WO2008061029A1 - Aryl sulfonamide derivatives and methods of their use - Google Patents

Aryl sulfonamide derivatives and methods of their use Download PDF

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Publication number
WO2008061029A1
WO2008061029A1 PCT/US2007/084321 US2007084321W WO2008061029A1 WO 2008061029 A1 WO2008061029 A1 WO 2008061029A1 US 2007084321 W US2007084321 W US 2007084321W WO 2008061029 A1 WO2008061029 A1 WO 2008061029A1
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dioxide
sulfonamide
fluoro
methyl
thioxanthene
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PCT/US2007/084321
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French (fr)
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Richard Eric Mewshaw
Cuijian Yang
Richard Edsall
William Jay Moore
Jeffrey Curtis Kern
Jason Michael Diffendal
Eugene John Trybulski
Matthew Alan Wilson
Gregory Scott Welmaker
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Wyeth
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C07D327/06—Six-membered rings
    • C07D327/08—[b,e]-condensed with two six-membered carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
    • C07D335/12—Thioxanthenes
    • C07D335/14—Thioxanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C07D335/16—Oxygen atoms, e.g. thioxanthones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/02—Seven-membered rings
    • C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D337/14—[b,f]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 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.
  • 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.
  • 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.
  • 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)- ⁇ , fibroblast growth factors (FGFs), nerve growth factor (NGF), and bone morphogenetic proteins (BMPs).
  • TGF transforming growth factor
  • FGFs fibroblast growth factors
  • NGF nerve growth factor
  • BMPs bone morphogenetic proteins
  • 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.
  • CCD cysteine-rich domain
  • LDL low-density lipoprotein
  • LRP low-density lipoprotein receptor-related proteins
  • the first secreted frizzled-related protein 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.
  • SFRP/SARP genes 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 (Leiffle 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.
  • SFRP-1 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.
  • the present invention is directed to certain aryl sulfonamide derivatives and to their use, for example, in medical treatment.
  • 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.
  • the present invention is directed to compounds of formula I:
  • 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, heterocycloal
  • 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, heterocycloalky
  • 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, cycloalky
  • 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-C ⁇ )alkyl, acetamide, alkylcarboxylate, sulfonylbenzene, sulfonylbenzoic acid, sulfonylphenylacetamide, carbothioamidobenzoic acid, oxoalkylpyridine, alkanoic acid, oxoalkanoic acid, cyano, or halo; and
  • compositions comprising: a. at least one compound of formula I; and b. at least one pharmaceutically acceptable carrier.
  • 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.
  • the present invention is directed to certain aryl sulfonamide derivatives and to their use, for example, in medical treatment.
  • the invention relates to ar ⁇ l 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.
  • alkyl 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).
  • 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.
  • 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.
  • hydroxyalkyl refers to the group -alkyl-OH where alkyl is an alkyl group as previously defined.
  • carboxyalkyl refers to the group -alkyl-C(O)OH where alkyl is an alkyl group as previously defined.
  • haloalkyl refers to the group -alkyl-halo where halo is a halogen atom and alkyl is an alkyl group as previously defined.
  • perfluoroalkyl 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.
  • perfluoroalkylalkyl refers to the group -alkyl- perfluoroalkyl where alkyl and perfluoroalkyl are as previously defined.
  • alkenyl 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.
  • 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.
  • alkynyl 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.
  • cycloalkyl 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.
  • alkylcycloalkyl 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.
  • cycloalkylalkyl refers to the group -alkylcycloalkyl in which alkyl is an alkyl group as previously defined and cycloalkyl is a cycloalkyl group as previously defined.
  • spirocycloalkyl 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.
  • heterocycloalkyl 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.
  • 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.
  • heterocycloalkyl includes "bridged" heterocycloalkyl groups which contain at least one carbon-carbon bond between non-adjacent carbon atoms of the heterocycloalkyl ring.
  • alkylheterocycloalkyl 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.
  • heterocycloalkylalkyl refers to the group -R'-heterocycloalkyl where R' is an alkyl group as previously defined and heterocycloalkyl is a heterocycloalkyl group as previously defined.
  • aryl refers to an optionally substituted carbocyclic aromatic ring, e.g., of 6 to 20, or 6 to 14 carbon atoms (C ⁇ - 14 aryl).
  • Aryl groups may be monocyclic or bicyclic. Exemplary aryl groups include phenyl and naphthyl.
  • carboxyaryl refers to the group -aryl-C(O)OH, where aryl is an aryl group as previously defined.
  • heteroaryl 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.
  • 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.
  • alkylheteroaryl refers to the group -heteroaryl- alkyl wherein heteroaryl is a heteroaryl group as previously defined and alkyl is an alkyl group as previously defined.
  • arylcarbonylalkyl 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.
  • fused cycloalkylaryl 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.
  • fused cycloalkylarylaminocarbonyl refers to the group -C(O)-N H-fused cycloalkylaryl where fused cycloalkylaryl is a fused cycloalkylaryl group as previously defined.
  • fused heterocycloalkylaryl 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.
  • fused heterocycloalkylarylcarbonyl refers to the group -C(O)- fused hetercycloalkylaryl where fused hetercycloalkylaryl is a fused hetercycloalkylaryl group as previously defined.
  • alkylcarbonyl refers to the group -C(O)R' where R' is an alkyl group as previously defined.
  • alkylthioalkylcarbonyl refers to the group -C(O)-R'-S-R' where R' is an alkyl group as previously defined.
  • alkylcarbonylamino refers to the group - NHC(O)R' where R' is an alkyl group as previously defined.
  • alkoxycarbonylamino refers to the group -NHC(O)OR' where R' is an alkyl group as previously defined.
  • alkylcarbonylalkylamino refers to the group -NH-R'-C(O)R' where R' is an alkyl group as previously defined.
  • alkylsulfonylamino refers to the group -NH 2 -S(O) 2 -R' where R' is an alkyl group as previously defined.
  • carboxyarylsulfonylamino refers to the group - NH 2 -S(O) 2 -aryl-C(O)OH where aryl is an aryl group as previously defined.
  • alkoxy refers to the group -O-R' where R' is an alkyl group as previously defined, preferably C-i- ⁇ alkyl.
  • perfluoroalkoxy refers to the group -O-R" where R" is a perfluoroalkyl group as previously defined.
  • aminoalkyl refers to the group -R 1 NH 2 where R' is an alkyl group as previously defined.
  • alkylcarbinol refers to an alkyl group as previously defined substituted with a hydroxyl group.
  • carbonyl refers to a bivalent carbon atom that is further bonded to an oxygen atom through a double bond.
  • thiocarbonyl refers to a bivalent carbon atom that is further bonded to a sulfur atom through a double bond.
  • halogen or halo
  • cyano or cyanoalkyl
  • alkoxyalkyl refers to the group -R'-alkoxy where R' is an alkyl group as previously defined and alkoxy is an alkoxy group as previously defined.
  • arylalkyl refers to the group -R'-aryl where aryl is an aryl group as previously defined, and R' is an alkyl group as previously defined.
  • heteroarylalkyl refers to the group -R'-heteroaryl where heteroaryl is a heteroaryl group as previously defined, and R' is an alkyl group as previously defined.
  • arylalkenyl refers to the group -alkenyl-aryl where aryl is an aryl group as previously defined, and alkenyl is an alkenyl group as previously defined.
  • arylalkynyl refers to the group -alkynyl-aryl where aryl is an aryl group as previously defined, and alkynyl is an alkynyl group as previously defined.
  • arylalkoxy refers to the group -alkoxy-aryl where aryl is an aryl group as previously defined and alkoxy is an alkoxy group as previously defined.
  • benzoxy refers to the group -O-Chfe-phenyl.
  • aminocarbonylalkoxy refers to the group - alkoxy-C(O)NH 2 where alkoxy is an alkoxy group as previously defined.
  • alkoxycarbonylalkoxy refers to the group - alkoxy-C(O)-alkoxy where alkoxy is an alkoxy group as previously defined.
  • carboxyalkoxy refers to the group -alkoxy- C(O)OH where alkoxy is an alkoxy group as previously defined.
  • arylalkylcarbonyl refers to the group - alkylcarbonyl-aryl wherein alkylcarbonyl is an alkylcarbonyl group as previously defined and aryl is an aryl group as previously defined.
  • dialkylaminoarylcarbonyl refers to the group — C(O)aryl-N(R')(R') where R' is an alkyl group as previously defined.
  • arylthio refers to the group -S-aryl where aryl is an aryl group as previously defined.
  • arylthiol refers to the group HS-aryl where aryl is an aryl group as previously defined.
  • arylsulfonyl refers to the group -S(O) 2 -aryl where aryl is an aryl group as previously defined.
  • arylsulfonylarylsulfonyl refers to the group -S(O) 2 -aryl-S(O) 2 -aryl where aryl is an aryl group as previously defined.
  • carboxyarylsulfonyl refers to the group -S(O) 2 -aryl-C(O)OH where aryl is an aryl group as previously defined.
  • aminosulfonyl refers to the group -S(O) 2 -NH 2 .
  • heteroarylsulfonyl refers to the group -S(O) 2 -heteroaryl where heteroaryl is a heteroaryl group as previously defined.
  • arylester refers to the group -C(O)O-aryl where aryl is an aryl group as previously defined.
  • alkylthiocarbonyl refers to the group -C(S)R' where R' is an alkyl group as previously defined.
  • alky lam inoalkylcarbonyl refers to the group -C(O)-R'-NH(R') where R' is an alkyl group as previously defined.
  • dialkylaminoalkylcarbonyl refers to the group -C(O)-R'-N(R')(R') where R' is an alkyl group as previously defined.
  • perfluoroalkylcarbonyl refers to the group - C(O)R" where R" is a perfluoroalkyl group as previously defined.
  • carboxyalkylcarbonyl refers to the group -C(O)-R'-C(O)OH where R' is an alkyl group as previously defined.
  • alkoxycarbonyl refers to the group -C(O)OR' where R' is an alkyl group as previously defined.
  • alkoxythiocarbonyl refers to the group -C(S)OR 1 where R' is an alkyl group as previously defined.
  • alkoxycarbonylalkyl refers to the group -R'- C(O)OR' where R' is an alkyl group as previously defined.
  • arylcarbonyl refers to the group -C(O)-aryl where aryl is an aryl group as previously defined.
  • heteroarylcarbonyl refers to the group -C(O)-heteroaryl where heteroaryl is a heteroaryl group as previously defined.
  • heteroarylalkylcarbonyl 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.
  • heterocycloalkylalkylcarbonyl 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.
  • heterocycloalkylalkylarninothiocarbonyl 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.
  • aryloxycarbonyl refers to the group
  • aryl is an aryl group as previously defined.
  • aryloxythiocarbonyl refers to the group -C(S)-O-aryl where aryl is an aryl group as previously defined.
  • cyanoarylcarbonyl refers to the group -C(O)-aryl-CN where aryl is an aryl group as previously defined.
  • arylalkylcarbonyl 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.
  • cycloalkylcarbonyl refers to the group -C(O)-cycloalkyl where cycloalkyl is a cycloalkyl group as previously defined.
  • heterocycloalkylcarbonyl refers to the group -C(O)-heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined.
  • heterocycloalkylthiocarbonyl refers to the group -C(S)-heterocydoalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined.
  • aminoalkylcarbonyl refers to the group -C(O)-R'-NH 2 where R' is an alkyl group as previously defined.
  • alkoxycarbonylaminothiocarbonyl refers to the group -C(O)-S-NH-C(O)-O-R' where R 1 is an alkyl group as previously defined.
  • alkoxycarbonylalkylaminothiocarbonyl refers to the group -C(O)-S-NH-R'-C(O)-O-R' where R' is an alkyl group as previously defined.
  • alkylthiocarbonylalkylcarbonyl refers to the group -C(O)-R'-C(O)-S-R' where R' is an alkyl group as previously defined.
  • cyanoalkoxycarbonyl refers to the group -C(O)-alkoxy-CN where alkoxy refers to an alkoxy group as previously defined.
  • alkylaryl refers to the group -aryl-R' where R' is an alkyl group as previously defined, and aryl is an aryl group as previously defined.
  • alkylester refers to the group -C(O)OR' wherein R' is an alkyl group as previously defined.
  • aminocarbonyl refers to the group
  • 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.
  • heterocycloalkylaminocarbonyl refers to the group -C(O)NH-heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined.
  • carboxyalkylaminocarbonyl 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.
  • alkoxycarbonylalkylaminocarbonyl 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.
  • aminocarbonylalkyl refers to the group -R'C(O)NH 2 where R' is an alkyl group as previously defined.
  • 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.
  • 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.
  • heterocycloalkylcarbonylalkyl 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.
  • arylaminocarbonyl refers to the group - C(O)NH(aryl), where aryl is an aryl group as previously defined.
  • heteroarylaminocarbonyl refers to the group -C(O)NH(heteroaryl), where heteroaryl is a heteroaryl group as previously defined.
  • heteroarylaminothiocarbonyl refers to the group -C(S)N H(heteroaryl), where heteroaryl is a heteroaryl group as previously defined.
  • arylaminothiocarbonyl refers to the group -C(S)N H(aryl), where aryl is an aryl group as previously defined.
  • cycloalkylaminocarbonyl refers to an alkylaminocarbonyl or dialkylaminocarbonyl group as previously defined in which at least one alkyl group is replaced by a cycloalkyl group.
  • alkylsulfonyl refers to the group -S(O)2-R * where R' is an alkyl group as previously defined.
  • alkylsulfinyl refers to the group -S(O)-R' where R' is an alkyl group as previously defined.
  • alkylthio refers to the group -S-R' where R' is an alkyl group as previously defined.
  • perfluoroalkylthio refers to the group -S-R" where R" is a perfluoroalkyl group as previously defined.
  • phosphonic acid alkyl refers to the group -R'-P(O)(OH)2 where R' is an alkyl group as previously defined.
  • dimethylphosphonatealkyl refers to the group - R'-P(O)(OCH 3 ) 2 where R' is an alkyl group as previously defined.
  • nitro refers to -NO 2 .
  • sulfonyl refers to -SO 2 -.
  • sulfoxide refers to -SO-.
  • 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, alkylamino
  • 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.
  • the term "optionally substituted aryl” is intended 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).
  • impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups.
  • impermissible substitution patterns are well known to the skilled artisan.
  • partially saturated refers to a nonaromatic cycloalkyl or heterocycloalkyl group containing at least one double bond and preferably one or two double bonds.
  • terapéuticaally effective amount 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.
  • pharmaceutically acceptable salts or “pharmaceutically acceptable salt” includes acid addition salts, namely salts derived from treating a 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.
  • patient refers to a mammal.
  • administer refers 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.
  • 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.
  • shocker and “suffering,” as used herein, refer to one or more conditions with which a patient has been diagnosed, or is suspected to have.
  • 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 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, heterocyclo
  • 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, heterocycloalky
  • 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, cycloalky
  • 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;
  • Ri is H, fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, butyoxy, phenyl, naphthyl, benzyl, trifluoromethyl, or trifluoromethoxy.
  • R 1 is H or fluoro.
  • R 2 is fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, butyoxy, phenyl, naphthyl, benzyl, trifluoromethyl, or trifluoromethoxy.
  • R 2 is chloro, methyl, isopropyl, trifluoromethyl, or trifluoromethoxy.
  • 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
  • R 3 is:
  • 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.
  • 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.
  • both R 5 groups together with the carbon atom through which they are attached, form spirocyclopentyl or spirocyclohexyl.
  • R 6 is methyl, hydroxy, hydroxyethyl, ethanolic acid, cyano, fluoro, or chloro.
  • Preferred embodiments of the compounds of formula I include:
  • the pharmaceutically acceptable salt is a hydrochloride salt.
  • 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 myeloid leukemia, wound healing, prostate cancer, autoimmune inflammatory disorders, such as Graves ophthalmopathy, and combinations thereof.
  • 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.
  • 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.
  • the compositions comprise mixtures of one or more compounds of formula I.
  • the invention relates to a process for the preparation of a compound of of formula I: 0
  • 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, dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloal
  • R 2 is halo, alkyl, alkoxy, alky lam ino, alkylthio, dialkylamino, ar ⁇ l, 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, heterocycloalky
  • 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, cycloalky
  • 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
  • the acid is polyphosphoric acid or sulfuric acid.
  • the reducing agent is sodium borohydride or triethylsilane.
  • the oxidizing agent is oxone or hydrogen peroxide and acetic acid.
  • the compound of formula IA is formed by: contacting a compound of formula IY with chlorosulfonic acid to form a mixture and heating the mixture:
  • 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).
  • 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.
  • 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.
  • 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.
  • An enantiomer can, in some embodiments of the invention, be provided substantially free of the corresponding enantiomer.
  • 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 means that a significantly lesser proportion of the corresponding enantiomer is present. In preferred embodiments, less than about 90 % by weight of the corresponding enantiomer is present relative to desired enantiomer, more preferably less than about 1% by weight.
  • Preferred enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC), and the formation and crystallization of chiral salts, or preferred enantiomers, can be prepared by methods described herein. Methods for the preparation of enantiomers are described, for example, in Jacques, et 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.
  • HPLC high performance liquid
  • 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. Scheme 2
  • 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.
  • 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.
  • 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.
  • 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.
  • the carrier is a finely divided solid that is in admixture with the finely divided active ingredient.
  • 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.
  • 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
  • oils e.g. fractionated coconut oil and arachis oil
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • 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.
  • the compounds of formula lean be administered rectally or vaginally in the form of a conventional suppository.
  • the compounds of formula lean 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.
  • the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
  • 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 capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • 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.
  • 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.
  • the present invention is directed to prodrugs of compounds of formula I.
  • prodrug 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).
  • Example 7 2,9,9-Trimethyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3- sulfonamide 10,10- dioxide.
  • Step 3. 9-Trimethyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulfonamide 10,10- dioxide.
  • Example 9 6-Fluoro-2-isopropyl-9,9-dimethyl-N-(tetrahydro-2H-pyran-4- ylmethyl)-9H- thioxanthene-3-sulf on amide 10,10-dioxide.
  • Example 10 6-Fluoro-2-isopropyl-9,9-dimethyl-N-(2-pyridin-4-ylethyl)-9H- thioxanthene-3- sulfonamide 10,10-dioxide.
  • Step 3. 9-Trimethyl- ⁇ /-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulfonamide 10,10- dioxide.
  • 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
  • Example 21 4-Oxo-4- ⁇ 4- ⁇ [(2,9,9-trimethyl-10,10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino ⁇ piperidin-1 -yl)butanoic acid
  • Example 22 ⁇ /- ⁇ 4-[(4- ⁇ [(2,9,9-Trimethyl-10,10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino ⁇ piperidin-1-yl)sulfonyl]phenyl ⁇ acetamide
  • Example 28 2'-Methyl-A/-(2-pyridin-4-ylethyl)spiro[cyclopentane-1 ,9'- thioxanthene]-3'-sulfonamide lO'.IO'-dioxide
  • Example 29 2 > -Methyl-/V-(tetrahydro-2H-pyran-4-yl)spiro[cyclopentane-1 ,9'- thioxanthene]-3'-sulfonamide 10',10'-dioxide
  • Example 32 yV-(2-Hydroxy-2-phenylethyl)-2'-methylspiro[cyclopentane-1 ,9'- thioxanthene]-3'-sulfonamide 10',10' -dioxide
  • Example 36 2'-Methyl-/V-piperidin-4-ylspiro[cyclopentane-1 ,9'-thioxanthene]- 3'-sulfonamide 10',10'-dioxide
  • Example 17 employing fert-butyl 4- ⁇ [(2'-methyl-10',10 l -dioxidospiro[cyclopentane- i . ⁇ '-thioxanthen ⁇ '-yOsulfonyllaminoJpiperidine-i-carboxylate to afford 673 mg (94
  • Example 37 3-[(4- ⁇ [(2 I -Methyl-10 i ,10'-dioxidospiro[cyclopentane-1 ,9'- thioxanthen]-3'-yl)sulfonyl]amino ⁇ piperidin-1-yl)sulfonyl]benzoic acid
  • Example 18 employing 2'-methyl- ⁇ /-piperidin-4-ylspiro[cyclopentane-1 ,9'- thioxanthene]-3'-sulfonamide 10',10'-dioxide (94.8 mg, 0.191 mmol) and 3-
  • Example 38 ferf-Butyl (4- ⁇ [(2 > -methyl-10 ⁇ ,10 > -dioxidospiro[cyclopentane-1,9 ⁇ - thioxanthen]-3'-yl)sulfonyl]amino ⁇ piperidin-1-yl)acetate
  • 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.
  • Example 40 2'-Methyl-/V-(2-pyridin-2-ylethyl)spiro[cyclohexane-1 ,9'- thioxanthene]-3' -sulfonamide 10',10'-dioxide
  • Example 26 (step 3) employing 2'-methylspiro[cyclohexane-1 ,9'-thioxanthene]
  • Example 26 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-aminotetrahydropyran hydrochloride to afford 55.7 mg (54 %) of desired product.
  • Example 48 ⁇ f-(2-Hydroxyethyl)-2'-methylspiro[cyclohexane-1,9'- thioxanthene]-3'-sulfonamide 10',10'-dioxide
  • Example 50 2 t -M ⁇ thyl-/V-piperidin-4-ylspiro[cyclohexane-1,9'-thioxanthene]-3 l - sulfonamide 10',10'-dioxide
  • Example 51 3-[(4- ⁇ [(2 I -Methyl-10' ) 10'-dioxidospiro[cyclohexane-1,9 1 - thioxanthen]-3'-yl)sulfonyl]amino ⁇ pipehdin-1-yl)sulfonyl]benzoic acid
  • 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.
  • 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.
  • 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.
  • Example 58 ⁇ /-(2-Cyanoethyl)-9,9-diethyl-2-methyl-9W-thioxanthene-3- sulfonamide 10,10-dioxide
  • 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.
  • 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.
  • 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.
  • Example 23 The title compound was prepared according to similar conditions used in Example 23 employing 9,9-diethyl-2-methyl- ⁇ /-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.
  • Example 65 3-[(4- ⁇ [(9,9-Diethyl-2-m ⁇ thyl-10,10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino ⁇ piperidin-1 -yl)sulfonyl]benzoic acid
  • 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.
  • Example 7 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.
  • Example 70 2-Chloro-6-fluoro-9,9-dimethyl-/V-piperidin-4-yl-9W-thioxanthene- 3-sulfonamide 10,10-dioxide 'NH
  • Example 24 employing te/f-butyl 4- ⁇ [ ⁇ 2-chloro-6-fluoro-9,9-dimethyl-10,10-dioxido-
  • 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.
  • Example 24 employing ferf-butyl (4- ⁇ [(2-chloro-6-fluoro-9,9-dimethyl-10,10-dioxido-
  • Example 74 3-[(4- ⁇ [(2-Chloro-6-fluoro-9,9-dimethyl-10,10-dioxido-9H- thioxanthen-3-yl)sulfonyl]amino ⁇ piperidin-1-yl)sulfonyl]benzoic acid
  • Example 129 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
  • Example 129 The title compounds were prepared according to similar conditions used in Example 129 (step 2) employing ⁇ -fluoro- ⁇ . ⁇ -dimethyl-S-nitro ⁇ trifluoromethyO- ⁇ H- 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).
  • Example 129 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.
  • Example 24 employing ferf-butyl 4-( ⁇ [6-fluoro-9,9-dimethyl-10,10-dioxido-2-
  • Example 18 The title compound was prepared according to similar conditions used in Example 18 employing 6-fluoro-9,9-dimethyl- ⁇ /-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.
  • Example 78 6-Fluoro-9,9-dimethyl- ⁇ /-(2-pyridin-3-ylethyl)-2-(trifluoromethyl)- 9tf-thioxanthene-3-sulfonamide 10,10-dioxide
  • Example 80 6-Fluoro-9,9-dimethyl-N-(2-pyridin-3-ylethyl)-2-(trif1uoromethoxy)- 9H- thioxanthene-3-sulfonamide 10,10-dioxide.
  • Step 7 6-Fluoro-9,9-dimethyl-10,10-dioxido-9H-thioxanthen-2-yl trifluoromethyl ether-3-sulfonyl chloride

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Abstract

Compounds of formula (I) and pharmaceutically acceptable salt thereof, which are modulators of secreted frizzled related protein-1, are disclosed. The compounds, and compositions containing the compounds, can be used 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.

Description

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:
Figure imgf000005_0001
I or a pharmaceutically acceptable salt thereof; wherein:
R1 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 R1 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;
R2 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 R2 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;
R3 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 R3 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 R3 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 R3 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 R3 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 R3 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 R3 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.
R4 is H or C1-C4 straight or branched alkyl;
R5 is, independently at each occurrence, H or C1-C4 straight or branched alkyl; or both R5 groups, together with the carbon atom through which they are attached form a Cs-Ce cycloalkyl;
R6 is Ci-C4 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- -(NR4)-, -S-, -[C(R5J2]- -(CH2-CHR4)-, -(C=O)-, Or-(C=O)-NR4
[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. [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 (C1-12 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 -NH2-S(O)2-R' where R' is an alkyl group as previously defined. [0045] The term "carboxyarylsulfonylamino," as used herein, refers to the group - NH2-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 -NH2, -NHR1, -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 -R1NH2 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)NH2 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-NH2.
[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)OR1 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'-NH2 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 R1 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)NH2. [0106] The terms "alkylaminocarbonyl," and "dialkylaminocarbonyl," as used herein, refer to the groups -C(O)NHR1 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)NH2 where R' is an alkyl group as previously defined.
[0111] The terms "alkylaminocarbonylalkyl," and "dialkylaminocarbonylalkyl," as used herein, refer to the groups -R1C(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. [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)(OCH3)2 where R' is an alkyl group as previously defined.
[0125] The term "nitro" as used herein, refers to -NO2.
[0126] The term "sulfonyl" refers to -SO2-.
[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 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 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:
Figure imgf000025_0001
or a pharmaceutically acceptable salt thereof; wherein:
R1 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 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;
R2 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 R2 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;
R3 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 R3 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 R3 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, 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 R3 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, alkylthiocarbonylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylaminoarylsulfonyl, and heteroarylsulfonyl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the heterocycloalkyl groups of R3 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 R3 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; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the amino substituents on the alkyl groups of R3 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.
R4 is H or C1-C4 straight or branched alkyl;
R5 is, independently at each occurrence, H or Ci-C4 straight or branched alkyl; or both R5 groups, together with the carbon atom through which they are attached form a Cs-Ce spirocycloalkyl;
R6 is Ci-C4 alkyl, hydroxy, hydroxy(Ci-C6)alkyl, acetamide, alkylcarboxylate, sulfonylbenzene, sulfonylbenzoic acid, sulfonylphenylacetamide, carbothioamidobenzoic acid, oxoalkylpyridine, alkanoic acid, oxoalkanoic acid, cyano, or halo; and X is -O- -(NR4)-, -S-, -[C(R5J2]- -(CH2-CHR4)-, -(C=O)-, Or-(C=O)-NR4
[0139] In certain embodiments of the compounds of formula I, Ri is H, fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, butyoxy, phenyl, naphthyl, benzyl, trifluoromethyl, or trifluoromethoxy. In certain preferred embodiments, R1 is H or fluoro.
[0140] In certain embodiments of the compounds of formula I, R2 is fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, butyoxy, phenyl, naphthyl, benzyl, trifluoromethyl, or trifluoromethoxy. In certain preferred embodiments, R2 is chloro, methyl, isopropyl, trifluoromethyl, or trifluoromethoxy.
[0141] In certain embodiments of the compounds of formula I, R3 is alkyl substituted with 1-3 R6, cycloalkyl substituted with 0-3 R6, heterocycloalkyl substituted with 0-3 R6, arylalkyl substituted with 0-3 R6, heteroarylalkyl substituted with 0-3 R6, heterocycloalkylalkyl substituted with 0-3 R6, fused cycloalkylaryl substituted with 0-3 R6, alkylaryloxy substituted with 0-3 R6 ,
Figure imgf000030_0001
r
Figure imgf000030_0002
Figure imgf000030_0003
Figure imgf000030_0004
HO
Figure imgf000030_0005
Figure imgf000030_0006
or
Figure imgf000031_0001
[0142] In certain embodiments of the compounds of formula I, R3 is:
Figure imgf000031_0002
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000033_0003
HO
Figure imgf000033_0002
CH
t
Figure imgf000033_0005
Figure imgf000033_0007
Figure imgf000033_0004
NH
Figure imgf000033_0008
^=N * or
X^
Figure imgf000033_0006
[0143] In certain embodiments of the compounds of formula I1 R4 is H, methyl, eetthhyyll,, nn--pprrooppyyll,, oorr iissoopprrooppyyll.. IInn cceerrttaaiinn pprreeffeerrrreedd eemmbodiments, R4 is H, methyl, or isopropyl. In certain preferred embodiments, R4 is H.
[0144] In certain embodiments of the compounds of formula I, R5 is, independently at each occurrence, H, methyl, or ethyl. In certain preferred embodiments, both R5 groups are H. In certain preferred embodiments, both R5 groups are methyl. In certain preferred embodiments, both R5 groups are ethyl.
[0145] In certain embodiments of the compounds of formula I, both R5 groups, together with the carbon atom through which they are attached, form spirocyclopentyl or spirocyclohexyl. [0146] In certain embodiments of the compounds of formula I, In certain eemmbbooddiimmeennttss ooff tthhee ccoommppoouunnddss ooff ffooirmula I, R6 is methyl, hydroxy, hydroxyethyl, ethanolic acid, cyano, fluoro, or chloro.
[0147] In certain embodiments of the compounds of formula I1 X is -[C(R5)2]- -(CH2-CHR4)-, -(C=O)-, or -(C=O)-NR4, especially where R4 is H or methyl and where R4 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-sulfonamide 10110- dioxide;
2-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H-thioxanthene-3-sulfonamide 10,10-dioxide;
2-methyl-9-oxo-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide;
6-fluoro-2-isopropyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulfonamide 10,10-dioxide;
6-fluoro-2-isopropyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H-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;
2,919-thmethyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulfonamide 10, 10- dioxide;
2,9,9-trimethyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide; 2,9I9-trimethyl-N-(tetrahydro-2H-pyran-4-yl)-9H-thioxanthene-3-sulfonamide 10,10-dioxide;
2,9>9-trimethyl-N-(2-pyridin-4-ylethyl)-9H-thioxanthene-3-sulfonamide 10,10- dioxide;
N-(2-cyanoethyl)-2,9,9-trimethyl-9H-thioxanthene-3-sulfonamide 10,10- dioxide; tert-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-sulfonamide 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-{[(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-10110-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]benzoic acid;
4-oxo-4-(4-{[(2,9,9-trimethyl-10110-dioxido-9H-thioxanthen-3- yl)sulfoπyl]amino}piperidin-1-yl)butanoic acid;
N-{4-[(4-{[(2,9l9-trimethyl-10,10-dioxido-9H-thioxanthen-3- yl)sulfonyl]am ino}piperidin-1 -yl)sulfonyl]phenyl}acetam ide tert-butyl (4-{[(2,9l9-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-(trans-4-hydroxycyclohexyl)-2,9,9-trimethyl-9H-thioxanthene-3-sulfonamide 10,10-dioxide;
2'-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; 2'-methyl-N-(tetrahydro-2H-pyran-4-yl)spiro[cyclopentane-1 )9l-thioxanthene]- 3'-sulfonamide 101, 10'-dioxide;
2'-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)spiro[cyclopentane-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)-2l-methylspiro[cyclopentane-1 l9'-thioxanthene]- 3'-sulfonamide 101, 1 O'-dioxide;
N^-hydroxy-i -methyl^-phΘnylethylJ-Z-methylspiroIcyclopΘntane-i .θ1- thioxanthene]-3'-sulfonamide 10', 10'-dioxide;
N^-hydroxyethylJ^'-methylspiroIcyclopentane-i .θ'-thioxanthenel-S1- 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-1,9l-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 101, 10'-dioxide;
2l-methyl-N-(2-pyridin-2-ylethyl)spiro[cyclohexane-1 ,9l-thioxanthene]-31- 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 ,9l-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[cyclohexane-1 ,9'- thioxanthene]-3'-sulfonamide 10', 10'-dioxide; 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)-2l-methylspiro[cyclohexane-1 ,9'-thioxanthene]-3'- sulfonamide 10',10'-dioxide; te/f-butyl 4-{[(2'-methyl-101, 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-101, 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 101, 10'-dioxide;
9,9-diethyl-2-methyl-N-(2-pyridin-2-ylethyl)-9H-thioxanthene-3-sulfonamide 10,10-dioxide;
9,9-diethyl-2-methyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulfonamide 10,10-dioxide;
9,9-diethyl-2-methyl-N-(2-pyridin-4-ylethyl)-9H-thioxanthene-3-sulfonamide 10,10-dioxide;
9,9-diethyl-2-methyl-N-(tetrahydro-2H-pyran-4-yl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide;
9,9-diethyl-2-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide;
N-(2-cyanoethyl)-9,9-diethyl-2-methyl-9H-thioxanthene-3-sulfonamide 10,10- dioxide;
9,9-diethyl-N-(2-hydroxy-2-phenylethyl)-2-methyl-9H-thioxanthene-3- sulfonamide 10,10-dioxide;
9,9-diethyl-N-(2-hydroxy-1-methyl-2-phenylethyl)-2-methyl-9H-thioxanthene-3- sulfonamide 10,10-dioxide; 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-10110-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-thioxanthene-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-thioxanthene-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-10110-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]benzoic acid; te/t-butyl 4-({[6-fluoro-9,9-dimethyl-10110-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; ^[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-(trifluoromethyl)-9H- thioxanthene-3-sulfonamide 10, 10-dioxide;
6-fluoro-9,9-dimethyl-N-(2-pyridin-4-ylethyl)-2-(trifluoronnethyl)-9H- thioxanthene-3-sulfonamide 10, 10-dioxide;
6-fluoro-9,9-dimethyl-N-(2-pyridin-3-ylethyl)-2-(trifluoromethoxy)-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 ,9l-thioxanthene]-3'- sulfonamide 10',10'-dioxide;
2'-chloro-6'-fluoro-N-[1-(phenylsulfonyl)piperidin-4-yl]spiro[cyclohexane-1 ,9'- thioxanthene]-3'-sulfonamide 10', 10'-dioxide;
2'-chloro-6'-fluoro-N-[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]spiro[cyclohexane- 1 ,9'-thioxanthene]-3'-sulfonamide 101, 10'-dioxide;
2'-chloro-6l-fluoro-N-(1-isonicotinoylpiperidin-4-yl)spiro[cyclohexane-1 ,9'- thioxanthene]-3'-sulfonamide 10', 10'-dioxide;
N-{4-[(4-{[(2'-chloro-6t-fluoro-10', 10'-dioxidospiro[cyclohexane-1 ,9'- thioxanthen]-3'-yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]phenyl}acetamide
4-(4-{[(2'-chloro-6l-fluoro-101, 10'-dioxidospiroIcyclohexane-i .θ'-thioxanthenl-S'- yl)sulfonyl]am ino}piperidin-1 -yl)-4-oxobutanoic acid;
5-(4-{[(2l-chloro-6l-fluoro-101, 10'-dioxidospiro[cyclohexane-1.θ'-thioxanthenl-S1- 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}benzoic acid;
3-{[(4-{[(2I-chloro-6'-fluoro-101 , 10'-dioxidospiroIcydohexane-i ,9'-thioxanthen]- 3'-yl)sulfonyl]amino}piperidin-1-yl)carbonothioyl]amino}benzoic acid;
4-[(4-{[(2'-chloro-6l-fluoro-101, 10'-dioxidospiro[cyclohΘxanθ-1 ,9'-thioxanthen]- 3'-yl)sulfonyl]amino}piperidin-1 -yl)sulfonyl]benzoic acid;
3-[(4-{[(2'-chloro-6l-fluoro-101, 10'-dioxidospiroIcyclohexane-i ,9'-thioxanthen]- 3'-yl)sulfonyl]amino}piperidin-1 -yl)sulfonyl]benzoic acid; 2-methyl-N-(2-phenylethyl)-10111 -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; 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)-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;
7-f luoro-2-isopropyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-10,11- 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; 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-sulfonam ide 10, 10-dioxide;
8-fluoro-3-methyl-N-(2-pyridin-2-ylethyl)phenoxathiin-2-sulfonamide 10, 10- dioxide;
8-fluoro-3-methyl-N-(2-pyridin-3-ylethyl)phenoxathiin-2-sulfonamide 10, 10- dioxide;
8-fluoro-3-methyl-N-(2-pyridin-4-ylethyl)phenoxathiin-2-sulfonamide 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)phenoxathiJn-2-sulfonamide 10,10-dioxide;
8-fluoro-3-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)phenoxathiin-2- sulfonamide 10,10-dioxide;
8-fluoro-3-methyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]phenoxathiin-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-sulfonam 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-sulfonamide 10, 10- dioxide;
8-fluoro-3-methyl-N-(pyridin-3-ylmethyl)phenoxathiin-2-sulfonamide 10, 10- dioxide;
8-fluoro-3-methyl-N-(pyridin-4-ylmethyl)phenoxathiin-2-sulfonamide 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; 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 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
Figure imgf000045_0001
^ ^^ H
I or a pharmaceutically acceptable salt thereof; wherein:
R1 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 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;
R2 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 R2 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;
R3 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 R3 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 R3 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, 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 R3 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, alkoxycarbonylalkylaminothiocarbonyl, alkylthiocarbonylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylaminoarylsulfonyl, and heteroarylsulfonyl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the heterocycloalkyl groups of R3 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 R3 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, heterocycloalkylthiocarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkoxythiocarbonyl, and aryloxythiocarbonyl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the amino substituents on the alkyl groups of R3 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.
R4 is H or C1-C4 straight or branched alkyl;
R5 is, independently at each occurrence, H or Ci-C4 straight or branched alkyl; or both R5 groups, together with the carbon atom through which they are attached form a Cs-Ce spirocycloalkyl; and
X is -O-, -(NR4)-, -S-, -[C(R5J2]- -(CH2-CHR4)-, -(C=O)-, or -(C=O)- NR4;
the process comprising: contacting a compound of formula IA with -NHR3:
Figure imgf000050_0001
wherein the compound of formula I is formed.
[0154] In another embodiment, wherein X is -(CH2-CHR4)-, the compound of formula IA is formed by:
(a) contacting a compound of formula IB:
,halo
Figure imgf000050_0002
R1
IB with a compound of formula IC:
HS
Figure imgf000050_0003
R2
IC to form a compound of formula ID:
Figure imgf000050_0004
Figure imgf000050_0005
ID;
(b) contacting the compound of formula ID with an acid to form a compound of formula IE:
Figure imgf000050_0006
IE;
(ci) if R4 is not H, contacting the compound of formula IE with a lithium or magnesium halide-activated R4 group to form a compound of formula IEE:
Figure imgf000051_0001
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:
R1—
Figure imgf000051_0002
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(R5)2]-, the compound of formula IA is formed by:
(a) contacting a compound of formula IJ:
Figure imgf000051_0003
R1
IJ with a compound of formula IC:
HS
Figure imgf000051_0004
IC to form a compound of formula IK:
Figure imgf000052_0001
Figure imgf000052_0002
R2
IK;
(b) contacting the compound of formula IK with an acid to form a compound of formula IL:
Figure imgf000052_0003
(c) reducing the compound of formula IL with a reducing agent to form a compound of formula IM:
Figure imgf000052_0004
IM
(d) oxidizing the compound of formula IM with an oxidizing agent to form a compound of formula IN:
Figure imgf000052_0005
IN
(e) if R5 is not H, contacting the compound of formula IN with a base and an activated R5 group, wherein each R5 group is the same or different, to form a compound of formula IH:
R1^ x
Figure imgf000052_0006
R2 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 R2 is -CF3, the compound of formula IA is formed by:
(a) contacting a compound of formula IB with 4-chlorobenzenethiol:
HO2C
A^halo
R1
IB to form a compound of formula IO:
Figure imgf000053_0001
Figure imgf000053_0002
10;
(b) contacting the compound of formula IO with an acid to form a compound of formula IP:
Figure imgf000053_0003
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:
R14 K
IR;
(e) reacting the compound of formula IR with difluorobromomethane to form
Figure imgf000053_0004
a compound of formula IS: Si_ϋ_ < I l
X
Figure imgf000054_0001
CF3
IS
(e) recting the compound of formula IS with a nitrating agent to form a compound of formula IT:
Figure imgf000054_0002
IT;
(f) reducing the compound of formula IT to form a compound of formula IV:
R1-^
Figure imgf000054_0003
IV; and (g) reacting the compound of formula IV with SO2 gas and CuCb to form the compound of formula IA.
[0157] In another embodiment, wherein X is -(C=O)-NR4, the compound of formula IA is formed by:
(a) contacting a compound of formula IJ:
halo
Figure imgf000054_0004
R1
IJ with a compound of formula IC:
HS
Figure imgf000054_0005
R2
IC to form a compound of formula IK:
Figure imgf000055_0001
Figure imgf000055_0002
R1 R
IK;
(b) contacting the compound of formula IK with an acid to form a compound of formula IL:
Figure imgf000055_0003
(c) oxidizing the compound of formula IL with an oxidizing agent to form a compound of formula IW:
Figure imgf000055_0004
O
IW;
(d) reacting the compound of formula IW with sodium azide and sulfuric acid to form a compound of formula IX:
Figure imgf000055_0005
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 IA1 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 mixture and heating the mixture:
Figure imgf000056_0001
IY wherein the compound of formula IA is formed.
[0160] In another embodiment, wherein, X is -[C(R5)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 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. Scheme 1
Figure imgf000058_0001
[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, R1 and R2 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 R3 and R4 are hydrogen, compound 1 could be further oxidized with potassium permanganate to afford the ketone derivatives. Scheme 2
Figure imgf000059_0001
Figure imgf000059_0002
CO2H
Figure imgf000059_0003
Figure imgf000059_0004
vii
Figure imgf000059_0005
Figure imgf000059_0006
[0167] A similar synthetic strategy is employed in Scheme 2 to afford the corresponding homologs (1). Cyclization of 4 to 5 was performed using 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
Figure imgf000060_0001
[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. Scheme S
Figure imgf000061_0001
16
Figure imgf000061_0002
Figure imgf000061_0003
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
Figure imgf000061_0004
Figure imgf000061_0006
vii
Figure imgf000061_0007
Figure imgf000061_0005
23 Scheme 7
BOC BOC
XV
Figure imgf000062_0002
25 R = Me, Et xvi
Figure imgf000062_0001
HCI
^. κ> ' /-"NH HCI
) 0
Figure imgf000062_0004
Figure imgf000062_0003
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. K2CO3, Cu; ii. H2SO4 or P2O5 ϊϊϊ BH3 ; iv. Oxone or H2O2/AcOH ; v. Chlorosulfonic acid; vi. Rl, NaH; vii. Amine, DCM; viii. Mn2O; ix. Et3SiH, TFAA; x. NaNO2, HCI, AcOH; xi.Cu, C1 Br2F2C; xii. H2, Pd/C; xiii. CuCI2, SO2(g) xiii. RLi or RMgX xiv. NaN3, H2SO4; xv. NaH, Rl; xvi. TFA1 CH2CI2
[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. 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 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 [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
Figure imgf000066_0001
Step 1. 2-[(4-Methylphenyl)thio]benzoic acid
CO2H
Figure imgf000066_0002
Figure imgf000066_0003
[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 Ci4Hi2O2S + H+, 245.06308; found (ESI, [M+H]+), 245.062
Step 2. 2 Methyl-9H-thioxanthen-9-one
Figure imgf000067_0001
[0182] A mixture of 2-(p-tolythio)benzoic acid (5 g, 20.5 mmol) and concentrated sulfuric acid (35 ml_) was heated at 1000C. 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 C1 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 Ci4H10OS + H+, 227.05251 ; found (ESI, [M+H]+), 227.0562
Step 3. 2-Methyl-9H-thioxanthene
Figure imgf000067_0002
[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 00C 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 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 Ci4Hi2S, 212.06597; found (El, M+.), 212.0703
Step 4. 2-Methyl-9H-thioxanthene-10, 10-dioxide
Figure imgf000068_0001
[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 Ci4Hi2O2S + H+, 245.06308; found (ESI, [M+H]+), 245.0623
Step 5. 2-Methyl-9H-thioxanthene-3-sulfonyl chloride-10,10-dioxide
Figure imgf000068_0002
[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
Figure imgf000069_0001
[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 C22H2I NO4S2 + H+, 428.09848; found (ESI-FTMS1 [M+H]1 t), 428.0988
Example 2: 2-Methyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulfonamide 10,10-dioxide
Figure imgf000069_0002
[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 C2IH20N2O4S2 + 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
Figure imgf000070_0001
^^
[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 C20H23NO5S2 0.33 H2O calculated: C, 56.19; H, 5.58; N1 3.28 Found: C1 56.07; H1 5.06; N, 2.91. MS (ES) m/z 420.0;
HRMS: calculated for C20H23NO5S2 + H+, 422.10904; found (ESI1 [M+H]+), 422.1 101
Example 4: 2-Methyl-9-oxo-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H- thioxanthene-3-sulfonamide 10,10-dioxide
Figure imgf000071_0001
[0193] A mixture of 2-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H-thioxanthene- 3-sulfonamide 10,10- dioxide (223 mg, 0.53 mmol), KMnθ4 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 C20H2INO6S2 + 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
Figure imgf000071_0002
Step 1. 4-Fluoro-2-[(4-isopropylphenyl)thio]benzoic acid CO2H
Figure imgf000072_0001
[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 15O0C 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 Ci6Hi5FO2S + H+, 291.08495; found (ESI, [M+H]+), 291.0835
Step 2. 6-Fluoro-2-isopropyl-9H-thioxanthen-9-one
CO2H
Figure imgf000072_0002
[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 1000C 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 Ci6H13FOS + H+, 273.07439; found (ESI, [M+H]+), 273.0752
Step 3. 6-Fluoro-2-isopropyl-9H-thioxanthene
Figure imgf000073_0001
[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 BH3 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 99-1000C. MS (El) m/z 258
Step 4. 6-Fluoro-2-isopropyl-9H-thioxanthene 10,10-dioxide
Figure imgf000073_0002
[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. 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
Figure imgf000074_0001
[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 1000C 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
Figure imgf000074_0002
[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 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 C23H23FN2O4S2 + H+, 475.11560; found (ESI1 [M+H]+), 475.1027
Example 6: 6-Fluoro-2-isopropyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H- thioxanthene-3- sulfonamide 10,10-dioxide
Figure imgf000075_0001
Figure imgf000075_0002
[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 C22H26FNOsS2 + 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.
Figure imgf000076_0001
Step 1. 6-Fluoro-2-isopropyl-9,9-dimethyl-9H-thioxanthene 10,10-dioxide
Figure imgf000076_0002
[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
Figure imgf000076_0003
[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 1000C for 8 h. The reaction was allowed to cool to room temperature and poured into ethyl acetate (150 ml_), washed with water, dried 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. 2,9I9-Trimethyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulfonamide 10,10- dioxide.
Figure imgf000077_0001
[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- 920C.
[0207] MS (ES) m/z 503.1 ;
HRMS: calculated for C25H27FN2O4S2 + H+, 503.14690; found (ESI1 [M+H]*), 503.1435
Example 8: 6-Fluoro-2-isopropyl-9,9-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-9H- thioxanthene- 3-sulfonamide 10,10-dioxide
Figure imgf000077_0002
Figure imgf000077_0003
[0208] 6-Fluoro-2-isopropyl-9,9-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-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 219-22O0C.
[0209] MS (ES) m/z 482.0;
HRMS: calculated for C23H28FNO5S2 + 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.
Figure imgf000078_0001
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 C24H30FNO5S2 + 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.
Figure imgf000078_0002
[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. MS (ES) m/z 503.0;
HRMS: calculated for C25H27FN2O4S2 + 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
Figure imgf000079_0001
Step 1. 2,9,9-Trimethyl-9H-thioxanthene 10,10-dioxide
Figure imgf000079_0002
[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 Ci6H16O2S + H+, 273.09438; found (ESI, [M+H]+), 273.0952
Step 2. 2,9,9-Trimethyl-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide
Figure imgf000079_0003
Figure imgf000079_0004
[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. 2,919-Trimethyl-Λ/-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulfonamide 10,10- dioxide.
Figure imgf000080_0001
[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 C23H24N2O4S2 + 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
Figure imgf000080_0002
Figure imgf000080_0003
[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 C22H27NO5S2 + H+, 450.14034; found (ESI1 [M+H]*), 450.1418
Example 13: 2,9,9-Trimethyl-/V-(tetrahydro-2 W-pyran-4-yl)-9W-thioxanthene-3- sulfonamide 10,10-dioxide
Figure imgf000081_0001
Figure imgf000081_0002
[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 C2I H25NO5S2 + 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
Figure imgf000081_0003
[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 C23H24N2O4S2 + 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
Figure imgf000082_0002
Figure imgf000082_0001
[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 C19H20N2O4S2 + 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
Figure imgf000082_0004
Figure imgf000082_0003
[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 C26H34N2O6S2 + H+, 535.19310; found (ESI, [M+H-C4H8]+), 479.1233
Example 17: 2,9,9-Trimethyl-Λ/-piperidin-4-yl-9H-thioxanthene-3-sulfonamide 10,10-dioxide
,Boc
Figure imgf000083_0001
Figure imgf000083_0002
[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 600C 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 C2I H26N2O4S2 + H+, 435.14067; found (ESI, [M+H]+), 435.1384
Example 18: 5-Oxo-5-<4-{[(2,9,9-trimethyl-10,10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1 -yl)pentanoic acid
Figure imgf000084_0001
[0229] A mixture of 2,9,9-trimethyl-Λ/-piperidin-4-yl-9H-thioxanthene-3-sulfonamide 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 C26H32N2O7S2 + 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
Figure imgf000084_0002
[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 C28H30N2O8S3 + H+, 619.12370; found (ESI, [M+H]+), 619.1246 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°JOH ^ ^^coon
H
Figure imgf000085_0001
[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 C28H30N2O8S3 + H+, 619.12370; found (ESI, [M+H]+),
619.1246
7
Example 21 : 4-Oxo-4-<4-{[(2,9,9-trimethyl-10,10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1 -yl)butanoic acid
O
v v N r r*^*r ^« ΪOOH JOH H
Figure imgf000085_0002
[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 C25H30N2O7S2 + 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
Figure imgf000086_0001
[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 C29H33N3O7S3 + 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
Figure imgf000086_0002
Figure imgf000086_0003
°
[0237] A mixture of 2,9,9-trimethyl-Λ/-piperidin-4-yl-9H-thioxanthene-3-sulfonamide 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 0C 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 C27H36N2O6S2 + 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
Figure imgf000087_0001
[0238] A solution of tert-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 C23H28N2O6S2 + H+, 493.14615; found (ESI, [M+H]+), 493.1437.
Example 25: N-(Trans-4-hydroxycyclohexyl)-2,9,9-trimethyl-9H-thioxanthene-3- sulfonamide 10,10-dioxide
Figure imgf000087_0002
[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 C22H27NO5S2 + H+, 450.14034; found (ESI, [M+H]+), 450.145
Example 26: 2'-Methyl-N-(2-pyridin-2-ylethyl)spiro[cyclopentane-1,9'- thioxanthene]-3'-sulfonamide 10',10'-dioxide
Figure imgf000088_0001
Step 1. 2'-Methylspiro[cyclopentane-1 ,9'-thioxanthene] 101, 10'-dioxide
Figure imgf000088_0002
[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 Ci8H18O2S + H+, 299.11003; found (ESI, [M+Hf), 299.1092
Step 2. 2'-Methylspiro[cyclopentane-1 ,9'-thioxanthene] 10',10'-dioxide-3'-sulfonyl chloride
Figure imgf000088_0003
[0241] The title compound was prepared according to Example 1 (step 5) using 2'- methylspiro[cyclopentane-1 ,9'-thioxanthene] 101, 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. Step 3. 2'-Methyl-Λ/-(2-pyridin-2-ylethyl)spiro[cyclopentane-1 ,9'-thioxanthene]-3'- sulfonamide 10',10'-dioxide
Figure imgf000089_0003
Figure imgf000089_0002
Figure imgf000089_0001
[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 N1N- 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 C25H26N2O4S2 + 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
Figure imgf000089_0004
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. MS (ES) m/z 483.2;
HRMS: calculated for C25H26N2O4S2 + 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
Figure imgf000090_0001
[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 C25H26N2O4S2 + 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
Figure imgf000090_0002
[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 C23H27NO5S2 + H+, 462.14034; found (ESI, [M+H]+), 462.1383 Example 30: 2f-Methyl-W-(tetrahydro-2H-pyran-4-ylmethyl)spiro[cyclopentane- 1.θ'-thioxanthenel-S1 -sulfonamide 10(,10'-dioxide
Figure imgf000091_0002
Figure imgf000091_0001
[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 C24H29NO5S2 + H+, 476.15599; found (ESI1 [M+H]+), 476.1529
Example 31 : Λ/-(2-Cyanoethyl)-2'-methylspiro[cyclopentane-1,9'-thioxanthene]- 3'-sulfonamide 10M0'-dioxide
/VN^CN
Figure imgf000091_0003
[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 C2I H22N2O4S2 + 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
Figure imgf000092_0001
[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 C26H2TNO5S2 + H+, 498.14034; found (ESI1 [M+H]+), 480.1298
Example 33: W-(2-Hydroxy-1-methyl-2-phenylethyl)-2'- methylspiro[cyclopentane-1,9'-thioxanthene]-3' -sulfonamide 10',10'-dioxide
Figure imgf000092_0002
[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 C27H29NO5S2 + 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
Figure imgf000092_0003
[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 C20H23NO5S2 + H+, 422.10904; found (ESI1 [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
Figure imgf000093_0001
[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 C28H36N2O6S2 + 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
Figure imgf000093_0004
Figure imgf000093_0002
Figure imgf000093_0003
[0251] The title compound was prepared according to similar conditions used in
Example 17 employing fert-butyl 4-{[(2'-methyl-10',10l-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 C23H28N2O4S2 + H+, 461.15632; found (ESI, [M+H]+),
461.1565
Example 37: 3-[(4-{[(2I-Methyl-10i,10'-dioxidospiro[cyclopentane-1 ,9'- thioxanthen]-3'-yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]benzoic acid
Figure imgf000094_0001
[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 C30H32N2O8S3 + 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
Figure imgf000094_0003
Hw
Figure imgf000094_0002
[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 C29H38N2O6S2 + 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
Figure imgf000095_0001
Figure imgf000095_0002
[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 C24H29NO5S2 + 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
Figure imgf000096_0001
step.1 2'-Methylspiro[cyclohexane-1 ,9'-thioxanthene] 101, 10'-dioxide
Figure imgf000096_0002
[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 Ci9H20O2S + H+, 313.12568; found (ESI, [M+H]+), 313.1259
Step 2. 2'-Methylspiro[cyclohexane-1 ,9'-thioxanthene] 10',10'-dioxide-3'-sulfonyl chloride
Figure imgf000096_0003
[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. Step 3. 2'-Methyl-/V-(2-pyridin-2-ylethyl)spiro[cyclohexane-1 ,9'-thioxanthene]-3'- sulfonamide 10',10'-dioxide
Figure imgf000097_0001
[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 C26H28N2O4S2 + H+, 497.15632; found (ESI, [M+H]+),
497.1589
Example 41 : 2'-Methyl-W-(2-pyridin-3-ylethyl)spiro[cyclohexane-1,9l- thioxanthene]-3'-sulfonamide 10',10' -dioxide
Figure imgf000097_0003
Figure imgf000097_0002
[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. MS (ES) m/z 497.2;
HRMS: calculated for C26H28N2O4S2 + 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
Figure imgf000098_0001
[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 C26H28N2O4S2 + H+, 497.15632; found (ESI1 [M+Hf), 497.158
Example 43: 2<-Methyl-/V-(tetrahydro-2H-pyran-4-yl)spiro[cyclohexane-1 ,9'- thioxanthene]-3' -sulfonamide 10',10'-dioxide
Figure imgf000098_0002
[0260] 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-aminotetrahydropyran hydrochloride to afford 55.7 mg (54 %) of desired product.
MS (ES) m/z 474.1 ;
HRMS: calculated for C24H29NO5S2 + H+, 476.15599; found (ESI, [M+H]+), 476.1512
Example 44: 2I-Methyl-/V-(tetrahydro-2H-pyran-4-ylmethyl)spiro[cyclohexane- 1,9'-thioxanthene]-3'-sulfonamide 10',10'-dioxide
Figure imgf000099_0001
[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 C25H3INO5S2 + H+, 490.17164; found (ESI1 [M+H]+)> 490.1738
Example 45: /V-(2-Cyanoethyl)-2'-methylspiro[cyclohexane-1 ,9'-thioxanthene]- 3'-sulfonamide 10',10'-dioxide
Figure imgf000099_0002
[0262] 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-amino-propionitrile to afford 48.7 mg (51 %) of desired product.
MS (ES) m/z 445.2;
HRMS: calculated for C22H24N2O4S2 + 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
Figure imgf000100_0002
Figure imgf000100_0001
[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 C27H29NO5S2 + H+, 512.15599; found (ESI1 [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
Figure imgf000100_0003
[0264] 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 norephedrine hydrochloride to afford 75.7 mg
(67 %) of desired product.
MS (ES) m/z 524.2;
HRMS: calculated for C28H3INO5S2 + 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
Figure imgf000101_0001
[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 C2I H25NO5S2 + H+, 436.12469; found (ESI, [M+H]+), 436.1245
Example 49: tert-Butyl 4-{[(2l-methyl-10l,10'-dioxidospiro[cyclohexane-1,9'- thioxanthen]-3'-yl)sulfonyl]amino}piperidine-1-carboxylate
^Boc
Figure imgf000101_0002
[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 C29H38N2O6S2 + H+, 575.22440; found (ESI, [M+H-TBOC]*),
475.1374
Example 50: 2t-Mβthyl-/V-piperidin-4-ylspiro[cyclohexane-1,9'-thioxanthene]-3l- sulfonamide 10',10'-dioxide
-Boo
Figure imgf000102_0002
Figure imgf000102_0001
Figure imgf000102_0003
[0267] The title compound was prepared according to similar conditions used in Example 17 employing te/f-butyl 4-{[(2l-methyl-10l,10'-dioxidospiro[cyclohexane-1 ,9l- 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 C24H30N2O4S2 + H+, 475.17197; found (ESI, [M+H]+), 475.1723
Example 51 : 3-[(4-{[(2I-Methyl-10')10'-dioxidospiro[cyclohexane-1,91- thioxanthen]-3'-yl)sulfonyl]amino}pipehdin-1-yl)sulfonyl]benzoic acid
COOH
Figure imgf000102_0004
[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 C3I H34N2O8S3 + 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
Figure imgf000103_0001
Figure imgf000103_0002
[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 C25H31NO5S2 + H+, 490.17164; found (ESI, [M+H]+), 490.1729
Example 53: 9,9-Diethyl-2-methyl-/V-(2-pyridin-2-ylethyl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide
Figure imgf000104_0001
Step 1. 9,9-Diethyl-2-methyl-9H-thioxanthene 10,10-dioxide
Figure imgf000104_0002
[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 Ci8H20O2S + H+, 301.12568; found (ESI, [M+H]+), 301.125
Step 2. 9,9-Diethyl-2-methyl-9H-thioxanthene-3-sulfonyl chloride 10,10-dioxide
Figure imgf000104_0003
[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-thioxanthene-3-sulfonamide 10,10-dioxide
Figure imgf000105_0001
[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 C25H28N2O4S2 + H+, 485.15632; found (ESI, [M+H]+),
485.1553
Example 54: 9,9-Diethyl-2-methyl-/V-(2-pyridin-3-ylethyl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide
Figure imgf000105_0003
Figure imgf000105_0002
[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 C25H28N2O4S2 + H+, 485.15632; found (ESI, [M+H]+),
485.1579 Example 55: 9,9-Diethyl-2-methyl-/V-(2-pyridin-4-ylethyl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide
Figure imgf000106_0001
[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 C25H28N2O4S2 + 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
Figure imgf000106_0002
[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 C23H29NO5S2 + 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
Figure imgf000107_0002
Figure imgf000107_0001
[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 C24H3I NO5S2 + H+, 478.17164; found (ESI1 [M+H]+), 478.1678
Example 58: Λ/-(2-Cyanoethyl)-9,9-diethyl-2-methyl-9W-thioxanthene-3- sulfonamide 10,10-dioxide
Figure imgf000107_0003
[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 C2I H24N2O4S2 + 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
Figure imgf000108_0001
[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 C26H29NO5S2 + 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
Figure imgf000108_0002
[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 C27H31NO5S2 + 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
Figure imgf000109_0001
Figure imgf000109_0002
[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 C20H25NO5S2 + H+, 424.12469; found (ESI1 [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
Figure imgf000109_0003
[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 C28H38N2O6S2 + 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
Figure imgf000110_0003
Figure imgf000110_0001
Figure imgf000110_0002
[0282] The title compound was prepared according to similar conditions used in
Example 17 employing te/f-butyl 4-{[(9l9-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 C23H30N2O4S2 + 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
Figure imgf000110_0004
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 C25H34N2O5S2 + 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
Figure imgf000111_0003
Figure imgf000111_0001
Figure imgf000111_0002
[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
Figure imgf000111_0005
Figure imgf000111_0004
[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 C29H40N2O6S2 + 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
V0 0V0 N
Figure imgf000112_0002
H
Figure imgf000112_0001
Figure imgf000112_0003
[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 C25H32N2O6S2 + 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
,ΛOH
H
Figure imgf000112_0004
[0286] The title compound was prepared according to similar conditions used in Example 39 employing 2'-methylspiro[cyclohexane-1 ,9l-thioxanthene] 10',1 O1- 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 C24H3I NO5S2 + 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,
SN
Figure imgf000113_0002
H
Figure imgf000113_0001
Step 1. 2-Chloro-6-fluoro-9,9-dimethyl-9H-thioxanthene 10,10-dioxide
Figure imgf000113_0003
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 Ci5Hi2CIFO2S, 310.02305; found (El, M+.), 310.0235;
Step 2. 2-Chloro-6-fluoro-9,9-dimethyl -9H-thioxanthene-3-sulfonyl chloride 10,10- dioxide
Figure imgf000114_0001
[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 0C 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-thioxanthen-3- yl)sulfonyl]am ino}piperidine-1 -carboxylate
Boc
Figure imgf000114_0002
[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 C25H30CIFN2O6S2 + H+, 573.12906; found (ESI, [M+H]*),
517.0661
Example 70: 2-Chloro-6-fluoro-9,9-dimethyl-/V-piperidin-4-yl-9W-thioxanthene- 3-sulfonamide 10,10-dioxide 'NH
Figure imgf000115_0001
[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-carboxylate (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 C20H22CIFN2O4S2 + 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
"
Figure imgf000115_0002
[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 C22H25CIFN3O5S2 + H+, 530.09809; found (ESI1 [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.
Figure imgf000116_0001
Figure imgf000116_0002
[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 C26H32CIFN2O6S2 + H+, 587.14471 ; found (ESI1 [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'
Figure imgf000116_0004
Figure imgf000116_0003
[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 C22H24CIFN2O6S2 + 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]benzoic acid
Figure imgf000117_0001
[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 C27H26CIFN2O8S3 + H+, 657.05966; found (ESI1 [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)piperidine-1-carboxylate
Boc
Figure imgf000117_0002
Step 1. 2-Chloro-6-fluoro-9,9-dimethyl-3-nitro-9H-thioxanthene 10,10-dioxide
Figure imgf000117_0003
[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-thioxanthene 10,10- dioxide and 3-fluoro-9,9-dimethyl-6-nitro-9H-thioxanthene 10,10-dioxide CL X)
Figure imgf000118_0001
Figure imgf000118_0002
[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-thioxanthene 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 CI6HHF4NO4S, 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 Ci5Hi2FNO4S, 321.0471 1 ; found (El, M+.), 321.0441
Step 3. 6-Fluoro-9,9-dimethyl-2-(trifluoromethyl)-9H-thioxanthen-3-amine 10,10- dioxide
Figure imgf000119_0001
A mixture of 6-fluoro-9,9-dimethyl-3-nitro-2-(trifluoromethyl)-9H-thioxanthene 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 0C 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 Ci6Hi3F4NO2S + 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
Figure imgf000119_0002
[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
Figure imgf000120_0002
Figure imgf000120_0001
[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 C26H30F4N2O6S2 + H+, 607.15542; found (ESI, [M+H-tbutyl]*), 551.0896
Example 76: 6-Fluoro-9,9-dimethyl-/V-piperidin-4-yl-2-<trifluoromethyl)-9H- thioxanthene-3-sulfonamide 10,10-dioxide
Figure imgf000120_0003
[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)piperidine-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 C2IH22F4N2O4S2 + H+, 507.10299; found (ESI, [M+H]*),
507.1023 Example 77: 3-{[4-{{[6-Fluoro-9,9-dimethyl-10,10-dioxido-2-(trifluoromβthyl)- 9H-thioxanthen-3-yl]sulfonyl}amino)pipehdin-1-yl]sulfonyl}benzoic acid
Figure imgf000121_0001
[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 C28H26F4N2O8S3 + H+, 691.08602; found (ESI, [M+H]+), 691.0819;
Example 78: 6-Fluoro-9,9-dimethyl-Λ/-(2-pyridin-3-ylethyl)-2-(trifluoromethyl)- 9tf-thioxanthene-3-sulfonamide 10,10-dioxide
Figure imgf000121_0003
Figure imgf000121_0002
[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 C23H20F4N2O4S2 + H+, 529.08734; found (ESI1 [M+H]+), 529.0815
Example 79: 6-Fluoro-9,9-dimethyl-Λ/-(2-pyridin-4-ylethyl)-2-(trifluoromethyl)- 9ft-thioxanthene-3-sulfonamide 10,10-dioxide
Figure imgf000122_0001
[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 C23H20F4N2O4S2 + H+, 529.08734; found (ESI1 [M+H]*), 529.0853
Example 80: 6-Fluoro-9,9-dimethyl-N-(2-pyridin-3-ylethyl)-2-(trif1uoromethoxy)- 9H- thioxanthene-3-sulfonamide 10,10-dioxide.
Figure imgf000122_0002
Step 1. 4-Fluoro-2-{[4-(trifluoromethoxy)phenyl]thio}benzoic acid CO2H
Br H
Figure imgf000123_0001
Figure imgf000123_0002
[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
CO2H
Figure imgf000123_0004
Figure imgf000123_0003
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 CuH6F4O2S + H+, 315.00974; found (ESI, [M+H]+), 315.009
Step 3. 6-Fluoro-2-(trifluoromethoxy)-9H-thioxanthene OCF,
Figure imgf000124_0002
Figure imgf000124_0001
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 Ci4H8F4OS1 300.02320; found (El1 M+.), 300.0233
Step 5. 6-Fluoro-10,10-dioxido-9H-thioxanthen-2-yl trifluoromethyl ether
Figure imgf000124_0003
OCF3
[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 Ci4H8F4O3S1 332.01303; found (El, M+.), 332.0135
Step 6. 6-Fluoro-9,9-dimethyl-10,10-dioxido-9H-thioxanthen-2-yl trifluoromethyl ether
Figure imgf000124_0004
[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 Ci6Hi2F4O3S, 360.04433; found (El1 M+.), 360.0444
Step 7. 6-Fluoro-9,9-dimethyl-10,10-dioxido-9H-thioxanthen-2-yl trifluoromethyl ether-3-sulfonyl chloride
Figure imgf000125_0001
Figure imgf000125_0002
[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 1000C 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-(trifluoromethoxy)-9H- thioxanthene-3-sulfonamide 10, 10-dioxide Y v8Y°
^OCF3
Figure imgf000126_0005
Figure imgf000126_0001
[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 C23H20F4N2O5S2 + H+, 545.08225; found (ESI1 [M+H]+), 545.0825
Example 81 : β-Fluoro-9,9-dimethyl-N-piperidin-4-yl-2-(trifluoromethoxy)-9H- thioxanthene-3- sulfonamide 10,10-dioxide
Figure imgf000126_0002
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
Figure imgf000126_0003
Figure imgf000126_0004
[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 C26H30F4N2O7S2 + 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
Figure imgf000127_0001
[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 6O0C 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 C2IH22F4N2O5S2 + H+, 523.09790; found (ESI1 [M+H]*), 523.0976
Example 82: 2'-Chloro-6'-fluoro-N-piperidin-4-ylspiro[cyclohexane-1 ,9'- thioxanthene]-3'- sulfonamide 10', 10" -dioxide
Figure imgf000128_0001
Step 1. 2-(4-Chlorophenylthio)-4-fluorobenzoic acid
CO2H
Figure imgf000128_0002
[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 15O0C 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
Figure imgf000129_0001
Figure imgf000129_0002
[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
Figure imgf000129_0004
Figure imgf000129_0003
[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 Ci3H8CIFS1 250.00192; found (El, M+.), 248.9955
Step 4. 2-Chloro-6-fluoro-9H-thioxanthene 10,10-dioxide
Figure imgf000129_0005
Figure imgf000129_0006
[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 Ci3H8CIFO2S, 281.99176; found (El1 M+.), 281.9943
Step 5. 2'-Chloro-6'-fluorospiro[cyclohexane-1 ,9'-thioxanthene] 10',10'-dioxide
Figure imgf000130_0001
Figure imgf000130_0002
[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 Ci8H16CIFO2S1 350.05435; found (El, M+.), 350.0548
Step 6. Z-Chloro-β'-fluorospiroIcyclohexane-i .θ'-thioxanthene] 10',10'-dioxide-3- sulfonyl chloride
Figure imgf000130_0003
[0319] To a solution of 2l-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-6l-fluoro-10',10'-dioxidospiro[cyclohexane-1 ,9l- thioxanthen]-3'-yl)sulfonyl]amino}piperidine-1-carboxylate
Figure imgf000131_0001
Figure imgf000131_0002
[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 C28H34CIFN2O6S2 + 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
Figure imgf000132_0001
Figure imgf000132_0002
[0322] A solution of tert-butyl 4-{[(2l-chloro-6'-fluoro-10l,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 C23H26CIFN2O4S2 + H+, 513.10793; found (ESI, [M+H]*), 513.1062
Example 83: 2l-Chloro-6'-fluoro-N-[1-(phenylsulfonyl)piperidin-4- yl]spiro[cyclohexane-1,9'- thioxanthene]-3' -sulfonamide 10',10' -dioxide
Figure imgf000132_0003
[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 C29H30CIFN2O6S3 + 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
VN
Figure imgf000133_0002
Figure imgf000133_0001
[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 C29H29CIFN3O5S2 + H+, 618.12939; found (HRMS, [M+H]+), 618.1245
Example 85: 2l-Chloro-6'-fluoro-N-(1-isonicotinoylpiperidin-4- y l)spiro[cyclohexane-1, 9'- thioxanthene]-3' -sulfonamide 10', 10' -dioxide
Figure imgf000133_0003
Figure imgf000133_0005
H
Figure imgf000133_0004
[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 C29H29CIFN3O5S2 + 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.
Figure imgf000134_0001
[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 C31H33CIFN3O7S3 + H+, 710.12259; found (HRMS, [M+H]+),
710.1235
Example. 87. 4-(4-{[(2'-Chloro-6t-fluoro-10\10'-dioxidospiro[cyclohexane-1 ,9'- thioxanthen]- 3'-yl)sulfonyl]amino}piperidin-1 -yl)-4-oxobutanoic acid.
Figure imgf000135_0001
[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 C27H30CIFN2O7S2 + H+, 613.12397; found (HRMS, [M+H]*), 613.12
Example 88: 5-(4-{[(2l-Chloro-6l-fluoro-10l,10l-dioxidospiro[cyclohexane-1,91- thioxanthen]- 3'-yl)sulfonyl]amino}piperidin-1-yl)-5-oxopentanoic acid.
O O
Qv JO "OH
%//
Figure imgf000135_0003
Figure imgf000135_0002
[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 C28H32CIFN2O7S2 + H+, 627.13962; found (HRMS, [M+H]+), 627.1426 Example 89: 4^[(4^[(2'-Chloro45'-fluoro-10\10'<lioxidospiro[cyclohexarιe-1,9l- thioxanthen]-3'-yl)sulfonyl]amino}pipehdin-1-yl)carbonothioyl]amino}benzoic acid.
Figure imgf000136_0001
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 C3IH3ICIFN3O6S3 + H+, 692.11203; found (HRMS, [M+H]+), 692.1133
Example 90: 3-{[(4-{[(2'-chloro-6'-fluoro-10',10'-dioxidospiro[cyclohexane-1,9'- thioxanthen]-3'-yl)sulfonyl]amino}piperidin-1-yl)carbonothioyl]amino}benzoic acid.
Figure imgf000136_0002
[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 C3IH3ICIFN3O6S3 + H+, 692.11203; found (HRMS, [M+H]+), 692.111
Example 91 : 4-[(4-([(2t-Chloro-€'-fluoro-10l,10'-dioxidospiro[cyclohexane-1,9'- thioxanthen]-3'-yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]benzoic acid.
O2
-SΛ /r00*"
Figure imgf000137_0001
[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 C30H30CIFN2O8S3 + H+, 697.09096; found (HRMS, [M+H]+), 697.0923
Example 92: 3-[(4-{[(2I-Chloro-6l-fluoro-10l,10l-dioxidospiro[cyclohexane-1,91- thioxanthen]-3'-yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]benzoic acid.
Figure imgf000137_0002
[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 C3OH30CIFN2O8S3 + 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.
Figure imgf000138_0001
Step 1. {2-[(4-Methylphenyl)thio]phenyl}acetic acid
Figure imgf000138_0003
Figure imgf000138_0002
CO2H
[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 Ci5Hi4O2S + H+, 259.07873; found (ESI, [M+Hf), 259.0786
Step 2. 8-Methyldibenzo[b,f]thiepin-10(11 H)-one
Figure imgf000139_0001
Figure imgf000139_0002
[0340] 2-[(4-Methylphenyl)thio]phenyl}acetic acid (15.2 g, 58.9 mmol) was added to polyphosphoric acid (160 g) at 11O0C 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 (ESI1 [M+H]+), 241.0674
Step 3. 2-Methyl-10,11-dihydrodibenzo[b,f]thiepine
Figure imgf000139_0003
[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
Figure imgf000140_0001
[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 Ci5Hi4O2S + 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
Figure imgf000140_0002
[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 Ci5Hi4O5S2 + 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.
Figure imgf000141_0001
Figure imgf000141_0002
[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 C23H23NO4S2 + 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.
"wv~,
Figure imgf000141_0003
"CH3
Figure imgf000141_0004
[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 C23H22FNO4S2 + H+, 460.10470; found (ESI1 [M+H]+), 460.1038
Example 95: 2- -Methyl-Λ/-(2-pyridin-2-ylethyl)-10,11- dihydrodibenzo[6,/]thiepine-3-sulfonamide 5,5-dioxide.
Figure imgf000142_0001
CH3
Figure imgf000142_0002
[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 C22H22N2O4S2 + 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.
Figure imgf000142_0003
Figure imgf000142_0004
[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 C22H22N2O4S2 + 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.
Figure imgf000143_0001
Figure imgf000143_0002
[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 C22H22N2O4S2 + 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.
Figure imgf000143_0003
Figure imgf000143_0004
[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 C24H23NO4S2 + 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.
Figure imgf000143_0005
Figure imgf000143_0006
[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 C20H23NO4S2 + 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.
Figure imgf000144_0001
Figure imgf000144_0002
[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 C2I H26N2O5S2 + 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.
Figure imgf000144_0004
Figure imgf000144_0003
■
[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 C22H28N2O5S2 + 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.
Figure imgf000145_0001
Figure imgf000145_0002
[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 C20H23NO5S2 + H+, 422.10904; found (ESI1 [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.
Figure imgf000145_0003
Figure imgf000145_0004
[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 C21 H25NO5S2 + H+, 436.12469; found (ESI1 [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.
Figure imgf000145_0006
Figure imgf000145_0005
[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 C22H27NO5S2 + H+, 450.14034; found (ESI1 [M+H]+), 450.1408 Example 105: N-(2-Hydroxy-2-phenylethyl)-2-methyl-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.
Figure imgf000146_0001
Figure imgf000146_0002
[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 C23H23NO5S2 + 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.
Figure imgf000146_0003
Figure imgf000146_0004
[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 C24H25NO5S2 + 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.
Figure imgf000146_0005
Figure imgf000146_0006
[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 Ci8H18N2O4S2 + 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.
Figure imgf000147_0001
[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 C20H24N2O4S2 + 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.
Figure imgf000147_0002
Step 1. {4-Fluoro-2-[(4-isopropylphenyl)thio]phenyl}acetic acid.
Figure imgf000147_0003
[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 Ci7Hi7FO2S - H+, 303.08605; found (ESI, [M-C02-H] ), 259.0960
Step 2. 3-Fluoro-8-isopropyldibenzo[b,f]thiepin-10(11H)-one
Figure imgf000148_0001
Figure imgf000148_0002
[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 Ci7H15FOS + H+, 287.09004; found (ESI, [M+H]+), 287.0916
Step 3. 7-Fuoro-2-isopropyl-10,11-dihydrodibenzo[b,f]thiepine
Figure imgf000148_0003
[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 Ci7Hi7FS, 272.10350; found (El1 M+.), 272.1040
Step 4. 7-Fluoro-2-isopropyl-10,1 1 -dihydrodibenzo[b,f]thiepine 5,5-dioxide
F
Figure imgf000149_0002
Figure imgf000149_0001
[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
Figure imgf000149_0003
[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.
Figure imgf000150_0001
Figure imgf000150_0002
[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 C25H26FNO4S2 + 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.
Figure imgf000150_0003
Figure imgf000150_0004
[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 C25H25F2NO4S2 + H+, 506.12658; found (ESI1 [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.
Figure imgf000151_0001
Figure imgf000151_0002
[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 C24H25FN2O4S2 + 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.
Figure imgf000151_0003
Figure imgf000151_0004
[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 C24H25FN2O4S2 + 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.
Figure imgf000152_0001
Figure imgf000152_0002
[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 C24H25FN2O4S2 + 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.
Figure imgf000152_0003
Figure imgf000152_0004
[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 C26H26FNO4S2 + 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.
Figure imgf000153_0001
Figure imgf000153_0002
[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 C22H26FNO4S2 + 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.
Figure imgf000154_0001
Figure imgf000154_0002
[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 C23H29FN2O5S2 + 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.
Figure imgf000154_0003
Figure imgf000154_0004
[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 C24H3IFN2O5S2 + 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.
Figure imgf000155_0001
Figure imgf000155_0002
[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 C22H26FNO5S2 + H+, 468.13092; found (ESI, [M+H]+), 468.1328
Example 119: 7-Fluoro-2-isopropyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide.
Figure imgf000155_0003
Figure imgf000155_0004
[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 C23H28FNO5S2 + H+, 482.14657; found (ESI1 [M+H]+), 482.1483
Example 120: 7-Fluoro-2-isopropyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide.
Figure imgf000156_0001
Figure imgf000156_0002
[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 C24H30FNO5S2 + H+, 496.16222; found (ESI1 [M+H]*), 496.1609
Example 121 : 7-Fluoro-2-isopropyl-N-(3-phβnylpropyl)-10,11- dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide.
Figure imgf000156_0003
Figure imgf000156_0004
[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 C26H28FNO4S2 + 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
Figure imgf000157_0001
Figure imgf000157_0002
[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 C25H26FNO5S2 + 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
Figure imgf000157_0003
Figure imgf000157_0004
[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 AlA1
MS (ESI) m/z 472;
HRMS: calculated for C24H24FNO4S2 + 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.
Figure imgf000158_0001
Step 1. {2-[(4-Chlorophenyl)thio]-4-fluorophenyl}acetic acid
Figure imgf000158_0002
[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
Figure imgf000158_0003
Figure imgf000158_0004
[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.
Figure imgf000159_0001
[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 Ci4Hi0CIFS, 264.01757; found (El1 M+.), 264.0168
Step 4. 2-Chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepine 5,5-dioxide.
Figure imgf000159_0002
[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-sulfonyl chloride 5,5- dioxide.
Figure imgf000159_0003
Figure imgf000159_0004
[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.
Figure imgf000160_0001
Figure imgf000160_0002
[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.
Figure imgf000160_0003
Figure imgf000160_0004
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-(2-aminoethyl)pyridine to afford 180 mg (66 %) of desired product. MS (ESI) m/z 481 ;
HRMS: calculated for C2I Hi8CIFN2O4S2 + H+, 481.04533; found (ESI1 [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.
Figure imgf000161_0001
Figure imgf000161_0002
[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 C2I Hi8CIFN2O4S2 + H+, 481.04533; found (ESI1 [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.
Figure imgf000161_0003
Figure imgf000161_0004
[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 C24H28CIFN2O6S2 + H+ + NH4 +, 577.14723; found (ESI1 [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.
Figure imgf000162_0001
[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 Ci9H20CIFN2O4S2 + 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
Figure imgf000162_0003
Figure imgf000162_0004
[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
Figure imgf000163_0001
[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 Ci5H7F4NO4S, 373.00319; found (El1 M+.), 373.0071
Step 3. 7-Fluoro-2-(trifluoromethyl)-10l11-dihydrodibenzo[b,f]thiepin-3-amine 5,5- dioxide and 7-fluoro-2-(trifluoromethyl)dibenzo[b,f]thiepin-3-amine 5,5-dioxide.
Figure imgf000163_0002
Figure imgf000163_0003
[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 CI5HHF4NO2S + H+, 346.05194; found (ESI, [M+H]+), 346.0509
MS (ES) m/z 343.7;
HRMS: calculated for Ci5H9F4NO2S + H+, 344.03629; found (ESI, [M+H]+), 344.0373
Step 4. 2-Trifluoromethyl-10,11-dihydrodibenzo[b,f]thiepine-3-sulfonyl chloride 5,5- dioxide
Figure imgf000164_0001
[0401] A suspension of CuCI2 in water (0.5 ml_) and acetic acid (10 ml_) was cooled to 0 C and SO2 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 (ESI1 [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
Figure imgf000165_0001
Figure imgf000165_0002
[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
^
Figure imgf000165_0003
Figure imgf000165_0004
[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 C20H20F4N2O4S2 + 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.
Figure imgf000166_0001
Step 1. 8, 10-Dimethyl-10, 11 -dihydrodibenzo[b,f]thiepin-10-ol
Figure imgf000166_0002
[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. NH4CI and ethyl ether. The organic layer was washed once with water and dried over MgSO4. The solvent was evaporated. The product was purified by chromatography with a gradient of hexane/CH2CI2 to afford 0.51 g (45%) of product as an oil.
[0406] MS (ES) m/z 239.1 ;
HRMS: calculated for Ci6Hi6OS - H+ + H+, 256.09218; found (ESI1 [M-H20+HD, 239.0892
Step 2. 2,11-Dimethyl-10,11-dihydrodibenzo[b,/]thiepine
Figure imgf000167_0001
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 Ci6H16S1 240.09727; found (El, M+.), 240.0976
Step 3. 2,11-Dimethyl-10,11-dihydrodibenzo[b,f]thiepine 5,5-dioxide
Figure imgf000167_0002
2,11-Dimethyl-10,11-dihydrodibenzo[b,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[b,f]thiepine-3- sulfonamide 5,5-dioxide
Figure imgf000167_0003
[0409] 2,11 -Dimethyl-10,11-dihydrodibenzo[b,f]thiepine 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[b,f]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/CH2CI2 to afford 32 mg (24%) of the title compound as a white solid.
[0410] MS (ESI) m/z 456;
HRMS: calculated for C24H25NO4S2 + 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
Figure imgf000168_0001
Step 1. 10-Ethyl-8-methyl-10,1 1-dihydrodibenzo[Λ,flthiepin-10-ol
Figure imgf000168_0002
[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 Ci7H18OS + H+, 271.1 1511 ; found (ESI1 [M+H]+), 271.1 15
Step 2. 1 1-Ethyl-2-methyl-10,1 1-dihydrodibenzo[ύ,/]thiepine
Figure imgf000168_0003
[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 Ci7Hi8S, 254.11292; found (El1 M+.), 254.1134
Step 3. 1 1-Ethyl-2-methyl-10,1 1-dihydrodibenzo[b,f]thiepine 5,5-dioxide
Figure imgf000169_0001
[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 Ci7Hi8O2S + 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
Figure imgf000169_0002
[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 CH2CI2 (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 H2O and dried over MgSO4. The solvent was evaporated. The product was purified by chromatography with a gradient of EtOAcZCH2CI2ZCH3OH to afford 34 mg (11 %) of the title compound as a white solid.
[0418] MS (ES) m/z 471.2;
HRMS: calculated for C24H26N2O4S2 + 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
Figure imgf000170_0001
Step 1. 10-Butyl-8-methyl-10, 11 -dihydrodibenzoβ, f|thiepin-10-ol
Figure imgf000170_0002
[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 Ci9H22OS + H+, 299.14641 ; found ([M+Hf), 281.1352
Step 2. 1 1-Butyl-2-methyl-10,1 1-dihydrodibenzo[/3,flthiepine
Figure imgf000171_0001
[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 C19H22S, 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
Figure imgf000171_0002
[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 C26H30N2O4S2 + 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
Figure imgf000172_0001
[0425] 11 -Butyl-2-methyl-Λ/-(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 44% yield.
[0426] MS (ES) m/z 499.2;
HRMS: calculated for C26H30N2O4S2 + 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
Figure imgf000172_0002
Step 1. 8-Methyl-10-propyl-10,11 -dihydrodibenzo[i),(|thiepin-10-ol
Figure imgf000172_0003
[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 Ci8H20OS + H+ - H+, 284.12348; found (ESI1 [M+H-H20]*), 267.1195
Step 2. 2-Methyl-11-propyl-10,11 -dihydrodibenzo[i),/]thiepine
Figure imgf000173_0001
[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 Ci8H20S1 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
Figure imgf000173_0002
[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 Ci8H20O2S + 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
Figure imgf000174_0001
[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 C25H28N2O4S2 + 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
Figure imgf000174_0002
Step 1. 10-lsopropyl-8-methyl-10,11-dihydrodibenzo[ib,/]thiepin-10-ol
Figure imgf000174_0003
[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 267.1
Step 2. 1 1-lsopropyl-2-methyl-10,11-dihydrodibenzo[b,f]thiepine
Figure imgf000175_0001
[0437] 10-lsopropyl-8-methyl-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 oil in 85% yield.
[0438] MS (El) m/z 268;
HRMS: calculated for C18H20S, 268.12857; found (El, M+.), 268.1295
Step 3. 11 -lsopropyl-2-methyl-Λ/-(2-pyridin-3-ylethyl)-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide
Figure imgf000175_0002
[0439] 11-lsopropyl-2-methyl-10,11-dihydrodibenzo[b,f]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 Ci8H20O2S + H+, 301.12568; found (ESI, [M+H]+), 301.1263
Step 4. 11 -lsopropyl-2-methyl-Λ/-(2-pyridin-3-ylethyl)-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide
Figure imgf000176_0001
[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 C2SH28N2O4S2 + 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
Figure imgf000176_0002
[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 C23H24N2O4S2 + H+, 457.12502; found (ESI, [M+H]+), 547.1264
Example 136: 8-Fluoro-3-methyl-W-(2-phβnylβthyl)phenoxathiin-2-sulfonamide 10,10-dioxide
Figure imgf000177_0001
Step 1. 8-Fluoro-3-methylphenoxathiin-2-sulfonyl chloride 10,10-dioxide
Figure imgf000177_0002
[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 1000C 3 h. The solvent was removed and 1 ml_ of chlorosulfonic acid was added and heated at 1800C . 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-sulfonamide 10,10- dioxide
Figure imgf000177_0003
[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 C2I H18FNO5S2 + H+, 448.06832; found (ESI1 [M+H]+), 448.0638;
Example 137: 8-Fluoro-3-methyl-/V-(2-pyridin-2-ylethyl)phenoxathiin-2- sulfonamide 10,10-dioxide
Figure imgf000178_0001
Figure imgf000178_0002
[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 C20Hi7FN2OsS2 + 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
Figure imgf000178_0003
[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 C20Hi7FN2O5S2 + H+, 449.06357; found (ESI1 [M+H]*), 449.0632;
Example 139: 8-Fluoro-3-methyl-/V-(2-pyridin-4-ylethyl)phenoxathiin-2- sulfonamide 10,10-dioxide
Figure imgf000179_0001
[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 C20Hi7FN2O5S2 + 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
Figure imgf000179_0002
[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 C22Hi8FNO5S2 + H+, 460.06832; found (ESI, [M+H]*),
460.0585
Example 141 : ΛΛCyclopentyl-β-fluoro^-methylphenoxathiin^-sulfonamide 10,10-dioxide
Figure imgf000180_0001
[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 Ci8H18FNO5S2 + 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.
Figure imgf000180_0002
[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 Ci9H2IFN2O6S2 + H+, 457.08978; found (ESI1 [M+H]*), 457.0901 ;
Example 143: 8-Fluoro-3-methyl-W-(3-morpholin-4-ylpropy l)phenoxathiin-2- sulfonamide 10,10-dioxide
Figure imgf000180_0003
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 C20H23FN2O6S2 + H+, 471.10543; found (ESI1 [M+H]+),
471.1062;
Example 144: 8-Fluoro-3-methyl-/V-(tetrahydro-2W-pyran-4-yl)phenoxathiin-2- sulfonamide 10,10-dioxide
Figure imgf000181_0001
[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 Ci8H18FNO6S2 + H+, 428.06323; found (ESI1 [M+H]*), 428.0589
Example 145: 8-Fluoro-3-methyl-iV-(tetrahydro-2H-pyran-4- ylmethyl)ρhenoxathiin-2-sulfonamide 10,10 -dioxide
Figure imgf000181_0002
[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 Ci9H20FNO6S2 + H+, 442.07888; found (ESI1 [M+H]*), 442.0772;
Example 146: 8-Fluoro-3-methyl-/V-[2-(tetrahydro-2H-pyran-4- yl)ethyl]phenoxathiin-2-sulfonamide 10,10-dioxide
Figure imgf000182_0001
[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 C20H22FNO6S2 + H+, 456.09453; found (ESI, [M+H]*), 456.0878
Example 147: 8-Fluoro-W-[3-<1W-imidazol-1-yl)propyl]-3-methylphenoxathiin-2- sulfonamide 10,10-dioxide
Figure imgf000182_0002
[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 Ci9Hi8FN3O5S2 + H+, 452.07447; found (ESI1 [M+H]+), 452.0732;
Example 148: 8-Fluoro-3-methyl-/V-(3-phenylpropyl)phβnoxathiin-2- sulfonamide 10,10-dioxide
Figure imgf000183_0002
Figure imgf000183_0001
[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 C22H20FNO5S2 + H+, 462.08397; found (ESI1 [M+H]*), 462.0851 ;
Example 149: A/-Benzyl-8-fluoro-3-methylphenoxathiin-2-sulfonamide 10,10- dioxide
SO2NH
Figure imgf000183_0004
Figure imgf000183_0003
[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 C20H16FNO5S2 + H+, 434.05267; found (ESI1 [M+H]*), 434.0527; Example 150: N-2-(4-chlorophenyl)βthyl]-8-fluoro-3-methylphenoxathiin-2- sulfonamide 10,10-dioxide
Figure imgf000184_0001
[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 C2i Hi7CIFNO5S2 + 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
Figure imgf000184_0002
[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 Ci9Hi5FN2O5S2 + 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
SO2NH
Figure imgf000185_0002
Figure imgf000185_0001
[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 Ci9Hi5FN2OsS2 + 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
Figure imgf000185_0003
[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 Ci9Hi5FN2OsS2 + H+, 435.04792; found (ESI1 [M+H]+), 435.0497; Example 154: 8-Fluoro-3-methyl-/V-(2-pyrrolidin-1 -ylethyl)phenoxathiin-2- sulfonamide 10,10-dioxide.
Figure imgf000186_0001
[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 C19H2IFN2O5S2 + H+, 441.09487; found (ESI, [M+H]+), 441.0948
Example 155: A/-Cyclohexyl-8-fluoro-3-methylphenoxathiin-2-sulfonamide 10,10-dioxide
Figure imgf000186_0002
[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 Ci9H20FNO5S2 + 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
Figure imgf000187_0001
Step 1. 6-Fluoro-2-isopropyl-9H-thioxanthen-9-one 10,10-dioxide
Figure imgf000187_0002
[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
Figure imgf000187_0003
[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[b,f][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
Figure imgf000188_0001
[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 0C. 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
Figure imgf000189_0001
[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[b,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/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 C23H22FN3O5S2 + 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
Figure imgf000190_0001
[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 C23H22FN3O5S2 + H+, 504.10577; found (ESI1 [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
Figure imgf000191_0001
[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[b,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-/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
Figure imgf000191_0002
[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}pipehdine-1-carboxylate
Figure imgf000192_0001
[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[b,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 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
Figure imgf000193_0001
[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 C2IH24FN3O5S2 + H+, 482.12142; found (ESI1 [M+H]+),
482.1221 ;
Example 162: 3-Fluoro-8-isopropyl-10-methyl-11-oxo-/V-piperidin-4-yl-10,11- dihydrodibenzo[6,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide hydrochloride
Figure imgf000194_0001
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-11-oxo- 10,11 -dihydrodibenzo[b,f][1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1 -carboxylate
Boc
Figure imgf000194_0002
Figure imgf000194_0003
[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
Figure imgf000195_0001
[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
Figure imgf000196_0001
Step 1. te/f-Butyl 4-{(2,4-dimethoxybenzyl)[(10-ethyl-3-fluoro-8-isopropyl-5,5-dioxido- 1 1-OXO-10.11-dihydrodibenzo[b,f][1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1- carboxylate
Boc
Figure imgf000196_0003
Figure imgf000196_0002
[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
Figure imgf000197_0001
[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-dihydrodibenzo[b,f][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 C23H28FN3O5S2 + 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
Figure imgf000198_0001
Step 1. 3-Fluoro-8-isopropyl-10,1 1 -dihydrodibenzo[b,fl[1,4]thiazepine 5,5-dioxide
Figure imgf000198_0002
[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
Figure imgf000199_0001
[0498] The mixture of 3-fluoro-8-isopropyl-10111 -dihydrodibenzo[b,/][1 ,4]thiazepine 5,5-dioxide and 7-fluoro-2-isopropyl-10, 1 1 -dihydrodibenzo[b,f][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 C26H34FN3O6S2 + 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
Figure imgf000200_0001
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 C2IH26FN3O4S2 + H+, 468.14215; found (ESI1 [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
Figure imgf000201_0001
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}piperidine-1-carboxylate
Step 1. 3-Fluoro-8-isopropyl-10-methyl-10,11 -dihydrodibenzo[b,/][1 ,4]thiazepine 5,5- dioxide
Figure imgf000201_0002
[0499] The mixture of 3-fluoro-8-isopropyl-10, 11 -dihydrodibenzo[b,/][1 ,4]thiazepine 5,5-dioxide and 7-fluoro-2-isopropyl-1011 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. 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
Figure imgf000202_0001
[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 027H3SFN3O6S2 + 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[b,f][1 ,4]thiazepine-7-sulfonamide 5,5-dioxide hydrochloride
Figure imgf000203_0001
[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 C22H28FN3O4S2 + H+, 482.15780; found (ESI1 [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
Figure imgf000204_0001
8-lsopropyldibenzo[b,/][1 ,4]thiazepin-11 (10H)-one 5,5-dioxide
Figure imgf000204_0002
[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[b,f][1 ,4]thiazepin-1 1 (10H)-one 5,5-dioxide as a mixture with 2- isopropyldibenzo[b,f][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
Figure imgf000205_0001
Figure imgf000205_0002
[0503] The mixture of 8-isopropyldibenzo[b,f][1 ,4]thiazepin-1 1 (10/-/)-one 5,5- dioxide and 2-isopropyldJbenzo[/j,/][1 l4]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 0C. 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
Figure imgf000206_0001
[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 C23H23N3O5S2 + 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
Figure imgf000207_0001
[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 C24H24N2O5S2 + 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
Figure imgf000208_0001
[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 C2I H24N2O6S2 + 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}piperidine-1-carboxylate Boc
Figure imgf000209_0001
[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 serum, 2mM GlutaMAX-1 , and 1%(v/v) Penicillin- Streptomycin]. The cells are maintained in vented flasks at 370C 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 225cm2 tissue culture flasks (T225) and incubated at 370C 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 370C 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 [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 40C 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 10C Freezing Container (Nalgene catalog # 5100-0001) containing 250 ml isopropyl alcohol. The sealed container is placed in a -8O0C freezer overnight to freeze the cells at a cooling rate of -1°C/minute. The frozen cells are then transferred to a -1500C 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 370C 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 370C 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. EC50 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 -200C. 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 = /(//)-/(±)÷/(//)+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 K0 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 IC50 determinations, the equation shown above was used in the program GraphPad Prism. The "Hillslope" was kept constant at 1. The value for "Bottom" was fixed, but was determined by the blank (probe-only) wells in the plate. The values for "Top" and "IC50" were determined by the data fit. The value for "Top" was typically close to 120, equivalent to approximately 50% bound probe, and the value for "Bottom" was around 30, due to free probe. If the test compound interfered with the probe in the fluorescence assay at high concentrations, the range for the fitted data was limited to the lower concentration range.
[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 2J
'/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.
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
[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.

Claims

We claim:
1. A compound of formula I:
Figure imgf000221_0001
I or a pharmaceutically acceptable salt thereof; wherein:
R1 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 R1 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;
R2 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 R2 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;
R3 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 R3 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 R3 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, carboxy aryl, 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, guanidine, and oxo, and the nitrogen atoms in the heteroaryl substituents may be optionally substituted with an oxygen atom; wherein the heterocycloalkyl groups of R3 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, alky lam inothiocarbonyl, dialkylaminothiocarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, cyanoarylcarbonyl, arylalkylcarbonyl, alkoxycarbonyl, alkoxyalkylcarbonyl, alkylthioalkylcarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocycloalkylalkylcarbonyl, heterocycloalkylalkylaminothiocarbonyl, 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 R3 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, carboxyarγlsulfonylamino, 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 R3 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, carboxyalkylcarbonyl, heterocycloalkylaminocarbonyl, 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 R3 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, alky lcarbony lam ino, alkylsulfonylamino, carboxyarγlsulfonylamino, 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.
R4 is H or C1-C4 straight or branched alkyl;
R5 is, independently at each occurrence, H or C1-C4 straight or branched alkyl; or both R5 groups, together with the carbon atom through which they are attached form a Cs-Ce cycloalkyl; and
X is -O- -(NR4)-, -S-, -[C(R5J2]- -(CH2-CHR4)-, -(C=O)-, Or-(C=O)-NR4
2. A compound according to claim 1 , wherein R1 is H or fluoro.
3. A compound according to claim 1 or claim 2, wwhheerreeiinn R2 is chloro, methyl, isopropyl, trifluoromethyl, or trifluoromethoxy.
4. A compound according to any one of claims 1 to 3, wherein R3 is alkyl substituted with 1-3 R6, cycloalkyl substituted with O- 3 R6, heterocycloalkyl substituted with 0-3 R6, arylalkyl substituted with 0-3 R6, heteroarylalkyl substituted with 0-3 R6, heterocycloalkylalkyl substituted with 0-3 R6, fused cycloalkylaryl substituted with 0-3 R6, alkylaryloxy substituted with 0-3 Rβ ,
Figure imgf000226_0001
and wherein R6 is C1-C4 alkyl, hydroxy, hydroxy(Ci-C6)alkyl, acetamide, alkylcarboxylate, sulfonylbenzene, sulfonylbenzoic acid, sulfonylphenylacetamide, carbothioamidobenzoic acid, oxoalkylpyήdine, alkanoic acid, oxoalkanoic acid, cyano or halo.
5. A compound according to claim 4, wherein R6 is methyl, hydroxy, hydroxyethyl, ethanolic acid, cyano, fluoro, or chloro.
6. A compound according to any one of claims 1 to 3, wherein R3 is:
Figure imgf000227_0001
Figure imgf000228_0001
, or
Figure imgf000229_0001
7. A compound according to any one of claims 1 to 6, wherein X is -[C(R5J2]- -(CH2-CHR4)-, -(C=O)-, Or -(C=O)-NR4.
8. A compound according to any one of claims 1 to 7, wherein R4 is H, methyl, ethyl, n-propyl, or isopropyl.
9. A compound according to any one of claims 1 to 7, wherein R5 is, independently at each occurrence, H, methyl, or ethyl.
10. A compound according to any one of claims 1 to 7, wherein both R5 groups, together with the carbon atom through which they are attached, form cyclopentyl or cyclohexyl.
1 1. A compound according to any one of claims 1 to 7, wherein both R5 groups are H.
12. A compound according to any one of claims 1 to 7, wherein both R5 groups are H.
13. A compound according to any one of claims 1 to 7, wherein both R5 groups are methyl.
14. A compound according to any one of claims 1 to 7, wherein both R5 groups are ethyl.
15. A compound according to claim 1 , selected from one of the following:
2-methyl-N-(2-phenylethyl)-9H-thioxanthene-3-sulfonamide 10110- dioxide;
2-methyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulfonamide 10,10- dioxide;
2-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide;
2-methyl-9-oxo-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide;
6-fluoro-2-isopropyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide;
6-fluoro-2-isopropyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H- 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;
2,9,9-trimethyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3-sulfonamide 10,10-dioxide;
2,9I9-trimethyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide;
2,9,9-trimethyl-N-(tetrahydro-2H-pyran-4-yl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide;
2,9I9-trimethyl-N-(2-pyridin-4-ylethyl)-9H-thioxanthene-3-sulfonamide 10,10-dioxide; N-(2-cyanoethyl)-2,9,9-trimethyl-9H-thioxanthene-3-sulfonamide 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-sulfonam ide 10,10- dioxide;
5-oxo-5-(4-{[(2I9,9-trimethyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1-yl)pentanoic acid;
3-[(4-{[(2,9,9-trimethyl-10110-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}pipehdin-1-yl)sulfonyl]benzoic acid;
4-[(4-{[(2,9,9-trimethyl-10110-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]benzoic acid;
4-oxo-4-(4-{[(2,9,9-trimethyl-10, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piρeridin-1-yl)butanoic acid;
N-{4-[(4-{[(2,9,9-triπnethyl-10,10-dioxido-9H-thioxanthen-3- yl)sulfonyl]am ino}piperidin-1 -yl)sulfonyl]phenyl}acetam ide te/f-butyl (4-{[(2,9,9-trimethyl-10110-dioxido-9H-thioxanthen-3- yl)sulfonyl]am ino}piperidin-1 -yl)acetate
(4-{[(2,9,9-trimethyl-10110-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperϊdin-1-yl)acetic acid;
N-(trans-4-hydroxycyclohexyl)-2,9,9-trimethyl-9H-thioxanthene-3- sυlfonamide 10,10-dioxide;
2'-methyl-N-(2-pyridin-2-ylethyl)spiro[cyclopentane-1 ,9'-thioxanthene]- 3'-sulfonamide 101, 10'-dioxide;
2'-methyl-N-(2-pyridin-3-ylethyl)spiro[cyclopentane-1 ,9'-thioxanthene]- 3'-sulfonamide 10', 10'-dioxide;
2'-methyl-N-(2-pyridin-4-ylethyl)spiro[cyclopentane-1 ,9'-thioxanthene]- 3'-sulfonamide 101, 10'-dioxide;
2'-methyl-N-(tetrahydro-2H-pyran-4-yl)spiro[cyclopentane-1 ,9'- thioxanthene]-3'-sulfonamide 10', 10'-dioxide;
2'-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)spiro[cyclopentane-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'-methylspiro[cyclopentane-1 ,9'- thioxanthene]-3' -sulfonamide 10', 10'-dioxide;
N-(2-hydroxy-1 -methyl-2-phenylethyl)-2'-nnethylspiro[cyclopentane-1 l9l- thioxanthene]-3'-sulfonamide 10', 10'-dioxide;
N-(2-hydroxyethyl)-2l-methylspiro[cyclopentane-1 ,9'-thioxanthene]-3l- sulfonamide 10',10'-dioxide; te/f-butyl 4-{[(2'-methyl-101, 10'-dioxidospiro[cyclopentane-1 ,9'- thioxanthen]-3'-yl)sulfonyl]am ino}piperidine-1 -carboxylate
2'-methyl-N-piperidin-4-ylspiro[cyclopentane-1,9l-thioxanthene]-3'- sulfonamide 10',10'-dioxide;
3-[(4-{[(2'-methyl-101, 10'-dioxidospiro[cyclopentane-1 , 9'-thioxanthen]-3'- yl)sulfonyl]amino}piρeridin-1-yl)sulfonyl]benzoic acid; tert-butyl (4-{[(2'-methyl-101, 10'-dioxidospiro[cyclopentane-1 ,9'- thioxanthen]-3'-yl)sulfonyl]amJno}piperidin-1-yl)acetate
N-(trans-4-hydroxycyclohexyl)-2'-methylspiro[cyclopentane-1 , 91- thioxanthene]-3'-sulfonamide 10', 10'-dioxide;
2'-methyl-N-(2-pyridin-2-ylethyl)spiro[cyclohexane-1 ,9'-thioxanthene]- 3'-sulfonamide 101, 10'-dioxide;
2'-methyl-N-(2-pyridin-3-ylethyl)spiro[cyclohexane-1 ,9'-thioxanthene]- 3'-sulfonamide 101, 10'-dioxide;
2'-methyl-N-(2-pyridin-4-ylethyl)spiro[cyclohexane-1 ,9l-thioxanthene]- 3'-sulfonamide 101, 10'-dioxide;
2'-methyl-N-(tetrahydro-2H-pyran-4-yl)spiro[cyclohexane-1 , 91- thioxanthene]-3'-sulfonamide 101, 10'-dioxide;
2'-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)spiro[cyclohexane-1 ,9'- thioxanthene]-3'-sulfonamide 10', 10'-dioxide;
N-(2-cyanoethyl)-2l-methylspiro[cyclohexane-1 ,9'-thioxanthene]-3l- 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'-methylspiro[cyclohexane-1 ,9'- thioxanthene]-3'-sulfonamide 101, 10'-dioxide;
N-(2-hydroxyethyl)-2'-methylspiro[cyclohexane-1 ,9'-thioxanthene]-3'- sulfonamide 10',10'-dioxide; te/f-butyl 4-{[(2'-methyl-10', 10'-dioxidospiro[cyclohexane-1 ,9'- thioxanthen]-3'-yl)sulfonyl]am ino}piperidine-1 -carboxylate
2'-methyl-N-piperidin-4-ylspiro[cyclohexane-1 ,9l-thioxanthene]-3l- sulfonamide 10',10'-dioxide;
3-[(4-{[(2'-methyl-10', 10'-dioxidospiro[cyclohexane-1 ,9'-thioxanthen]-3'- yl)sulfonyl]amino}pipehdin-1-yl)sulfonyl]benzoic acid;
N-^rans^-hydroxycyclohexylJ^'-methylspirotcyclohexane-i .θ'- thioxanthene]-3'-sulfonamide 10', 10'-dioxide;
9,9-diethyl-2-methyl-N-(2-pyridin-2-ylethyl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide;
9,9-diethyl-2-methyl-N-(2-pyridin-3-ylethyl)-9H-thioxanthene-3- sυlfonamide 10,10-dioxide;
9,9-diethyl-2-methyl-N-(2-pyridin-4-ylethyl)-9H-thioxanthene-3- sulfonamide 10,10-dioxide;
9,9-diethyl-2-methyl-N-(tetrahydro-2H-pyran-4-yl)-9H-thioxanthene-3- sulfonamidθ 10,10-dioxide;
9,9-diethyl-2-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-9H- thioxanthene-3-sulfonamide 10, 10-dioxide;
N-(2-cyanoethyl)-9,9-diethyl-2-methyl-9H-thioxanthene-3-sulfonamide 10,10-dioxide;
9,9-diethyl-N-(2-hydroxy-2-phenylethyl)-2-methyl-9H-thioxanthene-3- sulfonamide 10,10-dioxide;
9,9-diethyl-N-(2-hydroxy-1-methyl-2-phenylethyl)-2-methyl-9H- thioxanthene-3-sulfonamide 10, 10-dioxide;
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-thioxanthene-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/f-butyl (4-{[(9,9-diethyl-2-methyl-10110-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-thioxanthene-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}pipeιϊdine-1 -carboxylate
2-chloro-6-fluoro-9,9-dimethyl-N-piperidin-4-yl-9H-thioxanthene-3- sυlfonamide 10,10-dioxide;
2-(4-{[(2-chloro-6-fluoro-9,9-dimethyl-10110-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1-yl)acetamide te/f-butyl (4-{[(2-chloro-6-fluoro-9,9-dimethyl-10110-dioxido-9H- thioxanthen-3-yl)sulfonyl]am ino}piperidin-1 -yl)acetate
(4-{[(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, 10-dioxido-9H-thioxanthen-3- yl)sulfonyl]amino}piperidin-1-yl)sulfonyl]benzoic acid; te/f-butyl 4-({[6-fluoro-9,9-dimethyl-10, 10-dioxido-2-(trifluoromethyl)- 9H-thioxanthen-3-yl]sulfonyl}am ino)piperidine-1 -carboxylate
6-fluoro-9,9-dimethyl-N-piperidin-4-yl-2-(trifluoromethyl)-9H- thioxanthene-3-sulfonamide 10, 10-dioxide;
3-{[4-({[6-fluoro-9,9-dimethyl-10110-dioxido-2-(trifluoromethyl)-9H- thioxanthen-3-yl]sulfonyl}am ino)piperidin-1 -yl]sulfonyl}benzoic acid;
6-fluoro-9,9-dimethyl-N-(2-pyridin-3-ylethyl)-2-(trifluoromethyl)-9H- thioxanthene-3-sulfonamide 10, 10-dioxide; 6-fluoro-9,9-dimethyl-N-(2-pyridin-4-ylethyl)-2-(trifluoromethyl)-9H- thioxanthene-3-sulfonamide 10, 10-dioxide;
6-fluoro-9,9-dimethyl-N-(2-pyridin-3-ylethyl)-2-(trifluoromethoxy)-9H- thioxanthene-3-sulfonamide 10, 10-dioxide;
6-fluoro-9,9-dimethyl-N-piperidin-4-yl-2-(trifluorom©thoxy)-9H- thioxanthene-3-sulfonamide 10, 10-dioxide;
2'-chloro-6'-fluoro-N-piperidin-4-ylspiro[cyclohexane-1 ,9l-thioxanthene]- 3'-sulfonamide 101, 10'-dioxide;
2'-chloro-6'-fluoro-N-[1-(phenylsulfonyl)piperidin-4-yl]spiro[cyclohexane- 1 ,9'-thioxanthene]-3'-sulfonamide 101, 10'-dioxide;
2'-chloro-6'-fluoro-N-[1-(pyridin-3-ylcarbonyl)piperidin-4- yl]spiro[cyclohexane-1,9'-thioxanthene]-3'-sulfonamide 10',10'-dioxide;
2'-chloro-6'-fluoro-N-(1-isonicotinoylpiperidin-4-yl)spiro[cyclohexane- 1 ,9'-thioxanthene]-3'-sulfonamide 10', 10'-dioxide;
N-{4-[(4-{[(2l-chloro-6'-fluoro-10', 10'-dioxidospiro[cyclohexane-1 ,9'- thioxanthenl-S'-yOsulfonyllamJnoJpiperidin-i-ylJsulfonyllphenylJacetamide
4-(4-{[(2'-chlorc-6'-fluorc-101, 10'-dioxidospiroIcyclohexane-i ,9'- thioxanthen]-3'-yl)sulfonyl]am ino}piperidin-1 -yl)-4-oxobutanoic acid;
5-(4-{[(2'-chloro-6l-fluoro-101, 10'-dioxidospiro[cyclohexane-1 ,9'- thioxanthen]-3'-yl)sulfonyl]am ino}piperidin-1 -yl)-5-oxopentanoic acid;
4-{[(4-{[(2l-chloro-6'-fluoro-101 , 10'-dioxidospiro[cyclohexane-1 ,9'- thioxanthenl-S'-ylJsulfonyllaminoJpiperidin-i-ylJcarbonothioyllaminoJbenzoic acid;
3-{[(4-{[(2l-chloro-6'-fluoro-101 , 10'-dioxidospiro[cyclohexane-1 ,9'- thioxanthenl-S'-yOsulfonyllaminoJpiperidin-i-yOcarbonothioyllaminoJbenzoic acid;
4-[(4-{[(2'-chloro-6l-fluoro-10", 10'-dioxidospiro[cyclohexane-1 ,9'- thioxanthen]-3'-yl)sulfonyl]am ino}piperidin-1 -yl)sulfonyl]benzoic acid;
3-[(4-{[(2'-chloro-6l-fluoro-101, 10'-dioxidospiroIcyclohexane-i ,9'- thioxanthen]-3'-yl)sulfonyl]am ino}piperidin-1 -yl)sulfonyl]benzoic acid;
2-methyl-N-(2-phenylethyl)-10, 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-methyM 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- sulfonamide 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-sulfonamide 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;
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-f luoro-2-isopropyl-N-(2-pyridin-2-ylethyl)-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;
7-f luoro-2-isopropyl-N-(2-pyridin-3-ylethyl)-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;
7-f luoro-2-isopropyl-N-(2-pyridin-4-ylθthyl)-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-1011 1 -dihydrodibenzo[b,f]thiepine-3- sulfonamide 5,5-dioxide;
7-fluoro-2-isopropyl-N-(2-morpholin-4-ylethyl)-10,11- dihydrodibeπzo[b,f]thiepiπe-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)-10,11- dihydrodibenzo[b,f]thiepine-3-sulfonamide 5,5-dioxide;
7-f luoro-2-isopropyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]-10,11- 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-f luoro-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;
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]amino}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-pheny lethyl)-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-sulfonamide 5,5-dioxide;
2-methyl-11 -propyl-N-(2-pyridin-3-ylethyl)-10,11 - dihydrodibenzo[b,f]thiepine-3-sulfonamide 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-sulfonamide 5,5-dioxide;
8-fluoro-3-methyl-N-(2-phenylethyl)phenoxathiin-2-sulfonam ide 10,10- dioxide;
8-fluoro-3-methyl-N-(2-pyridin-2-ylethyl)phenoxathiin-2-sulfonamide 10,10-dioxide;
8-fluoro-3-methyl-N-(2-pyridin-3-ylethyl)phenoxathiin-2-sulfonamide 10,10-dioxide;
8-fluoro-3-methyl-N-(2-pyridin-4-ylethyl)phenoxathiin-2-sulfonamide 10,10-dioxide;
N-(2,3-dihydro-1 H-inden-2-yl)-8-fluoro-3-methylphenoxathiin-2- sulfonamide 10,10-dioxide;
N-cyclopentyl-β-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)phenoxathiin-2- sulfonamide 10,10-dioxide;
8-fluoro-3-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)phenoxathiin-2- sulfonamide 10,10-dioxide;
8-fluoro-3-methyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]phenoxathiin-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-sulfonam 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-sulfonamide 10,10-dioxide;
8-fluoro-3-methyl-N-(pyridin-3-ylmethyl)phenoxathiin-2-sulfonamide 10,10-dioxide;
8-fluoro-3-methyl-N-(pyridin-4-ylmethyl)phenoxathiin-2-sulfonamide 10,10-dioxide;
8-fluoro-3-methyl-N-(2-pyrrolidin-1-ylethyl)phenoxathiin-2-sulfonamide 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;
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-y lethyl)-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; terf-butyl-4-{[(8-isopropyl-5,5-dioxido-11 -oxo-10, 11 -dihydrodibenzo [b,f][1 ,4]thiazepin-7-yl)sulfonyl]amino}piperidine-1-carboxylate; or a pharmaceutically acceptable salt thereof.
16. A compound according to any one of claims 1 to 15, wherein said pharmaceutically acceptable salt is a hydrochloride salt.
17. A composition, comprising: a. at least one compound according to any one of claims 1 to 16; and b. at least one pharmaceutically acceptable carrier.
18. A method for treating a patient suffering from osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fracture, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, autoimmune inflammatory disorder, or combination thereof, comprising the step: administering to said patient an effective amount of a compound of formula I or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16.
19. A method of claim 18, wherein said patient suffers from osteoporosis or arthritis.
20. Use of a compound of formula I or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 in the preparation of a medicament for treating osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fracture, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, autoimmune inflammatory disorder, or combination thereof in a patient.
21. A compound of formula I or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 for use in treating osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fracture, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, autoimmune inflammatory disorder, or combination thereof in a patient.
22. A process for the preparation of a compound of of formula I:
Figure imgf000241_0001
I or a pharmaceutically acceptable salt thereof; wherein: R1 is H, halo, alky I, 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 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;
R2 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 R2 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;
R3 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 R3 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 alky I groups of R3 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, dialkylamiπoarylcarbonyl, dialkylaminoalkylcarbonyl, alkylthiocarbonyl, arylaminocarbonyl, heteroarylcarbonyl, heteroarylam inocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylamiπothiocarbonyl, heteroarylaminothiocarbonyl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfonylarylsulfonyl, carboxyarylsulfonyl, nitro, amino, dialkylamino, alky lcarbony lam ino, 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 R3 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, alky lam inothiocarbonyl, dialkylaminothiocarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, cyanoarylcarbonyl, arylalkylcarbonyl, alkoxycarbonyl, alkoxyalkylcarbonyl, alkylthioalkylcarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocycloalkylalkylcarbonyl, heterocycloalkylalkylaminothiocarbonyl, arylam inothiocarbonyl, heteroarylaminothiocarbonyl, heteroarylalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylaminothiocarbonyl, alkoxycarbonylalkylaminothiocarbonyl, alkylthiocarbonylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylaminoarylsulfonyl, and heteroarylsulfonyl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the heterocycloalkyl groups of R3 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 R3 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, carboxyalkylaminocarbonyl, carboxyalkylcarbonyl, heterocycloalky lam inocarbonyl, arylaminocarbonyl, arylcarbonyl, heteroarylaminocarbonyl, heterocycloalkylcarbonyl, arylaminothiocarbonyl, heteroary lam i noth iocarbonyl , heterocycloalkylam inocarbonyl, heterocycloalkylthiocarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkoxythiocarbonyl, and aryloxythiocarbonyl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents on the amino substituents on the alkyl groups of R3 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, alky lcarbony lam ino, 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.
R4 is H or C1-C4 straight or branched alkyl;
R5 is, independently at each occurrence, H or C1-C4 straight or branched alkyl; or both R5 groups, together with the carbon atom through which they are attached form a Cs-Cs cycloalkyl; and X is -O-, -(NR4)-, -S-, -[C(R5)2]- -(CH2-CHR4)-, -(C=O)-, or -(C=O)-
NR ,4.
the process comprising: contacting a compound of formula IA with -NHR3:
Cl
Figure imgf000246_0001
Figure imgf000246_0002
IA wherein the compound of formula I is formed.
23. The process of claim 22, wherein X is -(CH2-CHR4)- and the compound of formula IA is formed by:
(a) contacting a compound of formula IB:
HO2C.
.halo
Figure imgf000246_0003
IB with a compound of formula IC:
HS
Figure imgf000246_0004
R2
IC to form a compound of formula ID:
Figure imgf000246_0005
Figure imgf000246_0006
R2
ID;
(b) contacting the compound of formula ID with an acid to form a compound of formula IE:
Figure imgf000247_0001
IE;
(ci) if R4 is not H, contacting the compound of formula IE with a lithium or magnesium halide-activated R4 group to form a compound of formula IEE:
Figure imgf000247_0002
IEE;
(cii) reducing the compound of formula IE or IEE with a reducing agent to form a compound of formula IG:
R1_[L
IG;
(d) oxidizing the compound of formula IG with an oxidizing agent to form the compound of formula IH:
»1-U-
X
Figure imgf000247_0004
R2
IH; and (e) reacting the compound of formula IH with chlorosulfonic acid to form the compound of formula IA.
24. The process of claim 22, wherein X is -[C(R5)2]- and the compound of formula IA is formed by:
(a) contacting a compound of formula IJ:
halo
Figure imgf000247_0005
IJ with a compound of formula IC: HS
Figure imgf000248_0001
R2
IC to form a compound of formula IK:
Figure imgf000248_0002
Figure imgf000248_0003
R2
IK;
(b) contacting the compound of formula IK with an acid to form a compound of formula IL:
Figure imgf000248_0004
(c) reducing the compound of formula IL with a reducing agent to form a compound of formula IM:
Figure imgf000248_0005
IM
(d) oxidizing the compound of formula IM with an oxidizing agent to form a compound of formula IN:
Figure imgf000248_0006
IN
(e) if R5 is not H, contacting the compound of formula IN with a base and an activated R5 group, wherein each R5 group is the same or different, to form a compound of formula IH:
R1^
Figure imgf000248_0007
R2 IH; and (f) reacting the compound of formula IH or IN with chlorosulfonic acid to form the compound of formula IA.
25. The process of claim 22, wherein X is -(CH2-CH2)-, R2 is -CF3 and the compound of formula IA is formed by:
(a) contacting a compound of formula IB with 4-chlorobenzenethiol:
HO2C
R1
IB to form a compound of formula IO:
Figure imgf000249_0001
Figure imgf000249_0002
Rr^ ci
IO;
(b) contacting the compound of formula IO with an acid to form a compound of formula IP:
Figure imgf000249_0003
IP;
(c) reducing the compound of formula IP with a reducing agent to form a compound of formula IQ:
»iJL
Figure imgf000249_0004
X Cl
IQ;
(d) oxidizing the compound of formula IQ with an oxidizing agent to form the compound of formula IR: R " ^
Figure imgf000250_0001
Cl
IR;
(e) reacting the compound of formula IR with difluorobromomethane to form a compound of formula IS:
*i-M-
Figure imgf000250_0002
CF3
IS
(e) recting the compound of formula IS with a nitrating agent to form a compound of formula IT:
Figure imgf000250_0003
IT; (f) reducing the compound of formula IT to form a compound of formula IV:
NH5
R1-^
Figure imgf000250_0004
IV; and (g) reacting the compound of formula IV with SO2 gas and CuCb to form the compound of formula IA.
26. The process of claim 22, wherein X is -(C=O)-NR4 and the compound of formula IA is formed by:
(a) contacting a compound of formula IJ:
halo
Figure imgf000250_0005
R1
IJ with a compound of formula IC: HS
Figure imgf000251_0001
R2
IC to form a compound of formula IK:
Figure imgf000251_0002
Figure imgf000251_0003
R2
IK;
(b) contacting the compound of formula IK with an acid to form a compound of formula IL:
Figure imgf000251_0004
(C) oxidizing the compound of formula IL with an oxidizing agent to form a compound of formula IW:
Figure imgf000251_0005
(d) reacting the compound of formula IW with sodium azide and sulfuric acid to form a compound of formula IX:
R4 1
Figure imgf000251_0006
IX; and (e) reacting the compound of formula IX with chlorosulfonic acid to form the compound of formula IA.
27. The process of claim 22, wherein X is O and the compound of formula IA is formed by: contacting a compound of formula IY with chlorosulfonic acid to form a mixture and heating the mixture:
Figure imgf000252_0001
IY wherein the compound of formula IA is formed.
28. The process of any one of claims 23-26, wherein the acid is polyphosphoric acid or sulfuric acid.
29. The process of any one of claims 23-26, wherein the reducing agent is sodium borohydride or triethylsilane.
30. The process of any one of claims 23-26, wherein the oxidizing agent is oxone or hydrogen peroxide and acetic acid.
31. The process of claim 22, wherein:
(a) X is -[C(R5)2]- in the compound of formula I; and
(b) 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)-.
PCT/US2007/084321 2006-11-10 2007-11-09 Aryl sulfonamide derivatives and methods of their use WO2008061029A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109928951A (en) * 2017-12-19 2019-06-25 山东久日化学科技有限公司 The preparation method of 2- isopropyl thioxanthone
CN114702483A (en) * 2022-04-20 2022-07-05 贵州汇腾科技有限公司 Preparation and purification method of 2-substituted-10- (benzotriazole) -9-thiaanthracene

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Publication number Priority date Publication date Assignee Title
WO2002055547A2 (en) * 2001-01-10 2002-07-18 The Government Of The United States Of America, Asrepresented By The Secretary, Department Of Health And Human Services Sfrp and peptide motifs that interact with sfrp and methods of their use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002055547A2 (en) * 2001-01-10 2002-07-18 The Government Of The United States Of America, Asrepresented By The Secretary, Department Of Health And Human Services Sfrp and peptide motifs that interact with sfrp and methods of their use

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109928951A (en) * 2017-12-19 2019-06-25 山东久日化学科技有限公司 The preparation method of 2- isopropyl thioxanthone
CN109928951B (en) * 2017-12-19 2022-03-08 山东久日化学科技有限公司 Preparation method of 2-isopropyl thioxanthone
CN114702483A (en) * 2022-04-20 2022-07-05 贵州汇腾科技有限公司 Preparation and purification method of 2-substituted-10- (benzotriazole) -9-thiaanthracene
CN114702483B (en) * 2022-04-20 2024-01-30 贵州汇腾科技有限公司 Preparation and purification method of 2-substituted-10- (benzotriazole) -9-thioxanthene

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