propyl]carbamate (1.49 g, 2.77 mmol) prepared in example 927 was taken up in 25 ml of hydrochloric saturated ethyl acetate. The hydrochloric salt of the title compound N-[3-(methylamino)propyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide (1.29 g, 98%) crashed out of solution as a white solid. MS (ES-) m/z 434.7;

HPLC purity 98.4% at 210-370 nm, 6.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOrnin, hold 4min. HRMS: calcd for C ₁₇ H ₁₉ F ₃ N ₂ O ₄ S ₂ + H+, 437.08111; found (ESI, [M+H]+), 437.0803.

Example 930: 5-(phenylsulfonyl)-λ'-[l-(piperidin-4-ylcarbonyI)piperidin- 4-yl]-2- (trifluoromethyl)benzenesulfonamide

[1157] To a stirred solution of tert-butyl 4- { [4-( { [5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin- 1 -yl]carbonyl}ρiperidine- 1 -carboxylate (0.10 g, 0.15 mmol) in ethyl acetate (2 mL) was bubbled HCl gas. The resulting solution was stirred at room temperature overnight, and concentrated. Trituration in ethyl ether gave 5- (pheny lsulfonyl)-iV- [ 1 -(piperidin-4-y lcarbony l)piperidin-4-yl] -2- (trifluoromethyl)benzenesulfonamide. (0.085 g, 85%). MS (ES+) m/z 559.8;

HPLC purity 100% at 210-370 nm, 7.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₄ H ₂₈ F ₃ N ₃ O ₅ S ₂ + H+, 560.14952; found (ESI, [MMH] ⁺ ), 560.1478.

Example 931: tert-butyl 4-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]piperidine-l-ca rboxylate

[1158] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyi)- benzenesulfonyl chloride and 4-(aminoethyl)piperidine-l-carboxylic acid tert-butyl ester were used to prepare tert-butyl 4-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl] sulfonyl} amino)ethyl]piperidine- 1 -carboxylate. MS (ES) m/z 574.8;

HPLC purity 100% at 210-370 nm, 10.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 932: methyl 3-({[2-isopropyl-5-

(phenylsulfonyl)phenyl] sulfonyl} amino)cy clohexanecarboxylate [1159] In an analogous manner to Step 3, Example 295: 5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and methyl 3- aminocyclohexanecarboxylate were used to prepare methyl 3-({[2-isopropyl-5-

(phenylsulfonyl)phenyl]sulfonyl}amino)cyclohexanecarboxyl ate.

MS (ES) m/z 479.9;

HPLC purity 100% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₃ H ₂₉ NO ₆ S ₂ + H+, 480.15091; found (HRMS, [M+H] ⁺ ), 480.1512.

Example 933: methyl 4-({[2-isopropyl-5-

(phenylsulfonyl)phenyl]sulfonyl}amino)cyclohexanecarboxyl ate [1160] In an analogous manner to Step 3, Example 295: 5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and methyl 4- aminocyclohexanecarboxylate were used to prepare methyl 4-({[2-isopropyl-5-

(phenylsulfonyl)phenyl]sulfonyl}amino)cyclohexanecarboxyl ate.

MS (ES) m/z 479.8;

HPLC purity 94.0% at 210-370 nm, 9.7 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₃ H ₂₉ NO ₆ S ₂ + H+, 480.15091; found (ESI ₃ [M+H] ⁺ ), 480.1503.

Example 934: methyl tfrø«s-4-[({[2-isopropyl-5-

(phenylsulfonyl)phenyl]sulfonyl}amino)methyl]cyclohexanec arboxylate [1161] In an analogous manner to Step 3, Example 295: 5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and methyl trans-4-

(aminomethyl)-l-cyclohexanecarboxylate were used to prepare methyl /r<my-4-[({[2-isopropyl-

5-(phenylsulfonyl)phenyl]sulfonyl}amino)methyl]cyclohexan ecarboxylate.

MS (ES+) m/z 493.9;

HPLC purity 96.2% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₄ H ₃ iNO ₆ S ₂ + H+, 494.16656; found (ESI, [M+H] ⁺ ), 494.1669.

Example 935: 2-isopropyl-5-(phenyIsulfonyl)-iV-(2,2,6,6-tetramethylpiperi din-4- yl)benzenesulfonamide

[1162] In an analogous manner to Step 3, Example 295: 5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and 4-amino-2,2,6,6- tetramethylpiperidine were used to prepare 2-isopropyl-5-(phenylsulfonyl)-N-(2,2,6,6- tetramethylpiperidin-4-yl)benzenesulfonamide.

MS (ES) m/z 478.9;

HPLC purity 97.9% at 210-370 nm, 7.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₄ H ₃₄ N ₂ O ₄ S ₂ + H+, 479.20327; found (ESI, [M+H] ⁺ ) ₅ 479.2044.

Example 936: 2-isopropyI-5-(phenylsulfonyl)-λ'-(pyridin-4-yImethyl)benze nesulfonamide

[1163] In an analogous manner to Step 3, Example 295:

5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and 4-aminomethylpyridine were used to prepare 2-isopropyl-5-(phenylsulfonyl)-iV-(pyridin-4- ylmethy l)benzenesulfonamide . MS (ES) m/z 430.8; HPLC purity 100% at 210-370 nm, 8.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2

niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂ ]H ₂₂ N ₂ O ₄ S ₂ + H+, 431.10937; found (ESI, [M+H] ⁺ ), 431.1076.

Example 937: λ'-[2-(methyl{[(3S)-pyrroIidin-3-ylammo]carbonyI}amino)ethy I]-5- (phenylsulfonyI)-2-(trifluoromethyl)benzenesulfonamide

[1164] To a solution of tert-butyl (35)-3-[({methyl[2-({ [5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl} amino)ethyl] amino } carbonyl)amino]pyrrolidine- 1 -carboxylate (0.17 g, 0.27 mmol) from Example 926 in EtOAc (1 niL) was added EtOAc saturated with HCl. This mixture stood at room temperature for 18 hours but solid had not formed. The solvent was evaporated. The residue was dissolved in EtOH. No solid formed. The solvent was evaporated. The residue was dried at 100 ⁰ C for 0.75 hours to give 0.14 g (88%) of N-[2-(methyl{[(35)- pyrrolidin-3-ylamino]carbonyl}amino)ethyl]-5-(phenylsulfonyl )-2- (trifluoromethyl)benzenesulfonamide hydrochloride. MS (ES+) m/z 534.8; HRMS: calcd for C ₂₁ H ₂₅ F ₃ N ₄ O ₅ S ₂ + H+, 535.12912; found (HRMS, [M+H] ⁺ ), 535.1287.

Example 938: methyl 3-{[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]sulfon yl}benzoate

[1165] To a stirred solution of acyl chloride (0.1 mL, 1.4 mmol) in methanol (2 niL) was added 3 - { [4-( { [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl } amino)piperidin- 1 - yljsulfonyl} benzoic acid (0.10 g, 0.16 mmol). The resulting solution was heated to 50°C overnight and concentrated. Flash column separation using 0-10% methanol/methylene chloride gradient gave methyl 3-{[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]sύ lfonyl}benzoate. (0.075 g, 74%). MS (ES+) m/z 646.8;

HPLC purity 100% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₆ H ₂₅ F ₃ N ₂ O ₈ S ₃ + H+, 647.07979; found (HRMS, [M+H] ⁺ ), 647.0825.

Example 939: iV-[2-(4-methoxyphenyl)ethyl]-5-(phenylsuIfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1166] In an analogous manner to example 435, 2-trifluoromethyl-5-(ρhenylsulfonyl)- benzenesulfonyl chloride and 2-(4-methoxyphenyl)ethylamine were used to prepare N-[2-(4- methoxyphenyl)ethyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)b enzenesulfonamide. MS (ES+) m/z 499.8;

HPLC purity 100% at 210-370 run, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₀ F ₃ NO ₅ S ₂ + H+, 500.08077; found (HRMS, [M+H] ⁺ ), 500.0799.

Example 940: 5-(phenyIsuIfonyl)-JV-(2-piperidin-4-yIethyl)-2- (trifluoromethyl)benzenesulfonamide

[1167] In an analogous manner to example 930, tert-bnty\ 4-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]piperidine-l-ca rboxylate was used to prepare 5- (phenylsulfonyl)-N-(2-piperidin-4-ylethyl)-2-(trifluoromethy l)benzenesulfonamide. MS (ES+) m/z 476.8;

HPLC purity 97.8% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₃ F ₃ N ₂ O ₄ S ₂ + H+, 477.11241; found (HRMS, [M+H] ⁺ ), 477.1128.

Example 941: {4-[({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl] sulf ony 1} amino)methyl] piperidin-1 -yl} acetic acid

[1168] In an analogous manner to example 879, 5-(phenylsulfonyl)-7V-(piperidin-4- ylmethyl)-2-(trifluoromethyl)benzenesulfonamide and tert-butylbromoacetate were used to prepare {4-[({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl }amino)methyl]piperidin- 1-yl} acetic acid. MS (ES+) m/z 520.8;

HPLC purity 97.4% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 942: iV-(4-aminobenzyl)-5-(phenyIsuIfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1169] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 4-aminomethylphenylamine were used to prepare N-(4- aminobenzyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)benzenesu lfonamide. MS (ES+) m/z 470.8;

HPLC purity 98.1% at 210-370 nm, 8.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Bicarb Buff. Ph=9.5/ACN+MeOH) for lOmin, hold 4min.

Example 943: JV-[2-(4-hydroxyphenyI)ethyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1170] In an analogous manner to example 744, iV-[2-(4-methoxyphenyl)etliyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide was used to prepare N-[2-(4- hydroxyphenyl)ethyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)b enzenesulfonamide. MS (ES-) m/z 483.7;

HPLC purity 100% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₁₈ F ₃ NO ₅ S ₂ + H+, 486.06512; found (HRMS, [M+H] ⁺ ), 486.065.

Example 944: {4-[2-({[5-(phenylsulfonyI)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]piperidin-l-yl} acetic acid

[1171] In an analogous manner to example 879, 5-(phenylsulfonyl)-iV-(2-piperidin-4- ylethyl)-2-(trifluoromethyl)benzenesulfonamide and tert-butylbromoacetate were used to prepare {4-[2-( { [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl} amino)ethyl]piperidin- 1 - yl} acetic acid. MS (ES+) m/z 534.8;

HPLC purity 100% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₅ F ₃ N ₂ O ₆ S ₂ + H+, 535.11789; found (ESI, [M+H] ⁺ ), 535.1189.

Example 945: methyl 3-({[5-(phenylsulfonyI)-2- (trifluoromethyl)phenyl]sulfonyl}amino)cyclohexanecarboxylat e

[1172] In an analogous manner to Step 3, Example 677:

5-Benzenesulfonyl-2-trifluoromethyl-benzenesulfonyl chloride and methyl 3- aminocyclohexanecarboxylate were used to prepare methyl 3-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)cyclohexanecarboxylat e. MS (ES-) m/z 503.8;

HPLC purity 98.2% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₂₂ F ₃ NO ₆ S ₂ + H+, 506.09134; found (ESI, [M+H] ⁺ ), 506.0894.

Example 946: methyl 4-({[5-(phenylsuIfonyI)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)cyclohexanecarboxy late [1173] In an analogous manner to Step 3, Example 677: 5-Benzenesulfonyl-2-trifluoromethyl-benzenesulfonyl chloride and methyl 4- aminocyclohexanecarboxylate were used to prepare methyl 4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)cyclohexanecarboxy late.

MS (ES-) m/z 503.8;

HPLC purity 90.5% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₁ H ₂₂ F ₃ NO ₆ S ₂ + H+, 506.09134; found (ESI, [M+H] ⁺ ), 506.0928.

Example 947: methyl *ra«s-4-[({[5-(phenylsuIfonyl)-2- (trifluoromethyl)phenyl] sulfony 1} amino)methyl] cy clohexanecarboxylate

[1174] In an analogous manner to Step 3, Example 677:

5-Benzenesulfonyl-2-trifluoromethyl-benzenesulfonyl chloride and methyl trans-4- (aminomethy l)-l-cy clohexanecarboxylate were used to prepare methyl trans-4-[({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)me thyl]cyclohexanecarboxylate. MS (ES-) m/z 517.8;

HPLC purity 98.1% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₄ F ₃ NO ₆ S ₂ + H+, 520.10699; found (ESI, [M+H] ⁺ ), 520.108.

Example 948: 5-(phenylsulfonyl)-λ'-(2,2,6,6-tetramethylpiperidin-4-yl)-2 -

(trifluoromethyl)benzenesulfonamide

[1175] In an analogous manner to Step 3, Example 677:

5-Benzenesulfonyl-2-trifluoromethyl-benzenesulfonyl chloride and 4-amino-2,2,6,6- tetramethylpiperidine were used to prepare 5-(phenylsulfonyl)-N-(2,2,6,6-tetramethylpiperidin-4- yl)-2-(trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 504.9;

HPLC purity 98.0% at 210-370 urn, 7.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₇ F ₃ N ₂ O ₄ S ₂ + H+, 505.14371; found (ESI ₅ [M+H] ⁺ ), 505.1442.

Example 949: 5-(phenyIsuIfonyl)-A ^L (pyridin-4-yImethyI)-2- (trifluoromethyl)benzenesulfonamide

[1176] In an analogous manner to Step 3, Example 677: 5-Benzenesulfonyl-2-trifluoromethyl-benzenesulfonyl chloride and 4- aminomethylpyridine were used to prepare 5-(phenylsulfonyl)-iV-(pyridin-4-ylmethyl)-2-

(trifluoromethyl)benzenesulfonamide.

MS (ES+) m/z 456.8;

HPLC purity 97.7% at 210-370 nm, 8.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₁₉ H ₁₅ F ₃ N ₂ O ₄ S ₂ + H+, 457.04981; found (ESI, [M+H] ⁺ ), 457.0482.

Example 950: methyl 4-[({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]benzoate

[1177] In an analogous manner to Step 3, Example 677: 5-Benzenesulfonyl-2-trifluoromethyl-benzenesulfonyl chloride and methyl 4- aminomethylbenzoate were used to prepare methyl 4-[({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)methyl]benzoate.

MS (ES) m/z 513.7;

HPLC purity 100% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/AOSB-MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₂ H ₁₈ F ₃ NO ₆ S ₂ + H+, 514.06004; found (ESI, [MB-H] ⁺ ), 514.0614.

Example 951: methyl 4-[({[2-isopropyl-5-

(phenylsulfonyl)phenyl] sulfonyl} amino)methyl] benzoate

[1178] In an analogous manner to Step 3, Example 295: 5-Benzenesulfonyl-2-isopropyl-benzenesulfonyl chloride and methyl A- aminomethylbenzoate were used to prepare methyl 4-[({[2-isopropyl-5-

(phenylsulfonyl)phenyl] sulfonyl } amino)methyl]benzoate .

MS (ES-) rn/z 485.8;

HPLC purity 100% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₄ H ₂₅ NO ₆ S ₂ + H+, 488.11961; found (ESI, [M+H] ⁺ ) ₃ 488.1208.

Example 952: 3-({[2-isopropyl-5- (phenylsulfonyl)phenyl]sulfonyl}amino)cyclohexanecarboxylic acid

[1179] Methyl 3-({[2-isopropyl-5-

(phenylsulfonyl)phenyl]sulfonyl}amino)cyclohexanecarboxyl ate (example 932, 100 mg, 0.2 mmol) was dissolved in tetrahydrofuran (2 mL) and a 50% aqueous solution of sodium hydroxide (48 mg, 0.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction was concentrated and then water (2 mL) was added followed by extraction with ethyl acetate (2 x 2 mL). The aqueous phase was acidified with 2N HCl and extracted with ethyl acetate which when evaporated under reduced pressure afforded 3-({[2- isopropyl-5-(phenylsulfonyl)phenyl]sulfonyl}amino)cyclohexan ecarboxylic acid (92 mg, 95%) as an amorphous white solid. MS (ES-) m/z 464.1;

HPLC purity 97.9% at 210-370 nm, 9.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₇ NO ₆ S ₂ + H+, 466.13526; found (ESI, [M+H] ^4" ), 466.1344.

Example 953: 4-({[2-isopropyI-5-

(phenylsulfonyl)phenyl]sulfonyl}amino)cyclohexanecarboxyl ic acid [1180] In an analogous manner to Example 952:

methyl 4-( { [2-isopropy l-(phenylsulfony l)pheny 1] sulfony 1 } amino)cyclohexanecarboxylate (example 933) and 50% sodium hydroxide were used to prepare 4-({ [2-isopropy 1-5- (phenylsulfonyl)phenyl] sulfony 1 } amino)cyclohexanecarboxy Hc acid. MS (ES-) m/z 464.1;

HPLC purity 94.3% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₇ NO ₆ S ₂ + H+, 466.13526; found (ESI, [M+H] ⁺ ), 466.1345.

Example 954: tfrα«s-4-[({[2-isopropyI-5- (phenylsulfonyl)phenyl]sulfonyl}amino)methyl]cyclohexanecarb oxylic acid

[1181] In an analogous manner to Example 952:

Methyl trans-4-[({[2-isopτopyl-5-

(phenylsulfonyl)phenyl]sulfonyl}amino)methyl]cyclohexanec arboxylate (example 934) and 50% sodium hydroxide were used to prepare trαrø-4-[({[2-isopropyl-5- (phenylsulfony^phenyljsulfonyljamino^ethyljcyclohexanecarbox y lie acid. MS (ES-) m/z 478.1;

HPLC purity 97.8% at 210-370 nm, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 955: tert-butyl 4-[({methyl[3-({[5-(phenyIsuIfonyl)-2-

(trifluoromethy I)phenyl] sulf onyl} amino)propyl] amino} carbony l)amino] piperidine-1 - carboxylate

[1182] A mixture of N-[3-(methylamino)propyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide (202.5 mg, 0.43 mmol) prepared example 929 in dichloromethane (15 ml). Tert-butyl 4-(lH-imidazole-l-carboxamido)piperidine-l- carboxylate( 109.4 mg, 0.37 mmol) and 1.5 eq. of N,N-Diisoprpylethylamine was syringed into the reaction vial and was allowed to stir overnight at room temperature. The product was transferred onto a 40 g Isco RediSep® Normal Phase column and was purified by automated flash chromatography using a gradient of 20% to 100% hexane/ethyl acetate. Isolation of the main component gave the title compound tert-butyl 4-[({methyl[3-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfony 1 } amino)propyl] amino } carbony l)amino]piperidine- 1 -carboxylate (217.2 mg, 77%) as a white solid.

MS (ES-) m/z 661.2;

HPLC purity 98.2% at 210-370 nm, 9.8 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₈ H ₃₇ F ₃ N ₄ O ₇ S ₂ + H+, 663.21285; found (ESI ₅ [M+H]+) ₅ 663.2208.

Example 956: 3-{4-[({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]piperidin-l-yl }benzoic acid

[1183] In an analogous manner to example 891, 5-(phenylsulfonyl)-7V-(piperidin-4- ylmethyl)-2-(trifluoromethyl)benzenesulfonamide and 3-(tertbutoxycarbonyl)-phenylboronic acid were used to prepare 3-{4-[({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]piperidm-l-yl} benzoic acid. MS (ES+) m/z 583.1;

HPLC purity 100% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₆ H ₂₅ F ₃ N ₂ O ₆ S ₂ + H+, 583.11789; found (ESI, [M+H] ⁺ ), 583.1181.

Example 957: 3-{4-[2-({[5-(phenylsuIfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]piperidin-l-yl} benzoic acid

[1184] In an analogous manner to example 891, 5-(phenylsulfonyl)-iV-(2-piperidin-4- ylethyl)-2-(rrifluoromethyl)benzenesulfonamide and 3-(tertbutoxycarbonyl)-phenylboronic acid were used to prepare 3-{4-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]piperidin-l-yl} benzoic acid. MS (ES+) m/z 597.1;

HPLC purity 97.4% at 210-370 nm, 10.0 min.; Xterra RPl 8, 3.5u, 15O x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph-3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₇ H ₂₇ F ₃ N ₂ O ₆ S ₂ + H+, 597.13354; found (ESI, [M+HJ ⁺ ), 597.1345.

Example 958: N-{l-[(6-chloropyridin-3-yl)carbonyl]piperidin-4-yl}-5-(phen ylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1185] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 6-chloronicotinyl chloride were used to prepare N- {I-

[(6-chloropyridin-3-yl)carbonyl]piperidin-4-yl}-5-(phenyl sulfonyl)-2-

(trifluoromethyl)benzenesulfonamide.

MS (ES) m/z 588.0;

HPLC purity 100% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 959: A ^L (/rα«5-4-aminocyclohexyI)-5-(phenyIsuIfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1186] In an analogous manner to example 930, tert-butyl [trans-4-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)cy clohexyl] carbamate was used to prepare iV-(trαrø-4-aminocyclohexyl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 463.1;

HPLC purity 100% at 210-370 nm, 8.3 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Bicarb Buff. Ph=9.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₉ H ₂₁ F ₃ N ₂ O ₄ S ₂ + H+, 463.09676; found (ESI, [M+H] ⁺ ), 463.0959.

Example 960: JV-[2-(4-bromophenyl)ethyl]-5-(phenylsuIfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1187] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 2-(4-bromophenyl)ethylamine were used to prepare iV-[2-(4- bromophenyl)ethyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)ben zenesulfonamide. MS (ES-) m/z 546.0;

HPLC purity 100% at 210-370 nm, 10.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 961: ^rt-butyliV-methyI-iV-[2-({[5-(plienylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-β-alaninate

[1188] To a stirred suspension of iV-[2-(methylamino)ethyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide hydrochloride (0.13 g, 0.28 mmol) from Example 799 in EtOH (8.9 mL) was added fert-butyl acrylate (0.14 mL, 0.13 g, 0.97 mmol) and diisopropylethylamine (59 μL, 44 mg, 0.34 mmol). The mixture was stirred 6 h at 76 ⁰ C under

N ₂ . The solvent was evaporated and the residue was partitioned with water and CH ₂ Cl ₂ . The organic layer was washed with water. The solvent was evaporated. The residue was loaded directly onto a silica gel column and eluted with a gradient of hexane and ethyl acetate to give

0.10 g (64%) of tert-butyl N-methyl-N-[2-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfony 1} amino)ethyl]- β -alaninate .

MS (ESI+) m/z 551;

HRMS: calcd for C ₂₃ H ₂₉ F ₃ N ₂ O ₆ S ₂ + H+, 551.14919; found (ESI, [M+H] ⁺ ), 551.1503.

Example 962: ter^butylN-methyl-iV-[2-({[5-(phenylsuIfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]glycinate

[1189] In an analogous manner to Example 906, iV-[2-(methylamino)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 799 and tert-butyl bromoacetate were used to prepare tert-butyl N-methyl-iV-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]glycinate. MS (ES-) m/z 534.8; HRMS: calcd for C ₂₂ H ₂₇ F ₃ N ₂ O ₆ S ₂ + H+, 537.13354; found (ESI, [M+H] ⁺ ), 537.1312.

Example 963: 3-[({4-[({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]phenyl}amino)s ulfonyl]benzoic acid

[1190] In an analogous manner to example 462, N-(4-aminobenzyl)-5-(phenylsulfonyl)- 2-(trifluoromethyl)benzenesulfonamide and and 3-(chlorosulfonyl)benzoic acid were used to prepare 3-[({4-[({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)methyl]phenyl}amino)s ulfonyl]benzoic acid. HPLC purity 86.4% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₇ H ₂₁ F ₃ N ₂ O ₈ S ₃ + H+, 655.04849; found (ESI, [MH-H] ⁺ ), 655.0472.

Example 964: N-(4-bromobenzyl)-5-(phenyIsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1191] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 4-bromobenzyl amine were used to prepare 7V-(4-bromobenzyl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide.

MS (ES-) m/z 531.6;

HPLC purity 97.6% at 210-370 nm, 10.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HPLC purity 97.6% at 210-370 nm, 10.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 965: tert-butyl 4-{2-oxo-2-[4-({[5-(phenylsuIfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]ethyl} piperidine-l-carboxylate

[1192] In an analogous manner to example 915, 5-(phenylsulfonyl)-JV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and l-BOC-piperidin-4-ylacetic acid were used to prepare tert-butyl 4-{2-oxo-2-[4-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfony 1} amino)piperidin- 1 -yl] ethyl }piperidine- 1 -carboxylate . HPLC purity 97.7% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₃₀ H ₃₈ F ₃ N ₃ O ₇ S ₂ + H+, 674.21760; found (ESI, [M+H] ⁺ ), 674.2167.

Example 966: λ ^r -[2-(4-cyanophenyl)ethyI]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1193] In an analogous manner to example 376, N-[2-(4-bromophenyl)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide was used to prepare N-[2-(4- cyanophenyl)ethyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)ben zenesulfonamide. HPLC purity 100% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₁₇ F ₃ N ₂ O ₄ S ₂ + H+, 495.06546; found (ESI, [M+H] ⁺ ), 495.0669.

Example 967: 3-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)cyclohexanecarboxylic acid

[1194] In an analogous manner to Example 952:

Methyl 3-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)cyclohexanecarboxy late (example 945) and 50% sodium hydroxide were used to prepare 3-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)cyclohexanecarboxy lie acid.

HPLC purity 98.5% at 210-370 nm, 8.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₀ F ₃ NO ₆ S ₂ + H+, 492.07569; found (ESI, [M+H] ⁺ ), 492.075.

Example 968: 4-({[5-(phenylsuIfonyl)-2-

(trifluoromethyl)phenyl] sulfonyl} amino)cyclohexanecarboxylic acid

[1195] In an analogous manner to Example 952:

Methyl 4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl] sulfonyl }amino)cyclohexanecarboxy late (example 946) and 50% sodium hydroxide were used to prepare 4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl] sulfonyl }amino)cyclohexanecarboxy lie acid. HPLC purity 90.5% at 210-370 nm, 8.9 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₀ H ₂₀ F ₃ NO ₆ S ₂ + H+, 492.07569; found (ESI, [M+H] ⁺ ), 492.0756.

Example 969: #γms-4-[({[5-(phenyIsulfonyl)-2-

(trifluoromethyl)phenyl] sulfonyl} amino)methyl] cyclohexanecarboxylic acid

[1196] In an analogous manner to Example 952:

HPLC purity 98.4% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₂₂ F ₃ NO ₆ S ₂ + H+, 506.09134; found (ESI ₅ [M+H] ⁺ ), 506.089.

Example 970: 5-(phenylsulfonyl)-iV-[l-(piperidin-4-ylacetyl)piperidm-4-yl ]-2- (trifluoromethyl)benzenesulfonamide

[1197] In an analogous manner to example 930, tert-butyl 4-{2-oxo-2-[4-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)pi peridin-l-yl]ethyl}piperidine-l- carboxylate was used to prepare 5-(phenylsulfonyl)-iV-[l-(piperidin-4-ylacetyl)piperidin-4-y l]-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 573.9;

HPLC purity 98.0% at 210-370 nm, 7.3 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₃₀ F ₃ N ₃ O ₅ S ₂ + H+, 574.16517; found (ESI, [M+H] ⁺ ), 574.1636.

Example 971 : N-(3-{methyl[(piperidm-4-ylammo)carbonyl]amino}propyl)-5- (phenyIsulfonyl)-2-(trifluoromethyI)benzenesuIfonamide

[1198] Tert-butyl 4-[({methyl[3-({ [5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfonyl} amino)propyl] amino } carbonyl)amino]piperidine- 1 -carboxylate (156.3 mg, 0.23 mmol) prepared in example 955 was taken up in 25 ml of hydrochloric saturated ethyl acetate. The hydrochloric salt of the title compound N-(3-{methyl[(piperidin-4- ylamino)carbonyl]amino}propyl)-5-(phenylsulfonyl)-2-(trifluo romethyl)benzenesulfonamide (134.4 mg, 97%) crashed out of solution as a white solid. MS (ES+) m/z 562.9;

HPLC purity 98.4% at 210-370 urn, 7.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₉ F ₃ N ₄ O ₅ S ₂ + H+, 563.16042; found (ESI, [M+H]+), 563.1581.

Example 972: 4-[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]benzoi c acid

[1199] In an analogous manner to example 891, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 4-(tertbutoxycarbonyl)-phenylboronic acid were used to prepare 4-[4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfony l}amino)piperidin-l- yl]benzoic acid. HRMS: calcd for C ₂₅ H ₂₃ F ₃ N ₂ O ₆ S ₂ + H+, 569.10224; found (ESI, [M+H]+), 569.0995.

Example 973: methyl 4-[2-({[5-(phenylsulfonyI)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzoate

[1200] Step 1 : Following the same procedure described on example 938, 4-(2- aminoethyl)benzoic acid was used to prepare 4-(2-aminoethyl)benzoic acid methyl ester.

[1201] Step 2: Following the same procedure described on example 435, 2- trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 4-(2-aminoethyl)benzoic acid methyl ester were used to prepare methyl 4-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzoate.

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HPLC purity 92.4% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₀ F ₃ NO ₆ S ₂ + H+, 528.07569; found (ESI, [M+H]+), 528.0778.

Example 974: tert-butyl 4-({methyl[3-({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)propyl]amino}carbonyl )piperazine-l-carboxylate

[1202] In an analogous manner to example 955, tert-butyl methyl[3-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)pr opyl]carbamate (149.5 mg, 0.32mmol) prepare in example 927 and tert-butyl 4-(lH-imidazole-l-carboxamido)piperidine-l- carboxylate (78.1 mg, 0.28mmol) was used to prepare the title compound tert-butyl A- ({methyl[3-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny l]sulfonyl } amino)propyl] amino } carbony l)piρerazine- 1 -carboxylate (161.3 mg, 89%) as a white solid.

HPLC purity 96.8% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=θ.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₇ H ₃₅ F ₃ N ₄ O ₇ S ₂ + H+, 649.19720; found (ESI, [M+H]+), 649.1952.

Example 975: N-methyI-N-[3-({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)propyl]piperazine-l-c arboxamide

[1203] Tert-butyl 4-({methyl[3-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)propyl]amino}carbo nyl)piperazine-l-carboxylate (133.1 mg, 0.2mmol) prepared in example 974 was taken up in 25 ml of hydrochloric saturated ethyl acetate. The hydrochloric salt of the title compound N-methyl-N-[3-({[5-(phenylsulfonyl)- 2-(trifluoromethyl)phenyl]sulfonyl}amino)propyl]piperazine-l -carboxamide (118.7 mg, 98%) crashed out of solution as a yellow oil. MS (ES+) m/z 549.0;

HPLC purity 98.2% at 210-370 nm, 8.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Bicarb Buff. Ph=9.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₇ F ₃ N ₄ O ₅ S ₂ + H+, 549.14477; found (ESI, [M+H]+), 549.1434.

Example 976: 4'-[({[5-(phenyIsulfonyl)-2- (trifluoromethyI)phenyl]suIfonyl}amino)methyl]biphenyl-3-car boxyIic acid

[1204] Step 1 : To a stirred solution of N-(4-bromobenzyl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide (0.15 g, 0.28 mmol) in glyme (3.5 mL) was added 3-(tert- butoxycarbonylphenyl) boronic acid (0.094 g, 0.42 mmol), Pd(PPh ₃ ) ₄ (0.03 g, 0.03 mmol), and sodium carbonate (0.09 g, 0.84 mmol) predissolved in water (0.6 mL). The resulting solution was heated to reflux for 2.5hr, allowed to cool and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. Flash column separation using 0%-30% ethyl acetate/hexane gradient gave 4'-[({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]biphenyl-3-car boxylic acid tert-butyl ester.

[1205] Step 2: In an analogous manner to example 930, 4'-[({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]biphenyl-3-car boxylic acid tert-butyl ester was used to prepare 4'-[({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)methyl]biphenyl-3- carboxy lie acid. MS (ES-) m/z 573.9;

HPLC purity 100% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₇ H ₂₀ F ₃ NO ₆ S ₂ + H+, 576.07569; found (ESI, [M+H] ⁺ ), 576.0751.

Example 977: λ^-{l-[(2,5-dichloropyridin-3-yl)carbonyl]piperidin-4-yl}-5 -(phenyIsulfonyl)- 2-(trifluoromethyl)benzenesulfonamide

[1206] In an analogous manner to example 435, 5-(phenylsulfonyl)-JV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2,5-dichloropyridine-3-carbonyl chloride were used to prepare N-{\ -[(2,5-dichloropyridin-3-yl)carbonyl]piperidin-4-yl}-5-(phen ylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 621.9;

HPLC purity 96.3% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₂₀ Cl ₂ F ₃ N ₃ O ₅ S ₂ + H+, 622.02463; found (ESI, [M+H] ⁺ ), 622.0225.

Example 978: λ ^r -[l-(2-chloroisonicotinoyI)piperidin-4-yI]-5-(phenylsuIfonyI )-2- (trifluoromethyl)benzenesulfonamide

[1207] In an analogous manner to example 435, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-chloropyridine-4-carbonyl chloride were used to

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prepare N-[l-(2-chloroisonicotinoyl)ρiperidin-4-yl]-5-(phenylsulfon yl)-2-

(trifluoromethyl)benzenesulfonamide.

MS (ES+) m/z 588.0;

HPLC purity 97.7% at 210-370 run, 9.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₄ H ₂₁ ClF ₃ N ₃ O ₅ S ₂ + H+, 588.06360; found (ESI, [M+H] ⁺ ), 588.0627.

Example 979: 4'-[({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]suIfonyl}amino)methyl]biphenyl-4- carboxylic acid [1208] In an analogous manner to example 976, iV-(4-bromobenzyl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide and 4-(tert-butoxycarbonylphenyl) boronic acid were used to prepare 4'-[({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]biphenyl-4-car boxylic acid. MS (ES-) m/z 573.9;

HPLC purity 100% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 980: 4-{4-[({methyl[2-({[5-(phenyIsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbon yl)amino]piperidin-l-yl}-4- oxobutanoic acid

[1209] In an analogous manner to Example 897, N-(2-{niethyl[(piperidin-4- ylamino)carbonyl]amino}ethyl)-5-(phenylsulfonyl)-2-(trifluor omethyl)benzenesulfonamide hydrochloride from Example 881 and succinic anhydride were used to prepare crude product which was recrystallized from ethyl acetate/ethanol to give 4-{4-[({methyl[2-({[5- (phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) amino]piperidin-l-yl}-4- oxobutanoic acid. MS (ES+) m/z 649.0; HRMS: calcd for C ₂₆ H ₃₁ F ₃ N ₄ O ₈ S ₂ + H+, 649.16082; found (ESI ₅ [MfH] ⁺ ), 649.1613.

Example 981: 7V-methyl-iV-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]glycine

[1210] To a solution of tert-butyl N-methyl-N-[2-({ [5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]glycinate (87.9 mg, 0.164 mmol) from Example 962 in EtOAc (0.3 mL) was added EtOAc saturated with HCl (0.5 mL). The solution stood for 3 days and was then concentrated. νMR showed the reaction was incomplete. The mixture was dissolved in EtOAc saturated with HCl. The solution stood for 3 days and the solvent was removed by pipette. The solid was washed with EtOAc and dried to give 70.9 mg (90%) of N- methyl-N-[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl}amino)ethyl]glycine hydrochloride. MS (ES-) m/z 478.9; HRMS: calcd for C ₁₈ H ₁₉ F ₃ N ₂ O ₆ S ₂ + H+, 481.07094; found (ESI, [M+H] ⁺ ) ₅ 481.0704.

Example 982: iV-methyl-iV-[2-({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]- β-alanine

[1211] In an analogous manner to example 981 , tert-butyl N-methyl-N-[2-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)et hyl]- β-alaninate (99 mg, 0.18 mg) from Example 961 was dissolved in EtOAc (0.5 mL) saturated with HCl. After 3 days the solvent was removed by pipette. The solid was washed with EtOAc and dried to give 72 mg (81 %) of N-methyl-N-[2-({ [5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]- β-alanine hydrochloride. MS (ES+) m/z 495.0; HRMS: calcd for C ₁₉ H ₂₁ F ₃ N ₂ O ₆ S ₂ + H+, 495.08659; found (ESI, [M+H] ⁺ ) ₅ 495.088.

Example 983: 4-(bromomethyl)-iV-methyl-iV-[2-({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide

[1212] In an analogous manner to Example 833, N-[2-(methylamino)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 799 and 4-bromomethyl benzoyl bromide were reacted as described in the example. After 2.5 hours the reaction mixture was washed once with water. It was loaded directly onto a silica gel column and eluted with a gradient of hexane and ethyl acetate to give 4-(bromomethyl)-N-methyl-N-[2-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)et hyl]benzamide. MS (ES+) m/z 618.9; HRMS: calcd for C ₂₄ H ₂₂ BrF ₃ N ₂ O ₅ S ₂ + H+, 619.01783; found (ESI ₅ [M+H] ⁺ ), 619.0162.

W 2

- 367 -

Example 984: 5-(phenylsulfonyI)-iV-{2-[4-(2iy-tetrazoI-5-yl)phenyl]ethyl} -2- (trifluoromethyl)benzenesulfonamide

[1213] In an analogous manner to example 863, N-[2-(4-cyanophenyl)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide was used to prepare 5- (phenylsulfonyl)-iV-{2-[4-(2/f-tetrazol-5-yl)phenyl]ethyl}-2 - (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 538.0;

HPLC purity 95.7% at 210-370 nm, 8.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HEMS: calcd for C ₂₂ H ₁₈ F ₃ N ₅ O ₄ S ₂ + H+, 538.08251; found (ESI, [M+H] ⁺ ), 538.0812.

Example 985: iV-{l-[(3-cyanophenyl)sulfonyl]piperidin-4-yl}-5-(phenylsulf onyI)-2- (trifluoromethyl)benzenesulfonamide

[1214] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-piρeridin-4-yl~2- (trifluoromethyl)benzenesulfonamide and 3-cyanobenzenesulfonyl chloride were used to prepare 7V-{l-[(3-cyanophenyl)sulfonyl]piperidin-4-yl}-5-(phenylsulf onyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 613.9;

HPLC purity 98.4% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 986: iV-[l-(3-cyanophenyl)piperidm-4-yI]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1215] Step 1 : A solution of 4-aminopiperidine (0.50 g, 5.0 mmol) and 3- fluorobenzonitrile (0.60 g, 5.0 mmol) in dimethylacetamide (5 mL) was heated 200°C in a microwave for 20 minutes and partitioned between sodium bicarbonate solution (sat) and ethyl acetate. The organic layer was washed several times with water and concentrated. Flash column separation using 0%-10% methanol/methylene chloride gradient gave 3-(4-aminopiperidin-l-yl)- benzonitrile.

[1216] Step 2: In an analogous manner to example 435, 2-trifluoromethyl-5- (phenylsulfonyl)- benzenesulfonyl chloride and 3-(4-aminopiperidin-l-yl)-benzonitrile were

used to prepare N-[l-(3-cyanophenyl)piperidm-4-yl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide .

HRMS: calcd for C ₂₅ H ₂₂ F ₃ N ₃ O ₄ S ₂ + H+, 550.10766; found (ESI, [M+H] ⁺ ), 550.1066; HPLC purity 100% at 210-370 nm, 10.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 987: iV-(2-{4-[(methylsulfonyl)amino]phenyl}ethyl)-5-(phenylsulfo nyl)-2- (trifluoromethyl)benzenesulfonamide

[1217] In an analogous manner to example 435, iV-[2-(4-aminophenyl)ethyl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide and methane sulfonyl chloride were used to prepare N-(2-{4-[(methylsulfonyl)amino]ρhenyl}ethyl)-5-(ρhenylsulf onyl)-2- (trifluoromethyl)benzenesulfonamide.

HRMS: calcd for C ₂₂ H ₂₁ F ₃ N ₂ O ₆ S ₃ + H+, 563.05866; found (ESI, [M+H]+), 563.0579; HPLC purity 92.4% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 988: tert-butyl [3-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)propyl]carbamate

[1218] In an analogous manner to example 765, 5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonyl chloride (768.9mg, 2mmol) and tert-Butyl JV-(3- aminopropyl)carbamate (525 μL, 3mmol) was used to prepare the title compound tert-butyl [3- ({ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino )propyl]carbamate (1.0331 g 99%) as a white foam. MS (ES-) m/z 521.0;

HPLC purity 98.2% at 210-370 nm, 9.6 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₂₅ F ₃ N ₂ O ₆ S ₂ + H+, 523.11789; found (ESI, [M+H-tboc]+), 467.0599.

Example 989: tert-bntyl 4-[methyl({methyl[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbon yl)amino]piperidine-l- carboxylate

[1219] Step 1 : In an analogous manner to Example 866, Step I ₃ N ₃ N'- carbonyldiimidazole and 4-N-methylamino-l-BOC-piperidine were used to prepare the intermediate tert-butyl 4-[( lH-imidazol- 1 -ylcarbonyl)(methyl)amino]piperidine- 1 -carboxylate.

[1220] Step 2: In an analogous manner to Example 887, Step 2, iV-[2- (methylamino)ethyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)be iτzenesulfonamide hydrochloride from Example 799 and tert-butyl 4-[(lH-imidazol-l-ylcarbonyl)(methyl)amino]piperidine-l- carboxylate were used to prepare tert-butyl 4-[methyl({methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) amino]piperidine-l-carboxylate. MS (ES-) m/z 661.1; HRMS: calcd for C ₂₈ H ₃₇ F ₃ N ₄ O ₇ S ₂ + H+, 663.21285; found (ESI, [M+H] ⁺ ), 663.2126.

Example 990: tert-butyl (3i?)-3-[({methyl[2-({[5-(phenylsuIfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbon yl)amino]pyrrolidine-l- carboxylate

[1221] Step 1 :In an analogous manner to Example 866, Step 1, N ₃ N'- carbonyldiimidazole and (i?)-N-BOC-3-aminopyrrolidine were used to prepare the intermediate tert-butyl (3i?)-3-[(lϋT-imidazol- 1 -ylcarbonyl)amino]pyrrolidine- 1 -carboxylate.

[1222] Step 2: In an analogous manner to Example 866, Step 2, N-[2-

(methylamino)ethyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)be nzenesulfonamide hydrochloride from Example 799 and tert-butyl (3i?)-3-[(li- ^r -imidazol-l-ylcarbonyl)amino]pyrrolidine-l- carboxylate were used to prepare tert-butyl (3i?)-3-[({methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl} amino)ethyl]amino} carbonyl)amino]pyrrolidine- 1 -carboxylate. MS (ES-) m/z 633.0; HRMS: calcd for C ₂₆ H ₃₃ F ₃ N ₄ O ₇ S ₂ + H+ ₃ 635.18155; found (ESI ₃ [M+H] ⁺ ) ₃ 635.1808.

Example 991 : N-(5-methoxy-2,3-dihy dro-lH-inden-2-yl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1223] In an analogous manner to example 765, 5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonyl chloride (709.4 mg, l.Smmol) and 5-methoxy-2,3-dihydro-lH- inden-2-amine (361.1 mg, 2.2mmol) was used to prepare the title compound N-(5-methoxy-2,3- dihydro-lH-inden-2-yl)-5-(phenylsulfonyl)-2-(trifluoromethyl )benzenesulfonamide (723.5 mg, 77%) as a yellow solid.

MS (ESI+) m/z 512;

HPLC purity 99.2% at 210-370 ran, 10.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₀ F ₃ NO ₅ S ₂ + H+, 512.08077; found (ESI, [M+H]+), 512.0795.

Example 992: 4-{methyl[3-({[5-(phenyIsuIfonyl)-2-

(trifluoromethyI)phenyI]sulfonyl}amino)propyl]amino}-4-ox obutanoic acid [1224] A mixture of N-[3-(methylamino)propyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide (150.9 mg, 0.32 mmol) prepared example 929 in toluene (10 ml). Succinic anhydride (44.2 mg, 0.44 mmol) and 2 eq. of N,N-Diisoprpylethylamine was syringed into the reaction flask and was allowed to stir overnight at room temperature. The product was transferred onto a 12 g Isco RediSep® Normal Phase column and was purified by automated flash chromatography using a gradient of 20% to 100% hexane/ethyl acetate. Isolation of the main component gave the title compound of 4-{methyl[3-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)propyl]amino}-4-oxobu tanoic acid (121.3 mg, 71%) as an amorphous solid. MS (ES+) m/z 536.9;

HPLC purity 93.3% at 210-370 nm, 8.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C _2I H ₂₃ F ₃ N ₂ O ₇ S ₂ + H+, 537.09715; found (ESI, [M+H]+), 537.0928.

Example 993: N-(3-aminopropyl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1225] Tert-butyl [3-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)propyl]carbamate (800 mg, 1.53 mmol) prepared in example 988 was taken up in 25 ml of hydrochloric saturated ethyl acetate. The hydrochloric salt of the title compound N-(3-aminopropyl)-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide (697.3 mg, 99%) crashed out of solution as a white solid. MS (ES+) m/z 423.0;

HPLC purity 100% at 210-370 nm, 6.6 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₆ H _n F ₃ N ₂ O ₄ S ₂ + H+, 423.06546; found (ESI, [M+H]+), 423.0655.

Example 994: iV-(3-bromobenzyl)-5-(phenylsuIfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1226] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 3-bromobenzylamine were used to prepare iV-(3-bromobenzyl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide. MS (ES-) m/z 531.8;

HPLC purity 98.0% at 210-370 nm, 10.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 995: 5-(phenylsulfonyl)-λ'-(l-{[3-(2 _J fir-tetrazoI-5-yI)phenyl]sulfonyl}piperidin-4- yl)-2-(trifluoromethyl)benzenesulfonamide

[1227] In an analogous manner to example 863, 7V-{l-[(3- cyanophenyl)sulfonyl]piperidin-4-yl}-5-(phenylsulfonyl)-2-

(trifluoromethyl)benzenesulfonamide was used to prepare 5-(phenylsulfonyl)-N-(l-{[3-(2H- tetrazol-5-yl)phenyl]sulfonyl}piperidin-4-yl)-2-(trifluorome thyl)benzenesulfonamide. MS (ES+) m/z 657.0;

HPLC purity 93.4% at 210-370 nm, 8.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min.

Example 996: 3'-[({[5-(phenylsulfonyl)-2-

(trifluoromethy l)phenyl] sulfonyl} amino)methyl] biphenyl-3-carboxylic acid

[1228] In an analogous manner to example 976, N-(3-bromobenzyl)-5- (pheny lsulfonyl)-2-(trifluoromethy l)benzenesulfonamide and 3 -(tert-butoxy carbonylphenyl) boronic acid were used to prepare 3'-[({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]biphenyl-3-car boxy lie acid. MS (ES-) m/z 573.9;

HPLC purity 100% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: caled for C ₂₇ H ₂₀ F ₃ NO ₆ S ₂ + H+, 576.07569; found (ESI, [M+H] ⁺ ), 576.0735.

Example 997: 3'~[({[5-(phenylsulfonyI)-2-

(trifluoromethyl)phenyl] sulfonyl} amino)methyl] biphenyl-4-carboxyIic acid

[1229] In an analogous manner to example 976, N-(3-bromobenzyl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide and 4-(tert-butoxycarbonylphenyl) boronic acid were used to prepare 3'-[({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)methyl]biphenyl-4-car boxy lie acid. MS (ES-) m/z 573.9;

HPLC purity 100% at 210-370 nm, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: caled for C ₂₇ H ₂₀ F ₃ NO ₆ S ₂ + H+, 576.07569; found (ESI, [M+H] ⁺ ), 576.076.

Example 998: iV-[2-(4-{[amino(immo)methyl]amino}phenyl)ethyl]-5-(phenylsu Ifonyl)-2- (trifluoromethyl)benzenesulfonamide

[1230] A mixture of iV-[2-(4-aminoρhenyl)ethyl]-5-(ρhenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide (0.12 g, 0.25 mmol) and 3,5-dimethylpyrazole-l- carboxamidine nitrate (0.05 g, 0.25 mmol) were heated neat at 170°C for lOminutes. The resulting mixture was allowed to cool and flash column separation using 0%-10% methanol/methylene chloride gradient gave iV-[2-(4- {[amino(imino)methyl]amino}phenyl)ethyl]-5-(phenylsulfonyl)- 2- (trifluoromethyl)benzenesulfonamide. (0.036 g, 28%). MS (ES+) m/z 527.0;

HPLC purity 100% at 210-370 nm, 7.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂ ]F ₃ N ₄ O ₄ S ₂ + H+, 527.10291; found (ESI, [M+H] ⁺ ), 527.1037.

Example 999: 5-[(4-methoxyphenyI)sulfonyl]-iV-piperidm-4-yl-2- (trifluoromethyl)benzenesulfonamide

[1231] Step 1 : In an analogous manner to example 820, 2-trifluoromethyl-5-(4- methoxyphenylsulfonyl)-benzenesulfonyl chloride and 4-aminopiperidine-l- carboxylic acid fert-butyl ester were used to prepare tert-bntyl 4-({[5-(4-methoxyphenylsulfonyl)-2- (trifluoromethyl)pheny 1] sulfonyl } amino)piperidine- 1 -carboxy late .

[1232] Step 2: In an analogous manner to example 930, tert-bntyl 4-({[5-(4- methoxyphenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}am ino)piperidine-l-carboxylate was used to prepare 5-[(4-methoxyphenyl)sulfonyl]-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 479.0;

HPLC purity 95.9% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1000: λ'-[l-(iV-methylgIycyI)piperidin-4-yl]-5-(phenylsulfonyl)-2 - (trifluoromethyl)benzenesulfonamide

[1233] Step 1 : In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin- 4-yl-2-(trifluoromethyl)benzenesulfonamide and chloroacetyl chloride were used to prepare N- [l-(chloroacetyl)piperidin-4-yl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide.

[1234] Step 2: To a stirred solution of N-[l-(chloroacetyl)piperidin-4-yl]-5- (phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide (0.08 g, 0.15 mmol) in THF (1 mL) was added 33% methylamine in ethanol (0.1 mL) and the resulting solution was stirred overnight at room temperature. The mixture was concentrated and flash column separation using 0%-10% methanol/methylene chloride gradient gave N-[l-(iV-methylglycyl)piperidin-4-yl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide. (0.05 g, 61%). MS (ES+) m/z 520.0;

HPLC purity 100% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₂₄ F ₃ N ₃ O ₅ S ₂ + H+, 520.11822; found (ESI, [M+H] ⁺ ), 520.1174.

Example 1001 : 5-(phenylsuIfonyl)-iV-[l-(pyrrolidm-l-yIacetyl)piperidin-4-y l]-2- (trifluoromethyl)benzenesulfonamide

[1235] In an analogous manner to example 1000, N-[l-(chloroacetyl)piperidin-4-yl]-5- (phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide and pyrrolidine were used to prepare 5-(phenylsulfonyl)-iV-[l-(pyrrolidin-l-ylacetyl)piperidin-4- yl]-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 560.0; HPLC purity 100% at 210-370 nm, 7.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2

mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1002: A ^L [l-(morpholin-4-ylacetyl)piperidin-4-yI]-5-(phenylsulfonyl)- 2- (trifluoromethyl)benzenesulfonamide

[1236] In an analogous manner to example 1000, N-[I -(chloroacetyl)piperidin-4-yl]-5- (phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide and morpholine were used to prepare iV-[l-(morpholin-4-ylacetyl)pipeπdin-4-yl]-5-(phenylsulfony l)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 576.0;

HPLC purity 100% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₂₈ F ₃ N ₃ O ₆ S ₂ + H+, 576.14444; found (ESI, [M+H] ⁺ ), 576.1428.

Example 1003: 2-[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]propan amide

[1237] In an analogous manner to example 880, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-bromopropionamide were used to prepare 2-[4-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)pi peridin-l-yl]propanamide. MS (ES+) m/z 520.0;

HPLC purity 100% at 210-370 nm, 6.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₂₄ F ₃ N ₃ O ₅ S ₂ + H+, 520.11822; found (ESI, [M+H] ⁺ ), 520.1199.

Example 1004: N-(5-hydroxy-2,3-dihydro-lH-inden-2-yl)-5-(phenylsulfonyl)-2 - (trifluorometliyl)benzenesulfonamide

[1238] To a flame dried flask N-(5-methoxy-2,3-dihydro-lH-inden-2-yl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide (262.3 mg, 0.51 mmol) was taken up in 5 ml of dichloromethane and cooled to -78° C. 1.0M Boron tribromide (3 ml, 3 mmol) in dichloromethane was syringed into the flask and then was allowed to warm to room temperature. The reaction was quenched with water, partioned between dichloromethane, dried with magnesium sulfate, and the solvent was removed under reduced pressure. The product was transferred onto a 4 g Isco RediSep® Normal Phase column and was purified by automated flash

chromatography using a gradient of 20% to 100% hexane/ethyl acetate. Isolation of the main component gave the title compound N-(5-hydroxy-2,3-dihydro-lH-inden-2~yl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide (232.9 nig, 91%) as a white solid. MS (ES+) m/z 497.9;

[1239] HPLC purity 100% at 210-370 run, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. FOIΌI. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₁₈ F ₃ NO ₅ S ₂ + H+, 498.06512; found (ESI, [M+HJ+), 498.0631.

Example 1005 : 5-(pheny lsulf onyl)-iV- [1 -(piperazin-1 -ylacety l)piperidin-4-yl] -2- (trifluoromethyl)benzenesulfonamide

[1240] Step 1 : In an analogous manner to example 1000, N-[l-(chloroacetyl)piperidin- 4-yl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide and piperazine-1-carboxylic acid tert-butyl ester were used to prepare 5-(phenylsulfony I)-N- [l-(piperazin-l-y lacetyl-4-tert- butylcarboxylate)piperidin-4-yl]-2-(trifluoromethyl)benzenes ulfonamide.

[1241] Step 2: In an analogous manner to example 930, 5-(phenylsulfonyl)-N-[l- (piperazin- 1 -ylacetyl-4-ter/-butylcarboxylate)piperidin-4-yl]-2-

(trifluoromethyl)benzenesulfonamide was used to prepare 5-(phenylsulfonyl)-N-[l-(piperazin-l- ylacetyl)piperidin-4-yl]-2-(trifluoromethyl)benzenesulfonami de. MS (ES-) m/z 572.9;

HPLC purity 100% at 210-370 nm, 7.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min.

Example 1006: dimethyl [4-({methyl[2-({[5-(phenylsuIfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) benzyl]phosphonate [1242] A solution of 4-(bromomethyl)-N-methyl-N-[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamide (0.311 g, 0.503 mmol) from Example 983 in trimethylphosphite (2.0 mL) was stirred at HO ⁰ C for 6 h. The mixture was partitioned with 2ν HCl and EtOAc. The organic layer was washed with water and loaded directly onto a silica gel column and eluted with a gradient Of CH ₂ Cl ₂ and CH3OH to give 86.1 mg (26%) of dimethyl [4-( {methyl [2-({ [5-(phenylsulfonyl)-2- (trifluoromethyl)pheny 1] sulfonyl } amino)ethyl] amino } carbony l)benzy l]phosphonate .

MS (ES+) m/z 649.0;

HRMS: calcd for C ₂₆ H ₂₈ F ₃ N ₂ O ₈ PS ₂ + H+, 649.10496; found (ESI, [M+H] ⁺ ), 649.1035.

Example 1007: iV-[2-(methyI{[methyl(piperidm-4-yl)amino]carbonyl}amino)eth yl]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesuIfonamide

[1243] In an analogous manner to Example 937, tert-buty\ 4-[methyl({methyl[2-({[5- (phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl} amino)ethyl] amino } carbonyl)amino]piperidine- 1 -carboxylate from Example 989 was treated in EtOAc with HCl to give iV-[2-(methyl{[methyl(piperidin-4- yl)amino]carbonyl}amino)ethyl]-5-(phenylsulfonyl)-2-(trifluo romethyl)benzenesulfonamide hydrochloride. MS (ES+) m/z 563.2; HRMS: calcd for C ₂₃ H ₂₉ F ₃ N ₄ O ₅ S ₂ + H+, 563.16042; found (ESI, [M+H] ⁺ ), 563.1605.

Example 1008 : N- [2-(methy I { [(3i?)-py rrolidin-3-ylamino] carbonyl} amino)ethyl] -5- (phenyIsulfonyl)-2-(trifluoromethyl)benzenesulfonamide

[1244] In an analogous manner to Example 937, fert-butyl (3iζ)-3-[({methyl[2-({ [5- (phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) amino]pyrrolidine-l-carboxylate from Example 990 was treated in EtOAc with HCl. The solvent was removed by pipette from the solid that formed. The solid was washed with EtOAc and dried to give N-[2-(methyl{[(3i?)- pyrrolidin-3-ylamino]carbonyl}amino)ethyl]-5-(phenylsulfonyl )-2- (trifluoromethyl)benzenesulfonamide hydrochloride. MS (ES+) m/z 535.1; HRMS: calcd for C ₂₁ H ₂₅ F ₃ N ₄ O ₅ S ₂ + H+, 535.12912; found (ESI, [M+H] ⁺ ), 535.129.

Example 1009: tert-bniyl (3R)-3~ [({methyl [2-({[5-(pheny Isulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbon yl)amino]piperidme-l- carboxylate

[1245] Step 1 : In an analogous manner to Example 866, Stepl, N,N'- carbonyldiimidazole and (R)-l-BOC-3-amino-piperidine were used to prepare the intermediate tert-buty 1 (3i?)-3 - [( 1 /f-imidazol- 1 -ylcarbony l)amino]piperidine- 1 -carboxylate.

[1246] Step 2: In an analogous manner to Example 866, Step2, JV-[2- (methylamino)ethyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)be nzenesulfonamide hydrochloride from Example 799 and tert-butyl (3i?)-3-[(lH ^" -imidazol-l-ylcarbonyl)amino]piperidine-l- carboxylate were used to prepare tert-butyl (3i?)-3-[({methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) amino]piperidine-l-carboxylate. MS (ES-) m/z 647.2; HRMS: calcd for C ₂₇ H ₃₅ F ₃ N ₄ O ₇ S ₂ + H+, 649.19720; found (ESI, [M+H] ⁺ ), 649.1984.

Example 1010: tert-bntyl (3S)-3-[({methyl[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbon yl)amino]piperidine-l- carboxylate

[1247] Step 1 : In an analogous manner to Example 866, Stepl, N,N'- carbonyldiimidazole and (S)-l-BOC-3-amino-piperidine were used to prepare the intermediate ter/-butyl (3S)-3 - [( 1 H-imidazol- 1 -y lcarbonyl)amino]piperidine- 1 -carboxylate.

[1248] Step 2: In an analogous manner to Example 866, Step2, N-[2-

(methylamino)ethyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)be nzenesulfonamide hydrochloride from Example 799 and tøf-butyl (36)-3-[(l/f-imidazol-l-ylcarbonyl)amino]piperidine-l- carboxylate were used to prepare tert-butyl (3.S)-3-[({methyl[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) amino]piperidine-l-carboxylate. MS (ES+) m/z 649.2; HRMS: calcd for C ₂₇ H ₃₅ F ₃ N ₄ O ₇ S ₂ + H+, 649.19720; found (ESI, [M+H] ⁺ ), 649.1954.

Example 1011: tert-butyl (25)-2-{[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidm-l-yl]carb onyl}pyrrolidine-l-carboxylate [1249] In an analogous manner to example 915, N-(fer/~butoxycarbonyl)-L-proline and 5-(phenylsulfonyl)-N-piperidin-4-yl-2-(trifluoromethyl)benze nesulfonamide were used to prepare tert-butyl (2<S)-2-{[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]car bonyl}pyrrolidine-l -carboxylate . MS (ES-) m/z 644.2;

HPLC purity 100% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₈ H ₃₄ F ₃ N ₃ O ₇ S ₂ + H+, 646.18630; found (ESI, [M+H] ⁺ ), 646.188.

Example 1012: 5-(phenylsulfonyl)-iV-(l-L-prolylpiperidin-4-yl)-2- (trifluoromethyl)benzenesulfonamide

[1250] In an analogous manner to example 930, tert-butyl (2S)-2-{ [4-({ [5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl} amino)piperidin- 1 -yl]carbonyl}pyrrolidine- 1-carboxylate was used to prepare 5-(phenylsulfonyl)-N-(l-L-prolylpiperidin-4-yl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 546.1;

HPLC purity 100% at 210-370 nm, 7.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₆ F ₃ N ₃ O ₅ S ₂ + H+, 546.13387; found (ESI, [M+H] ⁺ ), 546.1358.

Example 1013: JV-(*ra«s-4-hydroxycyclohexyI)-5-(phenylsulfonyI)-2- (trifluoromethyl)benzenesulfonamide

[1251] In an analogous manner to example 654, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and trans-4-aminocyclohexanol were used to prepare N-(trans-4- hydroxycyclohexyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)ben zenesulfonamide. MS (ES-) m/z 462.1;

HPLC purity 93.3% at 210-370 nm, 8.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1014: tert-hntyl (2R)-2-{[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]carbon yl}pyrrolidine-l-carboxylate

[1252] In an analogous manner to example 915, N-(tert-butoxycarbonyl)-D-proline and 5-(phenylsulfonyl)-iV-piperidin-4-yl-2-(trifluoromethyl)benz enesulfonamide were used to prepare tert-butyl (2i?)-2-{[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl] sulfonyl} amino)piperidin- 1 -yl]carbonyl}pyrrolidine- 1 -carboxylate. MS (ES-) m/z 644.2;

HPLC purity 100% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₈ H ₃₄ F ₃ N ₃ O ₇ S ₂ + H+, 646.18630; found (ESI, [M+H] ⁺ ), 646.1856.

Example 1015: 5-(phenyIsuIfonyl)-iV-(l-D-prolyIpiperidin-4-yl)-2- (trifluoromethyl)benzenesulfonamide

[1253] In an analogous manner to example 930, tert-butyl (2i?)-2-{[4-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)pi peridin-l-yl]carbonyl}pyrrolidine- 1-carboxylate was used to prepare 5-(phenylsulfonyl)-N-(l-D-prolylpiperidin-4-yl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 546.1;

HPLC purity 97.7% at 210-370 ran, 7.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₆ F ₃ N ₃ O ₅ S ₂ + H+, 546.13387; found (ESI, [M+H]*), 546.1329.

Example 1016: iV-[4-(dimethyIamino)benzyI]-5-(phenyIsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1254] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 4-dimethylaminobenzylamine were used to prepare iV-[4-(dimethylamino)benzyl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 498.9;

HPLC purity 97.6% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₂ H ₂₁ F ₃ N ₂ O ₄ S ₂ + H+, 499.09676; found (ESI, [M+H] ⁺ ), 499.0995.

Example 1017: 5-(phenyIsulfonyl)-iV-{l - [(6-py rrolidin-1 -ylpy ridin-3-yI)carbonyl] piperidin- 4-yl}-2-(trifluoromethyl)benzenesulfonamide

[1255] Step 1 : In an analogous manner to example 435, piperidin-4-yl-carbamic acid tert-butyl ester and 2-chloropyridine-5-carbonyl chloride were used to prepare [l-(6-Chloro- pyridine-3-carbonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester.

[1256] Step 2: To a stirred solution of [l-(6-Chloro-pyridine-3-carbonyl)-piperidin-4- yl]-carbamic acid tert-butyl ester (0.50 g, 1.47 mmol) in THF (1 mL) was added pyrrolidine (0.5 mL, 6.0 mmol) and the resulting solution was 160°C in a microwave for 30 minutes and concentrated. Flash column separation using 0%-5% methanol/methylene chloride gradient gave [l-(6-Pyrrolidin-l-yl-pyridine-3-carbonyl)-piperidin-4-yl]-c arbamic acid tert-butyl ester.

[1257] Step 3: In an analogous manner to example 930, [l-(6-Pyrrolidin-l-yl-pyridme- 3-carbonyl)~piperidm-4-yl]-carbamic acid tert-butyl ester was used to prepare (4-Amino- piperidin- 1 -yl)-(6-pyrrolidin- 1 -y l-pyridin-3 -yl)-methanone .

[1258] Step 4: In an analogous manner to example 435, 2-trifluoromethyl-5- (phenylsulfonyl)- benzenesulfonyl chloride and (4-Amino-piperidin-l-yl)-(6-pyrrolidin-l-yl- pyridin-3-yl)-methanone were used to prepare 5-(phenylsulfonyl)-N-{l-[(6-pyrrolidin-l- ylpyridin-3-yl)carbonyl]piperidin-4-yl}-2-(trifluoromethyl)b enzenesulfonamide. MS (ES+) m/z 623.0;

HPLC purity 92.8% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1018: iV-(l-{[6-(dimethylamino)pyridm-3-yl]carbonyl}piperidin-4-yl )-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide

[1259] In an analogous manner to example 1017,

Step 2: [l-(6-Chloro-pyridine-3-carbonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and dimethylamine in THF were used to prepare [l-(6-Dimethylamino-pyridine-3-carbonyl)- piperidin-4-yl]-carbamic acid tert-butyl ester.

[1260] Step 3: In an analogous manner to example 930, [l-(6-Dimethylamino-pyridine- 3-carbonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester was used to prepare

(4-Amino-piperidin-l-yl)-(6-dimethylamino-pyridin-3-yl)-m ethanone.

[1261] Step 4: In an analogous manner to example 435, 2-trifluoromethyl-5- (phenylsulfonyl)- benzenesulfonyl chloride and (4-Amino-piperidin-l-yl)-(6-dimethylamino- pyridin-3-yl)-methanone were used to prepare N-(l-{[6-(dimethylamino)pyridin-3- yl]carbonyl}piperidin-4-yl)-5-(phenylsulfonyl)-2-(trifluorom ethyl)benzenesulfonamide. MS (ES+) m/z 597.0;

HPLC purity 100% at 210-370 nm, 8.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1019: iV-[l-(2-morpholin-4-ylethyl)piperidin-4-yl]-5-(phenylsulfon yl)-2- (trifluoromethyl)benzenesulfonamide

[1262] To a stirred solution of 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide (0.10 g, 0.223 mmol) in ethanol (1 niL) was added

triethylamine (0.1 mL, 0.72 mmol) and 4-(2-chloroethyl)-morpholine hydrochloride (0.042 g,

0.223 mmol) and heated 12O ⁰ C in a microwave for 10 minutes and concentrated. Flash column separation using 0%-10% methanol/methylene chloride gradient gave N-[l-(2-morpholin-4- ylethyl)piperidin-4-yl]-5-(phenylsulfonyl)-2-(trifluoromethy l)benzenesulfonamide. (0.074 g,

59%).

MS (ES+) m/z 562.0;

HPLC purity 100% at 210-370 nm, 12.1 min.; XTerra MS C18, 5u, 3xl50mm column, 0.5 mL/min, FA / MeOH gradient.

HRMS: calcd for C ₂₄ H ₃₀ F ₃ N ₃ O ₅ S ₂ + H+, 562.16517; found (ESI, [M+H] ⁺ ), 562.1645.

Example 1020: λ ^r -{l-[(6-oxo-l-{[5-(phenyIsulfonyl)-2-(trifluoromethyl)phenyl ]suIfonyI}-l,6- dihydropyridin-3-yl)carbonyl]piperidin-4-yl}-5-(phenylsuIfon yl)-2-

(trifluoromethyl)benzenesulfonamide

[1263] In an analogous manner to example 1017,

Step 2: [l-(6-Chloro-pyridine-3-carbonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and potassium tørtbutoxide in THF were used to prepare [l-(6-tert-Butoxy-pyridine-3-carbonyl)- piperidin-4-yl]-carbamic acid tert-butyl ester.

[1264] Step 3: In an analogous manner to example 930, [l-(6-tert-Butoxy-pyridine-3- carbonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester was used to prepare

5-(4-Amino-piperidine- 1 -carbonyl)- 1 H-pyridin-2-one.

[1265] Step 4: In an analogous manner to example 435, 2-trifluorornethyl-5- (phenylsulfonyl)- benzenesulfonyl chloride and 5-(4-Amino-piperidine-l -carbonyl)- 1 H-pyridin- 2-one were used to prepare 7V-{l-[(6-oxo-l-{[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}-l,6-dihydropyridin-3-yl)ca rbonyl]piperidin-4-yl}-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 917.9;

HPLC purity 85.0% at 210-370 nm, 19.9 min.; XTerra MS C18, 5u, 3xl50mm column, 0.5mL/min, formic acid / MeOH gradient.

Example 1021: iV-(2,4-dimethoxybenzyI)-5-(phenylsulfbnyl)-2- (trifluoromethyl)benzenesulfonamide

[1266] In an analogous manner to example 435, 2-txifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 2,4-dimethoxybenzylamine were used to prepare JV-(2,4- dimethoxybenzyl)-5-(phenylsulfonyl)-2-(trifluoromethyl)benze nesulfonamide. MS (ES-) m/z 513.9;

HPLC purity 100.0% at 210-370 urn, 18.7 min.; Xterra MS C18, 5u, 150 x 3.0 mm column, 0.5 mL/min, FA / MeOH grad.

Example 1022: iV-[2-(methyI{[(3i?)-piperidin-3-ylamino]carbonyl}amino)ethy l]-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesuIfonamide

[1267] In an analogous manner to Example 937, fert-butyl (3i?)-3-[({methyl[2-({[5- (phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) amino]piperidine-l-carboxylate from Example 1009 was used to prepare N-[2-(methyl{[(3i?)-piperidin-3- ylamino]carbonyl}amino)ethyl]-5-(phenylsulfonyl)-2-(trifluor omethyl)benzenesulfonamide hydrochloride. MS (ES+) m/z 549.0; HRMS: calcd for C ₂₂ H ₂₇ F ₃ N ₄ O ₅ S ₂ + H+, 549.14477; found (ESI ₅ [M+H] ⁺ ), 549.1461.

Example 1023: iV-[2-(methyl{[(3A-»)-piperidin-3-ylammo]carbonyI}amino)eth yl]-5- (phenyIsulfonyl)-2-(trifluoromethyl)benzenesulfonamide

[1268] In an analogous manner to Example 937, fert-butyl (35)-3-[({methyl[2-({ [5- (phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) amino]piperidine-l-carboxylate from Example 1010 was used to prepare N-[2-(methyl{[(35)-piperidin-3- ylamino]carbonyl}amino)ethyl]-5-(phenylsulfonyl)-2-(trifluor omethyl)benzenesulfonamide hydrochloride. MS (ES+) m/z 549.1; HRMS: calcd for C ₂₂ H ₂₇ F ₃ N ₄ O ₅ S ₂ + H+, 549.14477; found (ESI, [M+H] ⁺ ), 549.1456.

Example 1024: λ^-{l-[(6-phenylpyridin-3-yl)carbonyl]piperidin-4-yI}-5-(ph enyIsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1269] Step 1 : In an analogous manner to example 435, ρiperidin-4-yl-carbamic acid tert-butyl ester and 2-chloropyridine-5-carbonyl chloride were used to prepare [l-(6-Chloro- pyridine-3-carbonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester.

[1270] Step 2: In an analogous manner to example 976 step 1, [l-(6-Chloro-pyridine-3- carbonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and phenyl boronic acid were used to prepare tert-butyl { 1 -[(6-phenylpyridin-3-yl)carbonyl]piperidin-4-yl}cai-bamate.

[1271] Step 3: In an analogous manner to example 930, tert-butyl {l-[(6-phenylpyridin- 3 -yl)carbonyl]piperidin-4-yl} carbamate was used to prepare l-[(6-phenylpyridin-3- yl)carbony l]piperidin-4-amine .

[1272] Step 4: In an analogous manner to example 435, 2-trifluoromethyl-5- (phenylsulfonyl)- benzenesulfonyl chloride and l-[(6-ρhenylpyridin-3-yl)carbonyl]piperidm-4- amine were used to prepare N-{l-[(6-phenylpyridin-3-yl)carbonyl]piperidin-4-yl}-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 630.0;

HPLC purity 100.0% at 210-370 nm, 10.0 min.; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₃₀ H ₂₆ F ₃ N ₃ O ₅ S ₂ + H+, 630.13387; found (ESI, [M+H] ⁺ ), 630.135.

Example 1025: λ ^r -{l-[(6-morphoIin-4-ylpyridin-3-yl)carbonyl]piperidin-4-yl}- 5- (phenyIsulfonyI)-2-(trifluoromethyl)benzenesulfonamide

[1273] In an analogous manner to example 1017,

Step 2: [l-(6-chloro-pyridine-3-carbonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and morpholine in THF were used to prepare tert-butyl { l-[(6-morpholin-4-ylpyridin-3- yl)carbonyl]piperidin-4-yl } carbamate .

[1274] Step 3: In an analogous manner to example 930, tert-butyl {l-[(6-morpholin-4- ylpyridin-3-yl)carbonyl]piperidin-4-yl} carbamate was used to prepare l-[(6-morpholin-4-ylpyridin-3-yl)carbonyl]piperidin-4-amine.

[1275] Step 4: In an analogous manner to example 435, 2-trifluoromethyl-5- (phenylsulfonyl)- benzenesulfonyl chloride and l-[(6-morpholin-4-ylpyridin-3- yl)carbonyl]piperidin-4-amine were used to prepare N-{l-[(6-morpholm-4-ylpyridin-3- yl)carbonyl]piperidin-4-yl}-5-(phenylsulfonyl)-2-(trifluorom ethyl)benzenesulfonamide.

MS (ES+) m/z 639.1;

HPLC purity 98.3% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₈ H ₂₉ F ₃ N ₄ O ₆ S ₂ + H+, 639.15534; found (ESI, [M+H] ⁺ ), 639.1536.

Example 1026: fert-butyl 4-[({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)carbonyl]piperidine-l -carboxylate

[1276] Step 1 : In an analogous manner to example 930, N-(2,4-dimethoxybenzyl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide and TFA were used to prepare 5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide.

[1277] Step 2: To a stirred solution of 1 -BOC-piperidine-4-carboxylic acid (0.08g, 0.34 mmol) in methylene chloride (3mL) was added DMAP (0.05 g, 0.37 mmol) and EDC (0.08g, 0.40 mmol). The resulting solution was stirred at room temperature for 20 minutes. To the mixture was added 5-(phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide (0.11 g, 0.30 mmol). The resulting solution was stirred lhr, washed with ammonium chloride solution (sat), and concentrated. Flash column separation using 0%-5% methanol/methylene chloride gradient gave tert-butyl 4-[({[5~(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)carbonyl]piperidin e-l-carboxylate. (0.06 g, 34%). MS (ES-) m/z 575.0;

HPLC purity 100.0% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1027 : N- { [5-(phenylsulf onyl)-2-(trifluoromethyl)phenyl] sulfonyl}piperidine-4- carboxamide

[1278] In an analogous manner to example 930, fert-butyl 4-[({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)carbonyl]piperidine-l -carboxylate was used to prepare iV-{[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}p iperidine-4-carboxamide. MS (ES-) m/z 475.0;

HPLC purity 100.0% at 210-370 nm, 6.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₉ H ₁₉ F ₃ N ₂ O ₅ S ₂ + H+, 477.07602; found (ESI, [M+H] ⁺ ), 477.0748.

Example 1028: methyl {[2-({[5-(phenylsulfonyl)-2-(trifluoromethyI)phenyl]sulfonyl }amino)- 2,3-dihydro-lH-inden-5-yl]oxy}acetate

[1279] In an analogous manner to example 765, 5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonyl chloride (151.2 mg, 0.5 mmol) and methyl 2-(2-amino-2,3- dihydro-lH-inden-5-yloxy)acetate (155.3 mg, 0.6 mmol) was used to prepare the title compound methyl {[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl }amino)-2,3-dihydro-lH- inden-5-yl]oxy} acetate (176.2 mg, 62%) as a white solid. MS (ES+) m/z 569.8;

BPLC purity 97.1% at 210-370 run, 10.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₅ H ₂₂ F ₃ NO ₇ S ₂ + H+, 570.08625; found (ESI, [M+H]+), 570.085.

Example 1029 : 5-(phenylsulfonyl)-iV- [l-(2-pyrroIidin-l-ylisonicotinoyl)piperidin-4-yl]-2- (trifluoromethyl)benzenesulfonamide

[1280] Step 1 : In an analogous manner to example 435, piperidin-4-yl-carbamic acid fert-butyl ester and 2-chloropyridine-4-carbonyl chloride were used to prepare tert-butyl [l-(2- chloroisonicotinoyl)piperidin-4-yl]carbamate.

[1281] Step 2: In an analogous manner to example 1017 step 2, tert-butyl [l-(2- chloroisonicotinoyl)piperidin-4-yl]carbamate and pyrrolidine in THF were used to prepare tert- butyl [l-(2-pyrrolidin-l-ylisomcotinoyl)piperidin-4-yl]carbamate.

[1282] Step 3: In an analogous manner to example 930. tert-butyl [l-(2-pyrrolidin-l- ylisonicotinoyl)piperidin-4-yl]carbamate was used to prepare

1 -(2-pyrrolidin- 1 -ylisonicotinoyl)piperidin-4-amine.

[1283] Step 4: In an analogous manner to example 435, 2-trifluoromethyl-5- (phenylsulfonyl)- benzenesulfonyl chloride and l-(2-pyrrolidin-l-ylisonicotinoyl)piperidin-4- amine were used to prepare 5-(phenylsulfonyl)-N-[l-(2-pyrrolidin-l-ylisonicotinoyl)pipe ridin-4- yl]-2-(trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 623.1;

HPLC purity 98.5% at 210-370 nm, 8.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₈ H ₂₉ F ₃ N ₄ O ₅ S ₂ + H+, 623.16042; found (ESI, [M+H] ⁺ ), 623.1596.

Example 1030 : N- [(6-chIoropy ridin-3-y l)m ethyl] -5-(pheny lsulf onyI)-2- (trifluoromethyl)benzenesulfonamide

[1284] In an analogous manner to example 435, 2-trifluoromethyl-5-(phenylsulfonyl)- benzenesulfonyl chloride and 5-(aminomethyl)-2-chloropyridine were used to prepare N-[(6- chloropyridin-3-yl)methyl]-5-(phenylsulfonyl)-2-(trifluorome thyl)benzenesulfonamide. MS (ES+) m/z 490.8;

HPLC purity 98.4% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₉ H ₁₄ ClF ₃ N ₂ O ₄ S ₂ + H+, 491.01083; found (ESI, [M+H] ⁺ ), 491.0101.

Example 1031 : {[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyI]sulfonyl }amino)-2,3- dihydro-lH-inden-5-yl]oxy}acetic acid

[1285] Methyl { [2-({ [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl} amino)- 2,3 -dihydro-lH-inden-5-yl]oxy} acetate (125.3mg, 0.2mmol) prepare in example 1028 was taken up in 12.5 ml of a solution of 2:2:1 tetrahydrofuran:methanol:water. To the stirring solution 2N sodium hydroxide (220 μL, 0.44 mmol) was syringed into the reaction flask and allowed to stir overnight at room temperature. 2N Hydrochloric acid (230 μL, 0.46 mmol) was syringed into the reaction flask that allowed the title compound {[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)-2,3-dihydro-lH-inden -5-yl]oxy}acetic acid (117 mg, 96%) to crash out of solution as a white solid. MS (ES+) m/z 556.0;

HPLC purity 100.0% at 210-370 nm, 9.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₂₀ F ₃ NO ₇ S ₂ + H+, 556.07060; found (ESI, [M+H]+), 556.0712.

Example 1032: 5-(phenyIsulfonyl)-λ ^r -[(6-pyrroIidin-l-ylpyridin-3-yl)methyI]-2- (trifluoromethyl)benzenesulfonamide

[1286] In an analogous manner to example 1017 step 2, N-[(6-chloropyridin-3- yl)methyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)benzenesulf onamide and pyrrolidine were used to prepare 5-(phenylsulfonyl)-iV-[(6-pyrrolidin- 1 -ylpyridin-3-yl)methyl]-2- (trifluoromethyl)benzenesulfonamide.

MS (ES+) m/z 526.0;

HPLC purity 95.8% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1033: λ ^r -[(6-morpholin-4-ylpyridin-3-yI)methyl]-5-(phenylsulfonyl)-2 - (trifluoromethyl)benzenesulfonamide

[1287] In an analogous manner to example 1017 step 2, iV-[(6-chloropyridin-3- yl)methyl]-5-(phenylsulfonyl)-2-(trifluoromethyl)benzenesulf onamide and morpholine were used to prepare iV-[(6-morpliolin-4-ylpyridin-3-yl)methyl]-5-(phenylsulfonyl )-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 542.0;

HPLC purity 100.0% at 210-370 nm, 8.9 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₂ F ₃ N ₃ O ₅ S ₂ + H+ ₅ 542.10257; found (ESI, [M+H] ⁴ ), 542.1033.

Example 1034: 5-[(3-bromophenyl)sulfonyl]-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonainide

[1288] To a stirred solution of 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide (0.80 g, 1.78 mmol) in cone, sulfuric acid (13mL) and water (2 niL) was added NBS (0.32 g, 1.80 mmol) portionwise and the resulting solution was stirred overnight at room temperature. The solution was neutralized with aquous sodium hydroxide to pH ~8 and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. Achiral preparative super-critical fluid chromatography using 15%methanol/85% CO ₂ with 0.2% dimethylethylamine gave 5-[(3- bromophenyl)sulfonyl]-iV-piperidin-4-yl-2-(trifluoromethyl)b enzenesulfonamide. (0.52 g, 55%). MS (ES+) m/z 526.8;

HPLC purity 100.0% at 210-370 nm, 8.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₁₈ Hj ₈ BrF ₃ N ₂ O ₄ S ₂ + H+, 526.99162; found (ESI ₃ [M+H] ⁺ ), 526.9941.

Example 1035: _V-[(lfi*, 5S*)-8-Methyl-8-azabicyclo[3.2.1]oct-3-yl]-5-(phenyIsulfonyl )-2- (trifluoromethyl)benzenesulfonamide

[1289] A stirred solution of 5-(phenylsulfonyl)-2-(tπfluoromethyl)benzenesulfonyl chloride (0.38 g, 1.0 mmol) in 3:1 dichloromethane-acetonitrile (10 niL) was treated under nitrogen with e«(io-8-methyl-8-azabicyclo[3.2.1]octan-3-amine dihydrochloride (0.42 g, 2.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.52 g, 4.0 mmol). The reaction was stirred for 18 hours at room temperature. The crude product was purified by reverse phase preparative liquid chromatography on an Xterra MSCl 8, 50 x 250 mm prep column, eluting with a mixture of 60:40 water-methanol containing 0.1% formic acid at a flow rate of 100 mL/min, to afford, after concentration of the solvent and extraction with ethyl acetate (3x), an oil. The oil was crystallized from diethyl ether to afford N-[( IR*, δS^-S-meslkyl-S-εaabicycloiS.lλjoct-S-yϊl-S- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide_(0.09 g, 20%), as a homogeneous, colorless, crystalline solid, m.p. 154-57 °C; MS (-ESI), m/z: 486.9 [M-H] ^" ;

HRMS: calcd for C ₂₁ H ₂₃ F ₃ N ₂ O ₄ S ₂ + H+, 489.11241; found (ESI, [M+H] ⁺ ), 489.1109; HPLC purity 99.5% at 210-370 nm, 7.2 min.; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4 min.

Example 1036: [4-({methyl[2-({[5-(phenylsulfonyl)-2-

(trifluoromethy l)phenyl] sulf ony 1} amino)ethyl] amino} carbonyl)benzyl] phosphonic acid

[1290] To a stirring solution of dimethyl [4-({methyl[2-({ [5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) benzyl]phosphonate (0.282 g, 0.435 mmol) from Example 1006 in CH ₂ Cl ₂ (5 mL) under N ₂ at room temperature was added iodotrimethylsilane (0.13 mL, 0.18 g, 0.91 mmol). The mixture was stirred 2 days. The solvent and volatile components were evaporated. The residue was dissolved in CH ₃ OH (3 mL) and stirred overnight. Evaporation of the CH ₃ OH gave 0.06 g (22%) of [4-({methyl[2-({[5- (phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbonyl) benzyl]phosphonic acid. MS (ES+) m/z 620.8; HRMS: calcd for C ₂₄ H ₂₄ F ₃ N ₂ O ₈ PS ₂ + H+, 621.07365; found (ESI, [M+H] ⁺ ), 621.0723.

Example 1037: methyl 2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyI]sulfonyI}amino)indane-5-carboxylate

[1291] In an analogous manner to example 765, 5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonyl chloride (98.3 mg, 0.33 mmol) and methyl 2-amino-2,3- dihydro-lH-indene-5-carboxylate (74.7 mg, 0.39 mmol) was used to prepare the title compound methyl 2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}a mino)indane-5-carboxylate (79.1 mg, 45%) as a white solid. MS (ES-) m/z 537.7;

HPLC purity 100.0% at 210-370 nm, 10.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₄ H ₂₀ F ₃ NO ₆ S ₂ + H+, 540.07569; found (ESI, [M+H]+), 540.0762.

Example 1038: (22?)-2-[4-({[5-(phenylsulfonyI)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]propan amide

[1292] In an analogous manner to example 880, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-bromopropionamide were used to prepare 2-[4-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)pi peridin-l-yl]propanamide. This was chiral separated using column AD-H at 30% isopropyl alcohol to give (2i?)-2-[4-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)pi peridin-l-yl]propanamide. MS (ES+) m/z 520.0;

HPLC purity 100.0% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph-3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₁ H ₂₄ F ₃ N ₃ O ₅ S ₂ + H+, 520.11822; found (ESI, [M+H] ⁺ ), 520.1199.

Example 1039: (2S)-2-[4-({[5-(phenyIsuIfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]propan amide

[1293] In an analogous manner to example 880, 5-(phenylsulfonyl)-iV-piperidm-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-bromopropionamide were used to prepare 2-[4-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)pi peridin-l-yl]propanamide. This was chiral separated using column AD-H at 30% isopropyl alcohol to give (25)-2-[4-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl} amino)piperidin- 1 -yl]propanamide. MS (ES+) m/z 520.1;

HPLC purity 100.0% at 210-370 nm, 7.0 min.; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₁ H ₂₄ F ₃ N ₃ O ₅ S ₂ + H+, 520.11822; found (ESI, [M+H] ⁺ ), 520.118.

Example 1040: iV-{l-[(6-oxo-l,6-dihydropyridin-3-yl)carbonyI]piperidin-4-y I}-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide

[1294] In an analogous manner to example 1017,

Step 2: [l-(6-Chloro-pyridine-3-carbonyl)-piperidin-4-yl]-carbamic acid fert-butyl ester and potassium tertbutoxide in THF were used to prepare [l-(6-tert-Butoxy-pyridine-3-carbonyl)- piperidin-4-yl]-carbamic acid tert-butyl ester.

[1295] Step 3: In an analogous manner to example 435, 2-trifluoromethyl-5- (phenylsulfonyl)- benzenesulfonyl chloride and 5-(4-Amino-piperidine-l-carbonyl)-lH-pyridin- 2-one were used to prepare iV-{l-[(6-fert-butoxypyridin-3-yl)carbonyl]piperidin-4-yl}-5 - (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide.

[1296] Step 4: In an analogous manner to example 930, N- { 1 -[(6-tert-butoxypyridin-3- yl)carbonyl]piperidin-4-yl}-5-(phenylsulfonyl)-2-(trifluorom ethyl)benzenesulfonamide was used to prepare N- {1 -[(6-oxo- 1 ,6-dihydropyridin-3 -yl)carbonyl]piperidin-4-yl} -5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 569.8;

HPLC purity 98.4% at 210-370 nm, 7.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1041: N-[l-(l-acetyl-L-prolyl)piperidm-4-yl]-5-(phenylsulfonyl)-2- (trifluoroniethyl)benzenesulfonamide

[1297] In an analogous manner to example 1026 step 2, 5-(phenylsulfonyl)-N- piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide and N-aceyl-L-proline was used to prepare N-[I-(I -acetyl-L-prolyl)piperidin-4-y 1] -5-(pheny lsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 587.9;

HPLC purity 100.0% at 210-370 nm, 8.2 min.; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1042: tert-butyl (55)-2-oxo-5-{[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]carbon yl}pyrrolidine-l-carboxylate

[1298] In an analogous manner to example 1026 step 2, 5-(phenylsulfony I)-N- piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide and 5-oxo-pyrrolidine-l ,2-dicarboxylic acid 1-tert-butyl ester were used to prepare tert-butyl (5.S)-2-oxo-5-{[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl] sulfonyl} amino)piperidin- 1 -yl]carbonyl}pyiτolidine- 1 -carboxylate. MS (ES-) m/z 658.0;

HPLC purity 96.6% at 210-370 ran, 9.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Pb=3.5/ACν+MeOH) for lOmin, hold 4min.

Example 1043: λ ^L [l-(5-oxo-L-prolyl)piperidin-4-yl]-5-(phenylsuIfonyl)-2- (trifluoromethyl)benzenesulfonainide

[1299] In an analogous manner to example 930, tert-butyl (55)-2-oxo-5-{ [4-({ [5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)pi peridin-l-yl]carbonyl}pyrrolidine- 1 -carboxylate was used to prepare N-[l-(5-oxo-L-prolyl)piperidin-4-yl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 559.8;

HPLC purity 100.0% at 210-370 nm, 7.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Pb=3.5/ACν+MeOH) for lOmin, hold 4min.

Example 1044: N-(l-hydroxy-6-methoxy-2,3-dihydro-lH-inden-2-yl)-5-(phenyls ulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1300] In an analogous manner to example 765, 5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonyl chloride (151.7mg, 0.5 mmol) and 2-amino-6-methoxy-2,3- dihydro-lH-inden-1-ol (104.4 mg, 0.6 mmol) was used to prepare the title compound N-(I- hydroxy-6-methoxy-2,3-dihydro-lH-inden-2-yl)-5-(phenylsulfon yl)-2- (trifluoromethyl)benzenesulfonamide (171.6 mg, 65%) as a white solid. HPLC purity 98.0% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₃ H ₂₀ F ₃ NO ₆ S ₂ - H+, 526.06114; found (ESI, [+MH-H2O]+), 510.0851.

Example 1045: tert-butyl 4-[methyl({[2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbon yl)amino]piperidine-l- carboxylate

[1301] In an analogous manner to Example 887, Step 2, iV-2-(aminoethyl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 762 and tert-butyl 4-[(li7-imidazol-l-ylcarbonyl)(methyl)amino]piperidine-l-car boxylat from Example 989, Stepl, were used to prepare tert-butyl 4-[methyl({[2-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl} amino)ethyl]amino} carbonyl)amino]piperidine- 1 -carboxylate. MS (ES-) m/z 647.0; HRMS: calcd for C ₂₇ H ₃₅ F ₃ N ₄ O ₇ S ₂ + H+, 649.19720; found (ESI, [M+H] ⁺ ), 649.1974.

Example 1046: tert-butyl 4-[({[2-({[5-(phenylsulfonyI)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]amino}carbon yl)amino]piperidine-l- carboxylate

[1302] In an analogous manner to Example 866, Step 2, iV-2-(aminoethyl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride from Example 762 and tert-butyl 4- [(l//-imidazol-l-ylcarbonyl)amino]piperidine-l -carboxylate from Example 866, Step2, were used to prepare tert-butyl 4-[({[2-({[5-(phenylsulfonyl)-2-

(trifluoromethy^phenyljsulfonyllamii^ethyyaminojcarbony^amin ojpiperidine-l-carboxylate. MS (ESI-) m/z 633; HRMS: calcd for C ₂₆ H ₃₃ F ₃ N ₄ O ₇ S ₂ + H+, 635.18155; found (ESI, [MH-H] ⁺ ), 635.1825.

Example 1047: λ'-[l-(l-methyl-L-prolyl)piperidin-4-yl]-5-(phenylsulfonyl) -2- (trifluoromethyl)benzenesulfonamide

[1303] In an analogous manner to example 1026 step 2, 5-(phenylsulfonyl)-iV- piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide and N-methyl-L-proline were used to prepare iV-[l-(l-methyl-L-prolyl)piperidin-4-yl]-5-(phenylsulfonyl)- 2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 560.2;

HRMS: calcd for C ₂₄ H ₂₈ F ₃ N ₃ O ₅ S ₂ + H+, 560.14952; found (ESI, [M+H] ⁺ ), 560.1518; HPLC purity 100.0% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1048: 5-(phenylsulfonyl)-λ ^L [l-(pyridin-3-yIcarbonyI)piperidin-4-yl]-2- (trifluoromethyl)benzenesulfonamide

[1304] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and pyridine-3-carbonyl chloride were used to prepare 5- (pheny lsulfony I)-N- [ 1 -(pyridin-3 -ylcarbony l)piperidin-4-y 1] -2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 554.0;

HRMS: calcd for C ₂₄ H ₂₂ F ₃ N ₃ O ₅ S ₂ + H+, 554.10257; found (ESI, [MH-H] ⁺ ), 554.1022; HPLC purity 93.8% at 210-370 ran, 8.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1049: 5-(phenyIsulfonyl)-iV-[l-(pyridm-2-ylcarbonyl)piperidin-4-yl ]-2- (trifluoromethyl)benzenesulfonamide

[1305] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and pyridine-2-carbonyl chloride were used to prepare 5- (phenylsulfony I)-N- [ 1 -(pyridin-2-ylcarbonyl)piperidin-4-yl] -2- (trifluoromethyl)benzenesulfonamide. MS (ES) m/z 554.0;

HRMS: calcd for C ₂₄ H ₂₂ F ₃ N ₃ O ₅ S ₂ + H+, 554.10257; found (ESI, [M+H] ⁺ ), 554.1008; HPLC purity 94.8% at 210-370 nm, 8.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1050: iV-{l-[4-(methyIthio)benzoyI]piperidin-4-yl}-5-(phenylsulfon yl)-2- (trifluoromethyl)benzenesulfonamide

[1306] In an analogous manner to example 1026 step 2, 5-(phenylsulfonyl)-N-piperidin- 4-yl-2-(trifluoromethyl)benzenesulfonamide and 4-methylsulfanyl-benzoic acid were used to prepare N-{l-[4-(methylthio)benzoyl]piperidin-4-yl}-5-(phenylsulfony l)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 598.9;

HRMS: calcd for C ₂₆ H ₂₅ F ₃ N ₂ O ₅ S ₃ + H+, 599.09504; found (ESI, [M+H] ⁺ ), 599.0963; HPLC purity 100.0% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1051 : 5-(phenylsulfonyl)-2-(trifluoromethyl)-iV-(l-{[6-(trifluorom ethyI)pyridin-3- yl]carbonyl}piperidin-4-yl)benzenesulfonamide

[1307] In an analogous manner to example 462, 5-(phenylsurfonyi)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 6-trifluoromethyl-nicotinoyl chloride were used to prepare 5-(phenylsulfonyl)-2-(trifluoromethyl)-N-(l -{ [6-(trifluoromethyl)pyridin-3- yl]carbonyl}piperidin-4-yl)benzenesulfonamide. MS (ES+) m/z 621.9;

HRMS: calcd for C ₂₅ H ₂₁ F ₆ N ₃ O ₅ S ₂ + H+, 622.08996; found (ESI ₅ [M+H] ⁺ ), 622.0897; HPLC purity 100.0% at 210-370 nm, 9.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1052: λ-{l-[4-(methylsulfinyl)benzoyl]piperidin-4-yl}-5-(phenyIsu lfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1308] To a stirred solution of N-{l-[4-(methylthio)benzoyl]piperidin-4-yl}-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide (0.08g, 0.137 mmol) in methylene chloride (1 mL) was added mCPBA (0.31 g 77%, 0.137 mmol) and the resulting mixture was stirred at room temperature for 30min. The solution was washed with with sodium bicarbonate solution (sat) and concentrated. Flash column separation using 50%- 100% ethyl acetate/hexane gradient gave N-{ l-[4-(methylsulfinyl)benzoyl]piperidin-4-yl}-5-(phenylsulfon yl)-2- (trifluoromethyl)benzenesulfonamide. (0.058g, 69%). MS (ES+) m/z 614.9;

HRMS: calcd for C ₂₆ H ₂₅ F ₃ N ₂ O ₆ S ₃ + H+, 615.08996; found (ESI, [M+H] ⁺ ), 615.0925; HPLC purity 96.3% at 210-370 nm, 8.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1053: iV-{l-[3-(methylthio)propanoyl]piperidin-4-yl}-5-(phenylsuIf onyl)-2- (trifluoromethyl)benzenesulfonamide

[1309] In an analogous manner to example 1026 step 2, 5-(phenylsulfony I)-N- piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide and 3-methylsulfanyl-propionic acid were used to prepare N-{l-[3-(methylthio)propanoyl]piperidin-4-yl}-5-(phenylsulfo nyl)-2- (trifluoromethyl)benzenesulfonamide.

HRMS: calcd for C ₂₂ H ₂₅ F ₃ N ₂ O ₅ S ₃ + H+, 551.09504; found (ESI, [M+H] ^"1" ), 551.0927; HPLC purity 99.1% at 210-370 nm, 9.2 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1054: 7V-{l-[3-(methylsulfinyl)propanoyl]piperidin-4-yl}-5-(phenyl sulfonyI)-2- (trifluoromethyl)benzenesulfonamide

[1310] In an analogous manner to example 1052, N-{ 1 -[3- (methylthio)propanoyl]piperidin-4-yl}-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide was used to prepare 7V-{l-[3- (methylsulfinyl)propanoyl]piperidin-4-yl}-5-(phenylsulfonyl) -2- (trifluorometliyl)benzenesulfonamide.

HRMS: calcd for C ₂₂ H ₂₅ F ₃ N ₂ O ₆ S ₃ + H+, 567.08996; found (ESI, [M+H] ⁴ ), 567.0894; HPLC purity 100.0% at 210-370 nm, 7.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1055: tert-butyl (4R)-4-{[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]car bonyl}-l,3-thiazolidine-3- carboxylate

[1311] In an analogous manner to example 1026 step 2, 5-(phenylsulfonyl)-λ/- piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide and R-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester were used to prepare tert-butyl (4i-)-4-{[4-({[5-(phenylsulfonyl)-2- (trifluoromethy l)pheny 1] sulfony 1 } amino)piperidin- 1 -y 1] carbony 1 } - 1 , 3 -thiazolidine-3 - carboxylate. MS (ES-) m/z 661.9;

HRMS: calcd for C ₂₇ H ₃₂ F ₃ N ₃ O ₇ S ₃ + H+, 664.14272; found (ESI, [M+H] ⁺ ), 664.1432; HPLC purity 100.0% at 210-370 nm, 9.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1056: 5-(pheny lsulfonyl)-iV- {1 - [(4R)-1 ,3-thiazolidin-4-ylcarbonyl] piperidin-4-y 1}- 2-(trifluoromethyl)benzenesulfonamide

[1312] In an analogous manner to example 930, tert-butyl (4i?)-4-{[4-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)pi peridin-l-yl]carbonyl}-l,3-

thiazolidine-3-carboxylate was used to prepare 5-(phenylsulfonyl)-iV-{l-[(4i-)-l ₃ 3-thiazolidin-4- y lcarbonyl]piperidin-4-yl } -2-(trifluoromethy l)benzenesulfonamide . MS (ES+) m/z 563.8;

HPLC purity 100.0% at 210-370 nm, 8.6 min.; Xterra RP18, 3.5u, 15O x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1057: tert-butyl (3ϋT)-3-{[4-({[5-(phenylsulfonyI)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]carbon yl}pyrrolidine-l-carboxylate

[1313] In an analogous manner to example 1026 step 2, 5-(phenylsulfonyl)-iV- piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide and R-pyrrolidine-l,3-dicarboxylic acid 1-tert-butyl ester were used to prepare tert-butyl (3i?)-3-{[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]carbon yl}pyrrolidine-l-carboxylate. HRMS: calcd for C ₂₈ H ₃₄ F ₃ N ₃ O ₇ S ₂ + H+, 646.18630; found (ESI, [MfH] ⁺ ), 646.189; HPLC purity 100.0% at 210-370 nm, 9.8 min.; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1058: tert-butyl (3S)-3-{[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]carbon yl}pyrrolidine-l-carboxylate

[1314] In an analogous manner to example 1026 step 2, 5-(phenylsulfonyl)-N- piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide and S-pyrrolidine-l,3-dicarboxylic acid 1- tert-butyl ester were used to prepare fert-butyl (3ιS)-3-{[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]carbon yl}pyrrolidine-l-carboxylate. HRMS: calcd for C ₂₈ H ₃₄ F ₃ N ₃ O ₇ S ₂ + H+, 646.18630; found (ESI, [M+H] ⁺ ), 646.1891; HPLC purity 100.0% at 210-370 nm, 9.8 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1059 : 5-(pheny Isulf onyl)-iV- {1 - [(3J? )-py rrolidin-3-ylcarbonyl] piperidin-4-yI}-2- (trifluoromethyl)benzenesulfonamide

[1315] In an analogous manner to example 930, tert-butyl (3R)-3-{[4-({[5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)pi peridin-l-yl]carbonyl}pyrrolidine- 1-carboxylate was used to prepare 5-(phenylsulfonyl)-N-{l-[(3i?)-pyrrolidin-3- ylcarbonyl]piperidin-4-yl}-2-(trifluoromethyl)benzenesulfona mide.

HRMS: calcd for C ₂₃ H ₂₆ F ₃ N ₃ O ₅ S ₂ + H+, 546.13387; found (ESI, [M+H]+), 546.1336; HPLC purity 95.7% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1060: 5-(phenyIsulfonyl)-iV-{l-[(3iS)-pyrrolidin-3-ylcarbonyl]pipe ridin-4-yl}-2- (trifluoromethyl)benzenesulfonamide

[1316] In an analogous manner to example 930, tert-butyl (35)-3-{ [4-({ [5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}amino)pi peridin-l-yl]carbonyl}pyrrolidine- 1-carboxylate was used to prepare 5-(phenylsulfonyl)-iV-{l-[(3>S)-pyrrolidin-3- ylcarbonyl]piperidin-4-yl}-2-(trifluoromethyl)benzenesulfona mide. HRMS: calcd for C ₂₃ H ₂₆ F ₃ N ₃ O ₅ S ₂ + H+, 546.13387; found (ESI, [M+H]+), 546.1344; HPLC purity 90.4% at 210-370 nm, 7.3 min.; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1061: tert-butyl (4R)-4-{[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]car bonyl}-l,3-thiazolidine-3- carboxylate 1-oxide

[1317] In an analogous manner to example 1052, tert-butyl (4i?)-4- { [4-({ [5- (phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl} amino)piperidin- 1 -yljcarbonyl} - 1,3- thiazolidine-3-carboxylate was used to prepare tert-butyl (4i?)-4-{[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl} amino)piperidin-l -yl]carbonyl} - 1 ,3-thiazolidine-3-carboxylate 1-oxide.

MS (ES+) m/z 679.9;

HPLC purity 100.0% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1062: 2-{[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfon yl}amino)-2,3- dihydro-lH-inden-5-yl]oxy}acetamide

[1318] In an analogous manner to example 765, 5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonyl chloride (181.4 mg, 0.6 mmol) and 2-(2-amino-2,3-dihydro- lH-inden-5-yloxy)acetamide (145.7 mg, 0.6 mmol) was used to prepare the title compound 2-

{[2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfo nyl}amino)-2,3-diliydro-lH-inden-5- yl]oxy}acetamide (97.3 mg, 30%) as a yellow solid.

MS (ES+) m/z 554.8;

HPLC purity 95.0% at 210-370 nm, 9.1 min.; Xterra RP 18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

HRMS: calcd for C ₂₄ H _2J F ₃ N ₂ O ₆ S ₂ + H+, 555.08659; found (ESI, [M+HJ+), 555.0836.

Example 1063: methyl [4-({[5-(phenylsulfonyI)-2- (trifluoromethyl)phenyl] sulfonyl} amino)piperidin-l-yl] acetate

[1319] In an analogous manner to example 938, [4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]acetic acid was used to prepare methyl [4-( { [5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl} amino)piρeridin- 1 -yl]acetate. MS (ES+) m/z 520.8;

HPLC purity 96.3% at 210-370 nm, 6.9 min.; column, Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1064: iV-(l-{[(3if)-l-acetylpyrrolidin-3-yl]carbonyl}piperidin-4-y l)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide

[1320] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-{ 1 -[(3R)- pyrrolidin-3-ylcarbonyl]piperidin-4-yl} -2-(trifluoromethyl)benzenesulfonamide and acyl chloride were used to prepare λ/-(l-{[(3i?)-l-acetylpyrrolidin-3-yl]carbonyl}piperidin-4- yl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 587.8;

HPLC purity 95.1% at 210-370 nm, 8.2 min.; column, Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1065: iV-(l-{[(3 ₁ S)-l-acetylpyrrolidin-3-yl]carbonyl}piperidm-4-yl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide

[1321] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-{ 1 -[(3S)- pyrrolidin-3-ylcarbonyl]piperidin-4-yl} -2-(trifluoromethyl)benzenesulfonamide and acyl chloride were used to prepare iV-(l-{[(3 _J S)-l-acetylpyrrolidin-3-yl]carbonyl}piperidin-4-yl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide.

MS (ES+) m/z 587.8;

HPLC purity 100% at 210-370 nm, 8.2 min.; column, Xterra RP18, 3.5u, 150 x 4.6 mm column,

1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1066: 4-{[3-({[l-(før£-butoxycarbonyl)piperidin-4~yI]amino}sulfo nyl)-4- (trifluoromethyl)phenyl]sulfonyl}benzoic acid

[1322] Step 1 : To a stirred solution of tert-butyl 4-({ [5-[(4-fluorophenyl)sulfonyl]-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carboxyl ate (0.10 g, 0.18 mmol) in DMSO (1 mL) was added sodium cyanide (0.02 g, 0.35 mmol) and the resulting solution was heated to 120°C overnight. The solution was allowed to cool to room temperature, extracted with ethyl acetate and washed several times with water. The organic phase was concentrated. Flash column separation using 0%-30% ethyl acetate/hexane gradient gave 4-({[5-[(4-cyanophenyl)sulfonyl]- 2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carboxyl ate.

[1323] Step 2: To a stirred solution of 4-({ [5-[(4-cyanophenyl)sulfonyl]-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidine-l-carboxyl ate (0.10 g, 0.17 mmol) in glyme (1 mL) was added 2.5M KOH solution (0.5 mL) and the resulting solution was refluxed overnight. The solution was allowed to cool, neutralized with 2N HCl solution, and extracted with ethyl acetate. The organic phase was concentrated. Flash column separation using 0%-10% methanol/methylene chloride gradient gave 4-{[3-({[l-(feτt-butoxycarbonyl)piperidin-4- yl]amino}sulfonyl)-4-(trifluoromethyl)phenyl]sulfonyl}benzoi c acid. (0.05 g, 47%). MS (ES-) m/z 590.8;

HPLC purity 85.3% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1067: λ^-[l-(l-isobutyryl-L-proIyl)piperidin-4-yI]-5-(phenylsuIfo nyl)-2- (trifluoromethyl)benzenesulfonamide

[1324] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and isobutyryl chloride were used to prepare N-[I-(I -isobutyry 1-L-proly l)piperidin-4-yl] -5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 615.8; HPLC purity 100.0% at 210-370 nm, 9.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2

US2006/018886

λiYiiυj.o«j - 400 -

mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₇ H ₃₂ F ₃ N ₃ O ₆ S ₂ + H+, 616.17574; found (ESI ₅ [M+H] ⁺ ), 616.1791.

Example 1068: iV-{l-[l-(2,2-dimethylpropanoyl)-L-prolyl]piperidin-4-yl}-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide

[1325] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-(l-L- ρrolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and 2,2-dimethyl-proρionyl chloride were used to prepare iV-{l-[l-(2,2-dimethylpropanoyl)-L-prolyl]piperidin-4-yl}-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 629.8;

HPLC purity 95.8% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, holcUmin. HRMS: calcd for C ₂₈ H ₃₄ F ₃ N ₃ O ₆ S ₂ + H+, 630.19139; found (ESI, [M+H] ⁺ X 630.1919.

Example 1069: iV-{l-[l-(3,3-dimethylbutanoyl)-L-prolyl]piperidin-4-yl}-5-( phenylsulfonyl)- 2-(trifluoromethyl)benzenesulfoπamide

[1326] In an analogous manner to example 462, 5-(phenylsulfonyl)-7V-(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and 3,3-dimethyl-butyryl chloride were used to prepare iV-{l-[l-(3,3-dimethylbutanoyl)-L-prolyl]piperidin-4-yl}-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 643.9;

HPLC purity 94.6% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold4min.

Example 1070: iV-{l-[l-(cyclohexylcarbonyl)-L-prolyl]piperidin-4-yl}-5-(ph enylsulfonyl)-2- (trifluoromethyl)beπzenesuifonamide

[1327] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and cyclohexanecarbonyl chloride were used to prepare JV-{1 -[I -(cyclohexylcarbonyl)-L-prolyl]piperidin-4-yl} -5-(phenylsulfonyl)- 2-(trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 655.9; HPLC purity 100.0% at 210-370 nm, 8.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2

niL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1071: λ ^L {l-[l-(morpholin-4-ylcarbonyI)-L-prolyl]piperidin-4-yl}-5- (phenylsuIfonyl)-2-(trifluoromethyI)benzenesulfonamide

[1328] In an analogous manner to example 462, 5-(phenylsulfonyl)-λ ^r -(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and moφholine-4-carbonyl chloride were used to prepare N-{l-[l-(morpholin-4-ylcarbonyl)-L-prolyl]piperidin-4-yl}-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 658.8;

HPLC purity 100.0% at 210-370 urn, 9.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₈ H ₃₅ F ₃ N ₄ O ₆ S ₂ + H+, 645.20229; found (ESI, [M+H] ⁺ ), 645.2024.

Example 1072: (2S)-iV-(te^-butyl)-2-{[4-({[5-(phenyIsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]car bonyl}pyrrolidine-l- carboxamide

[1329] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-(l -L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and tert-butylisocyanate were used to prepare (25)-iV-(fert-butyl)-2-{[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)pheny 1] sulfonyl } amino)piperidin- 1 -yl] carbony 1} pyrrolidine- 1 -carboxamide. MS (ES+) m/z 644.9;

HPLC purity 100.0% at 210-370 ran, 10.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₂₈ H ₃₅ F ₃ N ₄ O ₆ S ₂ + H+, 645.20229; found (ESI, [M+H] ⁺ ), 645.2048.

Example 1074: (2S)-iV-phenyl-2-{[4-({[5-(phenyIsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]car bonyl}pyrrolidine-l- carboxamide

[1330] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and phenylisocyanate were used to prepare (2S)-iV-phenyl-2-{ [4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]carbon yl}pyrrolidine-l -carboxamide.

MS (ES+) m/z 664.8;

HPLC purity 100.0% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1075: λ^-{l-[l-(methylsulfonyl)-L-prolyl]piperidin-4-yI}-5-(pheny Isulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1331] In an analogous manner to example 462, 5-(ρhenylsulfonyl)-N-(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and methane sulfonyl chloride were used to prepare JV- {1 -[I -(methylsulfonyl)-L-prolyl]piperidin-4-yl}-5-(phenylsulfonyl )-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 623.8;

HRMS: calcd for C ₂₄ H ₂ SF ₃ N ₃ O ₇ S ₃ + H+, 624.11142; found (ESI, [M+H] ⁺ ), 624.1116; HPLC purity 100.0% at 210-370 nm, 8.5 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 niL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1076: iV-[l-(l -benzoyI-L-proIyl)piperidin-4-yl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1332] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and benzoyl chloride were used to prepare N-[l-(l-benzoyl-L-prolyl)piperidin-4-yl]-5-(phenylsulfonyl)- 2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 649.8;

HPLC purity 94.7% at 210-370 nm, 9.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₃₀ H ₃₀ F ₃ N ₃ O ₆ S ₂ + H+, 650.16009; found (ESI, [M+H] ⁺ ), 650.1616.

Example 1077: 7V-(l-{l-[4-(dimethylamino)benzoyl]-L-prolyl}piperidin-4-yl) -5- (phenyIsulfonyI)-2-(trifluoromethyI)benzenesuIfbnamide

[1333] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and 4-demethylaminobenzoyl chloride were used to prepare N-(l-{l-[4-(dimethylamino)benzoyl]-L-prolyl}piperidin-4-yl)- 5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide.

MS (ES+) m/z 692.9;

HPLC purity 94.2% at 210-370 nm, 9.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min. HRMS: calcd for C ₃₂ H ₃₅ F ₃ N ₄ O ₆ S ₂ + H+, 693.20229; found (ESI, [M+H] ⁴ ), 693.2034.

Example 1078: A ^L [l-(l-isonicotinoyI-L-prolyl)piperidin-4-yl]-5-(phenylsulfon yl)-2- (trifluoromethyl)benzenesulfonamide

[1334] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and isonicotinoyl chloride were used to prepare iV-[l-(l-isonicotinoyl-L-prolyl)piperidin-4-yl]-5-(phenylsul fonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 650.8;

HRMS: calcd for C ₂₉ H ₂₉ F ₃ N ₄ O ₆ S ₂ + H+, 651.15534; found (ESI, [M+H] ⁺ ), 651.1552; HPLC purity 100.0% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1079: iV-(l-{l-[(6-chloropyridin-3-yl)carbonyl]-L-prolyl}piperidin -4-yl)-5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide

[1335] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and 6-chloro-nicotinoyl chloride were used to prepare N-(l-{ l-[(6-chloropyridin-3-yl)carbonyl]-L-prolyl}piperidin-4-yl)- 5- (phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide. MS (ES-) m/z 684.8;

HPLC purity 100.0% at 210-370 nm, 9.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1080: 4-[((25)-2-{[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]car bonyl}pyrrolidin-l- yl)sulfonyl]benzoic acid

[1336] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and 4-(chlorosulfonyl)benzoic acid were used to prepare 4-[((2£)-2-{[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl] sulfonyl} amino)piperidin- 1 -yl]carbonyl}pyrrolidin- 1 - yl)sulfonyl]benzoic acid.

MS (ES+) m/z 729.8;

HPLC purity 100.0% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1081 : iV-[l-(i\yV-dimethylglycyl-L-proIyl)piperidin-4-yl]-5-(pheny ϊsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1337] In an analogous manner to example 462, 5-(phenylsulfonyl)-iV-(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and dimethylamino-acetyl chloride were used to prepare iV-[l-(λζN-dimethylglycyl-L-prolyl)pipeπdin-4-yl]-5-(phen ylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 630.9;

HPLC purity 87.6% at 210-370 nm, 7.4 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1082: 2-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}a mino)indane-5- carboxylic acid

[1338] Methyl 2-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)indane-5-carboxyla te (478.2mg, 0.9 mmol) prepare in example 1037 was taken up in 25 ml of a solution of 2:2:1 tetrahydrofuran:methanol: water. To the stirring solution 2N sodium hydroxide (880 μL, 1.76 mmol) was syringed into the reaction flask and allowed to stir overnight at room temperature. 2N Hydrochloric acid (900 μL, 1.8 mmol) was syringed into the reaction flask that caused a white solid to crash out of solution. The solid was collected by filtration and the product was transferred onto a 12 g Isco RediSep® Normal Phase column and was purified by automated flash chromatography using a gradient of 20% to 100% hexane/ethyl acetate. Isolation of the main component gave the title compound 2- ({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl}ami no)indane-5-carboxylic acid (122.2 mg, 26%) as a white solid. MS (ES-) m/z 525.7;

HPLC purity 97.2% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1083: 7V-methyl-2-[4-({[5-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]acetam ide

[1339] In an analogous manner to example 880, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-chloro-N-methyl-acetamide were used to prepare N- methyl-2-[4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)phenyl] sulfonyl}amino)piperidin-l- yl]acetamide. MS (ES+) m/z 519.8;

HPLC purity 100.0% at 210-370 nm, 7.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1084: JV-[I-(I -benzyl-L-prolyI)piperidin-4-yl]-5-(phenylsuIfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1340] In an analogous manner to example 880, 5-(phenylsulfonyl)-N-(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and benzyl bromide were used to prepare N-[l-(l-ben2yl-L-prolyl)piperidin-4-yl]-5-(phenylsulfonyl)-2 - (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 635.9;

HPLC purity 100.0% at 210-370 nm, 8.1 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min.

Example 1085: λyV-dimethyl-2-[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]acetam ide

[1341] In an analogous manner to example 880, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-chloro-ν,ν-dimethyl-acetamide were used to prepare N _r N-dimethyl-2-[4-( { [5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]acetam ide. MS (ES+) m/z 533.9;

HPLC purity 96.6% at 210-370 nm, 6.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACν+MeOH) for lOmin, hold 4min.

Example 1086: iV-isopropyl-2-[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]acetam ide

[1342] In an analogous manner to example 880, 5-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-chloro-N-isopropyl-acetamide were used to prepare N-isopropyl-2-[4-({[5-(phenylsulfonyl)-2-(trifluoromethyl)ph enyl]sulfonyl}amino)piperidin-l- yljacetamide. MS (ES-) m/z 547.8;

HPLC purity 95.1% at 210-370 nm, 7.6 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1087: iV-[l-(2-morphoHn-4-yl-2-oxoethyl)piperidin-4-yl]-5-(phenyls ulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1343] In an analogous manner to example 880, 5-(phenylsulfonyl)-iV-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 2-chloro-l-morpholin-4-yl-ethanone were used to prepare λ/-[l-(2-morpholin-4-yl-2-oxoethyl)piperidin-4-yl]-5-(pheny lsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 575.8;

HPLC purity 98.2% at 210-370 nm, 7.0 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1088: iV-{l-[l-(cyclohexylmethyl)-L-prolyl]piperidin-4-yl}-5-(phen ylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1344] To a stirred solution of 5-(phenylsulfonyl)-iV-(l -L-prolylpiperidin-4-yl)-2- (trifluoromethyl)benzenesulfonamide (0.09 g, 0.16 mmol) and cyclohexanecarbaldehyde (0.02 g, 0.16 mmol) in methanol (1 mL) was added triacetoxy sodium borohydride (0.05 g, 0.22 mmol) and the resulting solution was stirred overnight at room temperature. The crude mixture was concentrated. Flash column separation using 0%-10% methanol/methylene chloride gradient gave N- { 1 -[I -(cyclohexylmethyl)-L-prolyl]piperidin-4-yl) -5-(phenylsulfony l)-2- (trifluoromethyl)benzenesulfonamide. (0.025 g, 25%). MS (ES+) m/z 641.9;

HPLC purity 100.0% at 210-370 nm, 8.9 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example l089: iV-{l-[l-(3,3-dimethylbutyI)-L-prolyl]piperidin-4-yl}-5-(phe nylsulfonyl)-2- (trifluororaethyl)benzenesulfonamide

[1345] In an analogous manner to example 1088, 5-(phenylsulfonyl)-7V-(l-L- prolylpiρeridin-4-y l)-2-(trifluoromethy l)benzenesulfonamide and 3 ,3 -dimethyl-butyraldehyde were used to prepare iV-{l-[l-(3,3-dimethylbutyl)-L-prolyl]piperidin-4-yl}-5-(phe nylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 630.0;

HPLC purity 100.0% at 210-370 nm, 8.8 min.; Xterra RPl 8, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1090: 5-(phenyϊsuIfonyI)-iV-[l-(l,3-thiazol-4-ylcarbonyl)piperidi n-4-yl]-2- (trifluoromethyl)benzenesulfonamide

[1346] In an analogous manner to examplelO26 step 2, 5-(phenylsulfonyl)-N-piperidin- 4-yl-2-(trifluoromethyl)benzenesulfonamide and thiazole-4-carboxylic acid were used to prepare 5-(phenylsulfonyl)-iV-[l-(l,3-thiazol-4-ylcarbonyl)piperidin -4-yl]-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 559.6;

HPLC purity 98.5% at 210-370 nm, 8.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1091: (2S)-iV-ethyI-2-{[4-({[5-(phenyIsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]car bonyl}pyrrolidine-l- carboxamide

[1347] In an analogous manner to example 462, 5-(phenylsulfonyl)-7V-(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and ethylisocyanate were used to prepare (25)-N-ethyl-2-{[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]car bonyl}pyrrolidine-l-carboxamide. MS (ES+) m/z 616.8;

HPLC purity 100.0% at 210-370 nm, 8.6 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1092: (2S)-λyV-dimethyl-2-{[4-({[5-(phenylsulfonyl)-2-

(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]car bonyl}pyrrolidine-l- carboxamide

[1348] In an analogous manner to example 462, 5-(phenylsulfonyl)-N-(l-L- prolylpiperidin-4-yl)-2-(trifluoromethyl)benzenesulfonamide and dimethylaminocarbonyl chloride were used to prepare (25)-N,iV-dimethyl-2-{[4-({[5-(phenylsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]carbon yl}pyrrolidine-l-carboxamide. MS (ES+) m/z 616.8;

HPLC purity 100.0% at 210-370 ran, 8.7 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1093: iY-[l-(liϊ-imidazol-l-ylacetyl)piperidin-4-yl]-5-(phenyIsul fonyl)-2- (trifluoromethyl)benzenesulfonamide

[1349] In an analogous manner to example 1026 step 2, 5-(phenylsulfonyl)-iV- piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide and imidazol-1-yl-acetic acid were used to prepare N-[I -( 1/i-imidazol- 1 -ylacetyl)piperidin-4-yl]-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide. MS (ES+) m/z 556.8;

HPLC purity 99.2% at 210-370 nm, 7.3 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. for lOmin, hold 4min.

Example 1094: iV-(5-bromo-2,3-dihydro-l _J H-inden-2-yl)-5-(phenyIsulfonyl)-2- (trifluoromethyl)benzenesulfonamide

[1350] To a stirred suspension of 5-bromoindan-2 -amine hydrobromide (2.80 g, 9.56 mmol) in a solution of 5-(phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonyl chloride (3.67 g, 9.54 mmol) from Example 677 in CH ₂ Cl ₂ (75 mL) under N ₂ at room temperature was added diisopropylethylamine (5.00 mL, 3.71 g, 28.7 mmol). The mixture was stirred at room temperature for 1.5 hours. It was washed once with 2N HCl, twice with water and once with brine. The solvent was evaporated. The residue was dissolved again in CH ₂ Cl ₂ (18 mL) The solution was loaded directly onto a silica gel column and eluted with a gradient of hexane and CH ₂ Cl ₂ to give 4.11 g (77%) of N-(5-bromo-2,3-dihydro-lH-inden-2-yl)-5-(phenylsulfonyl)-2- (trifluoromethyl)benzenesulfonamide.

MS (ES-) m/z 557.6.

Example 1095: tert-butyl (2S)-2-{[4-({[5-[(3-cyanophenyl)sulfonyl]-2- (trifluoromethyl)phenyl]sulfonyl}amino)piperidin-l-yl]carbon yl}pyrrolidine-l-carboxylate

[1351] Step 1 : In an analogous manner to example 1026 step 2, 5-[(3- bromophenyl)sulfonyl]-N-piperidin-4-yl-2-(trifluoromethyl)be nzenesulfonamide and N-(te7t- butoxycarbonyl)-L-proline were used to prepare tert-butyl (2JS)-2-{[4-({[5-[(3- bromophenyl)sulfonyl]-2-(trifluoromethyl)phenyl]sulfonyl} amino)piperidin- 1 - yl]carbonyl}pyrrolidine-l-carboxylate.

[1352] Step 2: In an analogous manner to example 376, tert-butyl (2S)-2-{ [4-({ [5-[(3- bromophenyl)sulfonyl]-2-(trifluoromethyl)phenyl]sulfonyl}ami no)piperidin-l- yl]carbonyl}pyrrolidine-l-carboxylate was used to prepare tert-butyl (2£)-2-{[4-({[5-[(3- cyanophenyl)sulfonyl]-2-(trifluoromethyl)phenyl]sulfonyl} amino)piperidin- 1 - yljcarbonyljpyrrolidine-l-carboxylate. MS (ES+) m/z 670.7

HPLC purity 98.8% at 210-370 nm, 11.2 min.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for lOmin, hold 4min.

Example 1096: Fluorescence Polarization Binding Assay

[1353] The affinity of test compounds for SFPvP-I was determined using a fluorescence polarization binding assay. According to the assay design, a probe compound was bound to SFRP-I . The fluorescence anisotropy value of the probe compound is increased upon binding to SFRP-I. Upon the addition of a test compound, the fluorescence anisotropy value for the probe compound decreased due to competitive displacement of the probe by the test compound. The decrease in anisotropy as a function of increasing concentration of the test compound provides a direct measure of the test compound's binding affinity for SFRP-I .

[1354] To determine IC50 values, fluorescence polarization experiments were conducted in a 384-well format according to the following procedures. A 20 mM stock solution of the probe compound was prepared in 100 % DMSO and dispensed in 10 μL aliquots for long- term storage at -20 ⁰ C. The binding assay buffer was prepared by combining stock solutions of Tris-Cl, NacL, glycerol, and NP40 at final concentrations of 25 mM Tris-Cl pH 7.4, 0.5 M NaCl, 5% glycerol and 0.002 % NP40. Master stock solutions of the test compounds were prepared in

100 % DMSO at final concentrations of 20 niM. Typically the working stock solutions of the test compounds were prepared by serially diluting the 20 mM master stock solution to 5 mM, 2.5 mM, 1.25 mM, 0.625 mM, 0.3125 mM, 0.156 mM, 78 μM, 39 μM, 19.5 μM, 9.8 μM, 4.9 μM, 2.44 μM, 1.22 μM, 0.31 μM, 76 nM, and 19 nM in DMSO. The working stock solutions of the test compounds were further diluted by combining 6 μl of the solutions with 24 μL of Milli-Q purity water, resulting in working stock solutions (10x compound stocks) in 20 % DMSO.

[1355] The assay controls were prepared as follows. A 2 μL aliquot of the 20 mM fluorescence probe compound was diluted 1000-fold in 100 % DMSO to a final concentration of 20 μM. 6 μL of the 20 μM probe was combined with 5.4 mL of the assay buffer, mixed well, and 18 μL of the resulting solution was dispensed into 384-well plates.

[1356] SFRP-1/probe complex was prepared by combining 11 μL of 20 μM probe compound with 9.9 mL of the assay buffer and SFRP-I stock solution to final concentrations of 22 nM probe compound and 50 nM SFRP-1. 18 μL of the SFRP-1/probe complex was dispensed into the 384-well plates.

[1357] 2 μL aliquots of the test compounds from the 10x working stock solutions were removed and dispensed into the plate containing the SFRP-1/probe complex and the resultant solutions were mixed by pipetting up and down once. The final concentratons of SFRP-I and probe in the assay solutions were 45 nM and 20 nM, respectively. In a typical experiment, each plate was used to test 14 compounds.

[1358] The plate was incubated in the dark for 15 minutes. The fluorescence of the SFRP-1/probe complexs was read in the Tecan Ultra plate reader at excitation and emission maxima of 485 and 535 nm. The plate reader settings were as follows:

Mode: Fluorescence Polarization Plate definition: Matrical3841v.pdf (pdf stands for Plate Definition File) Excitation 485nm (bandwidth 20nm) Emission 535nm (bandwidth 30nm) G-factor: 1.03 # flashes / well: 10 integration time: lOOus time btwn move, flash: 60ms Z-position: 10730 um

Analysis of Results

[1359] Fluorescence anisotropy results from the emission of polarized light in the parallel and perpendicular directions when a fluorophore is excited with vertically polarized light. The anisotropy of the probe in the free and bound state was determined using the following equation: r = i(π)-i(±)*i(π)+ 2i(±) where I(II) and 1(1) are the parallel and perpendicular emission intensities, respectively.

[1360] Monitoring the anisotropy changes of the probe compound revealed that it bound saturably to SFRP-I with a K _D of 20-30 nM. The binding affinity was independently verified using a tryptophan fluorescence quenching assay.

[1361] The decrease in the anisotropy of the probe upon addition of the competing test compound was fitted to a sigmoidal dose response curve of the equation shown below:

(Top - Bottom)

Y = Bottom + ■

(1 + 10 X-LagIC50 \ * Hillslope

where "X" is the logarithm of concentration, "Y" is the anisotropy, and "Bottom" and "Top" correspond to the anisotropy values of the free and SFRP-I -bound probe prior to the addition of the test compound, respectively.

[1362] For automated IC50 determinations, the equation shown above was used in the program GraphPad Prism. The "Hillslope" was kept constant at 1. The value for "Bottom" was fixed, but was determined by the blank (probe-only) wells in the plate. The values for "Top" and "IC50" were determined by the data fit. The value for "Top" was typically close to 120, equivalent to approximately 50 % bound probe, and the value for "Bottom" was around 30, due to free probe. If the test compound interfered with the probe in the fluorescence assay at high concentrations, the range for the fitted data was limited to the lower concentration range. The data obtained from the experiments are shown in the table below.

6018886

-413-

λ.iViXUXOUJ -414-

018886

-416-

2006/018886

-418-

Example 1097: Cell-based Assay for in vitro Measurement of SFRP-1/SARP2 Antagonist Activity

[1363] The following cell-based assay can be used to identify inhibitors of SFRP-I . Materials and Methods

Cells

[1364] The osteosarcoma cell line, U2OS (ATCC, HTB 96), was passaged twice a week with growth medium (McCoy's 5 A medium containing 10% (v/v) fetal calf serum, 2mM GlutaMAX-1, and 1% (v/v) Penicillin- Streptomycin). The cells were maintained in vented flasks at 37 ⁰ C inside a 5% CU ₂ /95% humidified air incubator. One day prior to transfection, the cells were plated with growth medium at 25,000 cells/well into 96-well plates and incubated at 37 °C overnight.

Routine Co-Tr ansfection

[1365] The growth medium was removed, and the cells were washed once with OPTIMEM I (Gibco-BRL) medium (100 μL/well) to remove the serum and antibiotics. The wash medium was removed, and the cells were re-fed with OPTI-MEM I medium (100 μL/well). For each well of cells to be transfected, the following DNA' s were diluted together in 25 μL OPTI-MEM I medium: 0.1 μg 16x TCF-tk-Luciferase reporter, 0.02 μg Wnt 3, Wnt3A, Wnt 1 or empty vector (Upstate Biotechnology), 0.075 μg hSFRP-1 or empty vector (pcDNA3.1, Invitrogen), and 0.025 μg CMV-βgal (Clonetech). For each well of cells to be transfected, lμl of Lipofectamine 2000 reagent (Invitrogen) was diluted in 25 μl OPTI-MEM I medium and incubated at room temperature for 5 minutes. The diluted DNA' s were then combined with the diluted Lipofectamine 2000 (LF2000), and the mixture was incubated at room temperature for 20 minutes. Fifty μL of the DNA-LF 2000 mixture was added to each well, and the plate(s) were incubated at 37 °C in a 5% CO ₂ /95% humidified air incubator for 4 hours. The cells were washed once with 150 μL/well of experimental medium (phenol red-free RPMI Medium 1640

containing 2% fetal bovine serum, 2mM GlutaMAX-1, and 1% Penicillin-Streptomycin). Finally, the cells were treated overnight at 37 °C with 200 μL/well of experimental medium containing either vehicle (typically DMSO) or diluted compound in replicates of 8 wells/compound.

Dosing

[1366] Initial single dose screening of test compounds was done at 10 μM .

[1367] Dose-response experiments were initially performed with the compounds in log increases of concentration from 1-10,000 nM. From these dose-response curves, ECso values were generated.

Assay

[1368] After treatment, the cells were washed twice with 150 μL/well of PBS without calcium or magnesium and were lysed with 50 μL/well of IX cell culture lysis reagent (Promega Corporation) on a shaker at room temperature for 30 minutes. Thirty μL aliquots of the cell lysates were transferred to 96-well luminometer plates, and luciferase activity was measured in a MicroLumat PLUS luminometer (EG&G Berthold), or a Victor (PerkinElmer Life Sciences) using 100 μL/well of luciferase substrate (Promega Corporation). Following the injection of substrate, luciferase activity was measured for 10 seconds after a 1.6 second delay. Similarly, 10 μL aliquots of the cell lysates were transferred to separate 96-well luminometer plates, and 50 μL of Galacton chemiluminescent substrate (Tropix) was added to each well. The plates were covered and incubated on a rotary shaker at room temperature for one hour, βgal activity was measured in a MicroLumat PLUS luminometer or Victor using 100 μL/well of Light Emission Accelerator (Tropix). Following the injection of the accelerator, βgal activity was measured for 10 seconds after a 1.6 second delay. The luciferase and βgal activity data were transferred from the luminometer to a PC and analyzed using the SAS/Excel program. After the luciferase activity was normalized to βgal, the SAS/Excel program was used to determine the mean and standard deviation of each treatment, to analyze the data for statistical significance, and to determine EC _5O values (see the Table below).

Large-Scale Co-Transfection

[1369] As an alternative to co-transfection in a 96 well plate, the U2OS cells were transfected in T225 flasks and the transfected cells were frozen. The frozen cells were thawed and plated on a 96 well plate and the assay was carried out as detailed above. The growth

medium was removed from the T225 flasks, and the cells were washed once with OPTI-MEM I medium (approx. 25 ml/flask) to remove the serum and antibiotics. The wash medium was removed, and the cells were re-fed with OPTI-MEM I medium (59 ml/flask). For each T225 flask of cells to be transfected, the following DNA' s were diluted together in 5.9 ml OPTI-MEM I medium: 70.3 μg 16x TCF-tk-Luciferase reporter, 14.06 μg WNT3, 3A or Wntl or empty vector, 52.8 μg hSFRP-1 or empty vector, and 17.58 μg CMV-βgal. Separately, for each flask of cells to be transfected, 354 μL of Lipofectamine 2000 reagent (Invitrogen) was diluted in 5.9 mL OPTI-MEM I medium and incubated at room temperature for 5 minutes. The diluted DNA' s were then combined with the diluted Lipofectamine 2000 (LF2000), and the mixture was incubated at room temperature for 20 minutes. 11.8 mL of the DNA-LF 2000 mixture was added to each flask, and the flask(s) were incubated at 37 ⁰ C in a 5% CO ₂ /95% humidified air incubator for 4 hours. The medium was removed, and the cells were washed once with approximately 25 mL/flask of phenol red-free RPMI Medium 1640, then re-fed with 50 mL/flask of experimental medium (phenol red-free RPMI Medium 1640 containing 2% fetal bovine serum, 2 mM GlutaMAX-1, and 1% Penicillin- Streptomycin) and incubated at 37 ⁰ C overnight.

Freezing Cells

[1370] The transfected cells were washed twice with 25 mL/flask/wash of PBS without calcium or magnesium. Three ml of Trypsin-EDTA (0.05% Trypsin, 0.53 mM EDTA-4Na) was added to each flask, and the flasks were incubated at room temperature for approximately 5 minutes until the cells were rounded and detached from the surface of the flask(s). The cells were resuspended in 10 mL/flask of phenol red-free RPMI 1640 containing 10% fetal bovine serum and were pipetted up and down several times until a single cell suspension was formed. The resuspended cells were pooled and a 10 μL aliquot was removed and diluted at 1:10 in PBS. The diluted cells were counted using a hemacytometer to determine the total number of cells in the pool. The cells were transferred to sterile centrifuge tubes and pelletted at 1500 rpm in a Sorvall RC-3B refrigerated centrifuge at 4 ⁰ C for 5 minutes. The supernatant was aspirated and the cells were resuspended in cold, phenol red-free RPMI 1640 medium containing 50% FBS to a cell density of 2.5E+7 cells/ml. An equal volume of cold, 2x freezing medium (phenol red-free RPMI 1640 medium containing 50% FBS and 15% DMSO) was added slowly, dropwise to the resuspended cells with gentle mixing, resulting in a final cell density of 1.25E+7 cells/mL. The resuspended cells were placed on ice and aliquoted into sterile cryogenic vials. The vials were transferred to aNalgene Cryo 1°C freezing container (Nalgene catalog # 5100-0001) containing

250 mL isopropyl alcohol. The sealed container was placed in a -80 ⁰ C freezer overnight to freeze the cells at a cooling rate of -1 °C/minute. The frozen cells were then transferred to a - 150 °C freezer for long-term storage.

Benchtop Assay for Single Dose Confirmation of HTS Hits

[1371] Early in the morning, a vial of frozen transfected cells was thawed, and the cells were resuspended in phenol red-free RPMI 1640 medium to a final cell density of 150,000 cells/ml. The resuspended cells were then plated in white, 96-well polystyrene tissue culture treated CulturPlatesTM (Packard cat. # 6005180) at a volume of 100 μL of cell suspension/well (i.e. 15,000 cells/well). The plates were incubated at 37 °C inside a 5% CO ₂ /95% humidified air incubator for 6 hours or until the cells were attached and started to spread. Test compounds were then added to the wells (1 well/compound) and the plates were incubated at 37 ⁰ C overnight. After the overnight incubation, luciferase activity was measured using the Luc-Screen Luciferase Assay System (Tropix). Fifty μL of Luc-Screen buffer 1, warmed to room temperature, was added directly to the cells in the 96-well plates. Fifty μL of Luc-Screen buffer 2, warmed to room temperature, was then added, and the plates were incubated in the dark, at room temperature, for 10 minutes. The plates were transferred to a Packard Top Count Microplate Scintillation and Luminescence Counter (Packard), and the light emission was measured for 10 seconds after a 2 minute delay.

[1372] The luciferase activity data was transferred to a PC and analyzed using the SAS/Excel program as described above. Analysis of Results

[1373] The luciferase data was analyzed using the SAS/Excel program. For the initial single dose experiment, if the compound treatment resulted in increased reporter activity and was specific to SFRP-I inhibition, then the results were reported as fold induction over SFRP-I control (see the Table below). Compounds

[1374] A known inhibitor of GSK-3β, a key enzyme involved in the Wnt signaling pathway, served as an internal control for measurement of the cellular response to Wnt signaling. The inhibition of GSK-3 results in stabilization of β-catenin, leading to up-regulation of LEF/TCF regulated reporter genes.

[1375] The entire disclosure of each patent, patent application, and publication cited or described in this document is hereby incorporated by reference.