WO2013173382A1 - Benzothiophène sulfonamides et autres composés qui interagissent avec une protéine régulatrice de la glucokinase - Google Patents

Benzothiophène sulfonamides et autres composés qui interagissent avec une protéine régulatrice de la glucokinase Download PDF

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Publication number
WO2013173382A1
WO2013173382A1 PCT/US2013/041011 US2013041011W WO2013173382A1 WO 2013173382 A1 WO2013173382 A1 WO 2013173382A1 US 2013041011 W US2013041011 W US 2013041011W WO 2013173382 A1 WO2013173382 A1 WO 2013173382A1
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WIPO (PCT)
Prior art keywords
pyridinyl
methyl
benzothiophen
methylethyl
cyclopropanesulfonamide
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PCT/US2013/041011
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English (en)
Inventor
Kate Ashton
Michael D. Bartberger
Matthew Paul Bourbeau
Michael D. Croghan
Christopher H. Fotsch
Randall W. Hungate
Ke KONG
Nobuko Nishimura
Mark H. Norman
Lewis D. Pennington
Andreas Reichelt
Aaron C. Siegmund
Seifu Tadesse
David ST. JEAN Jr
Kevin C. Yang
Guomin Yao
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Amgen Inc.
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Publication of WO2013173382A1 publication Critical patent/WO2013173382A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to benzothiophene sulfonamides and other compounds, or pharmaceutically acceptable salts thereof, as defined herein, that interact with glucokinase regulatory protein.
  • the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the
  • Glucokinase is a member of a family of four hexokinases that are critical in the cellular metabolism of glucose. Specifically GK, also known as hexokinase IV or hexokinase D, facilitates glucose induced insulin secretion from pancreatic ⁇ -cells as well as glucose conversion into glycogen in the liver. GK has a unique catalytic activity that enables the enzyme to be active within the physiological range of glucose (from 5mM glucose to lOmM glucose).
  • mice lacking both copies of the GK gene die soon after birth from severe hyperglycemia, whereas mice lacking only one copy of the GK gene present with only mild diabetes. Mice that are made to overexpress the GK gene in their livers are hypoglycemic.
  • GK activity in the liver is transiently regulated by glucokinase regulatory protein (GK P).
  • GK catalytic activity is inhibited when GK is bound to GKRP. This interaction is antagonized by increasing concentrations of both glucose and fructose -1 -phosphate (F1P).
  • the complex of the two proteins is localized primarily to the nuclear compartment of a cell. Post prandially as both glucose and fructose levels rise, GK released from GKRP translocates to the cytoplasm. Cytoplasmic GK is now free of the inhibitory effects of GKRP and able to kinetically respond to glucose. Evidence from the Zucker diabetic fatty rat (ZDF) indicates that their glucose intolerance may be a result of this mechanism failing to function properly.
  • ZDF Zucker diabetic fatty rat
  • a compound that acts directly on GKRP to disrupt its interaction with GK and hence elevate levels of cytoplasmic GK is a viable approach to modulate GK activity. Such an approach would avoid the unwanted hypoglycemic effects of over stimulation of GK catalytic activity, which has been seen in the
  • GK activators A compound having such an effect would be useful in the treatment of diabetes and other diseases and/or conditions in which GKRP and/or GK plays a role.
  • the present invention provides compounds that bind GKRP and disrupts its interaction with GK.
  • the present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:
  • I * is a chiral center having the R configuration
  • X 1 is N or CH
  • X 2 is N or CH
  • X' is N or CH
  • X 4 is N or CH
  • X 5 is N or CH
  • heteroaryl group has from 1 to 4 heteroatoms independently selected from O, N or S, which cycloalkyl, aryl or heteroaryl group may be unsubstituted or substituted with from one to three substituents independently selected from halo, -OCi_ 6 alkyl, -OCi_ 6 haloalkyl,-OH, -NH 2 , Ci_ 6 alkyl or Ci_ 6 haloalkyl;
  • R 2 is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, where the phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl group can be unsubstituted or substituted with from one to three substituents independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2 _ 6 alkenyl, halo, -SCi_ 6 alkyl, -OCi_ 6 alkyl,
  • -OCi_ 6 haloalkyl -OH, -NH 2 , -N0 2 or -N(Ci_ 6 alkyl) 2 ;
  • n 0, 1, 2, 3 or 4;
  • R 4 is hydrogen or Ci_ 6 alkyl
  • R 5 is hydrogen, Ci_ 6 alkyl or Ci_ 6 haloalkyl.
  • the invention provides compounds in accordance with embodiment 1 , or pharmaceutically acceptable salts thereof, wherein Y is
  • the invention provides compounds in accordance with any one of embodiments 1 or 2, or pharmaceutically acceptable salts thereof, wherein X 1 is CH.
  • the invention provides compounds in accordance with any one of embodiments 1 or 2, or pharmaceutically acceptable salts thereof, wherein X 1 is N.
  • the invention provides compounds in accordance with any one of embodiments 1 to 4, or pharmaceutically acceptable salts thereof, wherein X 2 is CH.
  • the invention provides compounds in accordance with any one of embodiments 1 to 5, or pharmaceutically acceptable salts thereof, wherein X 3 is CH.
  • the invention provides compounds in accordance with any one of embodiments 1 to 6, or pharmaceutically acceptable salts thereof, wherein X 4 is CH.
  • the invention provides compounds in accordance with any one of embodiments 1 to 6, or pharmaceutically acceptable salts thereof, wherein X 4 is N.
  • the invention provides compounds in accordance with any one of embodiments 1 or 2, or pharmaceutically acceptable salts thereof, wherein X 1 , X 2 , X 3 , X 4 and X 5 are CH, and X 6 is S.
  • the invention provides compounds in accordance with any one of embodiments 1 or 2, or pharmaceutically acceptable salts thereof, wherein X 1 , X 2 , X 3 and X 4 are CH, X 5 is N, and X 6 is S.
  • the invention provides compounds in accordance with any one of embodiments 1 or 2, or pharmaceutically acceptable salts thereof, wherein X 1 is N, X 2 , X 3 and X 4 are CH, X 5 is CH, and X 6 is S.
  • the invention provides compounds in accordance with any one of embodiments 1 to 11 , or pharmaceutically acceptable salts thereof, wherein R 4 is hydrogen.
  • the invention provides compounds in accordance with any one of embodiments 1 to 12, or pharmaceutically acceptable salts thereof, wherein R 1 is Ci_ 6 alkyl, three to eight membered cycloalkyl, phenyl or pyridyl, which cycloalkyl, phenyl or pyridyl groups may be unsubstituted or substituted with from one to three substituents independently selected from halo, -OCi_ 6 alkyl, -NH 2 or Ci_ 6 alkyl.
  • the invention provides compounds in accordance with any one of embodiments 1 to 12, or pharmaceutically acceptable salts thereof, wherein R 1 is three to eight membered cycloalkyl, substituted phenyl or substituted pyridyl.
  • the invention provides compounds in accordance with any one of embodiments 1 to 12, or pharmaceutically acceptable salts thereof, wherein R 1 is cyclopropyl or substituted cyclopropyl.
  • the invention provides compounds in accordance with any one of embodiments 1 to 15, or pharmaceutically acceptable salts thereof, wherein R 2 is phenyl or substituted phenyl.
  • the invention provides compounds in accordance with any one of embodiments 1 to 15, or pharmaceutically acceptable salts thereof, wherein R 2 is pyridyl or substituted pyridyl.
  • the invention provides compounds in accordance with any one of embodiments 1 to 15, or pharmaceutically acceptable salts thereof, wherein R 2 is
  • the invention provides compounds in accordance with any one of embodiments 1 to 18, or pharmaceutically acceptable salts thereof, wherein R 3 is
  • the invention provides compounds in accordance with any one of embodiments 1 to 18, or pharmaceutically acceptable salts thereof, wherein R 3 is
  • the present invention also provides a compound, or a pharmaceutically acceptable salt thereof, selected from:
  • the present invention provides methods of treating type 2 diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, retinopathy, nephropathy, neuropathy, cataracts, glaucoma, Syndrome X, or polycystic ovarian syndrome, the methods comprising administering to a patient in need thereof a therapeutically effective amount of a compound in accordance with any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of embodiment 22 wherein the method of treatment is for type 2 diabetes.
  • the present invention provides pharmaceutical compositions comprising a compound in accordance with any one of
  • the present invention provides compounds of Formula
  • I * is a chiral center having the R configuration, except when X 6 is N, then * is a chiral center having the S configuration;
  • X 1 is N, CH or C-halo
  • X 2 is N, CH or C-halo
  • X 3 is N, CH or C-halo
  • X 4 is N or CH
  • X 5 is N or CH
  • X b is S or NH
  • R 1 is Ci_ 6 alkyl, -N(C 1-6 alkyl) 2 , -N(H)three to eight membered cycloalkyl,
  • cycloalkyl six to ten membered aryl or five to ten membered heteroaryl, where the heteroaryl group has from 1 to 4 heteroatoms independently selected from O, N or S, which cycloalkyl, aryl or heteroaryl group may be unsubstituted or substituted with from one to three substituents independently selected from halo, -OCi_ 6 alkyl, -OCi_ 6 haloalkyl,-OH, -NH 2 , Ci_ 6 alkyl or Ci_ 6 haloalkyl;
  • R is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or thiazolyl where the phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or thiazolyl group can be unsubstituted or substituted with from one to three substituents independently selected
  • n 0, 1, 2, 3 or 4
  • m 0, 1 or 2;
  • R 4 is hydrogen or Ci_6alkyl; hydrogen, Ci- 6 alkyl or Ci_ 6 haloalkyl;
  • R 6 is hydrogen or halo, provided that R 1 is not dimethoxyphenyl.
  • the present invention provides compounds in accordance with embodiment 1 A, or pharmaceutically acceptable salts thereof, wherein:
  • X 1 is N or CH
  • X 2 is N or CH
  • X 3 is N or CH;
  • R 1 is Ci_ 6 alkyl, -N(Ci_ 6 alkyl) 2 , three to eight membered cycloalkyl, six to ten membered aryl or five to ten membered heteroaryl, where the heteroaryl group has from 1 to 4 heteroatoms independently selected from O, N or S, which cycloalkyl, aryl or heteroaryl group may be unsubstituted or substituted with from one to three substituents independently selected from halo, -OCi_ 6 alkyl, -OCi_ 6 haloalkyl,-OH, -NH 2 , Ci_ 6 alkyl or Ci_ 6 haloalkyl;
  • R 2 is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, where the phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl group can be unsubstituted or substituted with from one to three substituents independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2 _ 6 alkenyl, halo, -SCi_ 6 alkyl, -OCi_ 6 alkyl,
  • the present invention provides compounds in accordance with any one of embodiments 1 A or 2A, or pharmaceutically acceptable salts thereof, wherein Y is
  • the present invention provides compounds in accordance with any one of embodiments 1 A or 3 A, or pharmaceutically acceptable salts thereof, wherein X 1 is CH.
  • the present invention provides compounds in accordance with any one of embodiments 1 A or 3 A, or pharmaceutically acceptable salts thereof, wherein X 1 is N.
  • the present invention provides compounds in accordance with any one of embodiments 1 A or 3 A to 5 A, or pharmaceutically acceptable salts thereof, wherein X 2 is CH.
  • the present invention provides compounds in accordance with any one of embodiments 1 A or 3 A to 5 A, or pharmaceutically acceptable salts thereof, wherein X 2 is C-halo.
  • the present invention provides compounds in accordance with any one of embodiments 1 A or 3 A to 7 A, or pharmaceutically acceptable salts thereof, wherein X 3 is CH.
  • the present invention provides compounds in accordance with any one of embodiments 1 A or 3 A to 7 A, or pharmaceutically acceptable salts thereof, wherein X 3 is N.
  • the present invention provides compounds in accordance with any one of embodiments 1 A to 9 A, or pharmaceutically acceptable salts thereof, wherein X 4 is CH.
  • the present invention provides compounds in accordance with any one of embodiments 1 A to 9 A, or pharmaceutically acceptable salts thereof, wherein X 4 is N.
  • the present invention provides compounds in accordance with embodiment 1 A, or pharmaceutically acceptable salts thereof, wherein X 1 , X 2 , X 3 , X 4 and X 5 are CH, and X 6 is S.
  • the present invention provides compounds in accordance with embodiment 1 A, or pharmaceutically acceptable salts thereof, wherein X 1 , X 2 , X 3 and X 4 are CH, X 5 is N, and X 6 is S.
  • the present invention provides compounds in accordance with embodiment 1 A, or pharmaceutically acceptable salts thereof, wherein X 1 is N, X 2 , X 3 and X 4 are CH, X 5 is CH, and X 6 is S.
  • the present invention provides compounds in accordance with any one of embodiments 1 A to 14A, or pharmaceutically acceptable salts thereof, wherein R 4 is hydrogen.
  • the present invention provides compounds in accordance with any one of embodiments 1A or 3 A to 15 A, or pharmaceutically acceptable salts thereof, wherein R 1 is Ci_ 6 alkyl, three to eight membered cycloalkyl, phenyl or pyridyl, which cycloalkyl, phenyl or pyridyl groups may be unsubstituted or substituted with from one to three substituents independently selected from halo, -OCi_ 6 alkyl, -NH 2 or Ci_ 6 alkyl.
  • the present invention provides compounds in accordance with any one of embodiments 1A or 3 A to 15 A, or pharmaceutically acceptable salts thereof, wherein R 1 is three to eight membered cycloalkyl, substituted phenyl or substituted pyridyl.
  • the present invention provides compounds in accordance with any one of embodiments 1A or 3 A to 15 A, or pharmaceutically acceptable salts thereof, wherein R 1 is cyclopropyl or substituted cyclopropyl.
  • the present invention provides compounds in accordance with any one of embodiments 1A or 3 A to 18 A, or pharmaceutically acceptable salts thereof, wherein R 2 is phenyl or substituted phenyl.
  • the present invention provides compounds in accordance with any one of embodiments 1A or 3 A to 18 A, or pharmaceutically acceptable salts thereof, wherein R 2 is pyridyl or substituted pyridyl.
  • the present invention provides compounds in accordance with any one of embodiments 1A or 3 A to 18 A, or pharmaceutically acceptable salts thereof, wherein R 2 is
  • the present invention provides compounds in accordance with any one of embodiments 1 A or 3 A to 21 A, or pharmaceutically acceptable salts thereof, wherein R 3 is
  • the present invention provides compounds in accordance with any one of embodiments 1 A or 3 A to 21 A, or pharmaceutically acceptable salts thereof, wherein R 3 is
  • the present invention provides compounds in accordance with any one of embodiments 1 A or 3 A to 21 A, or pharmaceutically acceptable salts thereof, wherein R 3 is
  • the present invention provides compounds in accordance with any one of embodiments 1 A or 3 A to 21 A, or pharmaceutically acceptable salts thereof, wherein R 3 is
  • the present invention provides compounds in accordance with any one of embodiments 1 A to 25 A, or pharmaceutically acceptable salts thereof, wherein m is 0.
  • the present invention provides compounds in accordance with any one of embodiments 1 A to 25 A, or pharmaceutically acceptable salts thereof, wherein m is 1.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, selected from:
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, selected from:
  • the present invention provides methods of treating type 2 diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, retinopathy, nephropathy, neuropathy, cataracts, glaucoma, Syndrome X, or polycystic ovarian syndrome, the methods comprising administering to a patient in need thereof a therapeutically effective amount of a compound in accordance with any one of embodiments 1 A to 29 A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides methods of embodiment 30A wherein the treatment is for type 2 diabetes.
  • the present invention provides pharmaceutical compositions comprising a compound in accordance with any one of
  • the present invention provides benzothiophene sulfonamides and other compounds, as defined above, or pharmaceutically acceptable salts thereof.
  • the present invention also provides pharmaceutical compositions comprising a compound of the present invention, or pharmaceutically acceptable salts thereof, and methods of treating diseases and/or conditions, such as diabetes, using compounds of the present invention, or pharmaceutically acceptable salts thereof.
  • alkyl means a straight or branched chain hydrocarbon.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl and hexyl.
  • Typical alkyl groups are alkyl groups having from 1 to 8 carbon atoms, which groups are commonly represented as Ci-galkyl.
  • haloalkyl mean a straight or branched chain hydrocarbon wherein one or more hydrogen atom is replaced with a halogen.
  • Typical haloalkyl groups are haloalkyl groups having from 1 to 8 carbon atoms, which groups are commonly represented as Ci-shaloalkyl.
  • Common haloalkyl groups include -CF 3 , -CHF 2 or -CH 2 F.
  • alkoxy means an alkyl group bonded to an oxygen atom.
  • alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy and isobutoxy.
  • Common alkoxy groups are Ci-galkoxy.
  • halogen or halo means chlorine, fluorine, bromine or iodine.
  • alkenyl means a branched or straight chain hydrocarbon having one or more carbon-carbon double bonds.
  • Representative examples alkenyl groups include ethenyl, propenyl, allyl, butenyl and 4-methylbutenyl.
  • Common alkenyl groups are C 2 - 8 alkenyl.
  • alkynyl means a branched or straight chain hydrocarbon having one or more carbon-carbon triple bonds. Representative examples of alkynyl groups include ethynyl, propynyl (propargyl) and butynyl. Common alkynyl groups are C 2 -g alkynyl.
  • cycloalkyl means a cyclic, nonaromatic hydrocarbon.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a cycloalkyl group can contain one or more double bond.
  • Examples of cycloalkyl groups that contain double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl and cyclobutadienyl.
  • Common cycloalkyl groups are C3-8 cycloalkyl groups.
  • perfluoroalkyl means an alkyl group in which all of the hydrogen atoms have been replaced with fluorine atoms.
  • perfluoroalkyl groups are Ci-sperfluoroalkyl.
  • An example of a common perfluoroalkyl group is CF 3 .
  • acyl means a group derived from an organic acid by removal of the hydroxy group (-OH).
  • aryl means a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Common aryl groups are six to thirteen membered rings.
  • heteroatom as used herein means an oxygen, nitrogen or sulfur atom.
  • heteroaryl means a cyclic, aromatic hydrocarbon in which one or more carbon atoms of an aryl group have been replaced with a heteroatom. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different.
  • heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, indolyl, triazolyl, pyridazinyl, indazolyl, purinyl, isoquinolyl, quinolyl, naphthyridinyl, quinoxalinyl, isothiazolyl and benzo[b]thienyl.
  • Common heteroaryl groups are five to thirteen membered rings that contain from 1 to 4 heteroatoms. Heteroaryl groups that are five and six membered rings that contain 1 to 3 heteroatoms are particularly common.
  • heterocycloalkyl means a cycloalkyl group in which one or more of the carbon atoms has been replaced with a heteroatom.
  • heterocycloalkyl group contains more than one heteroatom, the heteroatoms may be the same or different.
  • heterocycloalkyl groups include tetrahydrofuryl, morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl. It is also possible for the heterocycloalkyl group to have one or more double bonds, but is not aromatic. Examples of heterocycloalkyl groups containing double bonds include dihydrofuran.
  • Common heterocycloalkyl groups are three to ten membered rings containing from 1 to 4 heteroatoms. Heterocycloalkyl groups that are five and six membered rings that contain 1 to 2 heteroatoms are particularly common.
  • cyclic ring groups i.e., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, can comprise more than one ring.
  • the naphthyl group is a fused bicyclic ring system.
  • the present invention include ring groups that have bridging atoms, or ring groups that have a spiro orientation.
  • five to six membered aromatic rings are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl, and pyrazinyl.
  • Representative examples of partially saturated, fully saturated or fully unsaturated five to eight membered rings, optionally having one to three heteroatoms, are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl.
  • Further exemplary five membered rings are furyl, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H- imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl,
  • FIG. 1 For exemplary six membered rings are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1 ,2-dioxinyl, 1,3-dioxinyl, 1 ,4-dioxanyl, morpholinyl, 1,4- dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl, 4H-l,2-oxazinyl, 2H-l,3-oxazinyl, 6H-l,3-oxazinyl, 6H-l,2-oxazinyl, 1 ,4-oxazinyl, 2H-1,2- oxazinyl, 4H-l,4-oxazinyl
  • exemplary seven membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4-triazepinyl.
  • FIG. 1 Further exemplary eight membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.
  • Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, optionally having one to four heteroatoms, are indolizinyl, indolyl, isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, lH-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, is
  • a cyclic ring group may be bonded to another group in more than one way. If no particular bonding arrangement is specified, then all possible arrangements are intended.
  • pyridyl includes 2-, 3-, or 4- pyridyl
  • thienyl includes 2-, or 3-thienyl.
  • substituted means that a hydrogen atom on a molecule or group is replaced with a group or atom.
  • R x groups may be joined together with the nitrogen atom to form a ring.
  • a group or atom that replaces a hydrogen atom is also called a
  • Any particular molecule or group can have one or more substituent depending on the number of hydrogen atoms that can be replaced.
  • the symbol "-" represents a covalent bond and can also be used in a radical group to indicate the point of attachment to another group. In chemical structures, the symbol is commonly used to represent a methyl group in a molecule.
  • terapéuticaally effective amount means an amount of a compound that ameliorates, attenuates or eliminates one or more symptom of a particular disease or condition, or prevents or delays the onset of one of more symptom of a particular disease or condition.
  • patient means animals, such as dogs, cats, cows, horses, sheep and humans. Particular patients are mammals.
  • patient includes males and females.
  • pharmaceutically acceptable means that the referenced substance, such as a compound of the present invention or a formulation containing a compound of the present invention, or a particular excipient, are suitable for administration to a patient.
  • treating include preventative (e.g., prophylactic) and palliative treatment.
  • patient in need thereof means a patient who has or is at risk of having a GKRP/GK mediated disease or condition, such as type 2 diabetes.
  • excipient means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or
  • the compounds of the present invention are administered to a patient in a therapeutically effective amount.
  • the compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation.
  • the compounds or compositions can be administered all at once, as for example, by a bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. It is also noted that the dose of the compound can be varied over time.
  • the compounds of the present invention can be administered alone, in combination with other compounds of the present invention, or with other pharmaceutically active compounds.
  • the other pharmaceutically active compounds can be intended to treat the same disease or condition as the compounds of the present invention or a different disease or condition. If the patient is to receive or is receiving multiple pharmaceutically active compounds, the compounds can be administered simultaneously, or sequentially.
  • the active compounds may be found in one tablet or in separate tablets, which can be administered at once or sequentially in any order.
  • the compositions may be different forms. For example, one or more compound may be delivered via a tablet, while another is administered via injection or orally as a syrup. All combinations, delivery methods and administration sequences are contemplated.
  • the compounds of the present invention may be used in the manufacture of a medicament for the treatment of a disease and/or condition mediated by GKRP/GK, such as type 2 diabetes.
  • the compounds of the present invention may be used in combination with other pharmaceutically active compounds. It is noted that the term
  • pharmaceutically active compounds can include biologies, such as proteins, antibodies and peptibodies.
  • examples of other pharmaceutically active compounds include, but are not limited to: (a) dipeptidyl peptidase IV (DPP-IV) inhibitors such as Vildagliptin (Novartis), Sitagliptin (Merck&Co.), Saxagliptin (BMS) Alogliptin (Takeda); (b) insulin sensitizers including (i) PPARy agonists such as the glitazones (e.g., troglitazone, pioglitazone, edaglitazone,
  • DPP-IV dipeptidyl peptidase IV
  • glitazones e.g., troglitazone, pioglitazone, edaglitazone
  • PPARa/ ⁇ dual agonists such as muraglitazar (BMS) and tesaglitazar (AstraZeneca), and PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (II) biguanides such as metformin and phenformin, and (iii) protein tyrosine phosphatase-lB (PTP-1B) inhibitors; (c) insulin or insulin mimetics; (d) incretin and incretin mimetics such as (i) Exenatide available from Amylin Pharmaceuticals, (i) amylin and amylin mimetics such as pramlintide acetate, available as Symlin ® , (iii) GLP-1, GLP-1 mimetics, and GLP-1
  • dialkylaminoalkyl derivatives of a cross-linked dextran (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPARa/ ⁇ dual agonists such as muraglitazar (BMS) and tesaglitazar (AstraZeneca), (vi) inhibitors of cholesterol absorption, such as beta-sitosterol and ezetimibe, (vii) acyl CoAxholesterol acyltransferase inhibitors such as avasimibe, and (viii) antioxidants such as probucol; (j) PPAR5 agonists such as GW-501516 from GSK; (k) anti-obesity compounds such as fenfluramine, dexfenflur
  • the compounds of the present invention may also be used in combination with GPR40 agonists.
  • glucokinase activators that can be used in combination with the compounds of the present invention include those set forth in published PCT patent application no. WO 2009/042435, published April 2, 2009.
  • ILl-Rl compounds set forth in U.S. patent no. 7,438,910.
  • a particular disease that can be treated with the combination is type 2 diabetes.
  • the compounds of the present invention can also be used in combination with FGF-21 compounds, and particularly for the treatment of type 2 diabetes.
  • FGF-21 compounds are disclosed in U.S. patent no. 7,671,180; U.S. patent no. 7,667,008; U.S. patent no. 7,459,540; U.S. patent no. 7,696,172; PCT application publication no. WO 2010/042747; and PCT application publication no. WO 2009/149171.
  • the compounds of the present invention can be also be used in combination with anakinra, particularly for the treatment of type 2 diabetes.
  • the compounds of the present invention may be used in combination with metformin.
  • the compounds of the present invention are used in the treatment diseases or symptoms mediated by GKRP and/or GK (GKRP/GK).
  • diseases or symptoms mediated by GKRP/GK include, but are not limited to, Type II (type 2) diabetes and related disorders, such as hyperglycemia, low or impaired glucose tolerance, insulin resistance, obesity, lipid disorders such as
  • dyslipidemia hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis, and vascular restenosis, irritable bowel syndrome, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, other inflammatory conditions, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, cataracts, glaucoma, glomerulosclerosis, foot ulcerations and unlcerative colitis, altered gastrointestinal motility, Syndrome X, ovarian hyperandrogenism, polycystic ovarian syndrome, premenstrual syndrome, other disorders where insulin resistance is a component.
  • Syndrome X also known as Metabolic Syndrome
  • obesity is thought to promote insulin resistance, diabetes, dyslipidemia, hypertension, and increased cardiovascular risk, growth hormone deficiency, neutropenia, neuronal disorders, tumor invasion and metastasis, benign prostatic hypertrophy, gingivitis, osteoporosis, frailty of aging, intestinal injury, benign prostatic hypertrophy (BPH), and sperm motility/male contraception.
  • BPH benign prostatic hypertrophy
  • cardiovascular diseases or damages e.g. cardiac hypertrophy, cardiac remodeling after myocardial infarction, pulmonary congestion and cardiac fibrosis in dilated or in hypertrophic cardiomyopathy, cardiomyopathy such as dilated cardiomyopathy or hypertrophic
  • cardiomyopathy mesanglial hypertrophy, or diabetic cardiomyopathy, left or right ventricular hypertrophy, arrhythmia, cardiac dysrhythmia, syncopy, angina pectoris, cardiac bypass reocclusion, intermittent claudication, diastolic and/or systolic dysfunction, diabetic myopathy, stroke prevention in congestive heart failure, hypertrophic medial thickening in arteries and/or large vessels, mesenteric vasculature hypertrophy or atherosclerosis, preferably atherosclerosis in mammalian patients with hypertension of diabetes; (ii) renal diseases or damages like renal hyperfiltration such as after portal renal ablation, proteinuria in chronic renal disease, renal arteriopathy as a consequence of hypertension, nephrosclerosis, hypertensive nephrosclerosis or mesanglial hypertrophy; (iii) Heart Failure to be treated is secondary to idiopathic dilated cardiomyopathy and/or coronary ischemic disease.
  • the compounds of the present invention can also be used for the prevention, the delay of the onset, the delay of progression or the treatment of neurodegenerative disorders, cognitive disorders and for improving memory (both short term and long term) and learning ability wherein the (i)
  • neurodegenerative disorder is dementia, senile dementia, schizophrenia, mild cognitive impairment, Alzheimer related dementia, Huntington's chores, tardive dyskinesia, hyperkinesias, mania, Morbus Parkinson, Steel-Richard syndrome, Down's syndrome, myasthenia gravis, nerve and brain trauma, vascular amyloidosis, cerebral hamorrhage I with amyloidosis, brain inflammation, Friedrich ataxia, acute confusion disorders, acute confusion disorders with apoptotic necrocytosis, amyotrophic lateral sclerosis, glaucoma, and Alzheimer's disease; (ii) cognitive disorders like cognitive deficits associated with
  • the compounds of the present invention can also be used for stimulating an immune response in a subject having or at risk of having cancer wherein the cancer is selected from the group consisting of basal cell carcinomas including cancers of the binary tract, bladder, urinary system, bone, brain, breast, cervical, endometrial, ovarian, uterine, choriocarcinoma, central nervous system, colon and rectal cancers, connective tissue cancer, cancer of the digestive system, esophageal, gastric, stomach, larynx, liver, pancreatic, colorectal, renal cancers; cancers of the urinary system; cancers of eye, head and neck, oral cavity, skin, prostate; cancers of biliary tract, testicular, thyroid; intra- epithelial neoplasm, leukemia, acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia; and other cancers of the respiratory system, lung, small cell lung, non-small cell lung; lymphom
  • rhabdomyosarcoma and other cancers including neoplastic conditions, adipose cell tumors, adipose cell carcinomas, such as liposarcoma.
  • the compounds of the present invention can also be used for the treatment or prophylaxis of chronic inflammatory diseases such as autoimmune disorders like rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, allergies or asthma.
  • chronic inflammatory diseases such as autoimmune disorders like rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, allergies or asthma.
  • the compounds of the present invention can also be used in the treatment of pain, neuropathic pain, rheumatoid pain, osteoarthritis pain, anesthesia adjunct in mammalian patients undergoing surgery, chronic pain in advanced cancer, treatment of refractory diarrhea, biliary pain caused by gallstones.
  • the compounds of the present invention can also be used for the treatment of mammalian patients undergoing islet/pancreas transplantation, for the prevention or the delay of transplant rejection, or allograft rejection in transplantation, for improving pancreatic function by increasing the number and size of pancreatic beta-cells in the treatment of Type 1 diabetes patients, and for improving pancreatic function by increasing the number and size of pancreatic beta-cells in general.
  • the compounds of the present invention can be used for the treatment of mammalian patients with acne, skin disorders (e.g. pigmentation disorders or psoriasis), scleroderma, mycoses; anxiety, anxiety neurosis, major depression disorder, drug abuse, alcohol addiction, insomnia, chronic fatigue, sleep apnea; anorexia nervosa; epilepsy; migraine; encephalomyelitis;
  • osteoarthritis osteoporosis, calcitonin-induced osteoporosis; male and female sexual dysfunction, infertility; Type 1 diabetes; immunosuppression, HIV infection; hematopoiesis, anemia; and for weight reduction.
  • the compounds of the present invention are useful for the prevention, delay of progression or treatment of (i) bacterial infections from Escherichia coli, Staphylococcus, Streptoococcus, Pseudomonas, Clostridium difficile infection, Legionella, Pneumococcus, Haemophilus, Klebsiella,
  • cryptococcosis aspergillosis, chromomycosis, mycetoma infections
  • Trichomonas vaginalis Trichomonas vaginalis, Taenia, Hymenolepsis, Echinococcus, Schistosomiasis, neurocysticerosis, Necator americanus, and Trichuris trichuria.
  • kits comprises two separate pharmaceutical compositions: a compound of the present invention, and a second pharmaceutical compound.
  • the kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet.
  • kits include syringes, boxes and bags.
  • the kit comprises directions for the use of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc . . . Second Week, Monday, Tuesday, . . . " etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a compound of the present invention can consist of one tablet or capsule, while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this and aid in correct administration of the active agents.
  • a dispenser designed to dispense the daily doses one at a time in the order of their intended use.
  • the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
  • a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed.
  • a battery-powered microchip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
  • the compounds of the present invention and other pharmaceutically active compounds can be administered to a patient either orally, rectally, parenterally, (for example, intravenously, intramuscularly, or
  • compositions suitable for parenteral injection may comprise
  • aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • a coating such as lecithin
  • surfactants for reconstitution into sterile injectable solutions or dispersions.
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
  • Microorganism contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example, sugars, sodium chloride, and the like.
  • Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, mannitol, and silicic acid;
  • binders as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia;
  • humectants as for example, glycerol;
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
  • solution retarders as for example, paraffin;
  • absorption accelerators as for example, quaternary ammonium compounds;
  • wetting agents as for example, paraffin
  • the dosage forms may also comprise buffering agents.
  • Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizing
  • the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administration are preferable suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.
  • Dosage forms for topical administration of a compound of the present invention include ointments, powders, sprays and inhalants.
  • the active compound or fit compounds are admixed under sterile condition with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required.
  • Opthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 3,000 mg per day.
  • dosage levels in the range of about 0.1 to about 3,000 mg per day.
  • a dosage in the range of about 0.01 to about 100 mg per kilogram body weight is typically sufficient.
  • the specific dosage and dosage range that can be used depends on a number of factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosage ranges and optimal dosages for a particular patient is within the ordinary skill in the art.
  • the compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides or prodrugs.
  • salts refers to inorganic and organic salts of compounds of the present invention.
  • the salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
  • the salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium,
  • esters of the compounds of the present invention include Ci-Cg alkyl esters. Acceptable esters also include C5-C7 cycloalkyl esters, as well as arylalkyl esters such as benzyl. C 1 -C4 alkyl esters are commonly used. Esters of compounds of the present invention may be prepared according to methods that are well known in the art.
  • Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, primary Ci-Cs alkyl amines, and secondary Ci-Cg dialkyl amines. In the case of secondary amines, the amine may also be in the form of a 5 or 6 membered heterocycloalkyl group containing at least one nitrogen atom. Amides derived from ammonia, C 1 -C3 primary alkyl amines and C 1 -C 2 dialkyl secondary amines are commonly used. Amides of the compounds of the present invention may be prepared according to methods well known to those skilled in the art.
  • prodrug means compounds that are transformed in vivo to yield a compound of the present invention. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-Cg alkyl, (C 2 - Cl 2 )alkanoyloxymethyl, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms,
  • alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)aminomethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C i -C 2 )alkylamino(C 2 - C 3 )alkyl (such as ⁇ -dimethylaminoethyl), carbamoyl-(Ci-C 2 )alkyl, N,N-di(C 1 - C 2 )alkylcarbamoyl-(Ci-C 2
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-C6)alkanoyloxymethyl, 1- ((Ci-C6)alkanoyloxy)ethyl, 1 -methyl- l-((Ci-C6)alkanoyloxy)ethyl, (Ci- C6)alkoxycarbonyloxymethyl, N-(C i -C6)alkoxycarbonylaminomethyl, succinoyl, (Ci-C 6 )alkanoyl, a-amino(Ci-C4)alkanoyl, arylacyl and a-aminoacyl, or a- aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, -P(0)(OH) 2 , -P(0)(0(Ci-C6)
  • the compounds of the present invention may contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention contemplates all geometric and positional isomers. For example, if the compound contains a double bond, both the cis and trans forms (designated as S and E, respectively), as well as mixtures, are
  • stereoisomers such as diastereomeric mixtures
  • Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., an alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., an alcohol
  • Atropisomers e.g., substituted biaryls
  • the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrate), ethanol, and the like.
  • pharmaceutically acceptable solvents such as water (hydrate), ethanol, and the like.
  • the present invention contemplates and encompasses both the solvated and unsolvated forms.
  • compounds of the present invention may exist in different tautomeric forms. All tautomers of compounds of the present invention are contemplated. For example, all of the tautomeric forms of the tetrazole moiety are included in this invention. Also, for example, all keto-enol or imine- enamine forms of the compounds are included in this invention.
  • the present invention encompass compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.
  • the present invention also includes isotopically-labeled compounds, which are identical to those recited herein, 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.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1.
  • the compounds of the present invention contain one or more deuterium atoms (2H) in place of one or more hydrogen atoms.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detection. 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
  • Isotopically labeled compounds of this invention can generally be prepared by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • the compounds of the present invention may exist in various solid states including crystalline states and as an amorphous state.
  • crystalline states also called polymorphs, and the amorphous states of the present compounds are contemplated as part of this invention.
  • LG generally refer to groups that are displaceable by a nucleophile.
  • Such leaving groups are known in the art.
  • Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, CI), sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH 3 ), N- hydroxsuccinimide, N-hydroxybenzotriazole, and the like.
  • nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions) and the like.
  • This assay is used to directly measure the formation of 13 C-glucose-6- phosphate from 13 C-glucose by liquid chromatography-mass spectrometry (LC MS/MS).
  • CB Compound Buffer
  • EB Enzyme Buffer
  • EB 50mM Tris, pH 7.5 / 4mM MgCl 2 / 6% DMSO / fresh 0.1% BSA / fresh 0.01% Brij-35 (10% BSA and 1% Brij-35 stock).
  • GK (Glucokinase) Working Stock (5X): Dilute human His-hepatic GK to 30nM in EB buffer.
  • Substrate Working Stock (1.47X): Dilute 13C-D-glucose (Sigma-Aldrich, St. Louis, MO) to 7.35mM from 1M stock (1M 13 C-D-glucose 186.1 1 mg/ml in 50mM Tris pH 7.5, 4mM MgCl 2 ) and dilute ATP (EMD Chemical Inc., Gibbstown, NJ) to 0.3528mM from frozen lOOmM stock and dilute 20mM fructose-6-phosphate (F6P) (Sigma-Aldrich, St.
  • GKRP Glucokinase Regulatory Protein
  • G6P glucose-6-phosphate
  • Assay format is the same as for GKRP LC MS/MS Biochemical Assay with the following exceptions.
  • This assay is used to directly measure the interaction between glucokinase (GK) and glucokinase regulatory protein (GKRP).
  • GK glucokinase
  • GKRP glucokinase regulatory protein
  • Assay Buffer 20mM Tris, pH 7.5 / 0.05% BSA / ImM DTT / ⁇ sorbitol-6-phosphate.
  • Assay Procedure Dilute avi-tagged GKRP to 10.7 nM in assay buffer. Combine the following reagents in a white 96-well half area plate. Pipette 14 ⁇ 1 of the diluted avi-tagged GKRP into each well. Add ⁇ of compound to be tested and incubate at room temperature for 20 minutes.
  • This assay is used to directly measure the formation of 13 C-glucose-6- phosphate from 13 C-glucose by LC MS/MS.
  • CB Compound Buffer
  • EB Enzyme Buffer
  • EB 50mM Tris, pH 7.5 / 4mM MgCl 2 / 6% DMSO / fresh 0.1% BSA / fresh 0.01% Brij-35 (10% BSA and 1% Brij-35 stock).
  • GK (Glucokinase) Working Stock (5X): Dilute human His-hepatic GK to 30nM in EB buffer.
  • Substrate Working Stock (1.47X): Dilute 13 C-D-glucose (Sigma- Aldrich, St. Louis, MO) to 7.35mM from 1M stock and dilute ATP (EMD Chemical, Gibbstown, NJ) to 0.3528mM from frozen lOOmM stock in CB buffer (1M 13 C-D-glucose 186.1 1 mg/ml in water).
  • Dilute 20mM fructose-6-phosphate (F6P) (Sigma- Aldrich, St. Louis, MO) to 441 ⁇ in the substrate working stock.
  • GKRP Glucokinase Regulatory Protein
  • Lincoln, NE e.g., RediSep ®
  • Krackeler Scientific Albany, NY
  • Teflon ® is polyfluoroethylene, DuPont, Wilmington, DE
  • the cross coupling (Z a or Z b is a halogen or a metal salt of B, Zn, Mg, etc.) can be achieved using a transition metal catalyst (e.g., a salt of Pd, Ni, etc.) in either anhydrous (e.g., tetrahydrofuran, dioxane, etc.) or an aqueous (e.g., tetrahydrofuran-water, dioxane-water, etc.) solvent under an inert atmosphere (e.g., N 2 , Ar, etc.).
  • a transition metal catalyst e.g., a salt of Pd, Ni, etc.
  • anhydrous e.g., tetrahydrofuran, dioxane, etc.
  • an aqueous e.g., tetrahydrofuran-water, dioxane-water, etc.
  • solvent e.g., N 2 , Ar, etc.
  • the coupling of the heterocycle with the sulfinylimine can be executed by deprotonation of the heterocycle with an strong base (e.g., alkyllithium, amide, etc.), followed by exposure to the sulfinylimine, in an anhydrous solvent (e.g., tetrahydrofuran, toluene, etc.).
  • an strong base e.g., alkyllithium, amide, etc.
  • anhydrous solvent e.g., tetrahydrofuran, toluene, etc.
  • the sulfmamide can be converted to the sulfonamide by deprotection of the sulfmamide with acid (e.g., HC1, TFA, etc.) in either anhydrous (e.g., methanol, diethyl ether, etc.) or aqueous (e.g., methanol-water, diethyl ether- water, etc.) solvent followed by sulfonylation with a sulfonyl chloride in the presence of an amine base (e.g., triethylamine, diisopropylethylamine, etc.) in an anhydrous solvent (e.g., N,N- dimethylformamide, dichloromethane, etc.).
  • acid e.g., HC1, TFA, etc.
  • anhydrous e.g., methanol, diethyl ether, etc.
  • aqueous e.g., methanol-water, diethyl ether
  • the coupling of the heterocycle with the sulfinylimine can be executed by deprotonation of the heterocycle with a strong base (e.g., alkyllithium, amide, etc.), followed by exposure to the sulfinylimine in an anhydrous solvent (e.g., tetrahydrofuran, toluene, etc.).
  • a strong base e.g., alkyllithium, amide, etc.
  • an anhydrous solvent e.g., tetrahydrofuran, toluene, etc.
  • the sulfinamide can be converted to the sulfonamide by deprotection of the sulfinamide with an acid (e.g., HC1, TFA, etc.) in either anhydrous (e.g., methanol, diethyl ether, etc.) or aqueous (e.g., methanol-water, diethyl ether-water, etc.) solvent followed by sulfonylation with a sulfonyl chloride in the presence of an amine base (e.g., triethylamine, diisopropylethylamine, etc.) in an anhydrous solvent (e.g., N,N- dimethylformamide, dichloromethane, etc.).
  • an acid e.g., HC1, TFA, etc.
  • anhydrous e.g., methanol, diethyl ether, etc.
  • aqueous e.g., methanol-water, diethyl
  • the cross coupling (Z a or Z b is a halogen or a metal salt of B, Zn, Mg, etc.) can be achieved using a transition metal catalyst (e.g., a salt of Pd, Ni, etc.) in either anhydrous (e.g.,
  • tetrahydrofuran dioxane, etc.
  • an aqueous e.g., tetrahydrofuran-water, dioxane-water, etc.
  • an inert atmosphere e.g., N 2 , Ar, etc.
  • the heterocycle can be formylated by by deprotonation of the heterocycle with a strong base (e.g., alkyllithium, amide, etc.), followed by exposure to a formylation reagent (e.g., ⁇ , ⁇ -dimethylformamide, etc.) in an anhydrous solvent (e.g., tetrahydrofuran, toluene, etc.).
  • a strong base e.g., alkyllithium, amide, etc.
  • a formylation reagent e.g., ⁇ , ⁇ -dimethylformamide, etc.
  • anhydrous solvent e.g., tetrahydrofuran, toluene, etc.
  • the aldehyde can be converted to the sulfony limine by treatment with a sulfonamide and an acid (e.g., Montmorillonite K10 clay, p-toluenesulfonic acid, etc.) with removal of water (e.g., Dean-Stark trap, dessicant, etc.) in an anhydrous solvent (e.g., toluene, dichloromethane, etc.).
  • a sulfonamide and an acid e.g., Montmorillonite K10 clay, p-toluenesulfonic acid, etc.
  • water e.g., Dean-Stark trap, dessicant, etc.
  • an anhydrous solvent e.g., toluene, dichloromethane, etc.
  • R 2 deprotonation of R 2 with an strong base (e.g., alkyllithium, amide, etc.), followed by exposure to the sulfonylimine, in an anhydrous solvent (e.g., tetrahydrofuran, toluene, etc.).
  • anhydrous solvent e.g., tetrahydrofuran, toluene, etc.
  • the cross coupling (Z a or Z b is a halogen or a metal salt of B, Zn, Mg, etc.) can be achieved using a transition metal catalyst (e.g., a salt of Pd, Ni, etc.) in either anhydrous (e.g., tetrahydrofuran, dioxane, etc.) or aqueous (e.g., tetrahydrofuran-water, dioxane-water, etc.) solvent under an inert atmosphere (e.g., N 2 , Ar, etc.).
  • a transition metal catalyst e.g., a salt of Pd, Ni, etc.
  • anhydrous e.g., tetrahydrofuran, dioxane, etc.
  • aqueous e.g., tetrahydrofuran-water, dioxane-water, etc.
  • solvent e.g., N 2 , Ar, etc.
  • the coupling of the heterocycle with the sulfonylimine can be executed by deprotonation of the heterocycle with an strong base (e.g., alkyllithium, amide, etc.), followed by exposure to the sulfonylimine, in an anhydrous solvent (e.g., tetrahydrofuran, toluene, etc.).
  • an strong base e.g., alkyllithium, amide, etc.
  • anhydrous solvent e.g., tetrahydrofuran, toluene, etc.
  • n-Butyllithium (33 mL of a 2.5 M solution in toluene, 0.083 mol) was added to a stirring solution of 2-chloro-4-iodopyridine (20 g, 0.082 mol, Matrix Scientific, Columbia, SC) and tetrahydrofuran (200 mL) at -78 °C. After 15 min, 1,1,1-trifluoroacetone (28 g, 0.25 mol) was added. After 1 h, saturated aqueous ammonium chloride was added, the mixture was warmed to room temperature, partitioned between more saturated aqueous ammonium chloride and ethyl acetate.
  • Biotools/BoMem ChirallR instrument Biotools, Inc., Jupiter, FL
  • concentrations of about 30 mg/mL in CDCI 3 in a 100 ⁇ BaF2 cell over a 4 h acquisition time at 4 cm "1 resolution.
  • Step 1 n-Butyllithium (8.44 mL of a 1.6 M solution in hexanes, 13.5 mmol) was added to a solution of (2R)-2-(2-(l-benzothiophen-7-yl)-4-pyridinyl)- l,l,l-trifluoro-2-propanol (1.82 g, 5.63 mmol, Intermediate X4) in THF (27 mL) at -78 °C and the mixture was stirred at -78 °C for 10 min. A solution of N- ((S,E)-(2-chlorophenyl)methylidene)-2-methyl-2-propanesulfinamide
  • Step 2a Hydrogen chloride (8.16 mL of a 2 M solution in diethyl ether, 16.3 mmol) was added to a solution of (S)-N-((R)-(2-chlorophenyl)(7-(4-((lR)- 2,2,2-trif uoro- 1 -hydroxy- 1 -methylethyl)-2-pyridinyl)- 1 -benzothiophen-2- yl)methyl)-2-methyl-2-propanesulfinamide (1.85 g, 3.26 mmol) in Et 2 0 (24 mL) and the resulting suspension was stirred at room temperature for 18 h.
  • Step 2b Hydrogen chloride (0.97 mL of a 4.0 M solution in 1,4-dioxane, 3.9 mmol) was added to a stirring solution of (S)-N-((S)-(2-chlorophenyl)(7-(4- (( 1 R)-2,2,2-trifluoro- 1 -hydroxy- 1 -methylethyl)-2-pyridinyl)- 1 -benzothiophen-2- yl)methyl)-2-methyl-2-propanesulfinamide (0.22 g, 0.39 mmol) and methanol at room temperature.
  • Step 2a Hydrogen chloride (2.90 mL of a 2 M solution in Et 2 0, 5.80 mmol) was added to a solution of (S)-N-((R)-(2-chlorophenyl)(7-(4-((lS)-2,2,2- trifluoro- 1 -hydroxy- 1 -methylethyl)-2-pyridinyl)- 1 -benzothiophen-2-yl)methyl)- 2-methyl-2-propanesulfinamide (658 mg, 1.16 mmol) in Et 2 0 (8 mL) and the resulting suspension was stirred at room temperature for 6 h.
  • Step 2b Hydrogen chloride (261 of a 2 M solution in Et 2 0, 0.522 mmol) was added to a solution of (S)- N-((S)-(2-chlorophenyl)(7-(4-((lS)-2,2,2- trifluoro- 1 -hydroxy- 1 -methylethyl)-2-pyridinyl)- 1 -benzothiophen-2-yl)methyl)- 2-methyl-2-propanesulfinamide (74 mg, 0.130 mmol) in Et 2 0 (1 mL) and the resulting suspension was stirred at room temperature for 6 h.
  • Step 1 Trimethyl(trifiuoromethyl)silane (2.52 mL, 17.1 mmol) was added to a mixture of 2-chloro-4-pyridinecarbonyl chloride (1.00 g, 5.68 mmol, Sigma- Aldrich, St. Louis, MO) and tetramethylammonium fluoride (1.59 g, 17.1 mmol) in DME (15 mL) at -78 °C and the mixture was stirred for 17 h while it warmed to room temperature.
  • Step 2 A mixture of 2-(2-chloro-4-pyridinyl)-l,l,l,3,3,3-hexafluoro-2- propanol (1.27 g, 4.55 mmol), 2-(l-benzothiophen-7-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (2.01 g, 7.73 mmol, Intermediate Y2), dicyclohexyl(2',4',6'- tris(l-methylethyl)-2-biphenylyl)phosphane (108 mg, 0.227 mmol), chloro(2- propen-l-yl)palladium dimer (41.6 mg, 0.114 mmol), and sodium carbonate monohydrate (204 mg, 13.7 mmol) in 1 ,4-dioxane/water (4: 1, 10 mL) was stirred at 80 °C for 5 h.
  • the mixture was allowed to cool to room temperature, diluted with MeOH/DCM, absorbed onto silica gel, and purified by flash chromatography (100 g of silica gel, 10% to 30%> EtOAc/hexanes) to deliver 2- (2-(l-benzothiophen-7-yl)-4-pyridinyl)-l,l,l,3,3,3-hexafluoro-2-propanol (1.50 g) as an off-white solid.
  • Step 3 n-Butyllithium (3.32 mL of a 2.5M solution in toluene, 8.29 mmol) was added to a solution of 2-(2-(l-benzothiophen-7-yl)-4-pyridinyl)- l,l,l,3,3,3-hexaf uoro-2-propanol (1.49 g, 3.95 mmol) in THF (20 mL) at -78 °C.
  • Step 4 Hydrogen chloride (7.92 mL of a 1 M solution in Et 2 0, 7.92 mmol) was added to a solution of (S)-N-((R)-(2-chlorophenyl)(7-(4-(2,2,2- trifluoro- 1 -hydroxy- 1 -(trifluoromethyl)ethyl)-2-pyridinyl)- 1 -benzothiophen-2- yl)methyl)-2-methyl-2-propanesulfinamide (1.23 g, 1.98 mmol) in Et 2 0 (12 mL) and the resulting suspension was stirred at room temperature for 5 h.
  • Step 1 To a 2-L three-necked round-bottomed flask containing a solution of 7-bromo-l-benzothiophene (50 g, 236 mmol, Intermediate XI 3) in THF (400 mL) at -78 °C was added LDA (236 mL of a 1.8 M solution in THF, 472 mmol, Sigma- Aldrich, India) and the mixture was stirred at -78 °C for 45 min.
  • LDA 236 mL of a 1.8 M solution in THF, 472 mmol, Sigma- Aldrich, India
  • the resulting product was purified by column chromatography (basic alumina, 0% to 10% EtOAc/hexane to deliver (S)-N-((R)-(7-bromo-l-benzothiophen-2- yl)(2-chlorophenyl)methyl)-2-methyl-2-propanesulfinamide (25 g) as a pale- yellow liquid.
  • Step 2 To a 100-mLround-bottomed flask containing a solution of (S)-N- ((R)-(7-bromo-l-benzothiophen-2-yl)(2-chlorophenyl)methyl)-2-methyl-2- propanesulfmamide (5 g, 11.0 mmol) in MeOH (25 mL) at 0 °C was added saturated hydrogen chloride in 1 ,4-dioxane (20 mL) over the course of 5 min.
  • Step 3 To a 100-mL round-bottomed flask charged with a solution of (R)- 1 -(7-bromo- 1 -benzothiophen-2-yl)- 1 -(2-chlorophenyl)methanamine hydrochloride (4 g, 10.3 mmol) in N-methyl-2-pyrrolidinone (30 mL) at 0 °C was added triethylamine (3.14 g, 30.9 mmol). After 5 min at 0 °C,
  • cyclopropylsulfonyl chloride (4.34 g, 31.0 mmol) was added over the course of 5 min and the reaction was then stirred at room temperature for 16 h. The mixture was partitioned between EtOAc (100 mL) and water (50 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried (Na 2 S0 4 ), filtered, and concentrated under reduced pressure.
  • Step 1 Potassium carbonate (260 g, 1.9 mmol) was added to a stirring solution of 2-bromobenzenethiol (180 g, 0.96 mol, Matrix Scientific, Columbia, SC), 2-bromo-l,l-dimethoxy ethane (170 g, 1.0 mol, Spectrochem, India), and acetone (1.8 L) at room temperature, and then the reaction mixture was heated at 55 °C. After 4 h, the reaction mixture was cooled to room temperature, filtered, the filter cake was washed with acetone, and the combined filtrate was concentrated under a vacuum.
  • 2-bromobenzenethiol 180 g, 0.96 mol, Matrix Scientific, Columbia, SC
  • 2-bromo-l,l-dimethoxy ethane 170 g, 1.0 mol, Spectrochem, India
  • acetone 1.8 L
  • Step 2 Polyphosphoric acid (PPA) (100 g) was added to a stirring solution of l-bromo-2-((2,2-dimethoxyethyl)sulfanyl)benzene (220 g, 0.84 mol, from Step 1) and toluene (2.2 L) at room temperature, and then the reaction mixture was heated at 110 °C. After 12 h, the reaction mixture was cooled to room temperature and then partitioned between water and ethyl acetate. The layers were separated, the organic material was washed sequentially with water and brine, dried (sodium sulfate), filtered, and the filtrate was concentrated under a vacuum. The residue was subjected to flash chromatography on silica gel (49: 1 hexane-ethyl acetate) to give 7-bromo-l-benzothiophene (82 g) as a colorless liquid.
  • PPA Polyphosphoric acid
  • the mixture was stirred at 90 °C for 12 h, allowed to cool to room temperature, and filtered through a pad of diatomaceous earth, which was washed with toluene (100 mL). The combined filtrates were concentrated under reduced pressure, hexane (100 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h.
  • Titanium(IV) ethoxide (220 mL, 1100 mmol) was added to a stirring solution of (S)-2-methyl-2-propanesulfinamide (26 g, 210 mmol, AK Scientific, Mountain View, CA), dichloromethane (430 mL), and 2-chlorobenzaldehyde (30 g, 210 mmol, Sigma- Aldrich, St. Louis, MO), at room temperature. After 22 h, the reaction mixture was added to water and dichloromethane. The mixture was agitated vigorously and then filtered through a pad of diatomaceous earth.
  • the reaction mixture was cooled to room temperature, filtered through a pad of diatomaceous earth, and the filtrate was concentrated under a vacuum.
  • the residue was partitioned between water and ethyl acetate, the layers were separated, and the aqueous material was washed with ethyl acetate (2x).
  • the combined organic extracts were washed sequentially with water and brine, dried (sodium sulfate), filtered, and the filtrate was concentrated under a vacuum.
  • n-Butyllithium (8.4 mL of a 2.5 M solution in toluene, 0.021 mol) was added to a stirring solution of 2-chloro-4-iodopyridine (5.0 g, 0.021 mol, Matrix Scientific, Columbia, SC) and tetrahydrofuran (50 mL) at -78 °C. After 15 min, acetone (4.6 mL, 0.063 mol) was added, and the mixture was stirred at - 78 °C for an additional hour. Saturated aqueous ammonium chloride was added, the mixture was warmed to room temperature, partitioned between more saturated aqueous ammonium chloride and ethyl acetate.
  • allylpalladium(II) chloride dimer (0.16 g, 0.44 mmol), 9,9-dimethyl-4,5- bisdiphenylphosphino)xanthene (0.51 g, 0.89 mmol), and cesium fluoride (2.0 g, 13 mol) was heated at 80 °C under a nitrogen atmosphere. After 24 h, the reaction mixture was heated at 100 °C. After an additional 13h, the reaction mixture was allowed to cool to room temperature and concentrated under a vacuum. The residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate, the layers were separated, the organic material was washed sequentially with saturated aqueous sodium bicarbonate and brine.
  • Step 2 n-Butyllithium (1.4 mL of a 1.6 M solution in hexanes, 2.3 mmol) was added to a stirring solution of 2-(2-(l-benzothiophen-7-yl)-4-pyridinyl)- l,l,l-trifluoro-2-propanol (0.37 g, 1.1 mmol, Intermediate Y3) and
  • Step 3 Hydrogen chloride (5.0 mL of a 1.0 M solution with diethyl ether, 5.0 mmol) was added to a stirring solution of 2-methyl-N-(phenyl(7-(4-(2,2,2- trifluoro- 1 -hydroxy- 1 -methylethyl)-2-pyridinyl)- 1 -benzothiophen-2-yl)methyl)- 2-propanesulfinamide (0.15 g, 0.28 mmol, from Step 2) and ethyl acetate (10 mL) at room temperature.
  • Step 1 Montmorillonite K10 (2.2 g) was added to a stirring solution of 2- (methylsulfanyl)benzaldehyde (2.2 g, 14 mmol), 2-methyl-2-propanesulfinamide (1.8 g, 14 mmol, AK Scientific, Mountain View, CA), and toluene (100 mL).
  • the reaction vessel was fitted with a Dean-Stark trap and a reflux condenser, and then the reaction mixture was heated at reflux. After 3 h, the reaction mixture was allowed to cool to room temperature and filtered. Silica gel (2.0 g) was added to the filtrate, and the volatiles were removed under a vacuum.
  • Step 2 n-Butyllithium (0.41 mL of a 1.6 M solution in hexanes, 0.65 mmol) was added to a stirring solution of 2-(2-(l-benzothiophen-7-yl)-4- pyridinyl)-l,l,l-trifluoro-2-propanol (0.10 g, 0.31 mmol, Intermediate Y3) and THF (3.0 mL) at -78 °C under a nitrogen atmosphere.
  • Step 3 Hydrogen chloride (0.69 mL of a 1.0 M solution with diethyl ether, 0.69 mmol) was added to a stirring solution of 2-methyl-N-((2- (methylsulfanyl)phenyl)(7-(4-(2,2,2-trifluoro- 1 -hydroxy- 1 -methylethyl)-2- pyridinyl)-l-benzothiophen-2-yl)methyl)-2-propanesulfinamide (0.080 g, 0.14 mmol, from Step 2) and ethyl acetate (10 mL) at room temperature.
  • Step 1 n-Butyllithium (2.0 mL of a 1.6 M solution with hexanes, 3.2 mmol) was added to a stirring solution of 2-(2-(l-benzothiophen-7-yl)-4- pyridinyl)-l,l,l-trifluoro-2-propanol (0.51 g, 1.6 mmol, Intermediate Y3) and THF (7.9 mL) at -78 °C under a nitrogen atmosphere.
  • Step 2 Hydrogen chloride (2.56 mL of a 1.0 M solution with diethyl ether, 2.56 mmol) was added to a stirring solution of (S)-N-((R)-(2- chlorophenyl)(7-(4-(2,2,2-trifluoro- 1 -hydroxy- 1 -methylethyl)-2-pyridinyl)- 1 - benzothiophen-2-yl)methyl)-2-methyl-2-propanesulfinamide (0.29 g, 0.451 mmol, from Step 1) and ethyl acetate (10 mL) at room temperature.
  • Step 1 n-Butyllithium (3.9 mL of a 1.6 M solution in hexanes, 6.2 mmol) was added to a stirring solution of 4-bromo-2-chloropyridine (0.58 mL, 5.2 mmol, Alfa Aesar, Ward Hill, MA) and diethyl ether (26 mL) at -78 °C under a nitrogen atmosphere. After 15 min, acetaldehyde (1.5 mL, 26 mmol) was added. After an additional 10 min, water (5.0 mL) was added and the mixture was warmed to room temperature. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate.
  • Step 2 A stirring mixture of allylpalladium(II) chloride dimer (0.093 g, 0.25 mmol), 2-(dicyclohexylphosphino)-2',4',6',-tri-isopropyl-l, -biphenyl (0.24 g, 0.51 mmol), 1,4-dioxane (10 mL), 2-(l-benzothiophen-7-yl)-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (2.0 g, 7.6 mmol, Intermediate Y2), l-(2-chloro- 4-pyridinyl)ethanol (0.80 g, 5.1 mmol, from Step 1), water (3.0 mL), and sodium carbonate monohydrate (1.6 g, 15 mmol), was heated at 80 °C.
  • Step 1 n-Butyllithium (7.8 mL of a 1.6 M solution with hexanes, 12 mmol) was added to a stirring solution of 4-bromo-2-chloropyridine (1.2 mL, 10 mmol, Alfa Aesar, Ward Hill, MA) and diethyl ether (52 mL) at -78 °C. After 30 min, cyclobutanone (3.9 mL, 52 mmol) and water (50 mL) were added sequentially, and then the reaction mixture was warmed to room temperature, partitioned between ethyl acetate and more water, and the layers were separated.
  • 4-bromo-2-chloropyridine 1.2 mL, 10 mmol, Alfa Aesar, Ward Hill, MA
  • diethyl ether 52 mL
  • cyclobutanone 3.9 mL, 52 mmol
  • water 50 mL
  • reaction mixture was allowed to cool to room temperature, and partitioned between ethyl acetate and water. The layers were separated, the organic material was washed with brine, silica gel (1.0 g) was added, and the volatiles were removed under a vacuum. The residue was subjected to flash chromatography on silica gel (40 g RediSep ® normal phase column, gradient elution of 0% to 30% ethyl acetate-hexane, Teledyne Isco, Lincoln, NE) to afford l-(2-(l- benzothiophen-7-yl)-4-pyridinyl)cyclobutanol (0.49 g) as a clear oil.
  • silica gel 40 g RediSep ® normal phase column, gradient elution of 0% to 30% ethyl acetate-hexane, Teledyne Isco, Lincoln, NE
  • Step 1 n-Butyllithium (3.9 mL of a 1.6 M solution with hexanes, 6.2 mmol) was added to a stirring solution of 4-bromo-2-chloropyridine (0.63 mL, 5.7 mmol, Alfa Aesar, Ward Hill, MA) and diethyl ether (28 mL) at -78 °C under a nitrogen atmosphere. After 15 min, l-(tert-butyldimethylsilyloxy)-2-propanone (3.3 mL, 17 mmol, Sigma- Aldrich, St. Louis, MO) was added. After an additional 10 min, water (5.0 mL) was added, and then the reaction mixture was allowed to warm to room temperature and concentrated under a vacuum.
  • 4-bromo-2-chloropyridine (0.63 mL, 5.7 mmol, Alfa Aesar, Ward Hill, MA
  • diethyl ether 28 mL
  • Step 2 A stirring mixture of allylpalladium(II) chloride dimer (0.049 g, 0.13 mmol), 2-(dicyclohexylphosphino)-2',4',6',-tri-isopropyl-l, -biphenyl (X- Phos) (0.13 mg, 0.27 mmol), 1,4-dioxane (13 mL), 2-(l-benzothiophen-7-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.0 g, 4.0 mmol, Intermediate Y2), 1- ((tert-butyl(dimethyl)silyl)oxy)-2-(2-chloro-4-pyridinyl)-2-propanol (0.80 g, 2.7 mmol, from Step 1), water (4.0 mL), and sodium carbonate monohydrate (0.84 g, 8.0 mmol) was heated at 80 °C.
  • reaction mixture was cooled to room temperature, concentrated, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated, the organic material was washed with brine, dried (magnesium sulfate), filtered, silica gel (1.0 g) was added to the filtrate, and the volatiles were removed under a vacuum.
  • Step 1 A stirring mixture of di-tert-butyl (6-bromo-2- pyridinyl)imidodicarbonate (5.0 g, 13 mmol, Sigma- Aldrich, St. Louis, MO), potassium trifluoro(vinyl)borate (2.0 g, 15 mmol), cesium carbonate (13 g, 40 mmol), 2-(dicyclohexylphosphino)-2',4',6',-tri-isopropyll, -biphenyl (X-Phos) (0.64 g, 1.3 mmol), palladium(II) acetate (0.15 g, 0.67 mmol), tetrahydrofuran (60 mL) and water (7.0 mL) was heated at 80 °C.
  • Step 2 Sodium periodate (8.6 g, 40 mmol) was added to a stirring mixture of di-tert-butyl (6-ethenyl-2-pyridinyl)imidodicarbonate (4.3 g, 13 mmol, from Step 1), tetrahydrofuran (54 mL), water (14 mL), and osmium tetroxide (4.1 mL of a 4.0 wt% solution with water, 0.67 mmol) at room temperature. After 2 h, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated, the organic material was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried
  • Step 3 Copper(II) sulfate (6.4 g, 40 mmol) was added to a stirring solution of di-tert-butyl (6-formyl-2-pyridinyl)imidodicarbonate (4.3 g, 13 mmol, from Step 2), dichloromethane (53 mL), and (R)-2-methyl-2-propanesulfinamide (1.9 g, 16 mmol, AK Scientific, Mountain View, CA) at room temperature. After 50 h, the reaction mixture was filtered through a 0.45 ⁇ Teflon®
  • Step 4 n-Butyllithium (1.9 mL of a 2.5 M solution in toluene, 4.7 mmol) was added to a stirring solution of 2-(2-(l-benzothiophen-7-yl)-4-pyridinyl)- l,l,l-trifluoro-2-propanol (0.84 g, 2.6 mmol, Intermediate Y3) in tetrahydrofuran (20 mL) at -78 °C under a nitrogen atmosphere.
  • Step 5 Hydrogen chloride (2.7 mL of a 4.0 M solution with 1,4-dioxane, 11 mmol) was added to a stirring solution of di-tert-butyl (6-((S)-(((R)-tert- butylsulfinyl)amino)(7-(4-(2,2,2-trifluoro- 1 -hydroxy- 1 -methylethyl)-2- pyridinyl)- 1 -benzothiophen-2-yl)methyl)-2-pyridinyl)imidodicarbonate (0.82 g, containing about 7 mol% of tert-butyl (6-((S)-(((R)-tert-butylsulfmyl)amino)(7- (4-(2,2,2-trifluoro- 1 -hydroxy- 1 -methylethyl)-2-pyridinyl)- 1 -benzothiophen-2- yl)methyl)-2-
  • Step 6 4-(Dimethylamino)pyridine (0.013 g, 0.11 mmol) was added to a stirring solution of 2-(2-(2-((S)-amino(6-amino-2-pyridinyl)methyl)-l- benzothiophen-7-yl)-4-pyridinyl)-l,l,l-trifluoro-2-propanol (0.49 g, containing about 5 mol% of 2-(2-(2-((R)-amino(6-amino-2-pyridinyl)methyl)-l- benzothiophen-7-yl)-4-pyridinyl)-l,l,l-trifluoro-2-propanol, from Step 5), N,N- dimethylformamide (11 mL), N,N-diisopropylethylamine (0.96 mL, 5.5 mmol), and cyclopropanesulfonyl chloride (0.11 mL, 1.1 mmol
  • reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, and the layers were separated. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate (2x) and brine (2x), dried (sodium sulfate), filtered, the filtrate was concentrated. The residue was dissolved with
  • Step 1 n-Butyllithium (6.6 mL of a 2.5 M solution in toluene, 16 mmol) was added to a stirring solution of 2-(2-(l-benzothiophen-7-yl)-4-pyridinyl)-2- propanol (2.4 g, 9.0 mmol, Intermediate Y5) and tetrahydrofuran (74 mL) at -78 °C under a nitrogen atmosphere. After 10 min, a solution of N-((S,E)-(2- chlorophenyl)methylidene)-2-methyl-2-propanesulfinamide (2.0 g, 8.2 mmol, Intermediate Yl) in tetrahydrofuran (8.0 mL) was added.
  • Step 2 Hydrogen chloride (12 mL of a 4.0 M solution with 1,4-dioxane, 48 mmol) was added to a stirring solution of (S)-N-((R)-(2-chlorophenyl)(7-(4- ( 1 -hydroxy- 1 -methylethyl)-2-pyridinyl)- 1 -benzothiophen-2-yl)methyl)-2-methyl- 2-propanesulfmamide (2.5 g, 4.9 mol, from Step 1) and methanol (49 mL) at room temperature.
  • Step 3 4-(Dimethylamino)pyridine (0.060 g, 0.49 mmol) was added to a stirring solution of 2-(2-(2-((R)-amino(2-chlorophenyl)methyl)-l-benzothiophen- 7-yl)-4-pyridinyl)-2-propanol hydrochloride (2.0 g, 4.9 mmol, from Step 2), N,N- dimethylformamide (49 mL), N,N-diisopropylethylamine (8.5 mL, 49 mmol), and cyclopropanesulfonyl chloride (0.50 mL, 4.9 mmol, Matrix Scientific, Columbia, SC) at room temperature.
  • 2-(2-(2-(R)-amino(2-chlorophenyl)methyl)-l-benzothiophen- 7-yl)-4-pyridinyl)-2-propanol hydrochloride 2.0 g, 4.9 mmol, from Step 2)
  • Step 1 A stirring solution of 6-bromo-2-pyridinamine (15 g, 87 mmol, Sigma- Aldrich, St. Louis, MO), acetonitrile (170 mL), and N-chlorosuccinimide (14 g, 100 mmol) was heated at reflux under a nitrogen atmosphere. After 18 h, the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated, and the organic layer was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), and filtered. Silica gel (45 g) was added to the filtrate, and the volatiles were removed under a vacuum. The residue was subjected to flash chromatography on silica gel (gradient elution; 6: 1 to 4: 1 hexane-ethyl acetate). The isolated material was dissolved with
  • Step 2 Di-tert-butyl dicarbonate (19 g, 87 mmol) was added to a stirring mixture of 6-bromo-5-chloro-2-pyridinamine (8.6 g, 42 mmol, from Step 1), dichloromethane (83 mL), and N,N-diisopropylethylamine (22 mL, 120 mmol) at room temperature under a nitrogen atmosphere. After 14 h, 4- (dimethylamino)pyridine (0.51 g, 4.2 mmol) was added. After an additional 3 h, the reaction mixture was concentrated under a vacuum, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate.
  • the organic layer was isolated, and was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered, and concentrated under a vacuum.
  • the residue was dissolved with dichloromethane, silica gel (40 g) was added to the solution, and the volatiles were removed under a vacuum.
  • the residue was subjected to flash chromatography on silica gel (9: 1 hexane- ethyl acetate).
  • the isolated material was dissolved with dichloromethane, silica gel (20 g) was added to the solution, and the volatiles were removed under a vacuum.
  • Step 3 A stirring mixture of di-tert-butyl (6-bromo-5-chloro-2- pyridinyl)imidodicarbonate (3.0 g, 7.4 mmol, from Step 2), potassium trifluoro(vinyl)borate (1.1 g, 8.1 mmol), cesium carbonate (7.2 g, 22 mmol), 2- (dicyclohexylphosphino)-2',4',6',-tri-isopropyll, -biphenyl (0.35 g, 0.74 mmol), palladium(II) acetate (0.083 g, 0.37 mmol), tetrahydrofuran (33 mL) and water (4.0 mL) was heated at 80 °C.
  • reaction mixture was allowed to cool to room temperature, concentrated under a vacuum, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, and washed with brine, dried (sodium sulfate), filtered, then concentrated under a vacuum. The residue was dissolved with dichloromethane, silica gel (13 g) was added, and the volatiles were removed under a vacuum.
  • Step 4 Sodium periodate (1.1 g, 5.2 mmol) was added to a stirring mixture of di-tert-butyl (5-chloro-6-ethenyl-2-pyridinyl)imidodicarbonate (0.61 g, containing about 35 mol% of di-tert-butyl (6-bromo-5-chloro-2- pyridinyl)imidodicarbonate, from Step 3), tetrahydrofuran (7.0 mL), water (1.6 mL), and osmium tetroxide (0.53 mL of a 4.0 wt% solution with water, 0.086 mmol) at room temperature.
  • di-tert-butyl (5-chloro-6-ethenyl-2-pyridinyl)imidodicarbonate (0.61 g, containing about 35 mol% of di-tert-butyl (6-bromo-5-chloro-2- pyridinyl)imi
  • Step 5 Copper(II) sulfate (0.64 g, 4.0 mmol) was added to a stirring solution of di-tert-butyl (5-chloro-6-formyl-2-pyridinyl)imidodicarbonate (0.48 g, from Step 4), dichloromethane (5.4 mL), and (S)-2-methyl-2-propanesulfinamide (0.20 g, 1.6 mmol, AK Scientific, Mountain View, CA) at room temperature. After 43 h, the reaction mixture was filtered through a 0.20 ⁇ Teflon®
  • silica gel (3.0 g) was added to the filtrate, and the volatiles were removed under a vacuum. This material was subjected to flash chromatography on silica gel (9: 1 hexane-ethyl acetate) to give di-tert-butyl (6-((E)-(((S)-tert-butylsulfinyl)imino)methyl)-5- chloro-2-pyridinyl)imidodicarbonate (0.37 g) as a clear pale yellow tar.
  • Step 6 n-Butyllithium (0.62 mL of a 2.5 M solution in toluene, 1.6 mmol) was added to a stirring solution of 2-(2-(l-benzothiophen-7-yl)-4-pyridinyl)-2- propanol (0.23 g, 0.86 mmol, Intermediate Y5) and tetrahydrofuran (6.5 mL) at - 78 °C under a nitrogen atmosphere.
  • Step 7 Hydrogen chloride (0.93 mL of a 4.0 M solution with 1,4-dioxane, 3.7 mmol) was added to a stirring solution of di-tert-butyl (6-((R)-(((S)-tert- butylsulfinyl)amino)(7-(4-( 1 -hydroxy- 1 -methylethyl)-2-pyridinyl)- 1 - benzothiophen-2-yl)methyl)-5-chloro-2-pyridinyl)imidodicarbonate (0.27 g, containing about 17 mol% of di-tert-butyl (6-((S)-(((S)-tert- butylsulfinyl)amino)(7-(4-( 1 -hydroxy- 1 -methylethyl)-2-pyridinyl)- 1 - benzothiophen-2-yl)methyl)-5-chloro-2-pyridin
  • Step 8 4-(Dimethylamino)pyridine (0.0046 g, 0.038 mmol) was added to a stirring solution of 2-(2-(2-((R and S)-amino(6-amino-3-chloro-2- pyridinyl)methyl)-l-benzothiophen-7-yl)-4-pyridinyl)-2-propanol (0.16 g, 0.38 mmol, from Step 7), N,N-dimethylformamide (3.8 mL), N,N- diisopropylethylamine (0.33 mL, 1.9 mmol), and cyclopropanesulfonyl chloride (0.038 mL, 0.38 mmol, Matrix Scientific, Columbia, SC) at room temperature.
  • reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated, and the organic material was washed sequentially with saturated aqueous sodium bicarbonate (2x) and brine, dried (sodium sulfate), filtered, and then
  • Step 1 Montmorillonite K 10 (2.0 g) was added to a stirring mixture of 2- chloro-6-methoxybenzaldehyde (2.0 g, 12 mmol, Chem-Impex, Wood Dale, IL), cyclopropanesulfonamide (1.4 g, 12 mmol, Matrix, Columbia, SC), and toluene (59 mL).
  • the reaction vessel was fitted with a Dean-Stark trap and a reflux condenser, and then the reaction mixture was heated at reflux. After 15 h, the reaction mixture was filtered and the filtrate was allowed to cool to room temperature. The filtrate was concentrated under a vacuum to a volume of about 20 mL, and then filtered again.
  • Step 2 n-Butyllithium (0.73 mL of a 2.5 M solution in toluene, 1.8 mmol) was added to a stirring solution of 2-(2-(l-benzothiophen-7-yl)-4-pyridinyl)-2- propanol (0.27 g, 1.0 mmol, Intermediate Y5) and tetrahydrofuran (8.0 mL) at - 78 °C. After 10 min, a solution of N-((lE)-(2-chloro-6- methoxyphenyl)methylidene)cyclopropanesulfonamide (0.25 g, 0.91 mmol, from Step 1) in tetrahydrofuran (1.1 mL) was added.
  • Step 1 Methylmagnesium chloride (4.8 mL of a 3.0 mL solution with tetrahydrofuran, 14 mmol) was added to a stirring solution of methyl 2-chloro-4- pyrimidinecarboxylate (1.0 g, 5.8 mmol, Maybridge, Tintagel, England) in tetrahydrofuran (58 mL) at 0 °C under a nitrogen atmosphere. After 10 min, saturated aqueous sodium bicarbonate was added and the reaction mixture was allowed to warm to room temperature. The organics were partitioned between ethyl acetate and more saturated aqueous sodium bicarbonate.
  • Step 2 A stirring mixture of 2-(2-chloro-4-pyrimidinyl)-2-propanol (1.0 g, 5.8 mol, from Step 1), 2-(l-benzothiophen-7-yl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (1.8 g, 7.0 mol, Intermediate Y2), 1,4-dioxane (9.5 mL), water (2.5 mL), allylpalladium(II) chloride dimer (0.11 g, 0.29 mmol), 2- (dicyclohexylphosphino)-2',4',6',-tri-isopropyll, -biphenyl (X-Phos) (0.28 g, 0.58 mmol), and sodium carbonate (18 g, 17 mmol) was heated at 80 °C under a nitrogen atmosphere.
  • reaction mixture was allowed to cool to room temperature, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The layers were separated and the organic material was washed sequentially with saturated aqueous sodium bicarbonate (2x) and brine, dried (sodium sulfate), filtered, then concentrated under a vacuum. The residue was dissolved with dichloromethane, silica gel (10 g) was added to the solution, and the volatiles were removed under a vacuum.
  • Step 3 Triethylsilyl trifluoromethanesulfonate (0.43 mL, 1.9 mmol) was added to a stirring solution of 2-(2-(l-benzothiophen-7-yl)-4-pyrimidinyl)-2- propanol (0.47 g, 1.7 mmol, from Step 2), dichloroethane (8.7 mL), and N,N- diisopropylethylamine (0.91 mL, 5.2 mmol) at room temperature. After 1 h, additional triethylsilyl trifluoromethanesulfonate (0.22 mL, 0.95 mmol) was added.
  • Step 4 n-Butyllithium (0.23 mL of a 2.5 M solution with toluene, 0.57 mmol) was added to a stirring solution of 2,2,6,6-tetramethylpiperidine (0.097 mL, 57 mmol) and tetrahydrofuran (5.0 mL) at -78 °C under a nitrogen atmosphere. After 5 min, the reaction mixture was warmed to room temperature.
  • tetrahydrofuran (0.50 mL) was added. After another hour, the reaction mixture was allowed to warm to room temperature. After 3 h at rt, tetrabutylammonium fluoride (0.69 mL of a 1.0 M solution with tetrahydrofuran, 0.69 mmol) was added. After 25 min, saturated aqueous sodium bicarbonate was added, and the mixture was partitioned between ethyl acetate and more saturated aqueous sodium bicarbonate. The layers were separated, and the organic material was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered, and then concentrated. The residue was dissolved with dichloromethane, silica gel (1.5 g) was added to the solution, and the volatiles were removed under a vacuum. The residue was subjected to flash
  • Step 5 Hydrogen chloride (0.32 mL of a 4.0 M solution with 1,4-dioxane, 1.3 mmol) was added to a stirring solution of (S)-N-((R)-(2-chlorophenyl)(7-(4- ( 1 -hydroxy- 1 -methylethyl)-2-pyrimidinyl)- 1 -benzothiophen-2-yl)methyl)-2- methyl-2-propanesulfmamide (0.065 g, 0.13 mmol, from Step 4) and methanol (1.3 mL) at room temperature. After 15 min, the reaction mixture was
  • Step 6 4-(Dimethylamino)pyridine (1.5 mg, 12 ⁇ ) was added to a stirring solution of 2-(2-(2-((R)-amino(2-chlorophenyl)methyl)-l-benzothiophen- 7-yl)-4-pyrimidinyl)-2-propanol (0.049 g, 0.12 mmol, from Step 5), N,N- dimethylformamide (1.2 mL), N,N-diisopropylethylamine (0.10 mL, 0.60 mmol), and cyclopropanesulfonyl chloride (0.012 mL, 0.12 mmol, Matrix Scientific, Columbia, SC) at room temperature.
  • Step 1 n-Butyllithium (0.23 mL of a 2.5 M solution in toluene, 0.57 mmol) was added to a stirring solution of 1,1,1 -trifluoro-2-(2-thieno[2,3- c]pyridin-7-yl-4-pyridinyl)-2-propanol (0.10 g, 0.32 mmol, Intermediate Y6) in tetrahydrofuran (2.0 mL) at -78 °C under a nitrogen atmosphere.
  • Step 2 Hydrogen chloride (0.17 mL of a 4.0 M solution with 1,4-dioxane, 0.68 mmol) was added to a stirring solution of (S)-N-((R)-(2-chlorophenyl)(7-(4- (2,2,2-trifluoro- 1 -hydroxy- 1 -methylethyl)-2-pyridinyl)thieno[2,3-c]pyridin-2- yl)methyl)-2-methyl-2-propanesulfinamide (0.039 g, 0.069 mmol, from Step 1) and methanol (1.4 mL) at room temperature.
  • Step 3 4-(Dimethylamino)pyridine (0.83 mg, 6.8 ⁇ ) was added to a stirring solution of 2-(2-(2-((R)-amino(2-chlorophenyl)methyl)thieno[2,3- c]pyridin-7-yl)-4-pyridinyl)-l,l,l-trifluoro-2-propanol hydrochloride (0.034 g, 0.068 mmol, from Step 2), N,N-dimethylformamide (1.4 mL), N,N- diisopropylethylamine (0.071 mL, 0.41 mmol), and cyclopropanesulfonyl chloride (0.0069 mL, 0.068 mmol, Matrix Scientific, Columbia, SC) at room temperature.
  • Step 1 n-Butyllithium (0.25 mL of a 2.5 M solution in toluene, 0.61 mmol) was added to a stirring solution of 1,1,1 -trifluoro-2-(2-thieno[2,3- c]pyridin-7-yl-4-pyridinyl)-2-propanol (0.11 g, 0.34 mmol, Intermediate Y6) in tetrahydrofuran (2.5 mL) at -78 °C under a nitrogen atmosphere.
  • Step 3 4-(Dimethylamino)pyridine (1.3 mg, 11 ⁇ ) was added to a stirring solution of 2-(2-(2-((R)-amino(3-chloro-2-pyridinyl)methyl)thieno[2,3- c]pyridin-7-yl)-4-pyridinyl)-l,l,l-trifluoro-2-propanol hydrochloride (0.050 g, 0.11 mmol, from Step 2), N,N-dimethylformamide (1.1 mL), N,N- diisopropylethylamine (0.19 mL, 1.1 mmol), and cyclopropanesulfonyl chloride (0.011 mL, 0.11 mmol, Matrix Scientific, Columbia, SC) at room temperature.
  • Benzenesulfonyl chloride (0.019 mL, 0.15 mmol) was added to a stirring solution of 2-(2-(2-(amino(phenyl)methyl)- 1 -benzothiophen-7-yl)-4-pyridinyl)- l,l,l-trifluoro-2-propanol hydrochloride (0.035 g, 0.075 mmol, Intermediate Zl), N,N-diisopropylethylamine (0.065 mL, 0.38 mmol), and dichloromethane (5.0 mL) at room temperature. After 3 h, silica gel (1.0 g) was added and the volatiles were removed under a vacuum. The residue was subjected to flash
  • Step 1 Titanium(IV) ethoxide (34 mL, 160 mmol) was added to a stirring solution of 2-(methylsulfanyl)benzaldehyde (5.0 g, 33 mmol), (S)-2-methyl-2- propanesulfinamide (4.0 g, 33 mmol, AK Scientific, Mountain View, CA), and dichloromethane (66 mL) at room temperature. After 24 h, water (10 mL) was added and the resulting suspension was filtered through a pad of diatomaceous earth. The two layers comprising the filtrate were separated, and the organic material was washed with brine, dried (magnesium sulfate), filtered, and concentrated.
  • 2-(methylsulfanyl)benzaldehyde 5.0 g, 33 mmol
  • (S)-2-methyl-2- propanesulfinamide 4.0 g, 33 mmol, AK Scientific, Mountain View, CA
  • dichloromethane 66 mL
  • Step 2 n-Butyllithium (0.74 mL of a 1.6 M solution in hexanes, 1.2 mmol) was added to a stirring solution of 2-(2-(l-benzothiophen-7-yl)-4- pyridinyl)-l,l,l-trifluoro-2-propanol (0.20 g, 0.62 mmol, Intermediate Y3) in tetrahydrofuran (5.0 mL) at -78 °C under a nitrogen atmosphere.
  • Step 1 A solution of bromine (2.3 mL, 46 mmol) and chloroform (10 mL) was added to a stirring solution of l-methyl-2-pyridone (5.0 mL, 456 mmol) and chloroform (46 mL) at reflux. After 1 h, the reaction mixture was cooled to room temperature. After 72 h, the reaction mixture was filtered and the filter cake was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated, silica gel (1.0 g) was added to the organic material, and the volatiles were removed under a vacuum.
  • Step 2 n-Butyllithium (3.7 mL, 5.9 mmol) was added to a stirring solution of 5-bromo-l-methylpyridin-2(lH)-one (1.0 g, 5.3 mmol, from Step 1) in tetrahydrofuran (27 mL) at -78 °C. After 10 min, the reaction mixture was sparged with sulfur dioxide (0.27 mL, 5.3 mmol) for 2 min and then allowed to warm to room temperature. The mixture was concentrated under a vacuum and the residue was dissolved with dichloromethane (20 mL), and NCS (0.71 g, 5.3 mmol) was added.
  • Step 3 l-Methyl-6-oxo-l,6-dihydro-3-pyridinesulfonyl chloride (0.050 g, 0.24 mmol, from Step 2) was added to a stirring solution of 2-(2-(2-((R)- amino(2-chlorophenyl)methyl)- 1 -benzothiophen-7-yl)-4-pyridinyl)- 1,1,1- trifluoro-2-propanol hydrochloride (0.040 g, 0.080 mmol, Intermediate Z3), N,N- diisopropylethylamine (0.14 mL, 0.80 mmol), and dichloromethane (3.0 mL) at room temperature.
  • 6-Methoxy-3-pyridinesulfonyl chloride (0.025 mL, 0.12 mmol, Acros, Geel, Belgium) was added to a stirring solution of 2-(2-(2-((R)-amino(2- chlorophenyl)methyl)- 1 -benzothiophen-7-yl)-4-pyridinyl)- 1,1,1 -trifluoro-2- propanol hydrochloride (0.050 g, 0.10 mmol, Intermediate Z3), N,N- diisopropylethylamine (0.087 mL, 0.50 mmol), N,N-(dimethylamino)pyridine (0.12 mg, 1.0 ⁇ ), and dichloroethane (10 mL) at room temperature.
  • 6-Aminopyridine-3-sulfonyl chloride (0.039 g, 0.20 mmol) was added to a stirring mixture of 2-(2-(2-((R)-amino(2-chlorophenyl)methyl)-l- benzothiophen-7-yl)-4-pyridinyl)- 1,1,1 -trifluoro-2-propanol hydrochloride (0.10 g, 0.20 mmol, Intermediate Z3), dichloroethane (10 mL), N,N- diisopropylethylamine (0.17 mL, 1.0 mmol), and N,N-(dimethylamino)pyridine (0.024 mg, 0.20 ⁇ ) at room temperature.
  • the isolated material was subjected to flash chromatography on silica gel (40 g RediSep ® normal phase column, elution of 5% methanol (with 2.0 M NH 3 ) in dichloromethane, Teledyne Isco, Lincoln, NE) to afford 6-amino-N-((R)-(2- chlorophenyl)(7-(4-(2,2,2-trifluoro- 1 -hydroxy- 1 -methylethyl)-2-pyridinyl)- 1 - benzothiophen-2-yl)methyl)-3-pyridinesulfonamide (0.0058 g) as a colorless solid (mixture of 2 diastereomers).
  • Step 1 n-Butyllithium (3.8 mL of a 1.6 M solution in hexanes, 6.1 mmol) was added to a stirring solution of l-(2-(l-benzothiophen-7-yl)-4- pyridinyl)ethanol (0.77 g, 3.1 mmol, Intermediate Z4) and tetrahydrofuran (15 mL) at -78 °C under a nitrogen atmosphere. After 20 min, a solution of N-((S,E)- (2-chlorophenyl)methylidene)-2-methyl-2-propanesulfinamide (0.60 mg, 2.4 mmol, Intermediate Yl) in tetrahydrofuran (3.0 mL) was added.
  • Step 2 Hydrogen chloride (2.4 mL of a 1.0 M solution with diethyl ether, 2.4 mmol) was added to a stirring solution of (S)-N-((R)-(2-chlorophenyl)(7-(4- ( 1 -hydroxy ethyl)-2-pyridinyl)- 1 -benzothiophen-2-yl)methyl)-2-methyl-2- propanesulfmamide (0.24 g, containing about 15 mol% of (S)-N-((S)-(2- chlorophenyl)(7-(4-( 1 -hydroxy ethyl)-2-pyridinyl)- 1 -benzothiophen-2-yl)methyl)- 2-methyl-2-propanesulfinamide), from Step 1) and methanol (2.4 mL) at room temperature.
  • Step 3 N,N-(Dimethylamino)pvridine (0.029 g, 0.24 mmol) was added to a stirring solution of l-(2-(2-((R)-amino(2-chlorophenyl)methyl)-l- benzothiophen-7-yl)-4-pyridinyl)ethanol hydrochloride (0.21 g, 0.48 mmol, from Step 2), dichloromethane (2.4 mL), N,N-diisopropylethylamine (0.25 mL, 1.4 mmol), and cyclopropanesulfonyl chloride (0.098 mL, 0.96 mmol, Matrix Scientific, Columbia, SC) at room temperature.
  • Step 1 n-Butyllithium (2.2 mL of a 1.6 M solution with hexanes, 3.5 mmol) was added to a stirring solution of l-(2-(l-benzothiophen-7-yl)-4- pyridinyl)cyclobutanol (0.49 g, 1.7 mmol, Intermediate Z5) and tetrahydrofuran (17 mL) at -78 °C under a nitrogen atmosphere.
  • Step 2 Hydrogen chloride (0.45 mL of a 1.0 M solution with water, 15 mmol) was added to a stirring solution of N-((R)-(2-chlorophenyl)(7-(4-(l- hydroxycyclobutyl)-2-pyridinyl)-l-benzothiophen-2-yl)methyl)-2-methyl-2- propanesulfmamide (0.15 g, 0.29 mmol, from Step 1) and ethyl acetate (2.0 mL). After 1 h, the reaction mixture was concentrated under a vacuum. The residue was partitioned between saturated aqueous sodium bicarbonate and
  • Step 3 N,N-(Dimethylamino)pyridine (0.0036 mg, 0.029 mmol) was added to a stirring solution of l-(2-(2-((R)-amino(2-chlorophenyl)methyl)-l- benzothiophen-7-yl)-4-pyridinyl)cyclobutanol (0.12 mg, 0.29 mmol, from Step 2), N,N-diisopropylethylamine (0.25 mL, 1.5 mmol), N,N-dimethylformamide (3.0 mL), and cyclopropanesulfonyl chloride (0.30 mL, 2.9 mmol, Matrix Scientific, Columbia, SC) at room temperature.
  • reaction mixture was filtered and the filtrate was subjected to reversed-phase preparative HPLC (Phenomenex Gemini C 18 column (Phenomenex, Inc., Torrance, CA)(150 x 30 mm, 10 ⁇ ) eluting with 0.10% trifluoroacetic acid in acetonitrile-water, gradient of 0% to 100% over 10 min).
  • HPLC Henomenex Gemini C 18 column (Phenomenex, Inc., Torrance, CA)(150 x 30 mm, 10 ⁇ ) eluting with 0.10% trifluoroacetic acid in acetonitrile-water, gradient of 0% to 100% over 10 min).
  • the isolated material was subjected to flash chromatography on silica gel (40 g RediSep ® normal phase column, gradient elution of 0% to 100% ethyl acetate-hexane, Teledyne Isco, Lincoln, NE) to provide N-((R)-(2-chlorophenyl)(7-(4-( 1 -hydroxy cyclobutyl)-2-pyridinyl)- 1 - benzothiophen-2-yl)methyl)cyclopropanesulfonamide (0.014 g) as a colorless solid.
  • silica gel 40 g RediSep ® normal phase column, gradient elution of 0% to 100% ethyl acetate-hexane, Teledyne Isco, Lincoln, NE

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Abstract

La présente invention concerne des benzothiophène sulfonamides et d'autres composés qui interagissent avec une protéine régulatrice de la glucokinase. En outre, la présente invention concerne des méthodes de traitement du diabète de type 2, et d'autres maladies et/ou états pathologiques impliquant une protéine régulatrice de la glucokinase utilisant les composés ou leurs sels pharmaceutiquement acceptables, et des compositions pharmaceutiques qui contiennent les composés ou leurs sels pharmaceutiquement acceptables.
PCT/US2013/041011 2012-05-15 2013-05-14 Benzothiophène sulfonamides et autres composés qui interagissent avec une protéine régulatrice de la glucokinase WO2013173382A1 (fr)

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