WO2008061016A1 - Pipéridinyle 4-arylsulfonamides n-substitués utilisés comme modulateurs de la protéine 1 apparentée à une protéine frizzled secrétée - Google Patents

Pipéridinyle 4-arylsulfonamides n-substitués utilisés comme modulateurs de la protéine 1 apparentée à une protéine frizzled secrétée Download PDF

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WO2008061016A1
WO2008061016A1 PCT/US2007/084285 US2007084285W WO2008061016A1 WO 2008061016 A1 WO2008061016 A1 WO 2008061016A1 US 2007084285 W US2007084285 W US 2007084285W WO 2008061016 A1 WO2008061016 A1 WO 2008061016A1
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trifluoromethyl
piperidin
sulfonyl
amino
biphenyl
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PCT/US2007/084285
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English (en)
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William Jay Moore
Jeffrey Curtis Kern
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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel N-substituted piperidinyl 4-arylsulfonamides that act, for example, as modulators of secreted frizzled-related protein- 1.
  • the present invention also relates to processes for the preparation of N-substituted piperidinyl 4- aryl sulfonamides 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 al., J. Biol. Chem. 1996, 271:26131-26137; Jones & Jomary, Bioessays 2002, 24:811-820). The human homologue of the bovine gene has also been cloned. Unlike the frizzled proteins, however, Frzb does not contain a serpentine transmembrane domain, and appears to be a secreted receptor for Wnt.
  • Frzb does not contain a serpentine transmembrane domain, and appears to be a secreted receptor for Wnt.
  • 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 disappears toward the ossification center.
  • 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- l/SARP-2, SFRP-2/SDF-5/SARP-1, SFRP-3/Frzb-l/FrzB/Fritz, SFRP-4 and SFRP-5/SARP- 3 (Leimeister et al., Mechanisms of Development 1998, 75:29-42).
  • SFRP-I Secreted frizzled related protein-1
  • the present invention is directed to certain N-substituted piperidinyl 4- arylsulfonamides and to their use, for example, in medical treatment.
  • the invention relates to N-substituted piperidinyl 4-arylsulfonamides 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, heteroaryl, carboxyl, cyano, perfluoroalkyl, or perfluoroalkoxy;
  • R 2 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 Ra may be optionally substituted with 1 to 5 substituents, selected independently at each occurrence from the group consisting of alkyl, aryl, aryloxy, alkoxy, hydroxyl, carboxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, halo, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, dialkylaminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbony
  • R 3 is H, halo, alkyl, alkoxy, aryl, arylalkyl, or perfluoroalkyl;
  • R4 is halo, alkyl, cyano, cycloalkyl, arylalkyl, nitro, perfluoroalkyl, or perfluoroalkoxy;
  • R5 is H, alkyl, alkylamino, cycloalkyl, cycloalkylamino, alkoxy, alkoxyalkyl, aryl, arylalkyl, arylamino, aminocarbonyl, aminoalkyl, alkylaminocarbonylaminoalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, or heterocycloalkylamino, wherein any aryl, heteroaryl, or hetercycloalkyl portion of R5 may be optionally substituted with 1 to 5 substituents, selected independently at each occurrence from the group consisting of alkyl, aryl, alkoxy, oxo, alkoxyalkyl, alkylamino, dialkylamino, alkylaminoalkylamino, dialkylaminoalkylamino, alkylaminodialkylamino, dialkylaminodialkylamino, cyano, carboxy, halo, alkyl
  • X is carbonyl, thiocarbonyl, sulfonyl, sulfoxide, alkyl, alkenyl or absent.
  • R 5 is other than alkoxy when R 4 is nitro and X is carbonyl.
  • the invention relates to 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 disorder, such as Graves ophthalmopathy, or a combination thereof, comprising the step: administering to said patient an effective amount of a compound of formula I or pharmaceutically acceptable salt thereof.
  • the invention is directed to use of a compound as described herein 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 disorder, such as Graves ophthalmopathy, or a combination thereof.
  • the invention is directed to use of a compound as described herein in the preparation of a medicament 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 disorder, such as Graves ophthalmopathy, or a combination thereof.
  • the present invention is directed to certain N-substituted piperidinyl 4- arylsulfonamides and to their use, for example, in medical treatment.
  • the invention relates to N-substituted piperidinyl 4-aryl sulfonamides 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.
  • alkyl refers to an optionally substituted aliphatic hydrocarbon chain having 1 to 12 carbon atoms (C ⁇ .n 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. In one embodiment 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, preferably 1 to 3 carbon atoms, in which all hydrogens are replaced with fluorine.
  • perfluoroalkylalkyl refers to the group -alkyl- perfiuoroalkyl 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 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-l- enyl, or 2-methylvinyl.
  • alkynyl refers to an optionally substituted aliphatic straight or branched hydrocarbon chain having 2 to 8 carbon atoms that contains 1 to 3 triple bonds.
  • Straight chain alkynyl groups have 2 to 8 carbon atoms and branched chain alkynyl groups have 5 to 12 carbon atoms.
  • cycloalkyl refers to an optionally substituted hydrocarbon ring containing 3 to 12 carbon atoms (C3. 12 cycloalkyl) and preferably 3 to 6 carbon atoms (C3-6 cycloalkyl) . Cycloalkyl groups may be monocyclic or bicyclic, and may be saturated or partially saturated.
  • bicycloalkyl refers to a bicyclic cycloalkyl group of 8 to 12 ring carbon atoms (Cg-n bicyclic cycloalkyl).
  • “Bridged” cycloalkyl groups contain at least one carbon-carbon bond between two non-adjacent carbon atoms of the cycloalkyl ring.
  • alkylcycloalkyl refers to the group -cycloalkyl-f ⁇ lkyl),, 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 -alkyl-cycloalkyl 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 refers to the bicyclic structure formed when a heterocycloalkyl group is fused to another heterocycloalkyl group, to a cycloalkyl group, to an aryl group, or to a heteroaryl group.
  • Heterocycloalkyl groups also include "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
  • aryl refers to an optionally substituted carbocyclic aromatic ring e.g. having 6-14 ring carbon atoms.
  • Aryl groups may be monocyclic or bicyclic. Exemplary aryl groups include phenyl and naphthyl. Aryl groups preferably have 6 to 10 carbon atoms (Ce-io aryl).
  • 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 system 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, pyridazinyl, 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)-NH-ftised cycloalkylaryl where fused cycloalkylaryl is a fused cycloalkylaryl group as previously defined.
  • fused hetercycloalkylaryl 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 hetercycloalkylarylcarbonyl 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 3 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.
  • perfluoroalkoxy refers to the group -O-R" where R" is a perfluoroalkyl group as previously defined.
  • amino alkylamino
  • dialkylamino dialkylamino
  • imino alkyl group
  • alkyiaminoalkylamino, dialkylaminoalkylamino, alkylaminodialkylamino, dialkylaminodialkylamino refer to groups having the structure R'HN-R"-NH-, (R')_N-R"-NH-, (R')HN-R"-N(R") 2 -, OET) 2 N-R"- N(R") 2 -, where each R' is, independently, an alkyl group and each R" is independently a divalent alkyl group.
  • aminoalkyl refers to the group -R'NH2 where R' is an alkyl group as previously defined.
  • carbonyl refers to a bivalent carbon atom that is further bonded to an oxygen atom through a double bond.
  • aminocarbonyl refers to an amide substituent having the formula H 2 N-C(O)-.
  • 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
  • alkoxy alkyl 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-Cth-phenyl.
  • aminocarbonylalkoxy refers to the group -alkoxy- C(O)NH 2 where alkoxy is an alkoxy group as previously defined.
  • alkoxycarbonylalokxy 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.
  • arylcarbonyl refers to the group -C(O)-aryl, where aryl is an aryl group of 6 to 10 carbon atoms as previously defined.
  • dialkylaminoarylcarbonyl refers to the group -arylcarbonyl-N(R')(R') where arylcarbonyl is an arylcarbonyl group as previously defined.
  • arylthio refers to the group -S-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.
  • alkylaminoalkylcarbonyl refers to the group -C(O)R 5 NH(R') where R' is an alkyl group as previously defined.
  • dialkylaminoalkylcarbonyl refers to the group -C(O)R 5 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 5 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' where R' is an alkyl group as previously defined.
  • alkoxycarbonylalkyl refers to the group -R 5 C(O)OR' where R' is an alkyl 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 5 -heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined and R' is an alkyl group as previously defined.
  • heterocycloalkylalkylaminothiocarbonyl refers to the group -C(O)-S-NH-R'-heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined and R' is an alkyl group as previously defined.
  • aryloxy refers to the group -O-aryl where aryl is an aryl group as previously defined.
  • arylamino refers to the group -NH-aryl where 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.
  • cycloalkylamino referst to the group
  • 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)- heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined.
  • heterocycloalkylamino refers to the group -NH- heterocycloalkyl where heterocycloalkyl is as previously defined.
  • aminoalkylcarbonyl refers to the group -C(0)-R'-NH2 where R' is an alkyl group as previously defined.
  • alkoxycarbonylaminothiocarbonyl refers to the group - C(O)-S-NH-C(O)-O-R' where R' 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 -C(O)NH 2 .
  • alkylaminocarbonyl and “dialkylaminocarbonyl,” as used herein, refer to the groups -C(O)NHR' and -C(O)N(R' )2, respectively, where each R' is, independently, an alkyl group as previously defined.
  • heterocycloalkylaminocarbonyl refers to the group -C(0)NH-heterocycloalkyl where heterocycloalkyl is a heterocycloalkyl group as previously defined.
  • carboxyalkylcarbonylheterocycloalkylaminocarbonyl refers to the group -heterocycloalkylaminocarbonyl-C(0)-R'-C(0)OH where heterocycloalkylaminocarbonyl is a heterocycloalkylaminocarbonyl group as previously defined and R' is an alkyl group as previously defined.
  • carboxyalkylaminocarbonyl refers to the group -alkylaminocarbonyl-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 5 C(O)NH 2 where R' is an alkyl group as previously defined.
  • alkylaminocarbonylalkyl and “dialkylaminocarbonylalkyl,” as used herein, refer to the groups -R 5 C(O)NHR' and -R'C(O)N(R') 2 , respectively, where each R 3 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 3 J 2 , respectively, where each R' is, independently, an alkyl group as previously defined.
  • heterocycloalkylcarbonylalkyl refers to the group -R'C(0)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.
  • heteroarylamino refers to the group -NH(heteroaryl), where heteroaryl is a heteroaryl group as previously defined.
  • heteroarylaminothiocarbonyl refers to the group -C(S)NH(heteroaryl), where heteroaryl is a heteroaryl group as previously defined.
  • arylaminothiocarbonyl refers to the group -C(S)NH(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.
  • An exemplary oxo- substituted group is pyrrolidninone.
  • 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, aralkyl carbonyl, 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.
  • protecting group with respect to amine groups, hydroxyl groups and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art, such as those set forth in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999) which can be added or removed using the procedures set forth therein.
  • Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyl oxy methyl ether, t- butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxy ethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.
  • a reagent such as, but
  • Examples of protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; carbamates; e.g. BOC; imides, such as phthalimide, Fmoc, Cbz, PMB, benzyl, and dithiosuccinimide; and others.
  • Examples of protected or capped sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
  • activated or “an activating group” or “G A " as used herein indicates having an electrophilic moiety bound to a substituent, capable of being displaced by a nucleophile.
  • activating groups are halogens, such as Cl, Br or I, and F; triflate; mesylate, or tosylate; esters; aldehydes; ketones; epoxides; and the like.
  • An example of an activated group is acetyl chloride, which is readily attacked by a nucleophile, such as piperidine group to form a N-acetylpiperidine functionality.
  • deprotecting refers to removal of a protecting group, such as removal of a benzyl or BOC group bound to an amine. Deprotecting may be preformed by heating and/or addition of reagents capable of removing protecting groups. One preferred method of removing BOC groups from amino groups is to add HCl in ethyl acetate. Many deprotecting reactions are well known in the art and are described in Protective Groups in Organic Synthesis, Greene, T.W., John Wiley & Sons, New York, NY, (1st Edition, 1981).
  • the te ⁇ n "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.
  • terapéuticaally effective amount refers to the amount of a compound of formula 1 that, when administered to a patient, is effective to at least partially treat a condition from which the patient is suffering or is suspected to suffer.
  • Such conditions include, but are not limited to, osteoporosis, arthritis, chronic obstructive pulmonary disease, cartilage defects, bone fractures, leiomyoma, acute myeloid leukemia, wound healing, prostate cancer, autoimmune inflammatory disorders, such as Graves ophthalmopathy, and combinations thereof.
  • pharmaceutically acceptable salts or “pharmaceutically acceptable salt” includes acid addition salts, namely salts derived from treating a compound of formula 1 with an organic or inorganic acids or bases. Where the compound having formula I has an acidic function, the term “pharmaceutically acceptable salts” or “pharmaceutically acceptable salt” includes salts derived from bases, for instance, sodium salts.
  • patient refers to a mammal, preferably a human.
  • 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.
  • Ri is H, halo, alkyl, alkoxy, alkylamino, alkylthio, dialkylamino, aryl, aryloxy, arylalkyl, heteroaryl, carboxyl, cyano, perfluoroalkyl, or perfluoroalkoxy;
  • R. 2 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, aryl, aryloxy, alkoxy, hydroxy, carboxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, halo, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, dialkylaminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl;
  • Rj is H, halo, alkyl, alkoxy, aryl, arylalkyl, or perfluoroalkyl;
  • R 4 is halo, alkyl, cyano, cycloalkyl, arylalkyl, nitro, perfluoroalkyl, or perfluoroalkoxy;
  • R 5 is H, alkyl, alkylamino, cycloalkyl, cycloalkylamino, alkoxy, alkoxyalkyl, aryl, arylalkyl, arylamino, aminocarbonyl, aminoalkyl, alkylaminocarbonylaminoalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, or heterocycloalkylamino, wherein any aryl, heteroaryl, or heterocycloalkyl portion of Rs may be optionally substituted with 1 to 5 substituents, selected independently at each occurrence from the group consisting of alkyl, aryl, alkoxy, oxo, alkoxyalkyl, alkylamino, dialkylamino, alkylaminoalkylamino, dialkylaminoalkylamino, alkylaminodialkylamino, dialkylaminodialkylamino, cyano, carboxy, halo, alkylcarbonyl
  • X is carbonyl, thiocarbonyl, sulfonyl, sulfoxide, alkyl, alkenyl or absent.
  • R 5 is other than alkoxy when R 4 is nitro and X is carbonyl.
  • Ri is H, fiuoro, chloro, bromo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, butoxy, phenyl, naphthyl, benzyl, carboxyl, cyano, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, or trifluoromethyl.
  • Ri is H.
  • R 2 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 or 2 substituents, selected independently at each occurrence from the group consisting of alkyl, aryl, alkoxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, halo, hydroxy, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl.
  • R 2 is phenyl, o-aminocarbonyl-phenyl, o-chloro-phenyl, o-fluoro- phenyl, o-cyano-phenyl, o-fluoro-p-fluoro-phenyl, o-perfluoromethoxy-phenyl, or o- perfiuoromethoxy-o-fluoro-phenyl
  • R 2 is halo, alkyl, aryl, or arylsulfonyl, wherein any aryl portion of R 2 may be optionally substituted with 1 to 5 substituents selected, independently at each occurrence, from the group consisting of alkyl, aryl, alkoxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, halo, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl.
  • R2 is aryl optionally substituted with 1 to 5 substituents selected, independently at each occurrence, from the group consisting of alkyl, aryl, alkoxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, halo, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl.
  • R 2 is bromo, isopropyl, phenyl, or phenylsulfonyl.
  • R3 is H, fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, butyoxy, phenyl, naphthyl, benzyl, or trifluoromethyl. In certain preferred embodiments, R 3 is H.
  • R 4 is perfluoroalkyl. In certain preferred embodiments, R» is trifluoromethyl.
  • R5 is H, aryl, heteroaryl, or heterocycloalkyl.
  • X is absent (a direct bond). In certain other embodiments of the compounds of formula I, X is carbonyl. In certain embodiments of the compounds of formula I, X is sulfonyl
  • R2 is aryl optionally substituted with 1 to 2 substituents, selected independently at each occurrence from the group consisting of alkyl, aryl, alkoxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, halo, hydroxy, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl;
  • R5 is H
  • Rs is heteroaryl or heterocycloalkyl, wherein any heteroaryl or hetercycloalkyl portion of R5 may be optionally substituted with 1 to 5 substituents, selected independently at each occurrence from the group consisting of alkyl, aryl, alkoxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, halo, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl; and X is carbonyl.
  • R5 is 6-chloropyridiny-3-yl, 6-trifluoromethylpyridin-3-yl, or (5S)-N-tert-butyl-2-oxo-pyrrolidin-5-yl-l-carboxamide.
  • Rs is aryl optionally substituted with 1 to 5 substituents, selected independently at each occurrence from the group consisting of alky!, aryl, alkoxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, carboxy, halo, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl; and
  • X is sulfonyl
  • R5 is benzoic acid.
  • R 5 is benzoic acid and X is sulfonyl.
  • R 5 is heteroaryl or heterocycloalkyl, optionally substituted with 1 to 5 substituents, selected independently at each occurrence from the group consisting of alkyl, aryl, alkoxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, halo, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, arylaminothiocarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, perfluoroalkyl, perfluoroalkoxy, and perfluoroalkylcarbonyl; and
  • X is carbonyl
  • Preferred compounds of the invention include: tert-buty ⁇ 4-( ⁇ [2-(trifluoromethyl)phenyl]sulfonyl ⁇ amino)piperidine-l-carboxylate; tert-butyl 4-( ⁇ [5-bromo-2-(t ⁇ ifluoromethoxy)phenyl]sulfonyl ⁇ amino)piperidine-l- carboxylate;
  • 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 I or 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 stereoisomer 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.
  • Another aspect of the invention provides a process for the preparation of a compound of formula I:
  • Ri is H, halo, alkyl, alkoxy, alkylamino, alkylthio, dialkylamino, aryl, aryloxy, arylalkyl, heteroaryl, carboxyl, cyano, perfluoroalkyl, or perfluoroalkoxy;
  • R 2 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, aryl, aryloxy, alkoxy, hydroxy, carboxy, alkoxyalkyl, alkylamino, dialkylamino, cyano, halo, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, dialkylaminocarbonyl, arylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbony
  • R3 is H, halo, alkyl, alkoxy, aryl, arylalkyl, or perfluoroalkyl;
  • R 4 is halo, alkyl, cyano, cycloalkyl, arylalkyl, nitro, perfluoroalkyl, or perfluoroalkoxy;
  • Rj is H, alkyl, alkylamino, cycloalkyl, cycloalkylamino, alkoxy, alkoxyalkyl, aryl, arylalkyl, arylamino, aminocarbonyl, aminoalkyl, alkylaminocarbonylaminoalkyl, heteroaryl, heteroaryl amino, heterocycloalkyl, or heterocycloalkylamino, wherein any aryl, heteroaryl, or hetercycloalkyl portion of R5 may be optionally substituted with 1 to 5 substituents, selected independently at each occurrence from the group consisting of alkyl, aryl, alkoxy, oxo, alkoxyalkyl, alkylamino, dialkylamino, alkylaminoalkylamino, dialkylaminoalkylamino, alkylaminodialkylamino, dialkylaminodialkylamino, cyano, carboxy, halo, alkylcarbon
  • X is carbonyl, thiocarbonyl, sulfonyl, sulfoxide, alkyl, alkenyl or absent;
  • the activating group is selected from the group consisting of halo, tosylate, mesylate, triflate, an ester, epoxide or aldehyde.
  • the protecting group is selected from the group consisting of BOC, benzyl, acetyl, PMB, alkyl, Fmoc, Cbz, or trifluoroacetyl, tosyl and triphenylmethyl.
  • the invention generally relates to all stereoisomers of the compounds of formula I, as well as to mixtures of the stereoisomers.
  • 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.
  • 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 ai, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); EHeI, 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 chromatography
  • compounds of formula I can be prepared from intermediates Ia and Ib starting from suitably substituted aryl sulfonyl chlorides (II) and 4- amino piperidines (Ilia).
  • the sulfonyl chlorides can be obtained commercially, known in the literature, or prepared according to methods known and established for the preparation of sulfonyl chlorides, including procedures exemplified in the experimental section of this document, wherein Ri - R4 are as previously defined.
  • EQa wherein W is an acceptable protecting group known to one skilled in the art such as tert-butoxy carbonyl, t-Boc, or Boc, can be obtained commercially, known in the literature, or prepared according to methods known and established for the preparation of protected 4-amino piperidines.
  • Compounds of formula Ia can be treated with acid, or by an appropriate reagent system for alternative protecting groups, for several hours or longer where necessary to provide the intermediates Ib.
  • the intermediates of formula Ib can be treated with an electrophilic source such as, but not limited to, R5Z wherein Z is sulfonyl halide, activated acid, isocyanate, isothiocyanate, or halide in the presence of an acid scavenger when appropriate to yield a compound of formula I.
  • an electrophilic source such as, but not limited to, R5Z wherein Z is sulfonyl halide, activated acid, isocyanate, isothiocyanate, or halide in the presence of an acid scavenger when appropriate to yield a compound of formula I.
  • intermediate Ic can be converted to compounds or intermediates of formula Id, as defined herein, by treatment with a palladium catalyst in the presence of an aryl boronic acid, or any other suitable aryl boronate species.
  • Intermediates Ic can also be treated with a cyanide source such as zinc cyanide in the presence of a palladium catalyst to provide compounds or intermediates of formula Ie.
  • intermediates Ic can be undergo a metal halogen exchange with a reagent such as butyl lithium to form an aryl lithium complex that can be quenched with an electrophilic source such as an aryl sulfonyl fluoride to provide compounds or intermediates of formula If.
  • Compounds of formula Ic-f represent compounds of formula Ia and can be elaborated to compounds of formula Ib and I by methods previously described.
  • Reaction of Ih with electrophilic reagents such as ReZ (where Re is alkyl, alkoxy, aryl, arylalkyl, alkylamino, arylamino, heteroaryl, or heteroarylamino and Z is sulfonyl halide, activated acid, isocyanate, isothiocyanate, or halide in the presence of an acid scavenger when appropriate), in a suitable solvent such as DCM or THF provides compounds of formula Ii.
  • a suitable solvent such as DCM or THF
  • 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, emulsif ⁇ ers, 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
  • 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 I can be administered rectally or vaginally in the form of a conventional suppository.
  • the compounds of formula I can be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
  • the compounds of formula I can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is nontoxic 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 abso ⁇ tive 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.
  • compounds of formula I are provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications.
  • An amount adequate to accomplish this is defined as a "therapeutically effective amount.”
  • the dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician.
  • the variables involved include the specific condition and the size, age, and response pattern of the patient.
  • the compounds can be administered orally, rectally, parenterally, or topically to the skin and mucosa.
  • the usual daily dose depends on the specific compound, method of treatment and condition treated.
  • the usual daily dose is 0.01 - 1000 mg/kg for oral application, preferably 0.5 - 500 mg/kg, and 0.1 - 100 mg/kg for parenteral application, preferably 0.5 - 50 mg/kg.
  • the present invention is directed to prodrugs of compounds of formula 1.
  • 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 5 fcrt-butyl 4-( ⁇ [4-bromo-2- (trifluoromethyl)phenyl]sulfonyl ⁇ amino)piperidine-l-carboxylate
  • 4-bromo-2-(trifluoromethyl)benzenesulfonyl chloride was used to prepare tert-butyl 4-( ⁇ [4-bromo-2- (trifluoromethyl)phenyl]sulfonyl ⁇ amino)piperidine-l-carboxylate (412 mg, 84%).
  • example 5 was treated with a saturated solution of HCl in ethyl acetate to provide 4-bromo-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide as a hydrochloride salt (310 mg, 93%).
  • example 6 was treated with a saturated solution of HCl in ethyl acetate to provide 4-bromo-N-piperidin-4-yl-2- (trifluoromethoxy)benzenesulfonamide as a hydrochloride salt (335 mg, 99%).
  • Example 17 yV-piperidin-4-yl-2,5-bis(trifluoromethyl)benzenesuIfonamide
  • example 7 was treated with a saturated solution of HCl in ethyl acetate to provide iV-piperidin-4-yl-2,5- bis(trifluoromethyl)benzenesulfonamide as a hydrochloride salt (210 mg, 85%).
  • example 8 was treated with a saturated solution of HCl in ethyl acetate to provide 2-chloro-N-piperidin-4-yl-4- (trifluoromethyl)benzenesulfonamide as a hydrochloride salt (270 mg, 99%).
  • example 9 was treated with a saturated solution of HCl in ethyl acetate to provide 2-chloro-N-piperidin-4-yl-5- (trifluoromethyl)benzenesulfonamide as a hydrochloride salt (252 mg, 92%).
  • example 10 was treated with a saturated solution of HCl in ethyl acetate to provide 2,3-dichloro-N-piperidin-4-ylbenzenesulfonamide as a hydrochloride salt (250 mg, 99%).
  • example 11 was treated with a saturated solution of HCl in ethyl acetate to provide 2,4-dichloro-N-piperidin-4-ylbenzenesulfonamide as a hydrochloride salt (236 mg, 99%).
  • example 12 was treated with a saturated solution of HCl in ethyl acetate to provide 2-methyl- ⁇ » r -piperidin-4-ylbenzenesulfonamide as a hydrochloride salt (171 mg, 89%).
  • example 13 was treated with a saturated solution of HCl in ethyl acetate to provide 2-cyano- ⁇ T-piperidin-4-ylbenzenesulfonamide as a hydrochloride salt (58 mg, 92%).
  • example 14 was treated with a saturated solution of HCl in ethyl acetate to provide 2-nitro-N-piperidin-4-ylbenzenesulfonamide as a hydrochloride salt (219 mg, 94%).
  • Example 26 3- ⁇ [4-( ⁇ [4-bromo-2-(trifluoromethyl)phenyl]sulfonyl ⁇ amino)piperidin-l- yl]sulfonyl ⁇ benzoic acid [0236]
  • example 15 was treated with 3- (chlorosulfonyl)benzoic acid to provide 3- ⁇ [4-( ⁇ [4-bromo-2- (trifluoromethyl)phenyl]sulfonyl ⁇ amino)piperidin-l-yl]sulfonyl ⁇ benzoic acid (145 mg, 83%).
  • example 16 was treated with 3- (chlorosulfonyl)benzoic acid to provide 3- ⁇ [4-( ⁇ [4-bromo-2- (trifluoromethoxy)phenyl]sulfonyl ⁇ amino)piperidin-l-yl]sulfonyl ⁇ benzoic acid (152 mg,
  • example 17 was treated with 3- (chlorosulfonyl)benzoic acid to provide 3- ⁇ [4-( ⁇ [2,5- bis(trifluoromethyl)phenyl]sulfonyl ⁇ amino)piperidin-l-yl]sulfonyl ⁇ benzoic acid (166 mg,
  • example 18 was treated with 3- (chlorosulfonyl)benzoic acid to provide 3- ⁇ [4-( ⁇ [2-chloro-4- (trifluoromethyl)phenyl]sulfonyl ⁇ amino)piperidin-l-yl]sulfonyl ⁇ benzoic acid (130 mg, 70%).
  • example 19 was treated with 3- (chlorosulfonyl)benzoic acid to provide 3- ⁇ [4-( ⁇ [2-chloro-5- (trifluoromethyl)phenyl]sulfonyl ⁇ amino)piperidin-l-yl]sulfonyl ⁇ benzoic acid (110 mg, 60%).
  • example 24 was treated with 3- (chlorosulfonyl)benzoic acid to provide 3-[(4- ⁇ [(2-nitrophenyl)sulfonyl]amino ⁇ piperidin-l- yl)sulfonyl]benzoic acid (73 mg, 44%).
  • Example 32 4-bromo-./V- ⁇ l-[(3-cyanophenyl)sulfonyI]piperidin-4-y- ⁇ -2- (trifluoromethyl)benzenesulfonamide
  • Step 1 tert-butyl 4-( ⁇ [4-bromo-2-(trifluoromethyl)phenyl]sulfonyl ⁇ amino)piperidine-l- carboxylate
  • Step 2 4-bromo- ⁇ r -piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide hydrochloride
  • Step 3 4-bromo-N- ⁇ l-
  • Step 1 tert-butyl 4-( ⁇ [2-(trifluoromethyI)phenyl
  • Step 2 yV-piperidin-4-yl-2-(trifluoromethyl)benzeiiesuIfonamide hydrochloride
  • Step 3 iV- ⁇ l-[(3-cyanophenyl)sulfonyI]piperidin-4-yl ⁇ -2- (trifluoromethyl)benzenesulfonaniide
  • Step 1 In an analogous manner to example 42, piperidin-4-yl-carbamic acid terl- butyl ester and 2-chloropyridine-5-carbonyl chloride were used to prepare [l-(6-Chloro- pyridine-3-carbonyl)-piperidin-4-yl]-carbamic acid fert-buty ⁇ ester.
  • Step 2 In an analogous manner to example 54, [l-(6-Chloro-pyridine-3-carbonyl)- piperidin-4-yl]-carbamic acid terf-butyl ester was used to prepare l-[(6-chloropyridin-3- yl)carbonyl]piperidin-4-amine.
  • Step 3 In an analogous manner to example 42, l-[(6-chloropyridin-3- yl)carbonyl]piperidin-4-amine and 4-bromo-2-trifluoromethylbenzene sulfonyl chloride were used to prepare 4-bromo-iV- ⁇ l-[(6-chloropyridin-3-yl)carbonyl]piperidin-4-yl ⁇ -2- (trifluoromethyl)benzenesulfonamide.
  • Step 1 In an analogous manner to example 42, piperidin-4-yl-carbamic acid tert- butyl ester and 2-chloropyridine-4-carbonyl chloride were used to prepare tert-butyl [l-(2- chloroisonicotinoyl)piperidin-4-yl]carbamate.
  • Step 2 In an analogous manner to example 54, tert-butyl [l-(2- chloroisonicotinoyljpiperidin ⁇ -yljcarbamate was used to prepare l-(2- chloroisonicotinoyl)piperidin-4-amine.
  • Step 3 In an analogous manner to example 42, 1 -(2-chloroisonicotinoyl)piperidin-4- amine and 4-bromo-2-trifluoromethylbenzene sulfonyl chloride were used to prepare 4- bromo-N-[l-(2-chloroisonicotinoyl)piperidin-4-yl]-2-(trifluoromethyl)benzenesulfonamide.
  • Step 1 In an analogous manner to example 42, piperidin-4-yl-carbamic acid tert- butyl ester and 2-chloropyridine-5-carbonyl chloride were used to prepare [l-(6-Chloro- pyridine-3-carbonyl)-piperidin-4-yl]-carbamic acid /erf-butyl ester.
  • Step 2 In an analogous manner to example 54, [l-(6-Chloro-pyridine-3-carbonyl)- piperidin-4-yl]-carbamic acid tert-butyl ester was used to prepare l-[(6-chloropyridin-3- yl)carbonyl]piperidin-4-ami ne.
  • Step 3 In an analogous manner to example 42, l-[(6-chloropyridin-3- yl)carbonyl]piperidin-4-amine and 2-trifluoromethylbenzene sulfonyl chloride were used to prepare JV-(I -[(6-chloropyridin-3-yl)carbonyl]piperidin-4-yl ⁇ -2- (trifluoromethyl)benzenesulfonamide.
  • Step 1 N-[l-(2-chloroisonicotinoyl)piperidin-4-yl]-2- (trifluoromethyl)benzenesiilfonamide
  • Step 1 In an analogous manner to example 42, piperidin-4-yl-carbamic acid tert- butyl ester and 2-chloropyridine-4-carbonyl chloride were used to prepare tert-butyl [l-(2- chloroisonicotinoyljpiperidin ⁇ -yljcarbamate.
  • Step 2 In an analogous manner to example 54, tert-butyl [l-(2- chloroisonicotinoyl)piperidin-4-yl]carbamate was used to prepare l-(2- chloroisonicotinoyl)piperidin-4-amine.
  • Step 3 In an analogous manner to example 42, l-(2-chloroisonicotinoyl)piperidin-4- amine and 2-trifluoromethylbenzene sulfonyl chloride were used to prepare N-[I -(2- chloroisonicotinoyl)piperidin-4-yl]-2-(trifluoromethyl)benzenesulfonamide.
  • Example 54 7V-piperidin-4-yl-3-(trifluoroinethyl)biphenyl-4-sulfonamide
  • tert-buty ⁇ 4-( ⁇ [3-(trifluoromethyl)biphenyl-4- yl]sulfonyl ⁇ amino)piperidine-l-carboxylate (0.90 g, 1.86mmol) in ethyl acetate (3OmL) was bubbled in hydrogen chloride gas over several minutes.
  • the resulting solution was stirred room temperature overnight and concentrated to give N-piperidin-4-yl-3- (trifluoromethyl)biphenyl-4-sulfonamide. (0.76 g, 97%).
  • reaction solution was washed with 1 ⁇ aqueous sodium hydroxide (7.5 mL), water (7.5 mL) and saturated brine (7.5 mL), dried (MgSO 4 ) and concentrated under vacuum.
  • the residue was dissolved in a small volume of dichloromethane, loaded directly onto a 12 g ISCO column (silica gel) and eluted with ethyl acetate-hexanes (30-100 % solution @ 30 mL/min) to provide tert-butyl 4- ⁇ [4-( ⁇ [4-bromo-2-
  • N-piperidin-4-yl-3- (trifluoromethyl)biphenyl-4-sulfonamide and 3-(chlorosulfonyl)benzoic acid were used to prepare 3- ⁇ [4-( ⁇ [3-(trifluoromethyl)biphenyl-4-yl]sulfonyl ⁇ amino)piperidin-l- yl]sulfonyl ⁇ benzoic acid.
  • tert-butyl (25)-2- ⁇ [4-( ⁇ [3- (trifiuoromethyObiphenyl ⁇ -ylJsulfonylJaminoJpiperidin-l-y ⁇ carbonylJpyrrolidine-l- carboxylate was used to prepare N-(l-L-prolylpiperidin-4-yl)-3-(trifluoromethyl)biphenyl-4- sulfonamide.
  • Example 70 3- ⁇ [4-( ⁇ [4-(phenyIsulfonyl)-2- (trifluoromethyl)phenyl]sulfonyl ⁇ amino)piperidin-l-yl]sulfonyl ⁇ benzoic acid [0320]
  • 4-(phenylsulfonyl)-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonamide and 3-(chlorosulfonyl)benzoic acid were used to prepare 3- ⁇ [4-( ⁇ [4-(phenylsulfonyl)-2-(trifluoromethyl)phenyl]sulfonyl ⁇ amino)piperidin-l- yl]sulfonyl ⁇ benzoic acid.
  • Step 1 To a stirred solution of 4-fiuoro-2-trifluoromethylaniline (2.0 g, 1 1.16 mmol) in acetonitrile (80 mL) at 0 0 C was added concentrated acetic acid (8 mL) and concentrated hydrochloric acid (8 mL). To this solution was added sodium nitrite (0.92 g, 13.39 mmol) dissolved in water (1.25 mL) in a dropwise fashion. The resulting solution was stirred for 20 minutes, followed by bubbling in sulfur dioxide over 10 minutes.
  • Step 2 In an analogous manner to example 42, 4-fluoro-2-trifluoromethylbenzene sulfonyl chloride and 4-amino-piperidine-l-carboxylic acid tert-butyl ester were used to prepare /e/7-butyl 4-( ⁇ [4-fluoro-2-(trifluoromethyl)phenyl]sulfonyl ⁇ amino)piperidine-l - carboxylate.
  • HEMS calculated for Ci 5 H 2I F 3 N 2 O 2 S + H+, 351.13486; found (ESI, [M+H] + ), 351.1347;
  • N-[l-(2,4-difluorobenzoyl)piperidin-4-yl]-2-(trifluoromethyl)benzenesulfonamide (Example 40, 200 mg, 0.446 mmol) and N ( N-dimethylethylenediamine (d 0.807, 0.24 mL, 2.23 mmol) were combined in N,N-dimethylacetamide (1 mL) and heated at 200 0 C (microwave) for 20 minutes. The reaction mixture was taken up in ethyl acetate (20 mL) and washed with 1 N aqueous sodium hydroxide (20 mL), water (20 mL) and saturated brine (20 mL).
  • Example 90 ⁇ /-[l-(4-fluorobenzoyl)piperidin-4-yl]-2- (trifluoromethyl)benzenesulfonamide [0359] Starting from N-piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide hydrochloride (Example 37, Step 2) in place of 4-bromo-N-piperidin-4-yl-2- (trifiuoromethyl)benzenesulfonamide hydrochloride and 4-fluorobenzoyl chloride in place of 3-cyanobenzenesulfonyl chloride, N-[l-(4-fiuorobenzoyl)piperidin-4-yl]-2- (trifluoromethyl)benzenesulfonamide was synthesized in essentially the same manner as described in Example 32, Step 3. MS (ES) m/z 430.7 ([M+H] + ).
  • Example 93 3- ⁇ [4-( ⁇ [4-isopropyl-2-(trifluoromethyl)phenyl]suIfonyl ⁇ aniino)piperidiii-l- yl]sulfonyl ⁇ benzoir acid [0363]
  • 4-isopropyl-N-piperidin-4-yl-2- (trifluoromethyl)benzenesulfonaniide and 3-(chlorosulfonyl)benzoic acid were used to prepare 3- ⁇ [4-( ⁇ [4-isopropyl-2-(trifluoromethyl)phenyl]sulfonyl ⁇ amino)piperidin-l- yl]sulfonyl ⁇ benzoic acid.
  • Azidotrimethylsilane (d 0.876, 0.083 mL, 0.632 mmol) and trimethyl aluminum- toluene solution (2.0 M, 0.316 mL) were mixed briefly at 23 0 C and then added to a suspension of N- ⁇ l-[(3-cyanophenyl)sulfonyl]piperidin-4-yl ⁇ -2- (trifluoromethyl)benzenesulfonamide (Example 37, Step 3, 115 mg, 0.243 mmol) in dry toluene (0.20 mL) at 23 0 C. The mixture was heated at 80 0 C for 22 hours.
  • tert-butyl 4-( ⁇ [4-methoxy-2- (trifluoromethyl)phenyl]sulfonyl ⁇ amino)piperidine-l-carboxylate was used to prepare 4- methoxy-N-piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide.

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Abstract

La présente invention concerne des composés de formule (I) : [insérer ici la formule chimique telle qu'elle apparaît dans le résumé sur papier] et un sel pharmaceutiquement acceptable de ceux-ci, lesdits composés étant des modulateurs de la protéine 1 apparentée à une protéine Frizzled secrétée. Les composés et des compositions contenant les composés peuvent être utilisés pour traiter diverses maladies et affections dont l'ostéoporose, l'arthrite, la bronchopneumopathie chronique obstructive, les anomalies des cartilages, les fractures osseuses, le léiomyome, la leucémie myéloïde aiguë, la guérison des blessures, le cancer de la prostate, les troubles inflammatoires auto-immuns tels que l'ophtalmopathie de Graves et leurs combinaisons.
PCT/US2007/084285 2006-11-10 2007-11-09 Pipéridinyle 4-arylsulfonamides n-substitués utilisés comme modulateurs de la protéine 1 apparentée à une protéine frizzled secrétée WO2008061016A1 (fr)

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US8247442B2 (en) 2006-03-29 2012-08-21 Purdue Pharma L.P. Benzenesulfonamide compounds and their use
US8399486B2 (en) 2007-04-09 2013-03-19 Purdue Pharma L.P. Benzenesulfonyl compounds and the use thereof
US8765736B2 (en) 2007-09-28 2014-07-01 Purdue Pharma L.P. Benzenesulfonamide compounds and the use thereof
US8791264B2 (en) 2006-04-13 2014-07-29 Purdue Pharma L.P. Benzenesulfonamide compounds and their use as blockers of calcium channels
US8937181B2 (en) 2006-04-13 2015-01-20 Purdue Pharma L.P. Benzenesulfonamide compounds and the use thereof
US9000174B2 (en) 2004-10-14 2015-04-07 Purdue Pharma L.P. 4-phenylsulfonamidopiperidines as calcium channel blockers
JP2015078188A (ja) * 2008-10-09 2015-04-23 アメリカ合衆国 ヒトピルビン酸キナーゼ活性化剤
US9708267B2 (en) 2010-04-29 2017-07-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Activators of human pyruvate kinase
WO2020212581A1 (fr) 2019-04-18 2020-10-22 Modern Biosciences Limited Composés n-acyl-{4-[(4-aryl-phényl)sulfonylméthyl]pipéridine} et leur utilisation thérapeutique

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9000174B2 (en) 2004-10-14 2015-04-07 Purdue Pharma L.P. 4-phenylsulfonamidopiperidines as calcium channel blockers
US8247442B2 (en) 2006-03-29 2012-08-21 Purdue Pharma L.P. Benzenesulfonamide compounds and their use
US8791264B2 (en) 2006-04-13 2014-07-29 Purdue Pharma L.P. Benzenesulfonamide compounds and their use as blockers of calcium channels
US8937181B2 (en) 2006-04-13 2015-01-20 Purdue Pharma L.P. Benzenesulfonamide compounds and the use thereof
US8399486B2 (en) 2007-04-09 2013-03-19 Purdue Pharma L.P. Benzenesulfonyl compounds and the use thereof
US8765736B2 (en) 2007-09-28 2014-07-01 Purdue Pharma L.P. Benzenesulfonamide compounds and the use thereof
JP2015078188A (ja) * 2008-10-09 2015-04-23 アメリカ合衆国 ヒトピルビン酸キナーゼ活性化剤
US9707230B2 (en) 2008-10-09 2017-07-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Activators of human pyruvate kinase
US9708267B2 (en) 2010-04-29 2017-07-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Activators of human pyruvate kinase
WO2020212581A1 (fr) 2019-04-18 2020-10-22 Modern Biosciences Limited Composés n-acyl-{4-[(4-aryl-phényl)sulfonylméthyl]pipéridine} et leur utilisation thérapeutique
CN113766953A (zh) * 2019-04-18 2021-12-07 现代生物科学有限公司 N-酰基-{4-[(4-芳基-苯基)磺酰基甲基]哌啶}化合物及其治疗用途

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