WO2005060963A1 - Benzenesulfonylamino-pyridin-2-yl derivatives and related compounds as inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-hsd-1) for the treatment of diabetes and obesity - Google Patents

Benzenesulfonylamino-pyridin-2-yl derivatives and related compounds as inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-hsd-1) for the treatment of diabetes and obesity Download PDF

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Publication number
WO2005060963A1
WO2005060963A1 PCT/IB2004/004056 IB2004004056W WO2005060963A1 WO 2005060963 A1 WO2005060963 A1 WO 2005060963A1 IB 2004004056 W IB2004004056 W IB 2004004056W WO 2005060963 A1 WO2005060963 A1 WO 2005060963A1
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WIPO (PCT)
Prior art keywords
group
membered heterocyclyl
alkyl
aryl
independently selected
Prior art date
Application number
PCT/IB2004/004056
Other languages
French (fr)
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WO2005060963A8 (en
Inventor
Martin Paul Edwards
Theodore Otto Johnson, Jr.
Sajiv Krishnan Nair
Michael Siu
Wendy Dianne Taylor
Stephan James Cripps
Yong Wang
Hengmiao Cheng
Christopher Ronald Smith
Original Assignee
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority to EA200600990A priority Critical patent/EA200600990A1/en
Priority to MXPA06007077A priority patent/MXPA06007077A/en
Priority to CA002549651A priority patent/CA2549651A1/en
Priority to BRPI0417687-1A priority patent/BRPI0417687A/en
Priority to EP04801352A priority patent/EP1696915A1/en
Priority to AU2004305321A priority patent/AU2004305321A1/en
Priority to JP2006544581A priority patent/JP2007514731A/en
Priority to AP2006003633A priority patent/AP2006003633A0/en
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Publication of WO2005060963A1 publication Critical patent/WO2005060963A1/en
Publication of WO2005060963A8 publication Critical patent/WO2005060963A8/en
Priority to IS8473A priority patent/IS8473A/en
Priority to IL175949A priority patent/IL175949A0/en
Priority to TNP2006000185A priority patent/TNSN06185A1/en
Priority to NO20063298A priority patent/NO20063298L/en

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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme (11- ⁇ -hsd-1).
  • 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme 11- ⁇ -hsd-1.
  • 10 Background Of The Invention It has been known for more than half a century that glucocorticoids have a central role in diabetes. For example, the removal of the pituitary or the adrenal gland from a diabetic animal alleviates the most severe symptoms of diabetes and lowers the concentration of glucose in the blood (Long, C. D. and F.
  • the hepatic insulin sensitivity was improved in healthy human 20 volunteers treated with the non-specific 11- ⁇ -hsd-1 inhibitor carbenoxolone (Walker, B.R., et al. (1995) J. Clin. Endocrinol. Metab. 80: 3155-3159). Furthermore, the expected mechanism has been established by different experiments with mice and rats. These studies showed that the mRNA levels and activities of two key enzymes in hepatic glucose production were reduced, namely the rate-limiting enzyme in gluconeogenesis, phosphoenolpyruvate 25 carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase) catalyzing the last common step of gluconeogenesis and glycogenolysis.
  • PEPCK phosphoenolpyruvate 25 carboxykinase
  • G6Pase glucose-6-phosphatase
  • the present invention relates to a compound of formula (I):
  • R 1 N R 2 (") wherein: R 1 is selected from the group consisting of (Ct-Cejalkyl, -(CR 3 R 4 ) t (C 3 -C 12 )cycloalkyl,
  • b and k are each independently selected from 1 and 2; j is selected from the group consisting of 0, 1 , and 2; t, u, p, q, and v are each independently selected from the group consisting of 0, 1 , 2, 3, 4, and 5; T is a (6-10)-membered heterocyclyl containing at least one nitrogen atom; R 2 is selected from the group consisting of H, (C -C ⁇ Jalkyl, -(CR 3 R 4 C 3 -C ⁇ 2 )cycloalkyl, -(CR 3 R ),(C 6 -C ⁇ 2 )aryl, and -(CR 3 R ),(4-10)-membered heterocyclyl; each R 3 and R 4 is independently selected from H and (d-C 6 )alkyl; the carbon atoms of T, R 1
  • the invention relates to a compound according to formula (I), wherein b is 2.
  • the invention relates to a compound according to formula (I), wherein T is a 6-membered heterocyclyl containing at least one nitrogen atom.
  • the invention relates to a compound according to formula (I), wherein said T a (6-10)-membered heterocyclyl selected from the group consisting of
  • the invention relates to a compound according to formula
  • the invention relates to a compound according to formula , N ⁇ * (I), wherein T is r In an embodiment, the invention relates to a compound according to formula (I),
  • the invention relates to a compound according to formula (II):
  • R 1 is (d-C ⁇ Jalkyl, -(CR 7 R 8 ),(C 3 -C 10 )cycloalkyl, -(CR 7 R 8 ) t (C 6 -C 10 )aryl, or
  • each R 2 , R 3 , and R 4 are independently selected from the group consisting of H, (d-C 6 )alkyl, -(CR 7 R 8 ),(C 3 -C 10 )cycloalkyl, -(CR 7 R 8 ),(C 6 -C 10 )aryl, and -(CR 7 R 8 ) t (4-10)-membered heterocyclyl; each R 2 and R 3 may optionally be taken together with the nitrogen to which they are attached to form a (4-10)-membered heterocyclyl; each R 5 and R 6 are independently selected from the group consisting of H, (d-C 6 ) alkyl, -(CR 7 R 8 ),(C 3 -d 0 )cycloalkyl, -(CR 7 R 8 ),(C 6 -C 10 )aryl, and -(CR 7 R 8 ),(4-10)
  • the invention relates to a compound according to formula (II),
  • the invention relates to a compound according to formula (II), wherein W is a 5-membered heterocyclyl.
  • the invention relates to a compound according to formula (II), wherein said 5-membered heterocyclyl is selected from the group consisting of oxazolyl, thiazolyl, pyrazolyl, triazolyl, and oxadiazolyl.
  • the invention relates to a compound according to formula (II), wherein b is 2.
  • the invention relates to a compound according to formula (II), wherein T is a 6-membered heterocyclyl containing at least one nitrogen atom.
  • the invention relates to a compound according to formula (II), wherein said 6-membered heterocyclyl is selected from the group consisting of
  • the invention relates to a compound according to formula
  • each R 1 is phenyl or napthyl substituted by 1 to 5 R 9 groups; wherein: each R 9 is independently selected from the group consisting of halo, cyano, -CF 3 , hydroxy, (C ⁇ -C ⁇ )alkoxy.
  • the invention relates to a compound according to formula (II), wherein R 2 and R 3 are each independently selected from H and (d-C 6 )alkyl; wherein: said (Ci-C ⁇ ) alkyl is optionally substituted by (C 2 -C 6 ) alkenyl or -(CR 7 R 8 ),(C 3 -do)cycloalkyl.
  • the invention relates to a compound according to formula (II), wherein R 2 and R 3 are taken together with the nitrogen to which they are attached to form a (4-10)-membered heterocyclyl.
  • the invention relates to a compound according to fonnula (II), wherein said (4-10)-membered heterocyclyl is selected from the group consisting of:
  • the invention relates to a compound according to formula (II), wherein R 2 is (d-C 6 )alkyl. In an embodiment, the invention relates to a compound according to formula (II), wherein n is 0 and at least one of R 5 and R 6 is H. In another embodiment, the invention relates to a compound selected from the group consisting of:
  • An embodiment of the invention relates to a pharmaceutical composition comprising an effective amount of a compound according formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the invention relates to a method of treating a condition that is mediated by the modulation of 11- ⁇ -hsd-1, the method comprising administering to a mammal an effective amount of a compound according formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof.
  • the invention relates to a method of treating diabetes, metabolic syndrome, insulin resistance syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ, the method comprising administering to a mammal an effective amount of a compound according to formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties.
  • alkenyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above and including E and Z isomers of said alkenyl moiety.
  • alkynyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.
  • alkoxy as used herein, unless otherwise indicated, includes O-alkyl groups wherein alkyl is as defined above.
  • amino as used herein, is intended to include the -NH 2 radical, and any substitutions of the N atom.
  • halogen and halo, as used herein represent chlorine, fluorine, bromine or iodine.
  • trifluoromethyl as used herein, is meant to represent a -CF 3 group.
  • trifluoromethoxy as used herein, is meant to represent a -OCF 3 group.
  • cyano as used herein, is meant to represent a -CN group.
  • OMs as used herein, is intended to mean, unless otherwise indicated methanesulfonate.
  • Me as used herein, unless otherwise indicated, is intended to mean means methyl.
  • MeOH as used herein, unless otherwise indicated, is intended to mean means methanol.
  • Et as used herein, unless otherwise indicated, is intended to mean means ethyl.
  • Et 2 0 as used herein, unless otherwise indicated, is intended to mean means diethylether.
  • EtOH as used herein, unless otherwise indicated, is intended to mean means ethanol.
  • Et 3 N as used herein, unless otherwise indicated, is intended to mean means triethylamine.
  • EtOAc is ethyl acetate.
  • AIMe 2 CI as used herein, unless otherwise indicated, is intended to mean dimethyl aluminum chloride.
  • Ac as used herein, unless otherwise indicated, is intended to mean means acetyl.
  • TAA trifluoroacetic acid.
  • TEA triethanolamine.
  • HATU as used herein, unless otherwise indicated, is intended to mean ⁇ /, ⁇ /, ⁇ /' ⁇ /'-tetramethyluronium hexafluorophosphate.
  • THF tetrahydrofuran
  • TIOH thallium(l) hydroxide
  • TIOEt thallium(l) ethoxide
  • PCy 3 as used herein, is intended to mean tricyclohexylphosphine.
  • Pd 2 (dba) 3 is intended to mean tris(dibenzylideneacetone)dipalladium(0).
  • Pd(OAc) 2 is intended to mean palladium(ll) acetate.
  • Pd(PPh 3 ) 2 CI 2 is intended to mean dichlorobis(triphenylphosphine)palladium(ll).
  • Pd(PPh 3 ) 4 is intended to mean tetrakis(triphenylphophine)palladium(0).
  • Pd(dppf)CI 2 is intended to mean (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(ll), complex with dichloromethane (1:1).
  • G6P is intended to mean glucose-6-phosphate.
  • NIDDM is intended to mean non insulin dependent diabetes mellitus
  • NADPH is intended to mean nicotinamide adenine dinucleotide phosphate, reduced form.
  • CD 3 or CHLORFORM-D is intended to mean deuterochloroform.
  • CD 3 OD is intended to mean deuteromethanol.
  • CD 3 CN is intended to mean deuteroacetonitrile.
  • DEAD is intended to mean diethyl azodicarboxylate.
  • TsCH 2 NC is intended to mean tosylmethyl isocyanide.
  • CIS0 3 H is intended to mean chlorosulfonic acid.
  • DMSO-d 6 or DMSO-D 6 is intended to mean deuterodimethyl sulfoxide.
  • DME deuterodimethyl sulfoxide.
  • DMF di,2-dimethoxyethane.
  • DMF dimethylformamide.
  • DMSO dimethylsulfoxide.
  • Dl dimethylsulfoxide.
  • KOAc potassium acetate.
  • nitrogeneat as used herein, is meant to represent an absence of solvent.
  • the term “mmol” as used herein, is intended to mean millimole.
  • the term “equiv” as used herein, is intended to mean equivalent.
  • the term “mL” as used herein, is intended to mean milliliter.
  • the term “U” as used herein, is intended to mean units.
  • the term “mm” as used herein, is intended to mean millimeter.
  • the term “g” as used herein, is intended to mean gram.
  • the term “kg” as used herein, is intended to mean kilogram.
  • the term “h” as used herein, is intended to mean hour.
  • the term “min” as used herein, is intended to mean minute.
  • the term “ ⁇ L” as used herein, is intended to mean microliter.
  • ⁇ M micromolar.
  • ⁇ m as used herein, is intended to mean micrometer.
  • M as used herein, is intended to mean molar.
  • N as used herein, is intended to mean normal.
  • nm as used herein, is intended to mean nanometer.
  • nM as used herein, is intended to mean nanoMolar.
  • amu as used herein, is intended to mean atomic mass unit.
  • °C as used herein, is intended to mean Celsius.
  • m z as used herein, is intended to mean, unless otherwise indicated, mass/charge ratio.
  • wt/wt is intended to mean weight/weight.
  • v/v is intended to mean volume/volume.
  • mL/min is intended to mean milliliter/minute.
  • UV is intended to mean ultraviolet.
  • APCI-MS as used herein, is intended to mean atmospheric pressure chemical ionization mass spectroscopy.
  • HPLC as used herein, is intended to mean high performance liquid chromatograph.
  • LC as used herein, is intended to mean liquid chromatograph.
  • LCMS as used herein, is intended to mean liquid chromatography mass spectroscopy.
  • SFC supercritical fluid chromatography
  • sat as used herein, is intended to mean saturated.
  • aq as used herein, is intended to mean aqueous.
  • ELSD as used herein, is intended to mean evaporative light scattering detection.
  • MS as used herein, is intended to mean mass spectroscopy.
  • HRMS (ESI) as used herein, is intended to mean high resolution mass spectrometry (electrospray ionization).
  • Anaal as used herein, is intended to mean analytical.
  • Calcd as used herein, is intended to mean calculated.
  • NT as used herein, unless otherwise indicated, is intended to mean not tested.
  • NA as used herein, unless otherwise indicated, is intended to mean not tested.
  • RT as used herein, unless otherwise indicated, is intended to mean room temperature
  • Mth as used herein, unless otherwise indicated, is intended to mean Method
  • Ce te ® as used herein, unless otherwise indicated, is intended to mean a white solid diatomite filter agent commercially available from World Minerals located in Los Angeles, California USA
  • Eg as used herein, unless otherwise indicated, is intended to mean example Terms such as -(CR 3 R 4 ), or -(CR 10 R 11 ) V , for example, are used, R 3 , R 4 , R 10 and R 11 may vary with each iteration of t or v above 1 For instance, where t or v is 2 the terms - (CR 3 R ) V or -(CR 10 R 11 ), may equal -CH
  • cycloalkyl refers to a non- aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyc c or t ⁇ cyc c hydrocarbon referred to herein containing a total of from 3 to 10 carbon atoms, suitably 5-8 ring carbon atoms
  • exemplary cycloalkyls include rings having from 3-10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl
  • Illustrative examples of cycloalkyl are derived from, but not limited to, the following
  • aryl includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
  • (3-7)-membered heterocyclyl includes aromatic and non-aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 3-7, 6-10, or 4-10 atoms, respectively, in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • An example of a 3 membered heterocyclic group is aziridine, an example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine).
  • An example of a 5 membered heterocyclic group is thiazolyl, an example of a 7 membered ring is azepinyl, and an example of a 10 membered heterocyclic group is quinolinyl.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, di
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).
  • the 4-10 membered heterocyclic may be optionally substituted on any ring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring.
  • heterocyclic group wherein 2 ring carbon atoms are substituted with oxo moieties is 1,1-dioxo-thiomorpholinyl.
  • 4-10 membered heterocyclic are derived from, but not limited to, the following:
  • solvate is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound.
  • examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO (dimethylsulfoxide), ethyl acetate, acetic acid, or ethanolamine.
  • pharmaceutically acceptable salt(s) as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula (I) or formula (II).
  • the compounds of formula (I) or formula (II ) that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula (I) or formula (II) are those that form non-toxic acid addition salts, Le, salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochlor
  • liver is a target organ
  • diabetes hepatitis, liver cancer, liver fibrosis, and malaria.
  • Metabolic syndrome as used herein, unless otherwise indicated means psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases, galactosemia, maple syrup urine disease, phenylketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria, isovaleric acidemia, saccharopinuria, 4-hydroxybutyric aciduria, glucose-
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • modulate refers to the ability of a modulator for a member of the steroid/thyroid superfamily to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.
  • modulator refers to the ability of a modulator for a member of the steroid/thyroid superfamily to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.
  • hormone expression control or to repress expression of gene(s) maintained under such control.
  • “obese” is defined, for males, as individuals whose body mass index is greater than 27.8 kg/ m 2 , and for females, as individuals whose body mass index is greater than 27.3 kg/m 2 .
  • the invention method is not limited to those who fall within the above criteria. Indeed, the method of the invention can also be advantageously practiced by individuals who fall outside of these traditional criteria, for example, by those who may be prone to obesity.
  • inflammatory disorders refers to disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibromyalgia, and cachexia.
  • therapeutically effective amount refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 1 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically labeled compounds of fo ⁇ nula (I) or formula (II) of this invention thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compound of formula la may be prepared by reacting a compound of formula Ic, wherein the group C0 2 R 23 is an ester group such as methyl ester (C0 2 -CH 3 ) or ethyl ester (C0 2 -CH 2 CH 3 ), with aluminum amides (Me 2 AI-NR 2 R 3 ) or (MeAI(CI)-NR 2 R 3 ) in a suitable solvent (e.g. dichloromethane or toluene) advantageously, from room temperature to the boiling point of the solvent, typically from about 20 degrees Celsius to about 100 degrees Celsius.
  • a suitable solvent e.g. dichloromethane or toluene
  • the compound of formula la may also be prepared by reacting a compound of formula Ic, wherein the group C0 2 R 23 is a carboxylic acid (C0 2 H) with an amine of formula HNR 2 R 3 using standard amide coupling chemistry.
  • Compounds of formula Ic may be prepared by reacting a compound of formula lla, wherein the group C0 2 R 23 is an ester group such as methyl ester (C0 2 -CH 3 ) or ethyl ester (C0 2 -CH 2 CH 3 ), with a R 1 - sulfonyl halide or R 1 -sulfinyl halide.
  • the compound of formula la may be prepared by reacting a compound of formula Id with a R 1 -sulfonyl halide or R 1 -sulfinyl halide.
  • Compounds of formula Id may be prepared by reacting a compound of formula lla, wherein the group C0 2 R 23 is an ester group such as methyl ester (C0 2 -CH 3 ) or ethyl ester (C0 2 - CH 2 CH 3 ), with aluminum amides (Me 2 AI-NR 2 R 3 ) or (MeAI(CI)-NR 2 R 3 ) in a suitable solvent (e.g. dichloromethane or toluene) at a temperature from room temperature to the boiling point of the solvent, typically from about 20 degrees Celsius to about 100 degrees Celsius.
  • a suitable solvent e.g. dichloromethane or toluene
  • the compound of formula lb may be obtained by cyclodehydration of suitable amide la.
  • the compound of formula A may be prepared by reacting B with an R 1 -sulfonyl halide, R 1 -sulfinyl halide, or R 1 -sulfinate in the presence of a base such as an amine.
  • a base such as an amine.
  • bases include pyridine, triethylamine, and diisopropylethylamine.
  • Suitable solvents include pyridine, dichloromethane, or THF.
  • the aforementioned reaction can be conducted at room temperature or heated for an appropriate time period, such as 2 to 16 hours, depending on the solvent system used. After the reaction is substantially completed, the base may be removed in vacuo and the resulting residue may be purified using conventional purification techniques.
  • R 1 is a non-fused ring system of more than one ring of either an aryl or heterocyclyl.
  • the compound of formula A3 may be prepared by a palladium-catalyzed coupling reaction of A2 where X is a halo or trifluoromethylsulfonyl with a reagent Y-N where Y is aryl or heterocyclyl, N is boronic acid, boronate ester, stannane, or zincate.
  • Suitable palladium sources for this reaction include Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , Pd(PPh 3 ) 2 CI 2 or Pd(OAc) 2 .
  • Ligands such as diphenylphosphinoethane, diphenylphosphinoferrocene, or triphenylphosphine may also be added.
  • Suitable solvents for the palladium-catalyzed coupling reaction include dimethylformamide, tetrahydrofuran, or toluene.
  • the aforementioned reaction can be conducted at a temperature of about 50 °C to about 150 °C with or without microwave heating for a time period of about 15 min to about 16 hours.
  • base additives such as Na 2 C0 3 , Cs 2 C0 3 , TIOH, TIOEt may be added.
  • base additives such as Na 2 C0 3 , Cs 2 C0 3 , TIOH, TIOEt may be added.
  • Any of the above compounds of formula la, lb, Ic, Id, lla, A, B, A2, and A3 can be converted into another analogous compound by standard chemical manipulations. All starting materials, regents, and solvents are commercially available and are known to those of skill in the art unless otherwise stated. These chemical manipulations are known to those skilled in the art and include (a) removal of a protecting group by methods outlined in T. W. Greene and P.G.M.
  • the compounds of the present invention may have asymmetric carbon atoms.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.
  • the compounds of formula (I) or formula (II) that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula (I) or formula (II) from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol.
  • the desired solid salt is readily obtained.
  • the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
  • Those compounds of formula (I) or formula (II) that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula (I) or formula (II).
  • Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium, and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
  • the compounds of the present invention may be modulators of 11- ⁇ -hsd-1.
  • the compounds of the present invention may modulate processes mediated by 11- ⁇ -hsd-1 , which refer to biological, physiological, endocrinological, and other bodily processes which are mediated by receptor or receptor combinations which are responsive to the 11- ⁇ -hsd-1 inhibitors described herein (e.g., diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts and coronary artery diseases and the like), arteriosclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (e.g.
  • ischemic heart disease and the like cell injury (e.g.) brain injury induced by strokes and the like) induced by atherosclerosis or ischemic heart disease, gout, inflammatory diseases (e.g. arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergosis, asthma, Gl ulcer, cachexia, autoimmune diseases, pancreatitis and the like), cancer, osteoporosis and cataracts. Modulation of such processes can be accomplished in vitro or in vivo.
  • inflammatory diseases e.g. arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergosis, asthma, Gl ulcer, cachexia, autoimmune diseases, pancreatitis and the like
  • cancer osteoporosis and cataracts.
  • In vivo modulation can be carried out in a wide range of subjects, such as, for example, humans, rodents, sheep, pigs, cows, and the like.
  • the compounds according to the present invention may be used in several indications which involve modulations of 11- ⁇ -hsd-1 enzyme.
  • the compounds according to the present invention may be used against dementia (See WO97/07789), osteoporosis (See Canalis E 1996, "Mechanisms of Glucocorticoid Action in Bone: Implications to Glucocorticoid-lnduced Osteoporosis", Journal of Clinical Endocrinology and Metabolism, 81 , 3441-3447) and may also be used disorders in the immune system (see Franchimont, et.
  • 11 - ⁇ -hsd-1 is suggested to have a role in aqueous production, rather than drainage, but it is presently unknown if this is by interfering with activation of the glucocorticoid or the mineralocorticoid receptor, or both.
  • Bile acids inhibit 11- ⁇ -hydroxysteroid dehydrogenase type 2. This results in a shift in the overall body balance in favor of cortisol over cortisone, as shown by studying the ratio of the urinary metabolites (Quattropani C, Vogt B, Odermatt A, Dick B, Frey B M, Frey F J. 2001. J Clin Invest. Nov; 108(9): 1299-305.
  • the compounds of the present invention may also be useful in the treatment of other metabolic disorders associated with impaired glucose utilization and insulin resistance include major late-stage complications of NIDDM, such as diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation and glaucoma, and many other conditions linked to NIDDM, including dyslipidemia glucocorticoid induced insulin resistance, dyslipidemia, polycysitic ovarian syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesteremia, hypertriglyceridemia, hyperinsulinemia, and hypertension. Brief definitions of these conditions are available in any medical dictionary, for instance, Stedman's Medical Dictionary (10 th Ed.).
  • the 11 ⁇ -hsd-1 assay was performed in a 100mM Triethanolamine buffer pH 8.0, containing 200mM NaCI, 0.02% n-dodecyl ⁇ -D-maltoside, 5% glycerol, 5mM ⁇ - mercaptoethanol.
  • a typical reaction for the determination of Kj app values was carried at R.T. in a Corning ® u-bottom 96-well plate and is described as follows: 11 ⁇ -hsd-1 enzyme (5 nM, final concentration) was pre-incubated in the presence of the inhibitor and NADPH (500 ⁇ M, final concentration) for at least 30 minutes in the assay buffer.
  • the reaction was initiated by adding the regenerating system (2m M Glucose-6- Phosphate, 1U/mL Glucose-6-Phosphate dehydrogenase, and 6mM MgCI 2, all the concentration reported are final in the assay buffer), and 3H-cortisone (200 nM, final concentration). After 60 minutes, 60 ⁇ L of the assay mixture was transferred to a second 96- well plate and mixed with an equal volume of dimethylsulfoxide to stop the reaction.
  • the regenerating system 2m M Glucose-6- Phosphate, 1U/mL Glucose-6-Phosphate dehydrogenase, and 6mM MgCI 2, all the concentration reported are final in the assay buffer
  • 3H-cortisone 200 nM, final concentration
  • a 15 ⁇ L aliquot from the reaction mixture was loaded into a C-18 column (Polaris C18-A, 50 x 4.6mm, 5 ⁇ , 180 Angstrom from Varian) connected to an automated High-throughput Liquid Chromatography instrument developed by Cohesive Technologies, commercially available from Franklin, Massachusetts USA, with a ⁇ -RAM model 3 Radio-HPLC detector from IN/US, commercially available from Tampa, Florida USA.
  • the substrate and product peaks were separated by using an isocratic mixture of 43:57 methanol to water (v/v) at a flow rate of LOmUmin.
  • the initial reaction velocities were measured by stopping the reaction at 60 min and by measuring the area of product formation in the absence and the presence of various concentrations of inhibitors.
  • the K, a pp values were determined using the equation for tight- binding inhibitor developed by Morrison, JF. (Morrison JF. Biochim Biophys Acta. 1969; 185- 269-86).
  • the radiolabeled [1 ,2-3H]-cortisone is commercially available from American
  • the a pp values of the compounds of the present invention for the 11 - ⁇ -hsd-1 enzyme may lie typically between about 10 nM and about 10 ⁇ M.
  • the compounds of the present invention that were tested all have K a pp's in at least one of the above SPA assays of less than 1 ⁇ M, preferably less than 100 nM. Certain preferred groups of compounds possess differential selectivity toward the various 11- ⁇ -hsd's.
  • One group of preferred compounds possesses selective activity towards 11- ⁇ -hsd-1 over 11 ⁇ -hsd-2.
  • Another preferred group of compounds possesses selective activity towards 11 ⁇ hsd-2 over 11- ⁇ -hsd- 1. (Morrison JF. Biochim Biophys Acta. 1969; 185: 269-86). Percentage of inhibition was determined in a 100mM Triethanolamine buffer, pH 8.0, 200mM NaCI, 0.02% n-dodecyl ⁇ -D-maltoside and 5mM ⁇ -ME.
  • a typical reaction was carried on a Coming ® u-bottom 96-well plate and is described as follows: 11 ⁇ -hsd-1 enzyme (5 nM, final concentration) was pre-incubated in the presence of the inhibitor and NADPH (500 ⁇ M, final concentration) for at least 30 minutes in the assay buffer.
  • the reaction was initiated by adding the regenerating system (2mM Glucose-6- Phosphate, 1U/mL Glucose-6-Phosphate dehydrogenase, and 6mM MgCI 2 all the concentration reported are final in the assay buffer), and 3H-cort ⁇ sone (200 nM, final concentration)
  • 60 ⁇ L of the assay mixture was transferred to a second 96- well plate and mixed with an equal volume of dimethylsulfoxide to stop the reaction
  • a 15 ⁇ L aliquot from the reaction mixture was loaded into a C-18 column (Polaris C18-A, 50 x 4 6mm, 5 ⁇ , 180 Angstrom from Varian) connected to an automated High-throughput Liquid Chromatography instrument developed by Cohesive Technologies commercially available from Franklin, Massachusetts, with a ⁇ -RAM model 3 Radio-HPLC detector from IN/US commercially available from Tampa, Florida
  • the substrate and product peaks were separated by using an isocratic mixture
  • Percent Inhibition was calculated based on the following equation (100 - (3H-Cort ⁇ sol peak area with ⁇ nh ⁇ b ⁇ tor/3Hcort ⁇ sol peak area without inhibitor) x 100) Certain groups of compounds possess differential selectivity toward the various 11- ⁇ -hsd enzymes One group of compounds possesses selective activity towards 11 - ⁇ -hsd-1 enzyme over 11 ⁇ -hsd-2 enzyme While another group of compounds possesses selective activity towards 11 ⁇ hsd-2 enzymes over 11 - ⁇ -hsd-1 enzymes [1 ,2-3H]-cort ⁇ so ⁇ e is commercially available from American Radiolabeled Chemicals Inc of St Louis, Missouri USA NADPH while Glucose-6-Phosphate and Glucose-6- Phosphate dehydrogenase was purchased from Sigma ® Pharmaceutical Compositions/Formulations.
  • Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions normally contain active ingredients in admixture with excipients suitable for the manufacture of an aqueous suspension.
  • Such excipients may be a suspending agent, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; a dispersing or wetting agent that may be a naturally occurring phosphatide such as lecithin, a condensation product of ethylene oxide and a long chain fatty acid, for example polyoxyethylene stearate, a condensation product of ethylene oxide and a long chain aliphatic alcohol such as heptadecaethylenoxycetanol, a condensation product of ethylene oxide and a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate or a fatty acid hexitol anhydrides such as polyoxyethylene sorbitan monooleate.
  • a suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to know methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation may also be formulated as a suspension in a non toxic perenterally-acceptable diluent or solvent, for example as a solution in 1 ,3- butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringers solution and isotonic sodium chloride solution.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of formula (I) or formula (II) may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at about 25 Celsius but liquid at rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritating excipient that is solid at about 25 Celsius but liquid at rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials include cocoa butter and other glycerides.
  • topical use preparations for example, creams, ointments, jellies solutions, or suspensions, containing the compounds of the present invention are employed.
  • the compounds of formula (I) or formula (II) may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multimellar vesicles.
  • Liposomes can be formed from a variety of phospholipides, such as cholesterol, stearylamine or phosphatidylcholines.
  • Dosage levels of the compounds of the present invention are of the order of about 0.5 mg/kg body weight to about 100 mg/kg body weight.
  • a preferred dosage rate is between about 30 mg/kg body weight to about 100 mg/kg body weight.
  • Example 27 /V-Adama ⁇ tan-1-yl-2-[6-(3-chloro-2-methyl-benzenesulfonylamino)- pyridin-2-yl]-acetamide
  • Reactant A Reactant B 1 equiv 1 equiv A stir bar, the amine ⁇ Reactant B, 400 ⁇ L, 80 ⁇ mol, 1.00 equiv 0.2 M in anhydrous DMF), [6-(3-chloro-2-methyl-benzenesulfonylamino)-pyridin-2-yl]-acetic acid (Reactant A
  • HATU 160 ⁇ L, 80 ⁇ mol, 1.00 equiv 0.5 M in anhydrous DMF
  • 10 x 75 mm test tube The tube was sealed with cellophane and the reaction stirred for 16 h at ambient temperature.
  • the solvent was evaporated and the residue dissolved in DMSO containing 0.01 % BHT to yield a 0.05 M solution.
  • the solution was injected into an automated HPLC system for purification.
  • the solvent of the product containing fraction was evaporated, the residue dissolved in DMSO, analyzed, and submitted for screening.
  • the resulting residue was purified with radial chromatography (2 mm silica plate, 2:1 hexanes / ethyl acetate) to yield a clear oil.
  • the product was converted to a HCI salt by dissolving in 5 mL diethyl ether and adding 1 HCI in diethyl ether dropwise. The solid was triturated with additional ether and dried on high vacuum to afford the product (0.11 g, 29.5%).
  • 4'-Cya ⁇ o-biphenyl-4-sulfonic acid (6-cyclopropyl-pyridin-2-yl)-amide
  • 4'-cyano-biphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 6-cyclopropyl-pyridin-2-ylamine and making non-critical variations.
  • Example 115 5-Chloro-3-rnethyl-benzo[b]thiophene-2-sulfonic acid [6-(2-hydroxy- ethyl)-pyridin-2-yl]-amide Lithium aluminum hydride (0.015 g, 0.310 mmol, 1.3 equiv) was added in one portion to an ice-cooled solution of [6-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonylamino)-pyridin- 2-yl]-acetic acid ethyl ester (0.100 g, 0.235 mmol, 1 equiv) in tetrahydrofuran (4 mL).
  • reaction mixture was warmed to 24 °C for 16 h.
  • the reaction mixture was cooled to 0 °C, and excess lithium aluminum hydride was quenched with saturated aqueous ammonium chloride solution (10 mL).
  • the resulting solution was warmed to 24 °C and stirred for an additional 30 min.
  • the reaction mixture was filtered through a plug of Celite ® , and the resulting filtrate was extracted with dichloromethane (60 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by high performance flash chromatography (0 ⁇ 1% methanol in dichloromethane) yielded product (0.0421 g, 47%).
  • reaction mixtures were heated in a Personal Chemistry Microwave Synthesizer (SmithCreatorTM) for 15 min at 130 °C (energy-control setting for a high absorbing sample).
  • the septum caps were removed and the reaction mixture was transferred into a 13x100 mm test tube while leaving any solid material behind.
  • the microwave tubes were washed with DMF (1 mL) and the DMF was added to the receiving test tube. Next, the solvent was evaporated (SpeedVac, vaccum, medium heating, 16 h).
  • 6-(4-Cyano-phenyl)-pyridi ⁇ e-3-sulfonic acid 6-methyl-pyridin-2-yl)-amide
  • 6-chloro-pyridine-3-sulfonic acid 6-methyl-pyridin-2-yl)-amide
  • 4-cyanoboronic acid 88 mg, 0.602 mmol
  • Pd(PPh 3 ) 33 mg, 0.03 mmol
  • aqueous Na 2 C0 3 (0.72 mL, 1.43 mmol
  • 6-(4-Cyano-phenyl)-pyridine-3-sulfonic acid quinolin-2-ylamide 148 mg, 0.46 mmol
  • 4-cyanophenylboronic acid 136 mg, 0.92 mmol
  • DME 1.5 mL
  • N,N- dimethylacetamide 2.0 mL
  • H 2 0 0.5 mL
  • Cs C0 3 451 mg, 1.39 mmol
  • 6-(4-Cyano-phenyl)-pyridine-3-sulfonic acid (6-cyclopropyl-pyridin-2-yl)-amide
  • 6-chloro-pyridine-3-sulfonic acid (6- cyclopropyl-pyridin-2-yl)-amide and 4-cyanophenyl boronic acid and making non-critical variations.
  • Example 317 4-(4-Cyano-phenyl)-piperidine-1 -sulfonic acid (6-amino-pyridin-2-yl)- amide

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Abstract

The present invention relates to compounds with the formula (I), or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of (C1-C6)alkyl, -(CR3R4)t(C3-C12)cycloalkyl, -(CR3R4)t(C6-C12)aryl, and -(CR3R4)t(4-10)-membered heterocyclyl; b and k are each independently selected from 1 and 2; j is selected from the group consisting of 0, 1, and 2; t, u, p, q, and v are each independently selected from the group consisting of 0, 1, 2, 3, 4, and 5; T is a (6-10)-membered heterocyclyl containing at least one nitrogen atom; R2 is selected from the group consisting of H, (C1-C6)alkyl, -(CR3R4)t(C3-C12)cycloalkyl, -(CR3R4)t(C6-C12)aryl, and -(CR3R4)t(4-10)-membered heterocyclyl; each R3 and R4 is independently selected from H and (C1-C6)alkyl, the carbon atoms of T, R1, R2, R3 and R4 may each be optionally, substituted by I to 5 R5 groups; R5 is defined in the claims; The compounds of the present invention are 11 ß-hsd-1 inhibitors, and are therefore believed to be useful in the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, depression, hypertension, and metabolic diseases.

Description

BENZENESULF0NY AMIN0-PYRIDIN-2-YL DERIVATIVES AND RELATED COMPOUNDS AS
INHIBITORS OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1 (11-BETA-HSD-l ) FOR THE TREATMENT OF DIABETES AND OBESITY
This application claims the benefit of US Application Serial Number 60/531,186 filed December 19, 2003 and US Application Serial Number 60/556,921 filed March 26, 2004. 5 Field Of The Invention The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11-β-hydroxysteroid dehydrogenase type 1 enzyme (11-β-hsd-1). 10 Background Of The Invention It has been known for more than half a century that glucocorticoids have a central role in diabetes. For example, the removal of the pituitary or the adrenal gland from a diabetic animal alleviates the most severe symptoms of diabetes and lowers the concentration of glucose in the blood (Long, C. D. and F. D. W. Leukins (1936) J. Exp. Med. 63: 465-490; 15 Houssay, B. A. (1942) Endocrinology 30: 884-892). Additionally, it is also well established that glucocorticoids enable the effect of glucagon on the liver. The role of 11-β-hsd-1 as an important regulator of local glucocorticoid effects and thus of hepatic glucose production is well substantiated (see e.g. Jamieson et al. (2000) J. Endocrinol. 165: p. 685-692). The hepatic insulin sensitivity was improved in healthy human 20 volunteers treated with the non-specific 11-β-hsd-1 inhibitor carbenoxolone (Walker, B.R., et al. (1995) J. Clin. Endocrinol. Metab. 80: 3155-3159). Furthermore, the expected mechanism has been established by different experiments with mice and rats. These studies showed that the mRNA levels and activities of two key enzymes in hepatic glucose production were reduced, namely the rate-limiting enzyme in gluconeogenesis, phosphoenolpyruvate 25 carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase) catalyzing the last common step of gluconeogenesis and glycogenolysis. Finally, the blood glucose level and hepatic glucose production was reduced in mice having the 11-β-hsd-1 gene knocked-out. Data from this model also confirms that inhibition of 11-β-hsd-1 will not cause hypoglycemia, as predicted, since the basal levels of PEPCK and G6Pase are regulated independently of 30 glucocorticoids (Kotelevtsev, Y., et al., (1997) Proc. Natl. Acad. Sci. USA 94: 14924-14929). Abdominal obesity is closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and other factors of the so-called Metabolic Syndrome (e.g. raised blood pressure, decreased levels of HDL and increased levels of VLDL) (Montague & O'Rahilly, Diabetes 49: 883-888, 2000). Obesity is an important factor in Metabolic Syndrome as well as 35 in the majority (>80%) of type 2 diabetic, and omental fat appears to be of central importance. Inhibition of the enzyme in pre-adipocytes (stromal cells) has been shown to decrease the rate of differentiation into adipocytes. This is predicted to result in diminished expansion (possibly reduction) of the omental fat depot, i.e. reduced central obesity (Bujalska, I.J., Kumar, S., and Stewart, P.M. (1997) Lancet 349: 1210-1213). The compounds of the present invention are 11 β-hsd-1 inhibitors, and are therefore believed to be useful in the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, depression, hypertension, and metabolic diseases.
Summary of The Invention
The present invention relates to a compound of formula (I):
R1 N R2 (") wherein: R1 is selected from the group consisting of (Ct-Cejalkyl, -(CR3R4)t(C3-C12)cycloalkyl,
-(CR3R4),(C6-Cι2)aryl, and -(CR3R ),(4-10)-membered heterocyclyl; b and k are each independently selected from 1 and 2; j is selected from the group consisting of 0, 1 , and 2; t, u, p, q, and v are each independently selected from the group consisting of 0, 1 , 2, 3, 4, and 5; T is a (6-10)-membered heterocyclyl containing at least one nitrogen atom; R2 is selected from the group consisting of H, (C -CβJalkyl, -(CR3R4 C3-Cι2)cycloalkyl, -(CR3R ),(C6-Cι2)aryl, and -(CR3R ),(4-10)-membered heterocyclyl; each R3 and R4 is independently selected from H and (d-C6)alkyl; the carbon atoms of T, R1, R2, R3 and R4 may each be optionally substituted by 1 to 5 R5 groups; each R5 group is independently selected from the group consisting of halo, cyano, nitro, -CF3, -CHF2, -CH2F, trifluoromethoxy, azido, hydroxy, (Cι-C6)alkoxy, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(C=0)-R6, -(C=0)-0-R6, -0-(C=0)-R7, -0-(C=0)-NR7 ,
-NR8(C=0)-R9, -(C=0)-NR8R9, -NR8R9, -NR8OR9, -S(0)kNR8R9, -S(0),(Cι-Cβ)alkyl, -0-S02-R9, -NR8-S(0)k -R9, -(CR10R11)V(C6-C12 aryl), -(CR10R11)v(4-10)-membered heterocyclyl, -(CR10R11)q(C=O)(CR10R11)v(C6-C12)aryl, -(CR10R11)q(C=O)(CR10R11)v(4-10)-membered heterocyclyl, -(CR10R11)vO(CR10R11)q(C6-C12)aryl, -(CR10R11)vO(CR10R11)q(4-10)-membered heterocyclyl, -(CR 0R11)qS(O)j (CR10R11)V(C6-C12)aryl, and -(CR10R11)qS(O), (CR10R11)v(4-10)-membered heterocyclyl; any 1 or 2 carbon atoms of any (4-10)-membered heterocyclyl of the foregoing R6 groups are optionally substituted with an oxo (=0); any carbon atom of any (Cι-C6)alkyl, any (C6-Cι2)aryl, and any (4-10)-membered heterocyclyl of the foregoing R5 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, -CF3, -CFH2, -CF2H, trifluoromethoxy, azido, -OR12, -(C=0)-R12, -(C=0)-0-R13, -O-(C=0)-R13, -NR13(C=0)-R14, -(C=0)-NR15R16, -NR17R18, -NR14OR15, (CrCe)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(CR16R17)U(C6-C12)aryl, and -(CR16R17)u(4-10)-membered heterocyclyl; each R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 , R16 and R17 group is independently selected from the group consisting of H, (Cι-C6)alkyl, -(C=0)N(C1-C6)alkyl, -(CR18R19)P(C6-C12)aryl, and -(CR18R19)p(4-10)-membered heterocyclyl; any 1 or 2 carbon atoms of the (4-10)-membered heterocyclyl of each said R6, R7, R8,
R9, R10, R11, R12, R13, R14, R15, R16, R17 group is optionally substituted with an oxo (=0); any carbon atom of any (Cι-C6)alkyl, any (C6-C12)aryl, and any (4-10)-membered heterocyclyl of the foregoing R6, R7, R8, R9, R10, R11, R12, R 3, R14, R15, R16, R17 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, -NR^R22, -CF3, -CHF2, -CH2F, trifluoromethoxy, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, and (C- Ce) alkoxy; each R18, R19, R20, R21 and R22 group is independently selected from H and (C,-C6)alkyl; and wherein any of the above-mentioned substituents comprising a -CH3 (methyl), -CH2 (methylene), or -CH (methine) group which is not attached to a halo, -SO or -S02 group or to a N, O or S atom optionally bears on said group a substituent independently selected from the group consisting of hydroxy, halo, (CrC6)alkyl, (Cι-C6)alkoxy, -NH2, -NH(CrC6)(alkyl) and -N((C C6)(alkyl))2; or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, the invention relates to a compound according to formula (I), wherein b is 2. In yet another embodiment, the invention relates to a compound according to formula (I), wherein T is a 6-membered heterocyclyl containing at least one nitrogen atom. In an embodiment, the invention relates to a compound according to formula (I), wherein said T a (6-10)-membered heterocyclyl selected from the group consisting of
Figure imgf000004_0001
In yet another embodiment, the invention relates to a compound according to formula
(I) wherein T is
Figure imgf000004_0002
In yet another embodiment, the invention relates to a compound according to formula , N^ι * (I), wherein T is r In an embodiment, the invention relates to a compound according to formula (I),
wherein T is ,X In another embodiment, the invention relates to a compound according to formula (I), wherein each R1 is selected from the group consisting of phenyl, biphenyl, benzothiophenyl, and napthyl and may optionally be substituted by 1 to 5 R6 groups; wherein: each R6 group is independently selected from the group consisting of halo, cyano, -CF3, hydroxy, (d-C6)alkoxy, (d-C6)alkyl, (C2-C6)alkenyl, -(CR10R11)p(4-10)-membered heterocyclyl, -(C=0)-R6, -(C=0)-0-R6, -0-(C=0)-R7, -NR8(C=0)-R9, -(C=0)-NR8R9, -NR8R9, -NR8OR9, -(CR10R11)-O-(CR10R11)p(C6-C12)aryl, and
-(CR10R11)p-O-(CR10R11)p(4-10)-membered heterocyclyl. The invention relates to a compound according to formula (II):
Figure imgf000005_0001
wherein: R1 is (d-CβJalkyl, -(CR7R8),(C3-C10)cycloalkyl, -(CR7R8)t(C6-C10)aryl, or
-(CR7R8)t(4-10)-membered heterocyclyl; b and k are each independently selected from 1 and 2; n and j are each independently selected from the group consisting of 0, 1, and 2; t, u, p, q and v are each independently selected from the group consisting of 0, 1, 2, 3, 4, and 5; T is a (6-10)-membered heterocyclyl containing at least one nitrogen atom; W is selected from the group consisting of:
Figure imgf000005_0002
R2; (Ci -Cβ) alkyl; and a 5-membered heterocyclyl; each R2, R3, and R4are independently selected from the group consisting of H, (d-C6)alkyl, -(CR7R8),(C3-C10)cycloalkyl, -(CR7R8),(C6-C10)aryl, and -(CR7R8)t(4-10)-membered heterocyclyl; each R2 and R3 may optionally be taken together with the nitrogen to which they are attached to form a (4-10)-membered heterocyclyl; each R5 and R6 are independently selected from the group consisting of H, (d-C6) alkyl, -(CR7R8),(C3-d0)cycloalkyl, -(CR7R8),(C6-C10)aryl, and -(CR7R8),(4-10)-membered heterocyclyl; or R5 and R8 may optionally be taken together with the carbon to which they are attached to form a (C3-C6)cycloalkyl or a (3-7)-membered heterocyclyl; each R7 and R8 are independently selected from H and (d-C6)alkyl; the carbon atoms of T, R1, R2, R3, R , R5, R6, R7, R8 , and said W 5-membered heterocyclyl are optionally substituted by 1 to 5 R9 groups; each R9 group is independently selected from the group consisting of halo, cyano, nitro, -CF3, -CHF2, -CH2F, trifluoromethoxy, azido, hydroxy, (d-C6)alkoxy, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(C=0)-R10, -(C=0)-0-R11, -0-(C=0)-R11, -NR11(C=0)-R12, - (C=0)-NR11R12, -NR11R12, -NR11OR12, -S(0)kNR11R12, -S(0)j(d-C6)alkyl, -0-S02-R10, -NR11-S(0)k -R12,
Figure imgf000006_0001
aryl), -(CR13R14)v(4-10)-membered heterocyclyl, -(CR13R14)q(C=0)(CR13R14)v(C6-do)aryl, -(CR13R14)q(C=O)(CR13R14)v(4-10)-membered heterocyclyl, -(CR13R1 )vO(CR13R14)q(C6-C10)aryl, -(CR13R14)vO(CR13R14)q(4-10)-membered heterocyclyl, -(CR13R1 )qS(0)j(CR13R14)v(C6-C1o)aryl, and -(CR13R1 )qS(O)J(CR13R1 )ϊ(4-10)-membered heterocyclyl; any 1 or 2 carbon atoms of any (4-10)-membered heterocyclyl of the foregoing R9 groups are optionally substituted with an oxo (=0); any carbon atom of any (d-C6)alkyl, any (C6-d0)aryl and any (4-10)-membered heterocyclyl of the foregoing R9 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, -CF3, -CFH2, -CF2H, trifluoromethoxy, azido, -OR15, -(C=0)-R15, -(C=0)-0-R15, -0-(C=0)-R15, -NR15(C=0)-R16, -(C=0)-NR15R16, -NR15R16, -NR15OR16, (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(CR17R18)U(C6-C10)aryl, and -(CR17R18)u(4-10)-membered heterocyclyl; each R10, R11, R12, R13, R14, R15, R16, R17, and R18 group is independently selected from the group consisting of H, (d-C6)alkyl, -(CR19R20)p(C6-do)aryi, and -(CR19R2°)P(4-10)- membered heterocyclyl; any 1 or 2 carbon atoms of the (4-10)-membered heterocyclyl of said each R10, R11,
R12, R13, R14, R15, R16, R17, and R18 group is optionally substituted with an oxo (=0); any carbon atom of any (d-C6)alkyl, any (C6-d.)aryl and any (4-10)-membered heterocyclyl of the foregoing R10, R11, R12, R13, R14, R15, R16, R17, and R18 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, -NR 1R22, -CF3, -CHF2, -CH2F, trifluoromethoxy, (d-Cβ)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, and (CrC6) alkoxy; each R19, R20, R21, and R22 group is independently selected from H and (d-C6)alkyl; and wherein any of the above-mentioned substituents comprising a -CH3 (methyl), -CH2 (methylene), or -CH (methine) group which is not attached to a halo, -SO or -S02 group or to a N, O or S atom optionally bears on said group a substituent independently hydroxy, halo, (d-C6)alkyl, (d-C6)alkoxy, amino, -NH(d-C6)(alkyl) or -N(Cι-C6)(alkyl)(CrC6) alkyl; or a pharmaceutically acceptable salt or solvate thereof. In an embodiment, the invention relates to a compound according to formula (II), o wherein W is A,
In another embodiment, the invention relates to a compound according to formula (II),
wherein W is
Figure imgf000007_0001
In yet another embodiment, the invention relates to a compound according to formula (II), wherein W is a 5-membered heterocyclyl. In yet another embodiment, the invention relates to a compound according to formula (II), wherein said 5-membered heterocyclyl is selected from the group consisting of oxazolyl, thiazolyl, pyrazolyl, triazolyl, and oxadiazolyl. In another embodiment, the invention relates to a compound according to formula (II), wherein b is 2. In another embodiment, the invention relates to a compound according to formula (II), wherein T is a 6-membered heterocyclyl containing at least one nitrogen atom. In another embodiment, the invention relates to a compound according to formula (II), wherein said 6-membered heterocyclyl is selected from the group consisting of
Figure imgf000007_0002
In yet another embodiment, the invention relates to a compound according to formula
(II), wherein T is
Figure imgf000007_0003
In yet another embodiment, the invention relates to a compound according to formula
(II), wherein each R1 is phenyl or napthyl substituted by 1 to 5 R9 groups; wherein: each R9 is independently selected from the group consisting of halo, cyano, -CF3, hydroxy, (Cι-Cβ)alkoxy. (d-C6)alkyl, (C2-C6)alkenyl, -(C=0)-R10, -(C=0)-0-R11, -0-(C=0)-R11, -NR11(C=0)-R12, -(C=0)-NR11R12, -NR11R12, and -NR11OR12. In an embodiment, the invention relates to a compound according to formula (II), wherein R2 and R3 are each independently selected from H and (d-C6)alkyl; wherein: said (Ci-Cβ) alkyl is optionally substituted by (C2-C6) alkenyl or -(CR7R8),(C3-do)cycloalkyl. In another embodiment, the invention relates to a compound according to formula (II), wherein R2 and R3 are taken together with the nitrogen to which they are attached to form a (4-10)-membered heterocyclyl. In yet another embodiment, the invention relates to a compound according to fonnula (II), wherein said (4-10)-membered heterocyclyl is selected from the group consisting of:
Figure imgf000008_0001
In another embodiment, the invention relates to a compound according to formula (II), wherein R2 is (d-C6)alkyl. In an embodiment, the invention relates to a compound according to formula (II), wherein n is 0 and at least one of R5 and R6 is H. In another embodiment, the invention relates to a compound selected from the group consisting of:
Figure imgf000008_0002
Figure imgf000009_0001
or a pharmaceutically acceptable salt or solvate thereof. An embodiment of the invention relates to a pharmaceutical composition comprising an effective amount of a compound according formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. In yet another embodiment, the invention relates to a method of treating a condition that is mediated by the modulation of 11-β-hsd-1, the method comprising administering to a mammal an effective amount of a compound according formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof. In yet another embodiment, the invention relates to a method of treating diabetes, metabolic syndrome, insulin resistance syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ, the method comprising administering to a mammal an effective amount of a compound according to formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof.
Definitions As used herein, the terms "comprising" and "including" are used in their open, non- limiting sense. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties. The term "alkenyl", as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above and including E and Z isomers of said alkenyl moiety. The term "alkynyl", as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above. The term "alkoxy", as used herein, unless otherwise indicated, includes O-alkyl groups wherein alkyl is as defined above. The term "amino", as used herein, is intended to include the -NH2 radical, and any substitutions of the N atom. The terms "halogen" and "halo," as used herein represent chlorine, fluorine, bromine or iodine. The term "trifluoromethyl," as used herein, is meant to represent a -CF3 group. The term "trifluoromethoxy," as used herein, is meant to represent a -OCF3 group. The term "cyano," as used herein, is meant to represent a -CN group. The term, "OMs " as used herein, is intended to mean, unless otherwise indicated methanesulfonate. The term "Me" as used herein, unless otherwise indicated, is intended to mean means methyl. The term "MeOH" as used herein, unless otherwise indicated, is intended to mean means methanol. The term "Et" as used herein, unless otherwise indicated, is intended to mean means ethyl. The term "Et20 " as used herein, unless otherwise indicated, is intended to mean means diethylether. The term "EtOH " as used herein, unless otherwise indicated, is intended to mean means ethanol. The term "Et3N" as used herein, unless otherwise indicated, is intended to mean means triethylamine. The term "EtOAc" as used herein, unless otherwise indicated, is ethyl acetate. The term "AIMe2CI" as used herein, unless otherwise indicated, is intended to mean dimethyl aluminum chloride. The term "Ac" as used herein, unless otherwise indicated, is intended to mean means acetyl. The term "TFA" as used herein, unless otherwise indicated, is intended to mean trifluoroacetic acid. The term "TEA", as used herein, unless otherwise indicated, is intended to mean triethanolamine. The term "HATU", as used herein, unless otherwise indicated, is intended to mean Λ/,Λ/,Λ/'Λ/'-tetramethyluronium hexafluorophosphate. The term "THF", as used herein, unless otherwise indicated, is intended to mean tetrahydrofuran. The term "TIOH", as used herein, unless otherwise indicated, is intended to mean thallium(l) hydroxide. The term "TIOEt", as used herein, unless otherwise indicated, is intended to mean thallium(l) ethoxide. The term "PCy3" as used herein, is intended to mean tricyclohexylphosphine. The term "Pd2(dba)3", as used herein, unless otherwise indicated, is intended to mean tris(dibenzylideneacetone)dipalladium(0). The term "Pd(OAc)2", as used herein, unless otherwise indicated, is intended to mean palladium(ll) acetate. The term "Pd(PPh3)2CI2", as used herein, unless otherwise indicated, is intended to mean dichlorobis(triphenylphosphine)palladium(ll). The term "Pd(PPh3)4 ", as used herein, unless otherwise indicated, is intended to mean tetrakis(triphenylphophine)palladium(0). The term "Pd(dppf)CI2"as used herein, is intended to mean (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(ll), complex with dichloromethane (1:1). The term "G6P", as used herein, unless otherwise indicated, is intended to mean glucose-6-phosphate. The term "NIDDM, as used herein, unless otherwise indicated, is intended to mean non insulin dependent diabetes mellitus The term "NADPH", as used herein, unless otherwise indicated, is intended to mean nicotinamide adenine dinucleotide phosphate, reduced form. The term "CDCI3 or CHLORFORM-D" as used herein, is intended to mean deuterochloroform. The term "CD3OD" as used herein, is intended to mean deuteromethanol. The term "CD3CN" as used herein, is intended to mean deuteroacetonitrile. The term "DEAD" as used herein, is intended to mean diethyl azodicarboxylate. The term "TsCH2NC" as used herein, is intended to mean tosylmethyl isocyanide. The term "CIS03H" as used herein, is intended to mean chlorosulfonic acid. The term "DMSO-d6 or DMSO-D6" as used herein, is intended to mean deuterodimethyl sulfoxide. The term "DME" as used herein, is intended to mean 1 ,2-dimethoxyethane. The term "DMF" as used herein, is intended to mean Λ,Λ/-dimethylformamide. The term "DMSO", as used herein, is intended to mean, unless otherwise indicated dimethylsulfoxide. The term "Dl", as used herein, is intended to mean deionized. The term "KOAc" as used herein, is intended to mean potassium acetate. The term "neat" as used herein, is meant to represent an absence of solvent. The term "mmol" as used herein, is intended to mean millimole. The term "equiv" as used herein, is intended to mean equivalent. The term "mL" as used herein, is intended to mean milliliter. The term "U" as used herein, is intended to mean units. The term "mm" as used herein, is intended to mean millimeter. The term "g" as used herein, is intended to mean gram. The term "kg" as used herein, is intended to mean kilogram. The term "h" as used herein, is intended to mean hour. The term "min" as used herein, is intended to mean minute. The term "μL" as used herein, is intended to mean microliter. The term "μM" as used herein, is intended to mean micromolar. The term "μm" as used herein, is intended to mean micrometer. The term "M" as used herein, is intended to mean molar. The term "N" as used herein, is intended to mean normal. The term "nm" as used herein, is intended to mean nanometer. The term "nM" as used herein, is intended to mean nanoMolar. The term "amu" as used herein, is intended to mean atomic mass unit. The term "°C" as used herein, is intended to mean Celsius. The term "m z", as used herein, is intended to mean, unless otherwise indicated, mass/charge ratio. The term "wt/wt" as used herein, is intended to mean weight/weight. The term "v/v" as used herein, is intended to mean volume/volume. The term "mL/min" as used herein, is intended to mean milliliter/minute. The term "UV" as used herein, is intended to mean ultraviolet. The term "APCI-MS" as used herein, is intended to mean atmospheric pressure chemical ionization mass spectroscopy. The term "HPLC" as used herein, is intended to mean high performance liquid chromatograph. The term "LC" as used herein, is intended to mean liquid chromatograph. The term "LCMS" as used herein, is intended to mean liquid chromatography mass spectroscopy. The term "SFC" as used herein, is intended to mean supercritical fluid chromatography. The term "sat" as used herein, is intended to mean saturated. The term "aq" as used herein, is intended to mean aqueous. The term "ELSD" as used herein, is intended to mean evaporative light scattering detection. The term "MS" as used herein, is intended to mean mass spectroscopy. The term "HRMS (ESI)" as used herein, is intended to mean high resolution mass spectrometry (electrospray ionization). The term "Anal." as used herein, is intended to mean analytical. The term "Calcd", as used herein, is intended to mean calculated. The term "NT", as used herein, unless otherwise indicated, is intended to mean not tested. The term "NA", as used herein, unless otherwise indicated, is intended to mean not tested. The term "RT", as used herein, unless otherwise indicated, is intended to mean room temperature The term "Mth ", as used herein, unless otherwise indicated, is intended to mean Method The term "Ce te®", as used herein, unless otherwise indicated, is intended to mean a white solid diatomite filter agent commercially available from World Minerals located in Los Angeles, California USA The term "Eg ", as used herein, unless otherwise indicated, is intended to mean example Terms such as -(CR3R4), or -(CR10R11)V, for example, are used, R3, R4, R10and R11 may vary with each iteration of t or v above 1 For instance, where t or v is 2 the terms - (CR3R )V or -(CR10R11), may equal -CH2CH2-, or -CH(CH3)C(CH2CH3)(CH2CH2CH3)-, or any number of similar moieties falling within the scope of the definitions of R3, R4, R10and R11 The term "K,", as used herein, is intended to mean values of enzyme inhibition constant The term "K," app, as used herein, is intended to mean K, apparent The term "IC50", as used herein, is intended to mean concentrations required for at least 50% enzyme inhibition The term "substituted," means that the specified group or moiety bears one or more substituents The term "unsubstituted," means that the specified group bears no substituents The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents In accordance with convention, in some structural formula herein, the carbon atoms and their bound hydrogen atoms are not explicitly depicted e g , represents a methyl
group,
Figure imgf000013_0001
a cyclopentyl group, etc The term "cycloalkyl", as used herein, unless otherwise indicated, refers to a non- aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyc c or tπcyc c hydrocarbon referred to herein containing a total of from 3 to 10 carbon atoms, suitably 5-8 ring carbon atoms Exemplary cycloalkyls include rings having from 3-10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl Illustrative examples of cycloalkyl are derived from, but not limited to, the following
Figure imgf000014_0001
The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl. The term "(3-7)-membered heterocyclyl", "(6-10)-membered heterocyclyl", or "(4-10)- membered heterocyclyl", as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 3-7, 6-10, or 4-10 atoms, respectively, in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems. An example of a 3 membered heterocyclic group is aziridine, an example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl, an example of a 7 membered ring is azepinyl, and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the groups listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). The 4-10 membered heterocyclic may be optionally substituted on any ring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring. An example of a heterocyclic group wherein 2 ring carbon atoms are substituted with oxo moieties is 1,1-dioxo-thiomorpholinyl. Other Illustrative examples of 4-10 membered heterocyclic are derived from, but not limited to, the following:
Figure imgf000015_0001
Unless otherwise indicated, the term "oxo" refers to =0. A "solvate" is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO (dimethylsulfoxide), ethyl acetate, acetic acid, or ethanolamine. The phrase "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula (I) or formula (II). The compounds of formula (I) or formula (II )that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula (I) or formula (II) are those that form non-toxic acid addition salts, Le, salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phospate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts. The term "diseases in which the liver is a target organ", as used herein, unless otherwise indicated means diabetes, hepatitis, liver cancer, liver fibrosis, and malaria. The term "Metabolic syndrome", as used herein, unless otherwise indicated means psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases, galactosemia, maple syrup urine disease, phenylketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria, isovaleric acidemia, saccharopinuria, 4-hydroxybutyric aciduria, glucose-
6-phosphate dehydrogenase deficiency, and pyruvate dehydrogenase deficiency. The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. The term "modulate" or "modulating", as used herein, refers to the ability of a modulator for a member of the steroid/thyroid superfamily to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control. The term "obesity" or "obese", as used herein, refers generally to individuals who are at least about 20-30% over the average weight for his/her age, sex and height. Technically, "obese" is defined, for males, as individuals whose body mass index is greater than 27.8 kg/ m2, and for females, as individuals whose body mass index is greater than 27.3 kg/m2. Those of skill in the art readily recognize that the invention method is not limited to those who fall within the above criteria. Indeed, the method of the invention can also be advantageously practiced by individuals who fall outside of these traditional criteria, for example, by those who may be prone to obesity. The term "inflammatory disorders", as used herein, refers to disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibromyalgia, and cachexia. The phrase "therapeutically effective amount", as used herein, refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other. The phrase "amount effective to lower blood glucose levels", as used heren, refers to levels of compound sufficient to provide circulating concentrations high enough to accomplish the desired effect Such a concentration typically falls in the range of about 10 nM up to 2 μM, with concentrations in the range of about 100 nM up to 500 nM being preferred As noted previously, since the activity of different compounds which fall within the definition of formula (I) or formula (II) as set forth above may vary considerably, and since individual subjects may present a wide variation in severity of symptoms, it is up to the practitioner to determine a subject's response to treatment and vary the dosages accordingly The phrase "insulin resistance", as used herein, refers to the reduced sensitivity to the actions of insulin in the whole body or individual tissues, such as skeletal muscle tissue, myocardial tissue, fat tissue or liver tissue Insulin resistance occurs in many individuals with or without diabetes mellitus The phrase "insulin resistance syndrome", as used herein, refers to the cluster of manifestations that include insulin resistance, hypeπnsulinemia, NIDDM, arterial hypertension, central (visceral) obesity, and dyslipidemia Certain compounds of formula (I) or formula (II) may have asymmetric centers and therefore exist in different enantiomeπc forms All optical isomers and stereoisomers of the compounds of formula (I) or formula (II), and mixtures thereof, are considered to be within the scope of the invention With respect to the compounds of formula (I) or formula (II), the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof The compounds of formula (I) or formula (II) may also exist as tautomers This invention relates to the use of all such tautomers and mixtures thereof Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteπc groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al , Chem Rev, 1996, 96, 3147-3176 and references cited therein The subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) or formula (II), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and ^Cl, respectively Compounds of the present invention and pharmaceutically acceptable salts or solvates of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 1 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 1 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of foπnula (I) or formula (II) of this invention thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Other aspects, advantages, and features of the invention will become apparent from the detailed description below.
Detailed Description And Embodiments of The Invention The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, R1 - R22, T, and W in the reaction schemes and the discussion that follows are as defined above.
Scheme 1
Figure imgf000019_0001
la
Figure imgf000019_0002
lb
Referring to Scheme 1 above, the compound of formula la may be prepared by reacting a compound of formula Ic, wherein the group C02R23 is an ester group such as methyl ester (C02-CH3) or ethyl ester (C02-CH2CH3), with aluminum amides (Me2AI-NR2R3) or (MeAI(CI)-NR2R3) in a suitable solvent (e.g. dichloromethane or toluene) advantageously, from room temperature to the boiling point of the solvent, typically from about 20 degrees Celsius to about 100 degrees Celsius. The compound of formula la may also be prepared by reacting a compound of formula Ic, wherein the group C02R23 is a carboxylic acid (C02H) with an amine of formula HNR2R3 using standard amide coupling chemistry. Compounds of formula Ic may be prepared by reacting a compound of formula lla, wherein the group C02R23 is an ester group such as methyl ester (C02-CH3) or ethyl ester (C02-CH2CH3), with a R1- sulfonyl halide or R1-sulfinyl halide. Alternatively, the compound of formula la may be prepared by reacting a compound of formula Id with a R1-sulfonyl halide or R1-sulfinyl halide. Compounds of formula Id may be prepared by reacting a compound of formula lla, wherein the group C02R23 is an ester group such as methyl ester (C02-CH3) or ethyl ester (C02- CH2CH3), with aluminum amides (Me2AI-NR2R3) or (MeAI(CI)-NR2R3) in a suitable solvent (e.g. dichloromethane or toluene) at a temperature from room temperature to the boiling point of the solvent, typically from about 20 degrees Celsius to about 100 degrees Celsius. The compound of formula lb may be obtained by cyclodehydration of suitable amide la.
Scheme 2
Figure imgf000020_0001
Scheme 3
Figure imgf000020_0002
A2 A3
Referring to Scheme 2 above, the compound of formula A may be prepared by reacting B with an R1-sulfonyl halide, R1-sulfinyl halide, or R1 -sulfinate in the presence of a base such as an amine. Suitable bases include pyridine, triethylamine, and diisopropylethylamine. Suitable solvents include pyridine, dichloromethane, or THF. The aforementioned reaction can be conducted at room temperature or heated for an appropriate time period, such as 2 to 16 hours, depending on the solvent system used. After the reaction is substantially completed, the base may be removed in vacuo and the resulting residue may be purified using conventional purification techniques. Referring to Scheme 3, an alternative method of synthesis is shown for compounds where R1 is a non-fused ring system of more than one ring of either an aryl or heterocyclyl. The compound of formula A3, may be prepared by a palladium-catalyzed coupling reaction of A2 where X is a halo or trifluoromethylsulfonyl with a reagent Y-N where Y is aryl or heterocyclyl, N is boronic acid, boronate ester, stannane, or zincate. Suitable palladium sources for this reaction include Pd(PPh3)4, Pd2(dba)3, Pd(PPh3)2CI2 or Pd(OAc)2. Ligands such as diphenylphosphinoethane, diphenylphosphinoferrocene, or triphenylphosphine may also be added. Suitable solvents for the palladium-catalyzed coupling reaction include dimethylformamide, tetrahydrofuran, or toluene. The aforementioned reaction can be conducted at a temperature of about 50 °C to about 150 °C with or without microwave heating for a time period of about 15 min to about 16 hours. For couplings using boronic acids, base additives such as Na2C03, Cs2C03, TIOH, TIOEt may be added. Any of the above compounds of formula la, lb, Ic, Id, lla, A, B, A2, and A3 can be converted into another analogous compound by standard chemical manipulations. All starting materials, regents, and solvents are commercially available and are known to those of skill in the art unless otherwise stated. These chemical manipulations are known to those skilled in the art and include (a) removal of a protecting group by methods outlined in T. W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Second Edition, John Wiley and Sons, New York, 1991; (b) displacement of a leaving group (halide, mesylate, tosylate, etc) with a primary or secondary amine, thiol or alcohol to form a secondary or tertiary amine, thioether or ether, respectively; (c) treatment of primary and secondary amines with an isocyanate, acid chloride (or other activated carboxylic acid derivative), alkyl/aryl chloroformate or sulfonyl chloride to provide the corresponding urea, amide, carbamate or sulfonamide; (d) reductive amination of a primary or secondary amine using an aldehyde. The compounds of the present invention may have asymmetric carbon atoms. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention. The compounds of formula (I) or formula (II) that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula (I) or formula (II) from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid. Those compounds of formula (I) or formula (II) that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula (I) or formula (II). Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium, and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product. The compounds of the present invention may be modulators of 11-β-hsd-1. The compounds of the present invention may modulate processes mediated by 11-β-hsd-1 , which refer to biological, physiological, endocrinological, and other bodily processes which are mediated by receptor or receptor combinations which are responsive to the 11-β-hsd-1 inhibitors described herein (e.g., diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts and coronary artery diseases and the like), arteriosclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (e.g. ischemic heart disease and the like), cell injury (e.g.) brain injury induced by strokes and the like) induced by atherosclerosis or ischemic heart disease, gout, inflammatory diseases (e.g. arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergosis, asthma, Gl ulcer, cachexia, autoimmune diseases, pancreatitis and the like), cancer, osteoporosis and cataracts. Modulation of such processes can be accomplished in vitro or in vivo. In vivo modulation can be carried out in a wide range of subjects, such as, for example, humans, rodents, sheep, pigs, cows, and the like. The compounds according to the present invention may be used in several indications which involve modulations of 11-β-hsd-1 enzyme. Thus, the compounds according to the present invention may be used against dementia (See WO97/07789), osteoporosis (See Canalis E 1996, "Mechanisms of Glucocorticoid Action in Bone: Implications to Glucocorticoid-lnduced Osteoporosis", Journal of Clinical Endocrinology and Metabolism, 81 , 3441-3447) and may also be used disorders in the immune system (see Franchimont, et. al, "Inhibition of Th1 Immune Response by Glucocorticoids: Dexamethasone Selectively Inhibits IL-12-induced Stat 4 Phosphorylation in T Lymphocytes", The Journal of Immunology 2000, Feb 15, vol 164 (4), pages 1768-74) and also in the above listed indications. Inhibition of 11-β-hsd-1 in isolated murine pancreatic β-cells improves the glucose- stimulated insulin secretion (Davani, B., et al. (2000) J. Biol. Chem. Nov. 10, 2000; 275(45): 34841-4). Glucocorticoids were previously known to reduce pancreatic insulin release in vivo (Billaudel, B. and B. C. J. Sutter (1979) Horm. Metab. Res. 11: 555-560). Thus, inhibition of 11-β-hsd-1 is predicted to yield other beneficial effects for diabetes treatment, besides effects on liver and fat. Recent data suggests that the levels of the glucocorticoid target receptors and the 11- β-hsd-1 enzymes determine the susceptibility to glaucoma (Stokes, J., et al., (2000) Invest. Ophthalmol. 41:1629-1638). Further, inhibition of 11-β-hsd-1 was recently presented as a novel approach to lower the intraocular pressure (Walker E. A., et al, poster P3-698 at the Endocrine society meeting Jun. 12-15, 1999, San Diego). Ingestion of carbenoxolone, a nonspecific inhibitor of 11-β-hsd-1, was shown to reduce the intraocular pressure by 20% in normal subjects. In the eye, expression of 11 -β-hsd-1 is confined to basal cells of the corneal epithelium and the non-pigmented epithelialium of the cornea (the site of aqueous production), to ciliary muscle and to the sphincter and dilator muscles of the iris. In contrast, the distant isoenzyme 11 beta-hydroxysteroid dehydrogenase type 2 is highly expressed in the non-pigmented ciliary epithelium and corneal endothelium. None of the enzymes is found at the trabecular meshwork, the site of drainage. Thus, 11 -β-hsd-1 is suggested to have a role in aqueous production, rather than drainage, but it is presently unknown if this is by interfering with activation of the glucocorticoid or the mineralocorticoid receptor, or both. Bile acids inhibit 11-β-hydroxysteroid dehydrogenase type 2. This results in a shift in the overall body balance in favor of cortisol over cortisone, as shown by studying the ratio of the urinary metabolites (Quattropani C, Vogt B, Odermatt A, Dick B, Frey B M, Frey F J. 2001. J Clin Invest. Nov; 108(9): 1299-305. "Reduced Activity of 11 -beta-hydroxysteroid dehydrogenase in Patients with Cholestasis"). Reducing the activity of 11-β-hsd-1 in the liver by a selective inhibitor is predicted to reverse this imbalance, and acutely counter the symptoms such as hypertension, while awaiting surgical treatment removing the biliary obstruction. The compounds of the present invention may also be useful in the treatment of other metabolic disorders associated with impaired glucose utilization and insulin resistance include major late-stage complications of NIDDM, such as diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation and glaucoma, and many other conditions linked to NIDDM, including dyslipidemia glucocorticoid induced insulin resistance, dyslipidemia, polycysitic ovarian syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesteremia, hypertriglyceridemia, hyperinsulinemia, and hypertension. Brief definitions of these conditions are available in any medical dictionary, for instance, Stedman's Medical Dictionary (10th Ed.). Assav The 11 β-hsd-1 assay was performed in a 100mM Triethanolamine buffer pH 8.0, containing 200mM NaCI, 0.02% n-dodecyl β-D-maltoside, 5% glycerol, 5mM β- mercaptoethanol. A typical reaction for the determination of Kjapp values was carried at R.T. in a Corning® u-bottom 96-well plate and is described as follows: 11 β-hsd-1 enzyme (5 nM, final concentration) was pre-incubated in the presence of the inhibitor and NADPH (500 μM, final concentration) for at least 30 minutes in the assay buffer. When pre-incubation was completed, the reaction was initiated by adding the regenerating system (2m M Glucose-6- Phosphate, 1U/mL Glucose-6-Phosphate dehydrogenase, and 6mM MgCI2, all the concentration reported are final in the assay buffer), and 3H-cortisone (200 nM, final concentration). After 60 minutes, 60μL of the assay mixture was transferred to a second 96- well plate and mixed with an equal volume of dimethylsulfoxide to stop the reaction. A 15μL aliquot from the reaction mixture was loaded into a C-18 column (Polaris C18-A, 50 x 4.6mm, 5 μ, 180 Angstrom from Varian) connected to an automated High-throughput Liquid Chromatography instrument developed by Cohesive Technologies, commercially available from Franklin, Massachusetts USA, with a β-RAM model 3 Radio-HPLC detector from IN/US, commercially available from Tampa, Florida USA. The substrate and product peaks were separated by using an isocratic mixture of 43:57 methanol to water (v/v) at a flow rate of LOmUmin. The initial reaction velocities were measured by stopping the reaction at 60 min and by measuring the area of product formation in the absence and the presence of various concentrations of inhibitors. The K,app values were determined using the equation for tight- binding inhibitor developed by Morrison, JF. (Morrison JF. Biochim Biophys Acta. 1969; 185- 269-86). The radiolabeled [1 ,2-3H]-cortisone is commercially available from American
Radiolabeled Chemicals Inc of St. Louis, Missouri USA. NADPH, Glucose-6-Phosphate, and Glucose-6-Phosphate dehydrogenase were purchased from Sigma®. The app values of the compounds of the present invention for the 11 -β-hsd-1 enzyme may lie typically between about 10 nM and about 10 μM. The compounds of the present invention that were tested all have Kapp's in at least one of the above SPA assays of less than 1 μM, preferably less than 100 nM. Certain preferred groups of compounds possess differential selectivity toward the various 11-β-hsd's. One group of preferred compounds possesses selective activity towards 11-β-hsd-1 over 11β-hsd-2. Another preferred group of compounds possesses selective activity towards 11β hsd-2 over 11-β-hsd- 1. (Morrison JF. Biochim Biophys Acta. 1969; 185: 269-86). Percentage of inhibition was determined in a 100mM Triethanolamine buffer, pH 8.0, 200mM NaCI, 0.02% n-dodecyl β-D-maltoside and 5mM β-ME. A typical reaction was carried on a Coming® u-bottom 96-well plate and is described as follows: 11 β-hsd-1 enzyme (5 nM, final concentration) was pre-incubated in the presence of the inhibitor and NADPH (500 μM, final concentration) for at least 30 minutes in the assay buffer. When pre-incubation was completed, the reaction was initiated by adding the regenerating system (2mM Glucose-6- Phosphate, 1U/mL Glucose-6-Phosphate dehydrogenase, and 6mM MgCI2 all the concentration reported are final in the assay buffer), and 3H-cortιsone (200 nM, final concentration) After 60 minutes, 60μL of the assay mixture was transferred to a second 96- well plate and mixed with an equal volume of dimethylsulfoxide to stop the reaction A 15μL aliquot from the reaction mixture was loaded into a C-18 column (Polaris C18-A, 50 x 4 6mm, 5 μ, 180 Angstrom from Varian) connected to an automated High-throughput Liquid Chromatography instrument developed by Cohesive Technologies commercially available from Franklin, Massachusetts, with a β-RAM model 3 Radio-HPLC detector from IN/US commercially available from Tampa, Florida The substrate and product peaks were separated by using an isocratic mixture of 43 57 methanol to water (v/v) at a flow rate of
Percent Inhibition was calculated based on the following equation (100 - (3H-Cortιsol peak area with ιnhιbιtor/3Hcortιsol peak area without inhibitor) x 100) Certain groups of compounds possess differential selectivity toward the various 11-β-hsd enzymes One group of compounds possesses selective activity towards 11 -β-hsd-1 enzyme over 11β-hsd-2 enzyme While another group of compounds possesses selective activity towards 11 β hsd-2 enzymes over 11 -β-hsd-1 enzymes [1 ,2-3H]-cortιsoπe is commercially available from American Radiolabeled Chemicals Inc of St Louis, Missouri USA NADPH while Glucose-6-Phosphate and Glucose-6- Phosphate dehydrogenase was purchased from Sigma® Pharmaceutical Compositions/Formulations. Dosaαinq and Modes of Administration Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art In addition, those of ordinary skill in the art are familiar with formulation and administration techniques Such topics would be discussed, e g in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, current edition, Pergamon Press, and Remington's Pharmaceutical Sciences, current edition Mack Publishing, Co , Easton, PA These techniques can be employed in appropriate aspects and embodiments of the methods and compositions described herein The following examples are provided for illustrative purposes only and are not meant to serve as limitations of the present invention The compounds of formula (I) or formula (II) may be provided in suitable topical, oral and parenteral pharmaceutical formulations for use in the treatment of 11-β-hsd-1 mediated diseases The compounds of the present invention may be administered orally as tablets or capsules, as oily or aqueous suspensions, lozenges, troches, powders, granules, emulsions, syrups or elixirs The compositions for oral use may include one or more agents for flavoring, sweetening, coloring and preserving in order to produce pharmaceutically elegant and palatable preparations Tablets may contain pharmaceutically acceptable excipients as an aid in the manufacture of such tablets As is conventional in the art these tablets may be coated with a pharmaceutically acceptable enteric coating, such as glyceryl monostearate or glyceryl distearate, to delay disintegration and absorption in the gastrointestinal tract to provide a sustained action over a longer period. Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions normally contain active ingredients in admixture with excipients suitable for the manufacture of an aqueous suspension. Such excipients may be a suspending agent, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; a dispersing or wetting agent that may be a naturally occurring phosphatide such as lecithin, a condensation product of ethylene oxide and a long chain fatty acid, for example polyoxyethylene stearate, a condensation product of ethylene oxide and a long chain aliphatic alcohol such as heptadecaethylenoxycetanol, a condensation product of ethylene oxide and a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate or a fatty acid hexitol anhydrides such as polyoxyethylene sorbitan monooleate. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to know methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be formulated as a suspension in a non toxic perenterally-acceptable diluent or solvent, for example as a solution in 1 ,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringers solution and isotonic sodium chloride solution. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition fatty acids such as oleic acid find use in the preparation of injectables. The compounds of formula (I) or formula (II) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at about 25 Celsius but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and other glycerides. For topical use preparations, for example, creams, ointments, jellies solutions, or suspensions, containing the compounds of the present invention are employed. The compounds of formula (I) or formula (II) may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multimellar vesicles. Liposomes can be formed from a variety of phospholipides, such as cholesterol, stearylamine or phosphatidylcholines. Dosage levels of the compounds of the present invention are of the order of about 0.5 mg/kg body weight to about 100 mg/kg body weight. A preferred dosage rate is between about 30 mg/kg body weight to about 100 mg/kg body weight. It will be understood, however, that the specific dose level for any particular patient will depend upon a number of factors including the activity of the particular compound being administered, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. To enhance the therapeutic activity of the present compounds they may be administered concomitantly with other orally active antidiabetic compounds such as the sulfonylureas, for example, tolbutamide and the like. EXAMPLES The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art. The structures of the compounds are confirmed by either elemental analysis or NMR, where peaks assigned to the characteristic protons in the titled compound are presented where appropriate. 1H NMR shift (5H) are given in parts per million (ppm) down filed from an internal reference standard. The invention will now be described in reference to the following EXAMPLES. These EXAMPLES are not to be regarded as limiting the scope of the present invention, but shall only serve in an illustrative manner. Method A
Example 1: Ethyl [6-(3-Chloro-2-methyl-benzenesulfonylamino)-pyridin-2-yl]-acetate
Figure imgf000027_0001
3-Chloro-2-methylbenzenesulfonyl chloride (3.4 g, 15 mmol, 1.5 equiv) was added in one portion to a solution of ethyl (6-amino-pyridin-2-yl)-acetate (Goto, J.; Sakane, K.; Nakai, Y.; Teraji, T.; Kamiya, T J. Antibiot. 1984, 37, 532) (1.8 g, 10 mmol, 1 equiv) in pyridine (75 mL) at 24 °C. After 16 hours, the pyridine was removed in vacuo (<1 mm Hg), and the resulting residue was dissolved in ethyl acetate (200 mL). The organic solution was washed sequentially with water (3 χ 100 mL) and saturated aqueous sodium chloride (100 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by high performance flash chromatography (0→5% methanol in dichloromethane) yielded product (2.76g, 75%). PC26186A
- 27 -
Method B Example 8: 3-Chloro-2-methyl-rV-[6-(2-morpholin-4-yl-2-oxo-ethyl)-pyridin-2-yl]- benzenesulfona ide
Figure imgf000028_0001
Dimethylaluminum chloride (1.36 mL, 1.36 mmol, 5.0 equiv, 1.0 M in hexanes) was added dropwise to an ice-cooled solution of morpholine (0.119 mL, 1.36 mmol, 5.0 equiv) in dichloromethane (3 mL). The resulting solution was warmed to 24 °C for 1 hour before the addition of a solution of ethyl [6-(3-chloro-2-methyl-benzenesulfonylamino)-pyridin-2-yl]- acetate (0.100 g, 0.271 mmol, 1 equiv) in dichloromethane (2 mL). After 1 hour, 20% sodium potassium tartrate aqueous solution (5 mL) was slowly added to the reaction mixture, and the resulting suspension was stirred vigorously for an additional hour. The resulting mixture was extracted with dichloromethane (2 x 25 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by high performance flash chromatography (0→10% methanol in dichloromethane) yielded a light orange solid (0.107 g, 96%).
Method C Example 19: 2-[6-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonylamino)-pyridin-2- yl]-N,N-diethyl-acetamide
Figure imgf000028_0002
Preparation of (2-(6-Amino-pyridin-2-yl)-N,N-diethyl-acetamide o H2N' ^N' ^"^NEt2 Dimethylaluminum chloride (4.3 mL, 4.3 mmol, 5.0 equiv, 1.0 M solution in hexanes) was added to an ice-cooled solution of diethylamine (445 μL, 4.30 mmol, 5.0 equiv) in dichloromethane (4 mL). After 10 min, the solution was warmed to 24 °C for 1 h. Ethyl (6- amino-pyridin-2-yl)-acetate (Goto, J.; Sakane, K; Nakai, Y.; Teraji, T.; Kamiya, T. J. Antibiot. 1984, 37, 532) (155 mg, 0.860 mmol, 1 equiv) in dichloromethane (4 mL) was added at 24 °C. After 21.5 h, potassium sodium tartrate aqueous solution (20% wt wt, 10 mL) and hexanes (20 mL) were added sequentially, and the resulting mixture was stirred vigorously overnight. Saturated aqueous sodium chloride (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by high performance flash chromatography (0→4.5% methanol in dichloromethane + 0.1% ammonium hydroxide) provided product (120 mg, 67%). 1H NMR (400 MHz, CDCI3), δ: 7.37 (m, 1 H), 6.66 (d, J = 7.6 Hz, 1 H), 6.35 (d, J = 8.1 Hz, 1 H), 4.34 (br s, 2 H), 3.69 (s, 2 H), 3.30-3.44 (m, 4 H), 1.06-1.16 (m, 6 H).
2-[6-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonylamino)-pyridin-2-yl]-N,N-diethyl- acetamide 5-chloro-3-methylbenzo[Bjthiophene-2-sulfonyl chloride (163 mg, 0.580 mmol, 1.1 equiv) was added to a solution of 2-(6-amino-pyridin-2-yl)-Λ/,Λ-diethyl-acetamide (100 mg, 0.483 mmol, 1 equiv) in pyridine (4 mL) at 24 °C. After 18 h, the reaction mixture was diluted with ethyl acetate (30 mL). The resulting solution was washed with water (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by high performance flash chromatography (0→5% methanol in dichloromethane) provided the title compound (93 mg, 43%).
Method D Example 26: [6-(3-Chloro-2-methyl-benzenesulfonylamino)-pyridin-2-yl]-acetic acid
Figure imgf000029_0001
Potassium hydroxide (0.843 g, 15.0 mmol, 6.00 equiv) was added to a solution of [6- (3-chloro-2-methyl-benzenesulfonylamino)-pyridin-2-yl]-acetic acid ethyl ester (0.922 g, 2.50 mmol, 1 equiv) in 20:1 ethanol / water (21 mL) at 24 °C. After 1 h, the reaction mixture was concentrated in vacuo (-25 mm Hg), and the resulting residue was dissolved in water (50 mL). The aqueous solution was acidified by the addition of 10% hydrochloric acid aqueous solution until pH = 2. The heterogeneous solution was then filtered, and the solid was rinsed sequentially with water (50 mL) and diethyl ether (2 x 50 mL). The solid was dried in vacuo (<1 mm Hg, 50 °C) to provide product as a tan solid (0.810 g, 71%). Method E
Example 27: /V-Adamaπtan-1-yl-2-[6-(3-chloro-2-methyl-benzenesulfonylamino)- pyridin-2-yl]-acetamide
Figure imgf000029_0002
0-(7-Azabenzotriazol-1-yl-Λ,Λ/,Λ/',Λ/-tetramethyluronium hexafluorophosphate (0.11 g, 0.29 mmol, 0.98 equiv) was added in one portion to an ice-cooled solution of [6-(3-chloro-2- methyl-benzenesulfonylamino)-pyridin-2-yl]-acetic acid (0.100 g, 0.293 mmol, 1 equiv), 1- adamantanamine (0.200 g, 1.32 mmol, 4.51 equiv), and Λ/, /-diisopropylethylamine (0.462 mL, 2.65 mmol, 9.04 equiv) in dimethylformamide (5 mL). The solution was warmed to 24 °C and stirred overnight. Dimethylformamide was removed in vacuo (~ 1 mm Hg), and the resulting residue was dissolved in dichloromethane (20 mL). The organic was washed sequentially with deionized water (2 x 20 mL) and saturated aqueous sodium chloride (20 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the resulting residue by high performance flash chromatography (0->2% methanol in dichloromethane) yielded desired amide (82 mg, 65%). Alternative General Method for amide coupling
Figure imgf000030_0001
Reactant A Reactant B 1 equiv 1 equiv A stir bar, the amine {Reactant B, 400μL, 80 μmol, 1.00 equiv 0.2 M in anhydrous DMF), [6-(3-chloro-2-methyl-benzenesulfonylamino)-pyridin-2-yl]-acetic acid (Reactant A
200μL, 80 μmol, 1.00 equiv 0.2 M in anhydrous DMF), TEA (160μL, 80 μmol, 1.00 equiv 0.5
M in anhydrous DMF), HATU (160μL, 80 μmol, 1.00 equiv 0.5 M in anhydrous DMF) were placed into a 10 x 75 mm test tube. The tube was sealed with cellophane and the reaction stirred for 16 h at ambient temperature. The solvent was evaporated and the residue dissolved in DMSO containing 0.01 % BHT to yield a 0.05 M solution. The solution was injected into an automated HPLC system for purification. The solvent of the product containing fraction was evaporated, the residue dissolved in DMSO, analyzed, and submitted for screening.
General Analysis and Purification Procedures The crude reaction mixtures were analyzed by HPLC using Method 1. Prior to purification, all samples were filtered through Whatman® GF/F Unifilter (#7700-7210), commercially available from Whatman® of Clifton, New Jersey USA. Purification of samples was performed by reverse phase HPLC using the method 3. Fractions were collected in 23 mL pre-tared tubes and centrifugal evaporated to dryness. Dried product was weighed and dissolved in DMSO. Products were then analyzed using Method 5 and submitted for screening. Analytical LCMS Method 1 (Pre-purification) Column: Peeke Scientific® Hl-Q C-18, 50 x 4.6 mm, commercially available from
Peeke Scientific® of Redwood City, CA, 5μm, Eluent A: Water with 0.05% TFA, Eluent B: Acetonitrile with 0.05% TFA, Gradient: linear gradient of 0-100% B in 3.0 min, then 100% B for 0.5 min, then 100-0% B in 0.25 min, hold 100% A for 0.75 min, Flow: 2.25 mL/min, Column Temperature: 25°C, Injection Amount: 15 μl of a 286 μM crude solution in methanol/DMSO/water 90/5/5, UV Detection: 260 and 210 nm, Mass Spectrometry: APCI, positive mode, mass scan range 111.6-1000 amu. Preparative LC Method 3 (Gilson) Column: Peeke Scientific® Hl-Q C18, 50mm X 20mm, 5μm, Eluent A: 0.05% TFA in Water, Eluent B: 0.05% TFA in Acetonitrile, Pre-inject Equilibration: 0.50 min, Post-inject Hold: 0.16 min, Gradient: 0-100% B in 2.55 minutes, then ramp 100% back to 0% in 0.09min, Flow 50 0 mL/min, Column Temp Ambient, Injection Amount 1200 μL of filtered crude reaction mixture in DMSO, Detection UV at 210 nm or 260 nm Analytical LCMS Method 5 (Post-purification) Column Peeke Scientific® Hl-Q C-18, 50 x 46mm, 5 μm, Eluent A Water with 0 05% TFA, Eluent B Acetonitrile with 0 05% TFA, Gradient linear gradient of 0-100% B in 1 75 mm, then 100% B for 0 35 mm, then 100-50% B for 0 5 mm, Flow 3 00 mL/min, Column Temperature 25°C, Injection Amount 15 μl of a 300 μM solution in methanol/DMSO 99/1, UV Detection 260 nm, Mass Spectrometry APCI, positive mode, mass scan range 100-1000 amu, ELSD gaιn=9, temp 40°C, nitrogen pressure 3 5 bar
Method F Example 33: 4'-Cyano-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide
Figure imgf000031_0001
A solution of 4'-cyano-bιphenyl-4-sulfonyl chloride (32 00 g, 115 mmol) and 2-amιno- 6-pιcolιne (13 70 g, 127 mmol) in pyridine was stirred at room temperature for 18 h The solvent was removed and the residue was poured into water (500 mL) The product was extracted with ethyl acetate (4 * 200 mL) The combine organic extracts were washed with bnne and concentrated Purification by flash silica chromatography on silica gel (40% ethyl acetate in hexanes → ethyl acetate) gave the title compound (28 80 g, 72%) Preparation of Sodium 4'-Cyanobiphenyl-4-sulfonate (Modification of Himmelsbach, F , Austel, V , Pieper, H , Eisert, W , Mueller, T , Weisenberger, J , Linz, G , Krueger, G Eur Pat Appl 1992, EP 483667 A2) Chlorosulfonic acid (116 5 mL, 1 744 mmol) was added to a solution of 4-bιphenylcarbonιtrιle (156 2 g 0 872 mol) in dichloromethane (3 L) at -14 °C while maintaining the reaction temperature below -10 °C The mixture was warmed to 10 °C over 1 h and maintained at 8-10 °C for 6 h Triethylamine was added while maintaining the temperature below 12 °C The mixture was stirred for 15 mm until all black / brown solids were dissolved and a while precipitate formed Water (300 mL) was added, and the slurry was stirred for 10 m and concentrated A solution of sodium hydroxide (2 L, 15%) was added, and the reaction mixture was concentrated until at least half of the volume was distilled Concentrated hydrochloric acid (~300 mL) was added until a pH of 7 was reached, and the final volume was adjusted to 2 2 L by the addition of water A saturated solution of sodium chloride (2 2 L) was added, and the resulting mixture was stirred for 10 mm The solids were filtered and dried in a vacuum oven (80 °C) to afford 251 0 g of the product as a white to yellow solid The product contains a substantial amount of sodium chloride
Preparation of 4'-Cyanobiphenyl-4-sulfonyl chloride (Modification of Himmelsbach, F , Austel, V , Pieper, H , Eisert, W , Mueller, T , Weisenberger, J , Lmz, G , Krueger, G Eur Pat Appl 1992, EP 483667 A2) A mixture of sodium 4'-cyanobιphenyl-4-sulfonate (251 g) and phosphorous oxychloride was refluxed for 16 h The reaction mixture was poured into a large quantity of ice / water and the resulting slurry was extracted with dichloromethane (1 x 1 8 L) The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated to approximately 200 mL Hexanes (200 mL) was added The slurry was stirred for 30 mm, filtered, washed with 1 1 dichloromethane / hexanes, and dπed to give 82 1 g of product The mother liquor was concentrated and further purified by flash chromatography on silica gel (40→70% dichloromethane / hexanes) to give an additional 16 2 g of white solid 1H NMR (300 MHz, CDCI3) δ 8 13-8 19 (m, 2 H), 7 80-7 86 (m, 4 H), 7 72-7 77 (m, 2 H) 13C NMR (75 MHz, CDCI3) δ 146 2, 144 2, 143 0, 133 2, 128 7, 1284, 128 0, 118 5, 113 1 Alternative General Method for Sulfonamide Formation n pyridine O O (f + R^OzCI ► "g I M2I N CH3 RT, 24 h R," ^N^ ^CH3 The sulfonyl chloride (104 μmol, 1 3 equiv 400 μL of a 0 26 M solution in anhydrous pyridine) and 2-amιno-6-pιcolιne (80 μmol, 1 0 equiv 400 μL of a 0 2 M solution in anhydrous pyridine) were placed into a test tube (75x10 mm, dried by heating at 110 °C for 16 h) equipped with a stir bar The test tube was covered with Parafilm® and the reaction was stirred for 24 h at ambient temperature The solvent was evaporated and the residue was dissolved in EtOAc (1 mL) After dissolution was completed or a fine suspension had formed, NaHC03 (0 5 mL of a sat aq solution) was added The reaction mixture was vortexed and the phases were separated by centrifugation The organic layer was transferred into a new test tube (95x10 mm) and the aq phase was extracted with EtOAc (2x 0 8 mL) The organic phases were combined, the solvent was evaporated, and the residue was dissolved in DMSO (1 340 mL)
General Analysis and Purification Procedures The crude reaction mixtures were analyzed by SFC using Method 2 Prior to purification, all samples were filtered through Whatman® GF/F Unifilter (#7700-7210) Purification of samples was performed by SFC using the method 4 Fractions were collected in 23 mL pre-tared tubes and centπfugal evaporated to dryness Dried product was weighed and dissolved in DMSO Products were then analyzed using Method 5 and submitted for screening Analytical SFC Method 2 (Pre-purification) Column Zymor Pegasus, 150x4 6mm i d , 5um, Gradient 5% methanol-modified C02 ramped to 50% methanol @ 18%/mιn and held for 0 1 mm, Flow rate 56 mL/min, Column Temp =50C, Isobaπc pressure 140 bar, UV Detection = 260nm Preparative SFC Method 4 Column: Zymor Pegasus, 150x21.2mm i.d., 5 μ semi-preparative column, Lot 2174, Column Temp: 35 °C, Gradient: 5% methanol-modified C02 held for 0.1 minute, ramped to 60% methanol @ 10%/min and held for 1.0 minute, Flow Rate: 53 mL min, Isobaric pressure: 140 bar, UV Detection: 260nm. Analytical LCMS Method 5 (Post-purification) Column: Peeke Scientific® Hl-Q C-18, 50 x 4.6mm, 5 μm, Eluent A: Water with 0.05% TFA, Eluent B: Acetonitrile with 0.05% TFA, Gradient: linear gradient of 0-100% B in 1.75 min, then 100% B for 0.35 min, then 100-50% B for 0.5 min, Flow: 3.00 mL/min, Column Temperature: 25°C, Injection Amount: 15 μl of a 300 uM solution in methanol/DMSO 99/1 , UV Detection: 260 nm, Mass Spectrometry: APCI, positive mode, mass scan range 100-1000 amu, ELSD: gain=9, temp 40°C, nitrogen pressure 3.5 bar.
Method G Example 110: 4"-Cyano-biphenyl-4-sulfonic acid methyl-(6-methyl-pyridin-2-yl)-amide
Figure imgf000033_0001
To a solution of Λ/,6-dimethylpyridin-2-amine (0.15 g, 1.24 mmol) in THF (5 ml) was added NaHMDS (1.56 mL, 1.56 mmol) at R.T. After 15 min, 4'-cyanobiphenyl-4-sulfonyl chloride (0.28 g, 1.03 mmol) was added to the reaction mixture and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (2 X 30 mL). The collected organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified with radial chromatography (2 mm silica plate, 2:1 hexanes / ethyl acetate) to yield a clear oil. The product was converted to a HCI salt by dissolving in 5 mL diethyl ether and adding 1 HCI in diethyl ether dropwise. The solid was triturated with additional ether and dried on high vacuum to afford the product (0.11 g, 29.5%).
Method H Example 111: 4'-Cyano-biphenyl-4-sulfonic acid (6-isopropyl-pyridin-2-yl)-amide
Figure imgf000033_0002
Preparation of N-(6-Bromo-pyridin-2-yl)-2,2-dimethyl-propionamide
Figure imgf000033_0003
To an ice-cooled solution of 6-bromopyridin-2-amine (7.0 g, 40.5 mmol) in 60 mL of CH2CI2 was added 2,2-dimethylpropanoyl chloride (5.23 mL, 42.48 mL) and diisopropylethylamine (13.6 mL, 82.9 mmol) sequentially. The solution was stirred for 1h then diluted with 50 mL of diethyl ether. The mixture was washed with saturated aqueous sodium bicarbonate (2 x 50 mL). The organic layer was dried over Na2S0 , filtered, and concentrated. The residue was dissolved in ethyl acetate (10 mL) and hexane (20 mL) and allowed to stand for 3 h. The product was filtered, rinsed with 1:1 hexanes / ethyl acetate, and dried in vacuo to afford the title compound as a white solid (9.56 g, 93%). 1H NMR (400 MHz, CD3CN), δ: 8.22 (d, J = 8.4 Hz, 1 H), 7.99 (bs, 1 H), 7.55 (t, J = 8.1 Hz, 1 H), 7.22 (d, J = 7.3 Hz, 1 h), 1.31 (s, 9 H); LCMS (ESI): mlz: 258.0.
Preparation of N-(6-lsopropyl-pyridin-2-yl)-2,2-dimethyl-propionamide
Figure imgf000034_0001
Cu(l) (7.40 g, 38.8 mmmol) was added to a solution of Λ/-(6-bromopyridin-2-yl)-2,2- dimethylpropanamide (5.0 g, 19.4 mmol) in THF (100 mL) at -78 °C. After 0.5 hours, isopropylmagnesium chloride (48.5 mL, 1M in THF) was added dropwise at -78 °C, and the resulting solution was warmed to 25 °C for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) then diluted with ethyl acetate (100 mL). The solids were removed by filtration. The solution was washed sequentially with saturated aqueous ammonium chloride (2 x 50 mL) and saturated aqueous sodium bicarbonate (2 x 50 mL). The organic layer was dried over Na2S0 , filtered, and concentrated. Purification by flash column chromatography (2:1 hexane / ethyl acetate) afforded the title product as an amber oil (2.60 g, 60.4%). Η NMR (400 MHz, CD3CN), δ: 8.04 (d, J = 7.8 Hz, 1 H), 7.97 (bs, 1 H), 7.63 (t, J = 7.8 Hz, 1 H), 6.90 (d, J = 7.5 Hz, 1 H), 2.95-2.88 (m, 1 H), 1.34 (s, 9 H), 1.28 (d, J = 7.1 Hz, 6 H); LCMS (ESI): mlz: 221.2. Preparation of 6-lsopropyl-pyridin-2-ylamine
H2NAJγcH3 CH3 To a solution of Λ-(6-isopropylpyridin-2-yl)-2,2-dimethylpropanlamide (2.0 g, 9.08 mmol) in dioxane (5 mL) was added HCI (9N, 10 mL). The mixture was stirred for 18 hours at 80 °C. After cooling to 25 °C, the pH of the reaction mixture was adjusted with NaOH to achieve pH 9. The solution was diluted with ethyl acetate (120 mL) and washed with saturated aqueous sodium bicarbonate (2 x 30 mL). Next, the organic layer was azeotroped with toluene (10 mL) to afford 6-isopropylpyridin-2-amine as clear oil (0.68 g, 55%). 1H NMR(400 MHz, CD3CN), δ: 7.36 (t, J = 7.8 Hz, 1 H), 6.64 (d, J = 8.7, 1 H), 6.32 (d, J = 8.1 Hz, 1 H), 1.25 (d, J = 4.5 Hz, 9 H); LCMS (ESI): mlz: 137.2. 4'-Cyano-biphenyl-4-sulfonic acid (6-isopropyl-pyridin-2-yl)-amide 5/060963 - 34 -
Made following the procedure described for the preparation of 4'-cyano-biphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 6-isopropyl-pyridin-2-ylamine and making non-critical variations.
Method I Example 112: 4'-Cyano-biphenyl-4-sulfonic acid (6-cyclopropyl-pyridiπ-2-yl)-amide
Figure imgf000035_0001
Preparation of N-(6-Cyclopropyl-pyridin-2-yl)-2,2-dimethyl-propionamide
Figure imgf000035_0002
To a solution of Λ/-(6-bromopyridin-2-yl)-2,2-dimethylpropanamide (4.20 g, 16.3 mmol), cyclopropylboronic acid (1.82 g, 21.8 mmol), Pd(OAc)2 (0.18 g, 0.82 mmol) and PCy3 (0.38 g, 1.62 mmol) in toluene (20 mL) was added K3P04 (12.8 g, 60.3 mmol) and water (1 mL). The mixture was stirred at 95 °C for 12h, then cooled to 25 °C. The reaction mixture was diluted with Et20 (30 mL) and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over Na2S04, filtered, and concentrated to give a clear oil. The residue was purified by flash column chromatography (5:1 hexanes/Et20) to give the title product as a clear oil (2.25 g, 63.3%). 'H NMR (400 MHz, CDCI3), δ: 7.98 (d, J = 8.3, 1 H), 7.88 (bs, 1 H), 7.53 (t, J = 7.8 Hz, 1 H), 6.85 (d, J = 7.5 Hz, 1 H), 1.98-1.91 (m, 1 H), 1.32 (s, 9 H), 0.94 (d, J = 6.6 Hz, 4 H); LCMS (ESI): 219.2. Preparation of 6-Cyclopropyl-pyridin-2-ylamine
Figure imgf000035_0003
Made by following the procedure described for the preparation of 6-isopropyl-pyridin- 2-ylamine but substituting N-(6-cyclopropyl-pyridin-2-yl)-2,2-dimethyl-propionamide and making non-critical variations. 1H NMR(400 MHz, CDCI3), δ: 7.70 (t, J = 7.8, 1 H), 6.85 ((t, J = 7.4, 1 H), 6.65 (d, J = 7.5 Hz, 1 H), 4.79 (bs, 2 H); LCMS (ESI): mlz: 135.2. 4'-Cyaπo-biphenyl-4-sulfonic acid (6-cyclopropyl-pyridin-2-yl)-amide Made by following the procedure described for the preparation of 4'-cyano-biphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 6-cyclopropyl-pyridin-2-ylamine and making non-critical variations.
Method J Example 113: 4'-Cyano-biphenyl-4-sulfonic acid (6-amino-4-methyl-pyridin-2-yl)-amide
Figure imgf000036_0001
To a solution of 4-methylpyridine-2,6- diamine (J. Org. Chem. 2001, 61, 6513)(102 mg, 0.825 mmol) in THF (6 mL) was added diispropylethylamine (287 uL, 1.65 mmol) followed by 4-(dimethylamino)pyridine (5 mg, 0.04 mmol). To the resulting solution was added 4'-cyanobiphenyl-4-sulfonyl chloride in CH2CI2 (3 mL). The heterogeneous mixture was stirred at R.T. overnight. By morning all solids had dissolved and the solution was concentrated in vacuo. The residue was dissolved in MeOH/CH2CI2 and to the solution was added DOWEX® 50WX2-400 ion exchange resin, commercially available from DOW Company of Midland, Michigan USA, (2 wt equiv) and the mixture was stirred at R.T. for 1 hour. The mixture was filtered and the resin was washed with MeOH and CH2CI2. The resin was then cleaved by washing with 3.5 N methanolic ammonia and the mother liquor was concentrated in vacuo. To the residue was added MeOH, and the solids were filtered to afford the title compound (50 mg, 25%). Method K
Example 114: 3-Chloro-N-[6-(2-hydroxy-ethyl)-pyridin-2-yl]-2-methyl- benzenesulfonamide
Figure imgf000036_0002
Borane-tetrahydrofuran complex (0.924 mL, 0.924 mmol, 3.0 equiv, 1.0 M tetrahydrofuran solution) was added to an ice-cooled solution of [6-(3-chloro-2-methyl- benzenesulfonylamino)-pyridin-2-yl]-acetic acid (105 mg, 0.308 mmol, 1 equiv) in tetrahydrofuran. After 1 h, the reaction mixture was warmed to 24 °C for 17.5 h. Aqueous hydrochloric acid (3 mL, 5% wt) was added, and the resulting solution was stirred vigorously. After 30 min, saturated aqueous sodium bicarbonate solution (8 mL) was added, and the mixture was extracted with dichloromethane (3 x 15 mL). The collected organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by high performance flash chromatography (0->5% methanol in dichloromethane) yielded product (45.5 mg, 45%). Method L
Example 115: 5-Chloro-3-rnethyl-benzo[b]thiophene-2-sulfonic acid [6-(2-hydroxy- ethyl)-pyridin-2-yl]-amide
Figure imgf000037_0001
Lithium aluminum hydride (0.015 g, 0.310 mmol, 1.3 equiv) was added in one portion to an ice-cooled solution of [6-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonylamino)-pyridin- 2-yl]-acetic acid ethyl ester (0.100 g, 0.235 mmol, 1 equiv) in tetrahydrofuran (4 mL). After 5 min, the reaction mixture was warmed to 24 °C for 16 h. The reaction mixture was cooled to 0 °C, and excess lithium aluminum hydride was quenched with saturated aqueous ammonium chloride solution (10 mL). The resulting solution was wanned to 24 °C and stirred for an additional 30 min. The reaction mixture was filtered through a plug of Celite®, and the resulting filtrate was extracted with dichloromethane (60 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by high performance flash chromatography (0→1% methanol in dichloromethane) yielded product (0.0421 g, 47%).
Method M Example 118: 2-(4-Cyano-phenyl)-4-methyl-thiazole-5-sulfonic acid (6-methyl-pyridin- 2-yl)-amide
Figure imgf000037_0002
Preparation of N-[4-Methyl-5-(6-methyl-pyridin-2-ylsulfamoyl)-thiazol-2-yl]-acetamide
Figure imgf000037_0003
Made by following the procedure described for the preparation of 4'-cyano-biphenyl-4- sulfonic acid (6-methyl-pyridiπ-2-yl)-amide but substituting 2-acetamido-4-methyl-5-thiazole sulfonyl chloride and making non-critical variations. 1H NMR (400 MHz, CDCI3), δ: 7.56 (dd, J = 8.7, 7.2 Hz, 1 H), 7.10 (d, J = 8.6 Hz, 1 H), 6.58 (d, J = 7.3 Hz, 1 H), 2.53 (s, 3 H), 2.47 (s, 3 H), 2.24 (s, 3 H); MS (ESI) for C12H15N403S2 m/z: 327.0. Preparation of 2-Amino-4-methyl-thiazole-5-sulfonic acid (6-methyl-pyridin-2-yl)-amide
Figure imgf000037_0004
A solution of N-[4-methyl-5-(6-methyl-pyπdιn-2-ylsulfamoyl)-thιazol-2-yl]-acetarr de (2 15 g, 6 58 mmol, 1 equiv) and aqueous hydrochloric acid (1 6 mL, 12 M) in ethanol (30 mL) was refluxed overnight Upon cooling to 24 °C, the reaction mixture was concentrated in vacuo (~25 mm Hg) The resulting solid was dissolved in water (10 mL) The solution was neutralized with saturated aqueous sodium bicarbonate until pH = 7 The resulting solid was collected by filtration Lyophihzation of the solid provided an off-white solid (1 67 g, 89%) 1H NMR (400 MHz, DMSO-cfe), δ 7 64 (t, J = 8 0 Hz, 1 H), 744 (s, 2 H), 6 93 (m, 1 H), 6 70 (m, 1 H), 2 32 (s, 3 H), 2 27 (s, 3 H), MS (ESI) for C10H13N4O2S2 m/z 285 1 Preparation of 2-Bromo-4-methyl-thiazole-5-sulfonic acid (6-methyl-pyridin-2-yl)-amιde
Figure imgf000038_0001
To a suspension of 2-amιno-4-methyl-thιazole-5-sulfonιc acid (6-methyl-pyπdιn-2-yl)- amide (0 200 g, 0 703 mmol, 1 equiv) and copper (II) bromide (0 098 g, 0 68 mmol 0 62 equiv) in acetonitrile (6 mL) at 65 °C was added tert-butyl nitnte (0 128 mL, 1 08 mmol, 1 5 equiv) The reaction mixture changed from green to red and gas evolution was observed After 10 mm when gas evolution ceased, the reaction mixture was cooled to 24 °C and diluted with ethyl acetate (60 mL) The resulting mixture was washed with saturated aqueous sodium chloride (2 x 30 mL) The collect organic was dried over anhydrous sodium sulfate, filtered, and concentrated Purification by high performance flash chromatography (0→2% methanol in dichloromethane) provided product (0 156 g, 64%) 1H NMR (400 MHz, CDCI3), δ 7 61 (dd, J = 8 8, 7 1 Hz, 1 H), 7 00 (d, J = 8 8 Hz, 1 H), 6 58 (d, J = 7 3 Hz, 1 H), 2 65 (s, 3 H), 249 (s, 3 H), MS (ESI) for C1oH11BrN302S2 m/z 349 9 2-(4-Cyano-pheπyl)-4-methyl-thiazole-5-sulfonic acid (6-methyl-pyridin-2-yl)-amide A solution of 2-bromo-4-methyl-thιazole-5-sulfonιc acid (6-methyl-pyrιdιn-2-yl)-amιde (0 080 g, 0 23 mmol, 1 equiv), 4-cyanophenylboronιc acid (0 034 g, 0 23 mmol, 1 0 equiv) and cesium carbonate (0 225 g, 0 690 mmol, 3 00 equiv) in 2 1 dimethoxyethane / water (1 5 mL) was purged with nitrogen for 15 mm Dιchloro[1,1'-bιs(dιphenylphosphιne)ferrocene] palladium (II) chloride (0 008 g, 0 009 mmol, 0 04 equiv) was then added, and the resulting mixture was purged with nitrogen for another 15 minutes The reaction mixture was heated to 80 °C for 1 h After cooling to 24 °C, the resulting solution was diluted with ethyl acetate (40 mL) and washed with saturated aqueous sodium chloride (2 x 30 mL) The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated Purification by high performance flash chromatography (0→1% methanol in dichloromethane) provided the titled compound (62 mg, 73%) Method N
Preparation of 4-Bromo-N-(6-methyl-pyridin-2-yl)-benzenesulfonamide
Figure imgf000039_0001
Made by following the procedure described for the preparation of 4'-cyano-biphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 4-bromobenzenesulfonyl chloride and making non-critical variations. 1H NMR (400 MHz, CDCI3), δ ppm 7.61 - 7.68 (m, 2 H) 7.40 - 7.46 (m, 2 H) 7.36 (dd, J=8.6, 7.3 Hz, 1 H) 6.77 - 6.83 (d, J=8.8 Hz, 1 H) 6.42 (d, J=7.1 Hz, 1 H) 2.28 (s, 3 H). Preparation of 4-Bromo-2-methyl-N-(6-methyl-pyridin-2-yl)-benzenesulfonamide
Figure imgf000039_0002
Made by following the procedure described for the preparation of 4'-cyano-biphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 4-bromo-2-methylbenzene-1- sulfonyl chloride (commercially available from ASDI, Inc. of Newark, Delaware USA) and making non-critical variations. APCI+ 342 [M+H]+ 100%. Preparation of 4-Bromo-3-methyl-N-(6-methyl-pyridin-2-yl)-benzeπesulfonamide
Figure imgf000039_0003
Made by following the procedure described for the preparation of 4'-cyano-biphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 4-bromo-3-methylbenzene-1- sulfonyl chloride (available from Lancaster) and making non-critical variations. APCI+ 342 [M+H]+ 100%. General Method for Microwave Assisted Suzuki-Miyaura Cross-Coupling This protocol discloses a procedure for the synthesis of biaryls through a Suzuki- Miyaura cross-coupling of an 4-bromobenzenesulfonamide (Reactant A) and an aryl boronic- acid (Reactant B).
RI- OH + R Y lyiv Kjf Nl CH3 *•
Figure imgf000039_0004
Preferred Conditions:
In a glove box, the following was added to a 2.0 mL Personal Chemistry Microwave reaction tube: (1) one triangular stir bar, (2) 4-Bromobenzenesulfonamide (Reactant A, 320 μL, 80 μmol, 1.0 equiv, 0.25 M in anhydrous DMF), (3) the appropriate aromatic boronic acid (Reactant B, 320 μL, 80 μmol, 1.0 equiv, 0.25 M in anhydrous DMF), (4) the catalyst Pd(PPh3)4 (320 μL, 4 μmol, 0.05 equiv, 0.0125 M in anhydrous THF), and (5) K2C03 (100 μL, 200 μmol, 2.5 equiv, 2 M in degassed Dl water). (6) The microwave tube was sealed with a septum cap.
Outside the glove box, the reaction mixtures were heated in a Personal Chemistry Microwave Synthesizer (SmithCreator™) for 15 min at 130 °C (energy-control setting for a high absorbing sample). The septum caps were removed and the reaction mixture was transferred into a 13x100 mm test tube while leaving any solid material behind. The microwave tubes were washed with DMF (1 mL) and the DMF was added to the receiving test tube. Next, the solvent was evaporated (SpeedVac, vaccum, medium heating, 16 h). EtOAc (1 mL) and water (1.0 mL) were added and the mixture was vortexed at ambient temperature until the residue had dissolved (Note: Some of the palladium in the reaction mixture will form a small amount of a black material that will not dissolve). The test tubes were centrifuged until the phases had separated (some of the black palladium material will settle at the organic/aqueous interface). The organic layer was transferred into a new test tube (13x100 mm). The aq. layer was extracted with EtOAc (2x 1 mL) and the extracts were added to the test tube with the organic layer. The combined organic phase was washed with water (1 mL) followed by brine (1 mL). The solvent was evaporated and the residue dissolved in DMSO. Purification was peformed by reverse phase preparative HPLC. General Analysis and Purification Procedures The crude reaction mixtures were analyzed by HPLC using Method 1. Prior to purification, all samples were filtered through Whatman® GF/F Unifilter (#7700-7210). Purification of samples was performed by reverse phase HPLC using the method 3. Fractions were collected in 23 mL pre-tared tubes and centrifugal evaporated to dryness. Dried product was weighed and dissolved in DMSO. Products were then analyzed using Method 5 and submitted for screening. Analytical LCMS Method 1 (Pre-purification) Column: Peeke Scientific® Hl-Q C-18, 50 x 4.6 mm, 5μm, Eluent A: Water with 0.05% TFA, Eluent B: Acetonitrile with 0.05% TFA, Gradient: linear gradient of 0-100% B in 3.0 min, then 100% B for 0.5 min, then 100-0% B in 0.25 min, hold 100% A for 0.75 min, Flow: 2.25 ml/min, Column Temperature: 25°C, Injection Amount: 15 μl of a 286 μM crude solution in methanol/DMSO/water 90/5/5, UV Detection: 260 and 210 nm, Mass Spectrometry: APCI, positive mode, mass scan range 111.6-1000 amu. Preparative LC Method 3 (Gilson) Column: Peeke Scientific® Hl-Q C18, 50mm X 20mm, 5μm, Eluent A: 0.05% TFA in Water, Eluent B: 0.05% TFA in Acetonitrile, Pre-inject Equilibration: 0.50 min, Post-inject Hold: 0.16 min, Gradient: 0-100% B in 2.55 minutes, then ramp 100% back to 0% in 0.09 min, Flow: 50.0 mL/min, Column Temp: Ambient, Injection Amount: 1200 μL of filtered crude reaction mixture in DMSO, Detection: UV at 210 nm or 260 nm. Analytical LCMS Method 5 (Post-purification) Column: Peeke Scientific® Hl-Q C-18, 50 x 4.6mm, 5 μm, Eluent A: Water with 0.05% TFA, Eluent B: Acetonitrile with 0.05% TFA, Gradient: linear gradient of 0-100% B in 1.75 min, then 100% B for 0.35 min, then 100-50% B for 0.5 min, Flow: 3.00 mL/min, Column Temperature: 25°C, Injection Amount: 15 μl of a 300 μM solution in methanol/DMSO 99/1, UV Detection: 260 nm, Mass Spectrometry: APCI, positive mode, mass scan range 100-1000 amu, ELSD: gain=9, temperature 40°C, nitrogen pressure 3.5 bar.
Method O Example 249: 4'-Chloro-bipheπyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide
Figure imgf000041_0001
To a mixture of 4-Bromo-Λ/-(6-methyl-pyridin-2-yl)-benzenesulfonamide (160 mg, 0.489 mmol) and 4-chlorophenylboronic acid (76.5 mg, 0.489 mmol) in DMF (2 mL) was added aqueous Na2C03 (2.0 M, 0.625 mL; 1.25 mmol) followed by Pd(PPh3)4 (28 mg, 0.0245 mmol). The resulting mixture was heated at 130 °C for 15 min in microwave oven. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (50% EtOAc/Hexane) to yield the title compound as a yellow solid (130 mg, 74%). Method P Example 259: W-(6-Methyl-pyridin-2-yl)-4-pyridin-2-yl-benzenesulfonamide trifuoroacetate
Figure imgf000041_0002
A mixture of 4-Bromo- /- (6-methyl-pyridin-2-yl)-benzenesulfonamide (117 mg, 0.358 mmol), 2-pyridyltributyltin (197 mg, 0.536 mol) and Pd (PPh3)2CI2 (13 mg, 0.018 mmol) in DMF (2 mL) was heated in a microwave oven for 1 h. DMF was removed under vacuum. The residue was purified by reverse phase preparative HPLC to yield the title compound as white solid (42 mg, 0.129 mmol; 36%). Method Q Example 262: 4'-(6-Methyl-pyridin-2-ylsulfamoyl)-biphβnyl-4-carboxylic acid amide
Figure imgf000042_0001
To a solution of 4'-cyano-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide (144 mg, 0.286 mmol) in 30% H202 (1 mL) and EtOH (1 mL) was added 4N NaOH (0.2 mL). The mixture become clear. After 12 h, the mixture was partitioned between EtOAc and H20. The organic layer was washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed over silica gel (60% EtOAc/hexane) to give the title compound as a white solid.
Method R Example 263: 4'-(2-Amino-ethoxy)-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)- amide
Figure imgf000042_0002
To a yellow solution of 4-hydroxy-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)- amide (129 mg, 0.378 mmol), N-hydroxyethylphthaliamide (80 mg, 0.416 mmol), triphenylphosphine (119 mg, 0.454 mmol) in THF (3 mL) was added DEAD (72 μL, 0.454 mmol). After stirring overnight, the mixture was concentrated. The residue was chromatographed on silica gel (40-70% EtOAc/hexane) to give the ether intermediate (152 mg, 79%). To a solution of the above ether intermediate (152 mg, 0.3 mmol) in MeOH (3 mL) was added hydrazine (74 μL, 1.5 mmol). The mixture was stirred at R.T. for 2 h and concentrated to give a residue, which was purified by preparative HPLC to give the final product as a white solid (60 mg, 52%).
Method S Example 264: N-(6-Methyl-pyridin-2-yl)-4-oxazol-5-yl-benzenesulfonamide
Figure imgf000042_0003
Prepa ration of 4-Formyl-/V-(6-methyl-pyridin-2-yl)-benzenesulfonamide
Figure imgf000043_0001
Made by following the procedure descπbed for the preparation of 4'-cyano-bιphenyl-4- sulfonic acid (6-methyl-pyπdιn-2-yl)-amιde but substituting 4-formylbenzensulfonyl chloride N-(6-Methyl-pyridin-2-yl)-4-oxazol-5-yl-benzenesulfonamide
A solution of sulfonamide from step 1 (449 mg, 1 63 mmol), TsCH2NC (349 mg, 1 79 mmol) and K2C03 (450 mg, 3 25 mmol) in MeOH (5 mL) was refluxed for 12 h The mixture was cooled to R T and partitioned between EtOAc and water The organic layer was dried over sodium sulfate and concentrated to give a residue, which was purified by flash column chromatography (60% EtOAc / hexanes) to give the title compound as a white solid (301 mg, 58% yield) 1H NMR (400 MHz, CDCI3), δ 8 21 (s, 1 H), 7 90 (d, J=8 3 Hz, 1 H), 7 62 (d, J=8 3 Hz, 1 H), 7 56 (s, 1 H), 7 54 (m, 1 H), 7 04 (m, 1 H), 6 56 (m, 1 H), 2 30 (s, 3 H) Anal Calcd for C15H13N303S C, 57 13, H, 4 16, N, 13 33, Found C, 57 31, H, 4 22, N, 12 92
Method T Example 265: 4"-Cyano-biphenyl-4-sulfonic acid (2-dimethylamino-ethyl)-(6-methyl- pyridin-2-yl)-amide
Figure imgf000043_0002
2-(Dιmethylamιno)ethyl chloride hydrochloride (70 mg, 049 mmol, 1 8 equiv) was added to a solution of 4'-cyano-bιphenyl-4-sulfonιc acid (6-methyl-pyrιdιn-2-yl)-amιde (93 1 mg, 0266 mmol, 1 equiv), potassium carbonate (184 mg, 1 33 mmol, 5 00 equiv) in dimethylformamide (2 5 mL) at 24 °C The heterogenous solution was heated to 50 °C for 22 h Upon cooling to 24 °C, the reaction mixture was concentrated in vacuo (<1 mm Hg) The resulting residue was diluted with saturated aqueous sodium chloride (5 mL), saturated aqueous sodium bicarbonate (5 mL), and ethyl acetate (5 mL) The organic phase was separated, and the resulting aqueous solution was extracted with ethyl acetate (2 * 5 mL) The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated Purification by high performance flash chromatography (0→5% methanol / dichloromethane + 0 1% ammonium hydroxide) yielded alkylation product, which was converted to the hydrochloride salt by treatment with a methanolic hydrogen chloride solution (96 6 mg, 76%) Method U Example 266: 4'-Cyano-biphenyl-4-sulfonic acid (2-hydroxy-ethyl)-(6-mβthyl-pyridin-2- yl)-amide
Figure imgf000044_0001
Preparation of 4'-Cyaπo-biphenyl-4-sulfonic acid [2-(tert-butyl-dimethyl-silanyloxy)- ethyl]-(6-methyl-pyridin-2-yl)-amide
Figure imgf000044_0002
(2-Bromoethoxy)-tert-butyldimethylsilane (91 μL, 0.42 mmol, 1.5 equiv) was added to a solution of 4'-cyano-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide (99.1 mg, 0.284 mmol, 1 equiv) and potassium carbonate (202 mg, 1.46 mmol, 5.2 equiv) in dimethylformamide (2.5 mL) at 24 °C. The reaction mixture was maintained at 24 °C for 4.7 h before warming to 70 °C for 15.7 h. The reaction mixture was cooled to 24 °C and concentrated in vacuo (<1 mm Hg). The resulting residue was diluted with ethyl acetate (5 mL), saturated aqueous sodium chloride (3 mL), and saturated aqueous sodium bicarbonate (3 mL). The organic layer was separated, and the resulting aqueous layer was extracted with ethyl acetate (2 » 5 mL). The collected organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by high performance flash chromatography (12→50% ethyl acetate in hexanes) provided product (85.3 mg, 59%). 1H NMR (400 MHz, CDCI3), δ: 7.57-7.83 (m, 9 H), 7.40 (d, J = 8.1 Hz, 1 H), 6.99 (d, J = 7.6 Hz, 1 H), 4.00 (t, J = 6.2 Hz, 2 H), 3.78 (t, J = 6.2 Hz, 2 H), 2.41 (s, 3 H), 0.78 (s, 9 H), -0.03 (s, 6 H). 4'-Cyano-biphenyl-4-sulfonic acid (2-hydroxy-ethyl)-(6-methyl-pyridin-2-yl)-amide Tetrabutylammonium flouride (371 mL, 0.371 mmol, 2.0 equiv, 1.0 M in tetrahydrofuran) was added dropwise to an ice-cooled solution of 4'-Cyano-biphenyl-4- sulfonic acid [2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-(6-methyl-pyridin-2-yl)-amide (85.3 mg, 0.186 mmol, 1 equiv) in tetrahydrofuran (3 mL). After 50 min, saturated aqueous sodium chloride was added to the reaction mixture, and the resulting solution was extracted with ethyl acetate (3 * 5 mL). The collected organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by high performance flash chromatography (13% ethyl acetate in hexanes → ethyl acetate) provided product which was converted to the hydrochloride salt by treatment with a methanolic hydrogen chloride solution (58 mg, 76%). Method V Example 267: 6-(4-Cyano-phenyl)-pyridine-3-sulfonic acid (6-methyl-pyridin-2-yl)- amide
Figure imgf000045_0001
Preparation of 6-Chloro-pyridine-3-sulfonic acid (6-methyl-pyridin-2-yl)-amide
Figure imgf000045_0002
Made by following the procedure described for the preparation of 4'-cyano-biphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 6-chloro 3-pyridylsulfonyl chloride
(Naegeli, C; Kundig, W.; Brandenburger, H. Helv. Chem. Acta. 1939, 21, 1746) and making non-critical variations. APCI+ 284 [M+H]+ 100%.
6-(4-Cyano-phenyl)-pyridiπe-3-sulfonic acid (6-methyl-pyridin-2-yl)-amide A solution of 6-chloro-pyridine-3-sulfonic acid (6-methyl-pyridin-2-yl)-amide (188 mg, 0.573 mmol), 4-cyanoboronic acid (88 mg, 0.602 mmol), Pd(PPh3) (33 mg, 0.03 mmol), aqueous Na2C03 (0.72 mL, 1.43 mmol) in DMF (3 mL) was heated in microwave for 30 min.
The black mixture was partitioned between EtOAc and water. The organic layer was then washed with brine, dried over Na2S04 and concentrated to give an oil, which was chromatographed on silica gel to give title compound (86.3 mg, 43%) as a yellow solid.
Method W Example 269: N-(6-methylpyridin-2-yl)-6-piperidin-1-ylpyridine-3-sulfonamide
Figure imgf000045_0003
A mixture of 6-chloro-pyridine-3-sulfonic acid (6-methyl-pyridiπ-2-yl)-amide (233 mg,
0.823 mmol) and piperidine (4.17 mmol) in dioxane (5 mL) was heated at 100 °C in a Personal Chemistry Microwave oven for 30 min. The mixture was cooled and partitioned between EtOAc and water. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (50 to 70% EtOAc / Hexanes) furnished the title compound as a brown solid (177 mg, 65%). Method X Example 270: 4'-Cyano-3'-methoxy-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)- amide
Figure imgf000046_0001
Preparation of N-(6-Methyl-pyridin-2-yl)-4-(4,4,S,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- benzenesulfonamide
Figure imgf000046_0002
A mixture of 4-bromo-Λ/-(6-methyl-pyridin-2-yl)-benzenesulfonamide (13.7 g, 41.9 mmol), bis(pinacolato)diboron (10.7 g, 41.9 mmol), KOAc (14 g, 143mmol) and Pd(dppf)CI2 (1.7 g, 2.1 mmol) in DMSO (100 mL) was heated at 100 °C for 12 h. The mixture was cooled to room temperature, partitioned between EtOAc and water and filtered through Celite®. The organic layer was dried and concentrated. Purification by flash column chromatography (50% EtOAc / hexanes) furnished the boronate as a solid (15.5 g, 98%). 4'-Cyano-3'-methoxy-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide Made by following the procedure described for the preparation of 4'chlorobiphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting N-(6-methyl-pyridin-2-yl)-4- (4,4,5, 5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-benzenesulfonamide and 4-bromo-2- methoxybeπzonitrile and making non-critical variations.
Method Y Example 276: 4"-Cyano-3-methoxy-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)- amide
Figure imgf000046_0003
Preparation of 4-Bromo-2-methoxy-W-(6-methyl-pyridin-2-yl)-benzenesulfonamide To a solution of 1-bromo-3-methoxybenzene (3.1 g, 16.6 mmol) in CH2CI2 at 0 °C was added CIS03H (3.3 mL, 48 mmol). The mixture was warmed to R.T. and stirred for 2 h. The mixture was poured into ice and water and extracted with CH2CI2 (3X30 mL). The organic layer was dried over Na2S04, filtered, and concentrated to give a mixture of sulfonyl chlorides as an oil, which was used for the next reaction without purification. The above sulfonyl chloride was dissolved in pyridine (50 mL) and 2-methyl-6- aminopyridine (1.7 g, 16mmol) was added. The mixture was stirred overnight at R.T. The mixture was partitioned between EtOAc and water. The organic layer was dried and concentrated to the mixture of sulfonamides (3 to 1 by LCMS). The residue was purified by flash column chromatography to give the desired isomer as a white solid (0.87 g, 15% for two steps).
4'-Cyano-3-methoxy-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide Made by following the procedure described for the preparation of 4'-chlorobiphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 4-bromo-2-methoxy-Λ/-(6-methyl- pyridin-2-yl)-benzenesulfonamide and 4-cyanophenylboronic acid and making non-critical variations. Method Z
Example 277: 4'-Cyano-3-methyl-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)- amide
Figure imgf000047_0001
To a mixture of 4-bromo-2-methyl-N-(6-methyl-pyridin-2-yl)-benzenesulfonamide
(200mg, 0.6mmol) 4-cyanophenyl boronic acid (102mg, 0.7mmol) and cesium carbonate (585mg, 1.8mmol) in 1 ,4-dioxane (6mL) was added [2-[(D- κN)METHYL]PHENYL- κC](TRICYCLOHEXYLPHOSPHINE)(TRIFLUOROACETATO-κO-(SP-4-3)-PALLADIUM, (Bedford, R. B.; Cazin, C. S. J.; Coles, S. J.; Gelbrich, T.; Horton, P. N.; Hursthouse, M. B.; Light, M. E. Organometallics 2003, 22, 987), (2mg, 0.5mol%). Mixture heated at reflux for 4 hours. After such time reaction mixture was allowed to cool to ambient temperature, filtered through a pad of Celite® and concentrated in vacuo. Residue was purified by flash column chromatography (Si02 2g, dichloromenthane, methanol 0% & 1%) to return desired product as a white solid (19mg, O.Oδmmol, 9% yield). Method AA
Example 282: 4'-Cyano-3'-methyl-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)- amide
Figure imgf000047_0002
Preparation of 2-Methyl-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-benzonitrιle
Figure imgf000048_0001
Made following the procedur d for the preparation of N-(6-methyl-pyπdιn-2- yl)-4-(4,4,5,5-tetramethyl-[1 ,3,2]dιoxaborolan-2-yl)-benzenesulfonamιde but substituting 4- bromo-2-methyl-benzonιtrιle and making non-cπtical variations 1H NMR (400 MHz, CDCI3), δ ppm 7 63 (s, 1 H) 7 56 (d, J=7 6 Hz, 1 H) 745 (d, J=7 6 Hz, 1 H) 2 42 (s, 3 H) 1 24 (s, 12 H) 4"-Cyano-3'-methyl-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide Made by following the procedure described for the preparation of 4'chlorobιphenyl-4- sulfonic acid (6-methyl-pyπdιn-2-yl)-amιde but substituting 2-methyl-4-(4,4,5,5-tetramethyl- [1 ,3,2]dιoxaborolan-2-yl)-benzonιtrιle and N-(6-amιno-pyπdιn-2-yl)-4-bromo- benzenesulfonamide and making non-critical vanations
Method AB Example 283: 4'-Cyano-3-fluoro-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide
Figure imgf000048_0002
Preparation of 4-Bromo-2-fluoro-N-(6-methyl-pyridin-2-yl)-benzenesulfonamide Made following the procedure described for the preparation of 4'-cyano-bιphenyl-4- sulfonic acid (6-methyl-pyrιdιn-2-yl)-amιde but substituting 4-bromo-2-fluorobenzenesulfonyl chloride and making non-critical variations The crude material was earned to the next step 4'-Cyano-3-fluoro-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide Made following the procedure described for the preparation of 4'chlorobιphenyl-4- sulfonic acid (6-methyl-pyrιdιn-2-yl)-amιde but substituting 4-bromo-2-fluoro-N-(6-methyl- pyrιdιn-2-yl)-benzenesulfonamιde and 4-cyanophenylboronιc acid and making non-critical variations
Method AC Example 284: 4'-Cyano-2-fluoro-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide
Figure imgf000049_0001
Preparation of 4-Bromo-3-fluoro-N-(6-methyl-pyridin-2-yl)-benzenesulfonamide Made by following the procedure described for the preparation of 4'-cyano-biphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 4-bromo-3- (trifluoromethyl)benzenesulfonyl chloride and making non-critical variations. The crude material was carried to the next step. 4'-Cyano-2-fluoro-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide
Made by following the procedure described for the preparation of 4'chlorobiphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 4-bromo-3-fluoro-N-(6-methyl- pyridin-2-yl)-benzenesulfonamide and 4-cyanophenylboronic acid and making non-critical variations.
Method AD Example 285: 4"-Cyano-2-trifluoromethyl-biphenyl-4-sulfonic acid (6-methyl-pyridin-2- yl)-amide
Figure imgf000049_0002
Preparation of 4-Bromo-N-(6-methyl-pyridin-2-yl)-3-trifluoromethyl- benzenesulfonamide Made by following the procedure described for the preparation of 4'-cyano-biphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 4-bromo-3- (trifluoromethyl)beπzenesulfonyl chloride and making non-critical variations. The crude material was carried to the next step. 4'-Cyano-2-trifluoromethyl-biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide
Made by following the procedure described for the preparation of 4'chlorobiphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 4-bromo-N-(6-methyl-pyridin-2-yl)- 3-trifluoromethyl-benzenesulfonamide and 4-cyanophenylboronic acid and making non-critical variations.
Method AE Example 286: 4'-Cyano-3-hydroxy-bipheπyl-4-sulfonic acid (6-methyl-pyridin-2-yl)- amide
Figure imgf000050_0001
To a solution of 4'-cyano-3-methoxy-bιphenyl-4-sulfonιc acid (6-methyl-pyrιdιn-2-yl)- amide (28 mg, 0 073 mmol) in CH2CI2 (2 mL) was added BBr3 (02 mL, 1 0 M in CH2CI2) at 0 °C The mixture was warmed to 23 °C and stirred for 1 h The mixture was then quenched with saturated NaHC03 and extracted with EtOAc The organic layer was dried over sodium sulfate and concentrated to give a residue, which was purified by flash column chromatography to furnish the title compound as a white solid (17 mg, 65% yield) Method AF Example 287: 4-Pyridin-2-yl-N-quinolin-2-yl-benzenesulfonamide
Figure imgf000050_0002
Preparation of 4-bromo-Λ/-quinolin-2-ylbenzenesulfonamide
Figure imgf000050_0003
Made by following the procedure described for the preparation of 4'-cyano-bιphenyl-4- sulfonic acid (6-methyl-pyπdιn-2-yl)-amιde but substituting 6-bromophenylsulfonyl chloride and 2-amιnoquιnolιne and making non-critical variations 1H NMR (400 MHz, DMSO-d6), δ ppm 7 37 (t, J=7 58 Hz, 1 H) 744 - 7 51 (m, 1 H) 7 56 (d, =8 34 Hz, 1 H) 7 64 - 7 70 (m, 1 H) 7 70 - 7 74 (m, 2 H) 7 81 (d, J=8 59 Hz, 3 H) 8 23 (d, J=9 60 Hz, 1 H), APCI MS m/z 365 0 (M+2) 4-Pyridin-2-yl-N-quinolin-2-yl-benzβnesulfonamide To a solution of 4-bromo-Λ/-quιnolιn-2-ylbenzenesulfonamιde (50 mg) in 1,4 dioxane (2 0 ml) was added 2-bromopyπdιne (22 mg), tetrakιs(tπphenylphosphιne)palladιum (16 mg), hexamethylditin (50 mg) After the resulting mixture was heated in microwave at 130°C for 30 mins, it was filtered and concentrated under reduced pressure To the resulting residue was added 1 ,4 dioxane (2 0 mL), 2-bromopyπdιne (30 mg), tetrakιs(trιphenylphosphιne)palladιum (20 mg), hexamethylditin (50 mg) After the reaction mixture was heated in microwave at 130CC for 90 m , it was filtered and concentrated under reduced pressure The residue was purified using reversed phase Kromasil® C18, 0 05% TFA in water and acetonitrile to provide the titled product (5 4 mg) Method AG Example 290: 6-(4-Cyano-phenyl)-pyridine-3-sulfonic acid quinolin-2-ylamide
Figure imgf000051_0001
Preparation of 6-chloro-W-quinolin-2-ylpyridine-3-sulfonamide
Figure imgf000051_0002
Made by following the procedure describe for the preparation of 4'-cyano-biphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 2-aminoquinoline and 2-chloro- pyridin-5-sulfonyl chloride (Naegeli, C; Kundig, W.; Brandenburger, H. Helv. Chem. Acta. 1939, 21, 1746) and making non-critical variations.
6-(4-Cyano-phenyl)-pyridine-3-sulfonic acid quinolin-2-ylamide To a flask containing 6-chloro-Λ-quinolin-2-ylpyridine-3-sulfonamide (148 mg, 0.46 mmol) and 4-cyanophenylboronic acid (136 mg, 0.92 mmol) were added DME (1.5 mL), N,N- dimethylacetamide (2.0 mL), H20 (0.5 mL), Cs C03 (451 mg, 1.39 mmol). The reaction mixture was degassed by alternating between vacuum and nitrogen. After [1 ,1- bis(diphenylphosphino)-ferrocene]dichloropalladium (ll)-dicholoromethane complex (16 mg) was added, the reaction mixture was degassed again. After the resulting mixture was heated at 80°C for 19 hours, it was diluted with EtOAc (30 mL), sat NaHC03 (5mL). After the resulting mixture was stirred at R.T. for 5 min, it was filtered and diluted with sat NaHC03
(5mL). The layers were separated. The aqueous layer was extracted with EtOAc (2 x 15 L).
The combined organic extracts were dried with K2C03, filtered, and concentrated to give a solid. After triturating the resulting solid with CH2CI2, the desired product was obtained (59.7 mg). The mother liquor was purified using high performance flash chromatography (0→30% dichloromethane in acetone) to give an additional batch of desired product (33.3 mg).
Method AH
Example 293: 6-(4-Cyano-phenyl)-pyridine-3-sulfonic acid (6-cyclopropyl-pyridin-2-yl)- amidβ
Figure imgf000052_0001
Preparation of 6-Chloro-pyridine-3-sulfonic acid (6-cyclopropyl-pyridin-2-yl)-amide
Figure imgf000052_0002
Made by following the procedure described for the preparation of 4'-cyano-biphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 6-cyclopropyl-pyridin-2-ylamine and 6-chloro-3-pyridylsulfonyl chloride (Naegeli, C; Kundig, W.; Brandenburger, H. Helv. Chem. Acta. 1939, 21 , 1746) and making non-critical variations. 1H NMR (400 MHz, CDCI3), δ: 8.91 (d, J = 2.5 Hz, 1 H), 8.18 (dd, J = 8.4, 2.5 Hz, 1 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.43 (d, J = 8.3 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 1 H), 6.55 (d, J = 7.3 Hz, 1 H), 6.27 (d, J = 8.1 Hz, 1 H), 1.98-1.92 (m, 1 H), 1.14-1.09 (m, 2 H) 0.93-0.89 (m, 2 H); LCMS (ESI): 310.1.
6-(4-Cyano-phenyl)-pyridine-3-sulfonic acid (6-cyclopropyl-pyridin-2-yl)-amide Made by following the procedure described for the preparation of 4'chlorobiphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 6-chloro-pyridine-3-sulfonic acid (6- cyclopropyl-pyridin-2-yl)-amide and 4-cyanophenyl boronic acid and making non-critical variations.
Method Al Example 295: 5-Cyano-3-methyl-benzo[b]thiophene-2-sulfonic acid (6-methyl-pyridin- 2-yl)-amide
Figure imgf000052_0003
Preparation of 5-Bromo-3-methyl-benzo[b]thiophene-2-sulfonic acid (6-methyl-pyridin- 2-yl)-amide
Figure imgf000052_0004
Made by following the procedure described for the preparation of 4'-cyano-biphenyl-4- sulfonic acid (6-methyl-pyridin-2-yl)-amide but substituting 5-bromo-3-methyl- benzo[b]thiophene-2-sulfonyl chloride and making non-critical variations. 1H NMR (400 MHz, CDCI3), δ: 7.88 (d, J = 1.8 Hz, 1 H), 7.62 (d, J = 8.6 Hz, 1 H), 7.47-7.58 (m, 2 H), 7.11 (d, J = 9.1 Hz, 1 H), 6.54 (d, J = 7.3 Hz, 1 H), 2.68 (s, 3 H), 2.51 (s, 3 H); MS (ESI) for C15H14BrN2θ2S2 m/z 398.0. 5-Cyano-3-methyl-benzo[b]thiophene-2-sulfonic acid (6-methyl-pyridin-2-yl)-amide Copper (I) cyanide (43 mg, 0.476 mmol, 1.5 equiv) was added to a solution of 5- bromo-3-methyl-benzo[b]thiophene-2-sulfonic acid (6-methyl-pyridin-2-yl)-amide (126 mg, 0.317 mmol, 1 equiv) in dimethylformamide (2.5 mL) at 24 °C. The solution was heated to 250 °C by microwave for 10 min. Deionized water (5 mL), hexanes (2.5 mL), and diethyl ether (2.5 mL) were added, and the resulting tan solid was collected by filtration. Purification of the solid by preparative reverse phase HPLC (Kromasil® C18, 10μm, 250 x 50.8 mm, mobile phase: water / acetonitrile / 0.05% trifluoroacetic acid) provided the titled compound (30 mg, 27.5%).
Method AJ Example 296: Pyrrolidine-2-carboxylic acid [6-(3-chloro-2-methyl- benzenesulfonylamino)-pyridin-2-yl]-amide
Figure imgf000053_0001
A mixture of (6-amino-pyridin-2-yl)-3-chloro-2-methyl-benzenesulfonamide (140 mg,
0.47 mmol), pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (106 mg, 0.50 mmol), HATU (215 mg, 0.57 mmol) and Et3N (0.2 mL) in DMF (3 mL) was stirred at 23 °C for 12 h. The mixture was partitioned between EtOAc and water. The organic layer was dried and concentrated to give the crude amide as an oil, which was used directly in the next reaction. The amide was dissolved in CH2CI2 (2 mL), and HCI (4 ml; 4 N in dioxane) was added. The mixture was stirred at 23 °C for 12 h. The mixture was concentrated and the residue was purified by reverse-phase HPLC to give the title compound as a white solid (99 mg, 53%).
Method AK Example 297: 3-Pyridin-4-yl-pyrrolidine-1 -sulfonic acid (6-methyl-pyridin-2-yl)-amide
Figure imgf000053_0002
Preparation of W-(6-methylpyridin-2-yl)-2-oxo-1 ,3-oxazolidine-3-sulfonamide
Figure imgf000053_0003
Chlorosulfonyl isocyanate (0.27 mL, 4.1 mmol) was dissolved in 40 mL of CH2CI2 and cooled to 0 °C. Chloroethanol (0.27 mL, 4.1 mmol) was added slowly and the reaction mixture was stirred at 0 °C for 1.5 h. A solution of 6-methyl-2-aminopyridine (444 mg, 4.1 mmol) and E^ (1.3 ml, 12.4 mmol) in 50 mL of CH2CI2 was slowly added so that the reaction temperature did not exceed 5 °C. The reaction solution was slowly warmed to room temperature and stirred overnight. After acidic workup, the crude product was purified by triturating with CH2CI2 and hexane. 1H NMR (400 MHz, CDCI3) δ: 12.34 (s, 1 H) 7.62 (dd, J=8.8, 7.3 Hz, 1 H) 6.77 (d, J=8.8 Hz, 1 H) 6.57 (d, J=7Λ Hz, 1 H) 4.39 (t, J=8.0 Hz , 2 H) 4.15 (t, J=7.8 Hz, 2 H) 2.50 (s, 3 H). 3-Pyridin-4-yl-pyrrolidine-1 -sulfonic acid (6-methyl-pyridin-2-yl)-amide A solution of Λ/-(6-methylpyridin-2-yl)-2-oxo-1,3-oxazolidine-3-sulfonamide (0.23 g, 0.894 mmol), 4-pyrrolidin-3-ylpyridine (0.40 g, 2.23 mmol), and diisopropylethylamine (1 mL) in acetonitrile (3 mL) was heated to 130 °C using microwave heating for 0.5 hour. The reaction mixture was cooled to 25 °C, and diluted with ethyl acetate (50 mL). The resulting mixture was washed with saturated aqueous ammonium chloride (2 x 30 mL) and saturated aqueous sodium bicarbonate (2 x 30 mL). The organic layer was concentrated to give a clear oil. The residue was purified using radial chromatography (2 mm silica plate; 1:1 :0.1 dichloromethane / ethyl acetate / methanol). The product was triturated with additional diethyl ether and dried in vacuo to afford the title compound (0.19 g, 65.4%). Sulfamide formation may also occur without microwave by heating the reaction overnight to 82 °C in acetonitrile or 110 °C in dimethylformamide. Method AL
Example 317: 4-(4-Cyano-phenyl)-piperidine-1 -sulfonic acid (6-amino-pyridin-2-yl)- amide
Figure imgf000054_0001
Preparation of tert-Butyl (6-{[(2-oxo-1,3-oxazolidin-3-yl)sulfonyl]amino}pyridin-2- yl)carbamate
Figure imgf000054_0002
Made by following the procedure described for the preparation of /-(6-methylpyridin- 2-yl)-2-oxo-1 ,3-oxazolidine-3-sulfonamide but substituting tert-butyl (6-aminopyridin-2- yl)carbamate (Berl, et al Chem Eur J 2001, 7, 2798) and making non-critical variations. 1H NMR (400 MHz, CD2CI2), δ: 1.50 (s, 9 H) 4.05 - 4.11 (m, 2 H) 4.24 - 4.30 (m, 2 H) 6.64 (d, =7.83 Hz, 1 H) 7.32 (d, J=8.08 Hz, 1 H) 7.50 (t, J=8.08 Hz, 1 H). 4-(4-Cyano-phenyl)-piperidine-1 -sulfonic acid (6-amino-pyridin-2-yl)-amide A solution of tert-butyl (6-{[(2-oxo-1,3-oxazolidin-3-yl)sulfonyl]amino}pyridin-2- yl)carbamate (150 mg, 0.420 mmol), diisopropylethylamine (219 μL, 1.26 mmol), and 4-(4- cyanophenyl)piperidine (82 mg, 0.44 mmol) was subjected to microwaves at 110°C for 30 min. The reaction mixture was concentrated and the crude product was purified by flash chromatography eluting with hexanes/ ethyl acetate (0-25%). To a cooled (0-5cC) solution of the afforded material in CH2CI2 (1 mL) was added TFA (1 mL). After 2 hours, the reaction mixture was concentrated and the residue was partitioned between EtOAc (50 mL) and saturated NaHC03 (10 mL). The organic layer was separated and washed with brine (10 mL), dried (MgS04), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography eluting with CH2CI2/MeOH (0-5%) to afford the title compound (30 mg, 20%).
The structure, name, physical and biological data, and Methods are further described in tabular form below in Table 1. Table 1
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Various embodiments of the present invention have been described above but a person skilled in the art realizes further minor alterations that would fall into the scope of the present invention. The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

Claims

We Claim 1 A compound of formula (I) R1 N R2 (I) wherein R1 is selected from the group consisting of (Cι-C6)alkyl, -(CR3R )t(C3-C12)cycloalkyl,
-(CR3R4),(C6-C12)aryl, and -(CR3R )t(4-10)-membered heterocyclyl, b and k are each independently selected from 1 and 2, j is selected from the group consisting of 0, 1, and 2, t, u, p, q, and v are each independently selected from the group consisting of 0, 1 , 2, 3, 4, and 5, T is a (6-10)-membered heterocyclyl containing at least one nitrogen atom, R2 is selected from the group consisting of H, (d-C6)alkyl, -(CR3R4)t(C3-Cι2)cycloalkyl, -(CR3R ) (C6-Ci2)aryl, and -(CR3R4),(4-10)-membered heterocyclyl, each R3 and R4 is independently selected from H and (CrCβJalkyl, the carbon atoms of T, R1, R2, R3 and R4 may each be optionally substituted by 1 to 5 R5 groups, each R5 group is independently selected from the group consisting of halo, cyano, nitro, -CF3, -CHF2, -CH2F, trifluoromethoxy, azido, hydroxy, (d-CeJalkoxy, (d-CeJalkyl,
(C2-C6)alkenyl, (C2-C6)alkynyl, -(C=0)-R6, -(C=0)-0-R6, -0-(C=0)-R7, -0-(C=0)-NR7 , -NR8(C=0)-R9, -(C=0)-NR8R9, -NR8R9, -NR8OR9, -S(0)kNR8R9, -S(0),(C1-C6)alkyl, -0-S02-R9, -NR8-S(0)k -R9, -(CR10R11)V(C6-C12 aryl), -(CR10R11)v(4-10)-membered heterocyclyl, -(CR10R11)q(C=O)(CR10R11)v(C6-Ci2)aryl, -(CR10R11)q(C=O)(CR10R11)v(4-10)-membered heterocyclyl, -(CR10R11)vO(CR10R11)q(C6-C12)aryl, -(CR10R11)vO(CR10R11)q(4-10)-membered heterocyclyl, -(CR10R11)qS(O), (CR10R11)V(C6-Ci2)aryl, and -(CR^R^SfO), (CR10R11)v(4-10)-membered heterocyclyl, any 1 or 2 carbon atoms of any (4-10)-membered heterocyclyl of the foregoing R6 groups are optionally substituted with an oxo (=0), any carbon atom of any (CrCβJalkyl, any (C6-C12)aryl, and any (4-10)-membered heterocyclyl of the foregoing R5 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, -CF3, -CFH , -CF2H, trifluoromethoxy, azido, -OR12, -(C=0)-R12, -(C=0)-0-R13, -0-(C=0)-R13, -NR13(C=0)-R14, -(C=0)-NR15R16, -NR17R18, -NR14OR15, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(CR16R17)U(C6-C,2)aryl, and -(CR16R17)u(4-10)-membered heterocyclyl, each R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 , R16 and R17 group is independently selected from the group consisting of H, (C1-C6)alkyl, -(C=0)N(Ci-C6)alkyl, -(CR18R19)P(C6-C12)aryl, and -(CR18R19)p(4-10)-membered heterocyclyl, any 1 or 2 carbon atoms of the (4-10)-membered heterocyclyl of each said R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R 6 R17 group is optionally substituted with an oxo (=0); any carbon atom of any (CrC6)alkyl, any (C6-C12)aryl, and any (4-10)-membered heterocyclyl of the foregoing R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, -NR21R22, -CF3, -CHF2, -CH2F, trifluoromethoxy, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, and (CrC6) alkoxy; each R18, R19, R20, R21 and R22 group is independently selected from H and (Cι-Cβ)alkyl; and wherein any of the above-mentioned substituents comprising a -CH3 (methyl),
-CH2 (methylene), or -CH (methine) group which is not attached to a halo, -SO or -S02 group or to a N, O or S atom optionally bears on said group a substituent independently selected from the group consisting of hydroxy, halo, (d-C6)alkyl, (d-C6)alkoxy, -NH2, -NH(C C6)(alkyl) and -N((C1-C6)(alkyl))2; or a pharmaceutically acceptable salt or solvate thereof.
2. The compound according to claim 1 , wherein b is 2.
3. The compound according to claim 1 , wherein T is a 6-membered heterocyclyl containing at least one nitrogen atom.
4. The compound according to claim 1 wherein each R1 is selected from the group consisting of phenyl, biphenyl, benzothiophenyl, and napthyl and may optionally be substituted by 1 to 5 R6 groups; wherein: each R6 group is independently selected from the group consisting of halo, cyano, -CF3, hydroxy, (CrC6)alkoxy, (d-C6)alkyl, (C2-C6)alkenyl, -(CR10R11)p(4-10)-membered heterocyclyl, -(C=0)-R6, -(C=0)-0-R6, -0-(C=0)-R7, -NR8(C=0)-R9, -(C=0)-NR8R9, -NR8R9, -NR8OR9, -(CR10R11)-O-(CR10R11)p(C6-C12)aryl, and -(CR10R11)p-O-(CR10R11)p(4-10)- membered heterocyclyl.
5. A compound of formula (II):
Figure imgf000099_0001
wherein R1 is (Cι-C6)alkyl, -(CR7R8),(C3-Cιo)cycloalkyl, -(CR7R8),(C6-Cι0)aryl, or -(CR7R8)t(4-10)-membered heterocyclyl; b and k are each independently selected from 1 and 2; n and j are each independently selected from the group consisting of 0, 1, and 2; t. u, p, q and v are each independently selected from the group consisting of 0, 1 , 2,
3, 4, and 5; T is a (6-10)-membered heterocyclyl containing at least one nitrogen atom; W is selected from the group consisting of: v R2 ; R!; (d -C6) alkyl; and a 5-membered heterocyclyl; each R2, R3, and R are independently selected from the group consisting of H, (C,-C6)alkyl, -(CR7R8),(C3-C10)cycloalkyl, -(CR7R8),(C6-C10)aryl, and -(CR7R8)t(4-10)-membered heterocyclyl; each R2 and R3 may optionally be taken together with the nitrogen to which they are attached to form a (4-10)-membered heterocyclyl each R5 and R6 are independently selected from the group consisting of H, (Cι-C6) alkyl,
-((CCRR77R8)t(C3-C10)cycloalkyl, -(CR7R8),(C6-C10)aryl, and -(CR7R8),(4-10)-membered heterocyclyl or R5 and R6 may optionally be taken together with the carbon to which they are attached to form a (C3-C6)cycloalkyl or a (3-7)-membered heterocyclyl; each R7 and R8are independently selected from H and (d-C6)alkyl; the carbon atoms of T, R1, R2, R3, R4 , R5, R6, R7, R8 , and said W 5-membered heterocyclyl are optionally substituted by 1 to 5 R9 groups; each R9 group is independently selected from the group consisting of halo, cyano, nitro,
-CF3, -CHF2, -CH F, trifluoromethoxy, azido, hydroxy, (d-C6)alkoxy, (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(C=0)-R10, -(C=0)-0-R11, -0-(C=0)-R11, -NR11(C=0)-R12, -(C=0)-NR11R12, -NR11R12, -NR11OR12, -S(0)kNR11R12, -S O^d-Q alkyl, -0-S02-R1°, -NR11-S(0)k -R12, -(CR13R14)v(C6-Cιo aryl), -(CR13R1 )v(4-10)-membered heterocyclyl, -(CR13R1 )q(C=O)(CR13R14)v(C6-C10)aryl, -(CR13R14)q(C=O)(CR13R1 )v(4-10)-membered heterocyclyl, -(CR13R14)vO(CR13R1 )q(C6-C10)aryl, -(CR13R14)vO(CR13R14)q(4-10)-membered heterocyclyl, -(CR13R14)qS(0)J(CR13R1 )v(C6-Cio)aryl, and -(CR13R14)qS(O)J(CR13R14)v(4-10)-membered heterocyclyl; any 1 or 2 carbon atoms of any (4-10)-membered heterocyclyl of the foregoing R9 groups are optionally substituted with an oxo (=0); any carbon atom of any (CrCβJalkyl, any (C6-Cιo)aryl and any (4-10)-membered heterocyclyl of the foregoing R9 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, -CF3, -CFH2, -CF2H, trifluoromethoxy, azido, -OR15, -(C=0)-R15, -(C=0)-0-R15, -0-(C=0)-R15, -NR15(C=0)-R16, -(C=0)-NR15R16, -NR15R16, -NR15OR16, (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(CR17R18)u(C6-Cιo)aryl, and -(CR17R18)u(4-10)-membered heterocyclyl; each R10, R11, R12, R13, R14, R15, R16, R17, and R18 group is independently selected from the > ggιroup consisting of H, (CrC6)alkyl, -(CR19R20)P(C6-C10)aryl, and (CR19R20)P(4-10)-membered heterocyclyl; any 1 or 2 carbon atoms of the (4-10)-membered heterocyclyl of said each R10, R11, R12, R13, R14, R15, R16, R17, and R18 group is optionally substituted with an oxo (=0); any carbon atom of any (d-C6)alkyl, any (C6-C10)aryl and any (4-10)-membered heterocyclyl of the foregoing R , R R12, R13, ,14 R 15 ,16 R17, and R18 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, -NR21R22, -CF3, -CHF2, -CH2F, trifluoromethoxy, (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, and (d-C6) alkoxy; each R19, R20, R21, and R22 group is independently selected from H and (CrC6)alkyl; and wherein any of the above-mentioned substituents comprising a -CH3 (methyl), -CH2 (methylene), or -CH (methine) group which is not attached to a halo, -SO or -S02 group or to a N, O or S atom optionally bears on said group a substituent independently selected from the group consisting of hydroxy, halo, (d-C6)alkyl, (d-C6)alkoxy, amino, -NH(d-C6)(alkyl) and -N(C1-C6)(alkyl)(C1-C6) alkyl; or a pharmaceutically acceptable salt or solvate thereof.
6. The compound according to claim 5, wherein W is A.
7. The compound according to claim 5, wherein W is
Figure imgf000101_0001
8. The compound according to claim 5, wherein W is a 5-membered heterocyclyl. 9. The compound according to claim 8, wherein said 5-membered heterocyclyl is selected from the group consisting of oxazolyl, thiazolyl, pyrazolyl, tπazolyl, and oxadiazolyl. 10. The compound according to claim 5, wherein b is 2. 11. The compound according to claim 5, wherein T is a 6-membered heterocyclyl containing at least one nitrogen atom. 12. The compound according to claim 6, wherein R2 and R3 are taken together with the nitrogen to which they are attached to form a (4-10)-membered heterocyclyl. 13. A compound selected from the group consisting of:
Figure imgf000101_0002
Figure imgf000102_0001
or a pharmaceutically acceptable salt or solvate thereof. 14. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or claim 5, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. 15. A method of treating diabetes, metabolic syndrome, insulin resistance syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ, the method comprising administering to a mammal an effective amount of a compound according to claim 1 or claim 5 or a pharmaceutically acceptable salt or solvate thereof.
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