WO2004063194A1 - Composes heteroaryle - Google Patents

Composes heteroaryle Download PDF

Info

Publication number
WO2004063194A1
WO2004063194A1 PCT/US2003/037089 US0337089W WO2004063194A1 WO 2004063194 A1 WO2004063194 A1 WO 2004063194A1 US 0337089 W US0337089 W US 0337089W WO 2004063194 A1 WO2004063194 A1 WO 2004063194A1
Authority
WO
WIPO (PCT)
Prior art keywords
lower alkyl
hydrogen
compound
ring
sulfur
Prior art date
Application number
PCT/US2003/037089
Other languages
English (en)
Inventor
Andreas Gerhard Weichert
David Gene Barrett
Stefan Heuser
Rainer Riedl
Mark Joseph Tebbe
Andrea Zaliani
Original Assignee
Eli Lilly And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to AU2003294376A priority Critical patent/AU2003294376A1/en
Publication of WO2004063194A1 publication Critical patent/WO2004063194A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • Glucokinase (GK, Hexokinase IV) is one of four hexokinases that are found in mammals [Colowick, S.P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, NY, pages 1-48, 1973].
  • the hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate, Glucokinase has a limited cellular distribution, being found principally in pancreatic beta-cells and hepatocytes.
  • GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S.R., Kelly, K.L., and Ruderman, N.B. in Joslin 's Diabetes (CR. Khan and G.C. Wier, eds.), Lea and Febiger, Philadelphia, PA, pages 97-115, 1994].
  • concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM
  • the other three hexokinases are saturated with glucose at much lower concentrations ( ⁇ 1 mM).
  • GK plays a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grape, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in beta-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition.
  • Glucokinase activators will increase the flux of glucose metabolism in beta-cells and hepatocytes, which will be coupled to increased insulin secretion and increased glucose utilization and glycogen synthesis. Such agents would be useful for treating type II diabetes.
  • R is lower alkyl or halo lower alkyl having from 2 to 6 carbon atoms or arylalkyl or •
  • V is a 3 to 8-membered ring which is cycloalkyl, cycloalkenyl, or heterocycloalkyl having one heteroatom selected from oxygen and sulfur; s is independently 0, 1 or 2;
  • M is hydrogen or halo or lower alkyl or perfluoro-lower alkyl
  • Y is oxygen or sulfur
  • R 1 and R 2 are independently hydrogen, halo, amino, hydroxyamino, nifro, cyano, sulfonamido, lower alkyl, -OR 5 , -COOR 5 , perfluoro- lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl,
  • R 5 is hydrogen, lower alkyl or perfluoro-lower alkyl; or furthermore
  • R 6 and R 7 are independently hydrogen or lower alkyl; or together with the nifrogen atom to which they are attached form a five or six-membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from sulfur, oxygen or nifrogen; or a saturated 5- or 6- membered cycloheteroalkyl ring, which contains from 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nifrogen; or
  • R 10 is a heteroaromatic ring, connected by a ring carbon atom, which contains from 5 to 6 ring members with from 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen, or aryl containing 6 or 10 ring carbon atoms, or aryl containing 6 ring carbon atoms fused with a heteroaromatic ring containing 5 or 6 ring members with 1 or 2 heteroatoms in the ring being selected from the group consisting of nitrogen, oxygen or sulfur, or a saturated 5- or 6-membered cycloheteroalkyl ring, which contains from 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a cycloalkyl ring having 5 or 6 carbon atoms, or
  • R 11 and R 12 being independently hydrogen or lower alkyl; y is independently 0,1,2,3 or 4; z is independently 0,1; or
  • R 2 can be R 13 -(CH 2 )t-U-, with U is -NHCO-, -CONH, -NHSO 2 -, -SO 2 NH- and
  • R 13 in the same meaning of R 10 and perfluoro-lower alkyl, lower alkyl, lower alkoxycarbonyl or
  • R 14 and R 15 are independently hydrogen or lower alkyl; or together with the nitrogen atom to which they are attached form a five or six-membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from sulfur, oxygen or nifrogen; or a saturated
  • heterocycloalkyl ring which contains from 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; t is an integer being 0, 1, 2, 3 or 4;
  • R 4 is -C(O)NHR 16 , or is R 17 ;
  • R 16 is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl,
  • R is an unsubstituted, mono- or di-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide group shown, which five- or six-membered heteroaromatic ring contains from 1 to 4 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; said mono- or di-substituted heteroaromatic ring being mono- or di- substituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl, halo, nifro, cyano, -(CH 2 )n-OR 20 , -(CH 2 )n-COOR 21 , -(CH 2 )n-CONHR 22 , -(CH 2 )n-NHR 23 , n is O, 1, 2, 3 or 4; R 1S , R 19 , R 20 ,
  • the compounds of formula I have been found to activate glucokinase in vitro.
  • the compounds of formula I have an enhanced solubility profile and further, have improved metabolic stability over the compounds of the prior art. They are particularly useful for increasing insulin secretion in the freatment of type II diabetes.
  • the present invention provides pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof for use as a pharmaceutical; and a compound of formula I, or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of type II diabetes.
  • the present invention also provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the freatment or prophylaxis of disorders associated with GK dysfunction in mammals; the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of of type II diabetes.
  • the present invention further relates to processes for the preparation of the compounds of formula I, or pharmaceutically acceptable salts thereof.
  • the present invention relates to a method for the prophylactic or therapeutic freatment of type II diabetes, which method comprises administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; to a human being or an animal in need thereof.
  • the present invention includes the pharmaceutically acceptable salts of the compounds of formula I.
  • pharmaceutically acceptable salts include acid addition salts, including salts formed with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic or organic sulphonic acids, for example, acetoxybenzoic, citric, glycolic, o- mandelic-1, mandelic-dl, mandelic d, maleic, mesotartaric monohydrate, hydroxymaleic, fumaric, lactobionic, malic, methanesulphonic, napsylic, naphthalenedisulfonic, naphtoic, oxalic, palmitic, phenylacetic, propionic, pyridyl hydroxy pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, 2-hydroxyethane sulphonic
  • salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically acceptable, acid addition salts, or are useful for identification, characterisation or purification.
  • the compounds of the invention can contain one or more asymmetric carbon atoms which gives rise to isomers.
  • the "*" designates an asymmetric carbon atom in this compound.
  • the compound of formula I has the following spatial orientation:
  • ⁇ denotes compounds wherein "A” and “M” have a trans configuration across the double bond.
  • trans designates that the two substituents attached at each end of the double bond are on opposite sides of the double bond.
  • halogen and the term “halo”, unless otherwise stated, designate all four halogens, i.e. fluorine, chlorine, bromine and iodine.
  • a prefened halogen is chlorine or fluorine.
  • R and/or R is halo
  • chlorine is especially prefened.
  • M is halo
  • fluorine is especially prefened.
  • lower alkyl includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, preferably methyl and ethyl.
  • R 3 isopropyl and n-propyl are prefened, isobutyl is also prefened.
  • Halo lower alkyl designates a lower alkyl group wherein one or more of the hydrogens is replaced by a halogen as defined above, which replacement can be at any site on the lower alkyl, including the end, such as chloroethyl. With regard to R fluoro lower alkyl is prefened.
  • Fluoro lower alkyl designates a lower alkyl group wherein one or more of the hydrogens is replaced by fluorine, which replacement can be at any site on the lower alkyl, including the end, such as 1,1,1-trifluoroethane, 1,1,1- trifluoropropane and 1,1,1,3,3,3-hexafluoroisopropyl.
  • a prefened fluoro lower alkyl group is 1,1,1,3,3,3-hexafluoroisopropyl.
  • hydroxy lower alkyl includes any hydroxy lower alkyl group where lower alkyl is defined as above.
  • the hydroxy can be substituted at any place on the lower alkyl group such as hydroxy methyl, 1 -hydroxy ethyl, 2 -hydroxy propyl, 2-hydroxy isopropyl or 2-hydroxy-2-butyl.
  • Lower alkoxy lower alkyl denotes any hydroxy lower alkyl group wherein the hydrogen of the hydroxy moiety is substituted by lower alkyl.
  • perfluoro-lower alkyl means any lower alkyl group wherein all of the hydrogens of the lower alkyl group are substituted or replaced by fluoro.
  • prefened perfluoro-lower alkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc.
  • An especially prefened perfluoro-lower alkyl group is trifluoromethyl.
  • lower alkyl thio means a lower alkyl group as defined above where a thio group is bound to the rest of the molecule.
  • perfluoro-lower alkyl thio means a perfluoro-lower alkyl group as defined above where a thio group is bound to the rest of the molecule.
  • lower alkyl sulfonyl means a lower alkyl group as defined above where a sulfonyl group is bound to the rest of the molecule, preferably lower alkyl sulfonyl is methyl sulfonyl.
  • perfluoro-lower alkyl sulfonyl means a perfluoro- lower alkyl group as defined above where a sulfonyl group is bound to the rest of the molecule
  • hydroxyamino designates an amino group where one of the hydrogens is replaced by a hydroxy.
  • cycloalkyl means a saturated hydrocarbon ring having from 3 to
  • An especially prefened cycloalkyl is cyclopentyl.
  • heterocycloalkyl means a saturated hydrocarbon ring having from 3 to 8 carbon atoms, preferably from 5 to 7 carbon atoms, and having one to two heteroatoms which may be oxygen, sulfur or nifrogen. With regard to R 3 it is prefened to have a single heteroatom, preferably oxygen.
  • cycloalkenyl means a cycloalkyl ring having from 3 to 8, and preferably from 5 to 7 carbon atoms, where one of the bonds between the ring carbons is unsaturated.
  • lower alkenyl denotes an alkylene group having from 2 to 6 carbon atoms with a double bond located between any two adjacent carbons of the group, such as allyl and crotyl.
  • lower alkoxy includes both straight chain and branched chain alkoxy groups having from 1 to 7 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, preferably methoxy and ethoxy.
  • aryl signifies aryl mononuclear aromatic hydrocarbon groups such as phenyl, tolyl, etc. which can be unsubstituted or substituted in one or more positions with halogen, nifro, lower alkyl, or lower alkoxy substituents and polynuclear aryl groups, such as naphthyl, anthryl, and phenanthryl, which can be unsubstituted or substituted with one or more of the aforementioned groups.
  • Prefened aryl groups are the substituted and unsubstituted mononuclear aryl groups, such as phenyl.
  • arylalkyl denotes an alkyl group, preferably lower alkyl, in which one of the hydrogen atoms is replaced by an aryl group.
  • arylalkyl groups are benzyl, 2-phenylethyl, 3-phenylpropyl, 4-chlorobenzyl, 4- methoxybenzyl and the like.
  • lower alkanoic acid denotes lower alkanoic acids containing from 2 to 7 carbon atoms such as propionic acid, acetic acid and the like.
  • lower alkanoyl denotes monovalent alkanoyl groups having from 2 to 7 carbon atoms such as propionoyl, acetyl and the like.
  • aromatic acids denotes aryl alkanoic acids where aryl is as defined above and alkanoic contains from 1 to 6 carbon atoms.
  • aroyl denotes aroic acids wherein aryl is as defined hereinbefore, with the hydrogen group of the COOH moiety removed. Among the prefened aroyl groups is benzoyl.
  • the heteroaromatic ring in R 4 can be an unsubstituted, mono- or di-substituted five- or six-membered heteroaromatic ring having from 1 to 3 heteroatoms selected from the group consisting of oxygen, nifrogen or sulfur and connected by a ring carbon to the amine of the amide group shown.
  • the heteroaromatic ring contains a first nitrogen heteroatom adjacent to the connecting ring carbon atom and if present, the other heteroatoms can be sulfur, oxygen or nitrogen.
  • Heteroaromatic rings include, for example, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, thiadiazolyl (preferably 1,3,4-, 1,2,3-, 1,2,4-), triazinyl (preferably 1,3,5-, 1,2,4-), thiazolyl, oxazolyl, and imidazolyl.
  • the prefened heteroaromatic rings which constitute R 4 are connected via a ring carbon atom to the amide group to form the amides of formula I.
  • R 4 is preferably an unsubstituted, mono- or di-substituted five- or six-membered, heteroaromatic ring containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur, with one hetero atom being nitrogen and connected to the remainder of the molecule by a ring carbon atom.
  • the prefened rings are those which contain a nifrogen heteroatom adjacent to the connecting ring carbon.
  • R is an unsubstituted, mono- or di-substituted five- or six-membered heteroaromatic ring
  • the prefened rings are those which contain a nitrogen heteroatom adjacent to the connecting ring carbon and a second heteroatom adjacent to the connecting ring carbon or adjacent to said first heteroatom.
  • R 4 is a five-membered heteroaromatic ring.
  • the prefened five-membered heteroaromatic rings contain 2 or 3 heteroatoms. Examples of such five-membered heteroaromatic rings are thiazolyl, imidazolyl, oxazolyl and thiadiazolyl, with thiazolyl being especially prefened.
  • heteroaromatic ring is a six-membered heteroaromatic
  • the ring is connected by a ring carbon atom to the amine group shown, with one nitrogen heteroatom being adjacent to the connecting ring carbon atom.
  • the prefened six-membered heteroaromatic rings include, for example, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl with pyridinyl being especially prefened.
  • heteroaromatic rings R 4 may optionally be mono- or di-substituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting lower alkyl, halo, nifro, cyano, -(CH 2 )n-OR 20 , -(CH )n- C(O)OR 21 , -(CH 2 )n-CONHR 22 , -(CH 2 )n-NHR 23 , with n, R 20 , R 21 , R 22 and R 23 being as defined above.
  • hydrolyzable ester or ether protecting groups designates any ester or ether conventionally used for protecting carboxylic acids or alcohols which can be hydrolyzed to yield the respective hydroxyl or carboxyl group.
  • ester groups useful for those purposes are those in which the acyl moieties are derived from a lower alkanoic, aryl lower alkanoic, or lower alkane dicarboxcyclic acid.
  • activated acids which can be utilized to form such groups are acid anhydrides, acid halides, preferably acid chlorides or acid bromides derived from aryl or lower alkanoic acids.
  • anhydrides are anhydrides derived from monocarboxylic acid such as acetic anhydride, benzoic acid anhydride, and lower alkane dicarboxcylic acid anhydrides, e.g. succinic anhydride as well as chloro formats e.g. trichloro, ethylchloro formate being prefened.
  • Suitable ether protecting groups for alcohols are, for example, the tefrahydropyranyl ethers such as 4-methoxy-5,6-dihydroxy- 2H- pyranyl ethers. Others are aroylmethylethers such as benzyl, benzhydryl or trityl ethers or a-lower alkoxy lower alkyl ethers, for example, methoxymethyl or allylic ethers or alkyl silylethers such as trimethylsilylether.
  • amino protecting group designates any conventional amino protecting group which can be cleaved to yield the free amino group.
  • the prefened protecting groups are the conventional amino protecting groups utilized in peptide synthesis. Especially prefened are those amino protecting groups which are cleavable under mildly acidic conditions at about pH 3.0. Particularly preferred amino protecting groupsare t-butoxycarbonyl (BOC), carbobenzyloxy (CBZ) and 9- flurorenylmethoxycarbonyl(FMOC).
  • the compound of formula (I) of this invention constitutes two prefened species, i.e., the compound of formula
  • R 3 is lower alkyl having from 2 to 6 carbon atoms, prefened lower alkyl residues being isopropyl and n-propyl.
  • R 3 is isopropyl, in another R 3 is isobutyl.
  • R 3 is -(CH 2 )s-V where "s" and "V are as defined above, the preferred V substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms.
  • V is cyclopentyl, in another V is cyclohexyl.
  • R is halo lower alkyl having from 2 to 6 carbon atoms, prefened halo lower alkyl residues being fluoro lower alkyl as defined above.
  • Prefened R 4 substituent in accordance with the present invention is where R 4 is R 17 as defined above. Further prefened R 17 substituents are unsubstituted, mono- or di- substituted thiazolyl, imidazolyl, oxazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
  • R 17 is thiazolyl, in another R 17 is
  • the heteroaromatic ring R is either unsubstituted, mono- or di-substituted independently with lower alkyl, halogen or -(CH 2 )n-C(O)OR 21 , wherein n and R 21 are as defined above.
  • M is hydrogen, halo or lower alkyl.
  • Further prefened M subtituents are hydrogen, fluoro, methyl or ethyl. In one prefened embodiment M is hydrogen, in another M is methyl.
  • Prefened substituent R 1 is selected from the group consisting of hydrogen, halo, nitro, cyano, perfluoro lower alkyl, and lower alkyl sulfonyl.
  • a further prefened R 1 substituent is selected from the group consisting of hydrogen, halo, nitro, cyano or perfluoro lower alkyl.
  • R 1 is halo, in another R 1 is hydrogen.
  • Preferred substituent R 2 is selected from the group consisting of hydrogen, halo, nitro, cyano, perfluoro lower alkyl, lower alkyl sulfonyl, R 10 -[(CH 2 )y-W]z and R 13 -(CH )t-U- where R 10 , R 13 , W, U, t, y and z are as defined above. Further prefened R 2 substituents are halo, lower alkyl sulfonyl, R 10 -[(CH 2 )y-W]z and R 13 -(CH 2 )t-U- where R 10 , R 13 , W, U, t, y and z are as defined above.
  • R 2 is lower alkyl sulfonyl, in another R is R -[(CH )y-W]z where R , W, U, y and z are as defined above, in another R is R 13 -(CH )t-U- where R 13 , U and t, are as defined above.
  • R 2 is sulphonyl methyl, in another R 2 is R 10 -[(CH 2 )y-W]z where W is SO 2 and R 10 , U, y and z are as defined above.
  • R can be - (CH 2 )s-V where "s" and “N" are as defined above, the prefened V substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I-Al).
  • compound I-Al a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • Another embodiment of the compounds of formula (I- A) are those compounds where R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A2).
  • compound I-A2 is included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-A3).
  • compound I-A3 compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-Al (a)).
  • compound I-Al (a) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-A2(a)).
  • compound I-A2(a) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • A is
  • R 3 can be -(CH 2 )s-V where "s" and "V are as defined above, the prefened V substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I- A3 (a)).
  • compound I- A3 (a) Among the various embodiments of the compound I- A3 (a) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • the compound of formula I-A3 are those compounds where R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A3(b)).
  • R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl
  • compound I-A3(b) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • A is where Y is sulfur (compound I-A3(c)).
  • compound I-A3(c) is included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 3 can be -(CH 2 )s-V where "s" and "V are as defined above, the prefened V substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I-A4(a)).
  • compound I-A4(a) Among the various embodiments of the compound I-A4(a) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • the compound of formula I-A4 are those compounds where R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A4(b)).
  • R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl
  • compound I-A4(b) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-A4(c)).
  • compound I-A4(c) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 3 can be -(CH 2 )s-V where "s" and "V are as defined above, the prefened V substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I-A5(a)).
  • compound I-A5(a) Among the various embodiments of the compound I-A5(a) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • the compound of formula I-A5 are those compounds where R is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A5(b)).
  • R is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl
  • compound I-A5(b) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-A5(c)).
  • compound I-A5(c) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • Y is sulfur (compound I-Al (a- 1)).
  • compound I-Al(a-l) is included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • A is where Y is sulfur (compound I-Al(a-2)).
  • compound I-Al(a-2) is included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those
  • compound I-Al (b-1) compounds where R is a thiazole or pyridine ring
  • compound I-Al (b-1) compounds where R is a thiazole or pyridine ring
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-Al(c-l)).
  • compound I-Al(c-l) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • A is
  • compound I-A2(a-1) where Y is sulfur (compound I-A2(a-1)).
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • A is where Y is sulfur (compound I-A2(a-2)).
  • compound I-A2(a-2) is included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-A2(b-1)).
  • compound I-A2(b-1) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-A2(c-1)).
  • compound I-A2(c-1) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • A is
  • A is where Y is sulfur (compound I-A3(a-2)).
  • compound I-A3(a-2) is included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • compound I-A3(b-1) where Y is sulfur (compound I-A3(b-1)).
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • compound I-A3(b-2) where Y is sulfur (compound I-A3(b-2)).
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R can be -(CH )s-
  • V where "s" and “V are as defined above, the prefened V substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl
  • compound I-A3(c-1) (compound I-A3(c-1)).
  • M is hydrogen, halo or lower alkyl, particularly where
  • M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A3(c-2)).
  • compound I-A3(c-2) is included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 3 can be -(CH )s- V where "s" and "V are as defined above, the prefened V substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I-A3(d-1)).
  • compound I-A3(d-1) Among the various embodiments of the compound I-A3(d-1) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • the compound of formula I-A3(d) are those compounds where R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A3(d-2)).
  • R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl
  • compound I-A3(d-2) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-A4(a-1)).
  • compound I-A4(a-1) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-A4(b-1)).
  • compound I-A4(b-1) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 3 can be -(CH )s-
  • V where "s" and “V are as defined above, the prefened V substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I-A4(c-1)).
  • compound I-A4(c-1) Among the various embodiments of the compound I-A4(c-1) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • the compound of formula I-A4(c) are those compounds where R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A4(c-2)).
  • R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl
  • compound I-A4(c-2) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R is a thiazole or pyridine ring (compound I-A5(a-1)).
  • compound I-A5(a-1) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R is a thiazole or pyridine ring (compound I-A5(b-1)).
  • compound I-A5(b-1) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R can be -(CH )s-
  • V where "s" and “V are as defined above, the prefened V substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I-A5(c-1)).
  • compound I-A5(c-1) Among the various embodiments of the compound I-A5(c-1) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • the compound of formula I-A5(c) are those compounds where R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A5(c-2)).
  • R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl
  • compound I-A5(c-2) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 3 can be - (CH )s-V where "s" and “V" are as defined above, the prefened V substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I-Bl).
  • compound I-Bl a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • Another embodiment of the compounds of formula I-B are those compounds where R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-B2).
  • R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl
  • compound I-B2 include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-B3).
  • compound I-B3 include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • A is
  • Y is sulfur (compound I-B4).
  • compound I-B4 is included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • A is where Y is sulfur (compound I-B5).
  • compound I-B5 is included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those ⁇ n compounds where R is a thiazole or pyridine ring (compound I-B 1(a)).
  • compound I-B 1(a) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-B2(a)).
  • compound I-B2(a) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • I-B2(c) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 3 can be -(CH 2 )s-N where "s" and "V" are as defined above, the prefened V substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I-B3(a)).
  • compound I-B3(a) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • the compound of formula I-B3 are those compounds where R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-B3(b)).
  • R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl
  • the various embodiments of the compound I-B 3(b) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • A is
  • R 3 can be -(CH 2 )s-V where "s" and "V are as defined above, the prefened V substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I-B4(a)).
  • compound I-B4(a) Among the various embodiments of the compound I-B4(a) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • the compound of formula I-B4 are those compounds where R is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-B4(b)).
  • R is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl
  • compound I-B4(b) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-B4(c)).
  • compound I-B4(c) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 3 can be -(CH )s-V where "s" and “N" are as defined above, the prefened N substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I-B5(a)).
  • compound I-B5(a) Among the various embodiments of the compound I-B5(a) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • the compound of formula I-B 5 are those compounds where R is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-B5(b)).
  • R is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl
  • compound I-B5(b) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those
  • compound I-Bl(a-2) where Y is sulfur (compound I-Bl(a-2)).
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-Bl (b-1)).
  • compound I-Bl (b-1) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-Bl(c-l)).
  • compound I-Bl(c-l) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • A is
  • compound I-B2(a-1) where Y is sulfur (compound I-B2(a-1)).
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • compound I-B2(a-2) where Y is sulfur (compound I-B2(a-2)).
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-B2(b-1)).
  • compound I-B2(b-1) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-B2(c-1)).
  • compound I-B2(c-1) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • A is
  • compound I-B3(a-1) where Y is sulfur (compound I-B3(a-1)).
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • compound I-B3(a-2) where Y is sulfur (compound I-B3(a-2)).
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • compound I-B 3 (b-1) where Y is sulfur (compound I-B 3 (b-1)).
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • compound I-B3(b-2) where Y is sulfur (compound I-B3(b-2)).
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 3 can be -(CH )s- N where "s" and “N" are as defined above, the prefened N substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I-B3(c-1)).
  • compound I-B3(c-1) Among the various embodiments of the compound I-B3(c-1) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • the compound of formula I-B 3(c) are those compounds where R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-B3(c-2)).
  • R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl
  • compound I-B3(c-2) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 3 can be -(CH 2 )s- N where "s" and “N" are as defined above, the prefened N substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I-B3(d-1)).
  • compound I-B3(d-1) Among the various embodiments of the compound I-B3(d-1) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • the compound of formula I-B3(d) are those compounds where R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-B3(d-2)).
  • R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl
  • compound I-B3(d-2) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-B4(a-1)).
  • compound I-B4(a-1) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those compounds where R 17 is a thiazole or pyridine ring (compound I-B4(b-1)).
  • compound I-B4(b-1) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 3 can be -(CH 2 )s-
  • the prefened N substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I-B4(c-1)).
  • compound I-B4(c-1) a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl.
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • the compound of formula I-B4(c) are those compounds where R is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-B4(c-2)).
  • R is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl
  • compound I-B4(c-2) include those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those
  • R 4 is R 17 , which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those
  • R 3 can be -(CH 2 )s- N where "s" and “N" are as defined above, the prefened N substituent being a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl (compound I-B5(c-1)).
  • compound I-B5(c-1) a cycloalkyl group which contains from 3 to 8 carbon atoms, preferably cyclopentyl or cyclohexyl
  • M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • the compound of formula I-B5(c) are those compounds where R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-B5(c-2)).
  • R 3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl
  • compound I-B5(c-2) are included those compounds where M is hydrogen, halo or lower alkyl, particularly where M is hydrogen, fluoro or methyl, more particularly where M is hydrogen.
  • the compounds of the present invention may be prepared as is shown in the following reaction schemes. In the case when Z equals
  • amides of formula III these can be directly reacted with the deprotonated amines R 17 -NH , using appropriate Grignard reagents, preferably isopropyl magnesium chloride.
  • alkenoates of formula II can be hydrolyzed to the conesponding acids of formula V by known procedures of alkaline or acidic saponification. Subsequent activation of the acids
  • MS mass specfra
  • alkyl iodides mentioned below were reacted with ethyl propiolate in the presence of triethylborane as described (Y. Ichinose et al., Tet. Lett. 1989, 30(24), 3155- 3158)
  • Ethyl (E)-3-Cyclopentyl-2-(5-methylsulfonyl-thiophen-2-yl)-propenoate Ethyl (Z)-3-cyclopentyl-2-iodo-propenoate (O.lg, 0.34 mmol) was dissolved in 2 ml of DMSO.
  • Bis(pinacolato)diborane (0.093 g, 0.37 mmol), potassium acetate (0.1 g, 1.02 mmol) and Pd(dppf)Cl 2 (0.02g) were added at ambient temperature and then stined for 2h at 80°C under argon atmosphere.
  • E Ethyl
  • the compounds of the present invention may be used as medicaments in human or veterinary medicine.
  • the compounds may be administered by various routes, for example, by oral or rectal routes, topically or parenterally, for example by injection, and are usually employed in the form of a pharmaceutical composition.
  • compositions may be prepared by methods well known in the pharmaceutical art and normally comprise at least one active compound in association with a pharmaceutically acceptable diluent or carrier.
  • the active ingredient will usually be mixed with a carrier or diluted by a canier, and/or enclosed within a canier which may, for example, be in the form of a capsule, sachet, paper or other container.
  • the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
  • the composition maybe in the form of tablets, lozenges, sachets, cachets, elixirs, suspensions, solutions, syrups, aerosol (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, injection solutions and suspensions and sterile packaged powders.
  • suitable carriers are lactose, dextrose, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as starch and petroleum jelly, sucrose sorbitol, mannitol, starches, gum acacia,calcium phosphate, alginates, fragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl- hydrobenzoate, talc, magnesium stearate and mineral oil.
  • the compounds of formula (I) can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations.
  • compositions of the invention can be formulated so as to provide, quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 500 mg, more usually about 25 to about 300 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary doses for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
  • Tablets containing the following ingredients can be produced in a conventional manner:
  • Capsules containing the following ingredients can be produced in a conventional manner: Ingredients (mg per capsule)
  • GK enzymatic coupled glucokinase
  • the NADH production detected by absorbance at 340nm is used to monitor the enzymatic activity.
  • the human islet GK isoform was expressed in E.coli as (His) 6 -tagged fusion protein and purified with metal chelate affinity chromatography (Tiedge et al., 1997). After purification the enzyme was stored in aliquots at concentration 0.8 mg/ml in 25 mM NaH 2 PO 4 , 150 mM NaCl, 100 mM imidazole, 1 mM DTT, 50 % glycerol at -80°C The assay was performed in flat bottom 96-well plates in a final incubation volume of lOO ⁇ l.
  • the incubation mixture consisted of 25 mM HEPES (pH7.4), 50 mM KC1, 2.5 mM MgCl 2 , 2 mM dithiothreitol, 4 U/ml glucose-6-phosphate dehydrogenase from Leuconostoc mesenteroides, 5 mM ATP, 1 mM NAD and 10 mM glucose. All reagents were from Sigma-Aldrich Co. (St. Louis, MO). Test compounds were dissolved in DMSO and then added to the reaction mixture giving the final DMSO concentration of 10%. The reaction was initiated by addition of 20 ⁇ l GK and run for 20 min at 37°C. The amount of formed NADH was measured as an increase in absorbance at 340 nm using a microplate reader.
  • the concentration of activator that produced 50% of the maximum increase in the activity of GK (EC 50 ) was calculated
  • the preferred compounds of formula I described within the examples have an EC 50 less than or equal to 30 ⁇ M.
  • EC50 values shown in the above table are at lOmM glucose.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de formule (I), dans laquelle Z représente les formules (II) et (III), dans lesquelles R3 représente alkyle de faible poids moléculaire, ou halo alkyle de faible poids moléculaire comprenant de 2 à 6 atomes de carbone ou arylalkyle, ou -(CH2)s-V, V représentant un noyau comprenant 3 à 8 éléments, ledit noyau pouvant être cycloalkyle, cycloalcényle, ou hétérocycloalkyle présentant un hétéroatome sélectionné parmi oxygène et soufre ; s représente indépendamment 0, 1, ou 2 ; M représente hydrogène ou halo ou alkyle de faible poids moléculaire ou perfluoroalkyle de faible poids moléculaire. Dans la formule (I), A représente les formules (IV) et (V), dans lesquelles Y représente oxygène ou soufre. L'invention concerne également les sels pharmaceutiquement acceptables desdits composés, ces derniers étant utilisés dans le traitement du diabète de type II.
PCT/US2003/037089 2003-01-06 2003-12-16 Composes heteroaryle WO2004063194A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003294376A AU2003294376A1 (en) 2003-01-06 2003-12-16 Heteroaryl compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US43853803P 2003-01-06 2003-01-06
US60/438,538 2003-01-06

Publications (1)

Publication Number Publication Date
WO2004063194A1 true WO2004063194A1 (fr) 2004-07-29

Family

ID=32713342

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/037089 WO2004063194A1 (fr) 2003-01-06 2003-12-16 Composes heteroaryle

Country Status (2)

Country Link
AU (1) AU2003294376A1 (fr)
WO (1) WO2004063194A1 (fr)

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007026761A1 (fr) * 2005-08-31 2007-03-08 Astellas Pharma Inc. Dérivé de thiazole
US7199140B2 (en) 2001-06-26 2007-04-03 Astrazeneca Ab Vinyl phenyl derivatives as GLK activators
WO2007039177A2 (fr) 2005-09-29 2007-04-12 Sanofi-Aventis Derives de phenyl-1,2,4-oxadiazolone : procedes de preparation et utilisation comme produits pharmaceutiques
US7230108B2 (en) 2002-11-19 2007-06-12 Astrazeneca Ab Quinoline derivatives as glucokinase ligands
WO2007128761A2 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Utilisations d'inhibiteurs de l'enzyme dpp iv
WO2008084872A1 (fr) 2007-01-10 2008-07-17 Mitsubishi Tanabe Pharma Corporation Dérivé d'hydrazone
WO2009091014A1 (fr) 2008-01-18 2009-07-23 Astellas Pharma Inc. Dérivé de phénylacétamide
EP2106260A1 (fr) * 2007-01-25 2009-10-07 Verva Pharmaceuticals Ltd Sensibilisateurs a l'iinsuline et procédés de traitement
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
US7709505B2 (en) 2002-11-19 2010-05-04 Astrazeneca Ab Benzofuran derivatives, process for their preparation and intermediates thereof
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
US7750020B2 (en) 2004-04-02 2010-07-06 Novartis Ag Sulfonamide-thiazolpyridine derivatives as glucokinase activators useful the treatment of Type 2 diabetes
US7781451B2 (en) 2004-04-02 2010-08-24 Novartis Ag Thiazolopyridine derivatives, pharmaceut ical conditions containing them and methods of treating glucokinase mediated conditions
US7795257B2 (en) 2005-09-30 2010-09-14 Novartis Ag Organic compounds
US7812167B2 (en) 2002-10-03 2010-10-12 Novartis, Ag Substituted (thiazol-2-yl)-amides or sulfonamides as glucokinase activators useful in the treatment of type 2 diabetes
US7858644B2 (en) 2003-01-29 2010-12-28 Asterand Uk Limited EP4 receptor antagonists
US7902248B2 (en) 2006-12-14 2011-03-08 Hoffmann-La Roche Inc. Oxime glucokinase activators
US8008332B2 (en) 2006-05-31 2011-08-30 Takeda San Diego, Inc. Substituted indazoles as glucokinase activators
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
US8034819B2 (en) 2007-03-07 2011-10-11 Kyorin Pharmaceutical Co., Ltd. Glucokinase activator
US8034822B2 (en) 2006-03-08 2011-10-11 Takeda San Diego, Inc. Glucokinase activators
US8124617B2 (en) 2005-09-01 2012-02-28 Takeda San Diego, Inc. Imidazopyridine compounds
US8153677B2 (en) 2006-07-06 2012-04-10 Bristol-Myers Squibb Company Substituted pyrazolylamide compounds useful as glucokinase activators
US8163779B2 (en) 2006-12-20 2012-04-24 Takeda San Diego, Inc. Glucokinase activators
US8173649B2 (en) 2006-12-25 2012-05-08 Kyorin Pharmaceutical Co., Ltd. Glucokinase activator
US8173645B2 (en) 2007-03-21 2012-05-08 Takeda San Diego, Inc. Glucokinase activators
US8252931B2 (en) 2005-09-30 2012-08-28 Novartis Ag Thiazolo[5,4-B]pyridine glucokinase activators
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
CN101490064B (zh) * 2006-07-06 2012-10-10 百时美施贵宝公司 新颖葡萄糖激酶活化剂及其使用方法
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
US8946440B2 (en) 2008-04-28 2015-02-03 Kyorin Pharmaceutical Co., Ltd. Cyclopentylacrylamide derivative
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001012189A1 (fr) * 1999-08-12 2001-02-22 Pharmacia Italia S.P.A. Derives de 3(5)-amino-pyrazole, leur procede de fabrication et leur emploi comme agents anti-tumoraux
WO2001044216A1 (fr) * 1999-12-15 2001-06-21 F. Hoffmann-La Roche Ag Activateurs transolefiniques de glucokinase
WO2001085707A1 (fr) * 2000-05-08 2001-11-15 F. Hoffmann-La Roche Ag Activateurs de glucokinase de type phenylamides substitues para-amine
WO2002008209A1 (fr) * 2000-07-20 2002-01-31 F. Hoffmann-La Roche Ag Composes de benzene acetamide substitues par alpha-acyle et des alpha-heteroatomes en tant qu'activateurs de glucokinase
WO2002014312A1 (fr) * 2000-08-15 2002-02-21 F. Hoffmann-La Roche Ag Tétrazolyl-phényl acétamides activateurs de la glucokinase
WO2002048106A2 (fr) * 2000-12-13 2002-06-20 F. Hoffmann-La-Roche Ag Activateurs de l'isoindoline-1-one glucokinase
WO2003055482A1 (fr) * 2001-12-21 2003-07-10 Novo Nordisk A/S Derives amide utiles en tant qu'activateurs de la glucokinase
EP1336607A1 (fr) * 2002-02-19 2003-08-20 Novo Nordisk A/S Dérivés d'amides comme activateus de la glucokinase

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001012189A1 (fr) * 1999-08-12 2001-02-22 Pharmacia Italia S.P.A. Derives de 3(5)-amino-pyrazole, leur procede de fabrication et leur emploi comme agents anti-tumoraux
WO2001044216A1 (fr) * 1999-12-15 2001-06-21 F. Hoffmann-La Roche Ag Activateurs transolefiniques de glucokinase
WO2001085707A1 (fr) * 2000-05-08 2001-11-15 F. Hoffmann-La Roche Ag Activateurs de glucokinase de type phenylamides substitues para-amine
WO2002008209A1 (fr) * 2000-07-20 2002-01-31 F. Hoffmann-La Roche Ag Composes de benzene acetamide substitues par alpha-acyle et des alpha-heteroatomes en tant qu'activateurs de glucokinase
WO2002014312A1 (fr) * 2000-08-15 2002-02-21 F. Hoffmann-La Roche Ag Tétrazolyl-phényl acétamides activateurs de la glucokinase
WO2002048106A2 (fr) * 2000-12-13 2002-06-20 F. Hoffmann-La-Roche Ag Activateurs de l'isoindoline-1-one glucokinase
WO2003055482A1 (fr) * 2001-12-21 2003-07-10 Novo Nordisk A/S Derives amide utiles en tant qu'activateurs de la glucokinase
EP1336607A1 (fr) * 2002-02-19 2003-08-20 Novo Nordisk A/S Dérivés d'amides comme activateus de la glucokinase

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
WERMUTH ET AL: "The Practise of Medicinal Chemistry", PRACTICE OF MEDICINAL CHEMISTRY, XX, XX, 1996, pages 203 - 237, XP002190259 *
YOSHINA, S.; TANAKA,A.; USUI, T.: "Studies on heterocyclic compounds. XXIX. Synthesis of 2-[alpha-(N-substituted carbamoyl)-beta-(5-nitro-2-furyl)vinyl]furans and 2-[alpha-(N-substituted ureido)-beta-(5-nitro-2-furyl)vinyl] furans", YAKUGAKU ZASSHI, vol. 97, no. 9, 1977, pages 1007 - 1012, XP009028638 *

Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7199140B2 (en) 2001-06-26 2007-04-03 Astrazeneca Ab Vinyl phenyl derivatives as GLK activators
US7812167B2 (en) 2002-10-03 2010-10-12 Novartis, Ag Substituted (thiazol-2-yl)-amides or sulfonamides as glucokinase activators useful in the treatment of type 2 diabetes
US7230108B2 (en) 2002-11-19 2007-06-12 Astrazeneca Ab Quinoline derivatives as glucokinase ligands
US7709505B2 (en) 2002-11-19 2010-05-04 Astrazeneca Ab Benzofuran derivatives, process for their preparation and intermediates thereof
US7858644B2 (en) 2003-01-29 2010-12-28 Asterand Uk Limited EP4 receptor antagonists
US7750020B2 (en) 2004-04-02 2010-07-06 Novartis Ag Sulfonamide-thiazolpyridine derivatives as glucokinase activators useful the treatment of Type 2 diabetes
US7781451B2 (en) 2004-04-02 2010-08-24 Novartis Ag Thiazolopyridine derivatives, pharmaceut ical conditions containing them and methods of treating glucokinase mediated conditions
WO2007026761A1 (fr) * 2005-08-31 2007-03-08 Astellas Pharma Inc. Dérivé de thiazole
US8124617B2 (en) 2005-09-01 2012-02-28 Takeda San Diego, Inc. Imidazopyridine compounds
WO2007039177A2 (fr) 2005-09-29 2007-04-12 Sanofi-Aventis Derives de phenyl-1,2,4-oxadiazolone : procedes de preparation et utilisation comme produits pharmaceutiques
US8252931B2 (en) 2005-09-30 2012-08-28 Novartis Ag Thiazolo[5,4-B]pyridine glucokinase activators
US7795257B2 (en) 2005-09-30 2010-09-14 Novartis Ag Organic compounds
US8034822B2 (en) 2006-03-08 2011-10-11 Takeda San Diego, Inc. Glucokinase activators
WO2007128761A2 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Utilisations d'inhibiteurs de l'enzyme dpp iv
EP2351568A2 (fr) 2006-05-04 2011-08-03 Boehringer Ingelheim International GmbH Utilisations d'inhibiteurs de l'enzyme dpp iv
US8008332B2 (en) 2006-05-31 2011-08-30 Takeda San Diego, Inc. Substituted indazoles as glucokinase activators
US8394843B2 (en) 2006-05-31 2013-03-12 Takeda California, Inc. Substituted isoindoles as glucokinase activators
TWI418558B (zh) * 2006-07-06 2013-12-11 必治妥美雅史谷比公司 新穎葡萄糖激酶活化劑及彼等之使用方法
US8153677B2 (en) 2006-07-06 2012-04-10 Bristol-Myers Squibb Company Substituted pyrazolylamide compounds useful as glucokinase activators
US8614332B2 (en) 2006-07-06 2013-12-24 Bristol-Myers Squibb Company Substituted pyrazolylamides useful as glucokinase activators
CN101490064B (zh) * 2006-07-06 2012-10-10 百时美施贵宝公司 新颖葡萄糖激酶活化剂及其使用方法
US7902248B2 (en) 2006-12-14 2011-03-08 Hoffmann-La Roche Inc. Oxime glucokinase activators
US8163779B2 (en) 2006-12-20 2012-04-24 Takeda San Diego, Inc. Glucokinase activators
US8173649B2 (en) 2006-12-25 2012-05-08 Kyorin Pharmaceutical Co., Ltd. Glucokinase activator
US8314247B2 (en) 2007-01-10 2012-11-20 Mitsubishi Tanabe Pharma Corporation Hydrazone derivative
WO2008084872A1 (fr) 2007-01-10 2008-07-17 Mitsubishi Tanabe Pharma Corporation Dérivé d'hydrazone
US10172837B2 (en) 2007-01-25 2019-01-08 NAIA Metabolic, Inc. Insulin sensitisers and methods of treatment
EP2106260A1 (fr) * 2007-01-25 2009-10-07 Verva Pharmaceuticals Ltd Sensibilisateurs a l'iinsuline et procédés de traitement
US9452148B2 (en) 2007-01-25 2016-09-27 Verva Pharmaceuticals Ltd Insulin sensitisers and methods of treatment
EP2106260A4 (fr) * 2007-01-25 2010-05-26 Verva Pharmaceuticals Ltd Sensibilisateurs a l'iinsuline et procédés de traitement
JP2010516711A (ja) * 2007-01-25 2010-05-20 バーバ・ファーマシューティカルズ・リミテッド インスリン抵抗性改善薬および治療方法
US8455432B2 (en) 2007-01-25 2013-06-04 Verva Pharmaceuticals Ltd. Insulin sensitisers and methods of treatment
US8034819B2 (en) 2007-03-07 2011-10-11 Kyorin Pharmaceutical Co., Ltd. Glucokinase activator
US8173645B2 (en) 2007-03-21 2012-05-08 Takeda San Diego, Inc. Glucokinase activators
US8329707B2 (en) 2008-01-18 2012-12-11 Astellas Pharma Inc. Substituted pyrazine compounds
WO2009091014A1 (fr) 2008-01-18 2009-07-23 Astellas Pharma Inc. Dérivé de phénylacétamide
US9452977B2 (en) 2008-04-28 2016-09-27 Kyorin Pharmaceutical Co., Ltd. Cyclopentylacrylamide derivative
US8946440B2 (en) 2008-04-28 2015-02-03 Kyorin Pharmaceutical Co., Ltd. Cyclopentylacrylamide derivative
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
EP3243385A1 (fr) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques

Also Published As

Publication number Publication date
AU2003294376A1 (en) 2004-08-10

Similar Documents

Publication Publication Date Title
WO2004063194A1 (fr) Composes heteroaryle
KR100519826B1 (ko) 파라-아민 치환된 페닐아미드 글루코키나제 활성화제
EP1282612B1 (fr) Activateurs heteroaromatiques de la glucokinase a base d'alkynyle-phenyle
EP1349856B1 (fr) Activateurs de l'isoindoline-1-one glucokinase
EP1305301B1 (fr) Composes de benzene acetamide substitues par alpha-acyle et des alpha-heteroatomes en tant qu'activateurs de glucokinase
EP1282611B1 (fr) Phenylacetamides substitues et leur utilisation en tant qu'activateurs de la glucokinase
AU2001270494A1 (en) Alkynyl phenyl heteroaromatic glucokinase activators
AU2001265914A1 (en) Para-amine substituted phenylamide glucokinase activators
AU2001287600A1 (en) Alpha-acyl and Alpha-heteroatom-substituted Benzene Acetamide Glucokinase Activators
AU2002238415A1 (en) Isoindolin-1-one glucokinase activators
TW200402418A (en) Substituted-cycloalkyl and oxygenated-cycloalkyl glucokinase activators
US6489485B2 (en) Para-amine substituted phenylamide glucokinase activators
ZA200304265B (en) Isoindolin-1-one glucokinase activators.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP