WO2014035872A1 - Alcynes tricycliques qui interagissent avec la protéine régulatrice de glucokinase - Google Patents

Alcynes tricycliques qui interagissent avec la protéine régulatrice de glucokinase Download PDF

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WO2014035872A1
WO2014035872A1 PCT/US2013/056593 US2013056593W WO2014035872A1 WO 2014035872 A1 WO2014035872 A1 WO 2014035872A1 US 2013056593 W US2013056593 W US 2013056593W WO 2014035872 A1 WO2014035872 A1 WO 2014035872A1
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Prior art keywords
propyn
piperazinyl
sulfonyl
pharmaceutically acceptable
compound
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PCT/US2013/056593
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English (en)
Inventor
Kate Ashton
Christopher H. Fotsch
Roxanne K. KUNZ
Longbin Liu
Nobuko Nishimura
Mark H. Norman
Aaron C. Siegmund
Jr. David J. St. Jean
Nuria A. Tamayo
Kevin C. Yang
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Amgen Inc.
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Publication of WO2014035872A1 publication Critical patent/WO2014035872A1/fr

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    • 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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to tricyclic alkynes, 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 compounds, or the pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.
  • 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 (GKRP).
  • 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,
  • X 1 is N or CR a ;
  • X 2 is N or CH
  • X 3 is N or CH, provided that no more than one of X 1 , X 2 or X 3 is N;
  • R a is hydrogen, -CH 3 , -CF 3 or -F,
  • R 1 is -CH 3 , -CF 3 , C 3 _gcylcoalkyl or -Ci_ 6 alkylC 3 _ 8 Cycloalkyl;
  • R is hydrogen or -CH 3 ;
  • R 3 is hydrogen or Ci_ 6 alkyl;
  • R 4 is hydrogen, Ci_ 6 alkyl or -OCi_ 6 alkyl
  • each R 5 is independently selected from hydrogen, C 3 _ 8 Cycloalkyl, - CH 2 CF 3i Ci_ 6 alkyl or -Ci_ 6 alkylC 3 _ 8 cycloalkyl;
  • R 6 is hydrogen or Ci_ 6 alkyl
  • R 7 is hydrogen or -CH 3 ;
  • X 4 is N or CH
  • X 5 is N or CH
  • X 6 is N or CH;
  • X 7 is N or CH, provided that no more that two of X 4 , X 5 , X 6 and X 7 are
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 1 wherein X 1 is CH.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 1 wherein X 1 is N.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 3 wherein X 2 is CH.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 3 wherein X 2 is N.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 5 wherein X 3 is CH. In embodiment 7, the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 5 wherein X 3 is N.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 7 wherein Y is
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 8 wherein X 4 is CH.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 8 wherein X 4 is N.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 8 to 10 wherein X 5 is CH.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 8 to 10 wherein X 5 is N.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 8 to 12 wherein X 6 is N. In embodiment 14, the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 8 to 12 wherein X 6 is CH.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 8 to 14 wherein X is N.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 8 to 14 wherein X is CH.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 7 wherein Y is
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 17 wherein Q is
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 18 wherein R 1 is -CH 3 .
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 18 wherein R 1 is -CF 3 .
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 18 wherein R 1 is C 3 _ 8 Cycloalkyl.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 18 wherein R 1 is -Ci_ 6 alkylC 3 _8cycloalkyl.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 18 to 22 wherein R 2 is hydrogen.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 18 to 22 wherein R 2 is -CH 3 .
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 17 wherein Q is
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 25 wherein R 7 is hydrogen.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 25 wherein R 7 is -CH 3 .
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 17 wherein Q is
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 17 wherein Q is
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 17 wherein Q is
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 17 wherein Q is
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 17 wherein Q is
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 17 wherein Q is -S0 2 Ci_ 6 alkyl.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 17 wherein Q is C 2 - 6 alkenyl.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 17 wherein Q is -CH(CF 3 ) 2 .
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 17 wherein Q is -CH(CH 3 )(CF 3 );
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 17 wherein Q is -S0 2 R 3 .
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 38 wherein R 3 is hydrogen.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 38 wherein R 3 is Ci_ 6 alkyl.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 38 to 40 wherein R 4 is hydrogen.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 1 to 17 wherein Q is -S0 2 NR 5 R 6 .
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 42 wherein R 5 is hydrogen.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 42 wherein R 5 is Ci_ 6 alkyl.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 42 to 44 wherein R 6 is hydrogen.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodiments 42 to 44 wherein R 6 is Ci_ 6 alkyl.
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 1 wherein X 1 , X 2 and X 3 are CH and Y is
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 1 wherein X 3 is N X 1 and X 2 are CH and Y is In embodiment 49, the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with any one of embodimentss 47 to 48 wherein
  • the present invention provides compounds, or pharmaceutically acceptable salts thereof, in accordance with embodiment 1 , the compound 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 method comprising administering to a patient in need thereof a therapeutically effective amount of a compound in accordance with any one of embodiments 1 to 51 , or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of embodiment 51 wherein the treatment is for type 2 diabetes.
  • the present invention provides a pharmaceutical composition comprising a compound in accordance with any one of
  • embodiments 1 to 50 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present invention provides tricyclic alkynes 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.
  • alkoxy means an alkyl group bonded to an oxygen atom.
  • Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy and isobutoxy.
  • Common alkoxy groups are Ci-galkoxy.
  • 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 C 3 - 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, quinolizinyl, isoquinolyl, quinolyl,
  • 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 heterotaoms 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 heterotaoms 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, pyndazinyl, 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.
  • a group or atom that replaces a hydrogen atom is also called a substituent.
  • 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 excipent, 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
  • 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 GK P/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, rosiglitazone, and the like) and other PPAR ligands, including PPARa/ ⁇ dual agonists such as muraglitazar (BMS) and tesaglitazar (AstraZeneca), and PPARa agonists such as fenofibric acid derivatives (gemfibrozil
  • 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
  • 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 ulcerative 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 hemorrhage 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
  • 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 subcutaneously) intracisternally, intravaginally, intraperitoneally, intravesically, locally (for example, powders, ointments or drops), or as a buccal or nasal spray. All methods that are used by those skilled in the art to administer a patient.
  • 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
  • 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, palmitiate, 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
  • 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- ((C i -C6)alkanoyloxy)ethyl, 1 -methyl- 1 -((C i -C6)alkanoyloxy)ethyl, (C i- C6)alkoxycarbonyloxymethyl, N-(Ci-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)
  • 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
  • Mixture of stereoisomers can be separated into their individual stereochemical components on the basis of their physical chemical differences by known methods such as chromatography and/or fractional crystallization.
  • Enantiomers can also be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an
  • optically active compound e.g., an alcohol
  • separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers e.g., an alcohol
  • converting e.g., hydrolyzing
  • 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.
  • percent (%) refers to a percent by weight or volume with respect to the total. When a percent is given with respect to a liquid, it is percent by volume. When percent is given with respect to a solid, it is percent by weight.
  • GKRP LC MS/MS Biochemical Assay 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). Begin by preparing the following solutions. Assay Buffer: 20mM Tris, pH 7.5 / 0.05% BSA / ImM
  • 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
  • Pd 2 dba 3 or Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium(0)
  • the N-arylation can be conducted using a variety of bases (such as NaOt-Bu, K 3 PO 4 or LiHMDS), catalyst (such as Pd 2 (dba) 3 , Pd(OAc) 2 or
  • Pd(PPh 3 ) 4 catalyst ligands (such as RuPhos, BINAP or SPhos), catalyst-ligand complex (such as RuPhos palladacycle) and solvents (such as toluene or dioxane) under an inert atmosphere.
  • the amino group can be revealed after removal of protection group (such as 1-chloroethyl chlorocarbonate followed by MeOH for a Bn group or triflic acid in TFA for Cbz group).
  • the sulfonamide can be synthesized by the reaction of an amine with a Boc protected amino substituted aryl sulfonyl chloride in an anhydrous solvent (such as CH 2 CI 2 , THF or diethyl ether) in the presence of a base (either inorganic or amine) such as Et 3 N, DIPEA, K 2 C0 3 , Na 2 C0 3 , or NaOH.
  • a base either inorganic or amine
  • the deprotection in the case of a Boc group can be achieved with treatment of the compounds with acid (such as TFA, HC1) in an anhydrous solvent (such as CH 2 C1 2 , THF, 1,4-dioxane or diethyl ether).
  • the diol can be synthesized from corresponding ketone by converting carbonyl group to alkene using appropriate phosphorous ylids in the presence of base (such as nBuLi) in an anhydrous solvent (such as THF) under an inert atmosphere followed by dihydroxylation using osmium tetroxide in the presence of N-methylmorpholine N-oxide in a solvent system (such as acetone and water).
  • the diol can be protected, such as by an acetonide, by treating the diol with 2,2- dimethoxypropane in the presence of an acid (such as TsOH) in an anhydrous solvent (such as acetone, DCM, and THF) under an inert atmosphere.
  • the N- arylation can be conducted using a variety of bases (such as NaOt-Bu, K 3 PO 4 or LiHMDS), catalyst (such as Pd 2 (dba) 3 , Pd(OAc) 2 or Pd(PPh 3 ) 4 ), catalyst ligands (such as RuPhos, BINAP or SPhos), catalyst-ligand complex (such as RuPhos palladacycle) and solvents (such as toluene or dioxane) under inert atmosphere.
  • bases such as NaOt-Bu, K 3 PO 4 or LiHMDS
  • catalyst such as Pd 2 (dba) 3 , Pd(OAc) 2 or Pd(PPh 3 ) 4
  • catalyst ligands such as RuPhos, BINAP or SPhos
  • catalyst-ligand complex such as RuPhos palladacycle
  • solvents such as toluene or dioxane
  • the sulfonamide can be synthesized by the reaction of an amine with a Boc protected amino substituted aryl sulfonyl chloride in an anhydrous solvent (such as CH 2 CI 2 , THF or diethyl ether) in the presence of a base (either inorganic or amine) such as Et 3 N, DIPEA, K 2 CO 3 , Na 2 C03, or NaOH.
  • anhydrous solvent such as CH 2 CI 2 , THF or diethyl ether
  • a base either inorganic or amine
  • the diol can be converted to the epoxide by converting the primary hydroxyl group to a leaving group (such as tosylate and mesylate) followed by intramolecular substitution reaction in the presence of base ((either inorganic or amine) such as Et 3 N, DIPEA, K 2 CO 3 , Na 2 C03, or NaOH in an in an anhydrous solvent (such as CH 2 C1 2 , THF or diethyl ether). Finally the epoxide can be opened with various nuclephiles (such as NaOMe, KCN, NaN 3 , alkyl lithium, and NH 3 ) in appropriate solvents (such as THF and DMF).
  • bases (either inorganic or amine) such as Et 3 N, DIPEA, K 2 CO 3 , Na 2 C03, or NaOH
  • an anhydrous solvent such as CH 2 C1 2 , THF or diethyl ether.
  • nuclephiles such as NaOMe, KCN, NaN
  • tert-butyl (5-nitro-2- pyridinyl)carbamate 96.4 g, 403 mmol
  • Zinc 105 g, 1610 mmol, Strem Chemical Inc, Newburyport, MA
  • the filtrate was concentrated and then diluted with EtOAc and washed with water.
  • the organic extracts were dried over MgS0 4 , filtered, and concentrated.
  • the resulting solid was recrystallized from MeOH to give tert-butyl(5-amino-2-pyridinyl)carbamate (38.6 g) as a light-yellow solid.
  • STEP 3 TERT-BUTYL (5-(CHLOROSULFONYL)-2- PYRIDINYL)CARBAMATE
  • sodium nitrite (15.3 g, 221 mmol, J. T. Baker, Philipsburg, NJ)
  • MeCN MeCN
  • hydrochloric acid (231 mL, 2770 mmol) was slowly added keeping the internal temperature below 10 °C.
  • tert-butyl (5-amino-2-pyridinyl)carbamate 38.6 g, 184 mmol was added as a suspension in MeCN (200 mL). The mixture was stirred for 30 min, then 150 mL of AcOH, copper(ii) chloride (12.4 g, 92.2 mmol, Sigma-Aldrich, St. Louis, MO), and copper(i) chloride (0.183 g, 1.85 mmol, Strem Chemical Inc,
  • STEP 1 (35)-l-((6-CHLORO-3-PYRIDINYL)SULFONYL)-3-(l-PROPYN-l- YL)PIPERAZINE
  • benzyl (35)-3-(l-propyn-l-yl)-l- piperazinecarboxylate (2.51 g, 9.71 mmol, Intermediate E) in TFA (20 mL) in 250-mL round-bottomed flask
  • trifluoromethanesulfonic acid (2.59 mL, 29.1 mmol, Alfa Aesar, Ward Hill, MA) was added slowly at rt.
  • step 1 step 2
  • methyl phenylphosphonium bromide (25.4 g, 71.1 mmol, Sigma- Aldrich, St. Louis, MO) and toluene (75 mL). The resulting mixture was stirred for 5 min then concentrated and dried under high vacuum for 30 min. To this residue was added THF (300 mL) followed by n-butyllithium (2.5 M in hexanes, 29.0 mL, 71.1 mmol, Aldrich, St. Louis, MO) dropwise via an addition funnel.
  • the reaction mixture was degassed by bubbling N 2 through the solution for 5 min, then the vial was capped. The reaction mixture was heated at 80 °C for 30 min then allowed to cool to rt and partitioned between EtOAc (70 mL) and water (40 mL). The aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic layers were dried over MgS0 4 , filtered, and concentrated.
  • STEP 5 rEi?r-BUTYL(5-(((35)-3-(l-PROPYN-l-YL)-4-(4-(2,2,2- TRIFLUORO- 1 -HYDROXY- 1 -(HYDROXYMETH YL)ETHYL)PHENYL)- 1 - PIPERAZINYL)SULFONYL)-2-PYRIDINYL)CARBAMATE
  • Triethylamine (2.20 mL, 16.0 mmol, Sigma- Aldrich, St. Louis, MO) and tert-butyl (5-(chlorosulfonyl)-2-pyridinyl)carbamate (1.04 g, 3.60 mmol, Intermediate A) were added.
  • the reaction mixture was stirred at rt for 1 h then partitioned between DCM (70 mL) and water (30 mL). The aqueous layer was extracted with DCM (2 x 40 mL). The combined organic layers were dried over MgS0 4 , filtered, and concentrated.
  • the crude product was purified by column chromatography (120 g of silica, 10% to 40% acetone in hexanes) to afford tert-butyl (5-(((35)-3-(l-propyn-l-yl)-4-(4-(2,2,2-trifiuoro-l- hydroxy- 1 -(hydroxymethyl)ethyl)phenyl)- 1 -piperazinyl)sulfonyl)-2- pyridinyl)carbamate (1.0 g) as a yellow foam.
  • the crude product was purified by column chromatography (40 g of silica, 10 to 40%> acetone in hexanes) to afford tert-butyl (5-(((35)-3-(l-propyn-l-yl)-4-(4-(2- (trifluoromethyl)-2-oxiranyl)phenyl)- 1 -piperazinyl)sulfonyl)-2- pyridinyl)carbamate (0.240 g) as an off-white solid.
  • the resulting white cloudy mixture was stirred at about 1 °C for 6 h.
  • the reaction mixture was allowed to warm up to rt slowly and stirred for overnight at rt.
  • 2 M K 3 PO 4 50 mL was added slowly to the reaction mixture.
  • the mixture was extracted with EtOAc (2 x 50 mL), and the combined organic phases were washed with water (60 mL) and saturated aqueous sodium chloride (60 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under a vacuum.
  • thiourea (0.33 g, 4.4 mmol, Sigma-Aldrich, St. Louis, MO)
  • acetone 20 mL
  • tert-butyl (6- chloropyridazin-3-yl)carbamate
  • Trifluoromethanesulfonic acid (0.250 mL, 2.82 mmol, Alfa Aesar, Ward Hill, MA) was added slowly and the mixture was stirred at rt for 2 min.
  • the reaction mixture was added to ice water (70 mL) and 10 N NaOH (about 4 mL) was added slowly while stirring the mixture.
  • the aqueous phase was extracted with EtOAc (2 x 50 mL).
  • the combined organic phases were washed with water (50 mL) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under a vacuum.
  • the aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were washed with saturated aqueous NaHC0 3 (2 x 40 mL), water (40 mL), and saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under a vacuum. Upon addition of DCM to this residue, white precipitate came out of solution.
  • the individual diastereomers were isolated using chiral SFC.
  • the method used was as follows: Chiralpak ® AS-H (Daicel Inc., Fort Lee, NX) (250 x 21 mm, 5 ⁇ ) using 29% (20 mM NH 3 in methanol) in supercritical C0 2 (total flow was 75 mL/min) at 40 °C.
  • the first eluting peak was repurified using the following method: Chiralcel ® OJ-H Sepax (150 x 21 mm, 5 ⁇ ) using 25% (20 mM NH 3 in methanol) in supercritical C0 2 (total flow was 75 mL/min) at 40 °C. This produced the two diastereomers with diastereomeric excesses greater than 99%.
  • EXAMPLE 2 4-((2S)-4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l- PROP YN- 1 - YL)- 1 -PIPERAZINYL)BENZENESULFONAMIDE
  • reaction mixture was diluted with ice-cold water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na 2 S0 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel (100 to 200 mesh) column chromatography (elution 30% EtOAc-hexanes) to give 4-bromo-N- (cyclopropylmethyl)benzenesulfonamide (0.80 g) as a brown solid.
  • benzyl (35)-3-(l-propyn-l-yl)-l- piperazinecarboxylate (440 mg, 1.73 mmol, Intermediate E)
  • 4-bromo-N- (cyclopropylmethyl)benzenesulfonamide 500 mg, 1.73 mmol
  • 1,4-dioxane 5 mL
  • the solution was degassed by purging with argon gas for 20 min.
  • STEP 4 TERT-EUTYL (5 -(((3S)-3-(l -PROPYN- 1- YL)-4-(4- SULF AMO YLPHENYL)- 1 -PIPERAZINYL)SULFONYL)-2- PYRIDINYL)CARBAMATE
  • the reaction mixture was diluted with water (30 mL) and DCM (30 mL). The organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 and filtered. The filtrate was concentrated under reduced pressure and the residue obtained was purified by silica gel (60 to 120 mesh) column chromatography (eluent, 30% EtOAc-hexanes) to give tert-butyl (5-(((35)-3-(l-propyn-l-yl)-4-(4- sulfamoylphenyl)-l-piperazinyl)sulfonyl)-2-pyridinyl)carbamate (60 mg) as a white solid.
  • STEP 5 4-((25)-4-((6-AMINO-3-PYPJDINYL)SULFONYL)-2-(l-PROPYN-l- YL)- 1 -PIPERAZINYL)BENZENESULFONAMIDE
  • tert-butyl (5-(((35)-3-(l-propyn-l-yl)- 4-(4-sulfamoylphenyl)- 1 -piperazinyl)sulfonyl)-2-pyridinyl)carbamate (60 mg, 0.098 mmol) was dissolved in DCM (1.2 mL) and trifluoroacetic acid (0.6 mL, Spectrochem, India) was added at 0 °C. The reaction mixture was allowed to gradually warm to rt and stirred at rt for 2 h.
  • STEP 2 4-((25)-4-BENZYL-2-(l-PROPYN-l-YL)-l-PIPERAZINYL)-N- CYCLOPROPYLBENZENESULFONAMIDE
  • 35)-l-benzyl-3-(l-propyn-l- yl)piperazine 460 mg, 2.18 mmol
  • 4-bromo-N- cyclopropylbenzenesulfonamide 500 mg, 1.81 mmol
  • the solution was degassed by purging with argon gas at rt for 20 min.
  • RuPhos 42 mg, 0.090 mmol, Sigma- Aldrich, India
  • RuPhos palladacycle 42 mg, 0.055 mmol, Sigma- Aldrich, India
  • sodium tert- butoxide 440 mg, 4.54 mmol, Spectrochem, India
  • the reaction mixture was heated at 110 °C for 4 h.
  • the reaction mixture was allwed to cool to rt and filtered through a diatomaceous earth pad.
  • the filtrate was diluted with cold water (30 mL) and ethyl acetate (30 mL).
  • STEP 3 N-C YCLOPROP YL-4-((2iS)-2-( 1 -PROPYN- 1 - YL)- 1 - PIPERAZINYL)BENZENESULFONAMIDE
  • 4-((25)-4-benzyl-2-(l -propyn- l-yl)-l - piperazinyl)-N-cyclopropylbenzenesulfonamide 350 mg, 0.855 mmol
  • DCM 3.5 mL
  • STEP 5 4-((25)-4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l-PROPYN-l- YL)- 1 -PIPERAZINYL)-N-CYCLOPROPYLBENZENESULFONAMIDE
  • tert-butyl (5-(((35)-4-(4- (cyclopropylsulfamoyl)phenyl)-3 -( 1 -propyn- 1 -yl)- 1 -piperazinyl)sulfonyl)-2- pyridinyl)carbamate (200 mg, 0.347 mmol) was dissolved in DCM (4.0 mL) and trifluoroacetic acid (2.0 mL, Spectrochem, India) was added at 0 °C. The reaction mixture was gradually warmed to rt and stirred at rt for 2 h.
  • STEP 4 TERT-EUTYL (5-(((3S)-4-(4-(METHYLSULFINYL)PHENYL)-3-(l- PROP YN- 1 - YL)- 1 -PIPERAZINYL)SULFONYL)-2- PYRIDINYL)CAPvBAMATE
  • the resulting reaction mixture was stirred at rt under nitrogen atmosphere for 2 h.
  • the reaction mixture was diluted with cold water (20 mL) and DCM (50 mL).
  • the organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • STEP 5 5-(((35)-4-(4-(S-METHYLSULFONIMIDOYL)PHENYL)-3-(l- PPvOPYN- 1 -YL)- 1 -PIPERAZINYL)SULFONYL)-2-PYRIDIN AMINE
  • tert-butyl 5-(((3S)-4-(4-)
  • reaction mixture was diluted with ice-cold water (20 mL) and neutralized with Na 2 C0 3 solution (10%, 10 mL), before extracting with CHC1 3 (50 mL x 3).
  • the combined organic extracts were washed with water and brine, dried over anhydrous Na 2 S0 4 , filtered, and concentrated under reduced pressure.
  • the reaction mixture was diluted with ice-cold water (100 mL) and neutralized with Na 2 C0 3 solution (10%, 100 mL), before extracting with CHC1 3 (200 mL x 3).
  • the combined organic extracts were washed with water and brine, dried over anhydrous Na 2 S0 4 , filtered, and concentrated under reduced pressure.
  • the solid residue obtained was
  • STEP 6 5-(((35)-4-(4-(N ⁇ -DIMETHYLSULFONIMIDOYL)PHENYL)-3-(l- PROPYN- 1 -YL)- 1 -PIPERAZINYL)SULFONYL)-2-PYPJDIN AMINE
  • tert-butyl 5-(((3S)-4-(4-(NS- dimethylsulfonimidoyl)phenyl)-3 -( 1 -propyn- 1 -yl)- 1 -piperazinyl)sulfonyl)-2- pyridinyl)carbamate (0.36 g, 0.66 mmol) was dissolved in DCM (20 mL) and the solution was cooled to 0 °C.
  • Trifluoroacetic acid (1.2 mL, Spectrochem, India) was added to the above solution. The resulting mixture was warmed to rt and stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The residue obtained was neutralized with 10% Na 2 C03 solution and extracted with DCM (100 mL three times). The combined organic extract was washed with water and brine, dried over anhydrous Na 2 S0 4 , filtered, and concentrated under reduced pressure.
  • RuPhos (16 mg, 0.034 mmol, Sigma-Aldrich, India), Pd 2 (dba) 3 (55 mg, 0.058 mmol, Sigma-Aldrich, India) and sodium tert-butoxide (220 mg, 2.3 mmol, Spectrochem, India) were added sequentially to the above solution at rt under argon atmosphere.
  • the reaction tube was sealed under an argon atmosphere and resulting reaction mixture was heated at 100 °C for 2 h.
  • the reaction mixture was cooled to rt and filtered through a diatomaceous earth pad. The filtrate was diluted with cold water (30 mL) and ethyl acetate (30 mL).
  • (2S)-l-(4-(N-methyl-S- (trifluoromethyl)sulfonimidoyl)phenyl)-2-( 1 -propyn- 1 -yl)piperazine (220 mg, 0.636 mmol) was dissolved in THF (15 mL) at rt under nitrogen atmosphere.
  • Triethylamine (0.2 mL, SD Fine-Chem, India) and tert-butyl (5-(chlorosulfonyl)-
  • tert-butyl (5-(((3S)-4-(4-(N-methyl-S- (trifluoromethyl)sulfonimidoyl)phenyl)-3 -( 1 -propyn- 1 -yl)- 1 - piperazinyl)sulfonyl)-2-pyridinyl)carbamate (0.15 g, 0.25 mmol) was dissolved in DCM (10 mL) at rt. TFA (1 mL, Aldrich, India) was added to the above solution at rt. The resulting reaction mixture was stirred at rt for 2 h.
  • reaction mixture was diluted with ice-cold water (20 mL) and neutralized with saturated Na 2 C03 solution before extracting with EtOAc (50 mL x 3).
  • EtOAc 50 mL x 3
  • the combined organic extract was washed with water and brine, dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • the filtrate was diluted with cold water (30 mL) and ethyl acetate (30 mL). The organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 , and filtered. The filtrate was concentrated under reduced pressure and the residue obtained was purified by silica gel (60 to 120 mesh) column chromatography (eluent, 1% EtOAc-hexanes) to give of l-bromo-4- (cyclopropylsulfanyl)benzene (300 mg) as a white solid.
  • the reaction mixture was cooled to rt and filtered through a diatomaceous earth pad.
  • the filtrate was diluted with cold water (30 mL) and ethyl acetate (30 mL).
  • the organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 , and filtered.
  • the filtrate was concentrated under reduced pressure and the residue obtained was purified by silica gel (60 to 120 mesh) column chromatography (eluent, 10% EtOAc-hexanes) to give of (25)-4-benzyl-l-(4- (cyclopropylsulfanyl)phenyl)-2-(l-propyn-l-yl)piperazine (350 mg) as a white solid.
  • the resulting reaction mixture was stirred at 0 °C for 30 min and at rt for further 1 h.
  • the reaction mixture was diluted with saturated NaHC0 3 solution (30 mL) and EtOAc (30 mL). The organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 , and filtered.
  • tert-butyl (5-(((3S)-4-(4- (cyclopropylsulfinyl)phenyl)-3 -( 1 -propyn- 1 -yl)- 1 -piperazinyl)sulfonyl)-2- pyridinyl)carbamate (0.1 g, 0.2 mmol) in CHC1 3 (2 mL) was treated with NaN 3 (20 mg, 0.29 mmol, Spectrochem, India) at rt. The resulting mixture was cooled to 0 °C and cone.
  • H 2 S0 4 (95 mg, 0.97 mmol, Rankem, India) was added dropwise to the above solution.
  • the reaction mixture was allowed to warm to rt and stirred at rt for 6 h.
  • the reaction mixture was diluted with ice-cold water (20 mL) and neutralized with Na 2 C0 3 solution (10%, 10 mL) before extracting with EtOAc (50 mL x 3).
  • the combined organic extract was washed with water and brine, dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • EXAMPLE 8 4-((2S)-4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l- PROP YN- 1 - YL)- 1 -PIPERAZINYL)-N- (CYCLOPROPYLMETHYL)BENZENESULFONAMIDE
  • STEP 1 4-((2S)-4-BENZYL-2-(l-PROPYN-l-YL)-l-PIPERAZINYL)-N- (CYCLOPPvOPYLMETHYL)BENZENESULFONAMIDE
  • ((35)-l-benzyl-3-(l- propyn-l-yl)piperazine (440 mg, 2.08 mmol, Intermediate B) and 4-bromo-N- (cyclopropylmethyl)benzenesulfonamide (500 mg, 1.73 mmol, Example 2, Step 1) were dissolved in 1,4-dioxane (10 mL) at rt.
  • the solution was degassed by purging with argon gas at rt for 20 min.
  • RuPhos 40 mg, 0.086 mmol, Sigma- Aldrich, India
  • RuPhos palladacycle 40 mg, 0.051 mmol, Sigma-Aldrich, India
  • sodium tert-butoxide 330 mg, 3.46 mmol, Spectrochem, India
  • the reaction mixture was heated at 110 °C for 4 h.
  • the reaction mixture was cooled to rt and filtered through a diatomaceous earth pad.
  • the filtrate was diluted with cold water (30 mL) and ethyl acetate (30 mL).
  • STEP 3 TERT-EUTYL (5-(((3S)-4-(4- ((C YCLOPROP YLMETHYL)SULF AMO YL)PHENYL)-3 -( 1 -PROPYN- 1 - YL)- l-PIPERAZINYL)SULFONYL)-2-PYRIDINYL)CARBAMATE
  • N-(cyclopropylmethyl)-4-((25)-2-(l- propyn-l-yl)-l-piperazinyl)benzenesulfonamide 150 mg, 0.45 mmol
  • DCM 5 mL
  • Pyridine (0.75 mL, SD Fine-Chem, India
  • tert-butyl 5-(chlorosulfonyl)-2-pyridinyl)carbamate (197 mg, 0.67 mmol, Intermediate A) were added sequentially to the above solution at rt under nitrogen atmosphere.
  • the resulting reaction mixture was stirred at rt under nitrogen atmosphere for 1 h.
  • STEP 4 4-((2S)-4-BENZYL-2-(l -PROPYN- 1-YL)-1 -PIPERAZINYL)-N- (CYCLOPROPYLMETHYL)BENZENESULFONAMIDE
  • tert-butyl 5-(((3S)-4-(4-)
  • the reaction mixture was cooled to rt and filtered through a diatomaceous earth pad.
  • the filtrate was diluted with cold water (40 mL) and ethyl acetate (40 mL).
  • the organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 , and filtered.
  • the filtrate was concentrated under reduced pressure and the residue obtained was purified by silica gel (60 to 120 mesh) column chromatography (eluent, 25% EtOAc-hexanes) to give of (25)-4-benzyl-l-(4-(ethylsulfonyl)phenyl)-2-(l- propyn-l-yl)piperazine (400 mg) as an off-white solid.
  • (2S)-4-benzyl-l-(4- (ethylsulfonyl)phenyl)-2-(l-propyn-l-yl)piperazine (490 mg, 1.28 mmol) was dissolved in DCM (4.0 mL) at 0 °C.
  • K 2 C0 3 177 mg, 1.28 mmol, Spectrochem, India
  • 1-chloroethyl chlorocarbonate (0.42 mL, 3.8 mmol, Sigma- Aldrich, India) were added to the above solution at the same temperature.
  • the resulting reaction mixture was stirred at rt for 12 h.
  • the reaction mixture was diluted with water (50 mL) and DCM (50 mL). The organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 , and filtered. The filtrate was concentrated under reduced pressure and the residue obtained was purified by silica gel (60 to 120 mesh) column chromatography (eluent, 20% EtOAc-hexanes) to give tert-butyl (5-(((3S)-4-(4- (ethylsulfonyl)phenyl)-3 -( 1 -propyn- 1 -yl)- 1 -piperazinyl)sulfonyl)-2- pyridinyl)carbamate (470 mg) as a white solid.
  • STEP 4 5-(((3S)-4-(4-(ETHYLSULFONYL)PHENYL)-3-(l-PROPYN-l-YL)- l-PIPERAZINYL)SULFONYL)-2-PYRIDINAMINE
  • tert-butyl 5-(((3S)-4-(4-(ETHYLSULFONYL)PHENYL)-3-(l-PROPYN-l-YL)- l-PIPERAZINYL)SULFONYL)-2-PYRIDINAMINE
  • the reaction mixture was diluted with ice cold water (10 mL) and DCM (25 mL). The organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 , and filtered. The filtrate was concentrated under reduced pressure, and the solid obtained was washed with n-pentane to give to give 4-bromo-N-(2,2,2- trifluoroethyl)benzenesulfonamide (1 g) as a white solid.
  • STEP 3 4-(2-(l-PROPYN-l-YL)-l-PIPERAZINYL)-N-(2,2,2- TRIFLUOROETHYL)BENZENESULFONAMIDE
  • benzyl 3-(l-propyn-l-yl)-4-(4-((2,2,2- trifluoroethyl)sulfamoyl)phenyl)-l -piperazinecarboxylate 280 mg, 0.56 mmol
  • CHC1 3 (2 mL, Rankem, India
  • STEP 4 TERT-EUTYL (5-((3-(l-PROPYN-l-YL)-4-(4-((2,2,2- TRIFLUOROETHYL)SULF AMO YL)PHENYL)- 1 - PIPERAZINYL)SULFONYL)-2-PYRIDINYL)CARBAMATE
  • the resulting reaction mixture was stirred at rt under a nitrogen atmosphere for 2 h.
  • the reaction mixture was concentrated under reduced pressure.
  • the residue obtained was diluted with water (10 mL) and EtOAc (30 mL).
  • the organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 , and filtered.
  • STEP 5 4-(4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l-PROPYN-l-YL)- l-PIPERAZINYL)-N-(2,2,2-TRIFLUOROETHYL)BENZENESULFONAMIDE
  • tert-butyl (5-((3-(l-propyn-l-yl)-4-(4- ((2,2,2-trifluoroethyl)sulfamoyl)phenyl)-l-piperazinyl)sulfonyl)-2- pyridinyl)carbamate (200 mg, 0.32 mmol) was dissolved in DCM (4 mL) at rt and solution was cooled to 0 °C. TFA (2 mL, Spectrochem, India) was added to the above solution at the same temperature. The reaction mixture was allowed to gradually warm to rt and stirred at rt for 3 h.
  • RuPhos (59 mg, 0.13 mmol, Sigma-Aldrich, India), RuPhos palladacycle (61 mg, 0.75 mmol, Sigma-Aldrich, India) and sodium tert-butoxide (485 mg, 5.00 mmol, Spectrochem, India) were added sequentially to the above solution at rt under an argon atmosphere.
  • the reaction tube was sealed under an argon atmosphere and resulting reaction mixture was heated at 110 °C for 4 h.
  • the reaction mixture was cooled to rt and filtered through a diatomaceous earth pad. The filtrate was diluted with cold water (35 mL) and ethyl acetate (35 mL).
  • STEP 3 TERT-BUTYL (5 -(((35)-4-(4- ACETYLPHEN YL)-3 -( 1 -PROPYN- 1 - YL)- 1 -PIPERAZINYL)SULFONYL)-2-PYRIDINYL)C ARBAMATE
  • the reaction mixture was diluted with water (30 mL) and DCM (30 mL). The organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 and filtered. The filtrate was concentrated under reduced pressure and the residue obtained was purified by silica gel (60 to 120 mesh) column chromatography (eluent, 30% EtOAc-hexanes) to give tert- butyl (5-(((3S)-4-(4-acetylphenyl)-3-(l -propyn- 1 -yl)- 1 -piperazinyl)sulfonyl)-2- pyridinyl)carbamate (75 mg) as a white solid.
  • tert-bvXy ⁇ (5-(((35)-4-(4-acetylphenyl)- 3-(l-propyn-l-yl)-l-piperazinyl)sulfonyl)-2-pyridinyl)carbamate (75 mg, 0.15 mmol) was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL,
  • the individual diastereomers were isolated using chiral SFC.
  • the method used was as follows: Chiralpak ® AS-H column (Daicel Inc., Fort Lee, NJ) (21 x 250 mm, 5 ⁇ ) using 30% (240 mM NH 3 in methanol) in supercritical C0 2 (total flow was 70 mL/min). This produced the two diastereomers with diastereomeric and enanteomeric excesses greater than 98%.
  • Peak l STEP 2 / STEP S STEP 1 l-BROMO-4-((S)-5-
  • STEP 2 (2S)-4-BENZYL-2-(l -PROPY -l-YL)-l-(4-(S)-(5- (TRIFLUOROMETHYL)SULFONIMIDOYL)PHENYL)PIPERAZINE OR (25)-4-BENZ YL-2-( 1 -PROP YN- 1 - YL)- 1 -(4-(S)-(S- (TRIFLUOROMETHYL)SULFONIMIDOYL)PHENYL)PIPERAZINE
  • STEP 3 TERT-EUTYL (5-(((3S)-3-(l -PROPYN- l-YL)-4-(4-(S)-(5- (TRIFLUOROMETHYL)SULFONIMIDOYL)PHENYL)- 1 - PIPERAZINYL)SULFONYL)-2-PYRIDINYL)CARBAMATE
  • TERT- BUTYL (5-((3S)-3-(l-PROPYN-l-YL)-4-(4-(R)-(5-
  • TEA t- vXy ⁇ (5-(chlorosulfonyl)-2- pyridinyl)carbamate (9.18 g, 31.4 mmol, Intermediate A) in potions.
  • the ice-bath was removed and the mixture was stirred at rt for 1.5 h.
  • TEA 10 mL
  • tert- vXy ⁇ (5-(chlorosulfonyl)-2-pyridinyl)carbamate (0.804 g, 2.74 mmol, Intermediate A) were added at rt and the stirring at rt continued for additional 50 min.
  • the reaction mixture was diluted with water and the phases were separated.
  • the aqueous phase was extracted with DCM (200 mL). The combined organic phases were washed with water (400 mL) and saturated aqueous sodium chloride (400 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo.
  • tert-butyl (5-(((3S)-3-(l- propyn- 1 -yl)-4-(4-(5)-(5 , -(trifluoromethyl)sulfonimidoyl)phenyl)- 1 - piperazinyl)sulfonyl)-2-pyridinyl)carbamate or tert-butyl (5-(((35)-3-(l-propyn- 1 -yl)-4-(4-(i?)-(5'-(trifluoromethyl)sulfonimidoyl)phenyl)- 1 - piperazinyl)sulfonyl)-2-pyridinyl)carbamate (16.5 g, 28.0 mmol), TFA (75 mL, 973 mmol) and DCM (150 mL).
  • the mixture was stirred at rt for 1 h.
  • the volume of the reaction mixture was reduced to about 100 mL under reduced pressure.
  • the mixture was placed on an ice bath and 5 N NaOH (about 100 mL) was added slowly (pH about 10).
  • the mixture was partitioned between water (100 mL) and EtOAc (200 mL).
  • the aqueous phase was extracted with EtOAc (400 mL).
  • the combined organic phases were washed with water (300 mL) and saturated aqueous sodium chloride (300 mL).
  • the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo.
  • STEP 3 TERT-BUTYL (5-(((3S)-4-(4-(METHYLSULFAMOYL)PHENYL)-3- ( 1 -PROPYN- 1 - YL)- 1 -PIPERAZINYL)SULFONYL)-2- PYRIDINYL)CARBAMATE
  • EXAMPLE 14 4-(4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l-PROPYN- 1 - YL)- 1 -PIPERAZINYL)-N-METHYLBENZENESULFONAMIDE
  • benzyl 3-(l-propyn-l-yl)-l- piperazinecarboxylate 500 mg, 1.93 mmol, Intermediate E, Step 3
  • 4- bromo-N-methylbenzenesulfonamide 482 mg, 1.93 mmol
  • RuPhos (10 mg, 0.019 mmol, Sigma-Aldrich, India), RuPhos palladacycle (20 mg, 0.019 mmol, Sigma-Aldrich, India) and sodium tert- butoxide (560 mg, 5.79 mmol, Sigma-Aldrich, India) were added sequentially to the above solution at rt under argon atmosphere.
  • the reaction tube was sealed under argon and the reaction mixture was heated at 80 °C for 10 h.
  • the reaction mixture was cooled to rt and filtered through a diatomaceous earth pad. The filtrate was diluted with cold water (20 mL) and ethyl acetate (50 mL).
  • N-methyl-4-(2-(l-propyn-l-yl)-l- piperazinyl)benzenesulfonamide 300 mg, 1.02 mmol
  • DCM 10 mL
  • Triethylamine 0.4 mL, 3.1 mmol, SD Fine-Chem, India
  • tert-butyl (5-(chlorosulfonyl)pyridin-2-yl)carbamate 300 mg, 1.02 mmol, Intermediate A
  • reaction mixture was diluted with water (20 mL) and DCM (30 mL). The organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 and filtered. The filtrate was concentrated under reduced pressure and residue obtained was purified by silica gel (60 to 120 mesh) column chromatography (eluent, 25% EtOAc-hexanes) to give tert-butyl (5-((4-(4-(methylsulfamoyl)phenyl)-3-(l -propyn-1 -yl)- 1 -piperazinyl)sulfonyl)-2- pyridinyl)carbamate (200 mg) as a white solid.
  • STEP 5 4-(4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l-PROPYN-l-YL)- l-PIPERAZINYL)-N-METHYLBENZENESULFONAMIDE
  • tert-butyl (5-((4-(4- (methylsulfamoyl)phenyl)-3 -( 1 -propyn- 1 -yl)- 1 -piperazinyl)sulfonyl)-2- pyridinyl)carbamate (200 mg, 0.36 mmol) was dissolved in DCM (5 mL) and TFA (2 mL, Spectrochem, India) was added at 0 °C. The reaction mixture was gradually warmed to rt and stirred at rt for 1 h. The reaction mixture was neutralized with saturated NaHCOs solution and diluted with ethyl acetate (20 mL).
  • EXAMPLE 15 6-((2S)-4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l- PROPYN- 1 -YL)- 1 -PIPERAZINYL)-N-METHYL-3 - PYRIDINESULFONAMIDE
  • the crude product was purified by column chromatography (50 g of silica, 20 to 100% EtOAc in hexanes) followed by preparative HPLC (Phenomenex, Gemini NX 10 micron C18 100 x 50mm (Phenomenex, Torrance, CA), 10 to 100 % CH 3 CN w/ 0.1 % TFA/H 2 O w/ 0.1 % TFA in 15 min) to afford benzyl (3S)-4-(5- (methylsulfamoyl)-2-pyridinyl)-3 -( 1 -propyn- 1 -yl)- 1 -piperazinecarboxylate (0.309 g) as a white solid after free-basing the material.
  • STEP 3 6-((2S)-4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l-PROPYN-l- YL)- 1 -PIPERAZINYL)-N-METHYL-3-PYRIDINESULFONAMIDE
  • TEA tert-butyl (5- (chlorosulfonyl)pyridin-2-yl)carbamate (0.0865 g, 0.295 mmol, Intermediate A) was added. The mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated under a vacuum and redissolved into DCM (2 mL). TFA (1 mL) was added and the mixture was stirred at room temperature for 30 min. At that time, additional TFA (1 mL) was added. After 1 h 20 min of total stirring, the reaction mixture was concentrated under a vacuum.
  • EXAMPLE 16 4-(4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l-PROPYN- 1 -YL)- 1 -PIPERAZINYL)-N-ETHYLBENZENESULFONAMIDE
  • RuPhos (8 mg, 0.015 mmol, Sigma- Aldrich, India), RuPhos palladacycle (16 mg, 0.015 mmol, Sigma- Aldrich, India) and sodium tert- butoxide (500 mg, 4.65 mmol, Sigma- Aldrich, India) were added sequentially to the above solution at rt under argon atmosphere.
  • the reaction tube was sealed under an argon atmosphere and resulting reaction mixture was heated at 80 °C for 10 h.
  • the reaction mixture was cooled to rt and filtered through a diatomaceous earth pad. The filtrate was diluted with cold water (30 mL) and ethyl acetate (30 mL).
  • STEP 4 TERT-BUTYL (5-((4-(4-(ETHYLSULFAMOYL)PHENYL)-3-(l- PROPYN- 1 -YL)- 1 -PIPERAZINYL)SULFONYL)-2- PYRIDINYL)CARBAMATE
  • N-ethyl-4-(2-(l-propyn-l-yl)-l- piperazinyl)benzenesulfonamide 100 mg, 0.32 mmol
  • DCM 5 mL
  • Triethylamine 0.9 mL, 0.6 mmol, SD Fine- Chem, India
  • tert-butyl (5-(chlorosulfonyl)pyridin-2-yl)carbamate 95 mg, 0.32 mmol, Intermediate A
  • the resulting reaction mixture was stirred at rt under nitrogen atmosphere for 2 h.
  • the reaction mixture was diluted with water (30 mL) and DCM (30 mL).
  • the organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 and filtered.
  • the filtrate was
  • STEP 5 4-(4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l-PROPYN-l-YL)- l-PIPERAZINYL)-N-ETHYLBENZENESULFONAMIDE
  • tert-butyl (5-((4-(4- (ethylsulfamoyl)phenyl)-3 -( 1 -propyn- 1 -yl)- 1 -piperazinyl)sulfonyl)-2- pyridinyl)carbamate (100 mg, 0.17 mmol) was dissolved in DCM (1 mL) and TFA (1 mL, Spectrochem, India) was added at 0 °C. The reaction mixture was gradually warmed to rt and stirred at rt for 1 h.
  • reaction mixture was neutralized with saturated NaHCOs solution and diluted with ethyl acetate (20 mL). The organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 and filtered. The filtrate was concentrated under reduced pressure.
  • EXAMPLE 18 4-(4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l-PROPYN- 1 -YL)- 1 -PIPERAZINYL)-N-(1 -METHYLETHYL)BENZENESULFONAMIDE
  • STEP 5 4-(4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l-PROPYN-l-YL)- l-PIPERAZINYL)-N-(l-METHYLETHYL)BENZENESULFONAMIDE
  • tert-butyl (5-((4-(4-((l- methylethyl)sulfamoyl)phenyl)-3 -( 1 -propyn- 1 -yl)- 1 -piperazinyl)sulfonyl)-2- pyridinyl)carbamate (150 mg, 0.25 mmol) was dissolved in DCM (3 mL) at rt and the solution was cooled to 0 °C. TFA (1.5 mL, Spectrochem, India) was added to the above solution at the same temperature. The reaction mixture was gradually warmed to rt and stirred at rt for 3 h.
  • reaction mixture was neutralized with saturated NaHC0 3 solution and diluted with ethyl acetate (25 mL). The organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 and filtered. The filtrate was concentrated under reduced pressure.
  • EXAMPLE 19 4-(4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l-PROPYN- 1 - YL)- 1 -PIPERAZINYL)-N,N-DIMETHYLBENZENESULFONAMIDE
  • benzyl (3S)-3-(l-propyn-l-yl)-l- piperazinecarboxylate (273 mg, 1.15 mmol, Intermediate E, Step 3) was dissolved in toluene (10 mL) at rt. The solution was degassed by purging with argon gas at rt for 30 min.
  • the reaction mixture was cooled to rt and filtered through a diatomaceous earth pad.
  • the filtrate was diluted with cold water (30 mL) and ethyl acetate (30 mL).
  • the organic layer was separated, washed with water and brine, dried over anhydrous Na 2 S0 4 and filtered.
  • the filtrate was concentrated under reduced pressure and the residue obtained was purified by silica gel (60 to 120 mesh) column chromatography (eluent, 20% EtOAc- hexanes) to give benzyl 4-(4-(dimethylsulfamoyl)phenyl)-3-(l-propyn-l-yl)-l- piperazinecarboxylate (200 mg) as a white solid.
  • STEP 4 TERT-BUTYL (5-((4-(4-(DIMETHYLSULFAMOYL)PHENYL)-3-(l- PPvOPYN- 1 -YL)- 1 -PIPERAZINYL)SULFONYL)-2- PYRIDINYL)CAPvBAMATE
  • N,N-dimethyl-4-(2-(l-propyn-l-yl)-l- piperazinyl)benzenesulfonamide 250 mg, 0.81 mmol
  • DCM 10 mL
  • Triethylamine 0.3 mL, 2 mmol, SD Fine-Chem, India
  • tert-butyl 5-(chlorosulfonyl)-2-pyridinyl)carbamate
  • STEP 5 4-(4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l-PROPYN-l-YL)- l-PIPERAZINYL)-N,N-DIMETHYLBENZENESULFONAMIDE
  • tert-butyl (5-((4-(4- (dimethylsulfamoyl)phenyl)-3 -( 1 -propyn- 1 -yl)- 1 -piperazinyl)sulfonyl)-2- pyridinyl)carbamate (150 mg, 0.26 mmol) was dissolved in DCM (5 mL) and TFA (2 mL, Spectrochem, India) was added at 0 °C. The reaction mixture was gradually warmed to rt and stirred at rt for 1 h. The reaction mixture was neutralized with saturated NaHCOs solution and diluted with ethyl acetate (20 mL).
  • STEP 5 TERT-BUTYL (4-(((3S)-4-(5-(METHYLSULFAMOYL)-l,3- THIAZOL-2-YL)-3-(l -PROPYN- 1 -YL)- 1 - PIPERAZINYL)SULFONYL)PHENYL)CARBAMATE
  • EXAMPLE 22 5-(((3S)-4-(5-(l-METHYLETHENYL)-l,3-THIAZOL-2-YL)-3- (1 -PROPYN- 1 - YL)- 1 -PIPERAZINYL)SULFONYL)-2-PYRIDIN AMINE
  • STEP 4 TERT-BUTYL (5-(((3S)-4-(5-(l-METHYLETHENYL)-l,3- THIAZOL-2- YL)-3 -( 1 -PROPYN- 1 - YL)- 1 -PIPERAZINYL)SULFONYL)-2- PYRIDINYL)CARBAMATE
  • STEP 1 2-(4-((2S)-4-BENZYL-2-(l-PROPYN-l-YL)-l- PIPERAZINYL)PHENYL)-1 , 1 ,1 ,3,3,3-HEXAFLUORO-2-PROPANOL
  • a 20-mL vial was charged with (3S)-l-benzyl-3-(l-propyn-l- yl)piperazine (2.143 g, 10 mmol, Intermediate B), 2-(4-bromophenyl)- 1,1,1, 3,3, 3-hexafluoropropan-2-ol (3.09 g, 11.5 mmol, Bioorg. Med. Chem. Lett.
  • STEP 2 l,l,l,3,3,3-HEXAFLUORO-2-(4-((2S)-2-(l-PROPYN-l-YL)-l- PIPERAZINYL)PHENYL)-2-PROPANOL
  • STEP 3 TERT-BUTYL (5-(((3S)-3-(l-PROPYN-l-YL)-4-(4-(2,2,2- TRIFLUORO- 1 -HYDROXY- 1 -(TRIFLUOROMETHYL)ETHYL)PHENYL)- 1 - PIPERAZINYL)SULFONYL)-2-PYRIDINYL)CARBAMATE
  • STEP 2 2-(4-((2S)-4-((6-AMINO-3-PYRIDINYL)SULFONYL)-2-(l- PROP YN- 1 -YL)- 1 -PIPERAZINYL)PHENYL)- 1,1,1 -TRIFLUORO-4-PENT YN- 2-OL

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Abstract

La présente invention porte sur des composés alcynes tricycliques de formule I qui interagissent avec la protéine régulatrice de glucokinase. De plus, la présente invention porte sur des procédés de traitement du diabète de type 2 et d'autres maladies et/ou affections où la protéine régulatrice de glucokinase est impliquée, à l'aide des composés, ou de sels pharmaceutiquement acceptables de ceux-ci, et sur des compositions pharmaceutiques qui contiennent les composés ou des sels pharmaceutiquement acceptables de ceux-ci.
PCT/US2013/056593 2012-08-27 2013-08-26 Alcynes tricycliques qui interagissent avec la protéine régulatrice de glucokinase WO2014035872A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104557800A (zh) * 2014-12-31 2015-04-29 常州大学 2-苯氧基四氢呋（吡）喃衍生物及其在五氟磺草胺合成中的应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083465A2 (fr) * 2000-05-03 2001-11-08 F. Hoffmann-La Roche Ag Activateurs heteroaromatiques de la glucokinase a base d'alkynyle-phenyle
WO2012027261A1 (fr) * 2010-08-23 2012-03-01 Amgen Inc. Dérivés de sulfonylpipérazine qui interagissent avec la protéine régulatrice de la glucokinase pour le traitement du diabète

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083465A2 (fr) * 2000-05-03 2001-11-08 F. Hoffmann-La Roche Ag Activateurs heteroaromatiques de la glucokinase a base d'alkynyle-phenyle
WO2012027261A1 (fr) * 2010-08-23 2012-03-01 Amgen Inc. Dérivés de sulfonylpipérazine qui interagissent avec la protéine régulatrice de la glucokinase pour le traitement du diabète

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104557800A (zh) * 2014-12-31 2015-04-29 常州大学 2-苯氧基四氢呋（吡）喃衍生物及其在五氟磺草胺合成中的应用

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