WO2004063194A1 - Heteroaryl compounds - Google Patents

Heteroaryl compounds Download PDF

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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
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WIPO (PCT)
Prior art keywords
lower alkyl
hydrogen
compound
ring
sulfur
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PCT/US2003/037089
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French (fr)
Inventor
Andreas Gerhard Weichert
David Gene Barrett
Stefan Heuser
Rainer Riedl
Mark Joseph Tebbe
Andrea Zaliani
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Eli Lilly And Company
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Priority to AU2003294376A priority Critical patent/AU2003294376A1/en
Publication of WO2004063194A1 publication Critical patent/WO2004063194A1/en

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    • 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.

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Abstract

According to the present invention there is provided a compound of formula (I) wherein Z isR3 is lower alkyl or halo lower alkyl having from 2 to 6 carbon atoms or arylalkyl or -(CH2)s-V where 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;A is or where Y is oxygen or sulfur, and its pharmaceutically acceptable salts thereof. These compounds are considered to be useful for the treatment of type II Diabetes.

Description

HETEROARYL COMPOUNDS
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. In addition, 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]. The 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). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (~10-15 mM) levels following a carbohydrate-containing meal [Printz, R.G., Magnuson, M.A., and Granner, D.K. in. Ann. Rev. Nutrition Vol. 13 (R.E. Olson, D.M. Bier, and D.B. McCormick, eds.), Annual Review, Inc., Palo Alto, CA, pages 463-496, 1993]. These findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in beta-cells and hepatocytes (Meglasson, M.D. and Matschinsky, F.M. Amer. J. Physiol. 246, El-El 3, 1984). In recent years, studies in transgenic animals have confirmed that 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.
The finding that type II maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidence supporting an important role for GK in the regulation of glucose metabolism in humans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with an inappropriately elevated level of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998). While mutations of the GK gene are not found in the majority of patients with type II diabetes, compounds that activate GK and, thereby, increase the sensitivity of the GK sensor system will still be useful in the freatment of the hyperglycemia characteristic of all type II diabetes. 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.
According to the present invention there is provided compounds of formula (I):
Figure imgf000004_0001
wherein Z is
Figure imgf000004_0002
R is lower alkyl or halo lower alkyl having from 2 to 6 carbon atoms or arylalkyl or •
(CH2)s-V where 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;
A is
Figure imgf000004_0003
where Y is oxygen or sulfur, and
R1 and R2 are independently hydrogen, halo, amino, hydroxyamino, nifro, cyano, sulfonamido, lower alkyl, -OR5, -COOR5, perfluoro- lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl,
R5 is hydrogen, lower alkyl or perfluoro-lower alkyl; or furthermore
R2 can be -(CH2)n-NR6R7, with n=l ,2,3 or 4, and
R6 and R7 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 can be alkinyl, substituted with hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, an unsubstituted or hydroxy substituted cycloalkyl ring containing 5 or 6 carbon atoms, a five- or six-membered saturated heterocyclic ring which contains from 1 to 3 hetero atoms selected from the group consisting of sulfur, oxygen or nifrogen, or an unsubstituted five- or six-membered heteroaromatic ring, connected by a ring carbon atom, which contains from to 3 heteroatoms in the ring selected from the group consisting of sulfur, nitrogen and oxygen, or -(CH )n-NR R , with n=l,2, and R and R 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 nitrogen; 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 R2 can be R10-[(CH2)y-W]z-, with W is oxygen, sulfur, -SO-, -SO -, and
R10 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
-NRnR12, with R11 and R12 being independently hydrogen or lower alkyl; y is independently 0,1,2,3 or 4; z is independently 0,1; or
R2 can be R13-(CH2)t-U-, with U is -NHCO-, -CONH, -NHSO2-, -SO2NH- and
R13 in the same meaning of R10 and perfluoro-lower alkyl, lower alkyl, lower alkoxycarbonyl or
-NRI4R15, R14 and R15 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
5- or 6- membered 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;
R4 is -C(O)NHR16, or is R17; R16 is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl,
-(CH2)n-COOR18, -CO-(CH2)n-COOR19;
17
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, -(CH2)n-OR20, -(CH2)n-COOR21, -(CH2)n-CONHR22, -(CH2)n-NHR23, n is O, 1, 2, 3 or 4; R1S, R19, R20, R21, R22 and R23 are independently hydrogen or lower alkyl, and its pharmaceutically acceptable salts thereof.
The compounds of formula I have been found to activate glucokinase in vitro. Preferably 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.
Further, 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. In addition, 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. As used herein, the term "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, toluene-p-sulphonic, and xinafoic acids. The term "pharmaceutically acceptable salts" also includes any pharmaceutically acceptable base salt such as amine salts, trialkyl amine salts and the like.
In addition to the pharmaceutically acceptable salts, other 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.
It will be appreciated that the compounds of the invention can contain one or more asymmetric carbon atoms which gives rise to isomers. In the compound of formula I the "*" designates an asymmetric carbon atom in this compound. Preferably, the compound of formula I has the following spatial orientation:
Figure imgf000008_0001
wherein, A, M, R3 and R4 are as defined above. It will be appreciated that the specific configuration of the carbon to which A is attached, namely "R" or "S", will depend upon the definition of R3, M and Y and their respective priorities according to the Cahn-Ingold- Prelog sequence rules as described in J. March, Fourth Edition, Chapter 4, page 109. Where M is other than hydrogen an additional chiral center at the connecting carbon atom is generated. At this cenfre the compounds of formula I may be present as a racemate or in the "R" or "S" configuration. Racemic mixtures, enantiomers, diastereomers and individual isomers form part of the present invention, the compounds being employed as racemates or in enantiomerically pure form.
In accordance with this invention, for compounds of formula I where Z is
Figure imgf000008_0002
"Δ" denotes compounds wherein "A" and "M" have a trans configuration across the double bond. The term "trans" as utilized in this application, designates that the two substituents attached at each end of the double bond are on opposite sides of the double bond.
As used throughout this application, the term "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. When R and/or R is halo, chlorine is especially prefened. When M is halo, fluorine is especially prefened.
As used herein, the term "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. With regard to R3, isopropyl and n-propyl are prefened, isobutyl is also prefened.
As used herein, the term "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. As used herein, the term "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. The term "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. As used herein, "perfluoro-lower alkyl" means any lower alkyl group wherein all of the hydrogens of the lower alkyl group are substituted or replaced by fluoro. Among the prefened perfluoro-lower alkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc. An especially prefened perfluoro-lower alkyl group is trifluoromethyl. As used herein, "lower alkyl thio" means a lower alkyl group as defined above where a thio group is bound to the rest of the molecule. Similarly "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.
As used herein, "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. Similarly "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
As used herein, "hydroxyamino" designates an amino group where one of the hydrogens is replaced by a hydroxy. As used herein, "cycloalkyl" means a saturated hydrocarbon ring having from 3 to
8 carbon atoms, preferably from 5 to 6 carbon atoms, such as cyclopentyl and cyclohexyl.
An especially prefened cycloalkyl is cyclopentyl.
As used herein, "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 R3 it is prefened to have a single heteroatom, preferably oxygen.
As used herein, "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. As used herein, the term "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.
As used herein, the term "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.
As used herein, the term "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. As used herein, the term "arylalkyl" denotes an alkyl group, preferably lower alkyl, in which one of the hydrogen atoms is replaced by an aryl group. Examples of arylalkyl groups are benzyl, 2-phenylethyl, 3-phenylpropyl, 4-chlorobenzyl, 4- methoxybenzyl and the like. As used herein, the term "lower alkanoic acid" denotes lower alkanoic acids containing from 2 to 7 carbon atoms such as propionic acid, acetic acid and the like. The term "lower alkanoyl" denotes monovalent alkanoyl groups having from 2 to 7 carbon atoms such as propionoyl, acetyl and the like. The term "aroic acids" denotes aryl alkanoic acids where aryl is as defined above and alkanoic contains from 1 to 6 carbon atoms. The term "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 R4 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 R4 are connected via a ring carbon atom to the amide group to form the amides of formula I.
R4 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. In this case, the prefened rings are those which contain a nifrogen heteroatom adjacent to the connecting ring carbon. When 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. Preferably R4 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.
When the 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. Above heteroaromatic rings R4 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, -(CH2)n-OR20, -(CH )n- C(O)OR21, -(CH2)n-CONHR22, -(CH2)n-NHR23, with n, R20, R21, R22 and R23 being as defined above.
During the course of the synthetic sequence the various functional groups such as the free carboxylic acid or hydroxy groups will be protected via conventional hydrolyzable ester or ether protecting groups. As used herein the term "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. Exemplary 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. Among the 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. Example of 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.
As used herein, the term "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
Figure imgf000013_0001
wherein A, B, R3 and R are as above; and the compound of the formula
Figure imgf000013_0002
wherein A, M, R3 and R4 are as above.
In accordance with one preferable embodiment of the compound of formula I, R3 is lower alkyl having from 2 to 6 carbon atoms, prefened lower alkyl residues being isopropyl and n-propyl. In one prefened embodiment R3 is isopropyl, in another R3 is isobutyl. In another preferable embodiment R3 is -(CH2)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. In one prefened embodiment V is cyclopentyl, in another V is cyclohexyl. In another preferable embodiment 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 R4 substituent in accordance with the present invention is where R4 is R17 as defined above. Further prefened R17 substituents are unsubstituted, mono- or di- substituted thiazolyl, imidazolyl, oxazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In one preferred embodiment R17 is thiazolyl, in another R17 is
■ • 17 pyndinyl. In accordance with further preferable embodiments, the heteroaromatic ring R is either unsubstituted, mono- or di-substituted independently with lower alkyl, halogen or -(CH2)n-C(O)OR21, wherein n and R21 are as defined above. In another preferable embodiment 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.
In accordance with another preferable embodiment of the compound of formula (I), A is
Figure imgf000014_0001
wherein Y and R1 and R2 are as defined above, the prefened Y substituent being sulfur. Prefened substituent R1 is selected from the group consisting of hydrogen, halo, nitro, cyano, perfluoro lower alkyl, and lower alkyl sulfonyl. A further prefened R1 substituent is selected from the group consisting of hydrogen, halo, nitro, cyano or perfluoro lower alkyl. In one prefened embodiment R1 is halo, in another R1 is hydrogen. Preferred substituent R2 is selected from the group consisting of hydrogen, halo, nitro, cyano, perfluoro lower alkyl, lower alkyl sulfonyl, R10-[(CH2)y-W]z and R13-(CH )t-U- where R10, R13, W, U, t, y and z are as defined above. Further prefened R2 substituents are halo, lower alkyl sulfonyl, R10-[(CH2)y-W]z and R13-(CH2)t-U- where R10, R13, W, U, t, y and z are as defined above. In one prefened embodiment R2 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 R13-(CH )t-U- where R13, U and t, are as defined above. In a further prefened embodiment R2 is sulphonyl methyl, in another R2 is R10-[(CH2)y-W]z where W is SO2 and R10, U, y and z are as defined above.
In accordance with one embodiment of the compound of formula I- A, R can be - (CH2)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). Among the various embodiments of the compound I-Al 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. Another embodiment of the compounds of formula (I- A) are those compounds where R3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A2). Among the various embodiments of the compound I-A2 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.
Among the embodiments of the compound of formula I- A, R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-A3). Among the various embodiments of the compound I- A3 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.
Among the embodiments of the compound of formula I- A, A is
Figure imgf000015_0001
where Y is sulfur (compound I-A4). Among the various embodiments of the compound I- A4 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. Among the embodiments of the compound of formula I- A, A is
Figure imgf000015_0002
where Y is sulfur (compound I-A5). Among the various embodiments of the compound I- A5 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. Among the embodiments of the compound of formula I-Al, R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-Al (a)). Among the various embodiments of the 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.
Among the embodiments of the compound of formula I-Al, A is
Figure imgf000016_0001
where Y is sulfur (compound I-Al(b)). Among the various embodiments of the compound I-Al(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. Among the embodiments of the compound of formula I-Al, A is
Figure imgf000016_0002
where Y is sulfur (compound I- A 1(c)). Among the various embodiments of the compound I-Al(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.
Among the embodiments of the compound of formula I-A2, R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-A2(a)). Among the various embodiments of the compound I-A2(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. Among the embodiments of the compound of formula I-A2, A is
Figure imgf000017_0001
where Y is sulfur (compound I-A2(b)). Among the various embodiments of the compound I-A2(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.
Among the embodiments of the compound of formula I-A2, A is
Figure imgf000017_0002
where Y is sulfur (compound I-A2(c)). Among the various embodiments of the compound I-A2(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.
Among the embodiments of the compound of formula I- A3, R3 can be -(CH2)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)). 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. Among the embodiments of the compound of formula I-A3 are those compounds where R3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A3(b)). Among the various embodiments of the compound I-A3(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.
Among the embodiments of the compound of formula I-A3, A is
Figure imgf000018_0001
where Y is sulfur (compound I-A3(c)). Among the various embodiments of the compound I-A3(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.
Among the embodiments of the compound of formula I- A3, A is
Figure imgf000018_0002
where Y is sulfur (compound I-A3(d)). Among the various embodiments of the compound I-A3(d) 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.
Among the embodiments of the compound of formula I-A4, R3 can be -(CH2)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)). 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.
Among the embodiments of the compound of formula I-A4 are those compounds where R3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A4(b)). Among the various embodiments of the compound I-A4(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.
Among the embodiments of the compound of formula I-A4, R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-A4(c)). Among the various embodiments of the compound I-A4(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.
Among the embodiments of the compound of formula I-A5, R3 can be -(CH2)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)). 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. Among the embodiments of 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)). Among the various embodiments of the compound I-A5(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.
Among the embodiments of the compound of formula I-A5, R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-A5(c)). Among the various embodiments of the compound I-A5(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.
Among the embodiments of the compound of formula I-Al (a), A is
Figure imgf000019_0001
where Y is sulfur (compound I-Al (a- 1)). Among the various embodiments of the compound I-Al(a-l) 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. Among the embodiments of the compound of formula I-A 1 (a), A is
Figure imgf000020_0001
where Y is sulfur (compound I-Al(a-2)). Among the various embodiments of the compound I-Al(a-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.
Among the embodiments of the compound of formula I-Al(b), R4 is R17, which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those
1 compounds where R is a thiazole or pyridine ring (compound I-Al (b-1)). Among the various embodiments of the compound I-Al (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.
Among the embodiments of the compound of formula I-Al(c), R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-Al(c-l)). Among the various embodiments of the compound I-Al(c-l) 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. Among the embodiments of the compound of formula I-A2(a), A is
Figure imgf000020_0002
where Y is sulfur (compound I-A2(a-1)). Among the various embodiments of the compound I-A2(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.
Among the embodiments of the compound of formula I-A2(a), A is
Figure imgf000021_0001
where Y is sulfur (compound I-A2(a-2)). Among the various embodiments of the compound I-A2(a-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.
Among the embodiments of the compound of formula I-A2(b), R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-A2(b-1)). Among the various embodiments of the compound I-A2(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.
Among the embodiments of the compound of fonnula I-A2(c), R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-A2(c-1)). Among the various embodiments of the compound I-A2(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. Among the embodiments of the compound of formula I- A3 (a), A is
R2
where Y is sulfur (compound I-A3(a- "1)).X Among the various embodiments of the compound I-A3(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.
Among the embodiments of the compound of formula I-A3(a), A is
Figure imgf000022_0001
where Y is sulfur (compound I-A3(a-2)). Among the various embodiments of the compound I-A3(a-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.
Among the embodiments of the compound of formula I-A3(b), A is
Figure imgf000022_0002
where Y is sulfur (compound I-A3(b-1)). Among the various embodiments of the compound I-A3(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.
Among the embodiments of the compound of formula I-A3(b), A is
Figure imgf000022_0003
where Y is sulfur (compound I-A3(b-2)). Among the various embodiments of the compound I-A3(b-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.
Among the embodiments of the compound of formula I- A3 (c), 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)). Among the various embodiments of the compound I-A3(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. Among the embodiments of the compound of formula I-A3(c) are those compounds where R3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A3(c-2)). Among the various embodiments of the compound I-A3(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.
Among the embodiments of the compound of formula I- A3 (d), R3 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)). 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.
Among the embodiments of the compound of formula I-A3(d) are those compounds where R3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A3(d-2)). Among the various embodiments of the 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.
Among the embodiments of the compound of formula I-A4(a), R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-A4(a-1)). Among the various embodiments of the 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.
Among the embodiments of the compound of formula I-A4(b), R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-A4(b-1)). Among the various embodiments of the 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. Among the embodiments of the compound of formula I-A4 (c), R3 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)). 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.
Among the embodiments of the compound of formula I-A4(c) are those compounds where R3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A4(c-2)). Among the various embodiments of the 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.
Among the embodiments of the compound of formula I-A5(a), R4 is R17, 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)). Among the various embodiments of the compound I-A5(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. Among the embodiments of the compound of formula I-A5(b), R4 is R17, 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)). Among the various embodiments of the compound I-A5(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.
Among the embodiments of the compound of formula I-A5(c), 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)). 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. Among the embodiments of the compound of formula I-A5(c) are those compounds where R3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-A5(c-2)). Among the various embodiments of the 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.
In accordance with one embodiment of the compound of formula I-B, R3 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). Among the various embodiments of the compound I-Bl 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. Another embodiment of the compounds of formula I-B are those compounds where R3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-B2). Among the various embodiments of the compound I-B2 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.
Among the embodiments of the compound of formula I-B, R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-B3). Among the various embodiments of the compound I-B3 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. Among the embodiments of the compound of formula I-B, A is
Figure imgf000025_0001
where Y is sulfur (compound I-B4). Among the various embodiments of the compound I- B4 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. Among the embodiments of the compound of formula I-B, A is
Figure imgf000026_0001
where Y is sulfur (compound I-B5). Among the various embodiments of the compound I- B5 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. Among the embodiments of the compound of formula I-Bl, R4 is R17, which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those ι n compounds where R is a thiazole or pyridine ring (compound I-B 1(a)). Among the various embodiments of the compound I-B 1(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.
Among the embodiments of the compound of formula I-Bl, A is
R2
where Y is sulfur (compound I-B 1(b)) ". AmXong the various embodiments of the compound I-Bl (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.
Among the embodiments of the compound of formula I-Bl, A is
Figure imgf000026_0002
where Y is sulfur (compound I-B 1(c)). Among the various embodiments of the compound I-B 1(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. Among the embodiments of the compound of formula I-B2, R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-B2(a)). Among the various embodiments of the compound I-B2(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.
Among the embodiments of the compound of formula I-B2, A is
Figure imgf000027_0001
where Y is sulfur (compound I-B2(b)). Among the various embodiments of the compound I-B2(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.
Among the embodiments of the compound of formula I-B2, A is
Figure imgf000027_0002
where Y is sulfur (compound I-B2(c)). Among the various embodiments of the compound
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. Among the embodiments of the compound of formula I-B3, R3 can be -(CH2)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)). Among the various embodiments of the 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.
Among the embodiments of the compound of formula I-B3 are those compounds where R3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-B3(b)). Among 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. Among the embodiments of the compound of formula I-B3, A is
Figure imgf000028_0001
where Y is sulfur (compound I-B3(c)). Among the various embodiments of the compound I-B3(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.
Among the embodiments of the compound of formula I-B3, A is
Figure imgf000028_0002
where Y is sulfur (compound I-B3(d)). Among the various embodiments of the compound I-B3(d) 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.
Among the embodiments of the compound of formula I-B4, R3 can be -(CH2)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)). 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.
Among the embodiments of 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)). Among the various embodiments of the compound I-B4(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.
Among the embodiments of the compound of formula I-B4, R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-B4(c)). Among the various embodiments of the compound I-B4(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. Among the embodiments of the compound of formula I-B5, R3 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)). 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.
Among the embodiments of 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)). Among the various embodiments of the compound I-B5(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.
Among the embodiments of the compound of formula I-B5, R is R17, which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those
17 • compounds where R is a thiazole or pyridine ring (compound I-B5(c)). Among the various embodiments of the compound I-B5(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.
Among the embodiments of the compound of formula I-B 1(a), A is
Figure imgf000029_0001
where Y is sulfur (compound I-Bl(a-l)). Among the various embodiments of the compound I-Bl(a-l) 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.
Among the embodiments of the compound of formula I-B 1(a), A is
Figure imgf000030_0001
where Y is sulfur (compound I-Bl(a-2)). Among the various embodiments of the compound I-Bl(a-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.
Among the embodiments of the compound of formula I-Bl(b), R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-Bl (b-1)). Among the various embodiments of the compound I-Bl (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.
Among the embodiments of the compound of formula I-B 1(c), R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-Bl(c-l)). Among the various embodiments of the compound I-Bl(c-l) 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. Among the embodiments of the compound of formula I-B2(a), A is
Figure imgf000030_0002
where Y is sulfur (compound I-B2(a-1)). Among the various embodiments of the compound I-B2(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.
Among the embodiments of the compound of formula I-B2(a), A is
Figure imgf000031_0001
where Y is sulfur (compound I-B2(a-2)). Among the various embodiments of the compound I-B2(a-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.
Among the embodiments of the compound of formula I-B2(b), R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-B2(b-1)). Among the various embodiments of the compound I-B2(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.
Among the embodiments of the compound of formula I-B2(c), R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-B2(c-1)). Among the various embodiments of the compound I-B2(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. Among the embodiments of the compound of formula I-B3(a), A is
Figure imgf000031_0002
where Y is sulfur (compound I-B3(a-1)). Among the various embodiments of the compound I-B3(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.
Among the embodiments of the compound of formula I-B3(a), A is
Figure imgf000032_0001
where Y is sulfur (compound I-B3(a-2)). Among the various embodiments of the compound I-B3(a-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.
Among the embodiments of the compound of formula I-B3(b), A is
Figure imgf000032_0002
where Y is sulfur (compound I-B 3 (b-1)). Among the various embodiments of the compound I-B3(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.
Among the embodiments of the compound of formula I-B3(b), A is
Figure imgf000032_0003
where Y is sulfur (compound I-B3(b-2)). Among the various embodiments of the compound I-B3(b-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.
Among the embodiments of the compound of formula I-B3 (c), R3 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)). 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. Among the embodiments of the compound of formula I-B 3(c) are those compounds where R3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-B3(c-2)). Among the various embodiments of the 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.
Among the embodiments of the compound of formula I-B3 (d), R3 can be -(CH2)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)). 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.
Among the embodiments of the compound of formula I-B3(d) are those compounds where R3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-B3(d-2)). Among the various embodiments of the compound I-B3(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.
Among the embodiments of the compound of formula I-B4(a), R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-B4(a-1)). Among the various embodiments of the 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. Among the embodiments of the compound of formula I-B4(b), R4 is R17, 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 R17 is a thiazole or pyridine ring (compound I-B4(b-1)). Among the various embodiments of the 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. Among the embodiments of the compound of fonnula I-B4 (c), R3 can be -(CH2)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-B4(c-1)). Among the various embodiments of the compound I-B4(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.
Among the embodiments of 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)). Among the various embodiments of the compound I-B4(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.
Among the embodiments of the compound of formula I-B5(a), R4 is R17, which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those
17 compounds where R is a thiazole or pyridine ring (compound I-B5(a-1)). Among the various embodiments of the compound I-B5(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.
Among the embodiments of the compound of formula I-B5(b), R4 is R17, which can be an unsubstituted, mono- or di-substituted thiazole, imidazole, oxazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, or triazine ring, and particularly those
17 compounds where R is a thiazole or pyridine ring (compound I-B5(b-1)). Among the various embodiments of the compound I-B5(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.
Among the embodiments of the compound of formula I-B5(c), R3 can be -(CH2)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)). Among the various embodiments of the compound I-B5(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. Among the embodiments of the compound of formula I-B5(c) are those compounds where R3 is lower alkyl having from 2 to 6 carbon atoms, preferably lower alkyl residues being isobutyl or isopropyl (compound I-B5(c-2)). Among the various embodiments of the 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
Figure imgf000035_0001
the preparation of the compounds is outlined in Scheme I. The corresponding alkyl iodides are reacted with a propargyl ester to give the substituted 2-iodo alkenoates (see Y. Ichinose et al., Eet. Eett. 1989, 24, 3155). Alternatively, compounds where M equals hydrogen, can be prepared by reacting aldehydes R3-CHO with an appropriate Wittig reagent, preferedly triethyl phosphono acetate, to give the acrylic esters, which then are transformed into the 2-halo-alk-2-enoates by a halogenation / dehydro-halgenation procedure known in the art. Subsequent Pd(0)-catalyzed cross coupling with heteroaromatic boronic acids and boronic esters, respectively, yields the hetaryl- substituted alk-2-enoates of formula II. The latter intermediates can also be prepared from in situ formed olefinic boronic esters with the conesponding hetaryl bromides and iodides. For the preparation of compounds of formula II where M equals halo, the (hetero)aryl substituted -keto ester may be reacted with the appropriate halo-substituted organophosphonate using conditions known in the art. In order to prepare amides of formula III, these can be directly reacted with the deprotonated amines R17-NH , using appropriate Grignard reagents, preferably isopropyl magnesium chloride. Alternatively, 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
17 by known means in the area of peptide coupling, followed by reaction with ammes R - NH2 also yield the amides of formula III. For the synthesis of amides of the formula VI, the acids are reacted with substituted ureas H2N-CO-NH-R16. Reduction of compounds of formula III and VI can be carried out using hydride reagents, preferably sodium borohydride, to afford the saturated alkanoate amides of formula IV and VII.
Scheme I
Figure imgf000037_0001
Pd(0) cat.
A-B(OH)2 cross coupling A-X
olefination
Figure imgf000037_0002
Figure imgf000037_0003
reduction reduction
Figure imgf000037_0004
IV VII Experimentals: General Procedures:
All water or air-sensitive reactions were conducted in dry solvents under an inert atmosphere. Mass specfra (MS) were obtained on a Agilent 1100 MSD spectrometer operating in elecfrospray mode or on a Agilent 5973N GC-MSD.
List of abbreviations:
THF tetrahydrofuran
DMSO dimethylsulfoxide TBTU O-benzotriazol-l-yl-N,N.N',N' teframethyluroniumtetrafluoroborate
HATU O-(7-Aza-l-benzotriazolyl)-N.N.N\N'- teframethyluroniumhexafluorophosphate
DMF N.N-dimethylformamide
NMP l-methyl-2-pyrrolidinone brine saturated aqueous sodium chloride solution r.t. room temperature / ambient temperature
TBME 2-methoxy-2-methyl-propane
DMA N,N-dimethyl-acetamide
HPLC high pressure liquid chromatography TFA trifluoroacetic acid
ΝH3 ammonia
HO At l-hydroxy-7-azabenzotriazole
MTB ether 2-methoxy-2-methyl-propane
General Procedure I for the preparation of substituted 2-iodo-alk-2-enoates:
The 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)
(Z)-Ethyl 3-cyclohexyl-2-iodo-propenoate, MS(EI), M+= 308, reagent used: cyclohexyl iodide
(Z)-Ethyl 3-cyclopentyl-2-iodo-propenoate, MS(EI), M+= 294, reagent used: cyclopentyl iodide (Z)-Ethyl 2-iodo-4-methyl-pent-2-enoate. MS(EI), M+= 268, reagent used: 2-iodo-propane
General procedure II for the preparation of compounds of formula I: Add the heteroaromatic boronic acid (1.2 equiv. to vinyl halide) to a stined mixture of vinyl halide, palladium catalyst (5 mol%) and potassium carbonate (2.5 equiv) in toluene (3ml / 1.0 mmol vinyl halide) and heat the mixture at 70 °C for 14h. Subsequently filter the mixture, add water and extract with MTB ether. Combine the organic layers, dry over sodium sulfate and concenfrate under reduced pressure. Dissolve the crude product in ethanol (2 ml/mmol), add 2N sodium hydroxide solution (2ml/mmol) and heat at 70 °C for 14h. Acidify with IN hydrochloric acid, extract with MTB ether, dry combined organic layers over sodium sulfate and concentrate under reduced pressure. Dissolve the crude product in THF (3ml/mmol), add TBTU (1.5 equiv), triethylamine (2 equiv.) and the respective amine (1.5 equiv.) and stir for 14h at ambient temperature. Aqueous work-up using saturated sodium hydro gencarbonate solution / saturated citric acid and extraction with MTB ether gives the crude product. Purification by flash chromatography (silica) eluting with a mixture of hexanes / ethyl acetate yields the title compounds.
The following Examples illustrate compounds of the present invention and methods for their synthesis.
Example 1: (E)-3-Cyclohexyl-2-(5-chloro-thiophen-2-yl)-N-thiazol-2'-yl-propenylamide
Figure imgf000039_0001
a) (E)-3-Cyclohexyl-2-(5-chloro-thiophen-2-yl)-propenoic acid: reaction of 5-Chloro-thiophen-2-yl-boronic acid (0.63g, 3.9 mmol) with (Z)-Ethyl 3- cyclohexyl-2-iodo-propenoate (l.Og, 3.25 mmol) using Pd(dba)2 as catalyst as outlined in General Procedure II. b) (E)-3-Cyclohexyl-2-(5-chloro-thiophen-2-yl)-N-thiazol-2'-yl-propenylamide: reaction of 2-aminothiazole (0.35, 3.47mmol) with compound la) according to General Procedure II, 0.13g of a yellowish solid, MS(M++H)=353.
Example 2: (E)-3-Cyclopentyl-2-(thiophen-3-yl)-N-thiazol-2'-yI-propenylamide
Figure imgf000040_0001
a) (E)-3-Cyclopentyl-2-(thiophen-3-yl)-propenoic acid: reaction of thiophen-3-yl boronic acid (0.16g, 1.22 mmol) with (Z)-Ethyl 3-cyclopentyl-2- iodo-propenoate (0.30g, 1.02 mmol) using Pd(dba)2 as catalyst as outlined in General Procedure II. b) (E)-3-Cyclohexyl-2-(5-chloro-thiophen-2-yl)-N-thiazol-2'-yl-propenylamide: reaction of 2-aminothiazole (0.13g, 1.22 mmol) with compound 2a) according to General Procedure II, 0.53g of a yellowish solid, MS(M++H)=305.
Example 3: E)-3-Cyclohexyl-2-(benzothiophen-2-yI)-N-thiazol-2'-yl-propenylamide
Figure imgf000040_0002
a) (E)-3 -Cyclohexyl -2-(benzothiophen-2-yl)-propenoic acid : reaction of thiophen-3-yl boronic acid (0.69 g, 3.90 mmol) with (Z)-Ethyl 3-cyclohexyl-2- iodo-propenoate (1.0 g, 3.25 mmol) using Pd(dba) as catalyst as outlined in General
Procedure II. b) (E)-3-Cyclohexyl-2-(benzothiophen-2-yl)-N-thiazol-2'-yl-propenylamide: reaction of 2-aminothiazole (0.30g, 3.0 mmol) with compound 3a) according to General Procedure II, 0.40g of a solid, MS(M++H)=369.
Example 4: (E)-3-Cyclopentyl-2-(benzothiophen-2-yl)-N-thiazol-2'-yl-propenylamide
Figure imgf000041_0001
a) (E)-3-Cyclopentyl-2-(benzothiophen-2-yl)-propenoic acid reaction of benzothiophen-2-yl boronic acid (0.22g, 1.22 mmol) with (Z)-Ethyl 3- cyclopentyl-2-iodo-propenoate (0.30g, 1.02 mmol) using Pd(dba) as catalyst as outlined in General Procedure II. b) (E)-3-Cyclopentyl-2-(benzothiophen-2-yl)-N-thiazol-2'-yl-propenylamide: reaction of 2-aminothiazole (0.11 g, 1.06 mmol) with compound 4a) according to General Procedure II, 0.05g of a yellowish solid, MS(M++H)=355.
Example 5: (E)-3-Cyclohexyl-2-(benzofuran-2-yl)-N-thiazol-2'-yl-propenylamide
Figure imgf000041_0002
a) (E)-3-Cyclohexyl-2-(benzofuran-2-yl)-propenoic acid: reaction of benzofuran-2-yl -boronic acid (0.63g, 3.89 mmol) with (Z)-Ethyl 3-cyclohexyl- 2-iodo-propenoate (1.0g, 3.25 mmol) using Pd(dba)2 as catalyst as outlined in General Procedure II. b) (E)-3-Cyclohexyl-2-(benzofuran-2-yl)-N-thiazol-2'-yl-propenylamide: reaction of 2-aminothiazole (0.28, 2.80 mmol) with compound 5a) according to General Procedure II, 0.18 g of a yellowish solid, MS(M++H)=353. Example 6: (E)-4-Methyl-2-(5-bromo-thiophen-2-yl)-N-thiazol-2'-yl-pent-2-enylamide
Figure imgf000042_0001
a) (E)-4-Methyl-2-(5-bromo-thiophen-2-yl)-propenoic acid:
5-Bromo-thiophen-2-yl-zinc bromide (7.46 ml of a 0.5M solution in THF, 3.73 mmol) was added under argon atmosphere to a mixture containing (Z)-Ethyl 2-iodo-4-methyl-pent-2- enoate (0.5 g, 1.86 mmol), Pd(dppf)Cl2 (136 mg, 10 mol%) and copper(I) iodide (30mg, 10 mol%) in 5ml of anhydr. THF. The mixture was stined at reflux temperature for 14h. After cooling, the reaction was quenched with IN hydrochloric acid, followed by extraction with methylene dichloride. Hydrolysis of the ester was achieved as described according to the General procedure II. b) (E)-3-Cyclohexyl-2-(5-chloro-thiophen-2-yl)-N-thiazol-2'-yl-propenylamide: reaction of 2-aminothiazole (0.16, 1.60 mmol) with compound 8a) according to General Procedure II, 0.02 g ofa yellowish solid, MS(M++H)=358.
Example 7: (E)-3-Cyclohexyl-2-(5-chloro-thiophen-2-yI)-N-thiazoI-2'-yl-propionamide
Figure imgf000042_0002
Compound lb (0.11 g, 0.31 mmol) was dissolved in 2 ml of dry THF/EtOH (1:1), sodium borohydride (0.05 g, 1,32 mmol) was added at ambient temperature, and the reaction mixture was stined for 14h. Aqueous work-up and extraction with ethyl acetate gave a yellowish gum after evaporation, which crystallized from acetonitrile to yield 22 mg of a colorless solid, MS(M++H)=355. Example 8: (E)-3-Cyclohexyl-2-(benzothiophen-2-yl)-N-thiazol-2'-yl-propionamide
Figure imgf000043_0001
Compound 3b) (0.23 g, 0.62 mmol) was dissolved in 4 ml of dry THF/EtOH (1:1) and sodium borohydride (0.095 g, 2.51 mmol) was added at ambient temperature and stined forT4h. Aqueous work-up and extraction with ethyl acetate gave a yellowish gum after evaporation, which crystallized from acetonitrile to yield 85 mg of a colorless solid, MS(M++H)=371.
Example 9:
(E)-3-Cyclopentyl-2-(5-methylsulfonyl-thiophen-2-yI)-N-thiazoI-2'-yl-propenylamide
Figure imgf000043_0002
a) 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)Cl2 (0.02g) were added at ambient temperature and then stined for 2h at 80°C under argon atmosphere. After cooling, the mixture was added dropwise via a syringe to a solution of 2-iodo-5-methylsulfonyl-thiophene (0.036g, 0.12 mmol) in 2M sodium carbonate (0.29 ml) / DMSO (1 ml) at 50°C and stined for an additional 1.5h. Aqueous work-up, extraction with ethyl acetate, drying over sodium sulfate and evaporation gave the crude product. b) (E)-3-Cyclopentyl-2-(5-methylsulfonyl-thiophen-2-yl)-N-thiazol-2'-yl- propenylamide: To a solution of 2-aminothiazole (0.048g, 0.48 mmol) in THF (1 ml) was added isopropylmagnesium chloride (0.24 ml of a 2M solution in THF, 0.48 mmol) at -35°. The mixture was warmed and stirred under argon at ambient temperature for lh. After cooling to -35°C, crude compound 9a) (0.09g, 0.12 mmol) was added dropwise and stirred at 50°C overnight. Work-up with sat. ammonium chloride solution, extraction with ethyl acetate, drying over sodium sulfate and evaporation gave the crude product. RP-chromatography using water/acetonitrile as eluent system gave 15 mg of a yellowish solid, MS(M++H)=383.
Example 10:
(E)-3-CycIopentyl-2-(5-sulfamoyl-thiophen-2-yI)-N-thiazol-2'-yl-propenylamide
Figure imgf000044_0001
a) 5-Bromo-thiophen-2-sulfonic acid dimethylaminomethylene amide: to a solution of 5-bromo-2-thiophen sulfonamide (0.3 g, 1.24 mmol) in abs. DMF (3 ml) was added N,N-dimethylformamide dimethylacetal (0.17 ml, 1.24 mmol), and the reaction mixture was stined at ambient temperature overnight. Aqueous work-up, extraction with ethyl acetate, drying over sodium sulfate and evaporation gave the crude product as a colorless crystalline solid. b) Ethyl (E)-3-Cyclopentyl-2-[(5-dimethylaminomethylene sulfamoyl)-thiophen-2- yl]-propenoate: processed as described for compound 9a), using (Z)-Ethyl 3-cyclopentyl-
2-iodo-propenoate (0.44g, 1.49 mmol), compound 12a) (0.35g), bis(pinacolato)diborane (0.42 g, 1.64 mmol), potassium acetate (0.44 g, 4.47 mmol) and Pd(dppf)Cl2 (0.066g). c) (E)-3-Cyclopentyl-2-[(5-dimethylaminomethylene sulfamoyl)-thiophen-2-yl)-N- thiazol-2'-yl-propenoate: processed as described for compound 9b), using compound 10b) (0.61g, 1.59 mmol), 2-aminothiazole (0.47g, 4.72 mmol), isopropylmagnesium chloride (2.36 ml of a 2M solution in THF, 4.72 mmol). d) (E)-3-Cyclopentyl-2-(5-sulfamoyl-thiophen-2-yl)-N-thiazol-2'-yl-propenylamide: Compound 10c) (0.04g, 0.09mmol) was dissolved in a solution of ethanol / 5N HClaq (5 ml, 1:1 v:v) and heated at 80°C for 2h. Subsequent work-up with sat. sodium hydrogencarbonate solution and extraction with ethyl acetate yielded the crude product. Flash chromatography using methylene chloride/ethanol 98/2 as eluent system gave the product as a colorless solid, MS(M++H)=384.
Example 11:
(E)-3-Cyclopentyl-2-(5-N-morpholinosulfonyl-thiophen-2-yl)-N-thiazol-2'-yl- propenylamide
Figure imgf000045_0001
a) Ethyl (E)-3-Cyclopentyl-2-(5-N-mo holinosulfonyl-thiophen-2-yl)-propenoate: processed as described for compound 9a), using (Z)-Ethyl 3-cyclopentyl-2-iodo- propenoate (O.lg, 0.36 mmol), 2-bromo-5-N-morpholinosulfonyl-thiophen (0.078g, 0.25 mmol), bis(pinacolato)diborane (0.42 g, 1.64 mmol), potassium acetate (0.11 g, 1.1 mmol) and Pd(dppf)Cl2 (0.04g). b) (E)-3-Cyclopentyl-2-(5-N-moφholinosulfonyl-thiophen-2-yl)-N-thiazol-2'-yl- propenylamide: processed as described for compound 9a), using compound 11a) (0.2g, 0.25 mmol), 2-aminothiazole (0.14g, 1.44 mmol), isopropylmagnesium chloride (0.72 ml of a 2M solution in THF, 1.44 mmol). Flash chromatography using hexanes/ethyl ester 9/1 as eluent system gave the product, MS(M++H)=454.
Example 12: (Z)-3-Cyclopentyl-N-thiazol-2-yl-2-thiophen-3-yl-acryIamide:
Figure imgf000045_0002
a) (Z)-3-Cyclopentyl-2-thiophen-3-yl-acrylic acid: 5-Bromo-thiophen-2-yl-zinc bromide (20.4 ml of a 0.5M solution in THF, 10.2 mmol) was added under argon atmosphere to a mixture containing (Z)-ethyl 2-iodo-4-methyl-pent-2-enoate (1.5 g, 5.1 mmol), Pd(dppf)Cl (373 mg, 10 mol%) and copper(I) iodide (60 mg, 16 mol%) in 5 ml of anhydr. THF. The mixture was stined at 75°C for 14h. After cooling, the reaction mixture was quenched with IN hydrochloric acid, and extracted with MTB ether to afford 1.5 g of a red residue after removal of volatiles. This material was taken up in a mixture of EtOH (20 mL) and 2 N aqueous sodium hydroxide solution (20 mL). The resulting reaction mixture was stirred at 75 °C for 14h, cooled, and poured onto 1 N aqueous hydrochloric acid. The resulting mixture was extracted with MTB ether. The exfracts were dried over sodium sulfate and concentrated to afford 1.24 g of impure (Z)-3-cyclopentyl-2-thiophen- 3-yl-acrylic acid. b) (Z)-3-Cyclopentyl-N-thiazol-2-yl-2-thiophen-3-yl-acrylamide: reaction of 2- aminothiazole (0.16 g, 1.62 mmol) with compound 12a) (0.3 g, 1.35 mmol) according to General Procedure II, 94 mg of a solid, MS(M++H)=305
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.
Such 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. In making the compositions of the present invention, 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. Where 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. Thus, 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. Some examples of 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. The preparations indicated can be sterilized and/or can contain auxiliaries such as lubricants, preservatives, stabilizers and or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants, flavourings and/or one or more further active compounds, e.g. one or more vitamins. Compositions of the invention maybe 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.
The 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. The term "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.
Example A
Tablets containing the following ingredients can be produced in a conventional manner:
Ingredients (mg per capsule)
Compound of formula I 10.0 - 100.0 Lactose 125.0
Com starch 75.0
Talc 4.0
Magnesium stearate 1.0
Example B
Capsules containing the following ingredients can be produced in a conventional manner: Ingredients (mg per capsule)
Compound of formula I 25.0
Lactose 150.0
Corn starch 20.0 Talc 5.0
The pharmacological profile of the present compounds may be demonstrated as follows:
An enzymatic coupled glucokinase (GK) assay using purified recombinant human islet GK was used to evaluate effects of the activators. In this assay, GK catalyzes glucose phosphorylation in the presence of ATP. The product of this reaction, glucose-6- phosphate, is then oxidized by an excess of glucose-6-dehydrogenase to produce gluconate-6-phosphate with concomitant reduction of NAD+ to NADH (Davidson and Arion, 1987). The following outlines the two reactions involved:
Glucose + ATP → Glucose-6-P + ADP (Glucokinase)
Glucose-6-P + NAD → Gluconate-6-P + NADH (glucose-6-P dehydrogenase)
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 NaH2PO4, 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 lOOμl. The incubation mixture consisted of 25 mM HEPES (pH7.4), 50 mM KC1, 2.5 mM MgCl2, 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 μl 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 (EC50) was calculated The preferred compounds of formula I described within the examples have an EC50 less than or equal to 30 μM.
Figure imgf000049_0001
EC50 values shown in the above table are at lOmM glucose.
References:
Davidson A.L. and Arion W. J. Factors underlying significant underestimations of glucokinase activity in crude liver extracts: physiological implications of higher cellular activity. Arch. Biochem. Biophys. 253, 156-167, 1987.
Tidge M, Krag U. and Lenzen S. Modulation of human, glucokinase intristic activity by
SH reagents minors post-translational regulation of enzyme activity. Biochem. Biophys.
Acta 1337, 175-190, 1997.

Claims

Claims
A compound of formula
Figure imgf000050_0001
wherein Z is
Figure imgf000050_0002
R is lower alkyl or halo lower alkyl having from 2 to 6 carbon atoms or arylalkyl or - (CH2)s-N where N 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; A is
Figure imgf000050_0003
where Y is oxygen or sulfur, and
R1 and R2 are independently hydrogen, halo, amino, hydroxyamino, nitro, cyano, sulfonamido, lower alkyl, -OR5, -COOR5, perfluoro- lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfϊnyl,
R5 is hydrogen, lower alkyl or perfluoro-lower alkyl; or furthermore R2 can be -(CH2)n-ΝR6R7, with n=l,2,3 or 4, and R6 and R7 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 nitrogen; 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 R2 can be alkinyl, substituted with hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, an unsubstituted or hydroxy substituted cycloalkyl ring containing 5 or 6 carbon atoms, a five- or six-membered saturated heterocyclic ring which contains from 1 to 3 hetero atoms selected from the group consisting of sulfur, oxygen or nifrogen, or an unsubstituted five- or six-membered heteroaromatic ring, connected by a ring carbon atom, which contains from 1 to 3 heteroatoms in the ring selected from the group consisting of sulfur, nitrogen and oxygen, or -(CH )n-NR8R9, with n=l,2, and R and R 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 nitrogen; 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 R2 can be R10-[(CH2)y-W]z-, with W is oxygen, sulfur, -SO-, -SO2-, and
R10 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 nifrogen, 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
-NR 1 1 R19 , with R 1 1 and R 1 being independently hydrogen or lower alkyl; y is independently 0,1,2,3 or 4; z is independently 0,1; or R2 can be R13-(CH2)t-U-, with
U is -NHCO-, -CONH, -NHSO2-, -SO2NH- and
R13 in the same meaning of R10 and perfluoro-lower alkyl, lower alkyl, lower alkoxycarbonyl or -NR14R15, R14 and R15 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 nitrogen; or a saturated 5- or 6- membered 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; R4 is -C(O)NHR16, or is R17;
R16 is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl, -(CH2)n-COOR18, -CO-(CH2)n-COOR19; R17 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 nifrogen, 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, nitro, cyano, -(CH2)n-OR20, -(CH2)n-COOR21, -(CH2)n-CONHR22, -(CH2)n-NHR23, n is 0, 1, 2. 3 or 4; R18, R19, R20, R21, R22 and R23 are independently hydrogen or lower alkyl, and its pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 , wherein
R4 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 nifrogen 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, nitro, cyano, -(CH2)n-OR20, -(CH2)n-COOR21, -(CH2)n-CONHR22, -(CH2)n-NHR23, n is 0, 1, 2. 3 or 4;
R20, R21, R22 and R23 are independently hydrogen or lower alkyl, and its pharmaceutically acceptable salts thereof.
3. A compound according to any of claims 1 to 2, wherein R4 is an unsubstituted, mono- or di-substituted five- or six-membered heteroaromatic ring selected from the group consisting of thiazolyl, imidazolyl, oxazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.
4. A compound according to any of claims 1 to 3 wherein R4 is thiazolyl or pyridinyl, unsubstituted, mono- or di-substituted independently by halogen, lower alkyl or (CH2)n-C(O)OR21, wherein n is 0, 1 or 2 and R21 is lower alkyl.
A compound according to claim 1 , wherein R4 is -C(O)NHR16;
R , 16 is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl, -(CH2)n-COOR18, -CO-(CH2)n-COOR19; n is O, 1, 2. 3 or 4;
R18 and R19 are independently hydrogen or lower alkyl, and its pharmaceutically acceptable salts thereof.
6. A compound according to any of claims 1 or 5, wherein R4 is -C(0)NHR16, and R16 is lower alkyl or lower alkenyl.
7. A compound according to any of claims 1 to 6, wherein R1 is hydrogen, halo, nitro or cyano.
8. A compound according to any of claims 1 to 7, wherein R1 is hydrogen or halo.
9. A compound according to any of claims 1 to 8, wherein R is hydrogen, halo, nitro, cyano, sulfonamido, lower alkyl, -OR5, -COOR5, perfluoro- lower alkyl, lower alkyl sulfonyl; or
R2 can be R10-[(CH2)y-W]z-, where
W is oxygen, sulfur, -SO-, or -SO2-, and
R10 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
1 1 19 1 1 1 9
-NR R , with R and R being independently hydrogen or lower alkyl; y is independently 0,1,2,3 or 4; z is independently 0,1; or R2 can be R13-(CH2)t-U-, with
U is -NHCO-, -CONH, -NHSO2-, -SO2NH- and
R13 in the same meaning of R10 and perfluoro-lower alkyl, lower alkyl, lower alkoxycarbonyl or
-NR14R15, R14 and R15 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; t is an integer from 0 to 4.
10. A compound according to any of claims 1 to 9, wherein R2 is halo, lower alkyl sulfonyl or R1 °-[(CH2)y-W]z-.
11. A compound according to any of claims 1 to 10, wherein R is sulfonylmethyl or R10-[(CH2)y-W]z- where W is SO2.
12. A compound according to any of claims 1 to 11. wherein N is cyclopentyl, cyclohexyl or cycloheptyl.
13. A compound according to any of claims 1 tol2, wherein N is cyclopentyl.
14. A compound according to any of claims 1 to 11 , wherein R3 is isopropyl or n- propyl.
15. A compound according to any of claims 1 to 11, wherein R3 is isobutyl.
16. A compound according to any of claims 1 to 15, wherein Z is
Figure imgf000055_0001
17. A compound according to claim 16, wherein M is hydrogen, fluorine or methyl.
18. A compound according to any of claims 1 to 17, wherein A is
Figure imgf000055_0002
19. A compound according to any of claims 1 to 18, wherein Y is sulfur.
20. The use of the compounds according to any of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of type II diabetes.
21. A pharmaceutical composition comprising a compound of any of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
22. The use of a compound according to any of claims 1 to 19, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of type II diabetes.
23. A method for the prophylactic or therapeutic freatment of type II diabetes, which comprises administring a compound of any of claims 1 to 19, or a pharmaceutically acceptable salt thereof, to a human being or animal in need thereof.
24. A pharmaceutical composition for treating type II diabetes containing as an active ingredient a compound of any of claims 1 to 19, or a pharmaceutically acceptable salt thereof.
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