ARYL SULFONAMIDE DERIVATIVES AND METHODS OF THEIR USE

FIELD OF THE INVENTION

[0001] The present invention relates to novel aryl sulfonamide derivatives that act, for example, as modulators of secreted frizzled-related protein- 1. The present invention also relates to processes for the preparation of aryl sulfonamide derivatives and to their use in treating various diseases and disorders, including osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, autoimmune inflammatory disorders, such as Graves ophthalmopathy, and combinations thereof.

BACKGROUND OF THE INVENTION

[0002] 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.

[0003] 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, adipogenesis, 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).

[0004] Studies indicate that certain Wnt proteins interact with a family of proteins named "frizzled" that act as receptors for Wht proteins or as components of a Wnt receptor complex (in Moon et a/., Cell 1997, 88:725-728; Barth et a/., 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 a/., Nature Reviews Genetics 2004, 5:691-701).

[0005] 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 a/., 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.

[0006] 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-1/FrzA/FRP-1/SARP-2, SFRP-2/SDF-5/SARP-1, SFRP- 3/Frzb-1/FrzB/Fritz, SFRP-4 and SFRP-5/SARP-3 (Leimeister et ai, 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 as well as fibroblasts. 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-1 in mice has been shown to lead to decreased osteoblast/osteocyte apoptosis and to increased bone formation. (Bodine, P.V.N, et ai, MoI. Endocrinol., 2004, 18(5) 1222-1237.) Deletion of SFRP-1 in mice has also been shown to lead to an acceleration of chondrocyte differentiation. (Gaur, T., et ai, J. Cell. Physiol., 2006, 208(1 ) 87-96.) Modulation of SFRP-1 with an anti-SFRP- 1 antibody has been shown to enhance new connective tissue formation resulting in increases in palatal wound healing (Li, C. H. and Amar, S. J. Dent. Research, 2006, 85(4), 374-378. Overexpression of SFRP-1 has also been implicated in autoimmune inflammatory disorders such as Graves Ophthalmopathy by stimulating a pathogenic process of adipogensis (Kumar, S., et. ai, J. CHn. Endocrinol. Metab., 2005, 90, 4730^735).

[0007] A need exists in the art for the identification of modulators of SFRP-1 that can be used as novel agents for the treatment of bone disorders or bone fractures, including bone resorption disorders such as osteoporosis, and for regulation of bone formation in humans or for other diseases and disorders, such as arthritis, chronic obstructive pulmonary disease, cartilage defects, leiomyoma, acute myeloid leukemia, wound healing, prostrate cancer, autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof.

SUMMARY OF THE INVENTION

[0008] The present invention is directed to certain aryl sulfonamide derivatives and to their use, for example, in medical treatment. In one aspect, the invention relates to aryl sulfonamide derivatives that act as modulators of secreted frizzled related protein-1. The compounds can be used, for example, to treat various diseases and disorders, including osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, autoimmune inflammatory disorders such as Graves ophthalmopathy, and combinations thereof.

[0009] In certain aspects, the present invention is directed to compounds of formula I:

I or a pharmaceutically acceptable salt thereof; wherein:

R ¹ is H, halo, alkyl, alkoxy, alkylamino, alkylthio, dialkylamino, aryl, aryloxy, arylalkyl, arylthio, arylsulfonyl, heteroaryl, carboxyl, cyano, perfluoroalkyl, or perfluoroalkoxy, wherein any aryl or heteroaryl portion of R ¹ may be optionally substituted with 1 to 5 substituents, selected independently at each occurrence from the group consisting of alkyl, halo, carboxyl, aryl, alkoxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, alkylcarbonyl, aminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl;

R ² is halo, alkyl, alkoxy, alkylamino, alkylthio, dialkylamino, aryl, aryloxy, arylalkyl, arylthio, arylsulfonyl, heteroaryl, carboxyl, cyano, perfluoroalkyl, or perfluoroalkoxy, wherein any aryl or heteroaryl portion of R ² may be optionally

substituted with 1 to 5 substituents, selected independently at each occurrence from the group consisting of alkyl, halo, carboxyl, aryl, alkoxy, alkoxyalkyl, alky lam ino, dialkylamino, cyano, alkylcarbonyl, aminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl;

R ³ is an optionally substituted alkyl, cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, heteroarylalkyl, alkylaryl, alkylheteroaryl, alkenyl, alkynyl, fused cycloalkylaryl, fused heterocycloalkylaryl, cycloalkylcarbonyl, or heterocycloalkylcarbonyl group;wherein the alkyl, cycloalkyl, alkylheterocycloalkyl, heteroarylalkyl, alkylaryl, alkylheteroaryl, alkenyl, alkynyl, fused cycloalkylaryl, fused heterocycloalkylaryl, cycloalkylcarbonyl, and heterocycloalkylcarbonyl groups of R ³ may be, independently, optionally substituted with 1 to 5 substituents selected from the group consisting of 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; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the alkyl groups of R ³ may be, independently, optionally substituted with 1 to 5 substituents selected from the group consisting of 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; wherein the heterocycloalkyl groups of R ³ 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, alky lam ide, 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, heterocycloalkylalkylam inothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heteroarylalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylaminothiocarbonyl, alkoxycarbonylalkylaminothiocarbonyl, alkylthiocarbonylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylaminoarylsulfonyl, and heteroarylsulfonyl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the heterocycloalkyl groups of R ³ may be independently, optionally substituted with 1 to 5 substituents selected from the group consisting of 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, alkylamiπothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfonylarylsulfonyl, carboxyarylsulfonyl, nitro, amino, dialkylamino, alkylcarbonylamino, alkylsulfonylamino, carboxyarylsulfonylamino, hydroxy, carboxy, sulfonamide, alkylthio, halo, cyano, guanidine, and oxo, and the nitrogen atoms in the heteroaryl substituents may be optionally substituted with an oxygen atom; wherein the amino substituents on the alkyl groups of R ³ may be, independently, optionally substituted with 1 or 2 substituents selected from the group consisting of alkyl, hydroxyalkyl, carboxyalkyl, cycloalkyl, alkoxycarbonylalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylcarbonyl, cycloalkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkoxycarbonylalkylaminocarbonyl, carboxyalkylcarbonyl, carboxyalkylaminocarbonyl, carboxyalkylcarbonylheterocycloalkylaminocarbonyl, arylaminocarbonyl, arylcarbonyl, heteroarylaminocarbonyl, heterocycloalkylcarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocycloalkylaminocarbonyl, heterocycloalkylthiocarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkoxythiocarbonyl, and aryloxythiocarbonyl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the amino substituents on the alkyl groups of R ³ 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.

R ⁴ is H or C ₁ -C ₄ straight or branched alkyl;

R ⁵ is, independently at each occurrence, H or C ₁ -C ₄ straight or branched alkyl; or both R ⁵ groups, together with the carbon atom through which they are attached form a Cs-Ce cycloalkyl;

R ⁶ is Ci-C ₄ alkyl, hydroxy, hydroxy(Ci-Cβ)alkyl, acetamide, alkylcarboxylate, sulfonylbenzene, sulfonylbenzoic acid, sulfonylphenylacetamide, carbothioamidobenzoic acid, oxoalkylpyridine, alkanoic acid, oxoalkanoic acid, cyano, or halo; and

X is -O- -(NR ⁴ )-, -S-, -[C(R ⁵ J ₂ ]- -(CH ₂ -CHR ⁴ )-, -(C=O)-, Or-(C=O)-NR ⁴

[0010] In other embodiments, the invention relates to compositions, comprising: a. at least one compound of formula I; and b. at least one pharmaceutically acceptable carrier.

[0011] In yet other embodiments, the invention is directed to methods for treating a patient suffering from osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, autoimmune inflammatory disorders, such as Graves ophthalmopathy, or combination thereof, comprising the step: administering to said patient an effective amount of a compound of formula I or pharmaceutically acceptable salt thereof.

8

[0012] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0013] The present invention is directed to certain aryl sulfonamide derivatives and to their use, for example, in medical treatment. In one aspect, the invention relates to arγl sulfonamide derivatives that act as modulators of secreted frizzled related protein-1. The compounds can be used, for example, to treat various diseases and disorders, including osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, and autoimmune inflammatory disorders such as Graves ophthalmopathy.

[0014] The following definitions are provided for the full understanding of terms and abbreviations used in this specification.

[0015] The term "alkyl," as used herein, refers to an optionally substituted aliphatic hydrocarbon chain having 1 to 12 carbon atoms (C _1-12 alkyl), preferably 1 to 8 carbon atoms (Ci-8 alkyl), and more preferably 1 to 4 carbon atoms (C1-4 alkyl). 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.

[0016] The term "hydroxyalkyl," as used herein, refers to the group -alkyl-OH where alkyl is an alkyl group as previously defined.

[0017] The term "carboxyalkyl," as used herein, refers to the group -alkyl-C(O)OH where alkyl is an alkyl group as previously defined.

[0018] 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.

[0019] 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.

[0020] The term "perfluoroalkylalkyl," as used herein, refers to the group -alkyl- perfluoroalkyl where alkyl and perfluoroalkyl are as previously defined.

[0021] The term "alkenyl," as used herein, refers to an optionally substituted aliphatic straight or branched hydrocarbon chain having 2 to 12 carbon atoms (C2-12 alkenyl) 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-i-enyl, or 2-methylvinyl.

[0022] The term "alkynyl," as used herein, refers to an optionally substituted aliphatic straight or branched hydrocarbon chain having 2 to 12 carbon atoms (C2-12 alkynyl) 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.

[0023] 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 "cycloalkyl," as used herein, includes a bicyclic cycloalkyl group and "bridged" cycloalkyl groups which contain at least one carbon- carbon bond between two non-adjacent carbon atoms of the cycloalkyl ring.

[0024] 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.

[0025] The term "cycloalkylalkyl," as used herein, refers to the group -alkylcycloalkyl in which alkyl is an alkyl group as previously defined and cycloalkyl is a cycloalkyl group as previously defined.

[0026] 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.

[0027] 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 "heterocycloalkyl" includes bicyclic structures formed when a heterocycloalkyl group is fused to another heterocycloalkyl group, to a cycloalkyl group, to an aryl group, or to a heteroaryl group. The term "heterocycloalkyl" includes "bridged" heterocycloalkyl groups which contain at least one carbon-carbon bond between non-adjacent carbon atoms of the heterocycloalkyl ring.

[0028] 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.

[0029] 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.

[0030] The term "aryl," as used herein refers to an optionally substituted carbocyclic aromatic ring, e.g., of 6 to 20, or 6 to 14 carbon atoms (Cβ- ₁₄ aryl). Aryl groups may be monocyclic or bicyclic. Exemplary aryl groups include phenyl and naphthyl.

[0031] The term "carboxyaryl," as used herein, refers to the group -aryl-C(O)OH, where aryl is an aryl group as previously defined.

[0032] 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, pyhdazinyl, indolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, quinolyl, isoquinolyl, quinoxalinyl, and quinazolinyl.

[0033] 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.

[0034] 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.

[0035] 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.

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

[0037] The term, "fused heterocycloalkylaryl," 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.

[0038] The term "fused heterocycloalkylarylcarbonyl," as used herein, refers to the group -C(O)- fused hetercycloalkylaryl where fused hetercycloalkylaryl is a fused hetercycloalkylaryl group as previously defined.

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

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

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

[0042] The term "alkoxycarbonylamino," as used herein, refers to the group -NHC(O)OR' where R' is an alkyl group as previously defined.

[0043] The term "alkylcarbonylalkylamino," as used herein, refers to the group -NH-R'-C(O)R' where R' is an alkyl group as previously defined.

[0044] 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.

[0045] 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.

[0046] The term "alkylcarbonyloxime," as used herein, refers to the group -C(N=OR')R' where R' is an alkyl group as previously defined.

[0047] The term "alkoxy," as used herein, refers to the group -O-R' where R' is an alkyl group as previously defined, preferably C-i-β alkyl.

[0048] The term "perfluoroalkoxy," as used herein, refers to the group -O-R" where R" is a perfluoroalkyl group as previously defined.

[0049] The terms "amino," "alkylamino," "dialkylamino," and "imino," as used herein, refer to the groups -NH ₂ , -NHR ¹ , -N(R') _2l and -C=NH, respectively, where each R' is, independently, an alkyl group as previously defined.

[0050] The term "aminoalkyl," as used herein, refers to the group -R ¹ NH ₂ where R' is an alkyl group as previously defined.

[0051] The term "alkylcarbinol," as used herein, refers to an alkyl group as previously defined substituted with a hydroxyl group.

[0052] The term "carboxy," as used herein, refers to the group -COOH.

[0053] The term "carbonyl," as used herein, refers to a bivalent carbon atom that is further bonded to an oxygen atom through a double bond.

[0054] The term "thiocarbonyl," as used herein, refers to a bivalent carbon atom that is further bonded to a sulfur atom through a double bond.

[0055] The terms "halogen" or "halo," as used herein, refer to chlorine, bromine, fluorine or iodine.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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-Chfe-phenyl.

[0063] The term "aminocarbonylalkoxy," as used herein, refers to the group - alkoxy-C(O)NH ₂ where alkoxy is an alkoxy group as previously defined.

[0064] The term "alkoxycarbonylalkoxy," as used herein, refers to the group - alkoxy-C(O)-alkoxy where alkoxy is an alkoxy group as previously defined.

[0065] The term "carboxyalkoxy," as used herein, refers to the group -alkoxy- C(O)OH where alkoxy is an alkoxy group as previously defined.

[0066] 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.

[0068] The term "dialkylaminoarylcarbonyl," as used herein, refers to the group — C(O)aryl-N(R')(R') where R' is an alkyl group as previously defined.

[0069] The term "arylthio," as used herein, refers to the group -S-aryl where aryl is an aryl group as previously defined.

[0070] The term "arylthiol," as used herein, refers to the group HS-aryl where aryl is an aryl group as previously defined.

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

[0072] 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.

[0073] 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.

[0074] The term "aminosulfonyl," as used herein, refers to the group -S(O) ₂ -NH ₂ .

[0075] The term "heteroarylsulfonyl," as used herein, refers to the group -S(O) ₂ -heteroaryl where heteroaryl is a heteroaryl group as previously defined.

[0076] The term "arylester," as used herein, refers to the group -C(O)O-aryl where aryl is an aryl group as previously defined.

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

[0079] The term "alky lam inoalkylcarbonyl," as used herein, refers to the group -C(O)-R'-NH(R') where R' is an alkyl group as previously defined.

[0080] 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.

[0081] The term "perfluoroalkylcarbonyl," as used herein, refers to the group - C(O)R" where R" is a perfluoroalkyl group as previously defined.

[0082] The term "carboxyalkylcarbonyl," as used herein, refers to the group -C(O)-R'-C(O)OH where R' is an alkyl group as previously defined.

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

[0084] The term "alkoxythiocarbonyl," as used herein, refers to the group -C(S)OR ¹ where R' is an alkyl group as previously defined.

[0085] The term "alkoxycarbonylalkyl," as used herein, refers to the group -R'- C(O)OR' where R' is an alkyl group as previously defined.

[0086] The term "arylcarbonyl," as used herein, refers to the group -C(O)-aryl where aryl is an aryl group as previously defined.

[0087] The term "heteroarylcarbonyl," as used herein, refers to the group -C(O)-heteroaryl where heteroaryl is a heteroaryl group as previously defined.

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

[0089] The term "heterocycloalkylalkylcarbonyl," as used herein, refers to the group -C(O)-R'-heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined and R' is an alkyl group as previously defined.

[0090] The term "heterocycloalkylalkylarninothiocarbonyl," as used herein, refers to the group -C(O)-S-N H -R'-heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined and R' is an alkyl group as previously defined.

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

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

[0092] The term "aryloxythiocarbonyl," as used herein, refers to the group -C(S)-O-aryl where aryl is an aryl group as previously defined.

[0093] The term "cyanoarylcarbonyl," as used herein, refers to the group -C(O)-aryl-CN where aryl is an aryl group as previously defined.

[0094] 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.

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

[0096] The term "heterocycloalkylcarbonyl," as used herein, refers to the group

-C(O)-heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined.

[0097] The term "heterocycloalkylthiocarbonyl," as used herein, refers to the group -C(S)-heterocydoalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined.

[0098] The term "aminoalkylcarbonyl," as used herein, refers to the group -C(O)-R'-NH ₂ where R' is an alkyl group as previously defined.

[0099] The term "alkoxycarbonylaminothiocarbonyl," as used herein, refers to the group -C(O)-S-NH-C(O)-O-R' where R ¹ is an alkyl group as previously defined.

[0100] 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.

[0101] 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.

[0102] The term "cyanoalkoxycarbonyl," as used herein, refers to the group -C(O)-alkoxy-CN where alkoxy refers to an alkoxy group as previously defined.

[0103] 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.

[0104] The term "alkylester," as used herein, refers to the group -C(O)OR' wherein R' is an alkyl group as previously defined.

[0105] The term "aminocarbonyl," as used herein, refers to the group

-C(O)NH ₂ .

[0106] The terms "alkylaminocarbonyl," and "dialkylaminocarbonyl," as used herein, refer to the groups -C(O)NHR ¹ and -C(O)N(R') ₂ , respectively, where each R' is, independently, an alkyl group as previously defined.

[0107] The term "heterocycloalkylaminocarbonyl," as used herein, refers to the group -C(O)NH-heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined.

[0108] The term "carboxyalkylaminocarbonyl," as used herein, refers to the group -alky lam inocarbonyl-carboxy where carboxy is a carboxy group as previously defined and alkylaminocarbonyl is an alkylaminocarbonyl group as previously defined.

[0109] 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.

[0110] The term "aminocarbonylalkyl," as used herein, refers to the group -R'C(O)NH ₂ where R' is an alkyl group as previously defined.

[0111] The terms "alkylaminocarbonylalkyl," and "dialkylaminocarbonylalkyl," as used herein, refer to the groups -R ¹ C(O)NHR' and -R'C(O)N(R')2, respectively, where each R' is, independently, an alkyl group as previously defined.

[0112] 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.

[0113] 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.

20

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

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

[0116] The term "heteroarylaminothiocarbonyl," as used herein, refers to the group -C(S)N H(heteroaryl), where heteroaryl is a heteroaryl group as previously defined.

[0117] The term "arylaminothiocarbonyl," as used herein, refers to the group -C(S)N H(aryl), where aryl is an aryl group as previously defined.

[0118] 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.

[0119] The term "alkylsulfonyl," as used herein, refers to the group -S(O)2-R ^* where R' is an alkyl group as previously defined.

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

[0121] The term "alkylthio," as used herein, refers to the group -S-R' where R' is an alkyl group as previously defined.

[0122] The term "perfluoroalkylthio," as used herein, refers to the group -S-R" where R" is a perfluoroalkyl group as previously defined.

[0123] 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.

[0124] 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.

[0125] The term "nitro" as used herein, refers to -NO ₂ .

[0126] The term "sulfonyl" refers to -SO ₂ -.

[0127] The term "sulfoxide" refers to -SO-.

[0128] As used herein, the terms "optionally substituted" or "substituted or unsubstituted" are intended to refer to the optional replacement of up to four hydrogen atoms with up to four independently selected substituent groups as defined herein. Unless otherwise specificed, suitable substituent groups independently include hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl, aminocarbonyl, carbonylamino, carbonyl, oxo, guanidine, carboxyl, formyl, alkyl, perfluoroalkyl, alkyamino, dialkylamino, alkoxy, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, cyanoalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, alkoxycarbonyl, dialkylaminothiocarbonyl, hydroxyalkyl, carboxyalkyl, haloalkyl, perfluoroalkylalkyl, alkenyl, alkynyl, alkylcycloalkyl, cycloalkylalkyl, spirocycloalkyl, alkylheterocycloalkyl, carboxyaryl, alkylheteroaryl, arylcarbonylalkyl, alkylthioalkylcarbonyl, alky lcarbony lam ino, alkoxycarbonylamino, alkylcarbonylalkylamiπo, alkylsulfonylamino, carboxyarylsulfonylamino, alkylcarbonyloxime, perfluoroalkoxy, arylalkyl, aryloxy, heteroaryloxy, heteroarylalkyl, arylalkenyl, arylalkoxy, aminocarbonylalkoxy, alkoxycarbonylalkoxy, carboxyalkoxy, arylalkylcarbonyl, dialkylaminoarylcarbonyl, arylthio, arylsulfonyl, carboxyarylsulfonyl, aminosulfonyl, heteroarylsulfonyl, alkylthiocarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylaryl, alkylester, perfluoroalkylthio and the like. Substituent groups that have one or more available hydrogen atoms can in turn optionally bear further independently selected substituents, to a maximum of three levels of substitutions. For example, the term "optionally substituted aryl" is intended

22

to mean an aryl group that can optionaly have up to four of its hydrogen atoms replaced with substituent groups as defined above (i.e., a first level of substitution), wherein each of the substituent groups attached to the aryl group can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i.e., a second level of substitution), and each of the substituent groups of the second level of substitution can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i.e., a third level of substitution).

[0129] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkoxycabonyl" refers to the group (aryl)-(alkyl)-O- C(O)-.

[0130] It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.

[0131] 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.

[0132] The term "therapeutically effective amount," as used herein, refers to the amount of a compound of formula I 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 fracture, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, autoimmune inflammatory disorder, and combinations thereof.

[0133] The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable salt" includes acid addition salts, namely salts derived from treating a

23

compound of formula I with an organic or inorganic acids or bases. Where the compound having formula I has an acidic function, the term "pharmaceutically acceptable salts" or "pharmaceutically acceptable salt" includes salts derived from bases, for instance, sodium salts.

[0134] The term "patient," as used herein, refers to a mammal.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] Certain embodiments of the invention are directed to compounds of formula I:

or a pharmaceutically acceptable salt thereof; wherein:

R ¹ is H, halo, alkyl, alkoxy, alkylamino, alkylthio, dialkylamino, aryl, aryloxy, arylalkyl, arylthio, arylsulfonyl, heteroaryl, carboxyl, cyano, perfluoroalkyl, or perfluoroalkoxy, wherein any aryl or heteroaryl portion of R2 may be optionally

24

substituted with 1 to 5 substituents, selected independently at each occurrence from the group consisting of alkyl, halo, carboxyl, aryl, alkoxy, alkoxyalkyl, alky lam ino, dialkylamino, cyano, alkylcarbonyl, aminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl;

R ² is halo, alkyl, alkoxy, alky lam ino, alkylthio, dialkylamino, aryl, aryloxy, arylalkyl, arylthio, arylsulfonyl, heteroaryl, carboxyl, cyano, perfluoroalkyl, or perfluoroalkoxy, wherein any aryl or heteroaryl portion of R ₂ may be optionally substituted with 1 to 5 substituents, selected independently at each occurrence from the group consisting of alkyl, halo, carboxyl, aryl, alkoxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, alkylcarbonyl, aminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl;

R ₃ is an optionally substituted alkyl, cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, heteroarylalkyl, alkylaryl, alkylheteroaryl, alkenyl, alkynyl, fused cycloalkylaryl, fused heterocycloalkylaryl, cycloalkylcarbonyl, or heterocycloalkylcarbonyl group;wherein the alkyl, cycloalkyl, alkylheterocycloalkyl, heteroarylalkyl, alkylaryl, alkylheteroaryl, alkenyl, alkynyl, fused cycloalkylaryl, fused heterocycloalkylaryl, cycloalkylcarbonyl, and heterocycloalkylcarbonyl groups of R ₃ may be, independently, optionally substituted with 1 to 5 substituents selected from the group consisting of 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; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the alkyl groups of R ₃ may be, independently, optionally substituted with 1 to 5 substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl,

25

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, hθteroarylaminothiocarbonyl, aminosulfonyl, alkylsulfonyl, arylsulfoπyl, 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; wherein the heterocycloalkyl groups of R ₃ 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, heterocycloalkylalkylam inothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heteroarylalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylaminothiocarbonyl, alkoxycarbonylalkylaminothiocarbonyl,

26

alkylthiocarbonylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylaminoarylsulfonyl, and heteroarylsulfonyl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the heterocycloalkyl groups of R ₃ may be independently, optionally substituted with 1 to 5 substituents selected from the group consisting of 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, arylamiπocarboπyl, heteroarylcarbonyl, heteroarylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfoπylarylsulfoπyl, carboxyarylsulfonyl, nitro, amino, dialkylamino, alkylcarbonylamino, alkylsulfonylamino, carboxyarylsulfonylamino, hydroxy, carboxy, sulfonamide, alkylthio, halo, cyano, guanidine, and oxo, and the nitrogen atoms in the heteroaryl substituents may be optionally substituted with an oxygen atom; wherein the amino substituents on the alkyl groups of R ₃ may be, independently, optionally substituted with 1 or 2 substituents selected from the group consisting of alkyl, hydroxy a Iky I, carboxyalkyl, cycloalkyl, alkoxycarboπylalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylcarbonyl, cycloalkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkoxycarbonylalkylaminocarbonyl, carboxyalkylcarbonyl, carboxyalkylaminocarbonyl, carboxyalkylcarbonylheterocycloalkylaminocarbonyl, arylaminocarbonyl, arylcarbonyl, heteroarylaminocarbonyl, heterocycloalkylcarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocycloalkylaminocarbonyl, heterocycloalkylthiocarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkoxythiocarbonyl, and aryloxythiocarbonyl;

27

wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the amino substituents on the alkyl groups of R ₃ 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.

R ⁴ is H or C ₁ -C ₄ straight or branched alkyl;

R ⁵ is, independently at each occurrence, H or Ci-C ₄ straight or branched alkyl; or both R ⁵ groups, together with the carbon atom through which they are attached form a Cs-Ce spirocycloalkyl;

R ⁶ is Ci-C ₄ alkyl, hydroxy, hydroxy(Ci-C ₆ )alkyl, acetamide, alkylcarboxylate, sulfonylbenzene, sulfonylbenzoic acid, sulfonylphenylacetamide, carbothioamidobenzoic acid, oxoalkylpyridine, alkanoic acid, oxoalkanoic acid, cyano, or halo; and X is -O- -(NR ⁴ )-, -S-, -[C(R ⁵ J ₂ ]- -(CH ₂ -CHR ⁴ )-, -(C=O)-, Or-(C=O)-NR ⁴

[0139] In certain embodiments of the compounds of formula I, Ri is H, fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, butyoxy, phenyl,

28

naphthyl, benzyl, trifluoromethyl, or trifluoromethoxy. In certain preferred embodiments, R ¹ is H or fluoro.

[0140] In certain embodiments of the compounds of formula I, R ² is fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, butyoxy, phenyl, naphthyl, benzyl, trifluoromethyl, or trifluoromethoxy. In certain preferred embodiments, R ² is chloro, methyl, isopropyl, trifluoromethyl, or trifluoromethoxy.

[0141] In certain embodiments of the compounds of formula I, R ³ is alkyl substituted with 1-3 R ⁶ , cycloalkyl substituted with 0-3 R ⁶ , heterocycloalkyl substituted with 0-3 R ⁶ , arylalkyl substituted with 0-3 R ⁶ , heteroarylalkyl substituted with 0-3 R ⁶ , heterocycloalkylalkyl substituted with 0-3 R ⁶ , fused cycloalkylaryl substituted with 0-3 R ⁶ , alkylaryloxy substituted with 0-3 R ⁶ ,

r

HO

29

o o O

Il

N-S=O

OH

HO

CT CH

i — I " CH

NH

A-

^HN λ / N λ OH

^=N or

X^

CH

[0142] In certain embodiments of the compounds of formula I, R ³ is:

30

α

^ U DtO

λ r

O

_> CH ,OH x

CH CH r-

CH NHH ₂₂ c rrrt

HO U U

HO

O t

CH

K^"

HO

CH

t NH

^=N * or

X^

[0143] In certain embodiments of the compounds of formula I ₁ R ⁴ is H, methyl, eetthhyyll,, nn--pprrooppyyll,, oorr iissoopprrooppyyll.. IInn cceerrttaaiinn pprreeffeerrrreedd eemmbodiments, R ⁴ is H, methyl, or isopropyl. In certain preferred embodiments, R ⁴ is H.

[0144] In certain embodiments of the compounds of formula I, R ₅ is, independently at each occurrence, H, methyl, or ethyl. In certain preferred embodiments, both R ⁵ groups are H. In certain preferred embodiments, both R ⁵ groups are methyl. In certain preferred embodiments, both R ⁵ groups are ethyl.

[0145] In certain embodiments of the compounds of formula I, both R ⁵ groups, together with the carbon atom through which they are attached, form spirocyclopentyl or spirocyclohexyl.

32

[0146] In certain embodiments of the compounds of formula I, In certain eemmbbooddiimmeennttss ooff tthhee ccoommppoouunnddss ooff ffooirmula I, R ⁶ is methyl, hydroxy, hydroxyethyl, ethanolic acid, cyano, fluoro, or chloro.

[0147] In certain embodiments of the compounds of formula I ₁ X is -[C(R ⁵ )2]- -(CH ₂ -CHR ⁴ )-, -(C=O)-, or -(C=O)-NR ⁴ , especially where R ⁴ is H or methyl and where R ⁴ is H or methyl.

[0148] Preferred embodiments of the compounds of formula I include:

2-methyl-N-(2-phenylethyl)-9H-thioxanthene-3-sulfonamide 10, 10-dioxide;

2-methyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulfonami de 10 ₁ 10- dioxide;

2-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H-thioxanthe ne-3-sulfonamide 10,10-dioxide;

2-methyl-9-oxo-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H-thio xanthene-3- sulfonamide 10,10-dioxide;

6-fluoro-2-isopropyl-N-(2-pyridin-3-ylethyl)-9H-thioxanth ene-3-sulfonamide 10,10-dioxide;

6-fluoro-2-isopropyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9 H-thioxanthene-3- sulfonamide 10,10-dioxide;

6-fluoro-2-isopropyl-9,9-dimethyl-N-(2-pyridin-3-ylethyl) -9H-thioxanthene-3- sulfonamide 10,10-dioxide;

6-f luoro-2-isopropy I-9 , 9-dimethyl-N-(tetrahydro-2 H-pyran-4-yl )-9H- thioxanthene-3-sulfonamide 10, 10-dioxide;

6-fluoro-2-isopropyl-9,9-dimethyl-N-(tetrahydro-2H-pyran- 4-ylmethyl)-9H- thioxanthene-3-sulfonamide 10, 10-dioxide;

6-fluoro-2-isopropyl-9,9-dimethyl-N-(2-pyridin-4-ylethyl) -9H-thioxanthene-3- sulfonamide 10,10-dioxide;

2,9 ₁ 9-thmethyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulfona mide 10, 10- dioxide;

2,9,9-trimethyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H-thi oxanthene-3- sulfonamide 10,10-dioxide;

33

2,9 _I 9-trimethyl-N-(tetrahydro-2H-pyran-4-yl)-9H-thioxanthene-3-s ulfonamide 10,10-dioxide;

2,9 _> 9-trimethyl-N-(2-pyridin-4-ylethyl)-9H-thioxanthene-3-sulfon amide 10,10- dioxide;

N-(2-cyanoethyl)-2,9,9-trimethyl-9H-thioxanthene-3-sulfon amide 10,10- dioxide; te/f-butyl 4-{[(2,9,9-trimethyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]am ino}piperidine-1 -carboxylate

2,9,9-trimethyl-N-piperidin-4-yl-9H-thioxanthene-3-sulfon amide 10, 10-dioxide;

5-oxo-5-(4-{[(2,9,9-trimethyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}pipehdin-1-yl)pentanoic acid;

3-[(4-fl(2,9,9-trimethyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}pipehdin-1-yl)sulfonyl]benzoic acid;

4-[(4-{[(2,9,9-trimethyl-10 ₁ 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]benzoic acid;

4-oxo-4-(4-{[(2,9,9-trimethyl-10 ₁ 10-dioxido-9H-thioxanthen-3- yl)sulfoπyl]amino}piperidin-1-yl)butanoic acid;

N-{4-[(4-{[(2,9 _l 9-trimethyl-10,10-dioxido-9H-thioxanthen-3- yl)sulfonyl]am ino}piperidin-1 -yl)sulfonyl]phenyl}acetam ide tert-butyl (4-{[(2,9 _l 9-trimethyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]am ino}piperidin-1 -yl)acetate

(4-{[(2,9,9-trimethyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1-yl)acetic acid;

N-^rans^-hydroxycyclohexylJ^.θ.θ-trimethyl-θH-thioxant hene-S-sulfonamide 10,10-dioxide;

2 ^t -methyl-N-(2-pyridin-2-ylethyl)spiro[cyclopentane-1 ,9'-thioxanthene]-3'- sulfonamide 10',10'-dioxide;

2'-methyl-N-(2-pyridin-3-ylethyl)spiro[cyclopentane-1 ,9'-thioxanthene]-3'- sulfonamidθ 10',10'-dioxide;

2'-methyl-N-(2-pyridin-4-ylethyl)spiro[cyclopentane-1 ,9'-thioxanthene]-3'- sulfonamide 10',10'-dioxide;

34

2'-methyl-N-(tetrahydro-2H-pyran-4-yl)spiro[cyclopentane-1 ₎ 9 ^l -thioxanthene]- 3'-sulfonamide 10 ¹ , 10'-dioxide;

2'-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)spiro[cyclope ntane-1 ,9'- thioxanthene]-3' -sulfonamide 10', 10'-dioxide;

N-(2-cyanoethyl)-2'-methylspiro[cyclopentane-1 ,9'-thioxanthene]-3'- sulfonamide 10',10'-dioxide;

N-(2-hydroxy-2-phenylethyl)-2 ^l -methylspiro[cyclopentane-1 _l 9'-thioxanthene]- 3'-sulfonamide 10 ¹ , 1 O'-dioxide;

N^-hydroxy-i -methyl^-phθnylethylJ-Z-methylspiroIcyclopθntane-i .θ ¹ - thioxanthene]-3'-sulfonamide 10', 10'-dioxide;

N^-hydroxyethylJ^'-methylspiroIcyclopentane-i .θ'-thioxanthenel-S ¹ - sulfonamide 10',10'-dioxide; te/f-butyl 4-{[(2'-methyl-10', 10'-dioxidospiro[cyclopentane-1 ,9'-thioxanthen]-3'- yl)sulfonyl]am ino}piρeridine-1 -carboxylate

2'-methyl-N-piperidin-4-ylspiro[cyclopentane-1,9 ^l -thioxanthene]-3'-sulfonamide 10',10'-dioxide;

3-[(4-{[(2'-methyl-10', 10'-dioxidospiro[cyclopentane-1 , 9'-thioxanthen]-3'- yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]benzoic acid; te/f-butyl (4-{[(2'-methyl-10', 10'-dioxidospiro[cyclopentane-1 ,9'-thioxanthen]-3'- yl)sulfonyl]am ino}piperidin-1 -yl)acetate

N-(trans-4-hydroxycycl ohexyl)-2'-methy lspiro[cyclopentane-1 , 9'-th ioxanthene]- 3'-sulfonamide 10 ¹ , 10'-dioxide;

2 ^l -methyl-N-(2-pyridin-2-ylethyl)spiro[cyclohexane-1 ,9 ^l -thioxanthene]-3 ¹ - sulfonamide 10',10'-dioxide;

2'-methyl-N-(2-pyridin-3-ylethyl)spiro[cyclohexane-1 ,9'-thioxanthene]-3'- sulfonamide 10',10'-dioxide;

2'-methyl-N-(2-pyridin-4-ylethyl)spiro[cyclohexane-1 ,9 ^l -thioxanthene]-3'- sulfonamide 10',10'-dioxide;

2'-methyl-N-(tetrahydro-2H-pyran-4-yl)spiro[cyclohexane-1 ,9'-thioxanthene]- 3'-sulfonamide 10', 10'-dioxide;

2'-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)spiro[cyclohe xane-1 ,9'- thioxanthene]-3'-sulfonamide 10', 10'-dioxide;

35

N^-cyanoethyO-Z-methylspiroIcyclohexane-I .S'-thioxanthenel-S'- sulfonamide 10',10'-dioxide;

N-(2-hydroxy-2-phenylethyl)-2'-methylspiro[cyclohexane-1 ,9'-thioxanthene]-3'- sulfonamide 10',10'-dioxide;

N-(2-hydroxy-1 -methyl-2-phenylethyl)-2'-nnethylspiro[cyclohexane-1 ,9'- thioxanthene]-3'-sulfonamide 10', 10'-dioxide;

N-(2-hydroxyethyl)-2 ^l -methylspiro[cyclohexane-1 ,9'-thioxanthene]-3'- sulfonamide 10',10'-dioxide; te/f-butyl 4-{[(2'-methyl-10 ¹ , 10'-dioxidospiro[cyclohexane-1 ,9'-thioxanthen]-3'- yl)sulfonyl]am ino}piperidine-1 -carboxylate

2'-methyl-N-piperidin-4-ylspiro[cyclohexan9-1 ,9'-thioxanthene]-3'-sulfonamid9 10',10'-dioxide;

3-[(4-{[(2'-methyl-10 ¹ , 10'-dioxidospiro[cyclohexane-1 ,9'-thioxanthen]-3'- yl)sulfonyl]amino}piρeridin-1-yl)sulfonyl]benzoic acid;

N-(trans-4-hydroxycyclohexyl)-2'-methylspiro[cyclohexane-1 ,9'-thioxanthene]- 3'-sulfonamide 10 ¹ , 10'-dioxide;

9,9-diethyl-2-methyl-N-(2-pyridin-2-ylethyl)-9H-thioxanth ene-3-sulfonamide 10,10-dioxide;

9,9-diethyl-2-methyl-N-(2-pyridin-3-ylethyl)-9H-thioxanth ene-3-sulfonamide 10,10-dioxide;

9,9-diethyl-2-methyl-N-(2-pyridin-4-ylethyl)-9H-thioxanth ene-3-sulfonamide 10,10-dioxide;

9,9-diethyl-2-methyl-N-(tetrahydro-2H-pyran-4-yl)-9H-thio xanthene-3- sulfonamide 10,10-dioxide;

9,9-diethyl-2-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9 H-thioxanthene-3- sulfonamide 10,10-dioxide;

N-(2-cyanoethyl)-9,9-diethyl-2-methyl-9H-thioxanthene-3-s ulfonamide 10,10- dioxide;

9,9-diethyl-N-(2-hydroxy-2-phenylethyl)-2-methyl-9H-thiox anthene-3- sulfonamide 10,10-dioxide;

9,9-diethyl-N-(2-hydroxy-1-methyl-2-phenylethyl)-2-methyl -9H-thioxanthene-3- sulfonamide 10,10-dioxide;

36

9,9-diethyl-N-(2-hydroxyethyl)-2-methyl-9H-thioxanthene-3 -sulfonamide 10,10-dioxide; te/t-butyl 4-{[(9,9-diethyl-2-methyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]am ino}piperidine-1 -carboxylate

9,9-diethyl-2-methyl-N-piperidin-4-yl-9H-thioxanthen©-3- sulfonamide 10,10- dioxide;

9,9-diethyl-N-[1-(2-hydroxyethyl)piperidin-4-yl]-2-methyl -9H-thioxanthene-3- sulfonamide 10,10-dioxide;

3-[(4-{[(9,9-diethyl-2-methyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]benzoic acid; te/t-butyl (4-{[(9,9-diethyl-2-methyl-10 ₁ 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]am ino}piperidin-1 -yl)acetate

(4-{[(9,9-diethyl-2-methyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1-yl)acetic acid;

9,9-diethyl-N-(trans-4-hydroxycyclohexyl)-2-methyl-9H-thi oxanthene-3- sulfonamide 10,10-dioxide; te/t-butyl 4-{[(2-chloro-6-fluoro-9,9-dimethyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]am ino}piperidine-1 -carboxylate

2-chloro-6-fluoro-9,9-dimethyl-N-piperidin-4-yl-9H-thioxa nthene-3-sulfonamide 10,10-dioxide;

2-(4-{[(2-chloro-6-fluoro-9,9-dimethyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]am ino}piperidin-1 -yl)acetam ide te/t-butyl (4-{[(2-chloro-6-fluoro-9,9-dimethyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]am ino}piperidin-1 -yl)acetate

(4-t[(2-chloro-6-fluoro-9,9-dimethyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1-yl)acetic acid;

3-[(4-{[(2-chloro-6-fluoro-9,9-dimethyl-10 ₁ 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]benzoic acid; te/t-butyl 4-({[6-fluoro-9,9-dimethyl-10 ₁ 10-dioxido-2-(trifluoromethyl)-9H- thioxanthen-3-yl]sulfonyl}am ino)piperidine-1 -carboxylate

6-f luoro-9, 9-d imethy l-N-piperid in-4-y l-2-(trif Iuoromethyl)-9H -thioxanthene-3- sulfonamide 10,10-dioxide;

37

^[4^{[6-fluoro-9,9-dimethyl-10, 10-dioxido-2-(trifluoromethyl)-9H-thioxanthen- 3-yl]sulfonyl}amino)piperidin-1 -yl]sulfonyl}benzoic acid;

6-fluoro-9,9-dimethyl-N-(2-pyridin-3-ylethyl)-2-(trifluor omethyl)-9H- thioxanthene-3-sulfonamide 10, 10-dioxide;

6-fluoro-9,9-dimethyl-N-(2-pyridin-4-ylethyl)-2-(trifluor onnethyl)-9H- thioxanthene-3-sulfonamide 10, 10-dioxide;

6-fluoro-9,9-dimethyl-N-(2-pyridin-3-ylethyl)-2-(trifluor omethoxy)-9H- thioxanthene-3-sulfonamide 10, 10-dioxide;

6-f luoro-9, 9-d im ethy l-N-piperid in-4-y l-2-(trif luoromethoxy)-9H-th ioxanthene-3- sulfonamide 10,10-dioxide;

2'-chloro-6'-fluoro-N-piperidin-4-ylspiro[cyclohexane-1 ,9 ^l -thioxanthene]-3'- sulfonamide 10',10'-dioxide;

2'-chloro-6'-fluoro-N-[1-(phenylsulfonyl)piperidin-4-yl]s piro[cyclohexane-1 ,9'- thioxanthene]-3'-sulfonamide 10', 10'-dioxide;

2'-chloro-6'-fluoro-N-[1-(pyridin-3-ylcarbonyl)piperidin-4-y l]spiro[cyclohexane- 1 ,9'-thioxanthene]-3'-sulfonamide 10 ¹ , 10'-dioxide;

2'-chloro-6 ^l -fluoro-N-(1-isonicotinoylpiperidin-4-yl)spiro[cyclohexane-1 ,9'- thioxanthene]-3'-sulfonamide 10', 10'-dioxide;

N-{4-[(4-{[(2'-chloro-6 ^t -fluoro-10', 10'-dioxidospiro[cyclohexane-1 ,9'- thioxanthen]-3'-yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]ph enyl}acetamide

4-(4-{[(2'-chloro-6 ^l -fluoro-10 ¹ , 10'-dioxidospiroIcyclohexane-i .θ'-thioxanthenl-S'- yl)sulfonyl]am ino}piperidin-1 -yl)-4-oxobutanoic acid;

5-(4-{[(2 ^l -chloro-6 ^l -fluoro-10 ¹ , 10'-dioxidospiro[cyclohexane-1.θ'-thioxanthenl-S ¹ - yl)sulfonyl]am ino}piperidin-1 -yl)-5-oxopentanoic acid;

4-{[(4-{[(2'-chloro-6'-fluoro-10' , 10'-dioxidospiro[cyclohexane-1 ,9'-thioxanthen]- 3'-yl)sulfonyl]amino}piperidin-1-yl)carbonothioyl]amino}benz oic acid;

3-{[(4-{[(2 ^I -chloro-6'-fluoro-10 ¹ , 10'-dioxidospiroIcydohexane-i ,9'-thioxanthen]- 3'-yl)sulfonyl]amino}piperidin-1-yl)carbonothioyl]amino}benz oic acid;

4-[(4-{[(2'-chloro-6 ^l -fluoro-10 ¹ , 10'-dioxidospiro[cyclohθxanθ-1 ,9'-thioxanthen]- 3'-yl)sulfonyl]amino}piperidin-1 -yl)sulfonyl]benzoic acid;

3-[(4-{[(2'-chloro-6 ^l -fluoro-10 ¹ , 10'-dioxidospiroIcyclohexane-i ,9'-thioxanthen]- 3'-yl)sulfonyl]amino}piperidin-1 -yl)sulfonyl]benzoic acid;

38

2-methyl-N-(2-phenylethyl)-10 ₁ 11 -dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

N-[2-(2-fluorophenyl)ethyl]-2-methyl-10,11 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

2-methyl-N-(2-pyridin-2-ylethyl)-10, 11 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

2-methyl-N-(2-pyridin-3-ylethyl)-10, 11 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

2-methyl-N-(2-pyridin-4-ylethyl)-10, 11 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

N-(2,3-dihydro-1 H-inden-2-yl)-2-methyl-10,11 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

N-cyclopentyl-2-methyl-i 0, 11 -dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5- dioxide;

2-methyl-N-(2-morpholin-4-ylethyl)-10, 11 -dihydrodibenzo[b,f]thiepine-3- sυlfonamide 5,5-dioxide;

2-methyl-N-(3-morpholin-4-ylpropyl)-10,11 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

2-methyl-N-(tetrahydro-2H-pyran-4-yl)-10, 11 -dihydrodibenzo[b,f]thiepine-3- sulfonamidθ 5,5-dioxide;

2-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-10,1 1- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

2-methyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

N-(2-hydroxy-2-phenylethyl)-2-methyl-10, 11 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

N-(2-hydroxy-1 -methyl-2-phenylethyl)-2-methy 1-10,1 1- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

N-(2-cyanoethyl)-2-methyl-10,11 -dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

2-methyl-N-piperidin-4-yl-10, 1 1 -dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

39

7-fluoro-2-isopropyl-N-(2-phenylethyl)-10,11 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

7-fluoro-N-[2-(2-fluorophenyl)ethyl]-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

7-fluoro-2-isopropyl-N-(2-pyridin-2-ylethyl)-10, 11 -dihydrodibenzo[b,f]thiepine- 3-sulfonamide 5,5-dioxide;

7-fluoro-2-isopropyl-N-(2-pyridin-3-ylethyl)-10, 11 -dihydrodibenzo[b,f]thiepine- 3-sulfonamide 5,5-dioxide;

7-fluoro-2-isopropyl-N-(2-pyridin-4-ylethyl)-10, 11 -dihydrodibenzo[b,f]thiepine- 3-sulfonamide 5,5-dioxide;

N-(2,3-dihydro-1 H-inden-2-yl)-7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

N-cyclopentyl-7-fluoro-2-isopropyl-10, 1 1 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

7-fluoro-2-isopropyl-N-(2-morpholin-4-ylethyl)-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

7-fluoro-2-isopropyl-N-(3-morpholin-4-ylpropyl)-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

7-f luoro-2-isopropyl-N-(tetrahydro-2H-pyran-4-yl)-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

7-fluoro-2-isopropyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-1 0,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

7-f luoro-2-isopropyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-10,1 1- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

7-fluoro-2-isopropyl-N-(3-phenylpropyl)-10,11 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

7-fluoro-2-isopropyl-N-(2-phenoxyethyl)-10, 11 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

N-benzyl-7-fluoro-2-isopropyl-10, 11 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

2-chloro-7-fluoro-N-(tetrahydro-2H-pyran-4-yl)-10,1 1- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

40

2-chloro-7-fluoro-N-(2-pyridin-4-ylethyl)-10, 1 1 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

2-chloro-7-fluoro-N-(2-pyridin-3-ylethyl)-10, 1 1 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide; te/f-butyl 4-{[(2-chloro-7-fluoro-5,5-dioxido-10, 11 -dihydrodibenzo[b,f]thiepin-3- yl)sulfonyl]am ino}piperidine-1 -carboxylate

2-chloro-7-f luoro-N-piperidin-4-yl-10,11 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

7-fluoro-N-piperidin-4-yl-2-(trifluoromethyl)-10,11 -dihydrodibenzo[b,f]thiepine- 3-sulfonamide 5,5-dioxide;

2,11 -di methyl-N-(2-phenylethyl)-10, 11 -dihyd rodibenzo[b, f]thiepi ne-3- sulfonamide 5,5-dioxide;

1 1 -ethyl-2-methyl-N-(2-pyridin-3-ylethyl)-10,11 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;

1 1 -butyl-2-methyl-N-(2-pyridin-3-ylethyl)-10,11 -dihydrodibenzo[b,f]thiepine-3- sυlfonamide 5,5-dioxide;

2-methyl-11 -propyl-N-(2-pyridin-3-ylethyl)-10, 11 -dihydrodibenzo[b,f]thiepine- 3-sulfonamidθ 5,5-dioxide;

1 1-isopropyl-2-methyl-N-(2-pyridin-3-ylethyl)-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;

2,11 -dimethyl-N-(2-pyridin-3-ylethyl)-10, 1 1 -dihydrodibenzo[b,f]thiepine-3- sυlfonamide 5,5-dioxide;

8-fluoro-3-methyl-N-(2-phenylethyl)phenoxathiin-2-sulfona m ide 10, 10-dioxide;

8-fluoro-3-methyl-N-(2-pyridin-2-ylethyl)phenoxathiin-2-s ulfonamide 10, 10- dioxide;

8-fluoro-3-methyl-N-(2-pyridin-3-ylethyl)phenoxathiin-2-s ulfonamide 10, 10- dioxide;

8-fluoro-3-methyl-N-(2-pyridin-4-ylethyl)phenoxathiin-2-s ulfonamide 10, 10- dioxide;

N-(2,3-dihydro-1 H-inden-2-yl)-8-fluoro-3-methylphenoxathiin-2-sulfonamide 10,10-dioxide;

N-cyclopentyl-δ-fluoro-S-methylphenoxathiin^-sulfonamide 10, 10-dioxide;

8-fluoro-3-methyl-N-(2-morpholin-4-ylethyl)phenoxathiin-2 -sulfonamide 10,10- dioxide;

8-fluoro-3-methyl-N-(3-morpholin-4-ylpropyl)phenoxathiin- 2-sulfonamide 10,10-dioxide;

8-fluoro-3-methyl-N-(tetrahydro-2H-pyran-4-yl)phenoxathiJ n-2-sulfonamide 10,10-dioxide;

8-fluoro-3-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)pheno xathiin-2- sulfonamide 10,10-dioxide;

8-fluoro-3-methyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]ph enoxathiin-2- sulfonamide 10,10-dioxide;

8-fluoro-N-[3-(1 H-imidazol-1-yl)propyl]-3-methylphenoxathiin-2 -sulfonamide 10,10-dioxide;

8-fluoro-3-methyl-N-(3-phenylpropyl)phenoxathiin-2-sulfon am ide 10, 10- dioxide;

N-benzyl-8-fluoro-3-methylphenoxathiin-2-sulfonamide 10, 10-dioxide;

N-[2-(4-chlorophenyl)ethyl]-8-fluoro-3-methylphenoxathiin -2-sulfonamide 10,10-dioxide;

8-fluoro-3-methyl-N-(pyridin-2-ylmethyl)phenoxathiin-2-su lfonamide 10, 10- dioxide;

8-fluoro-3-methyl-N-(pyridin-3-ylmethyl)phenoxathiin-2-su lfonamide 10, 10- dioxide;

8-fluoro-3-methyl-N-(pyridin-4-ylmethyl)phenoxathiin-2-su lfonamide 10, 10- dioxide;

8-fluoro-3-methyl-N-(2-pyrrolidin-1 -ylethyl)phenoxathiin-2-sulfonam ide 10, 10- dioxide;

N-cyclohexyl-δ-fluoro-S-methylphenoxathiin^-sulfonam ide 10, 10-dioxide;

3-fluoro-8-isopropyl-11 -oxo-N-(2-pyridin-2-ylethyl)-10,1 1- dihydrodibenzo[b,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide;

3-fluoro-8-isopropyl-11 -oxo-N-(2-pyridin-3-ylethyl)-10,1 1- dihydrodibenzo[b,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide;

3-fluoro-8-isopropyl-11 -oxo-N-(2-phenylethyl)-10,11- dihydrodibenzo[b,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide;

42

3-fluoro-8-isopropyl-11 -oxo-N-(tetrahydro-2H-pyran-4-yl)-10,1 1- dihydrodibenzo[b,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide; te/f-butyl 4-{[(3-fluoro-8-isopropyl-5,5-dioxido-11 -oxo-10,11- dihydrodibenzo[b,f][1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1 -carboxylate

3-fluoro-8-isopropyl-11 -oxo-N-piperidin-4-yl-10,11- dihydrodibenzo[b,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide;

3-fluoro-8-isopropyl-10-methyl-1 1 -oxo-N-piperidin-4-yl-10,11- dihydrodibenzo[b,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide;

10-ethyl-3-fluoro-8-isopropyl-11 -oxo-N-piperidin-4-yl-10,11- dihydrodibenzo[b,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide;

3-fluoro-8-isopropyl-N-piperidin-4-yl-10, 1 1 -dihydrodibenzo[b,f][1 ,4]thiazepine- 7-sulfonamide 5,5-dioxide;

3-f luoro-8-isopropyl-10-methyl-N-piperidin-4-yl-10,11- dihydrodibenzo[b,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide;

8-isopropyl-11 -oxo-N-(2-pyridin-2-ylethyl)-10,11- dihydrodibenzo[b,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide;

8-isopropyl-11 -oxo-N-(2-phenylethyl)-10,11 - dihydrodibenzo[b,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide;

8-isopropyl-11 -oxo-N-(tetrahydro-2H-pyran-4-yl)-10,11 - dihydrodibenzo[b,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide; tert-butyl-4-{[(8-isopropyl-5,5-dioxido-11 -oxo-10, 11 -dihydrodibenzo [b,f][1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1 -carboxylate; and pharmaceutically acceptable salts thereof.

[0149] In certain embodiments of the compounds of formula I, the pharmaceutically acceptable salt is a hydrochloride salt.

[0150] Compounds of formula I 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, leiomyoma, acute

43

myeloid leukemia, wound healing, prostate cancer, autoimmune inflammatory disorders, such as Graves ophthalmopathy, and combinations thereof.

[0151] 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 lor a pharmaceutically acceptable salt thereof to a patient suspected to suffer from such a malady.

[0152] In other embodiments, the invention relates to compositions comprising at least one compound of formula I, 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 I.

[0153] In other embodiments, the invention relates to a process for the preparation of a compound of of formula I: ^{0 R I I ^ ^^ H}

I or a pharmaceutically acceptable salt thereof; wherein:

R ¹ is H, halo, alkyl, alkoxy, alkylamino, alkylthio, dialkylamino, aryl, aryloxy, arylalkyl, arylthio, arylsulfonyl, heteroaryl, carboxyl, cyano, perfluoroalkyl, or perfluoroalkoxy, wherein any aryl or heteroaryl portion of R ₂ may be optionally substituted with 1 to 5 substituents, selected independently at each occurrence from the group consisting of alkyl, halo, carboxyl, aryl, alkoxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, alkylcarbonyl, aminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl,

44

dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl;

R ² is halo, alkyl, alkoxy, alky lam ino, alkylthio, dialkylamino, arγl, aryloxy, arylalkyl, arylthio, arylsulfonyl, heteroaryl, carboxyl, cyano, perfluoroalkyl, or perfluoroalkoxy, wherein any aryl or heteroaryl portion of R ₂ may be optionally substituted with 1 to 5 substituents, selected independently at each occurrence from the group consisting of alkyl, halo, carboxyl, aryl, alkoxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, alkylcarbonyl, aminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl;

R ₃ is an optionally substituted alkyl, cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, heteroarylalkyl, alkylaryl, alkylheteroaryl, alkenyl, alkynyl, fused cycloalkylaryl, fused heterocycloalkylaryl, cycloalkylcarbonyl, or heterocycloalkylcarbonyl group;wherein the alkyl, cycloalkyl, alkylheterocycloalkyl, heteroarylalkyl, alkylaryl, alkylheteroaryl, alkenyl, alkynyl, fused cycloalkylaryl, fused heterocycloalkylaryl, cycloalkylcarbonyl, and heterocycloalkylcarbonyl groups of R ₃ may be, independently, optionally substituted with 1 to 5 substituents selected from the group consisting of 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; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the alkyl groups of R ₃ may be, independently, optionally substituted with 1 to 5 substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, spirocycloalkyl, perfluoroalkyl, haloalkyl,

45

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, heteroarylam inocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfonylarylsulfonyl, carboxyarylsulfonyl, nitro, amino, dialkylamino, alky lcarbony lam ino, alkylsulfonylamino, carboxyarylsulfonylamino, hydroxy, carboxy, sulfonamide, alkylthio, halogen, cyano, guanidiπe, and oxo, and the nitrogen atoms in the heteroaryl substituents may be optionally substituted with an oxygen atom; wherein the heterocycloalkyl groups of R ₃ 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, alky lam ide, 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,

46

alkoxycarbonylalkylaminothiocarbonyl, alkylthiocarbonylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylaminoarylsulfonyl, and heteroarylsulfonyl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the heterocycloalkyl groups of R ₃ may be independently, optionally substituted with 1 to 5 substituents selected from the group consisting of 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, heteroarylam inocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfonylarylsulfonyl, carboxyarylsulfonyl, nitro, amino, dialkylamino, alky lcarbony lam ino, alkylsulfonylamino, carboxyarylsulfonylamino, hydroxy, carboxy, sulfonamide, alkylthio, halo, cyano, guanidine, and oxo, and the nitrogen atoms in the heteroaryl substituents may be optionally substituted with an oxygen atom; wherein the amino substituents on the alkyl groups of R ₃ may be, independently, optionally substituted with 1 or 2 substituents selected from the group consisting of alkyl, hydroxyalkyl, carboxyalkyl, cycloalkyl, alkoxycarbonylalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylcarbonyl, cycloalkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkoxycarbonylalkylam inocarbonyl, carboxyalkylcarbonyl, carboxyalkylam inocarbonyl, carboxyalkylcarbonyl, heterocycloalkylam inocarbonyl, arylaminocarbonyl, arylcarbonyl, heteroarylaminocarbonyl, heterocycloalkylcarbonyl, arylaminothiocarbonyl, heteroarylam i noth iocarbony I , heterocycloalkylam inocarbonyl,

47

heterocycloalkylthiocarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkoxythiocarbonyl, and aryloxythiocarbonyl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the amino substituents on the alkyl groups of R ₃ 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, heteroarylam inocarbonyl, 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.

R ⁴ is H or C ₁ -C ₄ straight or branched alkyl;

R ⁵ is, independently at each occurrence, H or Ci-C ₄ straight or branched alkyl; or both R ⁵ groups, together with the carbon atom through which they are attached form a Cs-Ce spirocycloalkyl; and

X is -O-, -(NR ⁴ )-, -S-, -[C(R ⁵ J ₂ ]- -(CH ₂ -CHR ⁴ )-, -(C=O)-, or -(C=O)- NR ⁴ ;

the process comprising: contacting a compound of formula IA with -NHR ³ :

48

wherein the compound of formula I is formed.

[0154] In another embodiment, wherein X is -(CH ₂ -CHR ⁴ )-, the compound of formula IA is formed by:

(a) contacting a compound of formula IB:

,halo

R ¹

IB with a compound of formula IC:

HS R ²

IC to form a compound of formula ID:

ID;

(b) contacting the compound of formula ID with an acid to form a compound of formula IE:

IE;

(ci) if R ⁴ is not H, contacting the compound of formula IE with a lithium or

49

magnesium halide-activated R ⁴ group to form a compound of formula IEE:

IEE;

(cii) reducing the compound of formula IE or IEE with a reducing agent to form a compound of formula IG:

λ r\

IG;

(d) oxidizing the compound of formula IG with an oxidizing agent to form the compound of formula IH:

R ¹ —

IH; and (e) reacting the compound of formula IH with chlorosulfonic acid to form the compound of formula IA.

[0155] In another embodiment, wherein X is -[C(R ⁵ ) ₂ ]-, the compound of formula IA is formed by:

(a) contacting a compound of formula IJ:

R ¹

IJ with a compound of formula IC:

HS IC to form a compound of formula IK:

50

R ²

IK;

(b) contacting the compound of formula IK with an acid to form a compound of formula IL:

(c) reducing the compound of formula IL with a reducing agent to form a compound of formula IM:

IM

(d) oxidizing the compound of formula IM with an oxidizing agent to form a compound of formula IN:

IN

(e) if R ⁵ is not H, contacting the compound of formula IN with a base and an activated R ⁵ group, wherein each R ⁵ group is the same or different, to form a compound of formula IH:

R ¹ ^ x R ² IH; and (f) reacting the compound of formula IH or IN with chlorosulfonic acid to form the compound of formula IA.

[0156] In another embodiment, wherein X is -(CH2-CH2)- and R ² is -CF3, the compound of formula IA is formed by:

(a) contacting a compound of formula IB with 4-chlorobenzenethiol:

HO ₂ C

A^halo

R ¹

IB to form a compound of formula IO:

10;

(b) contacting the compound of formula IO with an acid to form a compound of formula IP:

IP;

(c) reducing the compound of formula IP with a reducing agent to form a compound of formula IQ:

IQ;

(d) oxidizing the compound of formula IQ with an oxidizing agent to form the compound of formula IR:

^R1 4 K

IR;

(e) reacting the compound of formula IR with difluorobromomethane to form a compound of formula IS:

52

Si_ϋ_ < I l

X CF ₃

IS

(e) recting the compound of formula IS with a nitrating agent to form a compound of formula IT:

IT;

(f) reducing the compound of formula IT to form a compound of formula IV:

R ¹ -^

IV; and (g) reacting the compound of formula IV with SO ₂ gas and CuCb to form the compound of formula IA.

[0157] In another embodiment, wherein X is -(C=O)-NR ⁴ , the compound of formula IA is formed by:

(a) contacting a compound of formula IJ:

halo

R ¹

IJ with a compound of formula IC:

HS R ²

IC to form a compound of formula IK:

53

R ^{1 R}

IK;

(b) contacting the compound of formula IK with an acid to form a compound of formula IL:

(c) oxidizing the compound of formula IL with an oxidizing agent to form a compound of formula IW:

O

IW;

(d) reacting the compound of formula IW with sodium azide and sulfuric acid to form a compound of formula IX:

IX; and (e) reacting the compound of formula IX with chlorosulfonic acid to form the compound of formula IA.

[0158] In a more particular embodiment of any of the foregoing processes for forming the compound of formula IA ₁ the acid is polyphosphoric acid or sulfuric acid. Alternatively, the reducing agent is sodium borohydride or triethylsilane. Alternatively, the oxidizing agent is oxone or hydrogen peroxide and acetic acid. [0159] In another embodiment, wherein X is O, the compound of formula IA is formed by: contacting a compound of formula IY with chlorosulfonic acid to form a

54

mixture and heating the mixture:

IY wherein the compound of formula IA is formed.

[0160] In another embodiment, wherein, X is -[C(R ⁵ )2]- in the compound of formula I; the process further comprises reacting the compound of formula I with potassium permanganate to form a compound of formula I wherein X is -(C=O)-. [0161] In other embodiments, each of the above process steps can be performed in isolation. Alternative embodiments include compounds comprising any one of the intermediates in the above process (e.g. IA-IY).

[0162] Certain of the compounds of formula I 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 I, 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.

[0163] 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

55

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 a/., Enantiomers,_Racemates and Resolutions (Wiley Interscience, New York, 1981 ); Wilen, S.H., et a/., 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.

[0164] The following synthetic schemes are designed to illustrate, but not limit, general procedures for the preparation of compounds of formula I. The reagents used can be either commercially obtained or can be prepared by standard procedures described in the literature. It is intended that the scope of this invention will cover all isomers (enantiomeric and diastereomeric) and all mixtures, including but not limited to racemic mixtures. The isomeric forms of the compounds of this invention may be separated or resolved using methods known to those skilled in the art or by synthetic methods that are stereospecific or asymmetric.

[0165] The synthetic schemes (Schemes 1 to 7) are designed to illustrate, but not limit, the general procedures for the preparation of compounds of formula I. The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature.

56

Scheme 1

[0166] In Scheme 1, step i, o-halogen substituted benzoic acid (2), either commercially available or known in the literature, and a benzenethiol (3) wherein, R ¹ and R ² are herein before defined is reacted using copper as a catalyst at reflux temperature to afford the couple thioether (4). Cyclization (step ii) to the ketone (5) was performed with either polyphosphoric acid or concentrated sulfuric acid according to literature procedures and as described herein. Reduction with borohydride afforded 6, which was oxidized to the corresponding sulfone using either oxone or hydrogen peroxide and glacial acetic acid to produce 7. Compound 7 could be alkylated using sodium hydride and an alkyl iodide or diiodoalkane to afford 8. Chlorosulfonation could be performed on either 7 or 8 to produce compounds 9. Treatment of 9 with various amines led to the desired target molecules (1). Where R ³ and R ⁴ are hydrogen, compound 1 could be further oxidized with potassium permanganate to afford the ketone derivatives.

57

Scheme 2

CO ₂ H

vii

[0167] A similar synthetic strategy is employed in Scheme 2 to afford the corresponding homologs (1). Cyclization of 4 to 5 was performed using

58

polyphosphoric acid. In Scheme 3, an alkyl lithium or grignard reagent was reacted with intermediate 5 followed by reduction with triethylsilane to afford 10 which was converted to the target molecules (i.e., 12) using in a similar fashion as described in Scheme 1.

Scheme 4

[0168] Scheme 4 describes the route employed to prepare the trifluoromethyl analog. Intermediate 7 is nitrated (step x) followed by the introduction of the trifluoromethyl group to afford 14. In step xii, reduction with palladium on carbon followed by diazotization of the anilinium hydrochloride salt under acidic conditions with sodium nitrite, followed by sulfonylation, led to sulfonyl chloride 8. Treatment of the appropriate amines gave the target molecules 1.

59

Scheme S

16

18

[0169] Shown in Scheme 5, an aryl ether 16 was treated with chlorosulfonic acid and heated to afford the cyclized product 18 which is treated with the appropriate amines to produce 1 (step vii). In Scheme 6, the known compound 19 was treated with sodium azide and sulfuric acid to form a mixture of amides with were further reacted to afford the sulfonyl chloride 22. Treatment of 22 with the appropriate amine gave the desired sulfonamide.

Scheme 6

xiv

vii

23

60

Scheme 7

BOC BOC

XV

25 R = Me, Et xvi HCI

^. κ> ' /-"NH HCI

) 0

27

[0170] In Scheme 7, compound 24 could be deprotected with trifluoroacetic acid to afford 26. Compound 24 was also alkylated using sodium hydride and an alkyl halide to produce 25, which was deprotected to afforded the final target molecules 27.

[0171] i. K ₂ CO ₃ , Cu; ii. H ₂ SO ₄ or P ₂ O ₅ ϊϊϊ BH ₃ ; iv. Oxone or H ₂ O ₂ /AcOH ; v. Chlorosulfonic acid; vi. Rl, NaH; vii. Amine, DCM; viii. Mn ₂ O; ix. Et ₃ SiH, TFAA; x. NaNO ₂ , HCI, AcOH; xi.Cu, C ₁ Br ₂ F ₂ C; xii. H ₂ , Pd/C; xiii. CuCI ₂ , SO ₂ (g) xiii. RLi or RMgX xiv. NaN ₃ , H ₂ SO ₄ ; xv. NaH, Rl; xvi. TFA ₁ CH ₂ CI ₂

[0172] In certain embodiments, the invention relates to compositions comprising at least one compound of formula I, 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 Remington's 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.

[0173] The compounds of formula I 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.

[0174] 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.

62

The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0175] 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.

[0176] The compounds of formula lean 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 lean be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of formula lean also be administered transdermal^ 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 skin, 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.

[0177] 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, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a

63

capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

[0178] 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 lare 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, parenteral^, 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.

[0179] In certain embodiments, the present invention is directed to prodrugs of compounds of formula I. 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 I. 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 al., 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.

EXAMPLES

64

[0180] 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.

Example 1 : 2-Methyl-N-(2-phenylethyl)-9H-thioxanthene-3-sulfonamide 10,10- dioxide

Step 1. 2-[(4-Methylphenyl)thio]benzoic acid

CO ₂ H

[0181] A mixture of 2-iodobenzoic acid (60.4 g, 0.243 mol), copper (2.3 g), potassium hydroxide (60 g) and benzenethiol (36.2 g, 0.29 mol) in water (700 ml_) was allowed to reflux for 6 h. The reaction mixture was filtered and the filtrate acidified and the white precipitate was filtered and triturated with methanol 920OmL) to afford 55.7 g (94%) of the title compound.

MS m/z 243;

HRMS: calculated for Ci ₄ Hi ₂ O ₂ S + H+, 245.06308; found (ESI, [M+H]+), 245.062

Step 2. 2 Methyl-9H-thioxanthen-9-one

65

[0182] A mixture of 2-(p-tolythio)benzoic acid (5 g, 20.5 mmol) and concentrated sulfuric acid (35 ml_) was heated at 100 ⁰ C. After 1 hour the reaction was complete and was allowed to cool to room temperature and poured into 200 ml_ of ice water. The solid was filtered and stirred for 10 min with 1 N NaOH at 50 C ₁ then again filtered, and washed with water (100 ml_). The solid organics were dissolved in ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the solid was recrystallized from warm ethyl acetate to afford 2.56 g of the desired product as a yellow solid. Another 1.1 g of product was isolated from the mother liquor upon trituration. Total yield: 3.39 g (79.7 %).

[0183] MS (ES) m/z 227 λ ;

HRMS: calculated for Ci ₄ H ₁₀ OS + H+, 227.05251 ; found (ESI, [M+H] ⁺ ), 227.0562

Step 3. 2-Methyl-9H-thioxanthene

[0184] To a solution of 2 methyl-9H-thioxanthen-9-one (3.3 g, 14.6 mmol) in tetrahydrofuran (30 ml_) was syringed 32 ml_ of 1.0 M borohydride in tetrahydrofuran over 10 minutes. The reaction was complete in 45 min and was cooled to 0 ⁰ C whereby water (20 ml_) was slowly added over 15 minutes. The solvent was removed under vacuum and the residue was washed with ethyl acetate (2x100 ml_), dried over anhydrous sodium sulfate and the solid was dissolved in a small amount

66

of ethyl acetate. Purification by column chromatography afforded 3.28 g (100 %) the desired product as a white solid.

[0185] MS (ES) m/z 213.1 ;

HRMS: calculated for Ci ₄ Hi ₂ S, 212.06597; found (El, M+.), 212.0703

Step 4. 2-Methyl-9H-thioxanthene-10, 10-dioxide

[0186] To a suspension of 2-methyl-9H-thioxanthene (2 g, 13.6 mmol) in methanol (100 ml_) was added a solution of oxone (25.2 g, 41 mmol) in water (120 ml_). The reaction was allowed to stir for 18 hours after which another 8 g of oxone was added. The reaction was heated to 60 C for one hour and stirred at room temperature overnight upon which the reaction was complete. The methanol was evaporated and the mixture dissolved in water and extracted with ethyl acetate (2 x 300 ml_), washed with brine, dried over anhydrous sodium sulfate and the solvent removed. The solid was dissolved in methylene chloride and the solvent slowly removed while crystals were formed to afford pure product. The mother liquor was concentrated to afford a total of 3 batches of product. Total yield: 3.13 g (94%).

MS (ES) m/z 245.0;

HRMS: calculated for Ci ₄ Hi ₂ O ₂ S + H+, 245.06308; found (ESI, [M+H] ⁺ ), 245.0623

Step 5. 2-Methyl-9H-thioxanthene-3-sulfonyl chloride-10,10-dioxide

67

[0187] To a solution of 2-methyl-9H-thioxanthene-10, 10-dioxide (1.88 g, 7.7 mmol) in dichloroethane (50 ml_) was added chlorosulfonic acid (1.28 ml_). The reaction was heated to 90 C under nitrogen for 4 hours and then poured into 150 m L of water. The mixture was extracted with ethyl acetate (2 x 200 ml_), dried over anhydrous sodium sulfate, filtered, and the solvent removed under vacuum. [0188] The solid was triturated with ether to afford 1.83 g (69.5 %) of the desired product as a pinkish solid.

Step 6. 2-Methyl-N-(2-phenylethyl)-9H-thioxanthene-3-sulfonamide 10,10-dioxide

[0189] To a solution of 2-methyl-9H-thioxanthene-3-sulfonyl chloride-10, 10-dioxide (250 mg, 0.73 mmol) in methylene chloride (10 ml.) and acetonitrile (1 mL) was added phenethylamine (0.132 g, 1.1 mmol) followed by Hunigs base (284 mg, 2.1 mmol). The reacton was stirred for 18 hours and poured into 1 N ammonium chloride and extracted with ethyl acetate (2x10OmL), dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum and the yellow oil purified by chromatography on a ISCO (ethyl acetate/hexanes) to afford 90 mg (30 %) of the desired product as a white solid: mp=166-168 C.

MS (ES) m/z 426.1 ;

HRMS: calculated for C ₂₂ H _2I NO ₄ S ₂ + H+, 428.09848; found (ESI-FTMS ₁ [M+H] ^{1 t} ), 428.0988

Example 2: 2-Methyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulfonami de 10,10-dioxide

68

[0190] Step 1. To a solution of 2-methyl-9H-thioxanthene-3-sulfonyl chloride- 10,10-dioxide (500 mg, 1.46 mmol) in methylene chloride (5 mL) was added 3-(2- aminoethyl)pyridine (267 mg, 2.2 mmol) followed by Hunigs base (567 mg, 4.4 mmol). The reacton was stirred for 1 hour and poured into water (100 mL) and extracted with ethyl acetate (2x10OmL) ₁ dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum and the yellow oil purified by chromatography on an ISCO (10% methanol/ethyl acetate) to afford 153 mg (24.4 %) of the desired product as a white solid: mp=192-194°C.

MS (ES) m/z 427.0;

HRMS: calculated for C _2I H ₂₀ N ₂ O ₄ S ₂ + H+, 429.09372; found (ESI-FTMS, [M+H] ^{1 *} ), 429.0941

Example 3: 2-Methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H-thioxanthene- 3- sulfonamide 10,10- dioxide

^^

[0191] To a solution of 2-methyl-9H-thioxanthene-3-sulfonyl chloride-10, 10-dioxide (500 mg, 1.46 mmol) in methylene chloride (20 mL) was added 4-aminomethyl pyran (252 mg, 2.2 mmol) followed by Hunigs base (379 mg, 2.9 mmol). The reaction was stirred for 30 min and poured into water (100 mL) and extracted with methylene chloride (2x150 mL), dried over anhydrous sodium sulfate and filtered. The crude product was dissolved in methylene chloride/methanol and filtered through a short plug of silica (ethyl acetate/methanol). The solvent was removed and the solid washed was ether to afford 428 mg (69.6 %) of the desired product as a white solid: mp=180-181°C.

[0192] Anal. For C ₂₀ H ₂₃ NO ₅ S ₂ 0.33 H ₂ O calculated: C, 56.19; H, 5.58; N ₁ 3.28 Found: C ₁ 56.07; H ₁ 5.06; N, 2.91.

69

MS (ES) m/z 420.0;

HRMS: calculated for C ₂₀ H ₂₃ NO ₅ S ₂ + H+, 422.10904; found (ESI ₁ [M+H] ⁺ ), 422.1 101

Example 4: 2-Methyl-9-oxo-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H- thioxanthene-3-sulfonamide 10,10-dioxide

[0193] A mixture of 2-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H-thioxanthene- 3-sulfonamide 10,10- dioxide (223 mg, 0.53 mmol), KMnθ ₄ and montmosillonite K10 (previously ground up) in a small amount of methylene chloride was allowed to stir overnight. The reaction was filtered through silica and then worked up with ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Upon evaporation a yellow foamy oil formed that was washed with ethyl acetate to for a yellowish white solid (75 mg, 33 %); mp= 204- 205 C.

MS (ESI) m/z 436;

HRMS: calculated for C ₂₀ H _2I NO ₆ S ₂ + H+, 436.08831 ; found (ESI, [M+H] ⁺ ), 436.0884

Example 5: 6-Fluoro-2-isopropyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene -3- sulfonamide 10,10-dioxide

Step 1. 4-Fluoro-2-[(4-isopropylphenyl)thio]benzoic acid

70

CO ₂ H

[0194] A mixture of 2-bromo-4-fluoro-benzoic acid (6.5 g, 29.7 mmol), 4-isopropyl benzenethiol (4.97 g, 32.6 mmol), potassium carbonate (8.2 g, 59.4 mmol) and copper powder (490 mg, 0.26 mmol) in anhydrous dimethylformamide (16 ml_) was heated to 15O ⁰ C for 2.5 h. The reaction was poured into water (300 mL) and neutralized with HCI, then extracted with methylene chloride (2 x 300 mL). The organic layers were dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum. The crude product was washed with methanol to afford a yellowish solid (3.0 g). The mother liquor was concentrated and allowed to stand overnight to afford another batch of desired product (1.61 g). Total yield: 4.61 g (53.4 %). A sample was recrystallized from ethanol; mp= 197-198 C.

[0195] MS (ES) m/z 289.1 ;

HRMS: calculated for Ci ₆ Hi ₅ FO ₂ S + H+, 291.08495; found (ESI, [M+H] ⁺ ), 291.0835

Step 2. 6-Fluoro-2-isopropyl-9H-thioxanthen-9-one

CO ₂ H

[0196] A mixture of 4-fluoro-2-[(4-isopropylphenyl)thio]benzoic acid (4.4 g, 15.1 mmol) and concentrated sulfuric acid was heated to 100 ⁰ C for 40 minutes. The reaction was poured into cold water (100 m L) and extracted with methylene chloride (2x150 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated to a solid. The solid was triturated (ether/hexanes) to afford 1.34 g of

desired product. Several batches were afforded by trituration of the mother liquors to afford a total of 3.64 g (88.2 %) of desired product; mp=106-108°C. MS (ES) m/z 273.1 ;

HRMS: calculated for Ci ₆ H ₁₃ FOS + H+, 273.07439; found (ESI, [M+H] ⁺ ), 273.0752

Step 3. 6-Fluoro-2-isopropyl-9H-thioxanthene

[0197] To a solution of 6-fluoro-2-isopropyl-9H-thioxanthen-9-one (3.5 g, 12.8 mmol) in dry tetrahydrofuran (20 ml_) at room temperature was slowly added 24 .1 ml_ of a 1 M solution of BH ₃ in THF. After an hour, the reaction was quenched by the slow addition of water (50 ml_) and extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The solid was passed through a short column of silica to afford 3.25 g (97.9 %) of desired product as an off white solid. A sample was recrystallized from ethyl acetate: mp 99-100 ⁰ C. MS (El) m/z 258

Step 4. 6-Fluoro-2-isopropyl-9H-thioxanthene 10,10-dioxide

[0198] A mixture of 6-fluoro-2-isopropyl-9H-thioxanthene (2.99 g, 11.57 mmol), glacial acetic acid (15 ml_) and 30 % hydrogen peroxide (10 ml_) was heated to reflux for 1.5 h. The reaction was poured into water (150 ml.) and extracted into ethyl acetate (250 ml_). The organic layer was washed with 5 % sodium bicarbonate (200 ml_), followed by water, brine, and dried over anhydrous magnesium sulfate.

72

Concentration of the solvent followed by chromatography (20 % ethyl acetate/hexanes) afforded 3.19 g (95 %) of desired product. MS (ES) m/z 291.0

Step 5. 6-Fluoro-2-isopropyl-9H-thioxanthene 3-sulfonyl 10,10-dioxide

[0199] To a solution of 6-fluoro-2-isopropyl-9H-thioxanthene 10,10-dioxide (900 mg, 3.1 mmol) in dichloroethane (25 ml_) was added 0.43 ml_ of chlorosulfonic acid (6.5 mmol) and heated to 100 ⁰ C for 3 hours afterwhich time another 0.18 ml. of chlorosulfonic acid was added. After a total of 5 hours of heating, the reaction was allowed to cool to room temperature and diluted with ethyl acetate (150 ml_) and washed with water (80 ml_). The aqueous layer was washed again with ethyl acetate (100 ml_) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford a light tan solid. Trituration of the solid with ether afforded 560 mg (46.4 %) of a light tan solid.

Step 6. 6-Fluoro-2-isopropyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene -3-sulfonamide

10,10-dioxide

[0200] To a mixture of 6-fluoro-2-isopropyl-9H-thioxanthene 3-sulfonyl 10,10- dioxide (250 mg, 0.64 mmol) in anhydrous methylene chloride (5 mL) was added 3- (2-aminoethyl) pyridine (1.2 g, 9.6 mmol) followed by triethylamine (3 equiv) at room temperature. After 10 min the reaction was diluted with ethyl acetate (100 mL) and water (50 mL) and the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent removed under vacuum. The crude product was purified

73

using the ISCO (0%-20 % methanol/methylene chloride) to afford 219 mg (68.7 %) of desired product as a solid.

[0201] MS (ES) m/z 473.1 ;

HRMS: calculated for C ₂₃ H ₂₃ FN ₂ O ₄ S ₂ + H+, 475.11560; found (ESI ₁ [M+H] ⁺ ), 475.1027

Example 6: 6-Fluoro-2-isopropyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H- thioxanthene-3- sulfonamide 10,10-dioxide

[0202] To a suspension of 6-fluoro-2-isopropyl-9H-thioxanthene 3-sulfonyl 10,10- dioxide (270 mg, 0.69 mmol) in anhydrous methylene chloride (6 ml.) was added tetrahydro-2H-pyran-4-methylamine (160 mg, 1.39 mmol) followed by triethylamine (210 mg, 2.1 mmol, 3 equiv) at room temperature. After 10 min the reaction was diluted with ethyl acetate (150 ml_) and water (100 ml.) and the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent removed under vacuum. The crude product was purified using the ISCO (0%-10 % methanol/methylene chloride) to afford 230 mg (71.2 %) of desired product as a solid.

[0203] MS (ES) m/z 466.1 ;

HRMS: calculated for C ₂₂ H ₂₆ FNOsS ₂ + H+, 468.13092; found (ESI, [M+H] ⁺ ), 468.13

Example 7: 2,9,9-Trimethyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3- sulfonamide 10,10- dioxide.

74

Step 1. 6-Fluoro-2-isopropyl-9,9-dimethyl-9H-thioxanthene 10,10-dioxide

[0204] To a suspension of 60 % sodium hydride in dry DMF (20 ml.) was added 6- fluoro-2-isopropyl-9H-thioxanthene 10,10-dioxide (2.1 g, 7.23 mmol) at room temperature and allowed to stir for 15 minutes. Methyl iodide (4.4 ml_, 10.2 g, 72.3 mmol) was added and the reaction was stirred for 30 min and poured into water (100 ml.) and extracted with ethyl acetate (2x120 ml_). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to anoil. Purification by chromatography (10 % ethyl acetate/hexanes) afforded 890 mg (39 %) of the desired product as a solid: mp=105-106°C; MS (ES) m/z 319.0.

Step 2. 6-Fluoro-2-isopropyl-9,9-dimethyl-9H-thioxanthene 3-sulfonyl chloride 10,10- dioxide

[0205] A mixture of 6-fluoro-2-isopropyl-9,9-dimethyl-9H-thioxanthene 10,10- dioxide (840 mg, 2.64 mmol) and chlorosulfonic acid (1.2 ml_) in 25 ml_ of dichloroethane was heated to 100 ⁰ C for 8 h. The reaction was allowed to cool to room temperature and poured into ethyl acetate (150 ml_), washed with water, dried

75

over anhydrous magnesium sulfate and concentrated to a solid. The solid was washed with ether to afford 680 mg (61.8 %) of a light tan solid.

Step 3. 2,9 _I 9-Trimethyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulfon amide 10,10- dioxide.

[0206] A solution of 3-(2-aminoethyl)pyridine (63 mg, 0.5 mmol), and thethylamine (104 mg, 1 mmol) in methylene chloride (5 ml.) was added to 6-fluoro-2-isoρropyl- 9,9-dimethyl-9H-thioxanthene 3-sulfonyl chloride 10,10-dioxide (143 mg, 0.34 mmol) at room temperature. The reaction was stirred for 30 min then diluted with ethyl acetate (80 ml_) and washed with 5 % sodium bicarbonate, brine, dried over anhydrous sodium sulfate and concentrated. Chromatography using the ISCO (0%- 15 % methanol/methylene chloride) afforded the desired product as a solid: mp=88- 92 ⁰ C.

[0207] MS (ES) m/z 503.1 ;

HRMS: calculated for C ₂₅ H ₂₇ FN ₂ O ₄ S ₂ + H+, 503.14690; found (ESI ₁ [M+H]*), 503.1435

Example 8: 6-Fluoro-2-isopropyl-9,9-dimethyl-N-(tetrahydro-2H-pyran-4-y l)-9H- thioxanthene- 3-sulfonamide 10,10-dioxide

76

[0208] 6-Fluoro-2-isopropyl-9,9-dimethyl-N-(tetrahydro-2H-pyran-4-y l)-9H- thioxanthene- 3-sulfonamide 10,10-dioxide was prepared in a similar manner as described above in Example 7 using 4-aminopyran in 65% yield; mp 219-22O ⁰ C.

[0209] MS (ES) m/z 482.0;

HRMS: calculated for C ₂₃ H ₂₈ FNO ₅ S ₂ + H+, 482.14657; found (ESI, [M+H] ⁺ ), 482.1469

Example 9: 6-Fluoro-2-isopropyl-9,9-dimethyl-N-(tetrahydro-2H-pyran-4- ylmethyl)-9H- thioxanthene-3-sulf on amide 10,10-dioxide.

The title compound was prepared in a similar fashion as Example 7 using tetrahydro- 2H-pyran-4-methylamine in 43 % yield: mp=206-207°C.

[0210] MS (ES) m/z 496.1 ;

HRMS: calculated for C ₂₄ H ₃₀ FNO ₅ S ₂ + H+, 496.16222; found (ESI, [M+H] ^* ), 496.1643

Example 10: 6-Fluoro-2-isopropyl-9,9-dimethyl-N-(2-pyridin-4-ylethyl)-9H - thioxanthene-3- sulfonamide 10,10-dioxide.

[0211] The title compound was prepared in a similar fashion as Example 7 using A- (2-aminoethyl) pyridine in 55 % yield: mp=195-196°C.

77

MS (ES) m/z 503.0;

HRMS: calculated for C ₂₅ H ₂₇ FN ₂ O ₄ S ₂ + H+, 503.14690; found (ESI, [M+H] ⁺ ), 503.1485

Example 11 : 2,9,9-Trimethyl-λ/-(2-pyridin-3-ylethyl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide

Step 1. 2,9,9-Trimethyl-9H-thioxanthene 10,10-dioxide

[0212] The title compound was prepared according to Example 7 (step 1 ) using 2- methyl-9H-thioxanthene 10,10-dioxide (488 mg, 2 mmol) and methyl iodide (2.83 g, 20 mmol) to afford after chromatography 340 mg (62.5 %) of desired product as a white solid.

[0213] MS (ES) m/z 273.1 ;

HRMS: calculated for Ci ₆ H ₁₆ O ₂ S + H+, 273.09438; found (ESI, [M+H] ⁺ ), 273.0952

Step 2. 2,9,9-Trimethyl-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide

78

[0214] The title compound was prepared according to Example 1 (step 5) using 2,9,9-trimethyl-9H-thioxanthene -10,10-dioxide (272 mg, 1 mmol) and chlorosulfonic acid (0.30 mL) to afford 350 mg (95 %) of desired product as a light brown solid.

Step 3. 2,9 ₁ 9-Trimethyl-λ/-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulf onamide 10,10- dioxide.

[0215] To a solution of 2,9,9-trimethyl-9H-thioxanthene-3-sulfonyl chloride 10,10- dioxide (150 mg, 0.405 mmol) in anhydrous methylene chloride (4 mL) was added 3- (2-aminoethyl)pyridine (74 mg, 0.608 mmol) followed by N.N-diisopropylethylamine (157 mg, 1.2 mmol, 3 equiv) at room temperature. The reaction was stirred overnight then absorbed into florisil and purified using the ISCO (0%-20 % methanol/methylene chloride) to afford 122 mg (66 %) of desired product as a yellow solid.

[0216] MS (ES) m/z 455.1 ;

HRMS: calculated for C ₂₃ H ₂₄ N ₂ O ₄ S ₂ + H+, 457.12502; found (ESI, [M+H] ⁺ ), 457.1241

Example 12: 2,9,9-Trimethyl-W-(tetrahydro-2W-pyran-4-ylmethyl)-9H- thioxanthene-3-sulfonamide 10,10-dioxide

79

[0217] The title compound was prepared in a similar fashion as Example 11 using (tetrahydro-2H-pyran-4-yl)methanamine to afford 123 mg (68%) of desired product as a yellowish solid.

[0218] MS (ES) m/z 448.1 ;

HRMS: calculated for C ₂₂ H ₂₇ NO ₅ S ₂ + H+, 450.14034; found (ESI ₁ [M+H]*), 450.1418

Example 13: 2,9,9-Trimethyl-/V-(tetrahydro-2 W-pyran-4-yl)-9W-thioxanthene-3- sulfonamide 10,10-dioxide

[0219] The title compound was prepared in a similar fashion as Example 11 using tetrahydro-2H-pyran-4-amine to afford 37 mg (67%) of desired product as an off white solid.

[0220] MS (ES) m/z 436.1 ;

HRMS: calculated for C ₂ I H ₂₅ NO ₅ S ₂ + H+, 436.12469; found (ESI, [M+H] ⁺ ), 436.1222

Example 14: 2,9,9-Trimethyl-/V-(2-pyridin-4-ylethyl)-9W-thioxanthene-3- sulfonamide 10,10-dioxide

80

[0221] The title compound was prepared in a similar fashion as Example 11 using 2-(pyridin-4-yl)ethanamine and purified using the ISCO (tetrahydrofuran/hexane) to afford 53 mg (54 %) of desired product as an off white solid.

[0222] MS (ES) m/z 456.θ;

HRMS: calculated for C ₂₃ H ₂₄ N ₂ O ₄ S ₂ + H+, 457.12502; found (ESI, [M+H] ⁺ ), 457.2147

Example 15: /V-(2-Cyanoβthyl)-2,9,9-trimethy l-9H-thioxanthene-3-sulfonamide 10,10-dioxide

[0223] The title compound was prepared in a similar fashion as Example 11 using 3-aminopropanenitrile and purified using the ISCO (tetrahydrofuran/hexane) to afford 45 mg (52 %) of desired product as a white solid.

[0224] MS (ES) m/z 404.7;

HRMS: calculated for C ₁₉ H ₂₀ N ₂ O ₄ S ₂ + H+, 405.09372; found (ESI, [M+H] ⁺ ), 405.0921

Example 16: ferf-Butyl 4-{[(2,9,9-trimethyl-10,10-dioxido-9H-thioxanthen-3- yl )sulf onyl]ami no}piperid ine-1 -carboxy late

,Boc

[0225] The title compound was prepared in a similar fashion as Example 11 using tert-butyl 4-aminopiperidine-i-carboxylate and triethylamine and purified using the ISCO (tetrahydrofuran/hexane) to afford 1.31 g (65 %) of desired product as a white solid.

[0226] MS (ES) m/z 532.8;

HRMS: calculated for C ₂₆ H ₃₄ N ₂ O ₆ S ₂ + H+, 535.19310; found (ESI, [M+H-C4H8] ⁺ ), 479.1233

Example 17: 2,9,9-Trimethyl-λ/-piperidin-4-yl-9H-thioxanthene-3-sulfona mide 10,10-dioxide

,Boc

[0227] A solution of terf-butyl 4-{[(2,9,9-trimethyl-10,10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidine-1-carboxylate (1.16 g, 2.17 mmol) in 4M HCI in 1 ,4- doxane (20 ml_) was heated to 60 ⁰ C for 2 hours. Diethyl ether (40 ml.) was added and the mixture was stirred at room temperature for 30 minutes. The solid was filtered, washed with ether (60 ml_) and dried to afford 0.91 g (89.4 %) of desired product as a white solid.

[0228] MS (ES) m/z 434.8;

HRMS: calculated for C _2I H ₂₆ N ₂ O ₄ S ₂ + H+, 435.14067; found (ESI, [M+H] ⁺ ), 435.1384

Example 18: 5-Oxo-5-<4-{[(2,9,9-trimethyl-10,10-dioxido-9H-thioxanthe n-3- yl)sulfonyl]amino}piperidin-1 -yl)pentanoic acid

82

[0229] A mixture of 2,9,9-trimethyl-λ/-piperidin-4-yl-9H-thioxanthene-3-sulfona mide 10,10-dioxide (100 mg, 0.212 mmol), triethylamine (3 equiv) and glutaric anhydride (24.2 mg, 0.212 mmol) in methylene chloride (4.5 ml.) was allowed to stir overnight at room temperature. The product was purified by ISCO chromatography unit (0%- 30% methanol/methylene chloride) to afford 82.3 mg (71 %) of desired product as a white solid

[0230] MS (ES) m/z 548.9;

HRMS: calculated for C ₂₆ H ₃₂ N ₂ O ₇ S ₂ + H+, 549.17237; found (ESI, [M+H] ⁺ ), 549.1729

Example 19: 3-[(4-{[(2,9,9-Thmethyl-10,10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1 -yl)sulfonyl]benzoic acid

[0231] The title compound was prepared in an analogous fashion to Example 18 using 3-(chlorosulfonyl)benzoic acid in 84 % yield.

[0232] MS (ES) m/z 616.7;

HRMS: calculated for C ₂₈ H ₃₀ N ₂ O ₈ S ₃ + H+, 619.12370; found (ESI, [M+H] ⁺ ), 619.1246

83

Example 20: 4-[(4-{[(2,9,9-Trimethyl-10,10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1 -yl)sulfonyl]benzoic acid

v° V°JO ^H ^ ^^coon

H

[0233] The title compound was prepared in an analogous fashion to Example 18 using 4-(chlorosulfonyl)benzoic acid in 94 % yield.

[0234] MS (ES) m/z 616.8;

HRMS: calculated for C ₂₈ H ₃₀ N ₂ O ₈ S ₃ + H+, 619.12370; found (ESI, [M+H] ⁺ ),

619.1246

7

Example 21 : 4-Oxo-4-<4-{[(2,9,9-trimethyl-10,10-dioxido-9H-thioxanthe n-3- yl)sulfonyl]amino}piperidin-1 -yl)butanoic acid

O v v r ^ ^« ϊOOH JO ^H N r *^*r H

[0235] The title compound was prepared in an analogous fashion to Example 18 using succinic anhydride in 91 % yield.

MS (ES) m/z 534.8;

HRMS: calculated for C ₂₅ H ₃₀ N ₂ O ₇ S ₂ + H+, 535.15672; found (ESI, [M+H] ⁺ ),

535.1594

Example 22: λ/-{4-[(4-{[(2,9,9-Trimethyl-10,10-dioxido-9H-thioxanthen-3 - yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]phenyl}acetamide

84

[0236] The title compound was prepared in an analogous fashion to Example 18 using N-acetylsulfanilyl chloride in 93 % yield.

MS (ES) m/z 631.8;

HRMS: calculated for C ₂₉ H ₃₃ N ₃ O ₇ S ₃ + H+, 632.15534; found (ESI, [M+H] ⁺ ),

632.1552

Example 23: fert-Butyl (4-{[(2,9,9-trimethyl-10,10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1-yl)acetate

H γΎΎ ^N °

[0237] A mixture of 2,9,9-trimethyl-λ/-piperidin-4-yl-9H-thioxanthene-3-sulfona mide 10,10-dioxide (150 mg, 0.319 mnnol), tert-butyl bromoacetate (98 mg, 0.510 mmol) and triethylamine (4 equiv) in 1.5 ml_ tetrahydrofuran was allowed to stir at 120 ⁰ C under microwave for 40 minutes. Then the reaction mixture was absorbed into florisil and purified using the ISCO (0%-20 % methanol/methylene chloride) to afford 143 mg (82 %) of desired product as a white solid.

MS (ES) m/z 549.0;

HRMS: calculated for C ₂₇ H ₃₆ N ₂ O ₆ S ₂ + H+, 549.20875; found (ESI, [M+H]*), 549.207

Example 24: (4-{[(2,9,9-Trimethyl-10,10-dioxido-9H-thioxanthen-3- y l)sulfonyl]amino}piperidin-1 -yl)acetic acid

85

^S N

[0238] A solution of te/f-butyl (4-{[(2,9,9-trimethyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1-yl)acetate (110 mg, 0.20 mmol) in ethyl acetate with saturated HCI (7 ml_) was stirred at room temperature for 3 days. Hexane (30 ml_) was added and the mixture was stirred at room temperature for 1 h. The solid was filtered, washed with hexane and dried to afford 92 mg (93 %) of desired product as a white solid.

MS (ES) m/z 492.9;

HRMS: calculated for C ₂₃ H ₂₈ N ₂ O ₆ S ₂ + H+, 493.14615; found (ESI, [M+H] ⁺ ), 493.1437.

Example 25: Af-(r/ans-4-hydroxycyclohexyl)-2,9,9-trimethyl-9H-thioxanthe ne-3- sulfonamide 10,10-dioxide

..*OH

[0239] The title compound was prepared in a similar fashion as Example 11 (step 3) using trans-4-aminocyclohexanol to afford 59 mg (53 %) of desired product as an off white solid.

MS (ES) m/z 447.8;

HRMS: calculated for C ₂₂ H ₂₇ NO ₅ S ₂ + H+, 450.14034; found (ESI, [M+H] ⁺ ), 450.145

Example 26: 2'-Methyl-/V-(2-pyridin-2-ylethyl)spiro[cyclopentane-1 ,9'- thioxanthene]-3'-sulfonamide lO'.IO'-dioxide

86

Step 1. 2'-Methylspiro[cyclopentane-1 ,9'-thioxanthene] 10 ¹ , 10'-dioxide

[0240] 2-Methyl-9H-thioxanthene-10,10-dioxide (1.7 g, 6.97 mmol) and 1 ,4- diiodobutane (2.27 g, 7.31 mmol) were reacted according to Example 7 (step 1 ) to afford 1.59 g (77 %) of the title compound as a white solid.

MS (ES) m/z 299.1 ;

HRMS: calculated for Ci ₈ H ₁₈ O ₂ S + H+, 299.11003; found (ESI, [M+Hf), 299.1092

Step 2. 2'-Methylspiro[cyclopentane-1 ,9'-thioxanthene] 10',10'-dioxide-3'-sulfonyl chloride

[0241] The title compound was prepared according to Example 1 (step 5) using 2'- methylspiro[cyclopentane-1 ,9'-thioxanthene] 10 ¹ , 10'-dioxide (1.42 g, 4.76 mmol) and chlorosulfonic acid (1.42 ml_) to afford 1.98 g (95 %) of desired product as a brown solid.

87

Step 3. 2'-Methyl-λ/-(2-pyridin-2-ylethyl)spiro[cyclopentane-1 ,9'-thioxanthene]-3'- sulfonamide 10',10'-dioxide

[0242] To a solution of 2'-methylspiro[cyclopentane-1 ,9'-thioxanthene] 10', 10'- dioxide-3'-sulfonyl chloride (89.8 mg, 0.216 mmol) in anhydrous methylene chloride (4 ml_) was added 2-(2-aminoethyl)pyridine (39.6 mg, 0.324 mmol) followed by N ₁ N- diisopropylethylamine (1 12.9 ul, 0.648 mmol, 3 equiv) at room temperature. The reaction was stirred overnight then absorbed into florisil and purified using the ISCO (methanol/methylene chloride) to afford 69.1 mg (66 %) of desired product. MS (ES) m/z 483.2;

HRMS: calculated for C ₂₅ H ₂₆ N ₂ O ₄ S ₂ + H+, 483.14067; found (ESI, [M+H] ⁺ ), 483.1412

Example 27: 2'-Methyl-W-(2-pyridin-3-ylethyl)spiro[cyclopentane-1 ,9'- thioxanthene]-3' -sulfonamide 10',10' -dioxide

The title compound was prepared in a similar fashion as Example 26 (step 3) using 3-(2-aminoethyl)pyridine to afford 66.2 mg (66%) of desired product.

88

MS (ES) m/z 483.2;

HRMS: calculated for C ₂₅ H ₂₆ N ₂ O ₄ S ₂ + H+, 483.14067; found (ESI, [M+H] ⁺ ), 483.1418

Example 28: 2'-Methyl-A/-(2-pyridin-4-ylethyl)spiro[cyclopentane-1 ,9'- thioxanthene]-3'-sulfonamide lO'.IO'-dioxide

[0243] The title compound was prepared in a similar fashion as Example 26 (step 3) using 4-(2-aminoethyl)pyridine to afford 59.8 mg (57 %) of desired product. MS (ES) m/z 483.1 ;

HRMS: calculated for C ₂₅ H ₂₆ N ₂ O ₄ S ₂ + H+, 483.14067; found (ESI, [M+H] ⁺ ), 483.1425

Example 29: 2 ^> -Methyl-/V-(tetrahydro-2H-pyran-4-yl)spiro[cyclopentane-1 ,9'- thioxanthene]-3'-sulfonamide 10',10'-dioxide

[0244] The title compound was prepared in a similar fashion as Example 26 (step

3) using 4-aminotetrahydropyran hydrochloride to afford 73.5 mg (74 %) of desired product.

MS (ES) m/z 460.1 ;

HRMS: calculated for C ₂₃ H ₂₇ NO ₅ S ₂ + H+, 462.14034; found (ESI, [M+H] ⁺ ), 462.1383

89

Example 30: 2 ^f -Methyl-W-(tetrahydro-2H-pyran-4-ylmethyl)spiro[cyclopentane - 1.θ'-thioxanthenel-S ¹ -sulfonamide 10 ⁽ ,10'-dioxide

[0245] The title compound was prepared in a similar fashion as Example 26 (step 3) using 4-aminomethyltetrahydropyran to afford 74.1 mg (72 %) of desired product. MS (ES) m/z 476.1 ;

HRMS: calculated for C ₂₄ H ₂₉ NO ₅ S ₂ + H+, 476.15599; found (ESI ₁ [M+H] ⁺ ), 476.1529

Example 31 : λ/-(2-Cyanoethyl)-2'-methylspiro[cyclopentane-1,9'-thioxant hene]- 3'-sulfonamide 10M0'-dioxide

/V _N ^CN

[0246] The title compound was prepared in a similar fashion as Example 26 (step

3) using 3-amino-propionitrile to afford 60.3 mg (65 %) of desired product.

MS (ES) m/z 431.1 ;

HRMS: calculated for C ₂ I H ₂₂ N ₂ O ₄ S ₂ + H+, 431.10937; found (ESI, [M+H] ⁺ ),

431.1083

Example 32: yV-(2-Hydroxy-2-phenylethyl)-2'-methylspiro[cyclopentane-1 ,9'- thioxanthene]-3'-sulfonamide 10',10' -dioxide

90

[0247] The title compound was prepared in a similar fashion as Example 26 (step 3) using 2-amino-1-phenyl-ethanol to afford 87.2 mg (81 %) of desired product. MS (ES) m/z 496.1 ;

HRMS: calculated for C ₂₆ H _2T NO ₅ S ₂ + H+, 498.14034; found (ESI ₁ [M+H] ⁺ ), 480.1298

Example 33: W-(2-Hydroxy-1-methyl-2-phenylethyl)-2'- methylspiro[cyclopentane-1,9'-thioxanthene]-3' -sulfonamide 10',10'-dioxide

[0248] The title compound was prepared in a similar fashion as Example 26 (step 3) using norephedrine hydrochloride to afford 86.5 mg (78 %) of desired product. MS (ES) m/z 510.2;

HRMS: calculated for C ₂₇ H ₂₉ NO ₅ S ₂ + H+ - H+, 511.14871 ; found (ESI, [M+H-H20D, 494.1417

Example 34: W-(2-Hydroxyethyl)-2'-methylspiro[cyclopentane-1,9'- thioxanthene]-3'-sulfonamide 10',10' -dioxide

H

[0249] The title compound was prepared in a similar fashion as Example 26 (step 3) using ethanolamine to afford 56.3 mg (62 %) of desired product. MS (ES) m/z 422.2;

HRMS: calculated for C ₂₀ H ₂₃ NO ₅ S ₂ + H+, 422.10904; found (ESI ₁ [M+H] ^* ), 422.1083

Example 35: fert-Butyl 4-{[(2'-methyl-10',10'-dioxidospiro[cyclopentane-1,9'- thioxanthen]-3'-yl)sulfonyl]amino}piperidine-1-carboxylate

Boc

[0250] The title compound was prepared in a similar fashion as Example 26 (step 3) using tert-butyl 4-aminopiperidine-1 -carboxylate and triethylamine and purified using the ISCO (tetrahydrofuran/hexane) to afford 1.06 g (86 %) of desired product.. MS (ES) m/z 559.2;

HRMS: calculated for C ₂₈ H ₃₆ N ₂ O ₆ S ₂ + H+, 561.20875; found (ESI, [M+H-TBUTYL]*), 505.1469

Example 36: 2'-Methyl-/V-piperidin-4-ylspiro[cyclopentane-1 ,9'-thioxanthene]- 3'-sulfonamide 10',10'-dioxide

92

[0251] The title compound was prepared according to similar conditions used in

Example 17 employing fert-butyl 4-{[(2'-methyl-10',10 ^l -dioxidospiro[cyclopentane- i .θ'-thioxanthen^'-yOsulfonyllaminoJpiperidine-i-carboxylate to afford 673 mg (94

%) of desired product as a white solid.

MS (ES) m/z 461.2;

HRMS: calculated for C ₂₃ H ₂₈ N ₂ O ₄ S ₂ + H+, 461.15632; found (ESI, [M+H] ⁺ ),

461.1565

Example 37: 3-[(4-{[(2 ^I -Methyl-10 ⁱ ,10'-dioxidospiro[cyclopentane-1 ,9'- thioxanthen]-3'-yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]be nzoic acid

[0252] The title compound was prepared according to similar conditions used in

Example 18 employing 2'-methyl-λ/-piperidin-4-ylspiro[cyclopentane-1 ,9'- thioxanthene]-3'-sulfonamide 10',10'-dioxide (94.8 mg, 0.191 mmol) and 3-

(chlorosulfonyl)benzoic acid (41.9 mg, 0.191 mmol) to afford 87 mg (71 %) of desired product.

MS (ES) m/z 645.0;

HRMS: calculated for C ₃₀ H ₃₂ N ₂ O ₈ S ₃ + H+, 645.13935; found (ESI, [M+H] ⁺ ),

645.1385

Example 38: ferf-Butyl (4-{[(2 ^> -methyl-10 ^< ,10 ^> -dioxidospiro[cyclopentane-1,9 ^< - thioxanthen]-3'-yl)sulfonyl]amino}piperidin-1-yl)acetate

w H

93

[0253] The title compound was prepared according to similar conditions used in Example 23 employing 2'-methyl-N-piperidin-4-ylspiro[cyclopentane-1 ,9'- thioxanthene]-3'-sulfonamide 10',10'-dioxide (135 mg, 0.272 mmol) and tert-butyl bromoacetate (89.3 mg, 0.463 mmol) to afford 155 mg (99 %) of desired product. MS (ES) m/z 575.0;

HRMS: calculated for C ₂₉ H ₃₈ N ₂ O ₆ S ₂ + H+, 575.22440; found (ESI, [M+H] ⁺ ), 575.2291

Example 39: /V-(rrans-4-hydroxycyclohexyl)-2'-methylspiro[cyclopentane-1 ,9'- thioxanthene]-3'-sulfonamide 10',10'-dioxide

[0254] A mixture of 2'-methylspiro[cyclopentane-1 ,9'-thioxanthene] 10', 10'-dioxide- 3'-sulfonyl chloride (99.4 mg, 0.251 mmol), trans-4-aminocyclohexanol (31.8 mg, 0.276 mmol) and

N,N-diisopropylethylamine (2.2 equiv) in methylene chloride (6 ml_) was allowed to stir overnight at room temperature. The reaction mixture was absorbed into florisil and purified using the ISCO (3%-10 % methanol/methylene chloride) to afford 63 mg (53 %) of desired product.

MS (ES) m/z 473.8;

HRMS: calculated for C ₂₄ H ₂₉ NO ₅ S ₂ + H+, 476.15599; found (ESI, [M+H] ⁺ ), 476.1584

Example 40: 2'-Methyl-/V-(2-pyridin-2-ylethyl)spiro[cyclohexane-1 ,9'- thioxanthene]-3' -sulfonamide 10',10'-dioxide

94

step.1 2'-Methylspiro[cyclohexane-1 ,9'-thioxanthene] 10 ¹ , 10'-dioxide

[0255] The title compound was prepared according to Example 7 (step 1 ) using 2- methyl-9H-thioxanthene 10,10-dioxide (1.7 g, 6.965 mmol) and 1 ,5-diiodopentane (2.368 g, 7.313 mmol) to afford after chromatography 1.09 g (50 %) of desired product as a white solid.

MS (ES) m/z 313.1 ;

HRMS: calculated for Ci ₉ H ₂₀ O ₂ S + H+, 313.12568; found (ESI, [M+H] ⁺ ), 313.1259

Step 2. 2'-Methylspiro[cyclohexane-1 ,9'-thioxanthene] 10',10'-dioxide-3'-sulfonyl chloride

[0256] The title compound was prepared according to Example 1 (step 5) using 2'- methylspiro[cyclohexane-1,9'-thioxanthene] 10',10'-dioxide (1.04 g, 3.33 mmol) and chlorosulfonic acid (1.107 ml.) to afford 1.39 g (100 %) of desired product as a brown solid.

95

Step 3. 2'-Methyl-/V-(2-pyridin-2-ylethyl)spiro[cyclohexane-1 ,9'-thioxanthene]-3'- sulfonamide 10',10'-dioxide

[0257] The title compound was prepared according to similar conditions used in

Example 26 (step 3) employing 2'-methylspiro[cyclohexane-1 ,9'-thioxanthene]

10',10'-dioxide-3'-sulfonyl chloride and 2-(2-aminoethyl)pyridine to afford 78.8 mg (74

%) of desired product.

MS (ES) m/z 497.2;

HRMS: calculated for C ₂₆ H ₂₈ N ₂ O ₄ S ₂ + H+, 497.15632; found (ESI, [M+H] ⁺ ),

497.1589

Example 41 : 2'-Methyl-W-(2-pyridin-3-ylethyl)spiro[cyclohexane-1,9 ^l - thioxanthene]-3'-sulfonamide 10',10' -dioxide

[0258] The title compound was prepared according to similar conditions used in Example 26 (step 3) employing 2'-methylspiro[cyclohexane-1 ,9'-thioxanthene] 10',10'-dioxide-3'-sulfonyl chloride and 3-(2-aminoethyl)pyridine to afford 52.1 mg (51 %) of desired product.

96

MS (ES) m/z 497.2;

HRMS: calculated for C ₂₆ H ₂₈ N ₂ O ₄ S ₂ + H+, 497.15632; found (ESI, [M+H] ⁺ ), 497.1632

Example 42: 2'-Methyl-λ/-(2-pyridin-4-ylethyl)spiro[cyclohexane-1 ,9'- thioxanthene]-3'-sulfonamide lO'.IO'-dioxide

[0259] The title compound was prepared according to similar conditions used in Example 26 (step 3) employing 2'-methylspiro[cyclohexane-1 ,9'-thioxanthene] 10',10'-dioxide-3'-sulfonyl chloride and 4-(2-aminoethyl)pyridine to afford 53.6 mg (50 %) of desired product.

MS (ES) m/z 497.2;

HRMS: calculated for C ₂₆ H ₂₈ N ₂ O ₄ S ₂ + H+, 497.15632; found (ESI ₁ [M+Hf), 497.158

Example 43: 2 ^< -Methyl-/V-(tetrahydro-2H-pyran-4-yl)spiro[cyclohexane-1 ,9'- thioxanthene]-3' -sulfonamide 10',10'-dioxide

[0260] The title compound was prepared according to similar conditions used in Example 26 (step 3) employing 2'-methylspiro[cyclohexane-1 ,9'-thioxanthene]

97

10',10'-dioxide-3'-sulfonyl chloride and 4-aminotetrahydropyran hydrochloride to afford 55.7 mg (54 %) of desired product.

MS (ES) m/z 474.1 ;

HRMS: calculated for C ₂₄ H ₂₉ NO ₅ S ₂ + H+, 476.15599; found (ESI, [M+H] ⁺ ), 476.1512

Example 44: 2 ^I -Methyl-/V-(tetrahydro-2H-pyran-4-ylmethyl)spiro[cyclohexane - 1,9'-thioxanthene]-3'-sulfonamide 10',10'-dioxide

[0261] The title compound was prepared according to similar conditions used in Example 26 (step 3) employing 2'-methylspiro[cyclohexane-1 ,9'-thioxanthene] lO'.IO'-dioxide-S'-sulfonyl chloride and 4-aminomethyltetrahydropyran to afford 64.6 mg (61 %) of desired product.

MS (ES) m/z 490.2;

HRMS: calculated for C ₂₅ H ₃ INO ₅ S ₂ + H+, 490.17164; found (ESI ₁ [M+H] ⁺ ) _> 490.1738

Example 45: /V-(2-Cyanoethyl)-2'-methylspiro[cyclohexane-1 ,9'-thioxanthene]- 3'-sulfonamide 10',10'-dioxide

[0262] The title compound was prepared according to similar conditions used in Example 26 (step 3) employing 2'-methylspiro[cyclohexane-1 ,9'-thioxanthene]

98

10',10'-dioxide-3'-sulfonyl chloride and 3-amino-propionitrile to afford 48.7 mg (51 %) of desired product.

MS (ES) m/z 445.2;

HRMS: calculated for C ₂₂ H ₂₄ N ₂ O ₄ S ₂ + H+, 445.12502; found (ESI, [M+H] ⁺ ),

445.1267

Example 46: λ/-(2-Hydroxy-2-phenylethyl)-2'-methylspiro[cyclohexane-1,9 '- thioxanthene]-3'-sulfonamide 10',10' -dioxide

[0263] The title compound was prepa red according to similar conditions used in Example 26 (step 3) employing 2'-methylspiro[cyclohexane-1 ,9'-thioxanthene] 10',10'-dioxide-3'-sulfonyl chloride and 2-amino-1 -phenyl-ethanol to afford 71.3 mg (65 %) of desired product.

MS (ES) m/z 510.2;

HRMS: calculated for C ₂₇ H ₂₉ NO ₅ S ₂ + H+, 512.15599; found (ESI ₁ [M+H] ⁺ ), 51 1.1549

Example 47: W-(2-Hydroxy-1-methyl-2-phenylβthyl)-2'- methylspiro[cyclohexane-1 ,9'-thioxanthene]-3'-sulfonamide 10', 10'-dioxide

[0264] The title compound was prepared according to similar conditions used in Example 26 (step 3) employing 2'-methylspiro[cyclohexane-1 ,9'-thioxanthene]

99

10',10'-dioxide-3'-sulfonyl chloride and norephedrine hydrochloride to afford 75.7 mg

(67 %) of desired product.

MS (ES) m/z 524.2;

HRMS: calculated for C ₂₈ H ₃ INO ₅ S ₂ + H+ - H+, 525.16436; found (ESI, [M+H-H20]*),

508.1564

Example 48: λf-(2-Hydroxyethyl)-2'-methylspiro[cyclohexane-1,9'- thioxanthene]-3'-sulfonamide 10',10'-dioxide

[0265] The title compound was prepared according to similar conditions used in Example 26 (step 3) employing 2'-methylspiro[cyclohexane-1 ,9'-thioxanthene] 10',10'-dioxide-3'-sulfonyl chloride and ethanolamine to afford 52.2 mg (56 %) of desired product.

MS (ES) m/z 436.2;

HRMS: calculated for C ₂ I H ₂₅ NO ₅ S ₂ + H+, 436.12469; found (ESI, [M+H] ⁺ ), 436.1245

Example 49: tert-Butyl 4-{[(2 ^l -methyl-10 ^l ,10'-dioxidospiro[cyclohexane-1,9'- thioxanthen]-3'-yl)sulfonyl]amino}piperidine-1-carboxylate

^Boc

[0266] The title compound was prepared according to similar conditions used in Example 26 (step 3) employing 2'-methylspiro[cyclohexane-1 ,9'-thioxanthene]

10',10'-dioxide-3'-sulfonyl chloride, tert-butyl 4-aminopiperidine-i-carboxylate and triethylamine to afford 394.8 mg (66 %) of desired product.

MS (ES) m/z 573.2;

HRMS: calculated for C ₂₉ H ₃₈ N ₂ O ₆ S ₂ + H+, 575.22440; found (ESI, [M+H-TBOC]*),

475.1374

Example 50: 2 ^t -Mβthyl-/V-piperidin-4-ylspiro[cyclohexane-1,9'-thioxanthen e]-3 ^l - sulfonamide 10',10'-dioxide

-Boo

[0267] The title compound was prepared according to similar conditions used in Example 17 employing te/f-butyl 4-{[(2 ^l -methyl-10 ^l ,10'-dioxidospiro[cyclohexane-1 ,9 ^l - thioxanthen]-3'-yl)sulfonyl]amino}piperidine-1-carboxylate to afford 262 mg (96 %) of desired product.

MS (ES) m/z 475.2;

HRMS: calculated for C ₂₄ H ₃₀ N ₂ O ₄ S ₂ + H+, 475.17197; found (ESI, [M+H] ⁺ ), 475.1723

Example 51 : 3-[(4-{[(2 ^I -Methyl-10' ₎ 10'-dioxidospiro[cyclohexane-1,9 ¹ - thioxanthen]-3'-yl)sulfonyl]amino}pipehdin-1-yl)sulfonyl]ben zoic acid

COOH

[0268] The title compound was prepared according to similar conditions used in Example 18 employing 2'-methyl-λ/-piperidin-4-ylspiro[cyclohexane-1 ,9'- thioxanthene]-3'-sulfonamide 10',10'-dioxide (97.4 mg, 0.191 mmol) and 3- (chlorosulfonyl)benzoic acid (41.9 mg, 0.191 mmol) to afford 96 mg (76 %) of desired product.

MS (ES) m/z 659.0;

HRMS: calculated for C ₃ I H ₃₄ N ₂ O ₈ S ₃ + H+, 659.15500; found (ESI, [M+H] ⁺ ), 659.1645

Example 52: N-( rrans-4-hydroxycyclohexyl)-2'-methylspiro[cyclohexane-1,9'- thioxanthene]-3'-sulfonamide 10',10'-dioxide

[0269] The title compound was prepared according to similar conditions used in Example 39 employing 2'-methylspiro[cyclohexane-1 ,9'-thioxanthene] 10',10'- dioxide-3'-sulfonyl chloride (80 mg, 0.195 mmol) and trans-4-aminocyclohexanol (24.7 mg, 0.215 mmol) to afford 46 mg (48 %) of desired product. MS (ES) m/z 487.8;

HRMS: calculated for C ₂₅ H ₃₁ NO ₅ S ₂ + H+, 490.17164; found (ESI, [M+H] ⁺ ), 490.1729

Example 53: 9,9-Diethyl-2-methyl-/V-(2-pyridin-2-ylethyl)-9H-thioxanthen e-3- sulfonamide 10,10-dioxide

Step 1. 9,9-Diethyl-2-methyl-9H-thioxanthene 10,10-dioxide

[0270] The title compound was prepared according to Example 7 (step 1 ) using 2- methyl-9H-thioxanthene 10,10-dioxide (1.7 g, 6.965 mmol) and iodo ethane (8.69 g, 55.72 mmol) to afford after chromatography 1.69 g (80.8 %) of desired product. MS (ES) m/z 301.1 ;

HRMS: calculated for Ci ₈ H ₂₀ O ₂ S + H+, 301.12568; found (ESI, [M+H] ⁺ ), 301.125

Step 2. 9,9-Diethyl-2-methyl-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide

[0271] The title compound was prepared according to Example 1 (step 5) using 9,9-diethyl-2-methyl-9H-thioxanthene 10,10-dioxide (1.60 g, 5.331 mmol) and chlorosulfonic acid (2.126 mL) to afford 2.12 g (100 %) of desired product as a brown solid.

Step 3. 9,9-Diethyl-2-methyl-λ/-(2-pyridin-2-ylethyl)-9H-thioxanthe ne-3-sulfonamide 10,10-dioxide

[0272] The title compound was prepared according to similar conditions used in

Example 26 (step 3) employing 9,9-diethyl-2-methyl-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide and 2-(2-aminoethyl)pyridine to afford 79.9 mg (76 %) of desired product.

MS (ES) m/z 485.1 ;

HRMS: calculated for C ₂₅ H ₂₈ N ₂ O ₄ S ₂ + H+, 485.15632; found (ESI, [M+H] ⁺ ),

485.1553

Example 54: 9,9-Diethyl-2-methyl-/V-(2-pyridin-3-ylethyl)-9H-thioxanthen e-3- sulfonamide 10,10-dioxide

[0273] The title compound was prepared according to similar conditions used in

Example 26 (step 3) employing 9,9-diethyl-2-methyl-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide and 3-(2-aminoethyl)pyridine to afford 71.4 mg (71 %) of desired product.

MS (ES) m/z 485.2;

HRMS: calculated for C ₂₅ H ₂₈ N ₂ O ₄ S ₂ + H+, 485.15632; found (ESI, [M+H] ⁺ ),

485.1579

Example 55: 9,9-Diethyl-2-methyl-/V-(2-pyridin-4-ylethyl)-9H-thioxanthen e-3- sulfonamide 10,10-dioxide

[0274] The title compound was prepared according to similar conditions used in

Example 26 (step 3) employing 9,9-diethyl-2-methyl-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide and 4-(2-aminoethyl)pyridine to afford 71.2 mg (68 %) of desired product.

MS (ES) m/z 485.1 ;

HRMS: calculated for C ₂₅ H ₂₈ N ₂ O ₄ S ₂ + H+, 485.15632; found (ESI, [M+H] ⁺ ),

485.1565

Example 56: 9,9-Diethyl-2-methyl-/V-(tetrahydro-2W-pyran-4-yl)-9W- thioxanthene-3-sulfonamide 10,10-dioxide

H

[0275] The title compound was prepared according to similar conditions used in Example 26 (step 3) employing 9,9-diethyl-2-methyl-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide and 4-aminotetrahydropyran hydrochloride to afford 63.2 mg (63 %) of desired product.

MS (ES) m/z 464.1 ;

HRMS: calculated for C ₂₃ H ₂₉ NO ₅ S ₂ + H+, 464.15599; found (ESI, [M+H] ⁺ ), 464.1559

Example 57: 9,9-Diethyl-2-methyl-λ/-(tetrahydro-2W-pyran-4-ylmethyl)-9H - thioxanthene-3-sulfonamide 10,10-dioxide

[0276] The title compound was prepared according to similar conditions used in Example 26 (step 3) employing 9,9-diethyl-2-methyl-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide and 4-aminomethyltetrahydropyran to afford 50.4 mg (49 %) of desired product.

MS (ES) m/z 478.1 ;

HRMS: calculated for C ₂₄ H ₃ I NO ₅ S ₂ + H+, 478.17164; found (ESI ₁ [M+H] ⁺ ), 478.1678

Example 58: λ/-(2-Cyanoethyl)-9,9-diethyl-2-methyl-9W-thioxanthene-3- sulfonamide 10,10-dioxide

[0277] The title compound was prepared according to similar conditions used in

Example 26 (step 3) employing 9,9-diethyl-2-methyl-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide and 3-amino-propionitrile to afford 69.6 mg (75 %) of desired product.

MS (ES) m/z 433.2;

HRMS: calculated for C _2I H ₂₄ N ₂ O ₄ S ₂ + H+, 433.12502; found (ESI, [M+H] ⁺ ),

433.1267

Example 59: 9,9-Diethyl-W-{2-hydroxy-2-phenylethyl)-2-methyl-9H- thioxanthene-3-sulfonamide 10,10-dioxide

[0278] The title compound was prepared according to similar conditions used in

Example 26 (step 3) employing 9,9-diethyl-2-methyl-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide and 2-amino-1-phenyl-ethanol to afford 80.4 mg (75 %) of desired product.

MS (ES) m/z 498.1 ;

HRMS: calculated for C ₂₆ H ₂₉ NO ₅ S ₂ + H+ - H+, 499.14871 ; found (ESI, [M+H-H20D,

482.1517

Example 60: 9,9-Diethyl-W-(2-hydroxy-1 -methyl-2-phenylethyl)-2-methyl-9H- thioxanthene-3-sulfonamide 10,10-dioxide

[0279] The title compound was prepared according to similar conditions used in Example 26 (step 3) employing 9,9-diethyl-2-methyl-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide and norephedrine hydrochloride to afford 86.4 mg (78 %) of desired product.

MS (ES) m/z 512.2;

HRMS: calculated for C ₂₇ H ₃₁ NO ₅ S ₂ + H+ - H+, 513.16436; found (ESI, [M+H-H20]*), 496.158

Example 61 : 9,9-Diethyl-λλ(2-hydroxyethyl)-2-methyl-9W-thioxanthene-3- sulfonamide 10,10-dioxide

[0280] The title compound was prepared according to similar conditions used in Example 26 (step 3) employing 9,9-diethyl-2-methyl-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide and ethanolamine to afford 64 mg (70 %) of desired product. MS (ES) m/z 424.2;

HRMS: calculated for C ₂₀ H ₂₅ NO ₅ S ₂ + H+, 424.12469; found (ESI ₁ [M+H] ⁺ ), 424.1253

Example 62: fert-Butyl 4-{[(9,9-diethyl-2-methyl-10,10-dioxido-9H-thioxanthen- 3-yl)sulfonyl]amino}piperidine-1-carboxylate

,Boc

[0281] The title compound was prepared according to similar conditions used in Example 26 (step 3) employing 9,9-diethyl-2-methyl-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide, tert-butyl 4-aminopiperidine-1-carboxylate and thethylamine to afford 1.31 g (94 %) of desired product.

MS (ES) m/z 561.2;

HRMS: calculated for C ₂₈ H ₃₈ N ₂ O ₆ S ₂ + H+, 563.22440; found (ESI, [M+H] ⁺ ), 563.2258

Example 63: 9,9-diethyl-2-methyl-λ/-piperidin-4-yl-9H-thioxanthene-3- sulfonamide 10,10-dioxide

[0282] The title compound was prepared according to similar conditions used in

Example 17 employing te/f-butyl 4-{[(9 _l 9-diethyl-2-methyl-10,10-dioxido-9H- thi oxanthen-3-y l)su lfonyl]amino}piperidine-1-carboxy late to afford 689 mg (88.4 %) of desired product.

MS (ES) m/z 463.2;

HRMS: calculated for C ₂₃ H ₃₀ N ₂ O ₄ S ₂ + H+, 463.17197; found (ESI, [M+H] ⁺ ),

463.1725

Example 64: 9,9-Diethyl-λ/-[1 -(2-hydroxyethyl)piperidin-4-yl]-2-methyl-9W- thioxanthene-3-sulfonamide 10,10-dioxide

The title compound was prepared according to similar conditions used in Example 23 employing 9,9-diethyl-2-methyl-λ/-piperidin-4-yl-9/-/-thioxanthene-3- sulfonamide

10,10-dioxide (99.6 mg, 0.20 mmol), 2-bromoethanol (138 mg, 1.1 mmol) and triethylamine (0.5 ml_) to afford 71 mg (70 %) of desired product.

MS (ES) m/z 507.1 ;

HRMS: calculated for C ₂₅ H ₃₄ N ₂ O ₅ S ₂ + H+, 507.19819; found (ESI, [M+H] ⁺ ),

507.1996

Example 65: 3-[(4-{[(9,9-Diethyl-2-mβthyl-10,10-dioxido-9H-thioxanthen- 3- yl)sulfonyl]amino}piperidin-1 -yl)sulfonyl]benzoic acid

[0283] The title compound was prepared according to similar conditions used in Example 18 employing 9,9-diethyl-2-methyl-W-piperidin-4-yl-9H-thioxanthene-3- sulfonamide 10,10-dioxide (95 mg, 0.191 mmol) and 3-(chlorosulfonyl)benzoic acid (41.9 mg, 0.191 mmol) to afford 40 mg (32 %) of desired product. MS (ES) m/z 647.0

Example 66: tert-Butyl (4-{[(9,9-diethyl-2-methyl-10,10-dioxido-9H-thioxanthen- 3-yl)sulfonyl]amino}piperidin-1-yl)acetate

^* N

[0284] The title compound was prepared according to similar conditions used in Example 23 employing 9,9-diethyl-2-methyl-λ/-piperidin-4-yl-9H-thioxanthene-3-

sulfonamide 10,10-dioxide (135.5 mg, 0.272 mmol) and tert-butyl bromoacetate

(89.3 mg, 0.463 mmol) to afford 149 mg (95 %) of desired product.

MS (ES) m/z 577.0;

HRMS: calculated for C ₂₉ H ₄₀ N ₂ O ₆ S ₂ + H+, 577.24005; found (ESI, [M+H] ⁺ ),

577.2479

Example 67: (4-{[(9,9-Diethyl-2-methyl-10,10-dioxido-9H-thioxanthen-3- y l)sulfonyl]amino}piperidin-1 -yl)acetic acid

V ^{0 0} V ⁰ N

H

[0285] The title compound was prepared according to similar conditions used in

Example 24 employing ferf-butyl (4-{[(9,9-diethyl-2-methyl-10,10-dioxido-9H- thioxanthen-3-yl)sulfonyl]amino}piperidin-1-yl)acetate (95.1 mg, 0.165 mmol) to afford 85.5 mg (100 %) of desired product.

MS (ES) m/z 521.0;

HRMS: calculated for C ₂₅ H ₃₂ N ₂ O ₆ S ₂ + H+, 521.17745; found (ESI, [M+H] ⁺ ),

521.1761

Example 68: 9,9-Diethyl-/V-(fraπs-4-hydroxycyclohexyl)-2-methyl-9H- thioxanthene-3-sulfonamide 10,10-dioxide

, _λ OH

H

[0286] The title compound was prepared according to similar conditions used in Example 39 employing 2'-methylspiro[cyclohexane-1 ,9 ^l -thioxanthene] 10',1 O ¹ - dioxide-3'-sulfonyl chloride (100 mg, 0.251 mmol) and trans-4-aminocyclohexanol (31.8 mg, 0.276 mmol) to afford 50 mg (42 %) of desired product. MS (ES) m/z 475.9;

HRMS: calculated for C ₂₄ H ₃ I NO ₅ S ₂ + H+, 478.17164; found (ESI, [M+H] ⁺ ), 478.1713

Example 69: fert-Butyl 4-{[(2-chloro-6-fluoro-9,9-dimethyl-10,10-dioxido-9H- thioxanthen-3-yl)sulfonyl]amino}piperidine-1-carboxylate

,Boc

*/> ⁰ ,

^S N H

Step 1. 2-Chloro-6-fluoro-9,9-dimethyl-9H-thioxanthene 10,10-dioxide

The title compound was prepared according to Example 7 (step 1) using 2-chloro-6- fluoro-9H-thioxanthene 10,10-dioxide (10 g, 35.5 mmol) and methyl iodide (25.2 g, 177.3 mmol) to afford after chromatography (tetrahydrofuran / hexane) 7.06 g (64 %) of desired product as a white solid.

MS (El) m/z 310;

HRMS: calculated for Ci ₅ Hi ₂ CIFO ₂ S, 310.02305; found (El, M+.), 310.0235;

Step 2. 2-Chloro-6-fluoro-9,9-dimethyl -9H-thioxanthene-3-sulfonyl chloride 10,10- dioxide

[0287] A mixture of 2-chloro-6-fluoro-9,9-dimethyl-9/-/-thioxanthene 10,10-dioxide (1.45 g, 4.78 mmol) in chlorosulfonic acid (6 ml_) in a sealed tube was allowed to stir at 120 ⁰ C for 8 hours and then transferred slowly by a pipette into ice water with stirring. The mixture was extracted with ethyl acetate (2 x 150). The organic layer was washed with brine and dried over anhydrous sodium sulfate. Purification by column chromatography (tetrahydrofuran / hexane) afforded 1.38 g (71 %) the desired product as an orange gum.

Step 3. te/f-Butyl 4-{[(2-chloro-6-fluoro-9,9-dimethyl-10,10-dioxido-9H-thioxan then-3- yl)sulfonyl]am ino}piperidine-1 -carboxylate

Boc

[0288] The title compound was prepared in a similar fashion as Example 11 using tert-butyl 4-aminopiperidine-1 -carboxylate and triethylamine and purified using the

ISCO (methanol/methylene chloride) to afford 0.70 g (46 %) of desired product as a yellowish solid.

MS (ES) m/z 571.0;

HRMS: calculated for C ₂₅ H ₃₀ CIFN ₂ O ₆ S ₂ + H+, 573.12906; found (ESI, [M+H]*),

517.0661

Example 70: 2-Chloro-6-fluoro-9,9-dimethyl-/V-piperidin-4-yl-9W-thioxant hene- 3-sulfonamide 10,10-dioxide

'NH

[0289] The title compound was prepared according to similar conditions used in

Example 24 employing te/f-butyl 4-{[{2-chloro-6-fluoro-9,9-dimethyl-10,10-dioxido-

9H-thioxanthen-3-yl)sulfonyl]amino}piperidine-1-carboxyla te (440 mg, 0.77 mmol) to afford 380 mg (97 %) of desired product as an off white solid.

MS (ES) m/z 473.0;

HRMS: calculated for C ₂₀ H ₂₂ CIFN ₂ O ₄ S ₂ + H+, 473.07663; found (ESI, [M+H] ^* ),

473.0777

Example 71: 2-(4-{[(2-Chloro-6-fluoro-9,9-dimethyl-10,10-dioxido-9H- thioxanthen-3-yl)sulfonyl]amino}piperidin-1-yl)acetamide

"

[0290] The title compound was prepared according to similar conditions used in Example 23 employing 2-chloro-6-fluoro-9,9-dimethyl-/V-piperidin-4-yl-9H- thioxanthene-3-sulfonamide 10,10-dioxide (90 mg, 0.177 mmol) and 2- bromoacetamide (36 mg, 0.266 mmOI) to afford 47 mg (47 %) of desired product. MS (ES) m/z 529.9;

HRMS: calculated for C ₂₂ H ₂₅ CIFN ₃ O ₅ S ₂ + H+, 530.09809; found (ESI ₁ [M+H]*), 530.098

Example 72: terf-Butyl (4-{[(2-chloro-6-fluoro-9,9-dimethyl-10,10-dioxido-9H- thioxanthen-3-yl)sulfonyl]amino}piperidin-1-yl)acetate

_. ^^- v ntV.

[0291] The title compound was prepared according to similar conditions used in Example 23 employing 2-chloro-6-fluoro-9,9-dimethyl-λ/-piperidin-4-yl-9H- thioxanthene-3-sulfonamide 10,10-dioxide (90 mg, 0.177 mmol) and tert-butyl bromoacetate (89.3 mg, 0.463 mmpl) to afford 152 mg (95 %) of desired product. MS (ES) m/z 586.9;

HRMS: calculated for C ₂₆ H ₃₂ CIFN ₂ O ₆ S ₂ + H+, 587.14471 ; found (ESI ₁ [M+H]*), 587.1503

Example 73: (4-{[(2-Chloro-6-fluoro-9,9-dimethyl-10,10-dioxido-9H- thioxanthen-3-yl)sulfonyl]amino}piperidin-1 -yl)acetic acid

OH r * N'

[0292] The title compound was prepared according to similar conditions used in

Example 24 employing ferf-butyl (4-{[(2-chloro-6-fluoro-9,9-dimethyl-10,10-dioxido-

9H-thioxanthen-3-yl)sulfonyl]amino}piperidin-1-yl)acetate (97 mg, 0.165 mmol) to afford 74.3 mg (79.3 %) of desired product as a white solid.

MS (ES) m/z 530.8;

HRMS: calculated for C ₂₂ H ₂₄ CIFN ₂ O ₆ S ₂ + H+, 531.08211 ; found (ESI, [M+H] ^* ),

531.0816

Example 74: 3-[(4-{[(2-Chloro-6-fluoro-9,9-dimethyl-10,10-dioxido-9H- thioxanthen-3-yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]benz oic acid

[0293] The title compound was prepared according to similar conditions used in Example 18 employing 2-chloro-6-fluoro-9,9-dimethyl-/V-piperidin-4-yl-9/-/- thioxanthene-3-sulfonamide 10,10-dioxide(83.8 mg, 0.165 mmol) and 3- (chlorosulfonyl)benzoic acid (36.3 mg, 0.165 mmol) to afford 46 mg (42 %) of desired product as an off white solid.

MS (ES) m/z 657.0;

HRMS: calculated for C ₂₇ H ₂₆ CIFN ₂ O ₈ S ₃ + H+, 657.05966; found (ESI ₁ [M+H] ⁺ ), 657.06

Example 75: tert-Butyl 4-({[6-fluoro-9,9-dimethyl-10,10-dioxido-2-

(trifluoromethyl)-9H-thioxanthen-3-yl]sulfonyl}amino)pipe ridine-1-carboxylate

Boc

Step 1. 2-Chloro-6-fluoro-9,9-dimethyl-3-nitro-9H-thioxanthene 10,10-dioxide

[0294] The title compound was prepared according to similar conditions used in Example 129 (step 1) employing 2-chloro-6-fluoro-9,9-dimethyl-9H-thioxanthene 10,10-dioxide

(2.93 g, 9.45 mmol) and fuming nitric acid (0.756 g, 12 mmol). Purification on ISCO

(tetrahydrofuran / hexane) afforded 2.7 g (82 %) of desired product as a yellowish solid.

MS (El) m/z 355

Step 2. 6-Fluoro-9,9-dimethyl-3-nitro-2-(trifluoromethyl)-9H-thioxan thene 10,10- dioxide and 3-fluoro-9,9-dimethyl-6-nitro-9H-thioxanthene 10,10-dioxide CL X ⁾

[0295] The title compounds were prepared according to similar conditions used in Example 129 (step 2) employing δ-fluoro-θ.θ-dimethyl-S-nitro^trifluoromethyO-θH- thioxanthene 10,10-dioxide (2.64 g, 7.4 mmol), copper powder (nanosize) (3.76 g, 59.2mmol), carbon (100 mesh, 1.42 g, 118.4 mmol) and difluorodibromomethane (4.68 g, 22.2 mmol). Purification on ISCO (tetrahydrofuran / hexane) afforded 1.68 g (58 %) of 6-fluoro-9,9-dimethyl-3-nitro-2-(trifluoromethyl)-9H-thioxan thene 10,10- dioxide as a white solid and 0.635 g (27 %) of 3-fluoro-9,9-dimethyl-6-nitro-9H- thioxanthene 10,10-dioxide as a yellowish solid.

[0296] 6-Fluoro-9,9-dimethyl-3-nitro-2-(trif luoromethyl)-9H-thioxanthene 10,10- dioxide

MS (El) m/z 389;

HRMS: calculated for CI ₆ HHF ₄ NO ₄ S, 389.03449; found (El, M+.), 389.0365;

[0297] 3-Fluoro-9,9-dimethyl-6-nitro-9H-thioxanthene 10,10-dioxide

MS (El) m/z 321 ;

HRMS: calculated for Ci ₅ Hi ₂ FNO ₄ S, 321.0471 1 ; found (El, M+.), 321.0441

Step 3. 6-Fluoro-9,9-dimethyl-2-(trifluoromethyl)-9H-thioxanthen-3-a mine 10,10- dioxide

A mixture of 6-fluoro-9,9-dimethyl-3-nitro-2-(trifluoromethyl)-9H-thioxan thene 10,10- dioxide (2.84 g, 7.3 mmol), Tin(ll) chloride (11.1 g, 58.4 mmol), methanol (66 ml_) and water (7.3 ml_) in a 350 ml_ sealed tube was stirred at 82 ⁰ C for 2 days. The reaction mixture was absorbed into florisil and purified using the ISCO (tetrahydrofuran/hexane) to afford 2.35 g (90 %) of desired product as a white solid. MS (ES) m/z 359.7;

HRMS: calculated for Ci ₆ Hi ₃ F ₄ NO ₂ S + H+, 360.06759; found (ESI, [M+H]*), 360.0649

Step 4. 6-Fluoro-9,9-dimethyl-2-(trifluoromethyl)-9H-thioxanthene-3- sulfonyl chloride 10,10-dioxide

[0298] The title compound was prepared according to similar conditions used in Example 129 (step 4) employing 6-fluoro-9,9-dimethyl-2-(trifluoromethyl)-9H- thioxanthen-3-amine 10,10-dioxide (359.1 mg, 1.0 mmol) to afford 209.9 mg (47.5 %) of desired product as a white solid.

Step 5. tert-B uty I 4-({[6-f luoro-9, 9-d imethy 1-10, 10-dioxido-2-(trif Iuoromethyl)-9H- thioxanthen-3-yl]sulfonyl}am ino)piperidine-1 -carboxylate

,Boc

[0299] A solution of tert-butyl 4-aminopipθridine-i-carboxylate (222 mg, 1.11 mmol) in methylene chloride (4 ml_) was added into a solution of 6-fluoro-9,9- dimethyl-2-(trifluoromethyl)-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide (140 mg, 0.317 mmol) in methylene chloride (6 ml_) and the mixture was stirred at room temperature overnight. The mixture was absorbed into florisil and purified by column chromatography to afford 125 mg (65 %) the desired product as a white solid. MS (ES) m/z 605.0;

HRMS: calculated for C ₂₆ H ₃₀ F ₄ N ₂ O ₆ S ₂ + H+, 607.15542; found (ESI, [M+H-tbutyl] ^* ), 551.0896

Example 76: 6-Fluoro-9,9-dimethyl-/V-piperidin-4-yl-2-<trifluoromethy l)-9H- thioxanthene-3-sulfonamide 10,10-dioxide

[0300] The title compound was prepared according to similar conditions used in

Example 24 employing ferf-butyl 4-({[6-fluoro-9,9-dimethyl-10,10-dioxido-2-

(trifluoromethyl)-9H-thioxanthen-3-yl]sulfonyl}amino)pipe ridine-1-carboxylate (400 mg, 0.66 mmol) to afford 341 mg (94 %) of desired product as a white solid.

MS (ES) m/z 506.8;

HRMS: calculated for C ₂ IH ₂₂ F ₄ N ₂ O ₄ S ₂ + H+, 507.10299; found (ESI, [M+H]*),

507.1023

Example 77: 3-{[4-{{[6-Fluoro-9,9-dimethyl-10,10-dioxido-2-(trifluoromβ thyl)- 9H-thioxanthen-3-yl]sulfonyl}amino)pipehdin-1-yl]sulfonyl}be nzoic acid

[0301] The title compound was prepared according to similar conditions used in Example 18 employing 6-fluoro-9,9-dimethyl-λ/-piperidin-4-yl-2-(trifluoromethyl) -9H- thioxanthene-3-sulfonamide 10,10-dioxide (90 mg, 0.165 mmol) and 3- (chlorosulfonyl)benzoic acid (36.3 mg, 0.165 mmol) to afford 79 mg (69 %) of desired product as a white solid.

MS (ES) m/z 689.1 ;

HRMS: calculated for C ₂₈ H ₂₆ F ₄ N ₂ O ₈ S ₃ + H+, 691.08602; found (ESI, [M+H] ⁺ ), 691.0819;

Example 78: 6-Fluoro-9,9-dimethyl-λ/-(2-pyridin-3-ylethyl)-2-(trifluoro methyl)- 9tf-thioxanthene-3-sulfonamide 10,10-dioxide

[0302] To a solution of 6-fluoro-9,9-dimethyl-2-(trifluoromethyl)-9H-thioxanthene-3- sulfonyl chloride 10,10-dioxide (100 mg, 0.226 mmol) in anhydrous methylene chloride (3 mL) was added 3-(2-aminoethyl)pyridine (1 10.5 mg, 0.905 mmol) in anhydrous methylene chloride (1 mL) at room temperature. The reaction was stirred overnight then absorbed into florisil and purified using the ISCO (0%-5 % methanol/methylene chloride) to afford 79.8 mg (66.9 %) of desired product as an off white solid.

MS (ES) m/z 529.0;

HRMS: calculated for C ₂₃ H ₂₀ F ₄ N ₂ O ₄ S ₂ + H+, 529.08734; found (ESI ₁ [M+H] ⁺ ), 529.0815

Example 79: 6-Fluoro-9,9-dimethyl-λ/-(2-pyridin-4-ylethyl)-2-(trifluoro methyl)- 9ft-thioxanthene-3-sulfonamide 10,10-dioxide

[0303] The title compounds were prepared according to similar conditions used in Example 26 employing 6-fluoro-9,9-dimethyl-2-(trifluoromethyl)-9H-thioxanthene-3- sulfonyl chloride 10,10-dioxide (64 mg, 0.145 mmol) and 4-(2-aminoethyl)pyridine (70.7 mg, 0.579 mmol) to afford 49.6 mg (65 %) of desired product as a white solid. MS (ES) m/z 529.0;

HRMS: calculated for C ₂₃ H ₂₀ F ₄ N ₂ O ₄ S ₂ + H+, 529.08734; found (ESI ₁ [M+H] ^* ), 529.0853

Example 80: 6-Fluoro-9,9-dimethyl-N-(2-pyridin-3-ylethyl)-2-(trif1uorome thoxy)- 9H- thioxanthene-3-sulfonamide 10,10-dioxide.

Step 1. 4-Fluoro-2-{[4-(trifluoromethoxy)phenyl]thio}benzoic acid

CO ₂ H

Br H

[0304] A mixture of 2-bromo-4-fluoro-benzoic acid (10 g, 45,7 mmol), 4- trifluoromethoxybenzenethiol (9.75 g, 50.2 mmol), potassium carbonate (6.3 g, 50.2 mmol) and copper powder (750 mg, 11.9 mmol) in DMF (50 ml_) were reacted according to Example 5 (step 1 ). Upon workup and trituration a total of 9.9 g (65.2 %) of desired product was afforded as a white solid: mp=176-177 C. MS (ES) m/z 331.0

Step 2. 6-Fluoro-2-(trifluoromethoxy)-9H-thioxanthen-9-one

CO ₂ H

F O

[0305] A mixture of -fluoro-2-{[4-(trifluoromethoxy)phenyl]thio}benzoic acid (9.5 g, 28.55 mmol) was reacted with concentrated sulfuric acid according to Example 5 (step 2) to afford 6.7 g (74.6 %) of desired product. Recrystallization from methanol afforded an analytical sample: mp=131-132°C.

MS (ES) m/z 315.0;

HRMS: calculated for CuH ₆ F ₄ O ₂ S + H+, 315.00974; found (ESI, [M+H] ⁺ ), 315.009

Step 3. 6-Fluoro-2-(trifluoromethoxy)-9H-thioxanthene

OCF,

To a solution of 6-fluoro-2-(trifluoromethoxy)-9H-thioxanthen-9-one (6.4 g, 20.4 mmol) was slowly added 1 M borane in THF (40 ml_) and heated to 50 C for 1 h. The reacton was quenched with water (100 ml.) and extracted with methylene chloride (2x 150 ml_), dried over anhydrous magnesium sulfate and concentrated to afford a yellow oil. Chromatography (15 % ethyl acetate/hexanes) afforded 5.5 g of desired product as a solid: mp=37-38°C;

MS (El) m/z 300;

HRMS: calculated for Ci ₄ H ₈ F ₄ OS ₁ 300.02320; found (El ₁ M+.), 300.0233

Step 5. 6-Fluoro-10,10-dioxido-9H-thioxanthen-2-yl trifluoromethyl ether

OCF ₃

[0306] A mixture of 6-fluoro-2-(trifluoromethoxy)-9H-thioxanthene (5.3 g, 17.6 mmol), 30% hydrogen peroxide (20 ml_) and glacial acetic acid (30 ml_) was reacted according to Example 5 (step 4) and worked up and purified (ISCO: 0%-20% ethyl acetate) to afford 5.1 g (87 %) of the desired product as a solid: mp=85-86°C. MS (ES) m/z 330.9;

HRMS: calculated for Ci ₄ H ₈ F ₄ O ₃ S ₁ 332.01303; found (El, M+.), 332.0135

Step 6. 6-Fluoro-9,9-dimethyl-10,10-dioxido-9H-thioxanthen-2-yl trifluoromethyl ether

[0307] The title compound was prepared according to Example 7 (step 1 ) using 6- fluoro-10,10-dioxido-9H-thioxanthen-2-yl trifluoromethyl ether (3.8 g, 11.4 mmol), 60 % sodium hydride (1.37 g, 34.3 mmol) and methyl iodide (6.84 g, 48.2 mmol) to afford after chromatography 3.86 g (93.6 %) of desired product as a white solid: mp=86-87°C.

MS (ES) m/z 361.0;

HRMS: calculated for Ci ₆ Hi ₂ F ₄ O ₃ S, 360.04433; found (El ₁ M+.), 360.0444

Step 7. 6-Fluoro-9,9-dimethyl-10,10-dioxido-9H-thioxanthen-2-yl trifluoromethyl ether-3-sulfonyl chloride

[0308] A mixture of 6-fluoro-9,9-dimethyl-10,10-dioxido-9H-thioxanthen-2-yl trifluoromethyl ether ( 2.37 g, 6.58 mmol) and chlorosulfonic acid (3.83 g, 32.9 mmol) was heated to 100 ⁰ C for 23 h. The reaction was allowed to cool to room temperature and poured into ethyl acetate and washed with water, brine, and dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the dark oily residue was triturated with ether. The mother liquor was concentrated and triturated with ether to afford 965 mg (32 %) of the desired product as a grayish solid.

Step 8. 6-Fluoro-9,9-dimethyl-N-(2-pyridin-3-ylethyl)-2-(trifluorome thoxy)-9H- thioxanthene-3-sulfonamide 10, 10-dioxide

Y v ⁸ Y°

^OCF ₃

[0309] A solution of 6-fluoro-9,9-dimethyl-10,10-dioxido-9H-thioxanthen-2-yl trifluoromethyl ether-3-sulfonyl chloride (590 mg, 1.28 mmol), 3-(2-aminoethyl) pyridine (236 mg, 1.93 mmol), triethylamine (375 mg, 3.72 mmol) in methylene chloride (6 ml_) was allowed to stir for 30 minutes. The solvent was removed and the crude residue purified by ISCO chromotrography (10%-100% ethyl acetate/hexanes) to afford 340 mg (48.8 %) of the desired product as a white solid: mp=199-200 C.

MS (ES) m/z 545.1 ;

HRMS: calculated for C ₂₃ H ₂₀ F ₄ N ₂ O ₅ S ₂ + H+, 545.08225; found (ESI ₁ [M+H] ⁺ ), 545.0825

Example 81 : β-Fluoro-9,9-dimethyl-N-piperidin-4-yl-2-(trifluoromethoxy) -9H- thioxanthene-3- sulfonamide 10,10-dioxide

Step 1. tert-Butyl 4-({[6-fluoro-9,9-dimethyl-10,10-dioxido-2-(trifluoromethoxy )-9H- thioxanthen-3-yl]sulfonyl}am ino)piperidine-1 -carboxylate OC

[0310] A solution of 6-fluoro-9,9-dimethyl-10,10-dioxido-9H-thioxanthen-2-yl trifluoromethyl ether-3-sulfonyl chloride (1.4 g, 3.05 mmol), tert-buty A-

aminopiperidine (918 mg, 4.6 mmol) triethylamine (924 mg, 9.1 mmol) in methylene chloride (50 ml_) was allowed to stir for 1.5 h. The solvent was removed to afford a foamy solid that was triturated with ether. The filtrate was concentrated and the solid triturated with hot ethyl acetate and filtered to afford 510 mg (27 %) of desired product as a tan solid: mp=236-238°C.

[0311] MS (ES) m/z 620.7;

HRMS: calculated for C ₂₆ H ₃₀ F ₄ N ₂ O ₇ S ₂ + H+, 623.15033; found (ESI, [M+H] ^* ), 567.0728

Step 2. 6-Fluoro-9,9-dimethyl-N-piperidin-4-yl-2-(trifluoromethoxy)- 9H-thioxanthene- 3- sulfonamide 10,10-dioxide

[0312] A mixture of tert-butyl 4-({[6-fluoro-9,9-dimethyl-10,10-dioxido-2-

(trifluoromethoxy)-9H- thioxanthen-3-yl]sulfonyl}amino)piperidine-1-carboxylate (295 mg, 0.48 mmol) and

4M HCI in dioxane (5 ml_) was heated to 6O ⁰ C for 15 minutes. The reaction was allowed to cooled to room temperature and the solid filtered to afford 269 mg (100

%) of the desired product as a white solid: mp=280-285°C.

MS (ES) m/z 522.8;

HRMS: calculated for C _2I H ₂₂ F ₄ N ₂ O ₅ S ₂ + H+, 523.09790; found (ESI ₁ [M+H] ^* ), 523.0976

Example 82: 2'-Chloro-6'-fluoro-N-piperidin-4-ylspiro[cyclohexane-1 ,9'- thioxanthene]-3'- sulfonamide 10', 10" -dioxide

Step 1. 2-(4-Chlorophenylthio)-4-fluorobenzoic acid

CO ₂ H

[0313] A mixture of 2-bromo-4-fluoro-benzoic acid (15 g, 68.5 mmol), 4-chloro benzenethiol (10.9 g, 75.3 mmol), potassium carbonate (18.9 g, 137 mmol) and copper powder (1.09 g, 17.1 mmol) in anhydrous dimethylformamide (100 ml_) was heated to 15O ⁰ C for 4 hours. The reaction was poured into water (200 ml_) and acidified with HCI , then extracted with methylene chloride (2x 30OmL). The organic layers were dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum. The crude product was washed with methanol to afford a yellowish solid (3.0 g). The mother liquor was concentrated and allowed to stand overnight to afford another batch of desired product (1.61 g). Total yield: 4.61 g (53.4 %). A sample was recrystallized from ethanol; mp= 197-198°C; MS (ESI) m/z 281.

Step 2. 2-Chloro-6-fluoro-9H-thioxanthen-9-one

[0314] 2-(4-Chlorophenylthio)-4-fluorobenzoic acid (16.8 g, 50.2 mmol) was treated with sulfuric acid according to Example 5 (step 2) to afford 14.8 g ( 93 %) of desired product as a light orange solid: MS (El) m/z 264.

Step 3. 2-Chloro-6-fluoro-9H-thioxanthene

[0315] 2-Chloro-6-fluoro-9H-thioxanthen-9-one (14.2 g, 53.6 mmol) was reacted according to Example 5 (step 3) to afford 13. 4 g (100 %) of desired product as a white solid.

[0316] MS (El) m/z 249;

HRMS: calculated for Ci ₃ H ₈ CIFS ₁ 250.00192; found (El, M+.), 248.9955

Step 4. 2-Chloro-6-fluoro-9H-thioxanthene 10,10-dioxide

[0317] 2-Chloro-6-fluoro-9H-thioxanthene (13.4 g, 53.4 mmol) was treated with 30

% hydrogen peroxide according to Example 5 (step 4) to afford 11.88 g (78.7 %) of desired product as a yellowish white solid.

MS (ES) m/z 282.7;

HRMS: calculated for Ci ₃ H ₈ CIFO ₂ S, 281.99176; found (El ₁ M+.), 281.9943

Step 5. 2'-Chloro-6'-fluorospiro[cyclohexane-1 ,9'-thioxanthene] 10',10'-dioxide

[0318] 2-Chloro-6-fluoro-9H-thioxanthene 10,10-dioxide (11.8 g, 41.7 mmol) and

1 ,5-diiodopentane (14.87 g, 45.9 mmol) were reacted according to Example 7 (step

1 ) to afford 8.2 g (56.4 %) the title compound.

MS (El) m/z 350;

HRMS: calculated for Ci ₈ H ₁₆ CIFO ₂ S ₁ 350.05435; found (El, M+.), 350.0548

Step 6. Z-Chloro-β'-fluorospiroIcyclohexane-i .θ'-thioxanthene] 10',10'-dioxide-3- sulfonyl chloride

[0319] To a solution of 2 ^l -chloro-6'-fluorospiro[cyclohexane-1 ,9'-thioxanthene] 10',10'-dioxide (1.27 g, 3.62 mmol) in dichloroethane (20 ml.) was added chlorosulfonic acid (1.26 g, 10.86 mmol) and heated at reflux overnight. Another portion of chlorosulfonic acid (10.86 mmol) was added and the reaction was allowed to stir at reflux for another 24 h. The reaction was allowed to cool to room temperature and poured into ethyl acetate (200 mL) and washed with water, dried

over anhydrous sodium sulfate and concentrated. Chromatography (10%-20% ethyl acetate/hexanes) afforded 750 mg (46.1 %) of the title compound.

Step 7. tert-Butyl 44[(2'^hloro-6 ^l -fluoro-10',10'-dioxidospiro[cyclohexane-1 ,9 ^l - thioxanthen]-3'-yl)sulfonyl]amino}piperidine-1-carboxylate

[0320] To a solution of 2'-chloro-6'-fluorospiro[cyclohexane-1 ,9'-thioxanthene] 10',10'-dioxide-3-sulfonyl chloride (750 mg, 1.67 mmol) and ), tert-buty A- aminopiperidine (0.501 g, 2.5 mmol) in methylene chloride (20 ml_) was added triethylamine (3 equiv) and allowed to stir for 1 h. The reaction mixture was poured into methylene chloride (100 ml_) and washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Chromatography using the ISCO (0% to 85 % ethyl acetate/hexanes) afforded 760 mg (74 %) of the desired product as a white solid.

[0321] MS (ES) m/z 610.7;

HRMS: calculated for C ₂₈ H ₃₄ CIFN ₂ O ₆ S ₂ + H+, 613.16036; found (ESI, [M+H- C4H8] ⁺ ), 557.0939

Step 8. 2'-Chloro-6'-fluoro-N-piperidin-4-ylspiro[cyclohexane-1 ,9'-thioxanthene]-3'- sulfonamide 10',10'-dioxide

[0322] A solution of tert-butyl 4-{[(2 ^l -chloro-6'-fluoro-10 ^l ,10'- dioxidospiro[cyclohexane-1 ,9'-thioxanthen]-3'-yl)sulfonyl]amino}piperidine-1- carboxylate (660 mg, 1.076 mmol) in 4 M HCI in doxane (10 ml_) was heated to 60 C for 30 minutes. The solid was filtered and washed with ether (20 ml_) and dried to afford 558 mg (99 %) of desired product: mp=208-212°C.

[0323] MS (ES) m/z 512.8;

HRMS: calculated for C ₂₃ H ₂₆ CIFN ₂ O ₄ S ₂ + H+, 513.10793; found (ESI, [M+H]*), 513.1062

Example 83: 2 ^l -Chloro-6'-fluoro-N-[1-(phenylsulfonyl)piperidin-4- yl]spiro[cyclohexane-1,9'- thioxanthene]-3' -sulfonamide 10',10' -dioxide

[0324] A mixture of 2'-chloro-6'-fluoro-N-piperidin-4-ylspiro[cyclohexane-1 ,9'- thioxanthene]-3'- sulfonamide 10',10'-dioxide (91 mg, 0.166 mmol), triethylamine (5 equiv) and benzenesulfonyl chloride in methylene chloride (8 ml_) was allowed to stir overnight at room temperature. The product was purified by ISCO chromatography unit (0% to 100% ethyl acetate in hexanes) to afford 93.7 mg (86.6 %) of desired product as a white solid.

MS (ES) m/z 650.8;

HRMS: calculated for C ₂₉ H ₃₀ CIFN ₂ O ₆ S ₃ + H+, 653.10113; found (HRMS, [M+H] ⁺ ), 653.1022

Example 84: 2'-Chloro-6'-fluoro-N-[1 -{pyιϊdin-3-ylcarbonyl)piperidin-4- yl]spiro[cyclohexane- 1,9'-thioxanthene]-3' -sulfonamide 10',1O" -dioxide

^V N

[0325] The title compound was prepared in an analogous fashion to Example 83 using nicotinyl chloride hydrochloride in 79.6 % yield.

[0326] MS (ESI) m/z 618;

HRMS: calculated for C ₂₉ H ₂₉ CIFN ₃ O ₅ S ₂ + H+, 618.12939; found (HRMS, [M+H] ⁺ ), 618.1245

Example 85: 2 ^l -Chloro-6'-fluoro-N-(1-isonicotinoylpiperidin-4- y l)spiro[cyclohexane-1, 9'- thioxanthene]-3' -sulfonamide 10', 10' -dioxide

H

[0327] The title compound was prepared in an analogous fashion to Example 83 using isonicotinyl chloride hydrochloride in 60.7 % yield.

MS (ESI) m/z 618;

HRMS: calculated for C ₂₉ H ₂₉ CIFN ₃ O ₅ S ₂ + H+, 618.12939; found (HRMS, [M+H] ⁺ ),

618.1147

Example 86: N-{4-[(4-{[(2 ^> -chloro-6 ^> -fluoro-10 ^> ,10 ^> -dioxidospiro[cyclohexane- 1 ,9'-thioxanthen]-3'-yl)sulfonyl]amino}piperidin-1 - yl)sulfonyl]phenyl}acetamide.

[0328] The title compound was prepared in an analogous fashion to Example 83 using 4-acetamidobenzene-1-sulfonyl chloride in 87.6 % yield.

MS (ES) m/z 709.8;

HRMS: calculated for C ₃₁ H ₃₃ CIFN ₃ O ₇ S ₃ + H+, 710.12259; found (HRMS, [M+H] ⁺ ),

710.1235

Example. 87. 4-(4-{[(2'-Chloro-6 ^t -fluoro-10\10'-dioxidospiro[cyclohexane-1 ,9'- thioxanthen]- 3'-yl)sulfonyl]amino}piperidin-1 -yl)-4-oxobutanoic acid.

[0329] The title compound was prepared in an analogous fashion to Example 83 using succinic anhydride in 73 % yield.

[0330] MS (ES) m/z 612.8;

HRMS: calculated for C ₂₇ H ₃₀ CIFN ₂ O ₇ S ₂ + H+, 613.12397; found (HRMS, [M+H]*), 613.12

Example 88: 5-(4-{[(2 ^l -Chloro-6 ^l -fluoro-10 ^l ,10 ^l -dioxidospiro[cyclohexane-1,9 ¹ - thioxanthen]- 3'-yl)sulfonyl]amino}piperidin-1-yl)-5-oxopentanoic acid.

O O

Q _v JO "OH

%//

[0331] The title compound was prepared in an analogous fashion to Example 83 using malonic anhydride in 76.3 % yield.

[0332] MS (ES) m/z 626.8;

HRMS: calculated for C ₂₈ H ₃₂ CIFN ₂ O ₇ S ₂ + H+, 627.13962; found (HRMS, [M+H] ⁺ ), 627.1426

Example 89: 4^[(4^[(2'-Chloro45'-fluoro-10\10'<lioxidospiro[cyclohexa rιe-1,9 ^l - thioxanthen]-3'-yl)sulfonyl]amino}pipehdin-1-yl)carbonothioy l]amino}benzoic acid.

The title compound was prepared in an analogous fashion to Example 83 using 4- isothiocyanatobenzoic acid in 45.6 % yield.

[0333] MS (ES) m/z 691.8;

HRMS: calculated for C ₃ IH ₃ ICIFN ₃ O ₆ S ₃ + H+, 692.11203; found (HRMS, [M+H] ⁺ ), 692.1133

Example 90: S^K^K∑'-chloro-β'-fluoro-IO'.IO'-dioxidospiroIcyclohexane -i ,9'- thioxanthen]-3'-yl)sulfonyl]amino}piperidin-1-yl)carbonothio yl]amino}benzoic acid.

O ₅ H

[0334] The title compound was prepared in an analogous fashion to Example 83 using 3-isothiocyanatobenzoic acid in 100 % yield.

MS (ES) m/z 691.8;

HRMS: calculated for C _3I H _3I CIFN ₃ O ₆ S ₃ + H+, 692.11203; found (HRMS, [M+H] ⁺ ), 692.111

Example 91 : 4-[(4-([(2 ^t -Chloro-€'-fluoro-10 ^l ,10'-dioxidospiro[cyclohexane-1,9'- thioxanthen]-3'-yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]be nzoic acid.

O ₂

- ^S λ /r ⁰⁰ *"

[0335] The title compound was prepared in an analogous fashion to Example 83 using 4-(chlorosulfoπyl)benzoic acid in 37 % yield.

[0336] MS (ES) m/z 694.8;

HRMS: calculated for C ₃₀ H ₃₀ CIFN ₂ O ₈ S ₃ + H+, 697.09096; found (HRMS, [M+H] ⁺ ), 697.0923

Example 92: 3-[(4-{[(2 ^I -Chloro-6 ^l -fluoro-10 ^l ,10 ^l -dioxidospiro[cyclohexane-1,9 ¹ - thioxanthen]-3'-yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]be nzoic acid.

[0337] The title compound was prepared in an analogous fashion to Example 83 using 3-(chlorosulfonyl)benzoic acid in 83.8 % yield.

MS (ES) m/z 694.8;

HRMS: calculated for C ₃ OH ₃₀ CIFN ₂ O ₈ S ₃ + H+, 697.09096; found (HRMS, [M+H] ⁺ ),

697.0897

Example 93: 2-Methyl-N-(2-phenylethyl)-10,11-dihydrodibenzo[b,f]thiepine -3- sulfonamide 5,5- dioxide.

Step 1. {2-[(4-Methylphenyl)thio]phenyl}acetic acid

CO ₂ H

[0338] A mixture of 4-methyl benzene thiol (12.85 g, 104 mmol), 2-iodo-phenyl acetic acid (24.7 g, 94.2 mmol), copper powder (1.01 g) and potassium hydroxide (26.1 g, 471 mmol) in water (600 ml_) was heated to reflux overnight. The reaction filtered to remove the copper salts and made acidic with concentrated HCI and diluted with water. The aqueous layer (1 L) was filtered to afford the desired product as a solid that was triturated with methanol to afford 13.36 g of white solid (55 %).

[0339] MS (ESI) m/z 257;

HRMS: calculated for Ci ₅ Hi ₄ O ₂ S + H+, 259.07873; found (ESI, [M+Hf), 259.0786

Step 2. 8-Methyldibenzo[b,f]thiepin-10(11 H)-one

[0340] 2-[(4-Methylphenyl)thio]phenyl}acetic acid (15.2 g, 58.9 mmol) was added to polyphosphoric acid (160 g) at 11O ⁰ C and allowed to stir for 18 h. The reaction mixture was cooled to room temperature and cautiously dissolved in water and neutralized with sodium carbonate. The mixture was extracted with ethyl acetate and the solvent removed under vacuum. The product was purified by chromatography (10 % ethyl aceate in hexanes) to afford 9.5 g (67 %) a light tan oil.

[0341] MS (ES) m/z 241.2;

HRMS: calculated for C15H12OS + H+, 241.06816; found (ESI ₁ [M+H] ⁺ ), 241.0674

Step 3. 2-Methyl-10,11-dihydrodibenzo[b,f]thiepine

[0342] A solution of 8-methyldibenzo[b,f]thiepin-10(11 H)-one (9.53 g, 39.71 mmol) and triethylsilane (20 ml_) in trifluoroacetic acid (40 ml_) was stirred at room temperature for 72 h. The reaction was quenched with aqueous sodium carbonate and extracted with ethyl acetate. Purification by chromatography on silica gel afforded 8.26 g (92 %) of product as a yellow oil.

[0343] MS (El) m/z 226;

HRMS: calculated for C15H14S, 226.08162; found (El, M+.), 226.0805

Step 4. 2-Methyl-10,11-dihydrodibenzo[b,f]thiepine 5,5-dioxide

[0344] To a mixture of 2-methyl-10,11 -dihydrodibenzo[b,f]thiepine (13.79 g, 61 mmol), oxone (113 g, 118 mmol) in water (400 ml) and methanol (400 mL) was allowed to stir overnight at room temperature. The reaction was extracted with ethyl aceate and washed with water and purified by chromatography (30 % ethyl acetate in hexanes) to afford 14 g (89 %) of desired product as a yellow solid.

[0345] MS (ES) m/z 259.2;

HRMS: calculated for Ci ₅ Hi ₄ O ₂ S + H+, 259.07873; found (ESI, [M+H] ⁺ ), 259.0781

Step 5. 2-Methyl-10,1 1-dihydrodibenzo[b,f]thiepine-3-sulfonyl chloride 5,5-dioxide

[0346] To a solution of 2-methyl-10,11-dihydrodibenzo[b,f]thiepine 5,5-dioxide (3.79 g, 14.7 mmol) in dichloroethane (125 mL) was added 1.1 mL of chlorosulfonic acid and heated overnight at reflux temperature. The reaction was diluted with water and extracted with ethyl acetate. Purification by chromatography afforded 2.14 g (43 %) of brown solid.

[0347] MS (ESI) m/z 337 (sulfonic acid);

HRMS: calculated for Ci ₅ Hi ₄ O ₅ S ₂ + H+, 339.03554; found (ESI-FTMS, [M+H] ^{1 +} ), 339.03596

Step 6. 2-Methyl-N-(2-phenylethyl)-10,11-dihydrodibenzo[b,f]thiepine -3-sulfonannide 5,5- dioxide.

[0348] A solution of 2-methyl-10,11-dihydrodibenzo[b,f]thiepine-3-sulfonyl chloride 5,5-dioxide (0.38 mmol), phenethylamine (0.418 mmol) and DIPEA (4 equiv) in acetonitrile (1 ml_) and methylene chloride (4 mL) was allowed to stir overnight at room temperature. The solvent was removed under vacuum, followed by purification by silica gel chromatography to afford 40 mg (24 %, 0.0912 mmol) of desired product.

[0349] MS (ES) m/z 442.1 ;

HRMS: calculated for C ₂₃ H ₂₃ NO ₄ S ₂ + H+, 442.11413; found (ESI, [M+H] ⁺ ), 442.1161

Example 94: N-[2-<2-Fluorophenyl)ethyl]-2-methyl-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

" ^w v~,

"CH ₃

[0350] The title compound was prepared in an analogous fashion to Example 93 (step 6) using 2-fluoro-phenethylamine in 77 % yield.

[0351] MS (ES) m/z 458.0;

HRMS: calculated for C ₂₃ H ₂₂ FNO ₄ S ₂ + H+, 460.10470; found (ESI ₁ [M+H] ⁺ ), 460.1038

Example 95: 2- -Methyl-λ/-(2-pyridin-2-ylethyl)-10,11- dihydrodibenzo[6,/]thiepine-3-sulfonamide 5,5-dioxide.

CH ₃

[0352] The title compound was prepared in an analogous fashion to Example 93 (step 6) using 2-(2-aminoethyl)pyridine in 53 % yield.

[0353] MS (ES) m/z 441.1 ;

HRMS: calculated for C ₂₂ H ₂₂ N ₂ O ₄ S ₂ + H+, 443.10937; found (ESI, [M+H] ⁺ ), 443.1109

Example 96: 2-Methyl-N-(2-pyridin-3-ylethyl)-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

[0354] The title compound was prepared in an analogous fashion to Example 93 (step 6) using 3-(2-aminoethyl)pyridine in 37 % yield.

[0355] MS (ES) m/z 441.1 ;

HRMS: calculated for C ₂₂ H ₂₂ N ₂ O ₄ S ₂ + H+, 443.10937; found (ESI, [M+H] ⁺ ), 443.1092

Example 97: 2-Methyl-N-(2-pyridin-4-ylethyl)-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

[0356] The title compound was prepared in an analogous fashion to Example 93 (step 6) using 4-(2-aminoethyl)pyridine in 33 % yield.

[0357] MS (ES) m/z 441.1 ;

HRMS: calculated for C ₂₂ H ₂₂ N ₂ O ₄ S ₂ + H+, 443.10937; found (ESI, [M+H] ⁺ ), 443.1101

Example 98: N-{2,3-dihydro-1H-inden-2-yl)-2-methyl-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

[0358] The title compound was prepared in an analogous fashion to Example 93 (step 6) using 2-aminoindane in 44 % yield.

MS (ES) m/z 454.1 ;

HRMS: calculated for C ₂₄ H ₂₃ NO ₄ S ₂ + H+, 454.11413; found (ESI, [M+H] ⁺ ), 454.1 173 Example 99: N-Cyclopentyl-2-methyl-10,11-dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5- dioxide.

[0359] The title compound was prepared in an analogous fashion to Example 93 (step 6) using cyclopentylamine in 54 % yield.

MS (ES) m/z 406.1 ;

HRMS: calculated for C ₂₀ H ₂₃ NO ₄ S ₂ + H+, 406.11413; found (ESI, [M+H] ⁺ ), 406.1134 Example 100: 2-Methyl-N-(2-morpholin-4-ylethyl)-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

[0360] The title compound was prepared in an analogous fashion to Example 93

(step 6) using 4-(2-aminoethyl)morpholine in 15 % yield.

MS (ES) m/z 449.1 ;

HRMS: calculated for C ₂ I H ₂₆ N ₂ O ₅ S ₂ + H+, 451.13559; found (ESI, [M+H] ⁺ ),

451.1379

Example 101 : 2-Methyl-N-(3-morpholin-4-ylpropyl)-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

^■

[0361] The title compound was prepared in an analogous fashion to Example 93

(step 6) using 4-(3-aminoethyl)morpholine in 43 % yield.

MS (ES) m/z 463.1 ;

HRMS: calculated for C ₂₂ H ₂₈ N ₂ O ₅ S ₂ + H+, 465.15124; found (ESI, [M+H] ⁺ ),

465.1536

Example 102: 2-Methyl-N-(tetrahydro-2H-pyran-4-yl)-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

[0362] The title compound was prepared in an analogous fashion to Example 93 (step 6) using 4-aminotetrahydropyran in 14 % yield.

MS (ES) m/z 420.1 ;

HRMS: calculated for C ₂₀ H ₂₃ NO ₅ S ₂ + H+, 422.10904; found (ESI ₁ [M+H] ⁺ ), 422.1101 Example. 103. 2-Methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

[0363] The title compound was prepared in an analogous fashion to Example 93 (step 6) using 4-aminomethyltetrahydropyran in 40 % yield.

MS (ES) m/z 434.1 ;

HRMS: calculated for C ₂₁ H ₂₅ NO ₅ S ₂ + H+, 436.12469; found (ESI ₁ [M+H] ⁺ ), 436.1258 Example 104: 2-Methy l-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-10,11 - dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide.

[0364] The title compound was prepared in an analogous fashion to Example 93 (step 6) using 4-aminoethylltetrahydropyran in 44 % yield.

MS (ES) m/z 448.1 ;

HRMS: calculated for C ₂₂ H ₂₇ NO ₅ S ₂ + H+, 450.14034; found (ESI ₁ [M+H] ⁺ ), 450.1408 Example 105: N-(2-Hydroxy-2-phenylethyl)-2-methyl-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

[0365] The title compound was prepared in an analogous fashion to Example 93

(step 6) using 2-amino-1-phenylethanol in 70 % yield.

MS (ES) m/z 456.1 ;

HRMS: calculated for C ₂₃ H ₂₃ NO ₅ S ₂ + H+ - H+, 457.10176; found (ESI, [M+H-H20] ^* ),

440.1071 ;

Example 106: N-(2-Hydroxy-1-methyl-2-phenylethyl)-2-methyl-10,11- dihydrodibenzo[b,f]thiepine- 3-sulfonamide 5,5-dioxide.

[0366] The title compound was prepared in an analogous fashion to Example 93

(step 6) using 2-amino-1-phenypropan-1-ol in 73 % yield.

MS (ES) m/z 470.0;

HRMS: calculated for C ₂₄ H ₂₅ NO ₅ S ₂ + H+ - H+, 471.11741 ; found (ESI, [M+H-H20]*),

454.131

Example 107: N-(2-cyanoethyl)-2-methyl-10,11-dihydrodibenzo[b,f|thiepine- 3- sulfonamide 5,5- dioxide.

[0367] The title compound was prepared in an analogous fashion to Example 93

(step 6) using 3-aminopropanenitrile in 91 % yield.

MS (ES) m/z 389.0;

HRMS: calculated for Ci ₈ H ₁₈ N ₂ O ₄ S ₂ + H+, 391.07807; found (ESI, [M+H] ⁺ ),

391.0794

Example 108: 2-Methyl-N-piperidin-4-yl-10,11-dihydrodibenzo[b,f]thiepine- 3- sulfonamide 5,5- dioxide.

[0368] The title compound was prepared in an analogous fashion to Example 82

(step 7) using tert-butyl-4-aminopiperidine in 84 % yield. This material was treated according to the conditions used in Example 81 (step 2) to afford the desired product in 47 % yield.

MS (ES) m/z 420.7;

HRMS: calculated for C ₂₀ H ₂₄ N ₂ O ₄ S ₂ + H+, 421.12502; found (ESI, [M+H] ⁺ ),

421.1238

Example 109: 7-Fluoro-2-isopropyl-N-(2-phenylethyl)-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

Step 1. {4-Fluoro-2-[(4-isopropylphenyl)thio]phenyl}acetic acid.

[0369] The title compound was prepared according to similar conditions used in Example 5 (step 1 ) starting with 4-isopropylbenzenethiol (15 g, 98.5 mmol) and 2-(2- bromo-4-fluorophenyl)acetic acid to afford 21.2 g (71 %) of a white solid.

MS (ES) m/z 303.1 ;

HRMS: calculated for Ci ₇ Hi ₇ FO ₂ S - H+, 303.08605; found (ESI, [M-C02-H] ), 259.0960

Step 2. 3-Fluoro-8-isopropyldibenzo[b,f]thiepin-10(11H)-one

[0370] To a solution of {4-fluoro-2-[(4-isopropylphenyl)thio]phenyl}acetic acid (17.56 g, 57.7 mmol) in THF (250 ml_) was added thionyl chloride (10.3 g, 86.5 mmol) followed by DMF (1 ml_). After 1.5 hours the THF was removed under vacuum and methylene chloride (250 ml_) was added, followed by aluminum chloride (9.2 g, 69.2 mmol) and allowed to stir at room temperature for 2 h. The reaction was poured into water (500 ml.) and extracted with ethyl acetate (2 x 300 ml_). The organic layer was washed with water and the solvent removed under vacuum. The product was purified by ISCO chromatography to afford 12.36 g (75 %) of a yellow solid.

MS (ES) m/z 287.1 ;

HRMS: calculated for Ci ₇ H ₁₅ FOS + H+, 287.09004; found (ESI, [M+H] ⁺ ), 287.0916

Step 3. 7-Fuoro-2-isopropyl-10,11-dihydrodibenzo[b,f]thiepine

[0371] The title compound was prepared according to similar conditions used in Example 93 (step 3) to afford 7.05 g (91 %) of a clear colorless oil. HRMS: calculated for Ci ₇ Hi ₇ FS, 272.10350; found (El ₁ M+.), 272.1040

Step 4. 7-Fluoro-2-isopropyl-10,1 1 -dihydrodibenzo[b,f]thiepine 5,5-dioxide

^F

[0372] The title compound was prepared according to similar conditions used in Example 1 (step 3) to afford 7.26 g (96 %) of a clear colorless oil.

Step 5. 7-Fluoro-2-isopropyl-10,1 1 -dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide

[0373] The title compound was prepared according to similar conditions used in Example 93 (step 5) to afford 4.65 g (94 %) of a tan solid.

Step 6. 7-Fluoro-2-isopropyl-N-(2-phenylethyl)-10,11 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

[0374] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide and phenethylamine to afford 273 mg (73 %) of desired product.

MS (ESI) m/z 488;

MS (ESI) m/z 486;

HRMS: calculated for C ₂₅ H ₂₆ FNO ₄ S ₂ + H+, 488.13600; found (ESI, [M+H] ⁺ ), 488.136

Example 110: 7-Fluoro-N-[2-<2-fluorophenyl)ethyl]-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide.

[0375] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide and 2-fluoro-phenethylamine to afford 271 mg (70 %) of desired product.

MS (ESI) m/z 506;

MS (ESI) m/z 504;

HRMS: calculated for C ₂₅ H ₂₅ F ₂ NO ₄ S ₂ + H+, 506.12658; found (ESI ₁ [M+H] ^* ), 506.1249

Example 111 : 7-Fluoro-2-isopropyl-N-(2-pyridin-2-ylethyl)-10,11- dihydrodibenzo[b,f]thiepine- 3-sulfonamide 5,5-dioxide.

[0376] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide and 2-(2-aminoethyl)pyridine to afford 275 mg (73 %) of desired product.

MS (ESI) m/z 489;

MS (ESI) m/z 487;

HRMS: calculated for C ₂₄ H ₂₅ FN ₂ O ₄ S ₂ + H+, 489.13125; found (ESI, [M+H] ⁺ ), 489.1358

Example 112: 7-Fluoro-2-isopropyl-N-(2-pyridin-3-ylethyl)-10,11 - dihydrodibenzo[b,f]thiepine- 3-sulfonamide 5,5-dioxide.

[0377] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide and 3-(2-aminoethyl)pyridine to afford 265 mg (70 %) of desired product.

MS (ESI) m/z 489;

MS (ESI) m/z 487;

HRMS: calculated for C ₂₄ H ₂₅ FN ₂ O ₄ S ₂ + H+, 489.13125; found (ESI, [M+H] ⁺ ), 489.131

Example 113: 7-Fluoro-2-isopropyl-N-(2-pyridin-4-ylethyl)-10,11- dihydrodibenzo[b,f]thiepine- 3-sulfonamide 5,5-dioxide.

[0378] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide and 4-(2-aminoethyl)pyridine to afford 221 mg (59 %) of desired product.

MS (ESI) m/z 489;

MS (ESI) m/z 487;

HRMS: calculated for C ₂₄ H ₂₅ FN ₂ O ₄ S ₂ + H+, 489.13125; found (ESI, [M+H] ⁺ ), 489.1294

Example 114: N-(2,3-Dihy dro-1 H-inden-2-y l)-7-fluoro-2-isopropyl-10,11 - dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide.

[0379] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide and 2-aminoindane to afford 265 mg (69 %) of desired product.

MS (ESI) m/z 500;

MS (ESI) m/z 498;

HRMS: calculated for C ₂₆ H ₂₆ FNO ₄ S ₂ + H+, 500.13600; found (ESI, [M+H]*), 500.1373

Example 115: N-cyclopentyl-7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

[0380] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide and cyclopentylamine to afford 255 mg (73 %) of desired product.

MS (ESI) m/z 452;

MS (ESI) m/z 450;

HRMS: calculated for C ₂₂ H ₂₆ FNO ₄ S ₂ + H+, 452.13600; found (ESI, [M+H] ⁺ ), 452.1351

Example 116: 7-Fluoro-2-isopropy l-N-(2-morpholin-4-ylethyl)-10,11 - dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide.

[0381] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide and 4-(2-aminoethyl)morpholine to afford 262 mg (69 %) of desired product.

MS (ESI) m/z 497;

MS (ESI) m/z 495;

HRMS: calculated for C ₂₃ H ₂₉ FN ₂ O ₅ S ₂ + H+, 497.15747; found (ESI, [M+H] ⁺ ), 497.1588

Example 117: 7-Fluoro-2-isopropyl-N-(3-morρholin-4-ylpropyl)-10,11 - dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide.

[0382] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide and 4-(3-aminopropyl)morpholine to afford 279 mg (71 %) of desired product.

MS (ESI) m/z 511 ;

MS (ESI) m/z 509;

HRMS: calculated for C ₂₄ H ₃ IFN ₂ O ₅ S ₂ + H+, 511.17312; found (ESI, [M+H] ⁺ ), 511.1709

Example 118: 7-Fluoro-2-isopropyl-N-(tetrahydro-2H-pyran-4-yl)-10,11 ■ dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide.

[0383] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide and 4-aminotetrahydropyran to afford 35 mg (10 %) of desired product.

MS (ESI) m/z 468;

MS (ESI) m/z 466;

HRMS: calculated for C ₂₂ H ₂₆ FNO ₅ S ₂ + H+, 468.13092; found (ESI, [M+H] ⁺ ), 468.1328

Example 119: 7-Fluoro-2-isopropyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-10,1 1- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide.

[0384] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide and 4- aminomethyltetrahydropyran to afford 285 mg (77 %) of desired product. MS (ESI) m/z 482;

MS (ESI) m/z 480;

HRMS: calculated for C ₂₃ H ₂₈ FNO ₅ S ₂ + H+, 482.14657; found (ESI ₁ [M+H] ⁺ ), 482.1483

Example 120: 7-Fluoro-2-isopropyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-1 0,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide.

[0385] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide and 4(2- aminoethyl)tetrahydropyran to afford 306 mg (80 %) of desired product. MS (ESI) m/z 496;

MS (ESI) m/z 494;

HRMS: calculated for C ₂₄ H ₃₀ FNO ₅ S ₂ + H+, 496.16222; found (ESI ₁ [M+H]*), 496.1609

Example 121 : 7-Fluoro-2-isopropyl-N-(3-phβnylpropyl)-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

[0386] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide and 3-phenyl-propylamine to afford 254 mg (66 %) of desired product.

MS (ESI) m/z 502;

MS (ESI) m/z 500;

HRMS: calculated for C ₂₆ H ₂₈ FNO ₄ S ₂ + H+, 502.15165; found (ESI, [M+H] ⁺ ), 502.1494

Example 122: 7-Fluoro-2-isopropyl-N-(2-phenoxyethyl)-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide

[0387] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 7-fluoro-2-isopropyl-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonyl 5,5-dioxide and 3-phenoxyethylamine to afford 274 mg (71 %) of desired product.

MS (ESI) m/z 504;

MS (ESI) m/z 502;

HRMS: calculated for C ₂₅ H ₂₆ FNO ₅ S ₂ + H+, 504.13092; found (ESI, [M+H] ⁺ ), 504.131

Example 123: N-Benzyl-7-fluoro-2-isopropyl-10,11- dihydrodi benzo[b,f]thi epi ne-3-sulf onami de 5,5-dioxide

[0388] The title compound was prepared according to similar conditions used in Example 93 (step 6) to afford 75 mg (21 %) of desired product.

MS (ESI) m/z AlA ₁

MS (ESI) m/z 472;

HRMS: calculated for C ₂₄ H ₂₄ FNO ₄ S ₂ + H+, 474.12035; found (ESI, [M+H] ⁺ ), 474.1222

Example 124: 2-Chloro-7-fluoro-N-(tetrahydro-2H-pyran-4-yl)-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide.

Step 1. {2-[(4-Chlorophenyl)thio]-4-fluorophenyl}acetic acid

[0389] The title compound was prepared according to similar conditions used in Example 5 (step 1 ) starting with 4-chlorobenzenethiol (18.7, 129 mmol) and 2-(2- bromo-4-fluorophenyl)acetic acid (25.1 g, 107 mmol) to afford 29.9 g (94 %) of a white solid.

Step 2. 8-Chloro-3-fluorodibenzo[b,f]thiepin-10(11 H)-one

[0390] The title compound was prepared according to similar conditions used in Example 93 (step 2) to afford 12.7 g (83 %) of desired product.

Step 3. 2-Chloro-7-fluoro-10,11-dihydroclibenzo[b,f]thiepine.

[0391] The title compound was prepared according to similar conditions used in Example 93 (step 3) to afford 10.75 g (89 %) of desired product. HRMS: calculated for Ci ₄ Hi ₀ CIFS, 264.01757; found (El ₁ M+.), 264.0168

Step 4. 2-Chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepine 5,5-dioxide.

[0392] The title compound was prepared according to similar conditions used in Example 5 (step 4) to afford 13.1 g (84 %) of desired product. MS (ES) m/z 296.8;

Step 5. 2-Chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepine-3-sulfon yl chloride 5,5- dioxide.

[0393] The title compound was prepared according to similar conditions used in Example 93 (step 5) to afford 1.33 g (40 %) of a white solid.

Step 6. 2-Chloro-7-fluoro-N-(tetrahydro-2H-pyran-4-yl)-10,11- dihydrodibeπzo[b,f]thiepine-3-sulfonamide 5,5-dioxide.

[0394] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepine- 3-sulfonyl 5,5-dioxide and 4-aminotetrahydropyran to afford 110 mg (43 %) of desired product. MS (ESI) m/z 458

Example 125: 2-Chloro-7-f1uoro-N-(2-pyridin-4-ylethyl)-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepine-3-sulfon yl 5,5-dioxide and 4-(2-aminoethyl)pyridine to afford 180 mg (66 %) of desired product. MS (ESI) m/z 481 ;

HRMS: calculated for C ₂ I Hi ₈ CIFN ₂ O ₄ S ₂ + H+, 481.04533; found (ESI ₁ [M+H]*), 481.0453

Example 126: 2-Chloro-7-fluoro-N-(2-pyridiπ-3-ylethyl)-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

[0395] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepine- 3-sulfonyl 5,5-dioxide and 3-(2-aminoethyl)pyridine to afford 180 mg (66 %) of desired product.

MS (ESI) m/z 481 ;

HRMS: calculated for C ₂ I Hi ₈ CIFN ₂ O ₄ S ₂ + H+, 481.04533; found (ESI ₁ [M+H] ⁺ ), 481.0437

Example 127: tert-Butyl 4-{[(2-chloro-7-fluoro-5,5-dioxido-10,11- dihydrodi benzo[b,f]thiepin- 3-yl)sulfonyl]amino}piperidine-1 -carboxylate.

[0396] The title compound was prepared according to similar conditions used in Example 93 (step 6) employing 2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepine- 3-sulfonyl 5,5-dioxide and tert-butyl-4-aminopiρeridine to afford 920 mg (99 %) of desired product.

MS (ESI) m/z 557;

HRMS: calculated for C ₂₄ H ₂₈ CIFN ₂ O ₆ S ₂ + H+ + NH ₄ ⁺ , 577.14723; found (ESI ₁ [M+H+NH4] ^* ), 576.1354

Example 128: 2-Chloro-7-fluoro-N-piperidin-4-yl-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.

[0397] The title compound was prepared according to similar conditions used in

Example 39 (step 8) employing tert-butyl 4-{[(2-chloro-7-fluoro-5,5-dioxido-10,11- dihydrodibenzo[b,f]thiepin- 3-yl)sulfonyl]amino}piperidine-1-carboxylate to afford 550 mg (81 %) of desired product.

MS (ES) m/z 458.6;

HRMS: calculated for Ci ₉ H ₂₀ CIFN ₂ O ₄ S ₂ + H+, 459.06098; found (ESI, [M+H] ^* ),

459.062

Example 129: 7-Fluoro-N-piperidin-4-yl-2-{trifluoromethyl)-10,11- dihydrodibenzo[b,f]thiepine- 3-sulfonamide 5,5-dioxide

Step 1. 2-Chloro-7-fluoro-3-nitro-10,11-dihydrodibenzo[b,f]thiepine 5,5-dioxide

[0398] To a solution of 2-chloro-7-fluoro-10,11 -dihydrodibenzo[b,f]thiepine 5,5- dioxide (1.0 g, 3.37 mmol) in 6 ml_ of concentrated sulfuric acid at 0 C was added nitric acid (0.21 g, 3.37 mmol) and allowed to stir for 2 minutes. The reaction was quenched by rapid addition of ice water. The resulting light yellow solid was collected by filtration, dried over anhydrous sodium sulfate, filtered, and dissolved in acetone and concentrated onto silica gel. Purification on ISCO ( 0 5- 40 % ethyl acetate in hexanes) afforded 0.72 g (63 %) of a light yellow solid. MS (ES) m/z 339.6

Step 2. 7-Fluoro-3-nitro-2-(trifluoromethyl)dibenzo[b,f]thiepine 5,5-dioxide

[0399] To a mixture of 2-chloro-7-fluoro-3-nitro-10,11-dihydrodibenzo[b,f]thiepine 5,5-dioxide (0.99 g, 2.9 mmol), copper powder (nanosize) (1.14 g, 17.4 mmol), carbon (100 mesh, 0.52 g, 43 mmol) in dimethylacetamide (20 ml_) at room temperature was added difluorodibromomethane (1.22g, 5.79 mmol). The reaction was overnight at 100 C. The reaction mixture was filtered through celite and rinsed with ethyl acetate (20 mL). The combined organic layers were washed with water, and the organic solvent removed and the product purified on silica using the ISCO to afford 300 mg (28 %) of the title compound as a yellow solid. MS (El) m/z 373;

HRMS: calculated for Ci ₅ H ₇ F ₄ NO ₄ S, 373.00319; found (El ₁ M+.), 373.0071

Step 3. 7-Fluoro-2-(trifluoromethyl)-10 _l 11-dihydrodibenzo[b,f]thiepin-3-amine 5,5- dioxide and 7-fluoro-2-(trifluoromethyl)dibenzo[b,f]thiepin-3-amine 5,5-dioxide.

[0400] A mixture of 7-fluoro-3-nitro-2-(trifluoromethyl)dibenzo[b,f]thiepine 5,5- dioxide (2.15 g, 5.75 mmol) Pd/C (200 mg) in ethanol (100 ml_) was shaken under hydrogen pressure (40 psi) overnight. Another portion of Pd/C (300 mg) was added and the reaction was shaken for another 24 hours under hydrogen pressure (40 psi). TLC indicated two products were formed. The reaction was filtered through celite and the solvent removed under vacuum. Purification using the ISCO (0 %-60%) afforded 510 mg (26 %) of 7-fluoro-2-(trifluoromethyl)-10,11- dihydrodibenzo[b,f]thiepin-3-amine 5,5- dioxide followed by the slightly more polar 7- fluoro-2-(trifluoromethyl)dibenzo[b,f]thiepin-3-amine 5,5-dioxide (600 mg, 30 %). MS (ES) m/z 345.7;

HRMS: calculated for CI ₅ HHF ₄ NO ₂ S + H+, 346.05194; found (ESI, [M+H] ⁺ ), 346.0509

MS (ES) m/z 343.7;

HRMS: calculated for Ci ₅ H ₉ F ₄ NO ₂ S + H+, 344.03629; found (ESI, [M+H] ⁺ ), 344.0373

Step 4. 2-Trifluoromethyl-10,11-dihydrodibenzo[b,f]thiepine-3-sulfon yl chloride 5,5- dioxide

[0401] A suspension of CuCI ₂ in water (0.5 ml_) and acetic acid (10 ml_) was cooled to 0 C and SO ₂ was bubbled in with stirring for 40 minutes. In another flash, to a suspension of 7-fluoro-2-(trifluoromethyl)-10,11 -dihydrodibenzo[b,f]thiepin-3- amine 5,5- dioxide (430 mg, 1.25 mmol) in acetic acid ( 5 ml_), 12 N HCI (5 ml_) and water (2 ml.) at 0 C was added sodium nitrite and stirred for 25 minutes. This solution was added to the C11CI2/SO2 mixture and allowed to stir for 30 minutes. The reaction was partitioned between water (100 ml_) and ethyl acetate (150 ml_). The organic layer was washed with water, brine, and dried over anhydrous sodium

sulfate. The solvent removed under vacuum and purified by silica chromatography (ISCO: 0%-60% ethyl acetate in hexanes) to afford 140 mg (26 %) of the desired product.

[0402] MS (ES) m/z 345.7;

HRMS: calculated for C15H11F4NO2S + H+, 346.05194; found (ESI ₁ [M+H]+),

346.0509;

Step 5. tert-Butyl 4-{[(2-(trifluoromethyl)-7-fluoro-5,5-dioxido-10,11- dihydrodibenzo[b,f]thiepin- 3-yl)sulfonyl]amino}piperidine-1-carboxylate

[0403] The title compound was prepared according to similar conditions used in Example 39 (step 7) employing 2-trifluoromethyl-10,11 -dihydrodibenzo[b,f]thiepine-3- sulfonyl chloride 5,5- dioxide (0.14 g, 33 mmol) and tert-butyl-4-aminopiperidine (2 equiv) to afford 120 mg (61 %) of desired product.

Step 6. 7-Fluoro-N-piperidin-4-yl-2-(trifluoromethyl)-10,11- dihydrodibenzo[b,f]thiepine- 3-sulfonamide 5,5-dioxide

^

[0404] The title compound was prepared according to similar conditions used in Example 82 (step 8) employing tert-butyl 4-{[(2-(trifluoromethyl)-7-fluoro-5,5-dioxido-

10,11-dihydrodibenzo[b,f]thiepin- 3-yl)sulfonyl]amino}piperidine-1-carboxylate (120 mg, 0.2 mmol) to afford 81 mg (82 %) of the title compound.

MS (ES) m/z 492.7;

HRMS: calculated for C ₂₀ H ₂₀ F ₄ N ₂ O ₄ S ₂ + H+, 493.08734; found (ESI, [M+H]*),

493.0883

Example 130: 2,11-Dimβthyl-/V-(2-phenylβthyl)-10,11- dihydrodibenzo[6,/]thiepine-3-sulfonamide 5,5-dioxide.

Step 1. 8, 10-Dimethyl-10, 11 -dihydrodibenzo[b,f]thiepin-10-ol

[0405] A solution of 8-methyldibenzo[b,f]thiepin-10(11H)-one (1.0 g, 4.4 mmol) in THF (17 mL) was added to a solution of methylmagnesium bromide/ethyl ether (1.6 mL, 3.0 M, 4.8 mmol) in THF (45 mL) at room temperature. The solution was stirred for 1.5 h. The solvent was evaporated. The residue was partitioned with sat. NH ₄ CI and ethyl ether. The organic layer was washed once with water and dried over MgSO ₄ . The solvent was evaporated. The product was purified by chromatography with a gradient of hexane/CH ₂ CI ₂ to afford 0.51 g (45%) of product as an oil.

[0406] MS (ES) m/z 239.1 ;

HRMS: calculated for Ci ₆ Hi ₆ OS - H+ + H+, 256.09218; found (ESI ₁ [M-H20+HD, 239.0892

Step 2. 2,11-Dimethyl-10,11-dihydrodibenzo[b,/]thiepine

8,10-Dimethyl-10,11-dihydrodibenzo[b,f]thiepin-10-ol was used in an analogous fashion to Example 93 (step 3) to give the title compound as a colorless oil in 71% yield.

[0407] MS (El) m/z 240;

HRMS: calculated for Ci ₆ H ₁₆ S ₁ 240.09727; found (El, M+.), 240.0976

Step 3. 2,11-Dimethyl-10,11-dihydrodibenzo[fc,r]thiepine 5,5-dioxide

2,11-Dimethyl-10,11-dihydrodibenzo[6,f]thiepine was used in an analogous fashion to Example 93 (step 4) to give the title compound as a oil in 75% yield.

[0408] MS (ES) m/z 273.1

Step 4. 2, 11 -Dimethyl-λ/-(2-phenylethyl)-10, 1 1 -dihydrodibenzo[6,/]thiepine-3- sulfonamide 5,5-dioxide

[0409] 2,11 -Dimethyl-10,11-dihydrodibenzo[/?,flthiepine 5,5-dioxide (80 mg, 0.29 mmol) was used in an analogous fashion to Example 93 (Step 5) to give without purification 66 mg of crude 2,1 1 -dimethyl-10,11 -dihydrodibenzo[i3,/]thiepine-3- sulfonyl chloride 5,5-dioxide. This was dissolved in CH2CI2 (1.5 ml_). To the stirring solution was added 2-phenylethylamine (0.05 ml_, 0.4 mmol). The solution was stirred 2 days at room temperature. It was diluted with EtOAc, washed with 2N HCI

and dried over MgSCV The solvent was evaporated. The product was purified by chromatography with a gradient of EtOAc/CH ₂ CI ₂ to afford 32 mg (24%) of the title compound as a white solid.

[0410] MS (ESI) m/z 456;

HRMS: calculated for C ₂₄ H ₂₅ NO ₄ S ₂ + H+, 456.12978; found ([M+H]*), 456.1255

Example 131: 11-Ethyl-2-methyl-λ/-{2-pyridin-3-ylethyl)-10,11- dihydrodibenzo[ϋ,/]thiepine-3-sulfonamide 5,5-dioxide

Step 1. 10-Ethyl-8-methyl-10,1 1-dihydrodibenzo[λ,flthiepin-10-ol

[0411] In an analogous fashion to Example 130 (step 1 ), ethylmagnesium bromide was used to give the title compound as a solid in 22% yield.

[0412] MS (ES) m/z 253.1 ;

HRMS: calculated for Ci ₇ H ₁₈ OS + H+, 271.1 1511 ; found (ESI ₁ [M+H] ⁺ ), 271.1 15

Step 2. 1 1-Ethyl-2-methyl-10,1 1-dihydrodibenzo[ύ,/]thiepine

[0413] 10-Ethyl-8-methyl-10,11 -dihydrodibenzo[d,/]thiepin-10-ol was used in an analogous fashion to Example 93 (step 3) to give the title compound as an oil in 93% yield.

[0414] MS (El) m/z 254;

HRMS: calculated for Ci ₇ Hi ₈ S, 254.11292; found (El ₁ M+.), 254.1134

Step 3. 1 1-Ethyl-2-methyl-10,1 1-dihydrodibenzo[6,/]thiepine 5,5-dioxide

[0415] 11-Ethyl-2-methyl-10,11-dihydrodibenzo[/),/]thiepine was used in an analogous fashion to Example 93 (step 4) to give the title compound as an oil in 63% yield.

[0416] MS (ES) m/z 287.1 ;

HRMS: calculated for Ci ₇ Hi ₈ O ₂ S + H+, 287.11003; found (ESI, [M+Hf), 287.1114

Step 4. 1 1 -Ethyl-2-methyl-λ/-(2-pyridin-3-ylethyl)-10, 11 -dihydrodibenzo[ύ,/]thiepine-3- sulfonamide 5,5-dioxide

[0417] 11-Ethyl-2-methyl-10,11-dihydrodibenzo[_3,/]thiepine 5,5-dioxide (0.18 mg, 0.63 mmol) was used in an analogous fashion to Example 93 (step 5) to give without purification crude 11 -ethyl-2-methyl-10, 11 -dihydrodibenzo[/5,/]thiepine-3-sulfonyl chloride 5,5-dioxide. This was dissolved in CH ₂ CI ₂ (10 ml_). To the stirred solution was added 3-(2-aminoethyl)pyridine (0.11 ml_, 0.91 mmol) and triethylamine (0.12 ml., 87 mg, 0.86 mmol). The solution was stirred 1 day at room temperature. It was

diluted with EtOAc, washed with H ₂ O and dried over MgSO ₄ . The solvent was evaporated. The product was purified by chromatography with a gradient of EtOAcZCH ₂ CI ₂ ZCH ₃ OH to afford 34 mg (11 %) of the title compound as a white solid.

[0418] MS (ES) m/z 471.2;

HRMS: calculated for C ₂₄ H ₂₆ N ₂ O ₄ S ₂ + H+, 471.14067; found (ESI, [M+H] ⁺ ), 471.1394;

Example 132: 11-Butyl-2-methyl-W-<2-pyridin-3-ylethyl)-10,11- dihydrodibenzo[6,/]thiepine-3-sulfonamide 5,5-dioxide

Step 1. 10-Butyl-8-methyl-10, 11 -dihydrodibenzoβ, f|thiepin-10-ol

[0419] In an analogous fashion to Example 130 (step 1) butylmagnesium chloride was used to give the title compound as a solid in 26% yield.

[0420] MS (ES) m/z 280.9;

HRMS: calculated for Ci ₉ H ₂₂ OS + H+, 299.14641 ; found ([M+Hf), 281.1352

Step 2. 1 1-Butyl-2-methyl-10,1 1-dihydrodibenzo[/3,flthiepine

[0421] 10-Butyl-8-methyl-10,1 1-dihydroclibenzo[i),f|thiepin-10-ol was used in an analogous fashion to Example 93 (step 3) to give the title compound as an oil in 87% yield.

[0422] MS (El) nVz 282.1450;

HRMS: calculated for C ₁₉ H ₂₂ S, 282.14422; found (El, M+.), 282.1450

Step 3. 1 1-Butyl-2-methyl-/V-(2-pyridin-3-ylethyl)-10,11 -dihydrodibenzo[/3,/]thiepine-3- sulfonamide 5,5-dioxide

[0423] 11-Butyl-2-methyl-10,1 1-dihydrodibenzo[ϋ,/]thiepine was used in an analogous fashion to Example 93 (step 4) to give the title compound as an oil in 97% yield.

[0424] MS (ES) m/z 499.2;

HRMS: calculated for C ₂₆ H ₃₀ N ₂ O ₄ S ₂ + H+, 499.17197; found (ESI, [M+H] ⁺ ), 499.1728

Step 4. 1 1 -Butyl-2-methyl-λ/-(2-pyridin-3-ylethyl)-10, 11 -dihydrodibenzo[ύ,/]thiepine-3- sulfonamide 5,5-dioxide

N

[0425] 11 -Butyl-2-methyl-λ/-(2-pyridin-3-ylethyl)-10, 11 -dihydrodibenzo[6,f]thiepine- 3-sulfonamide 5,5-dioxide was used in an analogous fashion to Example 131 (step 4) to give the title compound as an oil in 44% yield.

[0426] MS (ES) m/z 499.2;

HRMS: calculated for C ₂₆ H ₃₀ N ₂ O ₄ S ₂ + H+, 499.17197; found (ESI, [M+H] ⁺ ), 499.1728;

Example 133: 2-Methyl-11-propyl-λ/-(2-pyridin-3-ylethyl)-10,11- dihydrodibenzo[6,/|thiepine-3-sulfonamide 5,5-dioxide

Step 1. 8-Methyl-10-propyl-10,11 -dihydrodibenzo[i),(|thiepin-10-ol

[0427] In an analogous fashion to Example 130 (step 1) propylmagnesium chloride was used to give the title compound as a solid in 26% yield.

[0428] MS (ES) m/z 267.1 ;

HRMS: calculated for Ci ₈ H ₂₀ OS + H+ - H+, 284.12348; found (ESI ₁ [M+H-H20]*), 267.1195

Step 2. 2-Methyl-11-propyl-10,11 -dihydrodibenzo[i),/]thiepine

[0429] 8-Methyl-10-propyl-10,1 1-dihydrodibenzo[b,/]thiepin-10-ol was used in an analogous fashion to Example 93 (step 3) to give the title compound as an oil in 56% yield.

[0430] MS (El) m/z 268;

HRMS: calculated for Ci ₈ H ₂₀ S ₁ 268.12857; found (El, M+.), 268.1283

Step 3. 2-Methyl-11 -propyl-λ/-(2-pyridin-3-ylethyl)-10, 11 -dihydrodibenzo[b,r]thiepine- 3-sulfonamide 5,5-dioxide

[0431] 2-Methyl-11-propyl-10 ₎ 1 1-dihydrodibenzo[/>,/]thiepine was used in an analogous fashion to Example 93 (step 4) to give the title compound as an solid in 75% yield.

[0432] MS (ES) m/z 301.1 ;

HRMS: calculated for Ci ₈ H ₂₀ O ₂ S + H+, 301.12568; found (ESI, [M+H] ⁺ ), 301.1261

Step 4. 2-Methyl-11 -propyl-λ/-(2-pyridin-3-ylethyl)-10, 11 -dihydrodibenzo[b,/]thiepine- 3-sulfonamide 5,5-dioxide

[0433] 2-Methyl-11 -propyl-/V-(2-pyridin-3-ylethyl)-10,11- dihydrodibenzo[b,f|thiepine-3-sulfonamide 5,5-dioxide was used in an analogous fashion to Example 131 (step 4) to give the title compound as an oil in 53% yield.

[0434] MS (ES) m/z 485.2;

HRMS: calculated for C ₂₅ H ₂₈ N ₂ O ₄ S ₂ + H+, 485.15632; found (ESI, [M+H] ⁺ ), 485.1551 ;

Example 134: 11 -Isopropy l-2-methy l-W-(2-pyridin-3-ylethyl)-10,11 ■ dihydrodibenzo[6,/]thiepine-3-sulfonamide 5,5-dioxide

Step 1. 10-lsopropyl-8-methyl-10,11-dihydrodibenzo[ib,/]thiepin-10-o l

[0435] In an analogous fashion to Example 130 (step 1 ) isopropylmagnesium chloride was used to give the title compound as a solid in 19% yield.

[0436] MS (ES) m/z 267 A

Step 2. 1 1-lsopropyl-2-methyl-10,11<lihydrodibenzo[6,/]thiepine

[0437] 10-lsopropyl-8-methyl-10,11 -dihydrodibenzo[fc,/]thiepin-10-ol was used in an analogous fashion to Example 93 (step 3) to give the title compound as a oil in 85% yield.

[0438] MS (El) m/z 268;

HRMS: calculated for Ci ₈ H ₂₀ S, 268.12857; found (El, M+.), 268.1295

Step 3. 11 -lsopropyl-2-methyl-λ/-(2-pyridin-3-ylethyl)-10,11- dihydrodibenzo[b,/]thiepine-3-sulfonamide 5,5-dioxide

[0439] 11-lsopropyl-2-methyl-10,11-dihydrodibenzo[fc,/]thiepine was used in an analogous fashion to Example 5 (step 4) to give the title compound as a oil in 98% yield.

[0440] MS (ES) m/z 301.1 ;

HRMS: calculated for Ci ₈ H ₂₀ O ₂ S + H+, 301.12568; found (ESI, [M+Hf), 301.1263

Step 4. 11 -lsopropyl-2-methyl-λ/-(2-pyridin-3-ylethyl)-10,11- dihydrodibenzo[ϋ,f|thiepine-3-sulfonamide 5,5-dioxide

[0441] 11 -lsopropyl-2-methyl-λK2-pyridin-3-ylethyl)-10,11- dihydrodibenzo[ft,/]thiepine-3-sulfonamide 5,5-dioxide was used in an analogous fashion to Example 131 (step 4) to give the title compound as an oil in 36% yield.

[0442] MS (ES) m/z 483.1 ;

HRMS: calculated for C ₂ SH ₂₈ N ₂ O ₄ S ₂ + H+, 485.15632; found (ESI, [M+H] ⁺ ), 485.1559;

Example 135: 2,11-Dimethyl-λ/-(2-pyridin-3-ylethyl)-10,11- dihydrodibenzo[6,4]thiepine-3-sulfonamide 5,5-dioxide

[0443] 2, 11 -Dimethyl-λ/-(2-phenylethyl)-10, 1 1 -dihydrodibenzo[/?,/]thiepine-3- sulfonamide 5,5-dioxide was used in an analogous fashion to Example 131 (step 4) to give the title compound as a solid in 45% yield.

[0444] MS (ES) m/z 457.2;

HRMS: calculated for C ₂₃ H ₂₄ N ₂ O ₄ S ₂ + H+, 457.12502; found (ESI, [M+H] ⁺ ), 547.1264

Example 136: 8-Fluoro-3-methyl-W-(2-phβnylβthyl)phenoxathiin-2-sulfonam ide 10,10-dioxide

Step 1. 8-Fluoro-3-methylphenoxathiin-2-sulfonyl chloride 10,10-dioxide

[0445] To a solution of 1-(4-fluorophenoxy)-3-methyl benzene (9.23 g, 45.7 mmol) in dichloromethylene (250 ml_) was added chlorosulfonic acid (12.2 g, 2.3 equiv and allowed to stir at 100 ⁰ C 3 h. The solvent was removed and 1 ml_ of chlorosulfonic acid was added and heated at 180 ⁰ C . The residue was triturated with ether followed by a trituration with methanol to afford 3.03 g (19 %) of the desired product: MS (ES) m/z 342.9

Step 2. 8-Fluoro-3-methyl-λ/-(2-phenylethyl)phenoxathiin-2-sulfonam ide 10,10- dioxide

[0446] To a solution of 2-phenethylamine (1.2 equiv), triethylamine (3 equiv) in acetonitrile (2 ml_) containing methylene chloride ( 5 mL) was added 8-fluoro-3- methylphenoxathiin-2-sulfonyl chloride 10,10-dioxide (1 equiv). The reaction was stirred overnight and purified by chromatography to afford 99 mg (42 %) of the title compound.

[0447] MS (ES) m/z 446.1 ;

HRMS: calculated for C _2I H ₁₈ FNO ₅ S ₂ + H+, 448.06832; found (ESI ₁ [M+H] ⁺ ), 448.0638;

Example 137: 8-Fluoro-3-methyl-/V-(2-pyridin-2-ylethyl)phenoxathiin-2- sulfonamide 10,10-dioxide

[0448] The title compound was prepared employing the conditions from Example 136 (step 2) using 2-(pyridine-2-yl)ethanamine to afford 181 mg (77 %) of the desired product.

[0449] MS (ES) m/z 446.9;

HRMS: calculated for C ₂₀ Hi ₇ FN ₂ OsS ₂ + H+, 449.06357; found (ESI, [M+H] ⁺ ), 449.0638;

Example 138: 8-Fluoro-3-methyl-W-(2-pyridin-3-ylethyl)phenoxathiin-2- sulfonamide 10,10-dioxide

[0450] The title compound was prepared employing the conditions from Example 136 (step 2) using 2-(pyridine-3-yl)ethanamine to afford 167 mg (71 %) of the desired product.

[0451] MS (ES) m/z 447.0;

HRMS: calculated for C ₂₀ Hi ₇ FN ₂ O ₅ S ₂ + H+, 449.06357; found (ESI ₁ [M+H] ^* ),

449.0632;

Example 139: 8-Fluoro-3-methyl-/V-(2-pyridin-4-ylethyl)phenoxathiin-2- sulfonamide 10,10-dioxide

[0452] The title compound was prepared employing the conditions from Example 136 (step 2) using 2-(pyridine-4-yl)ethanamine to afford 135 mg (58 %) of the desired product

MS (ES) m/z 447.0;

HRMS: calculated for C ₂₀ Hi ₇ FN ₂ O ₅ S ₂ + H+, 449.06357; found (ESI, [M+H]*), 449.066

Example 140: W-(2,3-dihydro-1W-indβn-2-yl)-8-fluoro-3-methylphenoxathiin -2- sulfonamide 10,10-dioxide

[0453] The title compound was prepared employing the conditions from Example

136 (step 2) using 2-aminoindane to afford 31 mg (13 %) of the desired product.

[0454] MS (ES) m/z 458.0;

HRMS: calculated for C ₂₂ Hi ₈ FNO ₅ S ₂ + H+, 460.06832; found (ESI, [M+H]*),

460.0585

Example 141 : λλCyclopentyl-β-fluoro^-methylphenoxathiin^-sulfonamide 10,10-dioxide

[0455] The title compound was prepared employing the conditions from Example 136 (step 2) using cyclopentylamine to afford 147 mg (68 %) of the desired product

[0456] MS (ES) m/z 410.0;

HRMS: calculated for Ci ₈ H ₁₈ FNO ₅ S ₂ + H+, 412.06832; found (ESI, [M+H] ⁺ ), 412.067;

Example 142: 8-Fluoro-3-methyl-W-(2-morpholin-4-ylethyl)phenoxathiin-2- sulfonamide 10,10-dioxide.

[0457] The title compound was prepared employing the conditions from Example 136 (step 2) using 2-morpholinoethanamine to afford 196 mg (82 %) of the desired product

[0458] MS (ES) m/z 455.0;

HRMS: calculated for Ci ₉ H ₂ IFN ₂ O ₆ S ₂ + H+, 457.08978; found (ESI ₁ [M+H] ^* ), 457.0901 ;

Example 143: 8-Fluoro-3-methyl-W-(3-morpholin-4-ylpropy l)phenoxathiin-2- sulfonamide 10,10-dioxide

The title compound was prepared employing the conditions from Example 136 (step

2) using 3-morpholinopropan-1 -amine to afford 178 mg (72 %) of the desired product.

MS (ES) m/z 469.0;

HRMS: calculated for C ₂₀ H ₂₃ FN ₂ O ₆ S ₂ + H+, 471.10543; found (ESI ₁ [M+H] ⁺ ),

471.1062;

Example 144: 8-Fluoro-3-methyl-/V-(tetrahydro-2W-pyran-4-yl)phenoxathiin- 2- sulfonamide 10,10-dioxide

[0459] The title compound was prepared employing the conditions from Example 136 (step 2) using tetrahydro-2H-pyran-4-amine to afford 157 mg (70 %) of the desired product.

[0460] MS (ES) m/z 426.0;

HRMS: calculated for Ci ₈ H ₁₈ FNO ₆ S ₂ + H+, 428.06323; found (ESI ₁ [M+H] ^* ), 428.0589

Example 145: 8-Fluoro-3-methyl-iV-(tetrahydro-2H-pyran-4- ylmethyl)ρhenoxathiin-2-sulfonamide 10,10 -dioxide

[0461] The title compound was prepared employing the conditions from Example 136 (step 2) using (tetrahydro-2H-pyran-4-yl)methanamine to afford 169 mg (73 %)

of the desired product.

[0462] MS (ES) m/z 440.0;

HRMS: calculated for Ci ₉ H ₂₀ FNO ₆ S ₂ + H+, 442.07888; found (ESI ₁ [M+H]*), 442.0772;

Example 146: 8-Fluoro-3-methyl-/V-[2-(tetrahydro-2H-pyran-4- yl)ethyl]phenoxathiin-2-sulfonamide 10,10-dioxide

[0463] The title compound was prepared employing the conditions from Example 136 (step 2) using 2-(tetrahydro-2H-pyran-4-yl)ethanamine to afford 215 mg (90 %) of the desired product.

[0464] MS (ES) m/z 454.0;

HRMS: calculated for C ₂₀ H ₂₂ FNO ₆ S ₂ + H+, 456.09453; found (ESI, [M+H]*), 456.0878

Example 147: 8-Fluoro-W-[3-<1W-imidazol-1-yl)propyl]-3-methylphenoxath iin-2- sulfonamide 10,10-dioxide

[0465] The title compound was prepared employing the conditions from Example 136 (step 2) using 3-(1-H-imidazol-1-yl)propan-1 -amine to afford 1 15 mg (49 %) of the desired product.

[0466] MS (ES) m/z 450.0;

HRMS: calculated for Ci ₉ Hi ₈ FN ₃ O ₅ S ₂ + H+, 452.07447; found (ESI ₁ [M+H] ⁺ ), 452.0732;

Example 148: 8-Fluoro-3-methyl-/V-(3-phenylpropyl)phβnoxathiin-2- sulfonamide 10,10-dioxide

[0467] The title compound was prepared employing the conditions from Example 136 (step 2) using 3-phenρropan-1 -amine to afford 208 mg (86 %) of the desired product.

[0468] MS (ES) m/z 460.0;

HRMS: calculated for C ₂₂ H ₂₀ FNO ₅ S ₂ + H+, 462.08397; found (ESI ₁ [M+H] ^* ), 462.0851 ;

Example 149: A/-Benzyl-8-fluoro-3-methylphenoxathiin-2-sulfonamide 10,10- dioxide

SO ₂ NH

[0469] The title compound was prepared employing the conditions from Example 136 (step 2) using benzylamine to afford 194 mg (72 %) of the desired product.

[0470] MS (ES) m/z 432.0;

HRMS: calculated for C ₂₀ H ₁₆ FNO ₅ S ₂ + H+, 434.05267; found (ESI ₁ [M+H] ^* ), 434.0527;

Example 150: N-2-(4-chlorophenyl)βthyl]-8-fluoro-3-methylphenoxathiin-2- sulfonamide 10,10-dioxide

[0471] The title compound was prepared employing the conditions from Example 136 (step 2) using 4-chlorobenzylamine to afford 169 mg (82 %) of the desired product.

[0472] MS (ES) m/z 479.9;

HRMS: calculated for C ₂ i Hi ₇ CIFNO ₅ S ₂ + H+, 482.02934; found (ESI, [M+H] ⁺ ), 482.0304;

Example 151 : 8-Fluoro-3-methyl-W-(pyridin-2-ylmethyl)phenoxathiin-2- sulfonamide 10,10-dioxide

[0473] The title compound was prepared employing the conditions from Example 136 (step 2) using pyridine-ylmethanane to afford 169 mg (85 %) of the desired product.

[0474] MS (ES) m/z 433.0;

HRMS: calculated for Ci ₉ Hi ₅ FN ₂ O ₅ S ₂ + H+, 435.04792; found (ESI, [M+H]*), 435.0473;

Example 152: 8-Fluoro-3-methyl-/V-(pyridin-3-ylmethyl)phenoxathiin-2- sulfonamide 10,10-dioxide

SO ₂ NH

[0475] The title compound was prepared employing the conditions from Example 136 (step 2) using pyridine-3-ylmethanamine to afford 158 mg (74 %) of the desired product.

[0476] MS (ES) m/z 433.0;

HRMS: calculated for Ci ₉ Hi ₅ FN ₂ OsS ₂ + H+, 435.04792; found (ESI, [M+H] ⁺ ), 435.0478;

Example 153: 8--Fluoro-3-methyl-/V-(pyridin-4-ylmethyl)phenoxathiin-2- sulfonamide 10,10-dioxide

[0477] The title compound was prepared employing the conditions from Example 136 (step 2) using pyridine-4-ylmethanamine to afford 225 mg (70 %) of the desired product.

[0478] MS (ES) m/z 433.0;

HRMS: calculated for Ci ₉ Hi ₅ FN ₂ OsS ₂ + H+, 435.04792; found (ESI ₁ [M+H] ⁺ ), 435.0497;

Example 154: 8-Fluoro-3-methyl-/V-(2-pyrrolidin-1 -ylethyl)phenoxathiin-2- sulfonamide 10,10-dioxide.

[0479] The title compound was prepared employing the conditions from Example 136 (step 2) using 2-pyrolidine-1-yl)ethanamine to afford mg (98 %) of the desired product.

[0480] MS (ES) m/z 439.0;

HRMS: calculated for C ₁₉ H _2I FN ₂ O ₅ S ₂ + H+, 441.09487; found (ESI, [M+H] ⁺ ), 441.0948

Example 155: A/-Cyclohexyl-8-fluoro-3-methylphenoxathiin-2-sulfonamide 10,10-dioxide

[0481] The title compound was prepared employing the conditions from Example 136 (step 2) using cyclohexylamine to afford 168 mg (75 %) of the desired product.

[0482] (ES) m/z 424.0;

HRMS: calculated for Ci ₉ H ₂₀ FNO ₅ S ₂ + H+, 426.08397; found (ESI, [M+H]*), 426.0824;

Example 156: 3-Fluoro-8-isopropyl-11 -oxo-/V-(2-pyridin-2-ylethyl)-10,11 - dihydrodibenzo[6,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide

Step 1. 6-Fluoro-2-isopropyl-9H-thioxanthen-9-one 10,10-dioxide

[0483] A mixture of 6-fluoro-2-isopropyl-9H-thioxanthen-9-one (Protiva, M.; Rajsner, M.; Metysova, J. Czech. Patent 202229 B, 1982) (7.29 g, 26.8 mmol) and Oxone (98.7 g, 161 mmol) in methanol-water (1 :1 ) (300 ml.) was heated at reflux for 6 h. The mixture was cooled and poured into a mixture of water (1 L) and ethyl acetate (500 ml_). The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to afford 6-fluoro-2-isopropyl-9H-thioxanthen- 9-one 10,10-dioxide (4.65 g) as an off-white solid. MS (ES) m/z 304.9;

Step 2. 3-Fluoro-8-isopropyldibenzo[b,/][1 ,4]thiazepin-11 (10H)-one 5,5-dioxide

[0484] A mixture of 6-fluoro-2-isopropyl-9H-thioxanthen-9-one 10,10-dioxide (4.65 g, 15.3 mmol) and sodium azide (1.29 g, 19.9 mmol) in concentrated sulfuric acid (20 ml_) was stirred 20 hours at room temperature, then added dropwise to ice water. The aqueous mixture was extracted with dichloromethane, which was then washed with water and brine, then dried over magnesium sulfate, and concentrated to afford a brown oil which was purified by silica gel column chromatography (hexane/ethyl acetate, 90/10 to 0/100) to afford 3-fluoro-8-isopropyldibenzo[δ,/][1 ,4]thiazepin- 1 1(10H)-one 5,5-dioxide as a mixture with 7-fluoro-2- isopropyldibenzo[6,/][1 ,4]thiazepin-1 1 (10H)-one 5,5-dioxide (3.49 g) as an off-white solid which was used in the next step without further purification. MS (ES) m/z 319.9;

Step 3. 3-Fluoro-8-isopropyl-11 -oxo-10, 11 -dihydrodibenzo[ύ,/][1 ,4]thiazepine-7- sulfonyl chloride 5,5-dioxide

[0485] The mixture of 3-fluoro-8-isopropyldibenzo[b,/][1 ,4]thiazepin-1 1 (10H)-one 5,5-dioxide and 7-fluoro-2-isopropyldibenzo[6,f|[1 ,4]thiazepin-11 (10/-/)-one 5,5- dioxide (3.49 g, 10.9 mmol) was dissolved in chlorosulfonic acid (10 ml_) and heated for 3 hours at 120 ⁰ C. The mixture was cooled, poured into ice-water, and extracted thrice with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated to a volume of 50 ml_ to afford an approximately 0.124 M solution in dichloromethane of 3-fluoro-8-isopropyl-5,5- dioxido-11 -oxo-10,11-dihydrodibenzo[6,f|[1.4]thiazepine-7-sulfonyl chloride as a mixture with 7-fluoro-2-isopropyldibenzo[ft,/][1 ,4]thiazepin-11(10H)-one 5,5-dioxide, which was used in the next step without further purification.

Step 4. 3-Fluoro-8-isopropyl-5, 5-dioxido-1 1 -oxo-λ/-(2-pyridin-2-ylethyl)-10,11- dihydrodibenzo[/5,r][1 ,4]thiazepine-7-sulfonamide

[0486] Triethylamine (0.173 g, 1.71 mmol) and 2-(2-aminoethyl)pyridine (0.114 g, 0.930 mmol) were dissolved in dichloromethane (5 ml_), and 3-fluoro-8-isopropyl-5,5- dioxido-11-oxo-10,11-dihydrodibenzo[6,/][1 ,4]thiazepine-7-sulfonyl chloride (6.25 ml_ of 0.124 M solution, 0.775 mmol) was added as a solution in dichloromethane. The mixture was stirred 16 hours at room temperature, then poured into dilute hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate/methanol, 90/9/1 to 0/90/10) to afford 3-fluoro-8-isopropyl-11- oxo-λ/-(2-pyridin-2-ylethyl)-10, 11 -dihydrodibenzofjb, /][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide (0.103 g) as a white solid.

MS (ES) m/z 503.9;

HPLC purity 95.3% at 210-370 nm, 8.8 minutes.; 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 10 minutes, hold 4 minutes.

HRMS: calculated for C ₂₃ H ₂₂ FN ₃ O ₅ S ₂ + H+, 504.10577; found (ESI, [M+H] ⁺ ), 504.1076;

Example 157: 3-Fluoro-8-isopropyl-11 -oxo-/V-(2-pyridin-3-ylethyl)-10,11 - dihydrodibenzo[6,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide

[0487] Triethylamine (0.173 g, 1.71 mmol) and 3-(2-aminoethyl)pyridine (0.114 g, 0.930 mmol) were dissolved in dichloromethane (5 ml_), and 3-fluoro-8-isopropyl-5,5- dioxido-11-oxo-10,11-dihydrodibenzo[6,r][1 ,4]thiazepine-7-sulfonyl chloride (6.25 ml_ of 0.124 M solution, 0.775 mmol) was added as a solution in dichloromethane. The mixture was stirred 16 hours at room temperature, then poured into dilute hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate/methanol, 90/9/1 to 0/90/10) to afford 3-fluoro-8-isopropyl-11- oxo-/V-(2-pyridin-3-ylethyl)-10, 11 -dihydrodibenzo[6, /][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide (0.050 g) as a white solid.

MS (ES) m/z 503.8;

HPLC purity 95.5% at 210-370 nm, 8.5 minutes.; 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 10 minutes, hold 4 minutes.

HRMS: calculated for C ₂₃ H ₂₂ FN ₃ O ₅ S ₂ + H+, 504.10577; found (ESI ₁ [M+H] ⁺ ), 504.1046;

Example 158: 3-Fluoro-8-isopropyl-11 -oxo-/V-(2-phenylethyl)-10,11 - dihydrodibenzo[/),/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide

[0488] Triethylamine (0.173 g, 1.71 mmol) and phenethylamine (0.113 g, 0.930 mmol) were dissolved in dichloromethane (5 ml_), and 3-fluoro-8-isopropyl-5,5- dioxido-11-oxo-10,11-dihydrodibenzo[6,/][1 ,4]thiazepine-7-sulfonyl chloride (6.25 ml_ of 0.124 M solution, 0.775 mmol) was added as a solution in dichloromethane. The mixture was stirred 16 hours at room temperature, then poured into dilute hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 70/30 to 0/100) to afford 3-fluoro-8-isopropyl-11 -oxo-/V-(2- phenylethyl)-10, 1 1 -dihydrodibenzo[b,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide (0.020 g) as a white solid. MS (ES) m/z 502.8;

HPLC purity 98.4% at 210-370 nm, 10.3 minutes.; 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 10 minutes, hold 4 minutes.

Example 159: 3-Fluoro-8-isopropyl-11-oxo-/V-(tetrahydro-2W-pyran-4-yl)-10 ,11- dihydrodibenzo[6,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide

[0489] Triethylamine (0.173 g, 1.71 mmol), 7,11-diazabicyclo[5.4.0]undec-11 -ene (0.142 g, 0.930 mmol), and 4-aminotetrahydropyran hydrochloride (0.128 g, 0.930 mmol) were dissolved in dichloromethane (5 ml_), and 3-fluoro-8-isopropyl-5,5- dioxido-11 -oxo-10,11-dihydrodibenzo[6,f|[1 ,4]thiazepine-7-sulfonyl chloride (6.25 mL of 0.124 M solution, 0.775 mmol) was added as a solution in dichloromethane. The mixture was stirred 16 hours at room temperature, then poured into dilute hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 70/30 to 0/100) to afford 3-fluoro-8-isopropyl-11-oxo-λ/- (tetrahydro-2H-pyran-4-yl)-10, 11 -dihydrodibenzo[6, /][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide (0.129 g) as a white solid. MS (ES) m/z 482.8;

HPLC purity 100.0% at 210-370 nm, 8.8 minutes.; 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 10 minutes, hold 4 minutes.

Example 160: feit-Butyl 4-{[(3-fluoro-8-isopropyl-5,5-dioxido-11-oxo-10,11- dihydrodibenzo[ϋ,f|[1,4]thiazepin-7-yl)sulfonyl]amino}pipeh dine-1-carboxylate

[0490] Triethylamine (0.518 g, 5.12 mmol) and te/f-butyl 4-aminopiperidine-1- carboxylate (0.559 g, 2.79 mmol) were dissolved in dichloromethane (5 mL), and 3- fluoro-8-isopropyl-5,5-dioxido-11 -oxo-10, 11 -dihydrodibenzo[6,/][1 ,4]thiazepine-7- sulfonyl chloride (6.25 mL of 0.124 M solution, 0.775 mmol) was added as a solution in dichloromethane. The mixture was stirred 16 hours at room temperature, then

poured into dilute hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 70/30 to 0/100) to afford te/f-butyl 4- {[(3-fluoro-8-isopropyl-5,5-dioxido-11 -oxo-10,11-dihydrodibenzo[/>,/][1 ,4]thiazepin-7- yl)sulfonyl]amino}piperidine-1-carboxylate (0.555 g) as a white solid. MS (ES) m/z 579.8;

HPLC purity 100.0% at 210-370 nm, 10.2 minutes.; 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 10 minutes, hold 4 minutes.

Example 161: 3-Fluoro-8-isopropyl-11-oxo-/V-piperidin-4-yl-10,11- dihydrodibenzo[/>,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide hydrochloride

[0491] A solution of tert-butyl 4-{[(3-fluoro-8-isopropyl-5,5-dioxido-11 -oxo-10,11- dihydrodibenzo[/5,/][1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1 -carboxylate (0.210 g, 0.361 mmol) in ethyl ether (15 ml_) and dioxane (10 ml_) was treated with anhydrous hydrogen chloride (1 M solution in ethyl ether, 0.722 ml_, 0.722 mmol) and stirred at room temperature for 16 h. The precipitate was filtered to afford 3-fluoro-8- isopropyl-11 -oxo-λ/-piperidin-4-yl-10, 11 -dihydrodibenzo[b,/][1 ,4]thiazepine-7- sulfonamide 5,5-dioxide hydrochloride (0.075 g) as a white solid. MS (ES) m/z 481.8;

HPLC purity 100.0% at 210-370 nm, 7.0 minutes.; 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 10 minutes, hold 4 minutes.

HRMS: calculated for C ₂ IH ₂₄ FN ₃ O ₅ S ₂ + H+, 482.12142; found (ESI ₁ [M+H] ⁺ ),

482.1221 ;

Example 162: 3-Fluoro-8-isopropyl-10-methyl-11-oxo-/V-piperidin-4-yl-10,1 1- dihydrodibenzo[6,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide hydrochloride

Step 1. te/f-Butyl 4-(2,4-dimethoxybenzylamino)piperidine-1-carboxylate

[0492] A mixture of terf-butyl 4-oxopiperidine-1-carboxylate (21.0 g, 0.105 mol), 2,4-dimethoxybenzylamine (17.6 g, 0.105 mol), and sodium triacetoxyborohydride (55.8 g, 0.263 mol) were stirred in ethanol (500 ml_) 2 hours at room temperature. Aqueous sodium bicarbonate was added, and the mixture was extracted with dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate and concentrated to a volume of 325 ml_ to afford an approximately 0.323 M solution in dichloromethane of terf-butyl 4-(2,4-dimethoxybenzylamino)piperidine-1- -carboxylate which was used without further purification.

Step 2. tert-Butyl 4-{(2,4-dimethoxybenzyl)[(3-fluoro-8-isopropyl-5,5-dioxido-1 1-oxo- 10,11 -dihydrodibenzo[6,/][1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1 -carboxylate

Boc

[0493] Triethylamine (6.39 g, 63.1 mmol) and te/f-butyl 4-(2,4- dimethoxybenzylamino)piperidine-1-carboxylate (53.3 mL of 0.323 M solution, 17.2 mmol) as a solution in dichloromethane were mixed, and 3-fluoro-8-isopropyl-5,5- dioxido-11 -oxo-10, 11 -dihydrodibenzoβ, /][1 ,4]thiazepine-7-sulfonyl chloride (28.7 mmol) was added as a solution in dichloromethane. The mixture was stirred 16 hours at room temperature, then poured into dilute hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 80/20 to 20/80) to afford tert-butyl 4-{(2,4-dirnethoxybenzyl)[(3-fluoro-8-isopropyl-5,5-dioxido- 1 1-oxo-10,11-dihydrodibenzo[£>,/][1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1- carboxylate (1.2 g) as a yellow oil. MS (ES) m/z 729.9;

Step 3. ferf-Butyl 4-{(2,4-dimethoxybenzyl)[(3-fluoro-8-isopropyl-10-methyl-5,5 - dioxido-11 -oxo-10, 11 -dihydrodibenzotø, /][1 ,4]thiazepin-7- yl)sulfonyl]am ino}piperidine-1 -carboxylate

Boc

[0494] A mixture of tert-butyl 4-{(2,4-dimethoxybenzyl)[(3-fluoro-8-isopropyl-5,5- dioxido-11 -oxo-10, 11 -dihydrodibenzo[6, /][1 ,4]thiazepin-7- yl)sulfonyl]amino}piperidine-1 -carboxylate (0.500 g, 0.683 mmol) and sodium hydride (60% dispersion in mineral oil, 0.033 g, 0.820 mmol) in dimethylformamide (50 mL) was stirred 15 min at room temperature. Methyl iodide (0.116 g, 0.820 mmol) was added and the mixture stirred 2 hours at room temperature, then poured into 1 M

hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were washed thrice with 1 M hydrochloric acid, dried over magnesium sulfate, and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 80/20 to 40/60) to afford te/f-butyl 4-{(2,4-dimethoxybenzyl)[(3-fluoro-8-isopropyl-10-methyl-5,5 -dioxido-11 - oxo-10,11-dihydrodibenzo[6,f][1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1- carboxylatθ (0.200 g) as a yellow oil. MS (ES) m/z 744.3;

Example 163: 10-Ethyl-3-fluoro-8-isopropyl-11 -oxo-JV-piperidin-4-yl-10,11 - dihydrodibenzo[ϋ,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide hydrochloride

Step 1. te/f-Butyl 4-{(2,4-dimethoxybenzyl)[(10-ethyl-3-fluoro-8-isopropyl-5,5- dioxido- 1 1-OXO-10.11-dihydrodibenzo[6,/][1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1- carboxylate

Boc

[0495] A mixture of ferf-butyl 4-{(2,4-dimethoxybenzyl)[(3-fluoro-8-isopropyl-5,5- dioxido-11 -oxo-10, 11 -dihydrodibenzo[6, f][1 ,4]thiazepin-7- yl)sulfonyl]amino}pipehdine-1-carboxylate (0.540 g, 0.738 mmol) and sodium hydride

(60% dispersion in mineral oil, 0.044 g, 1.11 mmol) in dimethylformamide (50 ml_) was stirred 15 min at room temperature. Ethyl iodide (0.173 g, 1.11 mmol) was added and the mixture stirred 16 hours at room temperature, then poured into 1 M hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were washed thrice with 1 M hydrochloric acid, dried over magnesium sulfate, and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 80/20 to 40/60) to afford terf-butyl 4-{(2,4-dimethoxybenzyl)[(10-ethyl-3-fluoro-8-isopropyl-5,5- dioxido-11 -oxo- 10,11 -dihydrodibenzo[ύ,f][1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1 -carboxylate (0.217 g) as a yellow oil.

Step 2. 10-Ethyl-3-fluoro-8-isopropyl-11 -oxo-λ/-piperidin-4-yl-10,11- dihydrodibenzo[ϋ,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide hydrochloride

[0496] A mixture of ferf-butyl 4-{(2,4-dimethoxybenzyl)[(10-ethyl-3-fluoro-8- isopropyl-5,5-dioxido-11 -oxo-10,11 -dihydrodibenzo[fc,/][1 ,4]thiazepin-7- yl)sulfonyl]amino}piperidine-1 -carboxylate (0.20 g, 0.263 mmol) and trifluoroacetic acid (3 ml_) in dichloromethane (50 mL) was stirred 16 hours at room temperature, and the solvent was removed to afford a purple solid. The solid was dissolved in methanol/dichloromethane and extracted thrice with aqueous sodium bicarbonate. The solvent was removed and the resulting solid was dissolved in ethyl acetate. Anhydrous hydrogen chloride was bubbled through the solution for 5 min, and the mixture was allowed to stand for 16 h. The solvent was removed to afford 10-ethyl- 3-fluoro-8-isopropyl-11-oxo-λ/-piperidin-4-yl-10,11-dihydro dibenzo[6,/][1 ,4]thiazepine- 7 -sulfonamide 5,5-dioxide hydrochloride (0.072 g) as a white powder.

MS (ES) m/z 509.8;

HPLC purity 100.0% at 210-370 nm, 8.4 minutes.; 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 10 minutes, hold 4 minutes.

HRMS: calculated for C ₂₃ H ₂₈ FN ₃ O ₅ S ₂ + H+, 510.15272; found (ESI, [M+H] ⁺ ),

510.154;

Example 164: Step 3. 3-Fluoro-8-isopropyl-W-piperidin-4-yl-10,11- dihydrodibenzo[6,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide hydrochloride

Step 1. 3-Fluoro-8-isopropyl-10,1 1 -dihydrodibenzo[b,fl[1,4]thiazepine 5,5-dioxide

[0497] The mixture of 3-fluoro-8-isopropyldibenzo[ft,/][1 ,4]thiazepin-1 1 (10/-/)-one 5,5-dioxide and 7-fluoro-2-isopropyldibenzo[b,/][1 ,4]thiazepin-11 (10/-/)-one 5,5- dioxide (5.00 g, 15.7 mmol) and borane (1 M solution in THF, 62.6 ml_, 62.6 mmol) was heated 16 hours at reflux. The mixture was cooled and aqueous ammonium chloride was added. The mixture was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over magnesium sulfate.and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 90/10 to 30/70) to afford 3-fluoro-8-isopropyl-

lO.H-dihydrodibenzofø/fti .^thiazepine 5,5-dioxide as a mixture with 7-fluoro-2- isopropyl-10,11-dihydrodibenzo[£>,/][1 ,4]thiazepine 5,5-dioxide (3.9 g) as a white solid.

Step 2. ferf-Butyl 4-[[(3-fluoro-8-isopropyl-5,5-dioxido-10,11- dihydrodibenzo[b,fl[1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1 -carboxylate

[0498] The mixture of 3-fluoro-8-isopropyl-10 ₁ 11 -dihydrodibenzo[b,/][1 ,4]thiazepine 5,5-dioxide and 7-fluoro-2-isopropyl-10, 1 1 -dihydrodibenzo[6,/][1 ,4]thiazepine 5,5- dioxide (1.51 g, 4.94 mmol) and chlorosulfonic acid (2.30 g, 19.8 mmol) in dichloroethane (100 ml_) was stirred 16 hours at room temperature. The mixture was poured into ice-water, and extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated to a volume of approximately 100 ml_. This solution was added to a separately-prepared mixture of diisopropylethyamine (1.40 g, 10.9 mmol) and ferf-butyl 4-aminopiperidine-1- carboxylate (0.989 g, 4.94 mmol) in dichloromethane (50 mL) in a separate flask, and stirred 16 hours at room temperature. This mixture was then poured into dilute hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 90/10 to 0/100) to afford terf-butyl 4-{[(3-fluoro-8-isopropyl- 5,5-dioxido-10, 11 -dihydrodibenzo[ύ,/][1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1 - carboxylate (0.60 g) as a colorless oil.

HPLC purity 93.6% at 210-370 nm, 10.4 minutes.; 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 10 minutes, hold 4 minutes.

HRMS: calculated for C ₂₆ H ₃₄ FN ₃ O ₆ S ₂ + H+, 568.19458 - BOC = 468.14216; found (ESI, [M+H-tboc]*), 468.14;

Step 3. 3-Fluoro-8-isopropyl-λ/-piperidin-4-yl-10, 11 -dihydrodibenzo

[b,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide hydrochloride

7erf-butyl-4-{[(3-fluoro-8-isopropyl-5,5-dioxido-10, 11 -dihydrodibenzo [b,f\[1 ,4]thiaze pin-7-yl)sulfonyl]amino}piperidine-1-carboxylate (0.60 g, 1.06 mmol) was dissolved in ethyl acetate (20 ml_). Anhydrous hydrogen chloride was bubbled through the solution for 5 min, and the mixture was allowed to stand for 16 h. The precipitate was filtered to afford 3-fluoro-8-isopropyl-λ/-piperidin-4-yl-10,11- dihydrodibenzo[b,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide hydrochloride (0.375 g) as an off-white solid.

MS (ES) m/z 468.2;

HPLC purity 94.8% at 210-370 nm, 7.5 minutes.; 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 10 minutes, hold 4 minutes.

HRMS: calculated for C _2I H ₂₆ FN ₃ O ₄ S ₂ + H+, 468.14215; found (ESI ₁ [M+H] ⁺ ), 468.1421 ;

Example 165: 3-Fluoro-8-isopropyl-10-methyl-W-piperidin-4-yl-10,11 - dihydrodibenzo[A,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide hydrochloride

tert-Butyl 4-{[(3-fluoro-8-isopropy 1-10-methyl-5,5-dioxido-10,11 - dihydrodibenzo[ϋ,f|[1,4]thiazepin-7-yl)sulfonyl]amino}piper idine-1-carboxylate

Step 1. 3-Fluoro-8-isopropyl-10-methyl-10,11 -dihydrodibenzo[b,/][1 ,4]thiazepine 5,5- dioxide

[0499] The mixture of 3-fluoro-8-isopropyl-10, 11 -dihydrodibenzo[b,/][1 ,4]thiazepine 5,5-dioxide and 7-fluoro-2-isopropyl-10 ₁ 1 1 -dihydrodibenzo[d,/][1 ,4]thiazepine 5,5- dioxide (2.33 g, 7.63 mmol) and sodium hydride (60% dispersion in mineral oil, 0.46 g, 11.4 mmol) in dimethylformamide (50 ml_) was stirred 15 min at room temperature. Methyl iodide (1.62 g, 11.4 mmol) was added and the mixture stirred 2 hours at room temperature, then poured into 1 M hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were washed thrice with 1 M hydrochloric acid, dried over magnesium sulfate, and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 90/10 to 50/50) to afford 3-fluoro-8-isopropyl- 10-methyl-10,1 1 -dihydrodibenzo[fc,/][1,4]thiazepine 5,5-dioxide as a mixture with 7- fluoro-2-isopropyl-10-methyl-10,11-dihydrodibenzo[b,/][1 ,4]thiazepine 5,5-dioxide (1.51 g) as a white solid which was used without further purification.

200

Step 2. fe/f-Butyl 4-{[(3-fluoro-8-isopropyl-10-methyl-5,5-dioxido-10,11- dihydrodibenzoI/j^Ii .^thiazepin-Z-yOsulfonyllaminoJpiperidine-i -carboxylate _Boc

[0500] The mixture of 3-fluoro-8-isopropyl-10-methyl-10,11- dihydrodibenzo[b,r][1 ,4]thiazepine 5,5-dioxide and 7-fluoro-2-isopropyl-10-methyl- 10,11-dihydrodibenzo[6,r][1 ,4]thiazepine 5,5-dioxide (1.40 g, 4.38 mmol) and chlorosulfonic acid (2.04 g, 17.5 mmol) in dichloroethane (100 mL) was stirred 16 hours at room temperature. The mixture was poured into ice-water, and extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated to a volume of approximately 100 mL. This solution was added to a separately-prepared mixture of diisopropylethyamine (1.25 g, 9.64 mmol) and terf-butyl 4-aminopiperidine-1-carboxylate (0.877 g, 4.38 mmol) in dichloromethane (50 mL) in a separate flask, and stirred 16 hours at room temperature. This mixture was then poured into dilute hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 90/10 to 0/100) to afford terf-butyl 4-{[(3-fluoro-8-isopropyl-10-methyl-5,5-dioxido-10,11- dihydrodibenzo[/j,/][1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1 -carboxylate (0.64 g) as a colorless oil.

MS (ES) m/z 580.1 ;

HPLC purity 100.0% at 210-370 nm, 12.0 minutes.; 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 10 minutes, hold 4 minutes.

HRMS: calculated for 027H ₃ SFN ₃ O ₆ S ₂ + H+, 582.21023 - BOC = 482.15781 ; found (ESI, [M+H-tboc] ⁺ ), 482.1577;

Step 3. 3-Fluoro-8-isopropyl-10-methyl-λ/-piperidin-4-yl-10,11- dihydrodibenzo[6,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide hydrochloride

[0501] Te/f-butyl 4-{[(3-fluoro-8-isopropyl-10-methyl-5,5-dioxido-10 ₎ 11- dihydrodibenzo[b,f|[1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1 -carboxylate (0.64 g, 1.10 mmol) was dissolved in ethyl acetate (20 ml_). Anhydrous hydrogen chloride was bubbled through the solution for 5 min, and the mixture was allowed to stand for 16 h. The precipitate was filtered to afford 3-fluoro-8-isopropyl-10-methyl-λ/- piperidin-4-yl-10,1 1-dihydrodibenzo[/?,f|[1 ,4]thiazepine-7-sulfonamide 5,5-dioxide hydrochloride (0.50 g) as a white solid.

MS (ES) m/z 482.2;

HPLC purity 100.0% at 210-370 nm, 8.9 minutes.; 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 10 minutes, hold 4 minutes.

HRMS: calculated for C ₂₂ H ₂₈ FN ₃ O ₄ S ₂ + H+, 482.15780; found (ESI ₁ [M+H] ⁺ ), 482.1594;

Example 166: 8-lsopropyl-11-oxo-W-(2-pyridin-2-ylethyl)-10,11- dihydrodibenzo[ϋ,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide

202

8-lsopropyldibenzo[b,/][1 ,4]thiazepin-11 (10H)-one 5,5-dioxide

[0502] Step 1. A mixture of 2-isopropylthioxanthone (8 g, 31.5 mmol) and Oxone (58 g, 94.5 mmol) in methanol-water (1 :1 ) (412 ml_) was heated at reflux for overnight. The mixture was cooled and the methanol was evaporated and poured into a mixture of water (1 L) and ethyl acetate (500 ml_). The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The product was triturated with ether to afford 7.4 g of 2-isopropyl-9H-thioxanthen-9-one 10,10- dioxide (82 %) as a yellowish solid. A mixture of 2-isopropyl-9/-/-thioxanthen-9-one 10,10-dioxide (2.70 g, 9.44 mmol) and sodium azide (0.800 g, 12.3 mmol) in concentrated sulfuric acid (10 ml_) was stirred 20 hours at room temperature, then added dropwise to ice water. The aqueous mixture was extracted with dichloromethane, which was then washed with water and brine, then dried over magnesium sulfate, and concentrated to afford a tan solid which was purified by silica gel column chromatography (hexane/ethyl acetate, 80/20 to 0/100) to afford 8- isopropyldibenzo[6,/][1 ,4]thiazepin-1 1 (10H)-one 5,5-dioxide as a mixture with 2-

203

isopropyldibenzo[6,/][1 ,4]thiazepin-1 1 (10H)-one 5,5-dioxide (2.4 g) as an off-white solid which was used in the next step without further purification. MS (ES) m/z 301.9;

Step 2. 8-lsopropyl-5,5-dioxido-11-0X0-10,11 -dihydrodibenzo[λ,fl[1 ,4]thiazepine-7- sulfonyl chloride

[0503] The mixture of 8-isopropyldibenzo[b,f][1 ,4]thiazepin-1 1 (10/-/)-one 5,5- dioxide and 2-isopropyldJbenzo[/j,/][1 _l 4]thiazepin-11(10/-/)-one 5,5-dioxide (2.40 g, 7.96 mmol) was dissolved in chlorosulfonic acid (8 ml_) and heated for 3 hours at 120 ⁰ C. The mixture was cooled, poured into ice-water, and extracted thrice with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated to a volume of 50 ml_ to afford an approximately 0.159 M solution in dichloromethane of the mixture of 8-isopropyl-5,5-dioxido-11-oxo-10,11- dihydrodibenzo[ft,/][1 ,4]thiazepine-7-sulfonyl chloride and 2-isopropyl-5,5-dioxido-11- oxo-10,11-dihydrodibenzo[ϋ,/][1 ,4]thiazepine-3-sulfonyl chloride, which was used in the next step without further purification.

Step 3. 8-lsopropyl-1 1 -oxo-/V-(2-pyridin-2-ylethyl)-10,11- dihydrodibenzo[ft,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide

204

[0504] Triethylamine (0.222 g, 2.19 mmol) and 2-(2-aminoethyl)pyridine (0.146 g, 1.19 mmol) were dissolved in dichloromethane (5 mL), and 8-isopropyl-5,5-dioxido- 1 1-oxo-10,11-dihydrodibenzo[b,/][1 ,4]thiazepine-7-sulfonyl chloride (6.25 mL of 0.159 M solution, 0.994 mmol) was added as a solution in dichloromethane. The mixture was stirred 16 hours at room temperature, then poured into dilute hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate/methanol, 90/9/1 to 0/90/10) to afford 8-isopropyl-11 -oxo-/V-(2- py rid in-2-y lethy I )-10, 11 -dihydrodibenzo[6,f|[1 ,4]thiazepine-7-sulfonamide 5,5-dioxide (0.042 g) as a white solid. MS (ES) m/z 485.8;

HPLC purity 100.0% at 210-370 nm, 8.3 minutes.; 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 10 minutes, hold 4 minutes.

HRMS: calculated for C ₂₃ H ₂₃ N ₃ O ₅ S ₂ + H+, 486.11519; found (ESI, [M+H] ⁺ ), 486.1155;

Example 167: 8-lsopropyl-11-oxo-/V-(2-phenylethyl)-10,11- dihydrodibenzo[/),/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide

205

[0505] Triethylamine (0.222 g, 2.19 mmol) and phenethylamine (0.145 g, 1.19 mmol) were dissolved in dichloromethane (5 ml_), and 8-isopropyl-5,5-dioxido-11- oxo-10,11-dihydrodibenzo[b,r][1 ,4]thiazepine-7-sulfonyl chloride (6.25 mL of 0.159 M solution, 0.994 mmol) was added as a solution in dichloromethane. The mixture was stirred 16 hours at room temperature, then poured into dilute hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 70/30 to 0/100) to afford 8-isopropyl-11-oxo-/V-(2-phenylethyl)-10,11- dihydrodibenzo[b,f|[1 ,4]thiazepine-7-sulfonarnide 5,5-dioxide (0.078 g) as a white solid.

MS (ES) m/z 484.8;

HPLC purity 99.6% at 210-370 nm, 9.9 minutes.; Xterra RP 18, 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 10 minutes, hold 4 minutes.

HRMS: calculated for C ₂₄ H ₂₄ N ₂ O ₅ S ₂ + H+, 485.11994; found (ESI, [M+H] ⁺ ), 485.1249

Example 168: 8-lsopropy 1-11 -oxo-/V-(tetrahydro-2W-py ran -4-yl )-10,11 - dihydrodibenzo[/),/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide

206

[0506] Triethylamine (0.222 g, 2.19 mmol), 7,11-diazabicyclo[5.4.0]undec-11 -ene (0.182 g, 1.19 mnnol), and 4-aminotetrahydropyran hydrochloride (0.164 g, 1.19 mmol) were dissolved in dichloromethane (5 ml_), and 8-isopropyl-5,5-dioxido-11- oxo-10,11-dihydrodibenzo[6,f|[1 ,4]thiazepine-7-sulfonyl chloride (6.25 mL of 0.159 M solution, 0.994 mmol) was added as a solution in dichloromethane. The mixture was stirred 16 hours at room temperature, then poured into dilute hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 70/30 to 0/100) to afford 8-isopropyl-11 -oxo-/V-(tetrahydro-2H-pyran-4-yl)-10,11- dihydrodibenzo[ft,/][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide (0.87 g) as a white solid.

MS (ES) m/z 464.9;

HPLC purity 100.0% at 210-370 nm, 8.4 minutes.; 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 10 minutes, hold 4 minutes.

HRMS: calculated for C ₂ I H ₂₄ N ₂ O ₆ S ₂ + H+, 465.11485; found (ESI, [M+H] ⁺ ), 465.1219;

Example 169: tert-Butyl 4-{[(8-isopropyl-5,5-dioxido-11-oxo-10,11- dihydrodibenzo[6,/][1,4]thiazepin-7-yl)sulfonyl]amino}piperi dine-1-carboxylate

207

Boc

[0507] Triethylamine (0.665 g, 6.57 mmol) and te/f-butyl 4-aminopiperidine-1- carboxylate (0.717 g, 3.58 mmol) were dissolved in dichloromethane (10 ml_), and 8- isopropyl-5,5-dioxido-11 -oxo-10,11 -dihydrodibenzo[b,f][1 ,4]thiazepine-7-sulfonyl chloride (18.75 ml_ of 0.159 M solution, 2.98 mmol) was added as a solution in dichloromethane. The mixture was stirred 16 hours at room temperature, then poured into dilute hydrochloric acid. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over magnesium sulfate and concentrated to afford a brown oil, which was purified by silica gel column chromatography (hexane/ethyl acetate, 70/30 to 20/80) to afford terf-butyl A- {[(8-isopropyl-5,5-dioxido-11 -oxo-10, 11 -dihydrodibenzo[/),/][1 ,4]thiazepin-7- yl)sulfonyl]amino}piperidine-1-carboxylate (0.138 g) as a white solid.

[0508] MS (ES) ZiVz 561.9;

HPLC purity 100.0% at 210-370 nm, 9.9 minutes.; 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 10 minutes, hold 4 minutes.

Example 170: Biological Testing

U2OS-SFRP1-TCF-Luciferase Assay:

MATERIALS AND METHODS: Cells

[0509] The osteosarcoma cell line, U2OS (ATCC, HTB 96), is passaged twice a week with growth medium [McCoy's 5A medium containing 10% (v/v) fetal calf

208

serum, 2mM GlutaMAX-1 , and 1%(v/v) Penicillin- Streptomycin]. The cells are maintained in vented flasks at 37 ⁰ C inside a 5% CO2/95% humidified air incubator. One day prior to infection, the cells are plated with growth medium at 1.64E+7 cells/flask into 225cm ² tissue culture flasks (T ₂₂₅ ) and incubated at 37 ⁰ C overnight.

Large-Scale Infection

[0510] The growth medium is removed from one flask of cells, and the cells are washed twice with approx. 25m I/wash of PBS w/o calcium or magnesium. 3ml of Trypsin-EDTA (0.05% Trypsin, 0.53 mM EDTA-4Na) is added to the flask, and the flask is incubated at room temperature for approx. 5 minutes until the cells have rounded and detached from the surface of the flask. The cells are resuspended in 10ml of McCoy's 5A medium containing 10% fetal calf serum and pipetted up and down several times until a single cell suspension is formed. A 10 μl aliquot is removed and diluted at 1 :10 in PBS. The diluted cells are counted using a hemacytometer to determine the total number of cells in the flask. This cell count will be used to calculate the volume of the virus stocks needed for each infection.

[0511] The growth medium is removed from the remaining flasks of cells, and they are infected for 30 minutes at 37 ⁰ C with recombinant adenovirus 5 (Ad5)-WNT3 diluted to a multiplicity of infection (MOI) of 2 in 3m I/flask of experimental medium [McCoy's 5A medium containing 2%(v/v) fetal calf serum, 2mM GlutaMAX-1 , and 1 %(v/v) Penicillin-Streptomycin]. After the 30- minute incubation, both Ad5-SFRP-1 and Ad5-16xTCF-luciferase are added, each diluted to an MOI of 10 in 2m I/flask of experimental medium, and the flasks are incubated for one hour. The virus inoculum is then removed, and the cells are washed once with approximately 25ml/flask of McCoy's 5A medium, then refed with 50m I/flask of experimental medium and incubated for approximately 1 V2 hours for recovery prior to freezing.

Freezing Cells

209

[0512] The infected cells are washed and trypsinized as described above. The detached cells are resuspended in 10ml/flask of phenol red-free RPMI 1640 containing 10% fetal calf serum. The resuspended cells are pooled and counted, as described above, to determine the total number of cells in the pool. The cells are 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 is aspirated and the cells are resuspended in cold, phenol red- free RPMI 1640 medium containing 50% FBS to a cell density of 1.8E+7 cells/ml. An equal volume of cold, 2x freezing medium (phenol red-free RPMI 1640 medium containing 50% FBS and 15% DMSO) is added slowly, dropwise to the resuspended cells with gentle mixing, resulting in a final cell density of 9E+6 cells/ml. The resuspended cells are placed on ice and aliquoted into sterile cryogenic vials. The vials are transferred to a Nalgene Cryo 1 ⁰ C Freezing Container (Nalgene catalog # 5100-0001) containing 250 ml isopropyl alcohol. The sealed container is placed in a -8O ⁰ C freezer overnight to freeze the cells at a cooling rate of -1°C/minute. The frozen cells are then transferred to a -150 ⁰ C freezer for long term storage.

Benchtop Dose Response Assay

[0513] Early in the morning, a vial of frozen cells is thawed, and the cells are resuspended in plating medium [phenol red-free RPMI 1640 medium containing 5% fetal calf serum, 2mM GlutaMAX-1 , and 1 % (v/v) Penicillin- Streptomycin] to a final cell density of 1.5E +5 cells/ml. The resuspended cells are then plated in 96-well tissue culture treated plates at a volume of 10Oul of cell suspension/well {i.e., 1.5E+4 cells/well). The plates are incubated at 37 ⁰ C inside a 5% CO2/95% humidified air incubator for 5 hours or until the cells have attached and started to spread. Prior to the addition of test compounds, the medium is replaced with 50ul/well of phenol red-free RPMI 1640 containing 10% fetal calf serum, 2m M GlutaMAX-1 , and 1 %(v/v) Penicillin- Streptomycin. Test compounds, or vehicle (typically DMSO), diluted in phenol

red-free RPMI 1640 containing 2mM GlutaMAX-1 , and 1%(v/v) Penicillin- Streptomycin are then added to the wells in replicates of 4 wells/dilution and the plates are incubated at 37 ⁰ C overnight.

Dosing

[0514] Dose-response experiments are performed with the compounds in 2-fold serial dilutions from 10,000-4.9 nM. From these dose-response curves, EC50 values are generated.

Assay

[0515] After the overnight incubation, the cells are washed twice with 150 μl/well of PBS without calcium or magnesium and lysed with 5Ou I/well of 1X cell culture lysis reagent (Promega Corporation) on a shaker at room temperature for 30 minutes. Thirty microliter aliquots of the cell lysates are transferred to 96-well luminometer plates, and luciferase activity is measured in a MicroLumatPLUS luminometer (EG&G Berthold) using 100ul/well of luciferase substrate (Promega Corporation). Following the injection of substrate, luciferase activity is measured for 10 seconds after a 1.6 second delay. The luciferase activity data is transferred from the luminometer to a PC and analyzed using the SAS/Excel program to determine ECso values.

[0516] ANALYSIS OF RESULTS: The luciferase data is analyzed using the SAS/Excel program. EC ₅₀ determinations for dose response curves are determined using the SAS/Excel program.

REFERENCES:

[0517] Finch, P.W., He, X., Kelly, M.J., Uren, A., Schaudies, R.P., Popescu, N.C., Rudikoff, S., Aaronson S.A., Varmas, H. E., Rubin, J. S. Purification and molecular

cloning of a secreted, Frizzled -related antagonist of Wht action. 1997 Proc. Natl. Acad. Sci. U.S.A. 94, 6770-6775.

[0518] Coghlan, M.P., Culbert, AA, Cross, D.AE., Corcoran, S L, Yates, J.W., Pearce, N.J., Rausch, O.L, Murphy, G.J.,. Carter, P.S., Cox, L.R., Mills, D., Brown, M.J., Haigh, D., Ward, R.W., Smith, D.G., Murray, K.J., Reith, A.D., Holder, J.C. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. 2000, Chemistry and Biology, 7, 793- 803.

Fluorescence Polarization Binding Assay:

[0519] The affinity of test compounds for SFRP-1 was determined using a fluorescence polarization binding assay. According to the assay design, a probe compound was bound to SFRP-1. The fluorescence anisotropy value of the probe compound is increased upon binding to SFRP-1. 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-1.

[0520] To determine ICso values, fluorescence polarization experiments were conducted in a 384 -we 11 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-CI, NacL, glycerol, and NP40 at final concentrations of 25 mM Tris-CI pH 7.4, 0.5 M NaCI, 5% glycerol and 0.002% NP40. Master stock solutions of the test compounds were prepared in 100% DMSO at final concentrations of 20 mM. 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 MiIIi-Q purity water, resulting in working stock solutions (10x compound stocks) in 20 % DMSO.

[0521] 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.

[0522] 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-1 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.

[0523] 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 concentrations of SFRP-1 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.

[0524] The plate was incubated in the dark for 15 minutes. The fluorescence of the SFRP-1/probe complexes 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: Matrical384lv.pdf (pdf stands for Plate Definition File)

Excitation 485nm (bandwidth 20nm)

Emission 535nm (bandwidth 30nm)

G-factor: 1.03

# flashes / well: 10 integration time: 100us time between move, flash: 60 ms

Z-position: 10730 um

ANALYSIS OF RESULTS:

[0525] 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 = /(//)-/(±)í/(//)+2/(±) where l(ll) and I(I) are the parallel and perpendicular emission intensities, respectively.

[0526] Monitoring the anisotropy changes of the probe compound revealed that it bound saturably to SFRP-1 with a K ₀ of 20-30 nM. The binding affinity was independently verified using a tryptophan fluorescence quenching assay.

[0527] 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:

Y = Bottom + ^-/"ffi * 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-1 -bound probe prior to the addition of the test compound, respectively.

[0528] For automated IC ₅₀ 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.

[0529] The percent inhibition of the probe binding to SFRP-1 was determined at inhibitor concentration of 2.5 μg/mL. Equation is as follows:

TOp - A ₂ J

'/titthibJrion = • 100

Top - Bottom where A2.5 is the anisotropy at 2.5 μg/ml compound and the other values are as per above.

[0530] The data obtained from the experiments are shown in the table below.

[0531] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges specific embodiments therein are intended to be included.

[0532] The disclosures of each patent, patent application and publication cited or described in this document are hereby incorporated herein by reference, in its entirety.

[0533] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention.