WO1999065881A1 - Heterocyclic compounds as hypoglycemic agents - Google Patents

Heterocyclic compounds as hypoglycemic agents Download PDF

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Publication number
WO1999065881A1
WO1999065881A1 PCT/JP1999/003214 JP9903214W WO9965881A1 WO 1999065881 A1 WO1999065881 A1 WO 1999065881A1 JP 9903214 W JP9903214 W JP 9903214W WO 9965881 A1 WO9965881 A1 WO 9965881A1
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group
meo
compound
pro
hydrogen atom
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PCT/JP1999/003214
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French (fr)
Inventor
Mikio Suzuki
Keisuke Ohdoi
Katsuhiro Kato
Hiromitsu Matsumoto
Koji Toyama
Masaki Kitahara
Takashi Yotsumoto
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Nissan Chemical Industries, Ltd.
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Priority to AU41670/99A priority Critical patent/AU4167099A/en
Publication of WO1999065881A1 publication Critical patent/WO1999065881A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel 6-membered heterocyclic-compounds having a hypoglycemic effect, which are useful in medical and veterinary fields, particularly useful for preventing and treating diabetes and diabetic complications.
  • various sulfonylureas and biguanides have been widely used as oral hypoglycemic agents for lowering blood glucose level.
  • these agents have probabilities of causing serious hypoglycemic coma and lactic acidosis, and therefore every possible care must be taken for practical use.
  • Recently developed insulin sensitizers also have a hypoglycemic effect, they are particularly useful for obese Type II diabetes, and are noted as agents which hardly cause such hypoglycemic symptoms as caused by the above-mentioned oral hypoglycemic agents.
  • an adequate effect can not be obtained for patients with deficiency of insulin secretion.
  • the above-mentioned agents do not necessarily lower the blood glucose level during starvation.
  • CPT carnitine-palmitoyl transferase
  • Said CPT inhibitors have an effect of effectively lowering the blood glucose level.
  • their usefulness for preventing onset and progression of various complications caused by diabetes such as diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy and the like, has not been completely proved.
  • a CPT inhibitor suppresses the im uno pathological changes in kidney caused in db/db mice as models of Type II diabetes (Diabetes, vol.31, 12-18, 1982). Further, the progression of such complications is suppressed by strict control of blood glucose level. Accordingly, the CPT inhibitors are useful as pharmaceutical agents for preventing and treating such complications.
  • the CPT inhibitors have a strong effect for lowering ketone body level in the diabetic animals and diabetic patients (Proc. Soc. Exp. Biol. Med., vol.178, 288-296, 1985, Metabolism, vol.40, 1185-1190, 1991). It is expected that the CPT inhibitors inhibit all pathological conditions caused by cellular pathologically accelerated formation of ketone bodies as well as diabetes.
  • the present inventors have synthesized various 6-membered heterocyclic- compounds which are not disclosed in the above-mentioned literatures, and have studied the their properties. As the result, the present inventors have found a compound having more excellent hypoglycemic effect.
  • the present invention provides 6-membered heterocyclic- compounds capable of preventing and treating diabetes mellitus and diabetic complications.
  • the present invention relates to a 6- membered heterocyclic-compound or its salt represented by the formula [i] :
  • R is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a sulfonic acid group, a sulfonamide group, P0 2 H 2 , ⁇ 6
  • C(0)NRR (each of R and R which are independent of each other, is a hydrogen atom
  • R which are independent of each other, is a hydrogen
  • R is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a guanidyl group, an amidino
  • 11' ' R which are independent of one another, is a C 1 _ 7 alkyl
  • each of R and R which are independent of each other, is a C ⁇ _ 7 alkyl group, R is a hydrogen atom, a C ⁇ 7 alkyl group, a C ⁇ _ 7 aliphatic acyl group, a C 5 _ :3 aromatic acyl group or a protecting group ⁇ ;
  • D is a covalent bond, -CH,-, -0-, -S-, -S(0)-, -S(0) 2 -, -NR 12 -, -C(0)-NR 12 -, -NR 12 -C(0)- or -NR ⁇ '-C (0) -NR 12 - (each of R 12 and R 12' which are independent of each other, is a hydrogen atom or a C ⁇ , alkyl group) ;
  • each of R , R , R ' and R which are independent of one another, is a hydrogen atom, a halogen atom, a hydroxyl group, a C 1 _ 7 alkyl group or a C 1 _ 7 alkoxy group, each of
  • R may be a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a sulfonic acid group, a sulfonamide group, P0 2 H 2 , P0 3 H 2 , a 5-tetrazolyl
  • C(0)NRR (each of R and R which are independent of each other, is a hydrogen atom or a C ⁇ _ 7
  • R is a hydrogen atom or a C._ 7 alkyl group
  • R is more preferably C(0)0R °
  • the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, it is preferably a fluorine atom, a chlorine atom or a bromine atom
  • the C 1 _ 7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like;
  • R may be a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a guanidyl group, an ami .dm. o group, NR ⁇ oR 10 ' (,eac,h or R 10 and R 10 ' which are independent of each other, is a hydrogen atom, a C,_ 7 alkyl group, C 1 _ 7 aliphatic acyl, C 6 _ 10 aromatic acyl or a
  • R R R (each of R , R and R which are independent of one another, is a C._ 7 alkyl group) ; it is preferably a guanidyl group, an amidino group,
  • R R R (each of R , R and R which are independent of one another, is a C 1 _ 7 alkyl group) , it is
  • R R R (each of R , R and R which are independent of one another, is a C 1 7 alkyl group) ;
  • the C ⁇ _ 7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like;
  • the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, it is preferably a fluorine atom, a chlorine atom or a bromine atom;
  • each of R and R " which are independent of each other, may be a C 1-7 alkyl group;
  • the C 1 _ 1 alkyl group may be methyl, ethyl, n-prop
  • R may be a hydrogen atom, a C 1 _ 7 alkyl group, C,_ 7 aliphatic acyl, C 6 _ 1 classroom aromatic acyl or a protecting group, it is preferably a hydrogen atom or a C 1-7 alkyl group;
  • the C 1 _ 7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like;
  • the C 1 _ 7 aliphatic acyl may be formyl, acetyl, propionyl, butyryl , isobutyryl, valeryl, isovaleryl, pivaloyl or the like;
  • the C 6 _ 10 aromatic acyl may be benzoyl, 2-toluoyl, 3- toluo
  • aryloxymethyl group such as 30M: benzyloxymethy1 , PMBM: p-methoxybenzyloxymethyl or p-AOM: P-anisyloxymethyl, preferably e.g.
  • benzyloxymethyl , a C ⁇ _ 4 alkylaminomethyl group (such as dimethylaminomethyl) a substituted acetamidomethyl group (such as Acm: acetamidomethyl or Tac : trimethylacetamidomethyl) , a substituted thiomethyl group (such as MTM: methylthiomethyl, PTM: phenylthiomethyl or Btm: benzylthiomethyl) , a carboxyl group, a C ⁇ acyl group (such as formyl, acetyl, fluoroacetyl, difluoroacetyl , trifluoroacetyl, chloroacetyl, dichloroacetyl , trichloroacetyl, propionyl, Pv: pivaloyl or tigloyl) , an arylcarbonyl group (such as benzoyl, benzoylformyl, benzoylpropion
  • an aryloxycarbonyl group such as Z: benzyloxycarbonyl , p-nitrobenzyloxycarbonyl or MOZ : p- methoxybenzyloxycarbonyl
  • a C 1 4 alkylaminocarbonyl group methylcarbamoyl, Ec : ethylcarbamoyl or n- propylcarbamoyl
  • an arylaminocarbonyl group such as phenylcarbamoyl
  • a trialkylsilyl group such as TMS : trimethylsilyl, TES : triethylsilyl , TIPS: triisopropylsilyl
  • DEIPS diethylisopropylsilyl
  • DMIPS dimethylisopropylsilyl
  • DTBMS di-t-butylmethylsilyl
  • IPDMS isopropyldimethylsilyl
  • TBD isopropyldimethylsily
  • t-butyldimethylsilyl a trialkylarylsilyl group (such as DPMS : diphenylmethylsilyl, TBDPS : t-butyldiphenylsilyl, TBMPS : t-butyldimethoxyphenylsilyl or TPS : triphenylsilyl) , an alkylsulfonyl group (such as Ms: methanesulfonyl or ethanesulfonyl) , or an arylsulfonyl group (such as benzenesulfonyl, Ts : p-toluenesulfonyl, p- chlorobenzenesulfonyl, MBS: p-methoxybenzenesulfonyl , m- nitrobenzenesulfonyl , iMds : 2 , 6-dimethoxy-4- methylbenzene
  • D may be a covalent bond, -CH,-, -0-, -S-, -S(O)-, -S(0) 2 -, -NR -, -C(0)-NR X -, -NR -C(O)- or -NR -C ⁇ 0)-
  • NR - (each of R and R which are independent of each other, is a hydrogen atom or a C ⁇ ., alkyl group) ,
  • the C ⁇ _ 7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like.
  • Each of X , X , X , X and X which are independent of one another, may be a nitrogen atom or CR .
  • X , X , X and X which are independent of one another, may be a nitrogen atom or CR .
  • 2 another may be a nitrogen atom or CH, and each of X and
  • X which are independent of each other may be CR . More
  • X may be CR (R is a hydrogen atom or a halogen atom) .
  • R is a hydrogen atom or a halogen atom
  • at least one of X to X is a nitrogen atom.
  • R may be a hydrogen atom, a halogen atom or -E-G.
  • the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.
  • Each of R , R , R and R wnich are independent of one another, may be a hydrogen atom, a halogen atom, a hydroxyl group, a C ⁇ alkyl group or a C 1 7 alkoxy group.
  • each of R , R , R , and R which are independent of one another may be a hydrogen atom, a C 1 7 alkyl group or a C ⁇ _ 7 alkoxy group.
  • the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.
  • the C ⁇ _ 7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like.
  • the C ⁇ _ 7 alkoxy group may be methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t- butoxy, pentyloxy, hexyloxy, heptyloxy or the like.
  • each of R 1 and R l3' which are independent of each other, is a hydrogen atom, a C,_ 7 alkyl group or a C 6 ⁇ 14 aromatic group.
  • each of R 1 and R l3' which are independent of each other, is a hydrogen atom, a C,_ 7 alkyl group or a C 6 ⁇ 14 aromatic group
  • the C 1 _ 7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl or n-heptyl .
  • the C 6 _ 14 aromatic group may be phenyl, ⁇ -naphthyl, ⁇ -naphthyl, 1-indenyl, 2-indenyl, 3-indenyl, 4-indenyl, 5-indenyl, 6-indenyl, 7-indenyl, 1-indanyl, 2-indanyl, 4- indanyl, 5-indanyl, 1-fluorenyl, 2-fluorenyl, 3- fluorenyl, 4-fluorenyl, 9-fluorenyl or the like.
  • k is from 1 to 10
  • each of R and R " which are independent of each other, is a hydrogen atom or a C 1 7 alkyl group, may be mentioned, and preferably
  • G may be a hydrogen atom, a C 3 _ 10 cycloalkyl group, a C 3 _ 7 cycloalkenyl group, a C s _ 14 aromatic group, a C_ 12 heteroaromatic group or a C 4 _ 12 heteroalicyclic group, preferably a hydrogen atom, a C 5 _ 14 aromatic group, a C 4 _ 12 heteroaromatic group or a C 4 _ 12 heteroalicyclic group .
  • the C 3 _ 1Q cycloalkyl group may be cyclopropyl, 1- methylcyclopropyl, 2-methylcyclopropyl , 4- methylcyclohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[2.2. ljheptyl , bicyclo[3. i .
  • ljheptyl bicyclo[2.2.2]octyl, 1-adamantyl or 2-adamantyl, and the C 6 _ 10 cycloalkyl group may be preferably cyclohexyl, bicyclo[2.2. ljheptyl , bicyclo[3.1.
  • ljheptyl bicyclo[2.2.2]octyl, 1-adamantyl or 2-adamantyl; either of them may have at most 5 substituents in total (said substituent is a hydrogen atom, a C,_ 7 alkyl group, a C,_ 7 cycloalkyl group, a C 3 _ 7 cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a D hydroxyl group, a C._ 7 alkoxy group, a C ⁇ .
  • alkylthio group a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C 1 _, alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C 1 _ 7 alkylsilyloxy group, phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (each of said phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl may be substituted with at most 5 of C 1 _ 7 alkyl groups
  • substituents in total are hydrogen atom, a C ⁇ alkyl group, a C 3 7 cycloalkyl group, a C 3 _ 7 cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a C ⁇ _ 7 alkoxy group, a C ⁇ _ 7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C ⁇ _ 3 alkoxycarbonyl group,
  • the C ⁇ _ 7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like, preferably it may be methyl, ethyl, n-propyl or the like, and either of them may be substituted with a hydroxyl group;
  • the C 3 _ 7 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.
  • ljheptyl bicyclo[3.1. ljheptyl or the like, preferably it may be cyclopropyl, cyclohexyl or the like, and either of them may be substituted with a hydroxyl group;
  • the C 3 _ 7 cycloalkenyl group may be 1-cyclohexenyl, 2- cyclohexenyl, 3-cyclohexenyl , cyclopentadienyl, 2- bicyclo[2.2. ijheptenyl, 2 , 5-bicyclo[2.2.
  • the C ⁇ _ 7 alkoxy group may be methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t- butoxy, pentyloxy, hexyloxy, heptyloxy or the like
  • the C 1 _ 7 alkylthio group may be methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i- butylthio, s-butylthio, t-butylthio, pentylthio, hexylthio, heptylthio, or the like
  • the tri-C ⁇ _ 7 alkylsilyloxy group may be trimethylsilyloxy, triethylsilyloxy,
  • ' n' means normal, ' i' means iso, 's' means secondary, ' t' means tertiary, ' c' means cyclo, ' Me' means a methyl group, ⁇ t' means an ethyl group, 'Pr' means a propyl group, ' Bu' means a butyl group, 'Pen' means a pentyl group, ' Hex' means a hexyl group, 'Ph' means a phenyl group, and ' Hal'means a halogen atom.
  • the C 3 _ 7 cycloalkenyl group is cyclohexenyl, cyclopentadienyl, 2- bicyclo[2.2. ijheptenyl or 2 , 5-bicyclo[2.2.
  • the C 6 _ 14 aromatic group is phenyl, naphthyl, indenyl, indanyl or fluorenyl
  • the C 1 _ 12 heteroaromatic group is furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furazanyl, pyrazolyl, oxopyrazolyl , imidazolyl, oxoimidazolyl, triazolyl, oxotriazolyl, tetrazolyl, pyranyl, pyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrimidinyl, pyrimidinonyi , pyrazinyl, triazinyl, tetrazinyl, indolyl, quinolyl, quinolonyl,
  • each of R and R which are independent of each- other is a hydrogen atom, a C ⁇ _ 7 alkyl group, a C._ 7 cycloalkyl group, a C 3 _ 7 cycloalkenyl group (each of said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a C 1 _ 7 alkoxy group, a C,_ 7 alkylthio group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C, alkoxycarbonyl group, a nitrile group, a carbamoyl group, a
  • each of R and R which are independent of each other is a hydrogen atom, a C 1 7 alkyl group, a C 3 7 cycloalkyl group, a C 3 _ 7 cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a C,_ 7 alkoxy group, a C 1 _ 1 alkylthio group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C ⁇ _ 3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulf
  • R is a hydrogen atom or a C 17 alkyl group
  • 10 10' is a guanidyl group, an amidmo group, NR R (wherein
  • each of R and R which are independent of each other, is a hydrogen atom or a C 1 7 al -, ,kyl, group) or N + RIIR11'R11' ⁇
  • R is a hydrogen atom or a C 1 _ 1 alkyl group
  • D is -0- , -NR - (wherein R " is a hydrogen atom or a C,_ 7 alkyl group)
  • each of R , R , R and R which are independent of one another, is a hydrogen atom, a C 1-7 alkyl group or a C,_ 7
  • each of R and R which are independent of each other, is a hydrogen atom or a C 1 _ 1 alkyl group
  • R is C(0)OR (wherein R is a hydrogen atom or a
  • R is NR R (wherein each of R and
  • D is -O- or -NH-
  • X is CR (wherein R is a hydrogen atom or a halogen atom) .
  • the compound represented by the formula [ij of the present invention can be used for the purpose of the present invention either in the free form or in the form of a pharmaceutically acceptable salt.
  • the compound represented by the formula [ij, i.e. 6- membered heterocyclic-compound, can be prepared by the following synthetic methods.
  • a reaction solvent used in the preparation is stable under the reaction conditions, and is preferably so inert as not to inhibit the reaction.
  • the reaction solvent water, alcohols (such as methanol, ethanol, propanol, butanol and octanol) , cellosolves (such as methoxyethanol and ethoxyethanol) , aprotic polar organic solvents (such as dimethylformamide (DMF) , dimethylsulfoxide (DMSO) , dimethylacetamide, tetramethylurea, sulfolane, N,N- dimethylimidazolidinone (DMI), 1 , 3-dimethyl-3 , 4 , 5 , 6- tetrahydro-2 (IH) -pyrimidinone (DMPU) and hexamethylphosphoric triamide (HMPA) ) , ethers (such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane)
  • solvents are optionally selected depending upon the reactivity of the aimed reaction, and are respectively used alone or in a mixture. In some cases, they are used as a non-aqueous solvent by using a suitable dehydrating agent or a drying agent.
  • suitable dehydrating agent or a drying agent used as a suitable dehydrating agent.
  • the above- mentioned solvents are merely examples which can be used in the reaction of the present invention, and the present invention is not limited to these conditions.
  • R 16 and R is a suitable leaving group for the nucleophilic substitution in the reaction, including halogen such as chlorine, bromine or iodine, and an aromatic or aliphatic sulfonyloxy group such as p-toluenesulfonyloxy, benzenesulfonyloxy or methanesuIfonyloxy] .
  • halogen such as chlorine, bromine or iodine
  • an aromatic or aliphatic sulfonyloxy group such as p-toluenesulfonyloxy, benzenesulfonyloxy or methanesuIfonyloxy] .
  • NR (wherein R is as defined above)
  • NR can be obtained by reacting a compound of the formula [ii] with a compound of the formula [ill] without a catalyst or in the presence of a catalyst.
  • the reaction is conducted usually in an appropriate solvent in the presence of a base.
  • aprotic polar organic solvents such as dimethylformamide, dimethylacetamide, tetramethylurea, N,N-dimethylimidazolidinone (DMI) , 1,3- dimethyl-3,4, 5, 6-tetrahydro-2 (IH) -pyrimidinone (DMPU) and hexamethylphosphoric triamide (HMPA)
  • ethers aromatic hydrocarbons, halogenated hydrocarbons, ketones, lower aliphatic acid esters, alkoxy alkanes and acetonitrile may, for example, be mentioned.
  • organic amines such as diisopropylethylamine, trimethylamine, triethylamine, N- methylmorpholine and pyridine
  • metal alkoxides such as sodium methoxide, sodium ethoxide, lithium isopropoxide and potassium t-butoxide
  • inorganic alkali metal salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, sodium acetate and potassium acetate
  • alkali metal amides such as sodium amide
  • a group of palladium such as tetrakis ( triphenylpnosphme)palladium(0) , palladium (II) chloride and 1,3- bis (diphenylphosphino) propane/Pd 2 (dba) ,
  • a group of nickel such as dichloro[l , 3- bis (diphenylphosphino) propanejnickel (II) and tetrakis (triphenylphosphite) nickel (0)
  • a group of ruthenium such as dichlorotris (triphenylphosphine) ruthenium
  • a group of rhodium such as chlorotris (triphenylphosphine) rhodium
  • the reaction is conducted usually at a temperature ranging from -100°C to the boiling point of the solvent to be used in the reaction, preferably from 20°C to 150°C, for from 0.5 to 30 hours.
  • a temperature ranging from -100°C to the boiling point of the solvent to be used in the reaction preferably from 20°C to 150°C, for from 0.5 to 30 hours.
  • Examples for the reaction of a halopyridine with an alkylamine are described in J. Org. Chem, 1953, 18, 1484, Tetrahedron Lett, 1971, 1875, Chem. Ber, 1969, 102, 1161 and Reel. Trav. Chim. Pays-Bas, 1969, 88, 1391.
  • the reaction using a palladium catalyst is described in J. Org. Chem, 1996, 61, 7240 and ibid 1997, 62, 1568.
  • NR (wherein R is as defined above)
  • R is as defined above
  • NR can be obtained by nucleophilic substitution of a compound of the formula [vj with a compound of the formula [ivj .
  • R is chlorine, bromine or OC(0)OR (wherein R is a C ⁇ _ alkyl group or a phenyl group)].
  • a compound of the formula [l-2J can be obtained by nucleophilic substitution of a compound of the formula [vi] with a compound of the formula [lII-2J.
  • the reaction is usually conducted in a suitable organic solvent, and the reaction can be accelerated by using a suitable base as the case requires.
  • a suitable organic solvent aprotic polar organic solvents, ethers, aromatic hydrocarbons, halogenated hydrocarbons, alkoxy alkanes and acetonitrile may, for example, be mentioned.
  • organic amines such as diisopropylethylamine, trimethylamine, triethylamine, N- methylpiperidine, N-methylmorpholine, pyridine, 2,6- lutidine and collidine
  • metal alkoxides such as sodium methoxide, sodium ethoxide, lithium isopropoxide and potassium t-butoxide
  • inorganic alkali metal salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, sodium acetate and potassium acetate
  • alkali metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and 2,2,6,6- tetramethylpiperidide
  • alkali metals such as methyllithium, n-butyllithium
  • the reaction is conducted usually at a temperature ranging from -78°C to the boiling point of the solvent to be used in the reaction, for from 0.5 to 30 hours.
  • a compound of the formula [l-3J can be obtained by nucleophilic substitution of a compound of the formula [vilj with a compound of the formula [lV-2].
  • M is -NCO or -N(R )-C(0)-OR (wherein R is as defined above, R is a ⁇ _ 7 alkyl group or a phenyl group)].
  • R is as defined above, R is a ⁇ _ 7 alkyl group or a phenyl group.
  • NR - (wherein R is as defined above), i.e. a compound of the formula [l-4], can be obtained by reacting a compound of the formula [vill] with a compound of the formula [lll-2j.
  • the reaction can be conducted under the same conditions as in Process 3.
  • NR - (wherein R is as defined above), i.e. a compound of the formula [l-4], can be obtained by reacting a compound of the formula [lV-2] with a compound of the formula [ix] .
  • an intermediate of the formula [xill] can be obtained by solvolysis (by e.g. an alcohol or water) of a ⁇ -lactam of the formula [Xllj.
  • the ⁇ -lactarn can be obtained by cyclization of a compound of the formula [xi] that can be obtained by reacting a common olefination reagent (such as Wittig reagent) with a piperidone of the formula [xj, with a suitable isocyanate (such as ClS0 2 NCO) .
  • a common olefination reagent such as Wittig reagent
  • a piperidone of the formula [xj with a suitable isocyanate (such as ClS0 2 NCO) .
  • R and R are as defined above, and R is a hydrogen atom, C ⁇ _ 7 aliphatic acyl, C 5 _ 10 aromatic acyl or a protecting group].
  • an intermediate of the formula [xv] can be synthesized by conducting Arndt-Eistert reaction of a compound of the formula [XIVJ.
  • 4-amino-4-piperidyl acetate derivative can be obtained by reacting diazomethane with an acyl chloride or a mixed anhydride of the compound of the formula [XIVJ to obtain a diazoketone, followed by using a suitable catalyst (for example, a silver compound such as silver benzoate) or irradiating with light in the presence of a suitable alcohol.
  • a suitable catalyst for example, a silver compound such as silver benzoate
  • the protecting group is removed as the case requires, to obtain an intermediate of the formula [XIII].
  • the compound of the formula [XIVJ can be synthesized in accordance with a method as described in USP 3,313,819, USP 3,330,836 or J. Org. Chem., 1957, 22, 1061.
  • the protecting group is removed as the case requires, to obtain an intermediate of the formula [XVIJ .
  • NR (wherein R is as defined above) and Q is Li, Cu, MgBr, ZnBr, a trialkylstannyl group such as tributylstannyl or a trialkylsilyl group such as trimethylsilyl] .
  • the intermediate of the formula [XIIl] can be synthesized by various reactions from the compound of the formula [x] .
  • a compound of the formula LXIII-d] and a compound of the formula [xill-e] can be obtained, by reacting a compound of the formula [XXIIJ with a suitable oxidizing agent followed by suitable reaction treatment, and by reacting it with a suitable reducing agent, respectively.
  • the compound of the formula [xill-bj can be obtained by reacting the piperidone with a carboxylate derivative of the formula [XXIVJ .
  • the compound of the formula [xill-b] can be converted to a thiol of the formula [xill-2b] or 'an amine of the formula [xill-lbj, as the above-mentioned compound of the formula [xillj.
  • the compound of the formula [xxil] can be synthesized in accordance with a method as described in J. Org. Chem., 1998, 63, 4554. The protecting group is removed to obtain the intermediate of the formula [XIIl], [xill-bj, [xill-dj or [xill-ej if 1 required.
  • the intermediate of the formula [XIIl] can be synthesized also by Michael addition of various olefin derivatives.
  • malonate, malonitrile or a cyano acetate derivative is treated with a piperidone of the formula [x] to synthesize a compound of the formula [xxv], [XXVIJ or [XXVIIJ, respectively.
  • ammonia is added therewith, an azide is added therewith followed by reacting a suitable reducing agent therewith, or an amine having a suitable protecting group such as benzylamine is added therewith followed by removing the protecting group, to obtain a compound of the formula [XXVIII], [XXIX] or [XXXJ, respectively.
  • the compound of the formula [XXVIII] can be lead to an intermediate of the formula [xvj by known methods (such as hydrolysis of one ester followed by decarboxylation) , and the protecting group is removed to obtain the intermediate of the formula [XIIl] as the case requires.
  • the cyano group is hydrolyzed, and the intermediate of the formula [XIIl] can be obtained in the same manner as for the compound of the formula [XXVIIIJ.
  • a cyano acetate derivative of the formula [XXXIJ obtained by decarboxylation is hydrolyzed to obtain an intermediate of the formula [xv], and the protecting group is removed to obtain the intermediate of the formula [xillj.
  • an amide derivative of the formula [XXXIIJ and an alkyl amino of the formula [XXXIIIJ can be synthesized by known methods.
  • an amino group is introduced to an ⁇ -unsaturated carboxylic acid of the formula [XXXIV] or an ⁇ -unsaturated nitrile of the formula [XXXVJ, which can be synthesized by known methods, by Michael addition in the same manner as in the Reaction
  • an intermediate of the formula [xvi] or [XIIl] can be also obtained by means of Overman rearrangement (refer to e.g. J. Am. Chem. Soc. 1974, 96, 597) .
  • the compound of the formula [XXXVIIJ can be prepared by the treatment of the alcohol of the formula [XXVI] that is synthesized by known methods (such as Wittig reaction) with an acetonitrile derivative (such as Cl.CCN) .
  • the precursor can be converted to the compound of the formula [XXXVIII] under suitable conditions (for example, reflux under heating in a solvent having a high boiling point such as xylene, or a reaction under coexistence of a metal agent such as trifluoromercury acetate) .
  • suitable conditions for example, reflux under heating in a solvent having a high boiling point such as xylene, or a reaction under coexistence of a metal agent such as trifluoromercury acetate.
  • the vinyl group of the compound of the formula [XXXVIII] is converted to a carboxylate derivative by a suitable oxidation method (such as ozone oxidation) , and the protecting group is removed if necessary, to obtain the intermediate of the formula [XVI] .
  • the compound of the formula [XXXVIII] can be lead to the intermediate of the formula [XHI-d] in such a manner that it is lead to an alcohol by a known suitable reducing agent, and the protecting group is removed as the case requires .
  • the intermediate may be further oxidized by a known suitable oxidation method, the protecting group is removed as the case requires, and the intermediate of the formula [XIII] can be obtained.
  • G is a C._, 2 heteroaromatic group, a C,_.. heteroalicyclic group, a C 3 _ ⁇ z cycloalkyl group, a C,_ 7 cycloalkenyl group or a C,_ 14 aromatic group, and each of L and L which are independent of each other, is -0-, -S- or -NR - (wherein R " is as defined above)].
  • a compound of the formula [XXXXI] can be synthesized by nucleophilic substitution of a compound of the formula [XXXX] with an alcohol of the formula [XXXIX] wherein L is 0, a thiol of the formula [XXXIX] wherein L is S or an amine of the i . 15 15 formula [XXXIX] wherein L is NR (wherein R is as l ⁇ defined above) .
  • R is a suitable leaving group. The protecting group of the obtained compound of the formula [XXXI] is removed, as the case requires, and can be used as a substituent of R .
  • a phenol of the formula [XXXIX(G is a phenyl group)] wherein L is 0, and a thiophenol of the formula [XXXIX(G is a phenyl group)] wherein L is S, can be lead to alcohols of the formula [XXXXIIIJ by using a compound of the formula [XXXXIIJ. under suitable basic conditions, in accordance with methods as described in Bull. Chem. Soc.

Abstract

A 6-membered heterocyclic-compound or its salt represented by formula (I), wherein A is (a), (b) or (c).

Description

HETEROCYCLIC COMPOUNDS AS HYPOGLYCEMICAGENTS
BACKGROUND (TF~ THE INVK TTOJ TECHNICAL FIELD The present invention relates to novel 6-membered heterocyclic-compounds having a hypoglycemic effect, which are useful in medical and veterinary fields, particularly useful for preventing and treating diabetes and diabetic complications. BACKGROUND ART
Heretofore, various sulfonylureas and biguanides have been widely used as oral hypoglycemic agents for lowering blood glucose level. However, these agents have probabilities of causing serious hypoglycemic coma and lactic acidosis, and therefore every possible care must be taken for practical use. Recently developed insulin sensitizers also have a hypoglycemic effect, they are particularly useful for obese Type II diabetes, and are noted as agents which hardly cause such hypoglycemic symptoms as caused by the above-mentioned oral hypoglycemic agents. However, it has been known that an adequate effect can not be obtained for patients with deficiency of insulin secretion. The above-mentioned agents do not necessarily lower the blood glucose level during starvation. In recent years, it has been reported that carnitine-palmitoyl transferase (CPT) inhibitors have not only a hypoglycemic effect on various diabetic animals and diabetic patients (Hor . Metab. Res., vol.25, 9-12, 1993, JP-B-57-501233, JP-A-6-73077 , EP-0127098), but also an effect for lowering the blood glucose level during starvation (Metabolism, vol.40, 1185-1190, 1991). Therefore, they are noted as agents having an effect for lowering the blood glucose level during starvation, that hardly be achieved with conventional agents. The CPT inhibitors lower the blood glucose level in such a mechanism that they suppress gluconeogenesis in the liver independent of the insulin secretion from pancreas.
Therefore, it is expected that they are effective also for patients with deficiency of insulin secretion. It has also been confirmed that they have an effect to improve the lowered insulin sensitivity, i.e. glucose utilization, of the Type II diabetic patients (Horm. Metab. Res., vol.24; 115-118, 1992).
Said CPT inhibitors have an effect of effectively lowering the blood glucose level. However, their usefulness for preventing onset and progression of various complications caused by diabetes, such as diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy and the like, has not been completely proved. However, it has been reported that a CPT inhibitor suppresses the im uno pathological changes in kidney caused in db/db mice as models of Type II diabetes (Diabetes, vol.31, 12-18, 1982). Further, the progression of such complications is suppressed by strict control of blood glucose level. Accordingly, the CPT inhibitors are useful as pharmaceutical agents for preventing and treating such complications.
In addition, it has been proved that the CPT inhibitors have a strong effect for lowering ketone body level in the diabetic animals and diabetic patients (Proc. Soc. Exp. Biol. Med., vol.178, 288-296, 1985, Metabolism, vol.40, 1185-1190, 1991). It is expected that the CPT inhibitors inhibit all pathological conditions caused by cellular pathologically accelerated formation of ketone bodies as well as diabetes.
Under these circumstances, the present inventors have synthesized various 6-membered heterocyclic- compounds which are not disclosed in the above-mentioned literatures, and have studied the their properties. As the result, the present inventors have found a compound having more excellent hypoglycemic effect. Thus, the present invention provides 6-membered heterocyclic- compounds capable of preventing and treating diabetes mellitus and diabetic complications. DISCLOSURE OF THE INVENTION
Namely, the present invention relates to a 6- membered heterocyclic-compound or its salt represented by the formula [i] :
Figure imgf000005_0001
[wherein A is
Figure imgf000006_0001
{wherein each of m, n, n and n which are independent of one another, is 0, 1, 2 or 3 , R is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a sulfonic acid group, a sulfonamide group, P02H2, δ 6
P03H2 , a 5 - tetrazolyl group , C ( 0) OR ( R is a hydrogen
7 7' 7 T atom or a Cχ_7 alkyl group), C(0)NRR (each of R and R which are independent of each other, is a hydrogen atom
S 8 or a C1_7 alkyl group) , OR (R is a hydrogen atom, a C1_7
9 9' 9 alkyl group or a phenyl group) or NR R (each of R and
9'
R which are independent of each other, is a hydrogen
2 atom, a C,_7 alkyl group or a phenyl group) , R is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a guanidyl group, an amidino
10 10' , 10 10' group, NR R (each of R and R which are independent of each other, is a hydrogen atom, a C1 7 alkyl group, a C^, aliphatic acyl group, a C6_10 aromatic acyl group or a t 11 11' 11" 11 11' protecting group) or N R R R (each of R , R and
11' ' R which are independent of one another, is a C1_7 alkyl
3 3' group) , each of R and R which are independent of each other, is a Cχ_7 alkyl group, R is a hydrogen atom, a C^7 alkyl group, a Cχ_7 aliphatic acyl group, a C5_:3 aromatic acyl group or a protecting group};
D is a covalent bond, -CH,-, -0-, -S-, -S(0)-, -S(0)2-, -NR12-, -C(0)-NR12-, -NR12-C(0)- or -NR~'-C (0) -NR12 - (each of R12 and R12' which are independent of each other, is a hydrogen atom or a C^, alkyl group) ;
1 2 3 4 5 each of X , X , X , X and X which are independent of
5 f 5 . one another, is a nitrogen atom or CR \R is a hydrogen
1 13 13' 2 atom, a halogen atom or -E-G (E is -L - (CR R )k-L -
14 14' 3 (CR R ),-L - (k is from 1 to 10, 1 is from 0 to 10, and each of R , R , R ' and R which are independent of one another, is a hydrogen atom, a halogen atom, a hydroxyl group, a C1_7 alkyl group or a C1_7 alkoxy group, each of
1 2 3
L , L and L which are independent of one another, is a covalent bond, -0-, -S-, -S(0)-, -S(0)2-, -C(0)-, -C≡≡C-, -CR15=CRl3 -, -NR15-,-NR -C(O)-, -C(0)-NR - or -NR15-C(0)- NR - (each of R and R which are independent of each other, is a hydrogen atom, a C1_7 alkyl group or a C,_1 , aromatic group) ) , and G is a hydrogen atom, a C1_12 heteroaromatic group (said heteroaromatic group may contain at most 5 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms as constituents for the ring) , a C1_6 heteroalicyclic group (said heteroalicyclic group may contain at most 3 heteroatoms selected fror1 oxygen atoms, sulfur atoms and nitrogen atoms as constituents for the ring) , a C3_1C cycloalkyl group, a C3_7 cycloalkenyl group or a C,_1 aromatic group (said C1_12 heteroaromatic group, C:_, heteroalicyclic group, C3_10 cycloalkyl group, C,_7 cycloalkenyl group and C,_1 aromatic group may contain at most 5 substituents in total (said substituent is a hydrogen atom, a Cχ_7 alkyl group, a C3_7 cycloalkyl group, a C3_7 cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a C._7 alkoxy group, a C1 7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C1_3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C1_7 alkylsilyloxy group, phenyl, naphthyl, furyl, thienyl, imidazolyl; pyridyl or benzyl (each of said phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl may be substituted with at most 5 of C. _ alkyl groups, C3_7 cycloalkyl groups, Cχ_3 alkoxy groups, Cx_3 alkylthio groups, hydroxyl groups, halogen atoms, nitro groups and dimethylamino groups))))}, provided that at
1 5 . . η least one of X to X is a nitrogen atomj; and a pharmaceutical composition comprising it as an effective component . Substituents in the compound represented by the formula [I] are defined by illustrating examples, and preferred ones of each substituents are explained. However, the scope of the present invention is by no means limited to such examples.
Each substituent in the formula [I_ι is concretely illustrated hereinafter. A is
Figure imgf000009_0001
1 2 wherein each of m, n, n and n which are independent of one another, is 0, 1, 2 or 3 , and preferably 0 or 1; R may be a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a sulfonic acid group, a sulfonamide group, P02H2, P03H2, a 5-tetrazolyl
6 6 group, C(0)OR (R is a hydrogen atom or a Cχ_7 alkyl
7 7' 7 7' group), C(0)NRR (each of R and R which are independent of each other, is a hydrogen atom or a Cχ_7
S 3 . alkyl group) , OR (R is a hydrogen atom, a C1 7 alkyl
9 9' 9 9' group or a phenyl group) or NR R (each of R and R v/hich are independent of each other, is a hydrogen atom, a C1_7 alkyl group or a phenyl group) ; it is preferably a sulfonic acid group, PO,H2, a 5-
6 6 . tetrazolyl group or C(0)OR (R is a hydrogen atom or a C._7 alkyl group), it is more preferably C(0)0R° (R is a hydrogen atom or a Cχ_7 alkyl group) ; the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, it is preferably a fluorine atom, a chlorine atom or a bromine atom; the C1_7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like;
2
R may be a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a guanidyl group, an ami .dm. o group, NRιoR10' (,eac,h or R10 and R10' which are independent of each other, is a hydrogen atom, a C,_7 alkyl group, C1_7 aliphatic acyl, C6_10 aromatic acyl or a
+ 11 11' 11'' 11 11' protecting group) or N R R R (each of R , R and R which are independent of one another, is a C._7 alkyl group) ; it is preferably a guanidyl group, an amidino group,
10 10' . , 10 10'
NR R (wherein each of R and R which are independent of each other, is a hydrogen atom or a Cλ_7 alkyl group)
+ 11 11' 11" , ,. 11 11' 11" or N R R R (each of R , R and R which are independent of one another, is a C1_7 alkyl group) , it is
10 10' 10 10' more preferably NR R (each of R and R which are independent of each other, is a hydrogen atom or a C1 7
+ 11 11' 11" 11 11' 11" alkyl group) or N R R R (each of R , R and R which are independent of one another, is a C1 7 alkyl group) ; the Cχ_7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like; the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, it is preferably a fluorine atom, a chlorine atom or a bromine atom; each of R and R" which are independent of each other, may be a C1-7 alkyl group; the C1_1 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like;
4
R may be a hydrogen atom, a C1_7 alkyl group, C,_7 aliphatic acyl, C6_1„ aromatic acyl or a protecting group, it is preferably a hydrogen atom or a C1-7 alkyl group; the C1_7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like; the C1_7 aliphatic acyl may be formyl, acetyl, propionyl, butyryl , isobutyryl, valeryl, isovaleryl, pivaloyl or the like; the C6_10 aromatic acyl may be benzoyl, 2-toluoyl, 3- toluoyl, 4-toluoyl, α -naphthoyl , β -naphthoyl , cinnamoyl or the like; and the protecting group may be a Cχ_4 alkoxymethyl group (such as MOM: methoxymethyl, MEM: 2-methoxyethoxymethyl, ethoxymethyl , n-propoxymethyl , i-propoxymethyl , n- butoxymethyl , iBM: isobutyloxymethyl, BUM: t- butoxymethyl, POM: pivaloyloxymethyl or SEM: trimethylsilylethoxyr.ethyl, preferably e.g. a C._2 alkoxymethyl group), an aryloxymethyl group (such as 30M: benzyloxymethy1 , PMBM: p-methoxybenzyloxymethyl or p-AOM: P-anisyloxymethyl, preferably e.g. benzyloxymethyl) , a Cχ_4 alkylaminomethyl group (such as dimethylaminomethyl) a substituted acetamidomethyl group (such as Acm: acetamidomethyl or Tac : trimethylacetamidomethyl) , a substituted thiomethyl group (such as MTM: methylthiomethyl, PTM: phenylthiomethyl or Btm: benzylthiomethyl) , a carboxyl group, a C^ acyl group (such as formyl, acetyl, fluoroacetyl, difluoroacetyl , trifluoroacetyl, chloroacetyl, dichloroacetyl , trichloroacetyl, propionyl, Pv: pivaloyl or tigloyl) , an arylcarbonyl group (such as benzoyl, benzoylformyl, benzoylpropionyl or phenylpropionyl) , a Cχ_4 alkoxycarbonyl group (such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n- butoxycarbonyl , i-butoxycarbonyl , BOC : t-butoxycarbonyl , AOC: t-amyloxycarbonyl, VOC : vinyloxycarbonyl , AOC : allyloxycarbonyl, Teoc : 2- ( trimethylsilyl) ethoxycarbonyl or Troc : 2 , 2 , 2-trichloroethoxycarbonyl, preferably e.g. BOC), an aryloxycarbonyl group (such as Z: benzyloxycarbonyl , p-nitrobenzyloxycarbonyl or MOZ : p- methoxybenzyloxycarbonyl) , a C1 4 alkylaminocarbonyl group (methylcarbamoyl, Ec : ethylcarbamoyl or n- propylcarbamoyl) , an arylaminocarbonyl group (such as phenylcarbamoyl) , a trialkylsilyl group (such as TMS : trimethylsilyl, TES : triethylsilyl , TIPS: triisopropylsilyl, DEIPS: diethylisopropylsilyl , DMIPS: dimethylisopropylsilyl, DTBMS : di-t-butylmethylsilyl , IPDMS: isopropyldimethylsilyl, TBDMS : t- butyldimethylsilyl or TDS : thexyldimethylsilyl, preferably e.g. t-butyldimethylsilyl) , a trialkylarylsilyl group (such as DPMS : diphenylmethylsilyl, TBDPS : t-butyldiphenylsilyl, TBMPS : t-butyldimethoxyphenylsilyl or TPS : triphenylsilyl) , an alkylsulfonyl group (such as Ms: methanesulfonyl or ethanesulfonyl) , or an arylsulfonyl group (such as benzenesulfonyl, Ts : p-toluenesulfonyl, p- chlorobenzenesulfonyl, MBS: p-methoxybenzenesulfonyl , m- nitrobenzenesulfonyl , iMds : 2 , 6-dimethoxy-4- methylbenzenesulfonyl, Mds : 2 , 6-dimethyl-4- methoxybenzenesulfonyl, Mtb: 2,4,6- trimethoxybenzenesulfonyl, Mte : 2 , 3 , 5, 6-tetramethyl-4- methoxybenzenesulfonyl , Mtr : 2 , 3 , 6-trimethyl-4- methoxybenzenesulfonyl, Mts: 2,4,6- trimethylbenzenesulfonyl or Pme : pentamethylbenzenesulfonyl) , and it is preferably BOC, Z or the like.
D may be a covalent bond, -CH,-, -0-, -S-, -S(O)-, -S(0)2-, -NR -, -C(0)-NRX-, -NR -C(O)- or -NR -C{0)-
12' 12 12'
NR - (each of R and R which are independent of each other, is a hydrogen atom or a C^., alkyl group) ,
12 12 12 preferably -0-, -NR - or -C(0)-NR - (R is a hydrogen atom or a C1_7 alkyl group), more preferably -0- or -NH- . The Cλ_7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like.
Each of X , X , X , X and X which are independent of one another, may be a nitrogen atom or CR . Preferably,
1 3 5 each of X , X and X which are independent of one
2 another, may be a nitrogen atom or CH, and each of X and
4 5
X which are independent of each other, may be CR . More
4 5 5 preferably, X may be CR (R is a hydrogen atom or a halogen atom) . Here, at least one of X to X is a nitrogen atom.
5
R may be a hydrogen atom, a halogen atom or -E-G.
The halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.
1 13 13' 2 14 14' 3 E is -L-(CR R )k-L-(CR R ) χ-L - . k is from 1 to '10. 1 is from 0 to 10.
13 13' 14 14'
Each of R , R , R and R wnich are independent of one another, may be a hydrogen atom, a halogen atom, a hydroxyl group, a C^ alkyl group or a C1 7 alkoxy group.
13 13' 14 14' Preferably, each of R , R , R , and R which are independent of one another, may be a hydrogen atom, a C1 7 alkyl group or a Cχ_7 alkoxy group.
The halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.
The Cχ_7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like.
The Cχ_7 alkoxy group may be methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t- butoxy, pentyloxy, hexyloxy, heptyloxy or the like.
1 2 3 , Each of L , L , and L which are independent of one another, may be a covalent bond, -0-, -S-, -S(0)-, -S(0)2-, -C(0)-, -C≡C-, -CR15=CR15 -, -NR15-, -NR^-C (0) - , -C(0)-NR15- or -NR15-C(0)-NR~3 - (each of R1 and Rl3' which are independent of each other, is a hydrogen atom, a C,_7 alkyl group or a C6^14 aromatic group) . Preferably, each
1 2 3 of L , L and L which are independent of one another, may be a covalent bond, -0-, -C(0)-, -CR D=CR -, -NR" -, -NR -C(0)- or -C(0)-NR - (each of R and R which are independent of each other, is a hydrogen atom or a C,_7 alkyl group) .
The C1_7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl or n-heptyl .
The C6_14 aromatic group may be phenyl, α -naphthyl, β -naphthyl, 1-indenyl, 2-indenyl, 3-indenyl, 4-indenyl, 5-indenyl, 6-indenyl, 7-indenyl, 1-indanyl, 2-indanyl, 4- indanyl, 5-indanyl, 1-fluorenyl, 2-fluorenyl, 3- fluorenyl, 4-fluorenyl, 9-fluorenyl or the like.
As a specific example of E,
R15 R15
— 0-(CH2)k-o— , -0-(CH2)k-N_ , _N_(CH2)k-o— -
R .1 '5 J R 15' R150 15
II
— -(CH2)k-N. -O-(CH2)k. ■N-c- -0-(CH2)k-c R 15 R150 , 15 0 R 15' - CHZJK-N-C- ■N-(CH2)k-c-N- -(CH2)k-o-
,15 R150 O R 5
-(CH2)k-N_ II ■(CHzJk-N-c- -(CH2)k- -C-N—
O O R15
-(CH2)κ- , _£-(CH2)k-o- , -C-(CH2)k-N_
_
Figure imgf000016_0001
,
O R15 O R 5 O R15 R15'
■C-N-(CH2)k- _έ-N-(CH2)k-o- -C-N-(CH2)k-N_ ,
Figure imgf000016_0002
Figure imgf000016_0003
CH2)k_
O R15
-C-(CH2)k- , -c=C-(CH2)k-0- or -c=C-(CH2)k-N_
wherein k is from 1 to 10, and each of R and R" which are independent of each other, is a hydrogen atom or a C1 7 alkyl group, may be mentioned, and preferably
R15 Ri5
—0-(CH2)k-0— , —0-(CH2)k-N_ , _N_(CH2)k-o— ,
R15 R15' R15
-N-(CH2)k-N_ , _(CH2)k-0- , -(CH2)k-N_ , —O-CCHZJK— , —N-CCH^k— or —(CHaJk-
15 15' wherein k is from 1 to 10, and each of R and R which are independent of each other, is a hydrogen atom or a C1_1 alkyl group, may be mentioned.
G may be a hydrogen atom, a C3_10 cycloalkyl group, a C3_7 cycloalkenyl group, a Cs_14 aromatic group, a C_12 heteroaromatic group or a C4_12 heteroalicyclic group, preferably a hydrogen atom, a C5_14 aromatic group, a C4_12 heteroaromatic group or a C4_12 heteroalicyclic group .
As G, in addition to a hydrogen atom, the following may be mentioned; the C3_1Q cycloalkyl group may be cyclopropyl, 1- methylcyclopropyl, 2-methylcyclopropyl , 4- methylcyclohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[2.2. ljheptyl , bicyclo[3. i . ljheptyl , bicyclo[2.2.2]octyl, 1-adamantyl or 2-adamantyl, and the C6_10 cycloalkyl group may be preferably cyclohexyl, bicyclo[2.2. ljheptyl , bicyclo[3.1. ljheptyl , bicyclo[2.2.2]octyl, 1-adamantyl or 2-adamantyl; either of them may have at most 5 substituents in total (said substituent is a hydrogen atom, a C,_7 alkyl group, a C,_7 cycloalkyl group, a C3_7 cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a D hydroxyl group, a C._7 alkoxy group, a C^. alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C1_, alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C1_7 alkylsilyloxy group, phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (each of said phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl may be substituted with at most 5 of C1_7 alkyl groups, C3_7 cycloalkyl groups, C1_3 alkoxy groups, C,_, alkylthio groups, hydroxyl groups, halogen atoms, nitro groups and dimethylamino groups) ) ; the C3_7 cycloalkenyl group may be cyclohexenyl (said cyclohexenyl may be' 1-cyclohexenyl , 2-cyclohexenyl or 3- cyclohexenyl) , cyclopentadienyl, 2-bicyclo[2.2. ijheptenyl or 2 , 5-bicyclo[2.2. ljheptadienyl ; each of them may have at most 5 substituents in total (said substituent is a hydrogen atom, a C^ alkyl group, a C3 7 cycloalkyl group, a C3_7 cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a Cχ_7 alkoxy group, a Cχ_7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a Cχ_3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-Cχ_7 alkylsilyloxy group, phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (each of said phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl may be substituted with at most 5 of Cχ_7 alkyl groups, C3_7 cycloalkyl groups, C1_3 alkoxy groups, Cχ_3 alkylthio groups, hydroxyl groups, halogen atoms, nitro groups and dimethylamino groups) ) ; the C6_14 aromatic group may be phenyl, naphthyl ( α - naphthyl, β -naphthyl ) , indenyl (1-indenyl, 2-indenyl, 3- indenyl, 4-indenyl, 5-indenyl, 6-indenyl, 7-indenyl), indanyl (1-indanyl, 2-indanyl, 4-indanyl, 5-indanyl) or fluorenyl (1-fluorenyl, 2-fluorenyl, 3-fluorenyl, 4- fluorenyl, 9-fluorenyl) ; and preferably the C5_14 aromatic group may be phenyl, naphthyl (α -naphthyl, β -naphthyl) or fluorenyl (1-fluorenyl, 2-fluorenyl, 3-fluorenyl, 4- fluorenyl, 9-fluorenyl ) ; either of them may have at most 5 substituents in total (said substituent is a hydrogen atom, a C1 7 alkyl group, a C3 7 cycloalkyl group, a C3_7 cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a Cχ_7 alkoxy group, a Cχ_7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a Cn_, alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C1_7 alkylsilyloxy group, phenyl, naphthyl, furanyl, thienyl, imidazolyl, pyridyl or benzyl (each of said phenyl, naphthyl, furanyl , thienyl, imidazolyl, pyridyl and benzyl may be substituted with at most 5 of Cχ_7 alkyl groups, C3_7 cycloalkyl groups, C1_3 alkoxy groups, Cχ_3 alkylthio groups, hydroxyl groups, halogen atoms, nitro groups and dimethylamino groups)); the C1_12 heteroaromatic group means a 5- to 15- membered monocyclic or condensed-ring heteroaromatic group which may contain at most 5 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms, as constituents for the ring; specifically, it may be furyl (2-furyl, 3-furyl) , thienyl (2-thienyl, 3-thienyl), pyrrolyl (1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl) , oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl) , thiazolyl (2- thiazolyl, 4-thiazolyl, 5-thiazolyl) , isoxazolyl (3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl) , isothiazolyl (3- isothiazolyl, 4-isothiazolyl, 5-isothiazolyl) , furazanyl (3-furazanyl) , pyrazolyl (1-pyrazolyl, 3-pyrazolyl, 4- pyrazolyl) , oxopyrazolyl (3-oxopyrazol-l-yl , 3- oxopyrazol-2-yl, 3-oxopyrazol-3-yl , 3-oxopyrazol-4-yl , 4- oxopyrazol-3-yl) , imidazolyl ( 1-imidazolyl , 2-imidazolyl, 4-imidazolyl) , oxoimidazolyl (2-oxoimidazol-l-yl , 2- oxoimidazol-4-yl) , triazolyl ( 1 , 2 , 3-triazol-l-yl , 1,2,3- triazol-2-yl, 1 , 2 , 3-triazol-4-yl , 1 , 2 , 4-triazol-l-yl , l,2,4-triazol-3-yl, 1, 2 , 4-triazol-4-yl) , oxotriazolyl (3- oxo-1,2,4 (2H,4H)-triazol-2-yl, 3-oxo-l,2,4 (2H,4H)- triazol-4-yl, 3-oxo-l, 2 , 4 (2H, 4H) -triazol-5-yl , 3-oxo- l,2,4(lH,2H)-triazol-l-yl, 3-oxo-l, 2, 4 (1H,2H) -triazol-2- yl, 3-oxo-l,2,4 (IH, 2H) -triazol-5-yl) , tetrazolyl (1- tetrazolyl, 2-tetrazolyl, 5-tetrazolyl) , pyranyl (2- pyranyl, 3-pyranyl, 4-pyranyl) , pyridyl (2-pyridyl, 3- pyridyl, 4-pyridyl ) , pyridonyl (2-pyridon-l-yl , 2- pyridon-3-yl, 2-pyridon-4-yl, 2-pyridon-5-yl, 2-pyridon- 6-yl, 4-pyridon-l-yl, 4-pyridon-2-yl , 4-pyridon-3-yl) , pyridazinyl (3-pyridazinyl, 4-pyridazinyl) , pyridazinonyl (3 (2H) -pyridazinon-2-yl, 3 (2H) -pyridazinon-4-yl , 3(2H)- pyridazinon-5-yl, 3 (2H) -pyridazinon-6-yl, 4(1H)- pyridazinon-1-yl, 4 (IH) -pyridazinon-3-yl , 4(1H)- pyridazinon-5-yl , (IH) -pyridazinon-6-yl ) , pyrimidinyl (2-pyrimidinyl , 4-pyrimidinyl , 5-pyrimidinyl ) , pyrimidinonyl (2 (IH) -pyrimidinon-1-yl, 2 ( IH) -pyrimidinon- 4-yl, 2 (IH) -pyrimidinon-5-yl, 2 ( IH) -pyrimidinon-6-yl , 4 (3H) -pyrimidinon-2-yl, 4 (3H) -pyrimidinon-3-yl , 4(3H)- pyrimidinon-5-yl, 4 (3H) -pyrimidinon-6-yl , 4(1H)- pyrimidinon-1-yl, 4 (IH) -pyrimidinon-2-yl , 4(1H)- pyrimidinon-5-yl , 4 (IH) -pyrimidinon-6-yl) , pyrazinyl (2- pyrazinyl, 2 (IH) -pyrazin-1-yl, 2 ( IH) -pyrazin-3-yl, 2(1H)- pyrazin-5-yl, 2 (IH) -pyrazin-6-yl) , triazinyl (1,2,3- triazin-4-yl, 1, 2 , 3-triazin-5-yl , 1 , 2 , 4-triazin-3-yl , 1, 2, 4-triazin-5-yl, 1, 2 , 4-triazin-6-yl ) , tetrazinyl (1, 2, 3 , 4-tetrazin-5-yl, 1, 2 , 4 , 5-tetrazin-3-yl ) , indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl) , quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8- quinolyl) , quinolonyl (2-quinolon-l-yl, 2-quinolon-3-yl, 2-quinolon-4-yl, 2-quinolon-5-yl, 2-quinolon-6-yl , 2- quinolon-7-yl, 2-quinolon-8-yl , 4-quinolon-l-yl, 4- quinolon-2-yl, 4-quinolon-3-yl , 4-quinolon-5-yl , 4- quinolon-6-yl, 4-quinolon-7-yl, 4-quinolon-8-yl) , benzofuranyl (2-benzofuranyl , 3-benzofuranyl, 4- benzofuranyl, 5-benzofuranyl , 6-benzofuranyl, 7- benzofuranyl) , benzothienyl (2-benzothienyl, 3- benzothienyl, 4-benzothienyl , 5-benzothienyl , 6- benzothienyl, 7-benzothienyl) , isoquinolyl (1- isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl , 8-isoquinolyl) , isoquinolonyl (l-is©quinolon-2-yl , l-isoquinolon-3-yl , 1- isoquinolon-4-yl, l-isoquinolon-5-yl, l-isoquinolon-6-yl , l-isoquinolon-7-yl, l-isoquinolon-8-yl , 3-isoquinolon-2- yl, 3-isoquinolon-4-yl , 3-isoquinolon-5-yl, 3- isoquinolon-6-yl, 3-isoquinolon-7-yl , 3-isoquinolon-8- yl), benzoxazolyl (2-benzoxazolyl , 4-benzoxazolyl , 5- benzoxazolyl, 6-benzoxazolyl , 7-benzoxazolyl) , benzothiazolyl (2-benzothiazolyl , 4-benzothiazolyl , 5- benzothiazolyl, 6-benzothiazolyl , 7-benzothiazolyl ) , benzopyrazolyl (1-benzopyrazolyl, 2-benzopyrazolyl, 3- benzopyrazolyl, 4-benzopyrazolyl , 5-benzopyrazolyl , 6- benzopyrazolyl, 7-benzopyrazolyl) , benzimidazolyl (1- benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5- benzimidazolyl) , benzotriazolyl ( 1-benzotriazolyl, 4- benzotriazolyl, 5-benzotriazolyl) , benzopyranyl (2- benzopyranyl, 3-benzopyranyl, 4-benzopyranyl, 5- benzopyranyl, 6-benzopyranyl, 7-benzopyranyl , 8- benzopyranyl) , indolizinyl (1-indolizinyl, 2-indolizinyl, 3-indolizinyl , 5-indolizinyl , 6-indolizinyl, 7- indolizinyl, 8-indolizinyl) , purinyl (2-purinyl, 6- purinyl, 7-purinyl, 8-purinyl), phthalazinyl (1- phthalazinyl, 5-phthalazinyl, 6-phthalazinyl) , oxophthalazinyl (l-oxophthalazin-2-yl, l-oxophthalazin-4- yl, l-oxophthalazin-5-yl, l-oxophthalazin-6-yl , 1- oxophthalazin-7-yl , l-oxophthalazin-8-yl) , naphthyridinyl (2-naphthyridinyl, 3-naphthyridinyl, 4-naphthyridinyl ) , quinoxalinyl (2-quinoxalinyl, 5-quinoxalinyl , 6- quinoxalinyl) , quinazolinyl (2-quinazolinyl , 4- quinazolinyl, 5-quinazolinyl, 6-quinazolinyl , 7- quinazolinyl , 8-quinazolinyl) , cinnolinyl (3-cinnolinyl , 4-cinnolinyl , 5-cinnolinyl, 6-cinnolinyl , 7-cinnolinyl , 8-cinnolinyl) , benzodioxolyl (1, 3-benzodioxol-4-yl, 1,3- benzodioxol-5-yl) , benzodioxanyl (1 , 4-benzodioxan-2-yl , 1, 4-benzodioxan-5-yl , 1, 4-benzodioxan-6-yl) , oxonaphthalenyl (1 , 4-oxonaphthalen-2-yl , 1,4- oxonaphthalen-5-yl , 1 , 4-oxonaphthalen-6-yl) , 2,3- dihydrobenzofuranyl (2 , 3-dihydro-4-benzofuranyl , 2,3- dihydro-5-benzofuranyl, 2 , 3-dihydro-6-benzofuranyl, 2,3- dihydro-7-benzofuranyl) , benzothiazinyl (1,4- benzothiazin-2-yl, 1, 4-benzothiazin-3-yl , 1,4- benzothiazin-4-yl, 1 , 4-benzothiazin-5-yl , 1,4- benzothiazin-6-yl, 1, 4-benzothiazin-7-yl, 1,4- benzothiazin-8-yl) , pteridinyl (2-pteridinyl , 4- pteridinyl, 6-pteridinyl, 7-pteridinyl), pyrazolo[l, 5- ajpyrimidinyl (pyrazolo[l, 5-ajpyrimidin-2-yl , pyrazolo[l, 5-ajpyrimidin-3-yl, pyrazoloCl, 5-ajpyrimidin-5- yl, pyrazolo[l, 5-ajpyrimidin-6-yl, pyrazoloCl, 5- ajpyrimidin-7-yl) , pyrazolo[5 , 1-cj [l, 2 , 4jtriazinyl (pyrazolo[5, 1-c] [l, 2, 4Jtriazin-3-yl, pyrazolo[5 , 1-cj
[1,2, 4Jtriazin-4-yl, pyrazolo[5, 1-cj [l, 2, 4Jtriazin-7-yl, pyrazolo[5, 1-cj [l, 2, 4Jtriazin-8-yl) , thiazolo[3, 2- bjtriazolyl ( thiazolo[3 , 2-bjtriazol-2-yl, thiazolo[3 , 2- bjtriazol-5-yl, thiazolo[3 , 2-bjtriazol-6-yl) , benzopyrano[2, 3-bjpyridyl (benzopyrano[2 , 3-b]pyridin-2-yl , benzopyrano[2, 3-bjpyridin- 3 -yl, benzopyrano[2 , 3-bjpyridin- 4-yl, benzopyrano[2 , 3-bjpyridin- 5 -yl, benzopyrano[2 , 3- bjpyridin-6-yl , benzopyrano[2 , 3-bjpyridin-7-yl , benzopyrano[2 , 3-bjpyridin-8-yl, benzopyrano[2 , 3-bjpyridin- 9-yl) , 5H-5-oxo-benzopyrano[2 , 3-bjpyridyl (5H-5-oxo- benzopyrano[2 , 3-bjpyridin-2-yl , 5H-5-oxo-benzopyrano[2 , 3- b]pyridin-3-yl , 5H-5-oxo-benzopyrano[2 , 3-b]pyridin-4-yl , 5H-5-oxo-benzopyrano[2 , 3-bjpyridin-6-yl , 5H-5-oxo- benzopyrano[2 , 3-bjpyridin-7-yl , 5H-5-oxo-benzopyranoL2 , 3- b]pyridin-8-yl) , xanthenyl ( 1-xanthenyl , 2-xanthenyl, 3- xanthenyl , 4 -xanthenyl, 9 -xanthenyl ) , phenoxathiinyl (1- phenoxathiinyl , 2-phenoxathiinyl , 3 -phenoxathiinyl , 4- phenoxathiinyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl, 9-carbazolyl) , acridinyl (1- acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9- acridinyl) , phenazinyl (1-phenazinyl, 2-phenazinyl , 3- phenazinyl, 4-phenazinyl) , phenothiazinyl (1- phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4- phenothiazinyl, 10-phenothiazinyl) , phenoxazinyl (1- phenoxazinyl, 2-phenoxazinyl , 3-phenoxazinyl, 4- phenoxazinyl, 10-phenoxazinyl) , thianthrenyl (1- thianthrenyl, 2-thianthrenyl, 3 -thianthrenyl , 4- thianthrenyl, 6-thianthrenyl, 7-thianthrenyl , 8- thianthrenyl , 9-thianthrenyl) or the like; the preferred Cχ_12 heteroaromatic group may be furyl (2-furyl, 3-furyl), thienyl (2-thienyl, 3-thienyl), pyrrolyl (1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl) , thiazolyl (2- thiazolyl, 4-thiazolyl, 5-thiazolyl) , isoxazolyl (3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), isothiazolyl (3- isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl , 4-imidazolyl) , pyridyl (2- pyridyl, 3-pyridyl, 4-pyridyl) , pyridazinyl (3- pyridazinyl, 4-pyridazinyl), pyridazinonyl (3(2H)- pyridazinon-2-yl, 3 (2H) -pyridazinon-4-yl , 3(2H)- pyridazinon-5-yl, 3 (2H) -pyridazinon-6-yl) , pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl , 5-pyrimidinyl) , pyrazinyl (2-pyrazinyl) , indolyl (1-indolyl, 2-indolyl, 3-incolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), quinolyl (2- quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl) , benzoxazolyl (2-benzoxazolyl , 4- benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7- benzoxazolyl) , benzothiazolyl (2-benzothiazolyl, 4- benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7- benzothiazolyl) , benzimidazolyl (1-benzimidazolyl, 2- benzimidazolyl, 4-benzimidazolyl , 5-benzimidazolyl) , phthalazinyl (1-phthalazinyl, 5-phthalazinyl, 6- phthalazinyl) , quinoxalinyl (2-quinoxalinyl, 5- quinoxalinyl, 6 -quinoxalinyl) , benzodioxolyl (1,3- benzodioxol-4-yl, 1 , 3-benzodioxol-5-yl) , benzothiazinyl (1, 4-benzothiazin-2-yl, 1 , 4-benzothiazin-3-yl , 1,4- benzothiazin-4-yl, 1, 4-benzothiazin-5-yl, 1,4- benzothiazin-6-yl, 1, 4-benzothiazin-7-yl , 1,4- benzothiazin-8-yl) , pyrazolo[l, 5-ajpyrimidinyl
(pyrazolo[l, 5-ajpyrimidin-2-yl, pyrazolo[l, 5-ajpyrimidin- 3-yl, pyrazolo[l, 5-ajpyrimidin-5-yl , pyrazolo[l , 5- a]pyrimidin-6-yl, pyrazolo[l , 5-ajpyrimidin-7-yl) , pyrazolo[5, 1-cj [l, 2 , 4]triazinyl (pyrazolo[5, 1-cj [l, 2 , 4Jtriazin-3-yl, pyrazolo[5 , 1-c] [l , 2 , 4Jtriazin-4-yl , pyrazolo[5, 1-c] [l, 2 , 4Jtriazin-7-yl , pyrazolo[5, 1-cj [l, 2, 4Jtriazin-8-yl) , thiazolo[3 , 2-b]triazolyl ( thiazolo[3 , 2-b]triazol-2-yl , thiazolo[3 , 2-b]triazol-5-yl , thiazolo[3 , 2-b]triazol-6-yl) , benzopyrano[2 , 3-bjpyridyl (benzopyrano[2 , 3-b]pyridin-2-yl , benzopyrano[2 , 3- bjpyridin-3-yl , benzopyrano[2 , 3-b]pyridin-4-yl , benzopyrano[2 , 3-bjpyridin-5-yl, benzopyrano[2 , 3-bjpyridin- 6-yl, benzopyrano[2 , 3-b]pyridin-7-yl, benzopyrano[2 , 3- bjpyridin-8-yl, benzopyrano[2 , 3-bjpyridin-9-yl) or the like; and either of them may have at most 5 substituents in total (said substituent is a hydrogen atom, a Cχ_7 alkyl group, a C3_7 cycloalkyl group, a C3_7 cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a Cχ_7 alkoxy group, a C1 7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C1 3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C1 7 alkylsilyloxy group, phenyl, naphthyl, furanyl, thienyl, imidazolyl, pyridyl or benzyl (each of said phenyl, naphthyl, furanyl, thienyl, imidazolyl, pyridyl and benzyl may be substituted with at most 5 of Cχ_7 alkyl groups, C3_7 cycloalkyl groups, Cχ_3 alkoxy groups, C,_, alkylthio groups, hydroxyl groups, halogen atoms, nitro groups and dimethylamino groups) ) ; and the Cχ_6 heteroalicyclic group means a 3- to 8- membered monocyclic or condensed bicyclic heterocycle which may contain at most 3 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms, as constituents for the ring; specifically, it may be piperidyl (1-piperidyl , 2-piperidyl, 3-piperidyl, 4- piperidyl) , pyrrolidinyl (1-pyrrolidinyl , 2-pyrrolidinyl, 3-pyrrolidinyl) , imidazolidinyl (1-imidazolidinyl , 2- imidazolidinyl, 4-imidazolidinyl) , pyrazolidinyl (1- pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl) , morpholinyl (2-morpholinyl, 3-morpholinyl , 4- morpholinyl) , tetrahydrofuranyl ( 2-tetrahydrofuranyl, 3- tetrahydrofuranyl) or the like; and either of them may have at most 5 substituents in total (said substituent is a hydrogen atom, a Cχ_7 alkyl group, a C3_7 cycloalkyl group, a C3_7 cycloalkenyl group, (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a Cχ_7 alkoxy group, a C1 7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a Cχ_3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-Cχ_7 alkylsilyloxy group, phenyl, naphthyl, furanyl, thienyl, imidazolyl, pyridyl or benzyl (each of said phenyl, naphthyl, furanyl, thienyl, imidazolyl, pyridyl and benzyl may be substituted with at most 5 of C17 alkyl groups, C3 7 cycloalkyl groups, Cχ_3 alkoxy groups, Cχ_3 alkylthio groups, hydroxyl groups, halogen atoms, nitro groups and dimethylamino groups)). As Ra, R and R°; the Cχ_7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like, preferably it may be methyl, ethyl, n-propyl or the like, and either of them may be substituted with a hydroxyl group; the C3_7 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2. ljheptyl, bicyclo[3.1. ljheptyl or the like, preferably it may be cyclopropyl, cyclohexyl or the like, and either of them may be substituted with a hydroxyl group; the C3_7 cycloalkenyl group may be 1-cyclohexenyl, 2- cyclohexenyl, 3-cyclohexenyl , cyclopentadienyl, 2- bicyclo[2.2. ijheptenyl, 2 , 5-bicyclo[2.2. ljheptadienyl or the like, and either of them may be substituted with a hydroxyl group; the Cχ_7 alkoxy group may be methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t- butoxy, pentyloxy, hexyloxy, heptyloxy or the like; the C1_7 alkylthio group may be methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i- butylthio, s-butylthio, t-butylthio, pentylthio, hexylthio, heptylthio, or the like; the tri-Cχ_7 alkylsilyloxy group may be trimethylsilyloxy, triethylsilyloxy, triisopropylsilyloxy, diethylisopropylsilyloxy, dimethylisopropylsilyloxy, di- t-butylmethylsilyloxy, isopropyldimethylsilyloxy, t-butyldimethylsilyloxy, thexyldimethylsilyloxy or the like, and preferably it may be t-butyldimethylsilyloxy or the like; the naphthyl group may be a -naphthyl group and a β -naphthyl group, the furanyl group may be a 2-furanyl group or a 3-furanyl group, the thienyl group may be a 2- thienyl group or a 3-thienyl group, the imidazolyl group may be a 1-imidazolyl group, a 2-imidazolyl group or a 4- imidazolyl group, the pyridyl group may be a 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group, and either of them may be substituted with at most 5 of C1-7 alkyl groups, C3_7 cycloalkyl groups, C1_3 alkoxy groups, C, , alkylthio groups, hydroxyl groups, fluorine atoms, chlorine atoms, bromine atoms, nitro groups and dimethylamino groups ; the phenyl group and the benzyl group may be substituted with at' most 5 of Cχ_7 alkyl groups, C3_7 cycloalkyl groups, Cχ_3 alkoxy groups, C1 3 alkylthio groups, hydroxyl groups, fluorine atoms, chlorine atoms, bromine atoms, nitro groups and dimethylamino groups; the C1_3 alkoxycarbonyl group may be methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or the like; and the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, chlorine atom or a bromine atom.
In the present specification, 'n' means normal, 'i' means iso, 's' means secondary, 't' means tertiary, 'c' means cyclo, 'Me' means a methyl group, Εt' means an ethyl group, 'Pr' means a propyl group, 'Bu' means a butyl group, 'Pen' means a pentyl group, 'Hex' means a hexyl group, 'Ph' means a phenyl group, and 'Hal'means a halogen atom.
Preferred examples (1) to (8) of the compound represented by the formula [i] of the present invention are further illustrated hereinafter.
(1) A 6-membered heterocyclic-compound or its salt represented by the formula [ij, wherein as G, the C3_10 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[2.2. ljheptyl , bicyclo[3.1. ljheptyl , bicyclo[2.2.2]octyl or adamantyl , the C3_7 cycloalkenyl group is cyclohexenyl, cyclopentadienyl, 2- bicyclo[2.2. ijheptenyl or 2 , 5-bicyclo[2.2. ljheptadienyl , the C6_14 aromatic group is phenyl, naphthyl, indenyl, indanyl or fluorenyl, the C1_12 heteroaromatic group is furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furazanyl, pyrazolyl, oxopyrazolyl , imidazolyl, oxoimidazolyl, triazolyl, oxotriazolyl, tetrazolyl, pyranyl, pyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrimidinyl, pyrimidinonyi , pyrazinyl, triazinyl, tetrazinyl, indolyl, quinolyl, quinolonyl, benzofuranyl , benzothienyl, isoquinolyl, isoquinolonyl , benzoxazolyl , benzothiazolyl, benzopyrazolyl, benzimidazolyl , benzotriazolyl , benzopyranyl, indolizinyl, purinyl, phtharazinyl, oxophtharazinyl , naphthylidinyl , quinoxalinyl, quinazolinyl, cinnolinyl, benzodioxolyl , benzodioxanyl, oxonaphthalenyl , dihydrobenzofuranyl, benzothiazinyl, pteridinyl, pyrazolo[l, 5-a]pyrimidinyl , pyrazolo[5 , 1-c] [1,2, 4jtriazinyl, thiazolo[3 , 2-b]triazolyl, benzopyrano[2 , 3-bjpyridyl , 5H-oxo-benzopyrano [2, 3-bjpyridyl, xanthenyl, phenoxathiinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or thianthrenyl, and the CA_6 heteroalicyclic group is piperidyl, pyrrolidinyl , imidazolidinyl, pyrazolidinyl, morpholinyl or tetrahydrofuranyl, and the above-described C 3-ιo cycloalkyl group, C,_7 cycloalkenyl group, C6 1 aromatic group, Cχ_χ2 heteroaromatic group and Cχ_, heteroalicyclic group may have at most 5 substituents in total (wherein said- substituent is a hydrogen atom, a Cχ_7 alkyl group, a C3_7 cycloalkyl group, a C3_7 cycloalkenyl group (each of said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a C1 7 alkoxy group, a C1 7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C,_, alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-Cχ_7 alkylsilyloxy group, phenyl, naphthyl, furanyl, thienyl, imidazolyl, pyridyl or benzyl (said phenyl, naphthyl, furanyl, thienyl, imidazolyl, pyridyl and benzyl may be substituted with at most 5 of C1_7 alkyl groups, C3,7 cycloalkyl groups, C1_3 alkoxy groups, Cχ_, alkylthio groups, hydroxyl groups, halogen atoms, nitro groups and dimethylamino groups) ) .
(2) The 6-membered heterocyclic-compound or its salt as defined in the above-mentioned (1), wherein G is a hydrogen atom,
Figure imgf000033_0001
Figure imgf000034_0001
[wherein each of R and R which are independent of each- other, is a hydrogen atom, a Cχ_7 alkyl group, a C._7 cycloalkyl group, a C3_7 cycloalkenyl group (each of said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a C1_7 alkoxy group, a C,_7 alkylthio group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C, alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C1_7 alkylsilyloxy group, phenyl, α -naphthyl , β - naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (each of said phenyl, α -naphthyl, β -naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl may be substituted with at most 5 of C1_7 alkyl groups, C,_7 cycloalkyl groups, C,_3 alkoxy groups, Cχ 3 alkylthio groups, hydroxyl groups, fluorine atoms, chlorine atoms, bromine atoms, nitro groups and dimethylamino groups), c and R is a hydrogen atom, a Cχ_7 alkyl group, a C3 _ cycloalkyl group or a hydroxymethyl group].
(3) The 6-membered heterocyclic-compound or its salt as defined in the above-mentioned (2), wherein G is a hydrogen atom,
Figure imgf000035_0001
Figure imgf000036_0001
r a D
Lwherein each of R and R which are independent of each other, is a hydrogen atom, a C1 7 alkyl group, a C3 7 cycloalkyl group, a C3_7 cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a C,_7 alkoxy group, a C1_1 alkylthio group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a Cχ_3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C1_7 alkylsilyloxy group, phenyl, -naphthyl, β - naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (each of said phenyl, α -naphthyl, -naphthyl , furyl, thienyl, imidazolyl, pyridyl and benzyl may be substituted with at most 5 of Cχ_7 alkyl groups, C,_7 cycloalkyl groups, Cχ_3 alkoxy groups, C1 3 alkylthio groups, hydroxyl groups, fluorine atoms, chlorine atoms, bromine atoms, nitro groups and dimethylamino groups), c and R is a hydrogen atom, a C^, alkyl group, a C,_7 cycloalkyl group or a hydroxymethyl group].
(4) The 6-membered heterocyclic-compound or its salt as defined in the above-mentioned (3), wherein R~ is a sulfonic acid group, P03H2, a 5-tetrazolyl group, C(0)OR
6 2
(wherein R is a hydrogen atom or a C17 alkyl group) , R
10 10' is a guanidyl group, an amidmo group, NR R (wherein
10 10' each of R and R which are independent of each other, is a hydrogen atom or a C1 7 al -, ,kyl, group) or N+RIIR11'R11' ■
11 11 ' 11' ' (wherein each of R , R and R which are independent of one another, is a C._7 alkyl group), R is a hydrogen atom or a C1_1 alkyl group, D is -0- , -NR
Figure imgf000037_0001
- (wherein R" is a hydrogen atom or a C,_7 alkyl group),
13 13' 14 14' each of R , R , R and R which are independent of one another, is a hydrogen atom, a C1-7 alkyl group or a C,_7
1 2 3 alkoxy group, and each of L , and L which are independent of one another, is a covalent bond, -0- , -C(0)-, -CR15=CRlD -, -NR15-, -NR15-C(0)- or -C(0)-NR15-
15 15'
(wherein each of R and R which are independent of each other, is a hydrogen atom or a C1_1 alkyl group) .
(5) The 6-membered heterocyclic-compound or its salt as defined in the above-mentioned (4), wherein E is
R15 R15
— O-(CH2)k-O- • -o-(CH2)k-N— , _N-(CH2)k-0- -
.15 15' R150 O R15
R 1" R
-N-(CH2)k-N_ -0-(CH2)k-N_C- -0-(CH2)k-c-N-
15 O R 15'
R15 R15? R
-N-(CH2)κ-N-C- N-(CH2)k-C-N -(CH2)k-o-
R 15 R150 O R15
_(CH2)k-N— , _(CH2)k-N-C— , -(CH2)k-C-N— ,
O O R15
(CH2)k- , -C-(CH2)k-0- • -C-(CH2)k-N_ ,
R150 R150 R15' R1 Et>
-N-C-(CH2)k-o- - -N-C-(CH2)k-N_ , _N-C-(CH2)k-
_
Figure imgf000038_0001
Figure imgf000039_0001
H H ° R 15 R15
— C=C-C-N-(CH2)k-0- - — 0-(CH2)k- , _N-(CH2)k-
O M w 15
-C-(CH2)k- , -C-C-(CH2)k-0- or ~C=C-(CH2)k-N_
I- 15 15 '
Lwherein k is from 1 to 10, and each of R and R which are independent of each other, is a hydrogen atom or a C1 7 alkyl group] .
(6) The 6-membered heterocyclic-compound or its salt as defined in the above-mentioned (5), wherein each of
1 3 5
X , X and X which are independent of one another, is a
2 4 nitrogen atom or CH, and each of X and X which are independent of each other, is CR .
(7) The 6-membered heterocyclic-compound or its salt as defined in the above-mentioned (6), wherein E is
R 15 R15
-0-(CH2)k-0- . -0-(CH2)k-N_ , _N-(CH2)k-o- ,
R15 R15' R15
-N-(CH2)κ-N— _(CH2)k-0- .(CH2)k-N-
R 15
-O-(CH2)k- , _N_(CH2)k- or -(CH2)k—
15
[wherein k is from 1 to 10, and each of R and R" which are independent of each other, is a hydrogen atom or a C.._7 alkyl group].
(8) The 6-membered heterocyclic-compound or its salt as defined in the above-mentioned (7) , wherein each of m,
1 2 n, n and n which are independent of one another, is 0
1 δ . 6 , or 1, R is C(0)OR (wherein R is a hydrogen atom or a
2 . 10 10' . 10
Cχ_7 alkyl group) , R is NR R (wherein each of R and
10 ' R which are independent of each other, is a hydrogen
+ 11 11' 11'' atom or a C1-7 alkyl group) or N R R R (wherein each of R , R and R which are independent of one another, is a
4 5
C1_7 alkyl group), D is -O- or -NH-, and X is CR (wherein R is a hydrogen atom or a halogen atom) .
The compound represented by the formula [ij of the present invention can be used for the purpose of the present invention either in the free form or in the form of a pharmaceutically acceptable salt. The compound represented by the formula [ij, i.e. 6- membered heterocyclic-compound, can be prepared by the following synthetic methods.
A reaction solvent used in the preparation is stable under the reaction conditions, and is preferably so inert as not to inhibit the reaction. As the reaction solvent, water, alcohols (such as methanol, ethanol, propanol, butanol and octanol) , cellosolves (such as methoxyethanol and ethoxyethanol) , aprotic polar organic solvents (such as dimethylformamide (DMF) , dimethylsulfoxide (DMSO) , dimethylacetamide, tetramethylurea, sulfolane, N,N- dimethylimidazolidinone (DMI), 1 , 3-dimethyl-3 , 4 , 5 , 6- tetrahydro-2 (IH) -pyrimidinone (DMPU) and hexamethylphosphoric triamide (HMPA) ) , ethers (such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane) , aliphatic hydrocarbons (such as pentane, n- hexane, c-hexane, octane, decaline and petroleum ether) , aromatic hydrocarbons (such as benzene, chlorobenzene, nitrobenzene, toluene, xylene and tetralin) , halogenated hydrocarbons (such as chloroform, dichloromethane and dichloroethane) , ketones (such as acetone, methyl ethyl ketone and methyl butyl ketone) , lower aliphatic acid esters (such as methyl acetate, ethyl acetate and methyl propionate) , alkoxy alkanes (such as dimethoxyethane and diethoxyethane) and acetonitrile may, for example, be mentioned. These solvents are optionally selected depending upon the reactivity of the aimed reaction, and are respectively used alone or in a mixture. In some cases, they are used as a non-aqueous solvent by using a suitable dehydrating agent or a drying agent. The above- mentioned solvents are merely examples which can be used in the reaction of the present invention, and the present invention is not limited to these conditions. PROCESS 1
Figure imgf000041_0001
[ II ] [ I ]
1 2 " A 5
[wherein A, D, X , X~ , X ' , x" and X are as def ined above ,
16 and R is a suitable leaving group for the nucleophilic substitution in the reaction, including halogen such as chlorine, bromine or iodine, and an aromatic or aliphatic sulfonyloxy group such as p-toluenesulfonyloxy, benzenesulfonyloxy or methanesuIfonyloxy] . A compound of the formula [ij wherein D is 0, S or
12 12
NR (wherein R is as defined above) , can be obtained by reacting a compound of the formula [ii] with a compound of the formula [ill] without a catalyst or in the presence of a catalyst. The reaction is conducted usually in an appropriate solvent in the presence of a base. As the solvent, water, alcohols, cellosolves, aprotic polar organic solvents (such as dimethylformamide, dimethylacetamide, tetramethylurea, N,N-dimethylimidazolidinone (DMI) , 1,3- dimethyl-3,4, 5, 6-tetrahydro-2 (IH) -pyrimidinone (DMPU) and hexamethylphosphoric triamide (HMPA) ) , ethers, aromatic hydrocarbons, halogenated hydrocarbons, ketones, lower aliphatic acid esters, alkoxy alkanes and acetonitrile may, for example, be mentioned. As examples of the base, organic amines (such as diisopropylethylamine, trimethylamine, triethylamine, N- methylmorpholine and pyridine) , metal alkoxides (such as sodium methoxide, sodium ethoxide, lithium isopropoxide and potassium t-butoxide) , inorganic alkali metal salts (such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, sodium acetate and potassium acetate) and alkali metal amides (such as sodium amide) may, for example, be mentioned. They are optionally selected depending upon the reactivity of the aimed reaction. As the catalyst, a group of palladium such as tetrakis ( triphenylpnosphme)palladium(0) , palladium (II) chloride and 1,3- bis (diphenylphosphino) propane/Pd2 (dba) ,, a group of nickel such as dichloro[l , 3- bis (diphenylphosphino) propanejnickel (II) and tetrakis (triphenylphosphite) nickel (0) , a group of ruthenium such as dichlorotris (triphenylphosphine) ruthenium, and a group of rhodium such as chlorotris (triphenylphosphine) rhodium, may be used as the case requires .
The reaction is conducted usually at a temperature ranging from -100°C to the boiling point of the solvent to be used in the reaction, preferably from 20°C to 150°C, for from 0.5 to 30 hours. Examples for the reaction of a halopyridine with an alkylamine are described in J. Org. Chem, 1953, 18, 1484, Tetrahedron Lett, 1971, 1875, Chem. Ber, 1969, 102, 1161 and Reel. Trav. Chim. Pays-Bas, 1969, 88, 1391. The reaction using a palladium catalyst is described in J. Org. Chem, 1996, 61, 7240 and ibid 1997, 62, 1568. Examples for the reaction of a halopyridazine or a halopyrazine with an amine are described in Bull. Soc . Chim. Fr, 1970, 1346 and J . Chem. Soc, 1960, 242. Examples for the reaction of a halopyrimidine or a halotriazine with an alkylamine are described in J. Med. Chem, 1984, 27, 1621, J. Chem. Soc, 1946, 343, ibid 1965, 2778, Chem. Ber, 1963, 96, 2977, J. Org. Chem, 1953, 18, 1484, ibid 1961, 26, 2786 and J. Am. Chem. Soc, 1954, 73, 2981. Such reaction conditions can be applied to synthesis of the compound of the formula [ij wherein D is NR (wherein R is as defined above), in Process 1. PROCESS 2
Figure imgf000044_0001
[IV] [I] r 1 2 3 4 5 Iδ
Lwherem A, D, X , X' , X , X , X and R are as defined above] .
A compound of the formula [i] wherein D is 0, S or
12 12 .
NR (wherein R is as defined above) , can be obtained by nucleophilic substitution of a compound of the formula [vj with a compound of the formula [ivj .
The reaction can be conducted under the same conditions as in Process 1. PROCESS 3
[111-2]
Figure imgf000044_0002
[VI] [ i-2 ] r 1 2 3 4 5 ., 12
Lwhere A, X , X , X , X , X and R are as defined
17 above, and R is chlorine, bromine or OC(0)OR (wherein R is a Cχ_ alkyl group or a phenyl group)].
A compound of the formula [i] wherein D is -C(0)-NR -
12 (wherein R is as defined above), i.e. a compound of the formula [l-2J can be obtained by nucleophilic substitution of a compound of the formula [vi] with a compound of the formula [lII-2J.
The reaction is usually conducted in a suitable organic solvent, and the reaction can be accelerated by using a suitable base as the case requires. As the solvent, aprotic polar organic solvents, ethers, aromatic hydrocarbons, halogenated hydrocarbons, alkoxy alkanes and acetonitrile may, for example, be mentioned. As examples of the base, organic amines (such as diisopropylethylamine, trimethylamine, triethylamine, N- methylpiperidine, N-methylmorpholine, pyridine, 2,6- lutidine and collidine) , metal alkoxides (such as sodium methoxide, sodium ethoxide, lithium isopropoxide and potassium t-butoxide) , inorganic alkali metal salts (such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, sodium acetate and potassium acetate) , alkali metal amides (such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and 2,2,6,6- tetramethylpiperidide) and alkali metals (such as methyllithium, n-butyllithium) . They are optionally selected depending upon the reactivity of the aimed reaction.
The reaction is conducted usually at a temperature ranging from -78°C to the boiling point of the solvent to be used in the reaction, for from 0.5 to 30 hours.
PROCESS 4
[VII]
Figure imgf000046_0001
[ IV-2 ] [ I-3 ]
r , . 1 3 4 5 12 , 17
Lwherem A, X , X , X , X , X , R and R are as def ined above] .
A compound of the formula rLU i wherein D is -NR 12-C(O)-
12 .
(wherein R is as defined above), i.e. a compound of the formula [l-3J, can be obtained by nucleophilic substitution of a compound of the formula [vilj with a compound of the formula [lV-2].
The reaction can be conducted under the same conditions as in Process 3. PROCESS 5
[ 111-2 ] R
Figure imgf000046_0002
[ VI II ] [ I-4 ] r 1 2 3 4 5 ., 12 ^ . ,
[wherein A, X , X , X , X , X and R are as der eα
12 18 12 above, M is -NCO or -N(R )-C(0)-OR (wherein R is as
Figure imgf000047_0001
defined above, R is a χ_7 alkyl group or a phenyl group)]. A compound of the formula r [I IJ wherei ■n D is -NR 12 -C(0)-
12 12
NR - (wherein R is as defined above), i.e. a compound of the formula [l-4], can be obtained by reacting a compound of the formula [vill] with a compound of the formula [lll-2j. The reaction can be conducted under the same conditions as in Process 3. PROCESS 6
[IX]
Figure imgf000047_0002
[ IV-2 ] [ '- ]
r 1 2 3 4 5 12
[wherein A, X , X , X , X , X , R and M are as defined above]. r η . . 1
A compound of the rormula LU wherein D is -NR -C(O)-
12 12
NR - (wherein R is as defined above), i.e. a compound of the formula [l-4], can be obtained by reacting a compound of the formula [lV-2] with a compound of the formula [ix] .
The reaction can be conducted under the same conditions as in Process 3. Now, methods for producing intermediates for synthesis of the compound of the present invention will be explained hereinafter. REACTION FORMULA 1
Figure imgf000048_0001
4 6
[wherein R and R are as defined above] . As shown in the Reaction Formula 1, an intermediate of the formula [xill] can be obtained by solvolysis (by e.g. an alcohol or water) of a β-lactam of the formula [Xllj. The β -lactarn can be obtained by cyclization of a compound of the formula [xi] that can be obtained by reacting a common olefination reagent (such as Wittig reagent) with a piperidone of the formula [xj, with a suitable isocyanate (such as ClS02NCO) . REACTION FORMULA 2
R4 — - R4α- o,R' - RιC CO R^ ^^^0 ^NHR2° NHR2° 2
[ XIV] [ XV ]
[ X ]
Figure imgf000048_0002
[ XVI ] [ XIII ] r , . 4 6 20
Lwherem R and R are as defined above, and R is a hydrogen atom, Cχ_7 aliphatic acyl, C5_10 aromatic acyl or a protecting group].
As shown in the Reaction Formula 2, an intermediate of the formula [xv] can be synthesized by conducting Arndt-Eistert reaction of a compound of the formula [XIVJ. Namely, 4-amino-4-piperidyl acetate derivative can be obtained by reacting diazomethane with an acyl chloride or a mixed anhydride of the compound of the formula [XIVJ to obtain a diazoketone, followed by using a suitable catalyst (for example, a silver compound such as silver benzoate) or irradiating with light in the presence of a suitable alcohol. The protecting group is removed as the case requires, to obtain an intermediate of the formula [XIII].
The compound of the formula [XIVJ can be synthesized in accordance with a method as described in USP 3,313,819, USP 3,330,836 or J. Org. Chem., 1957, 22, 1061. The protecting group is removed as the case requires, to obtain an intermediate of the formula [XVIJ .
REACTION FORMULA 3
Figure imgf000050_0001
[XII b]
4 6
[wherein R4, R° and R are as defined above, D is 0, S 02 12 12
NR (wherein R is as defined above) and Q is Li, Cu, MgBr, ZnBr, a trialkylstannyl group such as tributylstannyl or a trialkylsilyl group such as trimethylsilyl] . As shown in the Reaction Formula 3, the intermediate of the formula [XIIl] can be synthesized by various reactions from the compound of the formula [x] .
A 4-hydroxy-4-piperidinyl acetate of the formula [XIII(D=0)J can be obtained by reacting an acetate of the formula [xvilj with a corresponding piperidone derivative under suitable basic conditions, or by reacting an enol ether of the formula [XVIIIJ with a corresponding piperidone derivative under a suitable Lewis acidic conditions. Further, it can be obtained by reacting an alkyne of the formula [xix] with a corresponding piperidone derivative to obtain a compound of the formula [xxj, followed by hydrolysis of the compound of the formula [xx] under suitable acidic conditions. Further, the compound of the formula [xiII(D=0)j can be obtained from a compound of the formula [XXIIJ that can be obtained by reacting a compound of the formula [XXIJ with a corresponding piperidone derivative by using a suitable oxidizing agent.
Further, the compound of the formula [XIII(D=0)] can be lead to a thiol of the formula [XIII-2J or an amine of the formula [xill-lj by known methods.
A compound of the formula LXIII-d] and a compound of the formula [xill-e] can be obtained, by reacting a compound of the formula [XXIIJ with a suitable oxidizing agent followed by suitable reaction treatment, and by reacting it with a suitable reducing agent, respectively. By reacting a compound of the formula [XXIIIJ with a piperidone of the formula [x(D=0)j, by the same method as the synthesis of the compound of the formula [XXIIJ, a compound of the formula [xill-cj can be obtained. It can be lead to the above-shown compound of the formula [XIII- d] or the formula [xill-ej, by selecting a suitable reducing agent.
The compound of the formula [xill-bj can be obtained by reacting the piperidone
Figure imgf000052_0001
with a carboxylate derivative of the formula [XXIVJ . The compound of the formula [xill-b] can be converted to a thiol of the formula [xill-2b] or 'an amine of the formula [xill-lbj, as the above-mentioned compound of the formula [xillj.
By the same method as described for the compound of the formula [XIII(D=0)J, 4-aminopiperidine derivative of the formula r[XIII (D=NR12) iJ can be obtained by using an i ine of the formula [X(D=NR12)] that is prepared from the corresponding piperidone derivative by known methods . Among these compounds, the compound of the formula [xxil] can be synthesized in accordance with a method as described in J. Org. Chem., 1998, 63, 4554. The protecting group is removed to obtain the intermediate of the formula [XIIl], [xill-bj, [xill-dj or [xill-ej if 1 required.
REACTION FORMULA 4
Figure imgf000053_0001
[XXV] [ XXVI ] [ XXVII ]
Figure imgf000053_0002
[XXVIII] [ XXIX ] [XXX]
Figure imgf000053_0003
[xv; [ XXXI ]
Figure imgf000053_0004
XXXI [wherein R", R and R " are as defined above].
As shown in the Reaction Formula 4, the intermediate of the formula [XIIl] can be synthesized also by Michael addition of various olefin derivatives. By known methods, malonate, malonitrile or a cyano acetate derivative is treated with a piperidone of the formula [x] to synthesize a compound of the formula [xxv], [XXVIJ or [XXVIIJ, respectively. Then, ammonia is added therewith, an azide is added therewith followed by reacting a suitable reducing agent therewith, or an amine having a suitable protecting group such as benzylamine is added therewith followed by removing the protecting group, to obtain a compound of the formula [XXVIII], [XXIX] or [XXXJ, respectively. The compound of the formula [XXVIII] can be lead to an intermediate of the formula [xvj by known methods (such as hydrolysis of one ester followed by decarboxylation) , and the protecting group is removed to obtain the intermediate of the formula [XIIl] as the case requires.
With regard to the compound of the formula [XXIXJ, the cyano group is hydrolyzed, and the intermediate of the formula [XIIl] can be obtained in the same manner as for the compound of the formula [XXVIIIJ. With regard to the compound of the formula [XXXJ, as mentioned above, a cyano acetate derivative of the formula [XXXIJ obtained by decarboxylation, is hydrolyzed to obtain an intermediate of the formula [xv], and the protecting group is removed to obtain the intermediate of the formula [xillj.
Further, from the cyano acetate derivative of the formula [xxxi], an amide derivative of the formula [XXXIIJ and an alkyl amino of the formula [XXXIIIJ can be synthesized by known methods.
REACTION FORMULA 5
R4α [ x :
Figure imgf000055_0001
R: 1 R4N^
N Xc02R° [ XXXIV ] [ XXXV ]
Figure imgf000055_0002
[ xv ; [ XXXI ]
Figure imgf000055_0003
XXXIII I [wherein R", R and R are as defined above].
As shown in the Reaction Formula 5, an amino group is introduced to an β -unsaturated carboxylic acid of the formula [XXXIV] or an α -unsaturated nitrile of the formula [XXXVJ, which can be synthesized by known methods, by Michael addition in the same manner as in the Reaction
Formula 4, to synthesize the intermediate of the formula
[XIIl].
REACTION FORMULA 6
Figure imgf000056_0001
[ XXXVIII ] [ Xlll-d ]
Figure imgf000056_0002
[ XVI ] [ XIIl ]
[wherein R , R and R are as defined above].
As shown in the Reaction Formula 6, an intermediate of the formula [xvi] or [XIIl] can be also obtained by means of Overman rearrangement (refer to e.g. J. Am. Chem. Soc. 1974, 96, 597) . The compound of the formula [XXXVIIJ can be prepared by the treatment of the alcohol of the formula [XXVI] that is synthesized by known methods (such as Wittig reaction) with an acetonitrile derivative (such as Cl.CCN) . The precursor can be converted to the compound of the formula [XXXVIII] under suitable conditions (for example, reflux under heating in a solvent having a high boiling point such as xylene, or a reaction under coexistence of a metal agent such as trifluoromercury acetate) . Then, the vinyl group of the compound of the formula [XXXVIII] is converted to a carboxylate derivative by a suitable oxidation method (such as ozone oxidation) , and the protecting group is removed if necessary, to obtain the intermediate of the formula [XVI] . Further, the compound of the formula [XXXVIII] can be lead to the intermediate of the formula [XHI-d] in such a manner that it is lead to an alcohol by a known suitable reducing agent, and the protecting group is removed as the case requires . The intermediate may be further oxidized by a known suitable oxidation method, the protecting group is removed as the case requires, and the intermediate of the formula [XIII] can be obtained. REACTION FORMULA 7
Figure imgf000057_0001
[ XXXIX ] [ XXXX ] *- G L1 (R k { -R" \ RH , XXXXI
Figure imgf000057_0002
[ XXXIX ] [ XXXXII ] [ XXXXIII ] [wherein k, 1, R", R , R"" , R~" , R and L~ are as defined above, G is a C._,2 heteroaromatic group, a C,_.. heteroalicyclic group, a C3_ιz cycloalkyl group, a C,_7 cycloalkenyl group or a C,_14 aromatic group, and each of L and L which are independent of each other, is -0-, -S- or -NR - (wherein R" is as defined above)].
As shown in the Reaction Formula 7, a compound of the formula [XXXXI] can be synthesized by nucleophilic substitution of a compound of the formula [XXXX] with an alcohol of the formula [XXXIX] wherein L is 0, a thiol of the formula [XXXIX] wherein L is S or an amine of the i . 15 15 formula [XXXIX] wherein L is NR (wherein R is as lδ defined above) . In the formula [XXXX] , R is a suitable leaving group. The protecting group of the obtained compound of the formula [XXXXI] is removed, as the case requires, and can be used as a substituent of R .
A phenol of the formula [XXXIX(G is a phenyl group)] wherein L is 0, and a thiophenol of the formula [XXXIX(G is a phenyl group)] wherein L is S, can be lead to alcohols of the formula [XXXXIIIJ by using a compound of the formula [XXXXIIJ. under suitable basic conditions, in accordance with methods as described in Bull. Chem. Soc.
Jpn., 1973, 46, 553 and Synthesis, 1975, 641, respectively. The compounds and their pharmaceutically acceptable salts shown in Table 1 to Table 9, are examples of the compound of the present invention. Tab le 1
Figure imgf000059_0001
Ra Rb Rc L1 L3 k V X3 X5 D R5
H H H _ _ N N N NH Cl
H MeO H - - N N N NH Cl
H n-PrO H - - N N N NH Cl
Figure imgf000059_0002
H Me H - - L N N N NH Cl
H MeNH H - - [ N N N NH Cl
H Cl H - - L N N N NH Cl
H F H - - L N N N NH Cl
Figure imgf000059_0003
H H H 0 - I N N N NH Cl
H MeO H 0 L N N N NH Cl
H n-PrO H 0 ] L N N N NH Cl
Figure imgf000059_0004
H Me H 0 L N N N NH Cl
H MeNH H 0 - I N N N NH Cl
H Cl H 0 - 1 N N N NH Cl
H F H 0 - 1 N N N NH Cl
Figure imgf000059_0005
5S
RJ Rb Rc L1 L3 k X1 X° X5 D R5
Figure imgf000060_0001
H H H - 0 1 N N N NH Cl
H MeO H - 0 1 N N N NH Cl
H n-PrO H - 0 1 N N N NH Cl
Figure imgf000060_0002
H Me H - 0 1 N N N NH Cl
H MeNH H - 0 1 N N N NH Cl
H Cl H - 0 1 N N N NH Cl
H F H - 0 1 N N N NH Cl
H NO 2 H - 0 1 N N N NH Cl
Figure imgf000060_0003
H H H NH - 1 N N N NH Cl
H MeO H NH - 1 N N N NH Cl
H n-PrO H NH - 1 N N N NH Cl
H n-CeHi 3O H NH - 1 N N N NH Cl
H Me H NH - 1 N N N NH Cl
H MeNH H NH - 1 N N N NH Cl
H Cl H NH - 1 N N N NH Cl
H F H NH - 1 N N N NH Cl
H NO 2 H NH - 1 N N N NH Cl
Figure imgf000060_0004
H H H - NH 1 N N N NH Cl
H MeO H - NH 1 N N N NH Cl
H n-PrO H - NH 1 N N N NH Cl
H n-CeHi 3O H - NH 1 N N N NH Cl
H Me H - NH 1 N N N NH Cl
H MeNH H - NH 1 N N N NH Cl
H Cl H - NH 1 N N N NH Cl
H F H - NH 1 N N N NH Cl
H NO 2 H - NH 1 N N N NH Cl
H CF3 H - NH 1 N N N NH Cl
H H H - - 2 N N N NH Cl
H MeO H - - 2 N N N NH Cl
H n-PrO H - - 2 N N N NH Cl
H n-CeH.sO H - - 2 N N N NH Cl
H Me H - - 2 N N N NH Cl
H MeNH H - - 2 N N N NH Cl Ra Rb Rl L L" k X' XJ X^ D R5
H Cl H _ _ 9 N N N NH Cl
H F H - - 2 N N N NH Cl
Figure imgf000061_0001
H H H 0 - 2 N N N NH Cl
H MeO H 0 - 2 N N N NH Cl
H n-PrO H 0 - 2 N N N NH Cl
Figure imgf000061_0002
H Me H 0 - 2 N N N NH Cl
H MeNH H 0 - 2 N N N NH Cl
H Cl H 0 - 2 N N N NH Cl
H F H 0 - 2 N N N NH Cl
Figure imgf000061_0003
H H H - 0 2 N N N NH Cl
H MeO H - 0 2 N N N NH Cl
H n-PrO H - 0 2 N N N NH Cl
Figure imgf000061_0004
H Me H - 0 2 N N N NH Cl
H MeNH H - 0 2 N N N NH Cl
H Cl H - 0 2 N N N NH Cl
H F H - 0 2 N N N NH Cl
Figure imgf000061_0005
H H H 0 0 2 N N N NH Cl
H MeO H 0 0 2 N N N NH Cl
H n-PrO H 0 0 2 N N N NH Cl
Figure imgf000061_0006
H Me H 0 0 2 N N N NH Cl
H MeNH H 0 0 2 N N N NH Cl
H Cl H 0 0 2 N N N NH Cl
H F H 0 0 2 N N N NH Cl
Figure imgf000061_0007
H OH H 0 0 2 N N N NH Cl
H CHO H 0 0 2 N N N NH Cl
Figure imgf000061_0008
60
Ra Rb Rc L1 L! k X! XJ X5 D R5
H COOH H 0 0 2 N N N NH Cl
H CH3C(0) H 0 0 2 N N N NH ClO 2 NO 2 H 0 0 2 N N N NH ClO H NO 2 0 0 2 N N N NH Cl
H CF3 H 0 0 2 N N N NH Cl
H H H 0 0 2 N N N 0 Cl
H MeO H 0 0 2 N N N 0 Cl
H n-PrO H 0 0 2 N N N 0 Cl
H n-C6Hι30 H 0 0 2 N N N 0 Cl
H Me H 0 0 2 N N N 0 Cl
H MeNH H 0 0 2 N N N 0 Cl
H Cl H 0 0 2 N N N 0 Cl
H F H 0 0 2 N N N 0 Cl
H NO H 0 0 2 N N N 0 Cl
H CF3 H 0 0 2 N N N 0 Cl
H H H 0 0 2 N N N 0 H
H MeO H 0 0 2 N N N 0 H
H n-PrO H 0 0 2 N N N 0 H
Figure imgf000062_0001
H Me H 0 0 2 N N N 0 H
H MeNH H 0 0 2 N N N 0 H
H Cl H 0 0 2 N N N 0 H
H F H 0 0 2 N N N 0 H
H NO 2 H 0 0 2 N N N 0 H
H CF3 H 0 0 2 N N N 0 H
H H H 0 0 2 N N N NH H
H MeO H 0 0 2 N N N NH H
H n-PrO H 0 0 2 N N N NH H
Figure imgf000062_0002
H Me H 0 0 2 N N N NH H
H MeNH H 0 0 2 N N N NH H
H Cl H 0 0 2 N N N NH H
H F H 0 0 2 N N N NH H
H NO 2 H 0 0 2 N N N NH H
Figure imgf000062_0003
H OH H 0 0 2 N N N NH H
H CHO H 0 0 2 N N N NH H Ra Rb Rc L! k X1 XJ X5 D R5
H CH.'OH H 0 0 2 N N N NH H
H COOH H 0 0 9 N N N NH H
H CHsC(O) H 0 0 2 N N N NH HO 2 NO 2 H 0 0 2 N N N NH HO 2 H NO 2 0 0 2 N N N NH H
H CF3 H 0 0 2 N N N NH H
H H H 0 0 2 N N N NH Me
H MeO H 0 0 2 N N N NH Me
H n-PrO H 0 0 2 N N N NH Me
Figure imgf000063_0001
H Me H 0 0 2 N N N NH Me
H MeNH H 0 0 2 N N N NH Me
H Cl H 0 0 2 N N N NH Me
H F H 0 0 2 N N N NH Me
H NO. H 0 0 2 N N N NH Me
H CF3 H 0 0 2 N N N NH Me
H H H 0 0 2 N N N NH MeO
H MeO H 0 0 2 N N N NH MeO
H n-PrO H 0 0 2 N N N NH MeO
H n-CeHi 3O H 0 0 2 N N N NH MeO
H Me H 0 0 2 N N N NH MeO
H MeNH H 0 0 2 N N N NH MeO
H Cl H 0 0 2 N N N NH MeO
H F H 0 0 2 N N N NH MeO
Figure imgf000063_0002
H H H NH - 2 N N N NH Cl
H MeO H NH - 2 N N N NH Cl
H n-PrO H NH - 2 N N N NH Cl
H n-CβHi sO H NH - 2 N N N NH Cl
H Me H NH - 2 N N N NH Cl
H MeNH H NH - 2 N N N NH Cl
H Cl H NH - 2 N N N NH Cl
H F H NH - 2 N N N NH Cl
H NO 2 H NH - 2 N N N NH Cl
Figure imgf000063_0003
H H H - NH 2 N N N NH Cl Ra Rb Rc L: L' k X' X3 X5 D R5
H MeO H _ NH 2 N N N NH Cl
H n-PrO H - NH 2 N N N NH Cl
H n-CeHi 3O H - NH 2 N N N NH Cl
H Me H - NH 2 N N N NH Cl
H MeNH H - NH 2 N N N NH Cl
H Cl H - NH 2 N N N NH Cl
H F H - NH 2 N N N NH Cl
H NO 2 H - NH 2 N N N NH Cl
H CF3 H - NH 2 N N N NH Cl
H H H NH NH 2 N N N NH Cl
H MeO H NH NH 2 N N N NH Cl
H n-PrO H NH NH 2 N N N NH Cl
H n-CeHi 3O H NH NH 2 N N N NH Cl
H Me H NH NH 2 N N N NH Cl
H MeNH H NH NH 2 N N N NH Cl
H Cl H NH NH 2 N N N NH Cl
H F H NH NH 2 N N N NH Cl
H NO 2 H NH NH 2 N N N NH Cl
Figure imgf000064_0001
H H H 0 0 3 N N N NH Cl
H MeO H 0 0 3 N N N NH Cl
H n-PrO H 0 0 3 N N N NH Cl
Figure imgf000064_0002
H Me H 0 0 3 N N N NH Cl
H MeNH H 0 0 3 N N N NH Cl
H Cl H 0 0 3 N N N NH Cl
H F H 0 0 3 N N N NH Cl
H NO 2 H 0 0 3 N N N NH Cl
Figure imgf000064_0003
H OH H 0 0 3 N N N NH Cl
H CHO H 0 0 3 N N N NH Cl
Figure imgf000064_0004
H COOH H 0 0 3 N N N NH Cl
H CH3C(0) H 0 0 3 N N N NH ClO 2 NO 2 H 0 0 3 N N N NH ClO H NO 2 0 0 3 N N N NH Cl
Figure imgf000064_0005
Ra Rb R" L' L3 k X' X3 X5 D R =
H H H 0 0 3 N N N 0 Cl
H MeO H 0 0 3 N N N 0 Cl
H n-PrO H 0 0 n 0 N N N 0 Cl
Figure imgf000065_0001
H Me H 0 0 3 N N N 0 Cl
H MeNH H 0 0 3 N N N 0 Cl
H Cl H 0 0 3 N N N 0 Cl
H F H 0 0 3 N N N 0 Cl
H NO 2 H 0 0 3 N N N 0 Cl
Figure imgf000065_0002
H H H 0 0 3 N N N NH H
H MeO H 0 0 3 N N N NH H
H n-PrO H 0 0 3 N N N NH H
Figure imgf000065_0003
H Me H 0 0 0 0 N N N NH H
H MeNH H 0 0 3 N N N NH H
H Cl H 0 0 3 N N N NH H
H F H 0 0 3 N N N NH H
H NO 2 H 0 0 3 N N N NH H
Figure imgf000065_0004
H OH H 0 0 3 N N N NH H
H CHO H 0 0 3 N N N NH H
Figure imgf000065_0005
H COOH H 0 0 3 N N N NH H
H CH3C(0) H 0 0 3 N N N NH HO 2 NO 2 H 0 0 3 N N N NH HO 2 H NO 2 0 0 3 N N N NH H
H CFs H 0 0 3 N N N NH H
H H H 0 0 3 N N N NH Me
H MeO H 0 0 3 N N N NH Me
H n-PrO H 0 0 3 N N N NH Me
Figure imgf000065_0006
H Me H 0 0 3 N N N NH Me
H MeNH H 0 0 3 N N N NH Me
H Cl H 0 0 3 N N N NH Me
H F H 0 0 3 N N N NH Me
H NO 2 H 0 0 N N N NH Me Ra Rb Rc V LJ k X' X3 X5 D R3
H CF3 H 0 0 3 N N N NH Me
H H H 0 0 3 N N N NH MeO
H MeO H 0 0 0 N N N NH MeO
H n-PrO H 0 0 3 N N N NH MeO
H n-CβHi 3O H 0 0 3 N N N NH MeO
H Me H 0 0 3 N N N NH MeO
H MeNH H 0 0 3 N N N NH MeO
H Cl H 0 0 3 N N N NH MeO
H F H 0 0 3 N N N NH MeO
H NO 2 H 0 0 3 N N N NH MeO
H CF3 H 0 0 3 N N N NH MeO
H H H - - 1 N CH CH NH Cl
H MeO H - - 1 N CH CH NH Cl
H n-PrO H - - 1 N CH CH NH Cl
H n-CeHi 3O H - - 1 N CH CH NH Cl
H Me H - - 1 N CH CH NH Cl
H MeNH H - - 1 N CH CH NH Cl
H Cl H - - 1 N CH CH NH Cl
H F H - - 1 N CH CH NH Cl
Figure imgf000066_0001
H CF3 H - - 1 N CH CH NH Cl
H H H 0 - 1 N CH CH NH Cl
H MeO H 0 - 1 N CH CH NH Cl
H n-PrO H 0 - 1 N CH CH NH Cl
H n-CeHi 3O H 0 - 1 N CH CH NH Cl
H Me H , 0 - 1 N CH CH NH Cl
H MeNH H 0 - 1 N CH CH NH Cl
H Cl H 0 - 1 N CH CH NH Cl
H F H 0 - 1 N CH CH NH Cl
Figure imgf000066_0002
H CF3 H 0 - 1 N CH CH NH Cl
H H H - 0 1 N CH CH NH Cl
H MeO H - 0 1 N CH CH NH Cl
H n-PrO H - 0 1 N CH CH NH Cl
H n-CeHi 3O H - 0 1 N CH CH NH Cl
H Me H - 0 1 N CH CH NH Cl
H MeNH H - 0 1 N CH CH NH Cl Ra Rb Rc L1 L3 k X1 X3 X5 D R5
H Cl H _ 0 1 N CH CH NH Cl
H F H - 0 1 N CH CH NH Cl
H NO 2 H - 0 1 N CH CH NH Cl
Figure imgf000067_0001
H H H NH - 1 N CH CH NH Cl
H MeO H NH - 1 N CH CH NH Cl
H n-PrO H NH - 1 N CH CH NH Cl -
H n-CβHi 3O H NH - 1 N CH CH NH Cl
H Me H NH - 1 N CH CH NH Cl
H MeNH H NH - 1 N CH CH NH Cl
H Cl H NH - 1 N CH CH NH Cl
H F H NH - 1 N CH CH NH Cl
H NO 2 H NH - 1 N CH CH NH Cl
Figure imgf000067_0002
H H H - NH 1 N CH CH NH Cl
H MeO H - NH 1 N CH CH NH Cl
H n-PrO H - NH 1 N CH CH NH Cl
H n-CsHi 3O H - NH 1 N CH CH NH Cl
H Me H - NH 1 N CH CH NH Cl
H MeNH H - NH 1 N CH CH NH Cl
H Cl H - NH 1 N CH CH NH Cl
H F H - NH 1 N CH CH NH Cl
H NO 2 H - NH 1 N CH CH NH Cl
H CF3 H - NH 1 N CH CH NH Cl
H H H - - 2 N CH CH NH Cl
H MeO H - - 2 N CH CH NH Cl
H n-PrO H - - 2 N CH CH NH Cl
H n-CeHi 3O H - - 2 N CH CH NH Cl
H Me H - - 2 N CH CH NH Cl
H MeNH H - - 2 N CH CH NH Cl
H Cl H - - 2 N CH CH NH Cl
H F H - - 2 N CH CH NH Cl
H NO 2 H - - 2 N CH CH NH Cl
Figure imgf000067_0003
H H H 0 - 2 N CH CH NH Cl
H MeO H 0 - 2 N CH CH NH Cl
H n-PrO H 0 - 2 N CH CH NH Cl 66
Ra Rb Rc L' L3 k X1 X3 X5 D R5
H n-CόHi 3O H 0 _ 2 N CH CH NH Cl
H Me H 0 - 2 N CH CH NH Cl
H MeNH H 0 - 2 N CH CH NH Cl
H Cl H 0 - 2 N CH CH NH Cl
H F H 0 - 2 N CH CH NH Cl
H NO 2 H 0 - 2 N CH CH NH Cl
H CF3 H 0 - 2 N CH CH NH Cl.
H H H - 0 2 N CH CH NH Cl
H MeO H - 0 2 N CH CH NH Cl
H n-PrO H - 0 2 N CH CH NH Cl
H n-CeHi 3O H - 0 2 N CH CH NH Cl
H Me H - 0 2 N CH CH NH Cl
H MeNH H - 0 2 N CH CH NH Cl
H Cl H - 0 2 N CH CH NH Cl
H F H - 0 2 N CH CH NH Cl
Figure imgf000068_0001
H CF3 H - 0 2 N CH CH NH Cl
H H H 0 0 2 N CH CH NH Cl
H MeO H 0 0 2 N CH CH NH Cl
H n-PrO H 0 0 2 N CH CH NH Cl
H n-CeHi 3O H 0 0 2 N CH CH NH Cl
H Me H 0 0 2 N CH CH NH Cl
H MeNH H 0 0 2 N CH CH NH Cl
H Cl H 0 0 2 N CH CH NH Cl
H F H 0 0 2 N CH CH NH Cl
Figure imgf000068_0002
H OH H 0 0 2 N CH CH NH Cl
H CHO H 0 0 2 N CH CH NH Cl
Figure imgf000068_0003
H COOH H 0 0 2 N CH CH NH Cl
H CH3C(0) H 0 0 2 N CH CH NH ClO 2 NO 2 H 0 0 2 N CH CH NH ClO 2 H NO 2 0 0 2 N CH CH NH Cl
Figure imgf000068_0004
H H H 0 0 2 N CH CH 0 Cl
H MeO H 0 0 2 N CH CH 0 Cl
Figure imgf000069_0001
67
Ra Rb Rc L1 L3 k x- X3 X5 D R5
H n-PrO H 0 0 2 N CH CH 0 Cl
H n-CaHi 3O H 0 0 2 N CH CH 0 Cl
H Me H 0 0 2 N CH CH 0 Cl
H MeNH H 0 0 2 N CH CH 0 Cl
H Cl H 0 0 0 N CH CH 0 Cl
H F H 0 0 2 N CH CH 0 Cl
H NO 2 H 0 0 2 N CH CH 0 Cl
H CF3 H 0 0 2 N CH CH 0 Cl
H H H 0 0 2 N CH CH 0 H
H MeO H 0 0 2 N CH CH 0 H
H n-PrO H 0 0 2 N CH CH 0 H
Figure imgf000069_0002
H Me H 0 0 2 N CH CH 0 H
H MeNH H 0 0 2 N CH CH 0 H
H Cl H 0 0 2 N CH CH 0 H
H F H 0 0 2 N CH CH 0 H
H NO 2 H 0 0 2 N CH CH 0 H
Figure imgf000069_0003
H H H 0 0 2 N CH CH NH H
H MeO H 0 0 2 N CH CH NH H
H n-PrO H 0 0 2 N CH CH NH H
H n-CeHi 3O H 0 0 2 N CH CH NH H
H Me H 0 0 2 N CH CH NH H
H MeNH H 0 0 2 N CH CH NH H
H Cl H 0 0 2 N CH CH NH H
H F H 0 0 2 N CH CH NH H
H NO 2 H 0 0 2 N CH CH NH H
Figure imgf000069_0004
H OH H 0 0 2 N CH CH NH H
H CHO H 0 0 2 N CH CH NH H
Figure imgf000069_0005
H COOH H 0 0 2 N CH CH NH H
H CH3C(0) H 0 0 2 N CH CH NH HO 2 NO 2 H 0 0 2 N CH CH NH HO 2 H NO. 0 0 2 N CH CH NH H
Figure imgf000069_0006
H H H 0 0 2 N CH CH NH Me 6S
Ra Rb Rc L1 L! k X1 X3 X5 D R5
H MeO H 0 0 2 N CH CH NH e
H n-PrO H 0 0 2 N CH CH NH Me
H n-CβHi sO H 0 0 2 N CH CH NH Me
H Me H 0 0 2 N CH CH NH Me
H MeNH H 0 0 2 N CH CH NH Me
H Cl H 0 0 2 N CH CH NH Me
H F H 0 0 2 N CH CH NH Me
H NO 2 H 0 0 2 N CH CH NH Me
H CF3 H 0 0 2 N CH CH NH Me
H H H 0 0 2 N CH CH NH MeO
H MeO H 0 0 2 N CH CH NH MeO
H n-PrO H 0 0 2 N CH CH NH MeO
H n-CaHi 3O H 0 0 2 N CH CH NH MeO
H Me H 0 0 2 N CH CH NH MeO
H MeNH H 0 0 2 N CH CH NH MeO
H Cl H 0 0 2 N CH CH NH MeO
H F H 0 0 2 N CH CH NH MeO
H NO 2 H 0 0 2 N CH CH NH MeO
H CF3 H 0 0 2 N CH CH NH MeO
H H H NH - 2 N CH CH NH Cl
H MeO H NH - 2 N CH CH NH Cl
H n-PrO H NH - 2 N CH CH NH Cl
H n-CβHi 3O H NH - 2 N CH CH NH Cl
H Me H NH - 2 N CH CH NH Cl
H MeNH H NH - 2 N CH CH NH Cl
H Cl H NH - 2 N CH CH NH Cl
H F H NH - 2 N CH CH NH Cl
Figure imgf000070_0001
H CF3 H NH - 2 N CH CH NH Cl
H H H - NH 2 N CH CH NH Cl
H MeO H - NH 2 N CH CH NH Cl
H n-PrO H - NH 2 N CH CH NH Cl
H n-CeHi 3O H - NH 2 N CH CH NH Cl
H Me H - NH 2 N CH CH NH Cl
H MeNH H - NH 2 N CH CH NH Cl
H Cl H - NH 2 N CH CH NH Cl
H F H - NH 2 N CH CH NH Cl Ra Rb Rc L! L3 k X1 X3 X5 D R5
H NO 2 H _ NH 2 N CH CH NH Cl
H CF3 H - NH 2 N CH CH NH Cl
H H H NH NH 2 N CH CH NH Cl
H MeO H NH NH 2 N CH CH NH Cl
H n-PrO H NH NH 2 N CH CH NH Cl
H n-CeHi 3O H NH NH 2 N CH CH NH Cl
H Me H NH NH 2 N CH CH NH Cl
H MeNH H NH NH 2 N CH CH NH Cl
H Cl H NH NH 2 N CH CH NH Cl
H F H NH NH 2 N CH CH NH Cl
H NO 2 H NH NH 2 N CH CH NH Cl
Figure imgf000071_0001
H H H 0 0 3 N CH CH NH Cl
H MeO H 0 0 3 N CH CH NH Cl
H n-PrO H 0 0 3 N CH CH NH Cl
H n-CeHi 3O H 0 0 3 N CH CH NH Cl
H Me H 0 0 3 N CH CH NH Cl
H MeNH H 0 0 3 N CH CH NH Cl
H Cl H 0 0 3 N CH CH NH Cl
H F H 0 0 3 N CH CH NH Cl
H NO 2 H 0 0 3 N CH CH NH Cl
Figure imgf000071_0002
H OH H 0 0 3 N CH CH NH Cl
H CHO H 0 0 3 N CH CH NH Cl
Figure imgf000071_0003
H COOH H 0 0 3 N CH CH NH Cl
H CH3C(0) H 0 0 3 N CH CH NH ClO 2 NO 2 H 0 0 3 N CH CH NH ClO 2 H NO 2 0 0 3 N CH CH NH Cl
Figure imgf000071_0004
H H H 0 0 3 N CH CH 0 Cl
H MeO H 0 0 3 N CH CH 0 Cl
H n-PrO H 0 0 3 N CH CH 0 Cl
H n-CeHi 3O H 0 0 3 N CH CH 0 Cl
H Me H 0 0 3 N CH CH 0 Cl
H MeNH H 0 0 3 N CH CH 0 Cl
H Cl H 0 0 3 N CH CH 0 Cl Ra Rb R L' L3 k X1 X3 X5 D R5
H F H 0 0 3 N CH CH 0 Cl
H NO 2 H 0 0 3 N CH CH 0 Cl
Figure imgf000072_0001
H H H 0 0 3 N CH CH NH H
H MeO H 0 0 3 N CH CH NH H
H n-PrO H 0 0 3 N CH CH NH H
H n-CeHi 3O H 0 0 3 N CH CH NH H .
H Me H 0 0 3 N CH CH NH H
H MeNH H 0 0 3 N CH CH NH H
H Cl H 0 0 3 N CH CH NH H
H F H 0 0 3 N CH CH NH H
H NO 2 H 0 0 3 N CH CH NH H
Figure imgf000072_0002
H OH H 0 0 3 N CH CH NH H
H CHO H 0 0 3 N CH CH NH H
Figure imgf000072_0003
H COOH H 0 0 3 N CH CH NH H
H CH3C(0) H 0 0 3 N CH CH NH H
Figure imgf000072_0004
O 2 H NO 2 0 0 3 N CH CH NH H
Figure imgf000072_0005
H H H 0 0 3 N CH CH NH Me
H MeO H 0 0 3 N CH CH NH Me
H n-PrO H 0 0 3 N CH CH NH Me
H n-CeHi 3O H 0 0 3 N CH CH NH Me
H Me H . 0 0 3 N CH CH NH Me
H MeNH H 0 0 3 N CH CH NH Me
H Cl H 0 0 3 N CH CH NH Me
H F H 0 0 3 N CH CH NH Me
H NO 2 H 0 0 3 N CH CH NH Me
Figure imgf000072_0006
H H H 0 0 3 N CH CH NH MeO
H MeO H 0 0 3 N CH CH NH MeO
H n-PrO H 0 0 3 N CH CH NH MeO
H n-CeHi 3O H 0 0 3 N CH CH NH MeO
H Me H 0 0 3 N CH CH NH MeO
H MeNH H 0 0 3 N CH CH NH MeO Ra Rb Rc L1 L3 k X1 X3 X5 D R5
H Cl H 0 0 3 N CH CH NH MeO
H F H 0 0 3 N CH CH NH MeO
Figure imgf000073_0001
H H H - - 1 CH CH N NH Cl
H MeO H - - 1 CH CH N NH Cl
H n-PrO H - - 1 CH CH N NH Cl
H n-CeHi3θ H - - 1 CH CH N NH Cl
H Me H - - 1 CH CH N NH Cl
H MeNH H - - 1 CH CH N NH Cl
H Cl H - - 1 CH CH N NH Cl
H F H - - 1 CH CH N NH Cl
Figure imgf000073_0002
H H H 0 - 1 CH CH N NH Cl
H MeO H 0 - 1 CH CH N NH Cl
H n-PrO H 0 - 1 CH CH N NH Cl
H n-CeH sO H 0 - 1 CH CH N NH Cl
H Me H 0 - 1 CH CH N NH Cl
H MeNH H 0 - 1 CH CH N NH Cl
H Cl H 0 - 1 CH CH N NH Cl
H F H 0 - 1 CH CH N NH Cl
Figure imgf000073_0003
H H H - 0 1 CH CH N NH Cl
H MeO H - 0 1 CH CH N NH Cl
H n-PrO H - 0 1 CH CH N NH Cl
H n-CeHi3θ H - 0 1 CH CH N NH Cl
H Me H - 0 1 CH CH N NH Cl
H MeNH H - 0 1 CH CH N NH Cl
H Cl H - 0 1 CH CH N NH Cl
H F H - 0 1 CH CH N NH Cl
Figure imgf000073_0004
H H H NH - 1 CH CH N NH Cl
H MeO H NH - 1 CH CH N NH Cl
H n-PrO H NH - 1 CH CH N NH Cl Ra Rb Rc L3 k X" X3 X5 D R5
H n-CeHi 3O H NH _ 1 CH CH N NH Cl
H Me H NH - 1 CH CH N NH Cl
H MeNH H NH - 1 CH CH N NH Cl
H Cl H NH - 1 CH CH N NH Cl
H F H NH - 1 CH CH N NH Cl
H NO 2 H NH - 1 CH CH N NH Cl
Figure imgf000074_0001
H H H - NH 1 CH CH N NH Cl
H MeO H - NH 1 CH CH N NH Cl
H n-PrO H - NH 1 CH CH N NH Cl
H n-CeHi 3O H - NH 1 CH CH N NH Cl
H Me H - NH 1 CH CH N NH Cl
H MeNH H - NH 1 CH CH N NH Cl
H Cl H - NH 1 CH CH N NH Cl
H F H - NH 1 CH CH N NH Cl
H NO 2 H - NH 1 CH CH N NH Cl
H CF3 H - NH 1 CH CH N NH Cl
H H H - - 2 CH CH N NH Cl
H MeO H - - 2 CH CH N NH Cl
H n-PrO H - - 2 CH CH N NH Cl
H n-CeHi 3O H - - 2 CH CH N NH Cl
H Me H - - 2 CH CH N NH Cl
H MeNH H - - 2 CH CH N NH Cl
H Cl H - - 2 CH CH N NH Cl
H F H - - 2 CH CH N NH Cl
H NO 2 H - - 2 CH CH N NH Cl
H CF3 H - - 2 CH CH N NH Cl
H H H 0 - 2 CH CH N NH Cl
H MeO H 0 - 2 CH CH N NH Cl
H n-PrO H 0 - 2 CH CH N NH Cl
H n-CβHi 3O H 0 - 2 CH CH N NH Cl
H Me H 0 - 2 CH CH N NH Cl
H MeNH H 0 - 2 CH CH N NH Cl
H Cl H 0 - 2 CH CH N NH Cl
H F H 0 - 2 CH CH N NH Cl
H NO 2 H 0 - 2 CH CH N NH Cl
Figure imgf000074_0002
Ra Rb Rc L1 L3 k X1 X3 X5 D R5
H H H _ 0 2 CH CH N NH Cl
H MeO H - 0 2 CH CH N NH Cl
H n-PrO H - 0 2 CH CH N NH Cl
H n-CsH i 3O H - 0 2 CH CH N NH Cl
H Me H - 0 2 CH CH N NH Cl
H MeNH H - 0 2 CH CH N NH Cl
H Cl H - 0 2 CH CH N NH Cl
H F H - 0 2 CH CH N NH Cl
H NO 2 H - 0 2 CH CH N NH Cl
H CF3 H - 0 2 CH CH N NH Cl
H H H 0 0 2 CH CH N NH Cl
H MeO H 0 0 2 CH CH N NH Cl
H n-PrO H 0 0 2 CH CH N NH Cl
H n-CeHi 3O H 0 0 2 CH CH N NH Cl
H Me H 0 0 2 CH CH N NH Cl
H MeNH H 0 0 2 CH CH N NH Cl
H Cl H 0 0 2 CH CH N NH Cl
H F H 0 0 2 CH CH N NH Cl
H NO 2 H 0 0 2 CH CH N NH Cl
Figure imgf000075_0001
H OH H 0 0 2 CH CH N NH Cl
H CHO H 0 0 2 CH CH N NH Cl
Figure imgf000075_0002
H COOH H 0 0 2 CH CH N NH Cl
H CH3C(0) H 0 0 2 CH CH N NH ClO 2 NO 2 H 0 0 2 CH CH N NH ClO 2 H NO 2 0 0 2 CH CH N NH Cl
H CF3 H 0 0 2 CH CH N NH Cl
H H H 0 0 2 CH CH N 0 Cl
H MeO H 0 0 2 CH CH N 0 Cl
H n-PrO H 0 0 2 CH CH N 0 Cl
H n-CeHi 3O H 0 0 2 CH CH N 0 Cl
H Me H 0 0 2 CH CH N 0 Cl
H MeNH H 0 0 2 CH CH N 0 Cl
H Cl H 0 0 2 CH CH N 0 Cl
H F H 0 0 2 CH CH N 0 Cl
H NO 2 H 0 0 2 CH CH N 0 Cl 74
Ra Rb Rc L: L3 k X1 X3 X5 D R5
Figure imgf000076_0001
H H H 0 0 2 CH CH N 0 H
H MeO H 0 0 2 CH CH N 0 H
H n-PrO H 0 0 2 CH CH N 0 H
Figure imgf000076_0002
H Me H 0 0 2 CH CH N 0 H
H MeNH H 0 0 2 CH CH N 0 H
H Cl H 0 0 2 CH CH N 0 H
H F H 0 0 2 CH CH N 0 H
H NO 2 H 0 0 2 CH CH N 0 H
Figure imgf000076_0003
H H H 0 0 2 CH CH N NH H
H MeO H 0 0 2 CH CH N NH H
H n-PrO H 0 0 2 CH CH N NH H
H n-CeHi 3O H 0 0 2 CH CH N NH H
H Me H 0 0 2 CH CH N NH H
H MeNH H 0 0 2 CH CH N NH H
H Cl H 0 0 2 CH CH N NH H
H F H 0 0 2 CH CH N NH H
H NO 2 H 0 0 2 CH CH N NH H
Figure imgf000076_0004
H OH H 0 0 2 CH CH N NH H
H CHO H 0 0 2 CH CH N NH H
Figure imgf000076_0005
H COOH H 0 0 2 CH CH N NH H
H CH3C(0) H , 0 0 2 CH CH N NH HO 2 NO 2 H 0 0 2 CH CH N NH HO 2 H NO 2 0 0 2 CH CH N NH H
Figure imgf000076_0006
H H H 0 0 2 CH CH N NH Me
H MeO H 0 0 2 CH CH N NH Me
H n-PrO H 0 0 2 CH CH N NH Me
H n-CβHi 3O H 0 0 2 CH CH N NH Me
H Me H 0 0 2 CH CH N NH Me
H MeNH H 0 0 2 CH CH N NH Me
H Cl H 0 0 2 CH CH N NH Me
H F H 0 0 2 CH CH N NH Me Ra Rb Rc L1 L3 k V X3 X5 D R5
H NO 2 H 0 0 9 CH CH N NH Me
H CF3 H 0 0 2 CH CH N NH Me
H H H 0 0 2 CH CH N NH MeO
H MeO H 0 0 2 CH CH N NH MeO
H n-PrO H 0 0 9 CH CH N NH MeO
H n-CeHi 3O H 0 0 2 CH CH N NH MeO
H Me H 0 0 2 CH CH N NH MeO .
H MeNH H 0 0 2 CH CH N NH MeO
H Cl H 0 0 2 CH CH N NH MeO
H F H 0 0 2 CH CH N NH MeO
H NO 2 H 0 0 2 CH CH N NH MeO
H CF3 H 0 0 2 CH CH N NH MeO
H H H NH - 2 CH CH N NH Cl
H MeO H NH - 2 CH CH N NH Cl
H n-PrO H NH - 2 CH CH N NH Cl
H n-CeHi 3O H NH - 2 CH CH N NH Cl
H Me H NH - 2 CH CH N NH Cl
H MeNH H NH - 2 CH CH N NH Cl
H Cl H NH - 2 CH CH N NH Cl
H F H NH - 2 CH CH N NH Cl
H NO 2 H NH - 2 CH CH N NH Cl
H CF3 H NH - 2 CH CH N NH Cl
H H H - NH 2 CH CH N NH Cl
H MeO H - NH 2 CH CH N NH Cl
H n-PrO H - NH 2 CH CH N NH Cl
H n-CβHi 3O H - NH 2 CH CH N NH Cl
H Me H - NH 2 CH CH N NH Cl
H MeNH H - NH 2 CH CH N NH Cl
H Cl H - NH 2 CH CH N NH Cl
H F H - NH 2 CH CH N NH Cl
H NO 2 H - NH 2 CH CH N NH Cl
H CF3 H - NH 2 CH CH N NH Cl
H H H NH NH 2 CH CH N NH Cl
H MeO H NH NH 2 CH CH N NH Cl
H n-PrO H NH NH 2 CH CH N NH Cl
H n-CβHi 3O H NH NH 2 CH CH N NH Cl
H Me H NH NH 2 CH CH N NH Cl 76
Ra Rb Rc L1 L3 k X1 X3 Xs D R5
H MeNH H NH NH 2 CH CH N NH Cl
H Cl H NH NH 2 CH CH N NH Cl
H F H NH NH 2 CH CH N NH Cl
H NO 2 H NH NH 2 CH CH N NH Cl
H CF3 H NH NH 2 CH CH N NH Cl
H H H 0 0 3 CH CH N NH Cl
H MeO H 0 0 3 CH CH N NH Cl
H n-PrO H 0 0 3 CH CH N NH Cl
H n-CβHi 3O H 0 0 3 CH CH N NH Cl
H Me H 0 0 3 CH CH N NH Cl
H MeNH H 0 0 3 CH CH N NH Cl
H Cl H 0 0 3 CH CH N NH Cl
H F H 0 0 3 CH CH N NH Cl
H NO 2 H 0 0 3 CH CH N NH Cl
Figure imgf000078_0001
H OH H 0 0 3 CH CH N NH Cl
H CHO H 0 0 3 CH CH N NH Cl
Figure imgf000078_0002
H COOH H 0 0 3 CH CH N NH Cl
H CH3C(0) H 0 0 3 CH CH N NH ClO 2 NO 2 H 0 0 3 CH CH N NH ClO 2 H NO 2 0 0 3 CH CH N NH Cl
H CF3 H 0 0 3 CH CH N NH Cl
H H H 0 0 3 CH CH N 0 Cl
H MeO H 0 0 3 CH CH N 0 Cl
H n-PrO H , , 0 0 3 CH CH N 0 Cl
H n-CβHi 3O H 0 0 3 CH CH N 0 Cl
H Me H 0 0 3 CH CH N 0 Cl
H MeNH H 0 0 3 CH CH N 0 Cl
H Cl H 0 0 3 CH CH N 0 Cl
H F H 0 0 3 CH CH N 0 Cl
H NO 2 H 0 0 3 CH CH N 0 Cl
Figure imgf000078_0003
H H H 0 0 3 CH CH N NH H
H MeO H 0 0 3 CH CH N NH H
H n-PrO H 0 0 3 CH CH N NH H
H n-CeHi 3O H 0 0 3 CH CH N NH H Ra Rb Rc L1 L3 k X' X3 X5 D R5
H Me H 0 0 0 CH CH N NH H
H MeNH H 0 0 3 CH CH N NH H
H Cl H 0 0 3 CH CH N NH H
H F H 0 0 3 CH CH N NH H
H NO 2 H 0 0 3 CH CH N NH H
H NH2 H 0 0 3 CH CH N NH H
H OH H 0 0 3 CH CH N NH H .
H CHO H 0 0 3 CH CH N NH H
Figure imgf000079_0001
H COOH H 0 0 3 CH CH N NH H
H CH3C(0) H 0 0 3 CH CH N NH HO 2 NO 2 H 0 0 3 CH CH N NH HO 2 H NO 2 0 0 3 CH CH N NH H
Figure imgf000079_0002
H H H 0 0 3 CH CH N NH Me
H MeO H 0 0 3 CH CH N NH Me
H n-PrO H 0 0 3 CH CH N NH Me
H n-CβHi 3O H 0 0 3 CH CH N NH Me
H Me H 0 0 3 CH CH N NH Me
H MeNH H 0 0 3 CH CH N NH Me
H Cl H 0 0 3 CH CH N NH Me
H F H 0 0 3 CH CH N NH Me
H NO 2 H 0 0 3 CH CH N NH Me
H CF3 H 0 0 3 CH CH N NH Me
H H H 0 0 3 CH CH N NH MeO
H MeO H 0 0 3 CH CH N NH MeO
H n-PrO H 0 0 3 CH CH N NH MeO
Figure imgf000079_0003
H Me H 0 0 3 CH CH N NH MeO
H MeNH H 0 0 n CH CH N NH MeO
H Cl H 0 0 3 CH CH N NH MeO
H F H 0 0 3 CH CH N NH MeO
H NO 2 H 0 0 3 CH CH N NH MeO
Figure imgf000079_0004
H H H - - 1 N N CH NH Cl
H MeO H - - 1 N N CH NH Cl
H n-PrO H - - 1 N N CH NH Cl 7S
Ra R° Rc L' L3 k x! X3 X3 D R5
H n-CβHisO H _ _ 1 N N CH NH Cl
H Me H - - 1 N N CH NH Cl
H MeNH H - - 1 N N CH NH Cl
H Cl H - - 1 N N CH NH Cl
H F H - - 1 N N CH NH Cl
Figure imgf000080_0001
H H H 0 - 1 N N CH NH Cl
H MeO H 0 - 1 N N CH NH Cl
H n-PrO H 0 - 1 N N CH NH Cl
H n-CeHisO H 0 - 1 N N CH NH Cl
H Me H 0 - 1 N N CH NH Cl
H MeNH H 0 - 1 N N CH NH Cl
H Cl H 0 - 1 N N CH NH Cl
H F H 0 - 1 N N CH NH Cl
Figure imgf000080_0002
H CF3 H 0 - 1 N N CH NH Cl
H H H - 0 1 N N CH NH Cl
H MeO H - 0 1 N N CH NH Cl
H n-PrO H - 0 1 N N CH NH Cl
H n-CeHisO H - 0 1 N N CH NH Cl
H Me H - 0 1 N N CH NH Cl
H MeNH H - 0 1 N N CH NH Cl
H Cl H - 0 1 N N CH NH Cl
H F H - 0 1 N N CH NH Cl
Figure imgf000080_0003
H H H NH - 1 N N CH NH Cl
H MeO H NH - 1 N N CH NH Cl
H n-PrO H NH - 1 N N CH NH Cl
H n-C6Hi3θ H NH - 1 N N CH NH Cl
H Me H NH - 1 N N CH NH Cl
H MeNH H NH - 1 N N CH NH Cl
H Cl H NH - 1 N N CH NH Cl
H F H NH - 1 N N CH NH Cl
Figure imgf000080_0004
H CF3 H NH - 1 N N CH NH Cl
H H H - NH 1 N N CH NH Cl
H MeO H - NH 1 N N CH NH Cl
H n-PrO H - NH 1 N N CH NH Cl
H n-CβHi3θ H - NH 1 N N CH NH Cl
H Me H - NH 1 N N CH NH Cl
H MeNH H - NH 1 N N CH NH Cl
H Cl H - NH 1 N N CH NH Cl
H F H - NH 1 N N CH NH Cl
H NO 2 H - NH 1 N N CH NH Cl
Figure imgf000080_0005
Ra Rb R L1 L3 k X1 X3 X5 D R5
H H H _ _ 2 N N CH NH Cl
Figure imgf000081_0001
H n-PrO H - - 2 N N CH NH Cl
H n-CeHi 3O H - - 2 N N CH NH Cl
H Me H - - 2 N N CH NH Cl
H MeNH H - - 2 N N CH NH Cl
H Cl H - - 2 N N CH NH Cl .
H F H - - 2 N N CH NH Cl
H NO 2 H - - 2 N N CH NH Cl
Figure imgf000081_0002
H H H 0 - 2 N N CH NH Cl
H MeO H 0 - 2 N N CH NH Cl
H n-PrO H 0 - 2 N N CH NH Cl
H n-CeHi 3O H 0 - 2 N N CH NH Cl
H Me H 0 - 2 N N CH NH Cl
H MeNH H 0 - 2 N N CH NH Cl
H Cl H 0 - 2 N N CH NH Cl
H F H 0 - 2 N N CH NH Cl
Figure imgf000081_0003
H H H - 0 2 N N CH NH Cl
H MeO H - 0 2 N N CH NH Cl
H n-PrO H - 0 2 N N CH NH Cl
H n-CeHi 3O H - 0 2 N N CH NH Cl
H Me H - 0 2 N N CH NH Cl
H MeNH H - 0 2 N N CH NH Cl
H Cl H - 0 2 N N CH NH Cl
H F H - 0 2 N N CH NH Cl
H NO 2 H - 0 2 N N C.H NH Cl
Figure imgf000081_0004
H H H 0 0 2 N N CH NH Cl
H MeO H 0 0 2 N N CH NH Cl
H n-PrO H 0 0 2 N N CH NH Cl
H n-CeHi 3O H 0 0 2 N N CH NH Cl
H Me H - 0 0 2 N N CH NH Cl
H MeNH H 0 0 2 N N CH NH Cl
H Cl H 0 0 2 N N CH NH Cl so
Ra Rb Rc L1 L- k X1 X3 X5 D Rs
H F H _ 0 2 N N CH NH Cl
H NO 2 H - 0 2 N N CH NH Cl
H CF3 H - 0 2 N N CH NH Cl
H H H 0 0 2 N N CH NH Cl
H MeO H 0 0 2 N N CH NH Cl
H n-PrO H 0 0 2 N N CH NH Cl
H n-CeHi 3O H 0 0 2 N N CH NH Cl
H Me H 0 0 2 N N CH NH Cl
H MeNH H 0 0 2 N N CH NH Cl
H Cl H 0 0 2 N N CH NH Cl
H F H 0 0 2 N N CH NH Cl
H NO 2 H 0 0 2 N N CH NH Cl
Figure imgf000082_0001
H OH H 0 0 2 N N CH NH Cl
H CHO H 0 0 2 N N CH NH Cl
Figure imgf000082_0002
H COOH H 0 0 2 N N CH NH Cl
H CH3C(0) H 0 0 2 N N CH NH ClO NO 2 H 0 0 2 N N CH NH ClO 2 H NO 2 0 0 2 N N CH NH Cl
H CF3 H 0 0 2 N N CH NH Cl
H H H 0 0 2 N N CH 0 Cl
H MeO H 0 0 2 N N CH 0 Cl
H n-PrO H 0 0 2 N N CH 0 Cl
Figure imgf000082_0003
H Me H , , 0 0 2 N N CH 0 Cl
H MeNH H 0 0 2 N N CH 0 Cl
H Cl H 0 0 2 N N CH 0 Cl
H F H 0 0 2 N N CH 0 Cl
H NO 2 H 0 0 2 N N CH 0 Cl
Figure imgf000082_0004
H H H 0 0 2 N N CH 0 H
H MeO H 0 0 2 N N CH 0 H
H n-PrO H 0 0 2 N N CH 0 H
Figure imgf000082_0005
H Me H 0 0 2 N N CH 0 H
H MeNH H 0 0 2 N N CH 0 H SI
R1 Rb Rc L' L3 k X1 X3 X5 D R5
H Cl H 0 0 2 N N CH 0 H
H F H 0 0 2 N N CH 0 H
H NO 2 H 0 0 2 N N CH 0 H
Figure imgf000083_0001
H H H 0 0 2 N N CH NH H
H MeO H 0 0 2 N N CH NH H
H n-PrO H 0 0 2 N N CH NH H
Figure imgf000083_0002
H Me H 0 0 2 N N CH NH H
H MeNH H 0 0 2 N N CH NH H
H Cl H 0 0 2 N N CH NH H
H F H 0 0 2 N N CH NH H
H NO 2 H 0 0 2 N N CH NH H
Figure imgf000083_0003
H OH H 0 0 2 N N CH NH H
H CHO H 0 0 2 N N CH NH H
Figure imgf000083_0004
H COOH H 0 0 2 N N CH NH H
H CH3C(0) H 0 0 2 N N CH NH HO 2 NO 2 H 0 0 2 N N CH NH HO 2 H NO 2 0 0 2 N N CH NH H
H CF3 H 0 0 2 N N CH NH H
H H H 0 0 2 N N CH NH Me
H MeO H 0 0 2 N N CH NH Me
H n-PrO H 0 0 2 N N CH NH Me
H n-CeHi 3O H 0 0 2 N N CH NH Me
H Me H 0 0 2 N N CH NH Me
H MeNH H 0 0 2 N N CH NH Me
H Cl H 0 0 2 N N CH NH Me
H F H 0 0 2 N N CH NH Me
H NO 2 H 0 0 2 N N CH NH Me
Figure imgf000083_0005
H H H 0 0 2 N N CH NH MeO
H MeO H 0 0 2 N N CH NH MeO
H n-PrO H 0 0 2 N N CH NH MeO
H n-C6H.3θ H 0 0 2 N N CH NH MeO
H Me H 0 0 2 N N CH NH MeO S2
Ra Rb Rc V L3 k X1 X3 X5 D R5
H MeNH H 0 0 2 N N CH NH MeO
H Cl H 0 0 2 N N CH NH MeO
H F H 0 0 2 N N CH NH MeO
H NO 2 H 0 0 2 N N CH NH MeO
H CF3 H 0 0 2 N N CH NH MeO
H H H NH - 2 N N CH NH Cl
H MeO H NH - 2 N N CH NH Cl
H n-PrO H NH - 2 N N CH NH Cl
H n-CeHi 3O H NH - 2 N N CH NH Cl
H Me H NH - 2 N N CH NH Cl
H MeNH H NH - 2 N N CH NH Cl
H Cl H NH - 2 N N CH NH Cl
H F H NH - 2 N N CH NH Cl
H NO 2 H NH - 2 N N CH NH Cl
Figure imgf000084_0001
H H H - NH 2 N N CH NH Cl
H MeO H - NH 2 N N CH NH Cl
H n-PrO H - NH 2 N N CH NH Cl
H n-CeHi 3O H - NH 2 N N CH NH Cl
H Me H - NH 2 N N CH NH Cl
H MeNH H - NH 2 N N CH NH Cl
H Cl H - NH 2 N N CH NH Cl
H F H - NH 2 N N CH NH Cl
H NO 2 H - NH 2 N N CH NH Cl
H CF3 H - NH 2 N N CH NH Cl
H H H NH NH 2 N N CH NH Cl
H MeO H NH NH 2 N N CH NH Cl
H n-PrO H NH NH 2 N N CH NH Cl
H n-CeHi 3O H NH NH 2 N N CH NH Cl
H Me H NH NH 2 N N CH NH Cl
H MeNH H NH NH 2 N N CH NH Cl
H Cl H NH NH 2 N N CH NH Cl
H F H NH NH 2 N N CH NH Cl
H NO 2 H NH NH 2 N N CH NH Cl
H CF3 H NH NH 2 N N CH NH Cl
H H H 0 0 3 N N CH NH Cl
H MeO H 0 0 3 N N CH NH Cl S3
Ra Rb Rc V L3 k X' X3 X5 D R5
H n-PrO H 0 0 3 N N CH NH Cl
Figure imgf000085_0001
H Me H 0 0 3 N N CH NH Cl
H MeNH H 0 0 3 N N CH NH Cl
H Cl H 0 0 3 N N CH NH Cl
H F H 0 0 3 N N CH NH Cl
H NO 2 H 0 0 3 N N CH NH Cl
Figure imgf000085_0002
H OH H 0 0 3 N N CH NH Cl
H CHO H 0 0 3 N N CH NH Cl
Figure imgf000085_0003
H COOH H 0 0 3 N N CH NH Cl
H CH3C(0) H 0 0 3 N N CH NH Cl
Figure imgf000085_0004
H H H 0 0 3 N N CH 0 Cl
H MeO H 0 0 3 N N CH 0 Cl
H n-PrO H 0 0 3 N N CH 0 Cl
Figure imgf000085_0005
H Me H 0 0 3 N N CH 0 Cl
H MeNH H 0 0 3 N N CH 0 Cl
H Cl H 0 0 3 N N CH 0 Cl
H F H 0 0 3 N N CH 0 Cl
H NO 2 H 0 0 3 N N CH 0 Cl
H CF3 H 0 0 3 N N CH 0 Cl
H H H 0 0 3 N N CH NH H
H MeO H 0 0 3 N N CH NH H
H n-PrO H 0 0 3 N N CH NH H
Figure imgf000085_0006
H Me H 0 0 3 N N CH NH H
H MeNH H 0 0 3 N N CH NH H
H Cl H 0 0 3 N N CH NH H
H F H 0 0 3 N N CH NH H
H NO 2 H . 0 0 3 N N CH NH H
Figure imgf000085_0007
H OH H 0 0 3 N N CH NH H Ra Rb Rc Ll L3 k X' X X5 D R5
H CHO H 0 0 3 N N CH NH H
Figure imgf000086_0001
H COOH H 0 0 3 N N CH NH H
H CH3C(0) H 0 0 3 N N CH NH HO 2 NO 2 H 0 0 3 N N CH NH HO 2 H NO 2 0 0 3 N N CH NH H
H CF3 H 0 0 3 N N CH NH H
H H H 0 0 3 N N CH NH Me
H MeO H 0 0 3 N N CH NH Me
H n-PrO H 0 0 3 N N CH NH Me
H n-CβHi 3O H 0 0 3 N N CH NH Me
H Me H 0 0 3 N N CH NH Me
H MeNH H 0 0 3 N N CH NH Me
H Cl H 0 0 3 N N CH NH Me
H F H 0 0 3 N N CH NH Me
H NO 2 H 0 0 3 N N CH NH Me
H CF3 H 0 0 3 N N CH NH Me
H H H 0 0 3 N N CH NH MeO
H MeO H 0 0 3 N N CH NH MeO
H n-PrO H 0 0 3 N N CH NH MeO
H n-CδHi 3O H 0 0 3 N N CH NH MeO
H Me H 0 0 3 N N CH NH MeO
H MeNH H 0 0 3 N N CH NH MeO
H Cl H 0 0 3 N N CH NH MeO
H F H 0 0 3 N N CH NH MeO
H NO 2 H , , 0 0 3 N N CH NH MeO
H CF3 H 0 0 3 N N CH NH MeO
H H H - - 1 CH N N NH Cl
H MeO H - - 1 CH N N NH Cl
H n-PrO H - - 1 CH N N NH Cl
H n-CeHi 3O H - - 1 CH N N NH Cl
H Me H - - 1 CH N N NH Cl
H MeNH H - - 1 CH N N NH Cl
H Cl H - - 1 CH N N NH Cl
H F H - - 1 CH N N NH Cl
H NO 2 H - - 1 CH N N NH Cl
H CF3 H - - 1 CH N N NH Cl S5
Ra Rb Rc L1 L3 k V X3 X5 D R5
H H H 0 _ 1 CH N N NH Cl
H MeO H 0 - 1 CH N N NH Cl
H n-PrO H 0 - 1 CH N N NH Cl
H n-CeHi 3O H 0 - 1 CH N N NH Cl
H Me H 0 - 1 CH N N NH Cl
H MeNH H 0 - 1 CH N N NH Cl
H Cl H 0 - 1 CH N N NH Cl .
H F H 0 - 1 CH N N NH Cl
H NO 2 H 0 - 1 CH N N NH Cl
Figure imgf000087_0001
H H H - 0 1 CH N N NH Cl
H MeO H - 0 1 CH N N NH Cl
H n-PrO H - 0 1 CH N N NH Cl
H n-CeHi 3O H - 0 1 CH N N NH Cl
H Me H - 0 1 CH N N NH Cl
H MeNH H - 0 1 CH N N NH Cl
H Cl H - 0 1 CH N N NH Cl
H F H - 0 1 CH N N NH Cl
H NO 2 H - 0 1 CH N N NH Cl
Figure imgf000087_0002
H H H NH - 1 CH N N NH Cl
H MeO H NH - 1 CH N N NH Cl
H n-PrO H NH - 1 CH N N NH Cl
H n-CeHi 3O H NH - 1 CH N N NH Cl
H Me H NH - 1 CH N N NH Cl
H MeNH H NH - 1 CH N N NH Cl
H Cl H NH - 1 CH N N NH Cl
H F H NH - 1 CH N N NH Cl
H NO 2 H NH - 1 CH N N NH Cl
Figure imgf000087_0003
H H H - NH 1 CH N N NH Cl
H MeO H - NH 1 CH N N NH Cl
H n-PrO H - NH 1 CH N N NH Cl
H n-CeHi 3O H - NH 1 CH N N NH Cl
H Me H - NH 1 CH N N NH Cl
H MeNH H - NH 1 CH N N NH Cl
H Cl H - NH 1 CH N N NH Cl R1 Rb Rc L1 L3 k V X3 X3 D R5
H F H _ NH 1 CH N N NH Cl
H NO H - NH 1 CH N N NH Cl
Figure imgf000088_0001
H H H - - 2 CH N N NH Cl
H MeO H - - 2 CH N N NH Cl
H n-PrO H - - 2 CH N N NH Cl
H n-CeHi 3O H - - 2 CH N N NH Cl
H Me H - - 2 CH N N NH Cl
H MeNH H - - 2 CH N N NH Cl
H Cl H - - 2 CH N N NH Cl
H F H - - 2 CH N N NH Cl
H NO 2 H - - 2 CH N N NH Cl
H CF3 H - - 2 CH N N NH Cl
H H H 0 - 2 CH N N NH Cl
H MeO H 0 - 2 CH N N NH Cl
H n-PrO H 0 - 2 CH N N NH Cl
H n-CeHi 3O H 0 - 2 CH N N NH Cl
H Me H 0 - 2 CH N N NH Cl
H MeNH H 0 - 2 CH N N NH Cl
H Cl H 0 - 2 CH N N NH Cl
H F H 0 - 2 CH N N NH Cl
H NO 2 H 0 - 2 CH N N NH Cl
Figure imgf000088_0002
H H H - 0 2 CH N N NH Cl
H MeO H - 0 2 CH N N NH Cl
H n-PrO H 0 2 CH N N NH Cl
H n-CθHi 3O H - 0 2 CH N N NH Cl
H Me H - 0 2 CH N N NH Cl
H MeNH H - 0 2 CH N N NH Cl
H Cl H - 0 2 CH N N NH Cl
H F H - 0 2 CH N N NH Cl
Figure imgf000088_0003
H CF3 H - 0 2 CH N N NH Cl
H H H 0 0 2 CH N N NH Cl
H MeO H 0 0 2 CH N N NH Cl
H n-PrO H 0 0 2 CH N N NH Cl
H n-CeH 13O H 0 0 2 CH N N NH Cl Ra Rb Rc L1 L3 k X' X3 X5 D R3
H Me H 0 0 2 CH N N NH Cl
H MeNH H 0 0 2 CH N N NH Cl
H Cl H 0 0 2 CH N N NH Cl
H F H 0 0 2 CH N N NH Cl
H NO 2 H 0 0 2 CH N N NH Cl
Figure imgf000089_0001
H OH H 0 0 2 CH N N NH Cl.
H CHO H 0 0 2 CH N N NH Cl
Figure imgf000089_0002
H COOH H 0 0 2 CH N N NH Cl
H CH3C(0) H 0 0 2 CH N N NH Cl
Figure imgf000089_0003
H CF3 H 0 0 2 CH N N NH Cl
H H H 0 0 2 CH N N 0 Cl
H MeO H 0 0 2 CH N N 0 Cl
H n-PrO H 0 0 2 CH N N 0 Cl
Figure imgf000089_0004
H Me H 0 0 2 CH N N 0 Cl
H MeNH H 0 0 2 CH N N 0 Cl
H Cl H 0 0 2 CH N N 0 Cl
H F H 0 0 2 CH N N 0 Cl
H NO 2 H 0 0 2 CH N N 0 Cl
Figure imgf000089_0005
H H H 0 0 2 CH N N 0 H
H MeO H 0 0 2 CH N N 0 H
H n-PrO H 0 0 2 CH N N 0 H
Figure imgf000089_0006
H Me H 0 0 2 CH N N 0 H
H MeNH H 0 0 2 CH N N 0 H
H Cl H 0 0 2 CH N N 0 H
H F H 0 0 2 CH N N 0 H
H NO 2 H 0 0 2 CH N N 0 H
H CF3 H 0 0 2 CH N N 0 H
H H H. 0 0 2 CH N N NH H
H MeO H 0 0 2 CH N N NH H
H n-PrO H 0 0 2 CH N N NH H Ra Rb Rc L: L3 k X1 X3 X3 D R5
Figure imgf000090_0001
H Me H 0 0 2 CH N N NH H
H MeNH H 0 0 2 CH N N NH H
H Cl H 0 0 2 CH N N NH H
H F H 0 0 2 CH N N NH H
H NO 2 H 0 0 2 CH N N NH H
Figure imgf000090_0002
H OH H 0 0 2 CH N N NH H
H CHO H 0 0 2 CH N N NH H
Figure imgf000090_0003
H COOH H 0 0 2 CH N N NH H
H CH3C(0) H 0 0 2 CH N N NH HO 2 NO 2 H 0 0 2 CH N N NH H
Figure imgf000090_0004
H H H 0 0 2 CH N N NH Me
H MeO H 0 0 2 CH N N NH Me
H n-PrO H 0 0 2 CH N N NH Me
H n-CeHi 3O H 0 0 2 CH N N NH Me
H Me H 0 0 2 CH N N NH Me
H MeNH H 0 0 2 CH N N NH Me
H Cl H 0 0 2 CH N N NH Me
H F H 0 0 2 CH N N NH Me
H NO 2 H 0 0 2 CH N N NH Me
H CF3 H 0 0 2 CH N N NH Me
H H H , 0 0 2 CH N N NH MeO
H MeO H 0 0 2 CH N N NH MeO
H n-PrO H 0 0 2 CH N N NH MeO
H n-CβHi 3O H 0 0 2 CH N N NH MeO
H Me H 0 0 2 CH N N NH MeO
H MeNH H 0 0 2 CH N N NH MeO
H Cl H 0 0 2 CH N N NH MeO
H F H 0 0 2 CH N N NH MeO
H NO 2 H 0 0 2 CH N N NH MeO
Figure imgf000090_0005
H H H NH - 2 CH N N NH Cl
H MeO H NH - 2 CH N N NH Cl Ra Rb Rc V L3 k X' X3 X3 D R3
H n-PrO H NH _ 2 CH N N NH Cl
H n-CβHi 3O H NH - 2 CH N N NH Cl
H Me H NH - 2 CH N N NH Cl
H MeNH H NH - 2 CH N N NH Cl
H Cl H NH - 2 CH N N NH Cl
H F H NH - 2 CH N N NH Cl
Figure imgf000091_0001
H H H - NH 2 CH N N NH Cl
H MeO H - NH 2 CH N N NH Cl
H n-PrO H - NH 2 CH N N NH Cl
H n-CsHi 3O H - NH 2 CH N N NH Cl
H Me H - NH 2 CH N N NH Cl
H MeNH H - NH 2 CH N N NH Cl
H Cl H - NH 2 CH N N NH Cl
H F H - NH 2 CH N N NH Cl
Figure imgf000091_0002
H CF3 H - NH 2 CH N N NH Cl
H H H NH NH 2 CH N N NH Cl
H MeO H NH NH 2 CH N N NH Cl
H n-PrO H NH NH 2 CH N N NH Cl
H n-CeHi 3O H NH NH 2 CH N N NH Cl
H Me H NH NH 2 CH N N NH Cl
H MeNH H NH NH 2 CH N N NH Cl
H Cl H NH NH 2 CH N N NH Cl
H F H NH NH 2 CH N N NH Cl
H NO 2 H NH NH 2 CH N N NH Cl
Figure imgf000091_0003
H H H 0 0 3 CH N N NH Cl
H MeO H 0 0 3 CH N N NH Cl
H n-PrO H 0 0 3 CH N N NH Cl
H n-CeHi 3O H 0 0 3 CH N N NH Cl
H Me H 0 0 3 CH N N NH Cl
H MeNH H 0 0 3 CH N N NH Cl
H Cl H 0 0 3 CH N N NH Cl
H F H 0 0 3 CH N N NH Cl
H NO 2 H 0 0 3 CH N N NH Cl Ra Rb Rr L1 L3 k X' X3 X3 D R3
Figure imgf000092_0001
H OH H 0 0 0 CH N N NH Cl
H CHO H 0 0 3 CH N N NH Cl
Figure imgf000092_0002
H COOH H 0 0 3 CH N N NH Cl
H CH3C(0) H 0 0 3 CH N N NH Cl
Figure imgf000092_0003
H CF3 H 0 0 3 CH N N NH Cl
H H H 0 0 3 CH N N 0 Cl
H MeO H 0 0 3 CH N N 0 Cl
H n-PrO H 0 0 3 CH N N 0 Cl
Figure imgf000092_0004
H Me H 0 0 D CH N N 0 Cl
H MeNH H 0 0 3 CH N N 0 Cl
H Cl H 0 0 3 CH N N 0 Cl
H F H 0 0 3 CH N N 0 Cl
H NO 2 H 0 0 3 CH N N 0 Cl
H CF3 H 0 0 3 CH N N 0 Cl
H H H 0 0 3 CH N N NH H
H MeO H 0 0 3 CH N N NH H
H n-PrO H 0 0 3 CH N N NH H
Figure imgf000092_0005
H Me H 0 0 3 CH N N NH H
H MeNH H 0 0 3 CH N N NH H
H Cl H . 0 0 3 CH N N NH H
H F H 0 0 3 CH N N NH H
H NO 2 H 0 0 3 CH N N NH H
Figure imgf000092_0006
H OH H 0 0 3 CH N N NH H
H CHO H 0 0 3 CH N N NH H
Figure imgf000092_0007
H COOH H 0 0 3 CH N N NH H
H CH3C(0) H 0 0 3 CH N N NH H O 2 NO 2 H 0 0 3 CH N N NH H
Figure imgf000092_0008
Ra Rb Rc L! L3 k X1 X3 X5 D R3
H H H 0 0 0 CH N N NH Me
H MeO H 0 0 n 0 CH N N NH Me
H n-PrO H 0 0 CH N N NH Me
H n-CβHisO H 0 0 3 CH N N NH Me
H Me H 0 0 3 CH N N NH Me
H MeNH H 0 0 3 CH N N NH Me
H Cl H 0 0 3 CH N N NH Me
H F H 0 0 3 CH N N NH Me
H NO 2 H 0 0 3 CH N N NH Me
H CF3 H 0 0 3 CH N N NH Me
H H H 0 0 3 CH N N NH MeO
H MeO H 0 0 3 CH N N NH MeO
H n-PrO H 0 0 3 CH N N NH MeO
H n-CeHi sO H 0 0 3 CH N N NH MeO
H Me H 0 0 3 CH N N NH MeO
H MeNH H 0 0 3 CH N N NH MeO
H Cl H 0 0 3 CH N N NH MeO
H F H 0 0 3 CH N N NH MeO
Figure imgf000093_0001
H H H - - 1 N CH N NH Cl
H MeO H - - 1 N CH N NH Cl
H n-PrO H - - 1 N CH N NH Cl
H n-CeHi 3O H - - 1 N CH N NH Cl
H Me H - - 1 N CH N NH Cl
H Cl H - - 1 N CH N NH Cl
H F H - - 1 N CH N NH Cl
Figure imgf000093_0002
H H H 0 - 1 N CH N NH Cl
H MeO H 0 - 1 N CH N NH Cl
H n-PrO H 0 - 1 N CH N NH Cl
H n-CβHi 3O H 0 - 1 N CH N NH Cl
H Me H 0 - 1 N CH N NH Cl
H MeNH H 0 - 1 N CH N NH Cl
H Cl H 0 - 1 N CH N NH Cl
H F H 0 - 1 N CH N NH Cl
H NO 2 H 0 - 1 N CH N NH Cl Ra Rb Rc L L' k X1 X3 X5 D R5
Figure imgf000094_0001
H H H 0 1 N CH N NH Cl
H MeO H 0 1 N CH N NH Cl
H EtO H 0 1 N CH N NH Cl
H n-PrO H 0 1 N CH N NH Cl
H i-PrO H 0 1 N CH N NH Cl
H c-PrO H 0 1 N CH N NH Cl
H n-BuO H 0 1 N CH N NH Cl
Figure imgf000094_0002
H n-CsH O H 0 1 N CH N NH Cl
H n-C 10H210 H 0 1 N CH N NH Cl
H Me H 0 1 N CH N NH Cl
H Et H 0 1 N CH N NH Cl
H n-Pr H 0 1 N CH N NH Cl
H i-Pr H 0 1 N CH N NH Cl
H c-Pr H 0 1 N CH N NH Cl
H n-Bu H 0 1 N CH N NH Cl
Figure imgf000094_0003
H MeNH H 0 1 N CH N NH Cl
H EtNH H 0 1 N CH N NH Cl
H n-PrNH H 0 1 N CH N NH Cl
H i-PrNH H . 0 1 N CH N NH Cl
H c-PrNH H 0 1 N CH N NH Cl
H n-BuNH H 0 1 N CH N NH Cl
H n-CsH..NH H 0 1 N CH N NH Cl
H n-CδH.3NH H 0 1 N CH N NH Cl
H n-C.H NH H 0 1 N CH N NH Cl
H n-C.oH2iNH H 0 1 N CH N NH Cl
H Cl H 0 1 N CH N NH Cl
H F H 0 1 N CH N NH Cl
H Br H 0 1 N CH N NH Cl
H NO 2 H 0 1 N CH N NH Cl
Figure imgf000094_0004
Ra Rb Rc L' L3 k V X3 X3 D R3
H OH H _ 0 1 N CH N NH Cl
H CHO H - 0 1 N CH N NH Cl
Figure imgf000095_0001
H COOH H - 0 1 N CH N NH Cl
H CH3C(0) H - 0 1 N CH N NH Cl
Figure imgf000095_0002
H H H NH - 1 N CH N NH Cl
H MeO H NH - 1 N CH N NH Cl
H n-PrO H NH - 1 N CH N NH Cl
H n-CeHi 3O H NH - 1 N CH N NH Cl
H Me H NH - 1 N CH N NH Cl
H MeNH H NH - 1 N CH N NH Cl
H Cl H NH - 1 N CH N NH Cl
H F H NH - 1 N CH N NH Cl
H NO 2 H NH - 1 N CH N NH Cl
Figure imgf000095_0003
H H H - NH 1 N CH N NH Cl
H MeO H - NH 1 N CH N NH Cl
H EtO H - NH 1 N CH N NH Cl
H n-PrO H - NH 1 N CH N NH Cl
H i-PrO H - NH 1 N CH N NH Cl
H c-PrO H - NH ] N CH N NH Cl
H n-BuO H - NH 1 N CH N NH Cl
H n-CsHi i0 H - NH 1 N CH N NH Cl
H n-CβHi 3O H - NH 1 N CH N NH Cl
H n-CsH rO H - NH 1 N CH N NH Cl
H n-C 10H210 H - NH 1 N CH N NH Cl
H Me H - NH 1 N CH N NH Cl
H Et H - NH 1 N CH N NH Cl
H n-Pr H - NH 1 N CH N NH Cl
H i-Pr H - NH 1 N CH N NH Cl
H c-Pr H - NH 1 N CH N NH Cl
H n-Bu H - NH 1 N CH N NH Cl
H n-CsHi 1 H - NH 1 N CH N NH Cl
H n-CβH 13 H - NH 1 N CH N NH Cl Ra Rb Rc L L3 k x- X3 X3 D Rs
Figure imgf000096_0001
H n-C 10H21 H NH 1 N CH N NH Cl
H MeNH H NH 1 N CH N NH Cl
H EtNH H NH 1 N CH N NH Cl
H n-PrNH H NH 1 N CH N NH Cl
H i-PrNH H NH 1 N CH N NH Cl
H c-PrNH H NH 1 N CH N NH Cl
H n-BuNH H NH 1 N CH N NH Cl
H n-C5Hι iNH H NH 1 N CH N NH Cl
H n-CδH.sNH H NH 1 N CH N NH Cl
H n-C8H.7NH H NH 1 N CH N NH Cl
H n-CιoH2ιNH H NH 1 N CH N NH Cl
H Cl H NH 1 N CH N NH Cl
H F H NH 1 N CH N NH Cl
H Br H NH 1 N CH N NH Cl
H NO 2 H NH 1 N CH N NH Cl
Figure imgf000096_0002
H OH H NH 1 N CH N NH Cl
H CHO H NH 1 N CH N NH Cl
Figure imgf000096_0003
H COOH H NH 1 N CH N NH Cl
H CH3C(0) H NH 1 N CH N NH Cl
Figure imgf000096_0004
H H H , - 2 N CH N NH Cl
H MeO H - 2 N CH N NH Cl
H n-PrO H - 2 N CH N NH Cl
Figure imgf000096_0005
H Me H - 2 N CH N NH Cl
H MeNH H - 2 N CH N NH Cl
H Cl H - 2 N CH N NH Cl
H F H - 2 N CH N NH Cl
H NO 2 H - 2 N CH N NH Cl
H CF3 H - 2 N CH N NH Cl
H H H 0 2 N CH N NH Cl
H MeO H 0 2 N CH N NH Cl Ra Rb Rc L' V k X' X Xs D R3
H n-PrO H 0 - 2 N CH N H Cl
H n- -C e H 130 H 0 - 2 N CH N NH Cl
H Me H 0 - 2 N CH N NH Cl
H MeNH H 0 - 2 N CH N NH Cl
H Cl H 0 - 2 N CH N NH Cl
H F H 0 - 2 N CH N NH Cl
H NO 2 H 0 - 2 N CH N NH CJ
Figure imgf000097_0001
H H H - 0 2 N CH N NH Cl
MeO H H - 0 2 N CH N NH Cl
H MeO H - 0 2 N CH N NH Cl
H H MeO - 0 2 N CH N NH Cl
EtO H H - 0 2 N CH N NH Cl
H EtO H - 0 2 N CH N NH Cl
H H EtO - 0 Δ N CH N NH Cl n-PrO H H - 0 2 N CH N NH Cl
H n-PrO H - 0 2 N CH N NH Cl
H H n- -PrO - 0 2 N CH N NH Cl i-PrO H H - 0 2 N CH N NH Cl
Figure imgf000097_0002
H H i- -PrO - 0 2 N CH N NH Cl c-PrO H H - 0 2 N CH N NH Cl
H c-PrO H - 0 2 N CH N NH Cl
H H c- -PrO - 0 2 N CH N NH Cl n-BuO H H - 0 2 N CH N NH Cl
H n-BuO H - 0 2 N CH N NH Cl
H H n- -BuO - 0 2 N CH N NH Cl n-CsHnO H H - 0 2 N CH N NH Cl
H n- -CsHi iO H - 0 2 N CH N NH Cl
H H n-C 5H1 iO - 0 2 N CH N NH Cl n-CoHi 3O H H - 0 2 N CH N NH Cl
H n- -C 0 H 130 H - 0 2 N CH N NH Cl
H H n-C δHi sO - 0 2 N CH N NH Cl n-CβH O H H - 0 2 N CH N NH Cl
H n- -C8H.7θ H - 0 2 N CH N NH Cl
H H n-C ?H, 7θ - 0 2 N CH N NH Cl n-C 10H210 H H - 0 2 N CH N NH Cl Ra Rb Rc L1 L3 k X1 X3 X5 D R3
H n-C 10H21 0 H 0 2 N CH N NH Cl
H H n-C. oH !θ 0 9 N CH N NH Cl
Me H H 0 2 N CH N NH Cl
H Me H 0 2 N CH N NH Cl
H H Me 0 2 N CH N NH Cl
Et H H 0 2 N CH N NH Cl
H Et H 0 2 N CH N NH Cl
H H Et 0 2 N CH N NH Cl n-Pr H H 0 2 N CH N NH Cl
H n-Pr H 0 2 N CH N NH Cl
H H n-Pr 0 2 N CH N NH Cl i-Pr H H 0 2 N CH N NH Cl
H i-Pr H 0 2 N CH N NH Cl
Figure imgf000098_0001
c-Pr H H 0 2 N CH N NH Cl
H c-Pr H 0 2 N CH N NH Cl
H H c-Pr 0 2 N CH N NH Cl n-Bu H H 0 2 N CH N NH Cl
H n-Bu H 0 2 N CH N NH Cl
H H n-Bu 0 2 N CH N NH Cl
Figure imgf000098_0002
H H n-CsH 11 0 2 N CH N NH Cl
Figure imgf000098_0003
H H n - C s H 17 0 2 N CH N NH Cl
Figure imgf000098_0004
MeNH H H 0 2 N CH N NH Cl
H MeNH H 0 2 N CH N NH Cl
EtNH H H 0 2 N CH N NH Cl
H EtNH H 0 2 N CH N NH Cl n-PrNH H H 0 2 N CH N NH Cl Ra Rb Rc L1 L3 k X' X3 X3 D R5
Figure imgf000099_0001
i-PrNH H H 0 2 N CH N NH Cl
Figure imgf000099_0002
c-PrNH H H 0 2 N CH N NH Cl
H < :-PrNH H 0 2 N CH N NH Cl n-BuNH H H 0 2 N CH N NH Cl
Figure imgf000099_0003
n-CsHnNH H H 0 2 N CH N NH Cl
H n- -C.Hi.NH H 0 2 N CH N NH Cl n-CβH.sNH H H 0 2 N CH N NH Cl
H n- -CδHisNH H 0 2 N CH N NH Cl n-CsH NH H H 0 2 N CH N NH Cl
H n- -CsHi7NH H 0 2 N CH N NH Cl n-CιoH2ιNH H H 0 2 N CH N NH Cl
H n- -C0H21NH H 0 2 N CH N NH Cl
Cl H H 0 2 N CH N NH Cl
H Cl H 0 2 N CH N NH Cl
H H Cl 0 2 N CH N NH Cl
F H H 0 2 N CH N NH Cl
H F H 0 2 N CH N NH Cl
H H F 0 2 N CH N NH Cl
Br H H 0 2 N CH N NH Cl
H Br H 0 2 N CH N NH Cl
H H Br 0 2 N CH N NH Cl
NO 2 H H 0 2 N CH N NH Cl
H NO 2 H 0 2 N CH N NH Cl
Figure imgf000099_0004
OH H H 0 2 N CH N NH Cl
H OH H 0 2 N CH N NH Cl
H H OH 0 2 N CH N NH Cl
CHO H H 0 2 N CH N NH Cl
H CHO H 0 2 N CH N NH Cl
H H CHO 0 2 N CH N NH Cl
Figure imgf000099_0005
Figure imgf000100_0001
98
Ra Rb Rc L' L3 k X' X X5 D R5
Figure imgf000100_0002
COOH H H 0 2 N CH N NH Cl
H COOH H 0 2 N CH N NH Cl
H H COOH 0 2 N CH N NH Cl
CH3C(0) H H 0 2 N CH N NH Cl
H CH3C(0) H 0 2 N CH N NH Cl
H H CH3C(0) 0 2 N CH N NH Cl
Figure imgf000100_0003
CF3 H H 0 2 N CH N NH Cl
Figure imgf000100_0004
H H CF3 0 2 N CH N NH Cl
H H H 0 2 N CH N NH H
H MeO H 0 2 N CH N NH H
H n-PrO H 0 2 N CH N NH H
Figure imgf000100_0005
H Me H 0 2 N CH N NH H
H MeNH H 0 2 N CH N NH H
H Cl H 0 2 N CH N NH H
H F H 0 2 N CH N NH H
Figure imgf000100_0006
H CF3 H 0 2 N CH N NH H
H H H 0 2 N CH N NH Me
H MeO H 0 2 N CH N NH Me
H n-PrO H , - 0 2 N CH N NH Me
H n- -CδH130 H ' - 0 2 N CH N NH Me
H Me H 0 2 N CH N NH Me
H MeNH H 0 2 N CH N NH Me
H Cl H 0 2 N CH N NH Me
H F H 0 2 N CH N NH Me
H NO 2 H 0 2 N CH N NH Me
Figure imgf000100_0007
H H H 0 2 N CH N NH MeO
H MeO H 0 2 N CH N NH MeO
H n-PrO H 0 2 N CH N NH MeO
H n -CβHisO H 0 2 N CH N NH MeO o o o o o o c. CL) V <V KV> <ϋ <U
O O O O O O CD O O O CD CD O CD CD CD O O O CD CD
©
32 32 32 32 32 32 32 32 32 32 32 32 32
H 2: 2: 22 2; 2; 2: 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 2 2; 2: 2 2: 2: 2 2 U
Figure imgf000101_0001
Ra Rb Rc L1 L: k X1 X3 X3 D R3
H i-PrO H 0 0 2 N CH N NH Cl
H H i-PrO 0 0 2 N CH N NH Cl c-PrO H H 0 0 2 N CH N NH Cl
H c-PrO H 0 0 2 N CH N NH Cl
H H c-PrO 0 0 2 N CH N NH Cl n-BuO H H 0 0 2 N CH N NH Cl
H n-BuO H 0 0 2 N CH N NH Cl
H H n-BuO 0 0 2 N CH N NH Cl n-CsH..0 H H 0 0 2 N CH N NH Cl
H n- -C.Hi iO H 0 0 2 N CH N NH Cl
H H n- -CsHi .0 0 0 2 N CH N NH Cl n-CeH i 3O H H 0 0 2 N CH N NH Cl
H n- -CδHι30 H 0 0 2 N CH N NH Cl
H H n- -CeH130 0 0 2 N CH N NH Cl n-CsH O H H 0 0 2 N CH N NH Cl
H n- -C.Hi 7O H 0 0 2 N CH N NH Cl
H H n- -CsHi τO 0 0 2 N CH N NH Cl n-C 10H210 H H 0 0 2 N CH N NH Cl
H n- -C 1 oH 210 H 0 0 2 N CH N NH Cl
H H n- -C10H21O 0 0 2 N CH N NH Cl
Me H H 0 0 2 N CH N NH Cl
H Me H 0 0 2 N CH N NH Cl
H H Me 0 0 2 N CH N NH Cl
Et H H 0 0 2 N CH N NH Cl
H Et H 0 0 2 N CH N NH Cl
H H Et , 0 0 2 N CH N NH Cl n-Pr H H 0 0 2 N CH N NH Cl
H n-Pr H 0 0 2 N CH N NH Cl
H H n-Pr 0 0 2 N CH N NH Cl
Figure imgf000102_0001
H i-Pr H 0 0 2 N CH N NH Cl
H H i-Pr 0 0 2 N CH N NH Cl c-Pr H H 0 0 2 N CH N NH Cl
H c-Pr H 0 0 2 N CH N NH Cl
H H c-Pr 0 0 2 N CH N NH Cl n-Bu H H 0 0 2 N CH N NH Cl
H n-Bu H 0 0 2 N CH N NH Cl Ra Rb R-" L1 L3 k X1 X3 X5 D R3
H H n-Bu 0 0 2 N CH N NH Cl
Figure imgf000103_0001
H n-C 6 H 13 H 0 0 2 N CH N NH Cl
H H n-C 6 H 13 0 0 2 N CH N NH Cl
Figure imgf000103_0002
n-C .0H2 i H H 0 0 2 N CH N NH Cl
H n-C 10 H 21 H 0 0 2 N CH N NH Cl
H H n-C 1 oH: 1 0 0 2 N CH N NH Cl
MeNH H H 0 0 2 N CH N NH Cl
H MeNH H 0 0 9 N CH N NH Cl
EtNH H H 0 0 2 N CH N NH Cl
H EtNH H 0 0 2 N CH N NH Cl n-PrNH H H 0 0 9 N CH N NH Cl
H n-PrNH H 0 0 2 N CH N NH Cl i-PrNH H H 0 0 2 N CH N NH Cl
H i-PrNH H 0 0 2 N CH N NH Cl c-PrNH H H 0 0 2 N CH N NH Cl
H c-PrNH H 0 0 2 N CH N NH Cl n-BuNH H H 0 0 2 N CH N NH Cl
H n-BuNH H 0 0 2 N CH N NH Cl n-CsH..NH H H 0 0 2 N CH N NH Cl
H n -C5H..NH H 0 0 2 N CH N NH Cl n-CδH.3NH H H 0 0 2 N CH N NH Cl
H n -CδH.sNH H 0 0 2 N CH N NH Cl n-C.H NH H H 0 0 2 N CH N NH Cl
H n -CβH NH H 0 0 2 N CH N NH Cl n-C.0H2.NH H H 0 0 2 N CH N NH Cl
H n -C.0H2.NH H 0 0 2 N CH N NH Cl
Cl H H 0 0 2 N CH N NH Cl
H Cl H 0 0 2 N CH N NH Cl
H H Cl 0 0 2 N CH N NH Cl
F H H 0 0 2 N CH N NH Cl Ra Rb Rc L1 I "' k X1 X3 X3 D R3
H F H 0 0 2 N CH N NH Cl
H H F 0 0 2 N CH N NH Cl
Br H H 0 0 2 N CH N NH Cl
H Br H 0 0 2 N CH N NH Cl
H H Br 0 0 2 N CH N NH Cl
NO 2 H H 0 0 2 N CH N NH Cl
H NO 2 H 0 0 2 N CH N NH Cl
Figure imgf000104_0001
OH H H 0 0 2 N CH N NH Cl
H OH H 0 0 2 N CH N NH Cl
H H OH 0 0 2 N CH N NH Cl
CHO H H 0 0 2 N CH N NH Cl
H CHO H 0 0 2 N CH N NH Cl
H H CHO 0 0 2 N CH N NH Cl
Figure imgf000104_0002
COOH H H 0 0 2 N CH N NH Cl
H COOH H 0 0 2 N CH N NH Cl
H H COOH 0 0 2 N CH N NH Cl
CH3C(0) H H 0 0 2 N CH N NH Cl
H CH3C(0) H 0 0 2 N CH N NH Cl
H H CH3C(0), 0 0 2 N CH N NH Cl
Figure imgf000104_0003
CF3 H H 0 0 2 N CH N NH Cl
H CF3 H 0 0 2 N CH N NH Cl
Figure imgf000104_0004
H H H 0 0 2 N CC1 N NH Cl
H MeO H 0 0 2 N CC1 N NH Cl
H n-PrO H 0 0 2 N CC1 N NH Cl
H n -CδH.30 H 0 0 2 N CC1 N NH Cl
H Me H 0 0 2 N CC1 N NH Cl
H MeNH H 0 0 2 N CC1 N NH Cl Ra Rb R: L! L3 k X! X3 X5 D R3
H Cl H 0 0 2 N CC1 N NH Cl
H F H 0 0 2 N CC1 N NH Cl
H NO 2 H 0 0 2 N CC1 N NH Cl
H CF3 H 0 0 2 N CC1 N NH Cl
H H H 0 0 2 N CMe N NH Cl
H MeO H 0 0 2 N CMe N NH Cl
H n-PrO H 0 0 2 N CMe N NH Cl
H n-CβH i 3O H 0 0 2 N CMe N NH Cl
H Me H 0 0 2 N CMe N NH Cl
H MeNH H 0 0 2 N CMe N NH Cl
H Cl H 0 0 2 N CMe N NH Cl
H F H 0 0 2 N CMe N NH Cl
H NO 2 H 0 0 2 N CMe N NH Cl
H CF3 H 0 0 2 N CMe N NH Cl
H H H 0 0 2 N COMe N NH Cl
H MeO H 0 0 2 N COMe N NH Cl
H n-PrO H 0 0 2 N COMe N NH Cl
H n-CδHi 3O H 0 0 2 N COMe N NH Cl
H Me H 0 0 2 N COMe N NH Cl
H MeNH H 0 0 2 N COMe N NH Cl
H Cl H 0 0 2 N COMe N NH Cl
H F H 0 0 2 N COMe N NH Cl
H NO 2 H 0 0 2 N COMe N NH Cl
H CF3 H 0 0 2 N COMe N NH Cl
H H H 0 0 2 N CH N NH H
MeO H H 0 0 2 N CH N NH H
H MeO H 0 0 9 N CH N NH H
H H MeO 0 0 2 N CH N NH H
EtO H H 0 0 2 N CH N NH H
H EtO H 0 0 2 N CH N NH H
H H EtO 0 0 2 N CH N NH H n-PrO H H 0 0 2 N CH N NH H
H n-PrO H 0 0 2 N CH N NH H
H H n-PrO 0 0 2 N CH N NH H i-PrO H H- 0 0 2 N CH N NH H
H i-PrO H 0 0 2 N CH N NH H
H H i-PrO 0 0 2 N CH N NH H o-
©
32 32 32 32 32 32 32 32 32 32 rc rc 32 32 32
I I Z l Z Z Z Z Z Z Z 22 22 22 2 22 2 22 2: 22 2 2: 32 32 32 32 32 32 32 rC 32 32 2. 22 22 2: 2: 2: 2: 2 2: 2: 2:
H Q υ
22 2 22 2: 2: 2 22 22 2 2. 2 2 2 2. 2 2. X2 2 2 X. 22 2 X:
2. 22 22 22 2 2 22 22 2 2 22 2 2:
32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 *-^- CD O CD CD O O CD O CD CD O O CD CD CD CD O O O O O O O 32 32 32 32 32 32 32 32 32 32 CD CD CD O O O O O O O O O
22 2 2 2; 2 22 2 2; 2 22 2 2 2 2 2 2 2: 2. 22 2 2 2 2;
CM
CM Cx) N N N N N N M N N N N N N N W IM N IM N M N N N
CM CM CM CM CM CM CM C l CM CM CM
O O O O O O O O O O O O O O O O O O O O O O O O O
CD O O O O O O O O O O
O OO OOO OOOO OO OOOOOO OOO OO
OO O O OO O O O O
3 CQ I c
32 32
32 - o
I c
Figure imgf000106_0001
Ra Rb Rc L1 L3 k X! X3 X3 D R3
Figure imgf000107_0001
H H n- -C 5 H 11 0 0 2 N CH N NH H
Figure imgf000107_0002
H H n- -C 6 H 13 0 0 2 N CH N NH H
Figure imgf000107_0003
H H n- -C 1 H 2. 0 0 2 N CH N NH H
MeNH H H 0 0 2 N CH N NH H
H MeNH H 0 0 2 N CH N NH H
EtNH H H 0 0 2 N CH N NH H
H EtNH H 0 0 2 N CH N NH H n-PrNH H H 0 0 2 N CH N NH H
H n-PrNH H 0 0 2 N CH N NH H i-PrNH H H 0 0 2 N CH N NH H
H i-PrNH H 0 0 2 N CH N NH H c-PrNH H H 0 0 2 N CH N NH H
H c-PrNH H 0 0 2 N CH N NH H n-BuNH H H 0 0 2 N CH N NH H
H n-BuNH H 0 0 2 N CH N NH H n-C5H..NH H H 0 0 2 N CH N NH H
H in-CsH..NH H 0 0 2 N CH N NH H n-CδH.3NH H H 0 0 2 N CH N NH H
H 1n-CδH.3NH H 0 0 2 N CH N NH H n-C8H.7NH H H 0 0 2 N CH N NH H
H in-CoH,7NH H 0 0 2 N CH N NH H n-C.0H2.NH H H 0 0 2 N CH N NH H
H ;n-C.0H2.NH H 0 0 2 N CH N NH H
Cl H H 0 0 2 N CH N NH H
H Cl H 0 0 2 N CH N NH H
H H Cl 0 0 2 N CH N NH H
F H H 0 0 2 N CH N NH H
H F H 0 0 2 N CH N NH H
H H F 0 0 2 N CH N NH H Ra RD Rc L1 L3 k X' X3 X3 D R5
Br H H 0 0 2 N CH N NH H
H Br H 0 0 2 N CH N NH H
H H Br 0 0 2 N CH N NH H
NO 2 H H 0 0 2 N CH N NH H
H NO 2 H 0 0 2 N CH N NH H
H H NO 2 0 0 2 N CH N NH H
Figure imgf000108_0001
OH H H 0 0 2 N CH N NH H
H OH H 0 0 2 N CH N NH H
H H OH 0 0 2 N CH N NH H
CHO H H 0 0 2 N CH N NH H
H CHO H 0 0 2 N CH N NH H
H H CHO 0 0 2 N CH N NH H
Figure imgf000108_0002
COOH H H 0 0 2 N CH N NH H
H COOH H 0 0 2 N CH N NH H
H H COOH 0 0 2 N CH N NH H
CH3C(0) H H 0 0 2 N CH N NH H
H CH3C(0) H 0 0 2 N CH N NH H
H H CH3C(0) 0 0 2 N CH N NH H
Figure imgf000108_0003
H H CF3 0 0 2 N CH N NH H
H H H 0 0 2 N CC1 N NH H
H MeO H 0 0 2 N CC1 N NH H
H n-PrO H 0 0 2 N CC1 N NH H
H n -CδH.sO H 0 0 2 N CC1 N NH H
H Me H 0 0 2 N CC1 N NH H
H MeNH H 0 0 2 N CC1 N NH H
H Cl H 0 0 2 N CC1 N NH H
H F H 0 0 2 N CC1 N NH H Ra Rb Rc L1 L3 k X1 X3 Xs D R3
H NO 2 H 0 0 2 N CC1 N NH H
Figure imgf000109_0001
H H H 0 0 2 N CMe N NH H
H MeO H 0 0 2 N CMe N NH H
H n-PrO H 0 0 2 N CMe N NH H
H n-CβHi 3O H 0 0 2 N CMe N NH H
H Me H 0 0 2 N CMe N NH H
H MeNH H 0 0 2 N CMe N NH H
H Cl H 0 0 2 N CMe N NH H
H F H 0 0 2 N CMe N NH H
Figure imgf000109_0002
H H H 0 0 2 N COMe N NH H
H MeO H 0 0 2 N COMe N NH H
H n-PrO H 0 0 2 N COMe N NH H
H n - C 6 H 130 H 0 0 2 N COMe N NH H
H Me H 0 0 2 N COMe N NH H
H MeNH H 0 0 2 N COMe N NH H
H Cl H 0 0 2 N COMe N NH H
H F H 0 0 2 N COMe N NH H
Figure imgf000109_0003
H H H 0 0 2 N CH N NH Me
H MeO H 0 0 2 N CH N NH Me
H EtO H 0 0 2 N CH N NH Me
H n-PrO H 0 0 2 N CH N NH Me
H i-PrO H 0 0 2 N CH N NH Me
H c-PrO H 0 0 2 N CH N NH Me
H n-BuO H 0 0 2 N CH N NH e
H n-CδH..0 H 0 0 2 N CH N NH Me
H n-CβHi 3O H 0 0 2 N CH N NH Me
H n-C.H O H 0 0 2 N CH N NH Me
H n-C. H2.0 H 0 0 2 N CH N NH Me
H Me H 0 0 2 N CH N NH Me
H Et H 0 0 2 N CH N NH Me
H n-Pr H 0 0 2 N CH N NH Me
H i-Pr H 0 0 2 N CH N NH Me Ra Rb Rc L1 L3 k X1 X3 X5 D R3
H c-Pr H 0 0 2 N CH N NH Me
H n-Bu H 0 0 2 N CH N NH Me
Figure imgf000110_0001
H n-C .0H21 H 0 0 2 N CH N NH Me
H MeNH H 0 0 2 N CH N NH Me
H EtNH H 0 0 2 N CH N NH Me
H n-PrNH H 0 0 2 N CH N NH Me
H i-PrNH H 0 0 2 N CH N NH Me
H c-PrNH H 0 0 2 N CH N NH Me
H n-BuNH H 0 0 2 N CH N NH Me
H n-CsH..NH H 0 0 2 N CH N NH Me
H n-CδH.sNH H 0 0 2 N CH N NH Me
H n-C8H.7NH H 0 0 2 N CH N NH Me
H n-C.0H2.NH H 0 0 2 N CH N NH Me
H Cl H 0 0 2 N CH N NH Me
H F H 0 0 2 N CH N NH Me
H Br H 0 0 2 N CH N NH Me
Figure imgf000110_0002
H OH H 0 0 2 N CH N NH Me
H CHO H 0 0 2 N CH N NH Me
Figure imgf000110_0003
H COOH H 0 0 2 N CH N NH Me
H CH3C(0) H , 0 0 2 N CH N NH Me
Figure imgf000110_0004
H CF3 H 0 0 2 N CH N NH Me
H H H 0 0 2 N CH N NH MeO
H MeO H 0 0 2 N CH N NH MeO
H EtO H 0 0 2 N CH N NH MeO
H n-PrO H 0 0 2 N CH N NH MeO
H i-PrO H 0 0 2 N CH N NH MeO
H c-PrO H 0 0 2 N CH N NH MeO
H n-BuO H 0 0 2 N CH N NH MeO
H n-CsH..0 H 0 0 2 N CH N NH MeO Ra R° Rc L; L3 k X1 X3 X3 D R3
H n-Cδ H .30 H 0 0 9 N CH N NH MeO
H n-CsH.70 H 0 0 2 N CH N NH MeO
H n-C. o H 2.0 H 0 0 2 N CH N NH MeO
H Me H 0 0 2 N CH N NH MeO
H Et H 0 0 2 N CH N NH MeO
H n-Pr H 0 0 2 N CH N NH MeO
H i-Pr H 0 0 2 N CH N NH MeO
H c-Pr H 0 0 2 N CH N NH MeO
H n-Bu H 0 0 2 N CH N NH MeO
H n-CsH i i H 0 0 2 N CH N NH MeO
H n-C H i 3 H 0 0 2 N CH N NH MeO
H n-CsH .7 H 0 0 2 N CH N NH MeO
H n-C ι oH 2 i H 0 0 2 N CH N NH MeO
H MeNH H 0 0 2 N CH N NH MeO
H EtNH H 0 0 2 N CH N NH MeO
H n-PrNH H 0 0 2 N CH N NH MeO
H i-PrNH H 0 0 2 N CH N NH MeO
H c-PrNH H 0 0 2 N CH N NH MeO
H n-BuNH H 0 0 2 N CH N NH MeO
H n-CsH..NH H 0 0 2 N CH N NH MeO
H n-CδH.3NH H 0 0 2 N CH N NH MeO
H n-CϊH NH H 0 0 2 N CH N NH MeO
H n-C.0H2.NH H 0 0 2 N CH N NH MeO
H Cl H 0 0 2 N CH N NH MeO
H F H 0 0 2 N CH N NH MeO
H Br H 0 0 2 N CH N NH MeO
Figure imgf000111_0001
H OH H 0 0 2 N CH N NH MeO
H CHO H 0 0 2 N CH N NH MeO
Figure imgf000111_0002
H COOH H 0 0 2 N CH N NH MeO
H CH3C(0) H 0 0 2 N CH N NH MeO
Figure imgf000111_0003
H H H 0 0 2 N CH N NH n-PrO Ra Rb Rc L1 L3 k X' X3 X5 D R5
H MeO H 0 0 2 N CH N NH n-PrO
H EtO H 0 0 2 N CH N NH n-PrO
H n-PrO H 0 0 2 N CH N NH n-PrO
H i-PrO H 0 0 2 N CH N NH n-PrO
H c-PrO H 0 0 2 N CH N NH n-PrO
H n-BuO H 0 0 2 N CH N NH n-PrO
H n-CsH..0 H 0 0 2 N CH N NH n-PrO
H n-CβHi 3O H 0 0 2 N CH N NH n-PrO
H n-C8H.7θ H 0 0 2 N CH N NH n-PrO
H n-C 10H210 H 0 0 2 N CH N NH n-PrO
H Me H 0 0 2 N CH N NH n-PrO
H Et H 0 0 2 N CH N NH n-PrO
H n-Pr H 0 0 2 N CH N NH n-PrO
H i-Pr H 0 0 2 N CH N NH n-PrO
H c-Pr H 0 0 2 N CH N NH n-PrO
H n-Bu H 0 0 2 N CH N NH n-PrO
H n-CsH 11 H 0 0 2 N CH N NH n-PrO
H n-CβH 13 H 0 0 2 N CH N NH n-PrO
H n-CsHi H 0 0 2 N CH N NH n-PrO
H n-C 10H21 H 0 0 2 N CH N NH n-PrO
H MeNH H 0 0 2 N CH N NH n-PrO
H EtNH H 0 0 2 N CH N NH n-PrO
H n-PrNH H 0 0 2 N CH N NH n-PrO
H i-PrNH H 0 0 2 N CH N NH n-PrO
H c-PrNH H 0 0 2 N CH N NH n-PrO
H n-BuNH H . 0 0 2 N CH N NH n-PrO
H n-CsH..NH H 0 0 2 N CH N NH n-PrO
H n-CδH.3NH H 0 0 2 N CH N NH n-PrO
H n-C8H,7NH H 0 0 2 N CH N NH n-PrO
H n-C.0H2.NH H 0 0 2 N CH N NH n-PrO
H Cl H 0 0 2 N CH N NH n-PrO
H F H 0 0 2 N CH N NH n-PrO
H Br H 0 0 2 N CH N NH n-PrO
H NO 2 H 0 0 2 N CH N NH n-PrO
Figure imgf000112_0001
H OH H 0 0 2 N CH N NH n-PrO
H CHO H 0 0 2 N CH N NH n-PrO Ra R° Rc L1 L3 k λ" X: X5 D R5
H CH2OH H 0 0 9 N CH N H n-PrO
Figure imgf000113_0001
H CH3C(0) H 0 0 2 N CH N NH n-PrO O NO 2 H 0 0 2 N CH N NH n-PrO
Figure imgf000113_0002
H H H 0 0 2 N CH N 0 Cl
H MeO H 0 0 2 N CH N 0 Cl
H n-PrO H 0 0 2 N CH N 0 Cl
Figure imgf000113_0003
H Me H 0 0 2 N CH N 0 Cl
H MeNH H 0 0 2 N CH N 0 Cl
H Cl H 0 0 2 N CH N 0 Cl
H F H 0 0 2 N CH N 0 Cl
H NO 2 H 0 0 2 N CH N 0 Cl
Figure imgf000113_0004
H H H 0 0 2 N CH N 0 H
H MeO H 0 0 2 N CH N 0 H
H n-PrO H 0 0 2 N CH N 0 H
Figure imgf000113_0005
H Me H 0 0 2 N CH N 0 H
H MeNH H 0 0 2 N CH N 0 H
H Cl H 0 0 2 N CH N 0 H
H F H 0 0 2 N CH N 0 H
H NO 2 H 0 0 2 N CH N 0 H
Figure imgf000113_0006
H H H 0 0 2 N CH N 0 Me
H MeO H 0 0 N CH . N 0 Me
H n-PrO H 0 0 2 N CH N 0 Me
Figure imgf000113_0007
H Me H 0 0 2 N CH N 0 Me
H MeNH H 0 0 2 N CH N 0 Me
H Cl H 0 0 2 N CH N 0 Me
H F H ■ 0 0 2 N CH N 0 Me
Figure imgf000113_0008
Ra Rb Rc L' L3 k X" X3 Xs D R5
Figure imgf000114_0001
H H H 0 0 2 N CH N 0 MeO
H MeO H 0 0 2 N CH N 0 MeO
H n-PrO H 0 0 2 N CH N 0 MeO
H n-CβHi 3O H 0 0 2 N CH N 0 MeO
H Me H 0 0 2 N CH N 0 MeO
H MeNH H 0 0 2 N CH N 0 MeO
H Cl H 0 0 2 N CH N 0 MeO
H F H 0 0 2 N CH N 0 MeO
H NO 2 H 0 0 2 N CH N 0 MeO
Figure imgf000114_0002
H H H NH 0 2 N CH N NH Cl
H MeO H NH 0 2 N CH N NH Cl
H n-PrO H NH 0 2 N CH N NH Cl
H n-CeHi 3O H NH 0 2 N CH N NH Cl
H Me H NH 0 2 N CH N NH Cl
H MeNH H NH 0 2 N CH N NH Cl
H Cl H NH 0 2 N CH N NH Cl
H F H NH 0 2 N CH N NH Cl
H NO 2 H NH 0 2 N CH N NH Cl
Figure imgf000114_0003
H H H NH 0 2 N CH N NH H
H MeO H NH 0 2 N CH N NH H
H n-PrO H NH 0 2 N CH N NH H
H n-CβHi 3O H NH 0 2 N CH N NH H
H Me H , NH 0 2 N CH N NH H
H MeNH H NH 0 2 N CH N NH H
H Cl H NH 0 2 N CH N NH H
H F H NH 0 2 N CH N NH H
H NO 2 H NH 0 2 N CH N NH H
Figure imgf000114_0004
H H H NMe 0 2 N CH N NH Cl
H MeO H NMe 0 2 N CH N NH Cl
H n-PrO H NMe 0 2 N CH N NH Cl
H n-CβHi 3O H NMe 0 2 N CH N NH Cl
H Me H NMe 0 2 N CH N NH Cl
H MeNH H NMe 0 2 N CH N NH Cl Ra Rb Rc L1 LJ k X' X3 X3 D R3
H Cl H NMe 0 2 N CH N NH Cl
H F H NMe 0 2 N CH N NH Cl
H NO 2 H NMe 0 2 N CH N NH Cl
H CF3 H NMe 0 2 N CH N NH Cl
H H H NMe 0 2 N CH N NH H
H MeO H NMe 0 2 N CH N NH H
H n-PrO H NMe 0 2 N CH N NH ■ H
H n-CeHi 3O H NMe 0 2 N CH N NH H
H Me H NMe 0 2 N CH N NH H
H MeNH H NMe 0 2 N CH N NH H
H Cl H NMe 0 2 N CH N NH H
H F H NMe 0 2 N CH N NH H
H NO 2 H NMe 0 2 N CH N NH H
H CF3 H NMe 0 2 N CH N NH H
H H H 0 NH 2 N CH N NH Cl
H MeO H 0 NH 2 N CH N NH Cl
H n-PrO H 0 NH 2 N CH N NH Cl
H n-CeH 13O H 0 NH 2 N CH N NH Cl
H Me H 0 NH 2 N CH N NH Cl
H MeNH H 0 NH 2 N CH N NH Cl
H Cl H 0 NH 2 N CH N NH Cl
H F H 0 NH 2 N CH N NH Cl
H NO 2 H 0 NH 2 N CH N NH Cl
Figure imgf000115_0001
H H H 0 NH 2 N CH N NH H
H MeO H 0 NH 2 N CH N NH H
H n-PrO H 0 NH 2 N CH N NH H
H n-CeH.3O H 0 NH 2 N CH N NH H
H Me H 0 NH 2 N CH N NH H
H MeNH H 0 NH 2 N CH N NH H
H Cl H 0 NH 2 N CH N NH H
H F H 0 NH 2 N CH N NH H
H NO 2 H 0 NH 2 N CH N NH H
H CF3 H 0 NH 2 N CH N NH H
H H H NH - 2 N CH N NH Cl
H MeO H NH - 2 N CH N NH Cl
H n-PrO H NH - 2 N CH N NH Cl Ra Rb Rc L1 V k X1 X3 X5 D R5
H n-Cβ H i 30 H NH - 2 N CH N NH Cl
H Me H NH - 2 N CH N NH Cl
H MeNH H NH - 2 N CH N NH Cl
H Cl H NH - 2 N CH N NH Cl
H F H NH - 2 N CH N NH Cl
H CF3 H NH - 2 N CH N NH Cl
H H H - NH 9 N CH N NH Cl
H MeO H - NH 2 N CH N NH Cl
H EtO H - NH 2 N CH N NH Cl
H n-PrO H - NH 2 N CH N NH Cl
H i-PrO H - NH 2 N CH N NH Cl
H c-PrO H - NH 2 N CH N NH Cl
H n-BuO H - NH 2 N CH N NH Cl
H n-CsH..0 H - NH 2 N CH N NH Cl
H n-CeH.30 H - NH 2 N CH N NH Cl
H n-CsH.70 H - NH 2 N CH N NH Cl
H n-C.oH2.0 H - NH 2 N CH N NH Cl
H Me H - NH 2 N CH N NH Cl
H Et H - NH 2 N CH N NH Cl
H n-Pr H - NH 2 N CH N NH Cl
H i-Pr H - NH 2 N CH N NH Cl
H c-Pr H - NH 2 N CH N NH Cl
H n-Bu H - NH 2 , . N CH N NH Cl
H n-CδH i i H - NH 2 N CH N NH Cl
H n-CβH i 3 H - NH 2 N CH N NH Cl
H n-CβHi 7 H . - NH 2 N CH N NH Cl
H n-C 10H2 i H - NH 2 N CH N NH Cl
H MeNH H - NH 2 N CH N NH Cl
H n-PrNH H - NH 2 N CH N NH Cl
H i-PrNH H - NH 2 N CH N NH Cl
H c-PrNH H - NH 2 N CH N NH Cl
H n-BuNH H - NH 2 N CH N NH Cl
H n-C5H. ,NH H - NH 2 N CH N NH Cl
H n-CδH.3NH H - NH 2 N CH N NH Cl
H n-C8H,7NH H - NH 2 N CH N NH Cl
H n-C.0H2.NH H - NH 2 N CH N NH Cl
H Cl H - NH 2 N CH N NH Cl Ra Rb R L1 LJ k X1 X! X3 D R3
H F H _ NH 2 N CH N NH Cl
H Br H - NH 2 N CH X NH Cl
H NO 2 H - NH 2 N CH N NH Cl
H NH.> H - NH 2 N CH N NH Cl
H OH H - NH 2 N CH N NH Cl
H CHO H - NH 2 N CH N NH Cl
Figure imgf000117_0001
H COOH H - NH 2 N CH N NH Cl
H CH3C(0) H - NH 2 N CH N NH Cl
Figure imgf000117_0002
H H H NH NH 2 N CH N NH Cl
H MeO H NH NH 2 N CH N NH Cl
H n-PrO H NH NH 2 N CH N NH Cl
H n-CδH.30 H NH NH 2 N CH N NH Cl
H Me H NH NH 2 N CH N NH Cl
H MeNH H NH NH 2 N CH N NH Cl
H Cl H NH NH 2 N CH N NH Cl
H F H NH NH 2 N CH N NH Cl
H NO 2 H NH NH 2 N CH N NH Cl
Figure imgf000117_0003
H H H - - 3 N CH N NH Cl
H MeO H - - 3 N CH N NH Cl
H n-PrO H - - 3 N CH N NH Cl
H n-CeHi 3O H - - 3 N CH N NH Cl
H Me H - - 3 N CH N NH Cl
H MeNH H - - 3 N CH N NH Cl
H Cl H - - 3 N CH N NH Cl
H F H - - 3 N CH N NH Cl
H NO 2 H - - 3 N CH N NH Cl
Figure imgf000117_0004
H H H 0 - 3 N CH N NH Cl
H MeO H 0 - 3 N CH N NH Cl
H n-PrO H 0 - 3 N CH N NH Cl
H Me H 0 - 3 N CH N NH Cl
H MeNH H 0 - 3 N CH N NH Cl Ra RD Rc L1 L3 k x: X3 X3 D R5
H Cl H 0 _ n 0 N CH N NH Cl
H F H 0 - N CH N NH Cl
H NO 2 H 0 - 3 N CH N NH Cl
H CF3 H 0 - 3 N CH N NH Cl
H H H - 0 3 N CH N NH Cl
H MeO H - 0 D N CH N NH Cl
H EtO H - 0 3 N CH N NH Cl
H n-PrO H - 0 0 N CH N NH Cl
H i-PrO H - 0 3 N CH N NH Cl
H c-PrO H - 0 3 N CH N NH Cl
H n-BuO H - 0 3 N CH N NH Cl
H n-CsH..0 H - 0 3 N CH N NH Cl
H n-CβHi 3O H - 0 3 N CH N NH Cl
H n-CsH.7O H - 0 3 N CH N NH Cl
H n-CioHaiO H - 0 0 N CH N NH Cl
H Me H - 0 3 N CH N NH Cl
H Et H - 0 3 N CH N NH Cl
H n-Pr H - 0 3 N CH N NH Cl
H i-Pr H - 0 3 N CH N NH Cl
H c-Pr H - 0 3 N CH N NH Cl
H n-Bu H - 0 3 N CH N NH Cl
Figure imgf000118_0001
H n-C .0 H 21 H - 0 3 N CH N NH Cl
H MeNH H , - 0 3 N CH N NH Cl
H EtNH H - 0 3 N CH N NH Cl
H n-PrNH H - 0 3 N CH N NH Cl
H i-PrNH H - 0 0 N CH •N NH Cl
H c-PrNH H - 0 3 N CH N NH Cl
H n-BuNH H - 0 3 N CH N NH Cl
H n-CsH..NH H - 0 3 N CH N NH Cl
H n-CeH.3NH H - 0 3 N CH N NH Cl
H n-CβH NH H - 0 3 N CH N NH Cl
H n-C.0H2.NH H - 0 3 N CH N NH Cl
H Cl H - 0 3 N CH N NH Cl
H F H - 0 D N CH N NH Cl Ra Rb Rc L' L3 k X' X3 X3 D R3
H Br H _ 0 3 N CH N NH Cl
H NO 2 H - 0 3 N CH N NH Cl
Figure imgf000119_0001
H OH H - 0 3 N CH N NH Cl
H CHO H - 0 3 N CH N NH Cl
Figure imgf000119_0002
H COOH H - 0 3 N CH N NH Cl
H CH3C(0) H - 0 3 N CH N NH Cl
Figure imgf000119_0003
H H H 0 0 3 N CH N NH Cl
H MeO H 0 0 3 N CH N NH Cl
H EtO H 0 0 3 N CH N NH Cl
H n-PrO H 0 0 3 N CH N NH Cl
H i-PrO H 0 0 3 N CH N NH Cl
H c-PrO H 0 0 3 N CH N NH Cl
H n-BuO H 0 0 3 N CH N NH Cl
H n-CsH..0 H 0 0 3 N CH N NH Cl
H n-CeHi 3O H 0 0 3 N CH N NH Cl
H n-CβH O H 0 0 3 N CH N NH Cl
H n-C 10H210 H 0 0 3 N CH N NH Cl
H Me H 0 0 3 N CH N NH Cl
H Et H 0 0 3 N CH N NH Cl
H n-Pr H 0 0 3 N CH N NH Cl
H i-Pr H 0 0 3 N CH N NH Cl
H c-Pr H 0 0 3 N CH N NH Cl
H n-Bu H 0 0 3 N CH N NH Cl
H n-CsH 11 H 0 0 3 N CH N NH Cl
Figure imgf000119_0004
H n-CsH 17 H 0 0 3 N CH N NH Cl
H n-C .0H21 H 0 0 3 N CH N NH Cl
H MeNH H 0 0 3 N CH N NH Cl
H EtNH H 0 0 3 N CH N NH Cl
H n-PrNH H 0 0 3 N CH N NH Cl
H i-PrNH H 0 0 3 N CH N NH Cl
H c-PrNH H 0 0 3 N CH N NH Cl Ra Rb Rc Ll L3 k X' X3 X5 D R3
H n-BuNH H 0 0 3 N CH N NH Cl
H n-C5H..NH H 0 0 0 N CH N NH Cl
H n-CδH.3NH H 0 0 3 N CH N NH Cl
H n-C8H.7NH H 0 0 3 N CH N NH Cl
Figure imgf000120_0001
H Cl H 0 0 0 N CH N NH Cl
H F H 0 0 3 N CH N NH Cl
H Br H 0 0 3 N CH N NH Cl
H NO 2 H 0 0 3 N CH N NH Cl
Figure imgf000120_0002
H OH H 0 0 3 N CH N NH Cl
H CHO H 0 0 3 N CH N NH Cl
Figure imgf000120_0003
H COOH H 0 0 3 N CH N NH Cl
H CH3C(0) H 0 0 3 N CH N NH Cl
Figure imgf000120_0004
H H H 0 0 3 N CC1 N NH Cl
H MeO H 0 0 3 N CC1 N NH Cl
H n-PrO H 0 0 3 N CC1 N NH Cl
H n-CβHi 3O H 0 0 3 N CC1 N NH Cl
H Me H 0 0 3 N CC1 N NH Cl
H MeNH H 0 0 3 N CC1 N NH Cl
H Cl H 0 0 3 N CC1 N NH Cl
H F H , 0 0 3 N CC1 N NH Cl
H NO 2 H 0 0 3 N CC1 N NH Cl
H CF3 H 0 0 3 N CC1 N NH Cl
H H H 0 0 3 N CMe N NH Cl
H MeO H 0 0 3 N CMe N NH Cl
H n-PrO H 0 0 3 N CMe N NH Cl
H n-CβHi 3O H 0 0 3 N CMe N NH Cl
H Me H 0 0 3 N CMe N NH Cl
H MeNH H 0 0 3 N CMe N NH Cl
H Cl H 0 0 3 N CMe N NH Cl
H F H 0 0 3 N CMe N NH Cl
H NO 2 H 0 0 3 N CMe N NH Cl Ra Rb Rc L' L3 k X1 X3 X5 D R3
H CF3 H 0 0 3 N CMe N H Cl
H H H 0 0 3 N COMe N NH Cl
H MeO H 0 0 3 N COMe N NH Cl
H n-PrO H 0 0 3 N COMe N NH Cl
H n-CeHi 3O H 0 0 3 N COMe N NH Cl
H Me H 0 0 3 N COMe N NH Cl
H MeNH H 0 0 3 N COMe N NH Cl
H Cl H 0 0 3 N COMe N NH Cl
H F H 0 0 3 N COMe N NH Cl
H NO 2 H 0 0 3 N COMe N NH Cl
Figure imgf000121_0001
H H H 0 0 3 N CH N NH H
H MeO H 0 0 3 N CH N NH H
H EtO H 0 0 3 N CH N NH H
H n-PrO H 0 0 3 N CH N NH H
H i-PrO H 0 0 3 N CH N NH H
H c-PrO H 0 0 3 N CH N NH H
H n-BuO H 0 0 3 N CH N NH H
H n-CsH..0 H 0 0 3 N CH N NH H
Figure imgf000121_0002
H n-C 10H210 H 0 0 3 N CH N NH H
H Me H 0 0 3 N CH N NH H
H Et H 0 0 3 N CH N NH H
H n-Pr H 0 0 3 N CH N NH H
H i-Pr H 0 0 3 N CH N NH H
H c-Pr H 0 0 3 N CH N NH H
H n-Bu H 0 0 3 N CH N NH H
Figure imgf000121_0003
H n-C 1 oH 21 H 0 0 3 N CH N NH H
H MeNH H 0 0 3 N CH N NH H
H EtNH H 0 0 3 N CH N NH H
H n-PrNH H 0 0 3 N CH N NH H
H i-PrNH H 0 0 3 N CH N NH H
H c-PrNH H 0 0 3 N CH N NH H Ra Rb Rc L' L3 k X' X X3 D R5
H n-BuNH H 0 0 3 N CH N NH H
H n-CsHnNH H 0 0 3 N CH N NH H
H n-CeHi 3NH H 0 0 3 N CH N NH H
H n-CβH.7NH H 0 0 3 N CH N NH H
H n-C.0H2.NH H 0 0 3 N CH N NH H
H Cl H 0 0 3 N CH N NH H
H F H 0 0 3 N CH N NH H .
H Br H 0 0 3 N CH N NH H
H NO 2 H 0 0 3 N CH N NH H
Figure imgf000122_0001
H OH H 0 0 3 N CH N NH H
H CHO H 0 0 3 N CH N NH H
Figure imgf000122_0002
H COOH H 0 0 3 N CH N NH H
H CH3C(0) H 0 0 3 N CH N NH HO 2 NO 2 H 0 0 3 N CH N NH H
Figure imgf000122_0003
H CF3 H 0 0 3 N CH N NH H
H H H 0 0 3 N CC1 N NH H
H MeO H 0 0 3 N CC1 N NH H
H n-PrO H 0 0 3 N CC1 N NH H
H n-CeHi 3O H 0 0 3 N CC1 N NH H
H Me H 0 0 3 N CCl N NH H
H MeNH H 0 0 3 N CC1 N NH H
H Cl H 0 0 3 N CCl N NH H
H F H , 0 0 3 N CCl N NH H
H NO 2 H 0 0 3 N CCl N NH H
Figure imgf000122_0004
H H H 0 0 3 N CMe N NH H
H MeO H 0 0 3 N CMe N NH H
H n-PrO H 0 0 3 N CMe N NH H
H n-CβHi 3O H 0 0 3 N CMe N NH H
H Me H 0 0 3 N CMe N NH H
H MeNH H 0 0 3 N CMe N NH H
H Cl H 0 0 3 N CMe N NH H
H F H 0 0 3 N CMe N NH H
H NO 2 H 0 0 3 N CMe N NH H Ra Rb Rc L1 L3 k X' X X3 D R3
H CF3 H 0 0 3 N CMe N NH H
H H H 0 0 ύ N COMe N NH H
H MeO H 0 0 0 D N COMe N NH H
H n-PrO H 0 0 3 N COMe N NH H
H n-CeH.3O H 0 0 3 N COMe N NH H
H Me H 0 0 3 N COMe N NH H
H MeNH H 0 0 3 N COMe N NH H
H Cl H 0 0 3 N COMe N NH H
H F H 0 0 3 N COMe N NH H
H NO 2 H 0 0 3 N COMe N NH H
Figure imgf000123_0001
H H H 0 0 3 N CH N NH Me
H MeO H 0 0 3 N CH N NH Me
H EtO H 0 0 3 N CH N NH Me
H n-PrO H 0 0 3 N CH N NH Me
H i-PrO H 0 0 3 N CH N NH Me
H c-PrO H 0 0 3 N CH N NH Me
H n-BuO H 0 0 3 N CH N NH Me
H n-CsH..0 H 0 0 3 N CH N NH Me
H n-CeHi 3O H 0 0 3 N CH N NH Me
H n-CsH O H 0 0 3 N CH N NH Me
H n-C 10H2 iO H 0 0 3 N CH N NH Me
H Me H 0 0 3 N CH N NH Me
H Et H 0 0 3 N CH N NH Me
H n-Pr H 0 0 3 N CH N NH Me
H i-Pr H 0 0 3 N CH N NH Me
H c-Pr H 0 0 3 N CH N NH Me
H n-Bu H 0 0 3 N CH N NH Me
H n-CsH 1. H 0 0 3 N CH N NH Me
H n-C e H 13 H 0 0 3 N CH N NH Me
Figure imgf000123_0002
H n-C 10H21 H 0 0 3 N CH N NH Me
H MeNH H 0 0 3 N CH N NH Me
H EtNH H 0 0 3 N CH N NH Me
H n-PrNH H 0 0 3 N CH N NH Me
Figure imgf000123_0003
H c-PrNH H 0 0 3 N CH N NH Me Ra Rb Rc L1 L3 k X' X3 X3 D R5
H n-BuNH H 0 0 3 N CH N NH Me
H n-CsH..NH H 0 0 3 N CH N NH Me
H n-CeH.3NH H 0 0 3 N CH N NH Me
H n-C8H.7NH H 0 0 3 N CH N NH Me
H n-C.0H2.NH H 0 0 3 N CH N NH Me
H Cl H 0 0 3 N CH N NH Me
H F H 0 0 3 N CH N NH Me
H Br H 0 0 3 N CH N NH Me
H NO 2 H 0 0 3 N CH N NH Me
Figure imgf000124_0001
H OH H 0 0 3 N CH N NH Me
H CHO H 0 0 3 N CH N NH Me
Figure imgf000124_0002
H COOH H 0 0 D N CH N NH Me
H CH3C(0) H 0 0 3 N CH N NH MeO 2 NO 2 H 0 0 3 N CH N NH MeO 2 H NO 2 0 0 3 N CH N NH Me
H CF3 H 0 0 3 N CH N NH Me
H H H 0 0 3 N CH N NH MeO
H MeO H 0 0 3 N CH N NH MeO
H EtO H 0 0 3 N CH N NH MeO
H n-PrO H 0 0 3 N CH N NH MeO
H i-PrO H 0 0 3 N CH N NH MeO
H c-PrO H 0 0 3 N CH N NH MeO
H n-BuO H 0 0 3 N CH N NH MeO
H n-CsH..0 H , 0 0 3 N CH N NH MeO
H n-CeH.3O H 0 0 3 N CH N NH MeO
H n-CβH.70 H 0 0 3 N CH N NH MeO
H n-C 10H2 iO H 0 0 3 N CH N NH MeO
H Me H 0 0 3 N CH N NH MeO
H Et H 0 0 3 N CH N NH MeO
H n-Pr H 0 0 3 N CH N NH MeO
H i-Pr H 0 0 3 N CH N NH MeO
H c-Pr H 0 0 3 N CH N NH MeO
H n-Bu H 0 0 3 N CH N NH MeO
H n-CsH.1 H 0 0 3 N CH N NH MeO
H n-CeH .3 H 0 0 3 N CH N NH MeO Ra Rb Rc L1 L3 k X1 X3 X3 D R3
H n-CsH 1 r H 0 0 0 X CH X XH MeO
Figure imgf000125_0001
H MeNH H 0 0 D X CH N NH MeO
H EtNH H 0 0 3 X CH N NH MeO
H n-PrNH H 0 0 3 X CH N NH MeO
H i-PrNH H 0 0 3 N CH N NH MeO
H c-PrNH H 0 0 3 N CH N NH MeO
H n-BuNH H 0 0 3 N CH N NH MeO
H n-CsH..NH H 0 0 3 X CH N NH MeO
H n-CeH.3NH H 0 0 3 N CH N NH MeO
H n-CβH NH H 0 0 0 0 N CH N NH MeO
H n-C.0H2.NH H 0 0 3 N CH N NH MeO
H Cl H 0 0 3 N CH N NH MeO
H F H 0 0 0 N CH N NH MeO
H Br H 0 0 3 X CH N NH MeO
H NO 2 H 0 0 n 0 X CH N NH MeO
Figure imgf000125_0002
H OH H 0 0 3 N CH N NH MeO
H CHO H 0 0 3 N CH N NH MeO
Figure imgf000125_0003
H COOH H 0 0 3 N CH N NH MeO
H CH3C(0) H 0 0 3 N CH N NH MeO O 2 NO 2 H 0 0 3 N CH N NH MeO
Figure imgf000125_0004
H CF3 H 0 0 3 N CH N NH MeO
H H H 0 0 3 N CH N NH n-PrO
H MeO H 0 0 3 N CH N NH n-PrO
H EtO H 0 0 n O N CH N NH n-PrO
H n-PrO H 0 0 n N CH N NH n-PrO
H i-PrO H 0 0 3 N CH N NH n-PrO
H c-PrO H 0 0 n O N CH N NH n-PrO
H n-BuO H 0 0 n N CH N NH n-PrO
H n-CsH..0 H 0 0 3 N CH N NH n-PrO
H n-CβHi 3O H 0 0 3 N CH N NH n-PrO
H n-C«H.7θ H 0 0 3 N CH N NH n-PrO
H n-C 10H210 H 0 0 3 N CH N NH n-PrO
H Me H 0 0 3 N CH N NH n-PrO Ra Rb Rc L1 L3 k X1 X3 X5 D R5
H Et H 0 0 3 N CH N NH n-PrO
H n-Pr H 0 0 3 N CH N NH n-PrO
H i-Pr H 0 0 3 N CH N NH n-PrO
H c-Pr H 0 0 3 N CH N NH n-PrO
H n-Bu H 0 0 3 N CH N NH n-PrO
H n-CsHi 1 H 0 0 3 N CH N NH n-PrO
H n-CβH.3 H 0 0 3 N CH N NH n-PrO
H n-CsHi 7 H 0 0 3 N CH N NH n-PrO
H n-C 10H21 H 0 0 3 N CH N NH n-PrO
H MeNH H 0 0 3 N CH N NH n-PrO
H EtNH H 0 0 3 N CH N NH n-PrO
H n-PrNH H 0 0 3 N CH N NH n-PrO
H i-PrNH H 0 0 3 N CH N NH n-PrO
H c-PrNH H 0 0 3 N CH N NH n-PrO
H n-BuNH H 0 0 3 N CH N NH n-PrO
H n-CsH. iNH H 0 0 3 N CH N NH n-PrO
H n-CeH.3NH H 0 0 3 N CH N NH n-PrO
H n-CsH NH H 0 0 3 N CH N NH n-PrO
H n-C.0H2.NH H 0 0 3 N CH N NH n-PrO
H Cl H 0 0 3 N CH N NH n-PrO
H F H 0 0 3 N CH N NH n-PrO
H Br H 0 0 3 N CH N NH n-PrO
H NO 2 H 0 0 3 N CH N NH n-PrO
Figure imgf000126_0001
H OH H 0 0 3 N CH N NH n-PrO
H CHO H , 0 0 3 N CH N NH n-PrO
H CH2OH H 0 0 3 N CH N NH n-PrO
H COOH H 0 0 3 N CH N NH n-PrO
H CH3C(0) H 0 0 3 N CH N NH n-PrO O 2 NO 2 H 0 0 3 N CH N NH n-PrO
Figure imgf000126_0002
H H H 0 0 3 N CH N 0 Cl
H MeO H 0 0 3 N CH N 0 Cl
H n-PrO H 0 0 3 N CH N 0 Cl
Figure imgf000126_0003
H Me H 0 0 3 N CH N 0 Cl Ra Rb Rc L1 L3 k X' X3 Xs D R5
H MeNH H 0 0 3 N CH N 0 Cl
H Cl H 0 0 3 N CH N 0 Cl
H F H 0 0 3 N CH N 0 Cl
H NO 2 H 0 0 3 N CH N 0 Cl
Figure imgf000127_0001
H CF3 H 0 0 3 N CH N 0 Cl
H H H 0 0 3 N CH N 0 H
H MeO H 0 0 3 N CH N 0 H
H n-PrO H 0 0 3 N CH N 0 H
Figure imgf000127_0002
H Me H 0 0 3 N CH N 0 H
H MeNH H 0 0 3 N CH N 0 H
H Cl H 0 0 3 N CH N 0 H
H F H 0 0 3 N CH N 0 H
H NO 2 H 0 0 3 N CH N 0 H
H CF3 H 0 0 3 N CH N 0 H
H H H 0 0 3 N CH N 0 Me
H MeO H 0 0 3 N CH N 0 Me
H n-PrO H 0 0 3 N CH N 0 Me
Figure imgf000127_0003
H Me H 0 0 3 N CH N 0 Me
H MeNH H 0 0 3 N CH N 0 Me
H Cl H 0 0 3 N CH N 0 Me
H F H 0 0 3 N CH N 0 Me
H NO 2 H 0 0 3 N CH N 0 Me
Figure imgf000127_0004
H H H 0 0 3 N CH N 0 MeO
H MeO H 0 0 3 N CH N 0 MeO
H n-PrO H 0 0 3 N CH N 0 MeO
H n-CδHi 3O H 0 0 3 N CH N 0 MeO
H Me H 0 0 3 N CH N 0 MeO
H MeNH H 0 0 3 N CH N 0 MeO
H Cl H 0 0 3 N CH N 0 MeO
H F H 0 0 3 N CH N 0 MeO
H NO 2 H 0 0 3 N CH N 0 MeO
H CF3 H 0 0 3 N CH N 0 MeO Ra Rb Rc L1 L3 k X1 X3 X5 D R5
H H H NH 0 3 N CH N NH Cl
H MeO H NH 0 3 N CH N NH Cl
H n-PrO H NH 0 3 N CH N NH Cl
H n-CeH.3O H NH 0 3 N CH N NH Cl
H Me H NH 0 3 N CH N NH Cl
H MeNH H NH 0 3 N CH N NH Cl
H Cl H NH 0 3 N CH N NH Cl
H F H NH 0 3 N CH N NH Cl
Figure imgf000128_0001
H CF3 H NH 0 3 N CH N NH Cl
H H H NH 0 3 N CH N NH H
H MeO H NH 0 0 N CH N NH H
H n-PrO H NH 0 3 N CH N NH H
H n-CeH 13O H NH 0 3 N CH N NH H
H Me H NH 0 D N CH N NH H
H MeNH H NH 0 3 N CH N NH H
H Cl H NH 0 3 N CH N NH H
H F H NH 0 3 N CH N NH H
H NO 2 H NH 0 3 N CH N NH H
H CF3 H NH 0 3 N CH N NH H
H H H NMe 0 3 N CH N NH Cl
H MeO H NMe 0 3 N CH N NH Cl
H n-PrO H NMe 0 3 N CH N NH Cl
H n-CeHi 3O H NMe 0 3 N CH N NH Cl
H Me H NMe 0 3 N CH N NH Cl
H MeNH H , , NMe 0 3 N CH N NH Cl
H Cl H NMe 0 3 N CH N NH Cl
H F H NMe 0 3 N CH N NH Cl
H NO 2 H NMe 0 3 N CH N NH Cl
H CF3 H NMe 0 3 N CH N NH Cl
H H H NMe 0 3 N CH N NH H
H MeO H NMe 0 3 N CH N NH H
H n-PrO H NMe 0 3 N CH N NH H
H n-CeHi 3O H NMe 0 3 N CH N NH H
H Me H NMe 0 3 N CH N NH H
H MeNH H NMe 0 3 N CH N NH H
H Cl H NMe 0 3 N CH N NH H Ra Rb Rc L1 L3 k X1 X3 X3 D R5
H F H NMe 0 3 X CH N NH H
H NO 2 H NMe 0 3 X CH N NH H
Figure imgf000129_0001
H H H 0 NH 3 X CH N NH Cl
H MeO H 0 NH 3 N CH N NH Cl
H n-PrO H 0 NH 3 N CH N NH Cl
H n-CeHi 3O H 0 NH 3 N CH N NH Cl
H Me H 0 NH 3 N CH N NH Cl
H MeNH H 0 NH 3 N CH N NH Cl
H Cl H 0 NH 3 N CH N NH Cl
H F H 0 NH 3 N CH N NH Cl
H NO 2 H 0 NH 3 N CH N NH Cl
Figure imgf000129_0002
H H H 0 NH 3 N CH N NH H
H MeO H 0 NH 3 N CH N NH H
H n-PrO H 0 NH 3 N CH N NH H
H n-CeHi 3O H 0 NH 3 N CH N NH H
H Me H 0 NH 3 N CH N NH H
H MeNH H 0 NH 3 N CH N NH H
H Cl H 0 NH 3 N CH N NH H
H F H 0 NH 3 N CH N NH H
H NO 2 H 0 NH 3 N CH N NH H
Figure imgf000129_0003
H H H NH - 3 N CH N NH Cl
H MeO H NH - 3 N CH N NH Cl
H n-PrO H NH - 3 N CH N NH Cl
H n-CβHi 3O H NH - 3 N CH N NH Cl
H Me H NH - 3 N CH N NH Cl
H MeNH H NH - 3 N CH N NH Cl
H Cl H NH - 3 N CH N NH Cl
H F H NH - 3 N CH N NH Cl
H NO 2 H NH - 3 N CH N NH Cl
Figure imgf000129_0004
H H H - NH 3 N CH N NH Cl
H MeO H - NH 3 N CH N NH Cl
H EtO H - NH 3 N CH N NH Cl
H n-PrO H - NH 3 N CH N NH Cl
Figure imgf000130_0001
12S
Ra Rb Rc L L3 k X1 X3 X5 D R5
H i-PrO H NH 3 N CH N NH Cl
H c-PrO H NH 3 N CH N NH Cl
H n-BuO H NH 3 N CH N NH Cl
H n-CsH..0 H NH 3 N CH N NH Cl
H n-CδHi 3O H NH 3 N CH N NH Cl
H n-CsH O H NH 3 N CH N NH Cl
H n-C 10H210 H NH 3 N CH N NH Cl
H Me H NH 3 N CH N NH Cl
H Et H NH 3 N CH N NH Cl
H n-Pr H NH 3 N CH N NH Cl
H i-Pr H NH 3 N CH N NH Cl
H c-Pr H NH 3 N CH N NH Cl
H n-Bu H NH 3 N CH N NH Cl
Figure imgf000130_0002
H n-C εH 13 H NH 3 N CH N NH Cl
Figure imgf000130_0003
H n-C 10H21 H NH 3 N CH N NH Cl
H MeNH H NH 3 N CH N NH Cl
H EtNH H NH 3 N CH N NH Cl
H n-PrNH H NH 3 N CH N NH Cl
H i-PrNH H NH 3 N CH N NH Cl
H c-PrNH H NH 3 N CH N NH Cl
H n-BuNH H NH 3 N CH N NH Cl
H n-CsH..NH H NH 3 N CH N NH Cl
H n-CβH.3NH H NH 3 N CH N NH Cl
H n-C8H.7NH H , NH 3 N CH N NH Cl
H n-C.0H2.NH H NH 3 N CH N NH Cl
H Cl H NH 3 N CH N NH Cl
H F H NH 3 N CH N NH Cl
H Br H NH 3 N CH N NH Cl
H NO 2 H NH 3 N CH N NH Cl
Figure imgf000130_0004
H OH H NH 3 N CH N NH Cl
H CHO H NH 3 N CH N NH Cl
Figure imgf000130_0005
H COOH H NH 3 N CH N NH Cl
H CH3C(0) H NH 3 N CH N NH Cl Ra Rb Rc L1 L3 k X' X3 X5 D R5O 2 NO 2 H _ NH 3 N CH N NH ClO 2 H NO 2 - NH 3 N CH N NH Cl
H CF3 H - NH 3 N CH N NH Cl
H H H NH NH 3 N CH N NH Cl
H MeO H NH NH 3 N CH N NH Cl
H n-PrO H NH NH 3 N CH N NH Cl
H n-CβHi 3O H NH NH 3 N CH N NH Cl
H Me H NH NH 3 N CH N NH Cl
H MeNH H NH NH 3 N CH N NH Cl
H Cl H NH NH 3 N CH N NH Cl
H F H NH NH 3 N CH N NH Cl
H NO 2 H NH NH 3 N CH N NH Cl
H CF3 H NH NH 3 N CH N NH Cl
H H H - - 4 N CH N NH Cl
H MeO H - - 4 N CH N NH Cl
H n-PrO H - - 4 N CH N NH Cl
H n-CβH.3O H - - 4 N CH N NH Cl
H Me H - - 4 N CH N NH Cl
H MeNH H - - 4 N CH N NH Cl
H Cl H - - 4 N CH N NH Cl
H F H - - 4 N CH N NH Cl
H NO 2 H - - 4 N CH N NH Cl
H CF3 H - - 4 N CH N NH Cl
H H H 0 - 4 N CH N NH Cl
H MeO H 0 - 4 N CH N NH Cl
H n-PrO H 0 - 4 N CH N NH Cl
H n-CβHi 3O H 0 - 4 N CH N NH Cl
H Me H 0 - 4 N CH N NH Cl
H MeNH H 0 - 4 N CH N NH Cl
H Cl H 0 - 4 N CH N NH Cl
H F H 0 - 4 N CH N NH Cl
H NO 2 H 0 - 4 N CH N NH Cl
Figure imgf000131_0001
H H H - 0 4 N CH N NH Cl
H MeO H - 0 4 N CH N NH Cl
H n-PrO H - 0 4 N CH N NH Cl
H n-CβHi 3O H - 0 4 N CH N NH Cl Ra Rb Rc L1 L3 k X1 X3 X5 D R5
H Me H _ 0 4 N CH N NH Cl
H MeNH H - 0 4 N CH N NH Cl
H Cl H - 0 4 N CH N NH Cl
H F H - 0 4 N CH N NH Cl
H NO 2 H - 0 4 N CH N NH Cl
H COOH H - 0 4 N CH N NH Cl
H CF3 H - 0 4 N CH N NH Cl
H H H 0 0 4 N CH N NH Cl
H MeO H 0 0 4 N CH N NH Cl
H n-PrO H 0 0 4 N CH N NH Cl
H n-CeHi 3O H 0 0 4 N CH N NH Cl
H Me H 0 0 4 N CH N NH Cl
H MeNH H 0 0 4 N CH N NH Cl
H Cl H 0 0 4 N CH N NH Cl
H F H 0 0 4 N CH N NH Cl
H NO 2 H 0 0 4 N CH N NH Cl
H CF3 H 0 0 4 N CH N NH Cl
H H H NH 0 4 N CH N NH Cl
H MeO H NH 0 4 N CH N NH Cl
H n-PrO H NH 0 4 N CH N NH Cl
H n-CβHi 3O H NH 0 4 N CH N NH Cl
H Me H NH 0 4 N CH N NH Cl
H MeNH H NH 0 4 N CH N NH Cl
H Cl H NH 0 4 N CH N NH Cl
H F H NH 0 4 N CH N NH Cl
H NO 2 H , NH 0 4 N CH N NH Cl
H CF3 H NH 0 4 N CH N NH Cl
H H H NMe 0 4 N CH N NH Cl
H MeO H NMe 0 4 N CH N NH Cl
H n-PrO H NMe 0 4 N CH N NH Cl
H n-CβHi 3O H NMe 0 4 N CH N NH Cl
H Me H NMe 0 4 N CH N NH Cl
H MeNH H NMe 0 4 N CH N NH Cl
H Cl H NMe 0 4 N CH N NH Cl
H F H NMe 0 4 N CH N NH Cl
Figure imgf000132_0001
Ra Rb Rc L1 L3 k X1 X3 X3 D R5
H H H 0 NH 4 N CH N NH Cl
H MeO H 0 NH 4 N CH N NH Cl
H n-PrO H 0 NH 4 N CH N NH Cl
H n-CeHi 3O H 0 NH 4 N CH N NH Cl
H Me H 0 NH 4 N CH N NH Cl
H MeNH H 0 NH 4 N CH N NH Cl
H Cl H 0 NH 4 N CH N NH Cl
H F H 0 NH 4 N CH N NH Cl
Figure imgf000133_0001
H CF3 H 0 NH 4 N CH N NH Cl
H H H NH - 4 N CH N NH Cl
H MeO H NH - 4 N CH N NH Cl
H n-PrO H NH - 4 N CH N NH Cl
H n-CeHi 3O H NH - 4 N CH N NH Cl
H MeNH H NH - 4 N CH N NH Cl
H Cl H NH - 4 N CH N NH Cl
Figure imgf000133_0002
H CF3 H NH - 4 N CH N NH Cl
H H H - NH 4 N CH N NH Cl
H MeO H - NH 4 N CH N NH Cl
H n-PrO H - NH 4 N CH N NH Cl
H n-CeHi 3O H - NH 4 N CH N NH Cl
H Me H - NH 4 N CH N NH Cl
H MeNH H - NH 4 N CH N NH Cl
H Cl H - NH 4 N CH N NH Cl
H F H - NH 4 N CH N NH Cl
H NO 2 H - NH 4 N CH N NH Cl
H CF3 H - NH 4 N CH N NH Cl
H H H NH NH 4 N CH N NH Cl
H MeO H NH NH 4 N CH N NH Cl
H n-PrO H NH NH 4 N CH N NH Cl
H n-CeHi 3O H NH NH 4 N CH N NH Cl
H Me H NH NH 4 N CH N NH Cl
H MeNH H NH NH 4 N CH N NH Cl
H Cl H . NH NH 4 N CH N NH Cl
H F H NH NH 4 N CH N NH Cl
Figure imgf000133_0003
Ra Rb Rc L1 L3 k X' X3 X5 D R3
Figure imgf000134_0001
H H H - - 5 N CH N NH Cl
H MeO H - - 5 N CH N NH Cl
H n-PrO H - - 5 N CH N NH Cl
H n-CeHi 3O H - - 5 N CH N NH Cl
H Me H - - 5 N CH N NH Cl
H MeNH H - - 5 N CH N NH Cl
H Cl H - - 5 N CH N NH Cl
H F H - - 5 N CH N NH Cl
H NO 2 H - - 5 N CH N NH Cl
Figure imgf000134_0002
H H H 0 - 5 N CH N NH Cl
H MeO H 0 - 5 N CH N NH Cl
H n-PrO H 0 - 5 N CH N NH Cl
H n-CeH.3O H 0 - 5 N CH N NH Cl
H Me H 0 - 5 N CH N NH Cl
H MeNH H 0 - 5 N CH N NH Cl
H Cl H 0 - 5 N CH N NH Cl
H F H 0 - 5 N CH N NH Cl
Figure imgf000134_0003
H H H - 0 5 N CH N NH Cl
H MeO H - 0 5 N CH N NH Cl
H n-PrO H - 0 5 N CH N NH Cl
H n-CeH.3O H - 0 5 N CH N NH Cl
H Me H - 0 5 N CH N NH Cl
H MeNH H 0 5 N CH N NH Cl
H Cl H - 0 5 N CH N NH Cl
H F H - 0 5 N CH N NH Cl
Figure imgf000134_0004
H CF3 H - 0 5 N CH N NH Cl
H H H 0 0 5 N CH N NH Cl
H MeO H 0 0 5 N CH N NH Cl
H n-PrO H 0 0 5 N CH N NH Cl
H n-CβHi 3O H 0 0 5 N CH N NH Cl
H Me H 0 0 5 N CH N NH Cl
H MeNH H 0 0 5 N CH N NH Cl
H Cl H 0 0 5 N CH N NH Cl Ra Rb Rc L1 L3 k X' X3 X3 D R3
H F H 0 0 5 N CH N H Cl
H NO 2 H 0 0 5 N CH N NH Cl
Figure imgf000135_0001
H H H NH - 5 N CH N NH Cl
H MeO H NH - 5 N CH N NH Cl
H n-PrO H NH - 5 N CH N NH Cl
H n-BuO H NH - 5 N CH N NH Cl
H n-CβHi 3O H NH - 5 N CH N NH Cl
H Me H NH - 5 N CH N NH Cl
H MeNH H NH - 5 N CH N NH Cl
H Cl H NH - 5 N CH N NH Cl
H F H NH - 5 N CH N NH Cl
H NO 2 H NH - 5 N CH N NH Cl
Figure imgf000135_0002
H H H - NH 5 N CH N NH Cl
H MeO H - NH 5 N CH N NH Cl
H n-PrO H - NH 5 N CH N NH Cl
H n-CsH..0 H - NH 5 N CH N NH Cl
H n-CeHi 3O H - NH 5 N CH N NH Cl
H Me H - NH 5 N CH N NH Cl
H MeNH H - NH 5 N CH N NH Cl
H Cl H - NH 5 N CH N NH Cl
H F H - NH 5 N CH N NH Cl
H NO 2 H - NH 5 N CH N NH Cl
Figure imgf000135_0003
H H H NH NH 5 N CH N NH Cl
H MeO H NH NH 5 N CH N NH Cl
H n-PrO H NH NH 5 N CH N NH Cl
H n-CeHi 3O H NH NH 5 N CH N NH Cl
H Me H NH NH 5 N CH N NH Cl
H MeNH H NH NH 5 N CH N NH Cl
H Cl H NH NH 5 N CH N NH Cl
H F H NH NH 5 N CH N NH Cl
H NO 2 H NH NH 5 N CH N NH Cl
H CF3 H NH NH 5 N CH N NH Cl
H H H - - 6 N CH N NH Cl
H MeO H - - 6 N CH N NH Cl Ra Rb Rc L1 L3 k X1 X3 X3 D R5
H n-PrO H _ _ 6 N CH N NH Cl
H n-CeHi3θ H - - 6 N CH N NH Cl
H Me H - - 6 N CH N NH Cl
H MeNH H - - 6 N CH N NH Cl
H Cl H - - 6 N CH N NH Cl
H F H - - 6 N CH N NH Cl
Figure imgf000136_0001
H CF3 H - - 6 N CH N NH Cl
H H H 0 - 6 N CH N NH Cl
H MeO H 0 - 6 N CH N NH Cl
H n-PrO H 0 - 6 N CH N NH Cl
H n-CδHi3θ H 0 - 6 N CH N NH Cl
H Me H 0 - 6 N CH N NH Cl
H MeNH H 0 - 6 N CH N NH Cl
H Cl H 0 - 6 N CH N NH Cl
H F H 0 - 6 N CH N NH Cl
H NO 2 H 0 - 6 N CH N NH Cl
H CF3 H 0 - 6 N CH N NH Cl
H H H - 0 6 N CH N NH Cl
H MeO H - 0 6 N CH N NH Cl
H n-PrO H - 0 6 N CH N NH Cl
H n-CeH.3O H - 0 6 N CH N NH Cl
H Me H - 0 6 N CH N NH Cl
H MeNH H - 0 6 N CH N NH Cl
H Cl H - 0 6 N CH N NH Cl
H F H 0 6 N CH N NH Cl
Figure imgf000136_0002
H CF3 H - 0 6 N CH N NH Cl
H H H 0 0 6 N CH N NH Cl
H MeO H 0 0 6 N CH N NH Cl
H n-PrO H 0 0 6 N CH N NH Cl
H n-CeH.30 H 0 0 6 N CH N NH Cl
H Me H 0 0 6 N CH N NH Cl
H MeNH H 0 0 6 N CH N NH Cl
H Cl H 0 0 6 N CH N NH Cl
H F H 0 0 6 N CH N NH Cl
Figure imgf000136_0003
135
Ra Rb Rc L1 L3 k X1 X3 V D R5
Figure imgf000137_0001
H H H NH - 6 N CH N NH Cl
H MeO H NH - 6 N CH N NH Cl
H n-PrO H NH - 6 N CH N NH Cl
H n-CβHi 3O H NH - 6 N CH N NH Cl
H Me H NH - 6 N CH N NH Cl
H MeNH H NH - 6 N CH N NH Cl
H Cl H NH - 6 N CH N NH Cl
H F H NH - 6 N CH N NH Cl
H NO 2 H NH - 6 N CH N NH Cl
H CF3 H NH - 6 N CH N NH Cl
H H H - NH 6 N CH N NH Cl
H MeO H - NH 6 N CH N NH Cl
H n-PrO H - NH 6 N CH N NH Cl
H n-CeH.sO H - NH 6 N CH N NH Cl
H Me H - NH 6 N CH N NH Cl
H MeNH H - NH 6 N CH N NH Cl
H Cl H - NH 6 N CH N NH Cl
H F H - NH 6 N CH N NH Cl
H NO 2 H - NH 6 N CH N NH Cl
H CF3 H - NH 6 N CH N NH Cl
H H H NH NH 6 N CH N NH Cl
H MeO H NH NH 6 N CH N NH Cl
H n-PrO H NH NH 6 N CH N NH Cl
H n-CeH.30 H NH NH 6 N CH N NH Cl
H Me H NH NH 6 N CH N NH Cl
H MeNH H NH NH 6 N CH N NH Cl
H F H NH NH 6 N CH N NH Cl
H NO 2 H NH NH 6 N CH N NH Cl
Figure imgf000137_0002
Table 2
Figure imgf000138_0001
w1 w2 ff3 W4 ws
C N C H 0 C H c N C H . s C H c 0 C H N C H
C s C H N C H
C N NM e N C H c 0 C H C H C H
C C H C H 0 C H
C S C H C H C H
C C H C H S C H
C N NM e C H C H
C NM e N C H C H
C C H NM e N C H c NM e C H C H C H
C C H C H NM e C H
C NM e C H N C H
C N C H NM e C H
C NM e C H C H N
N C H C H C H C H
N C H C H C H N
C C H C H N 0
C C H N 0 C H
C N 0 C H C H
N C H N C H C H 37
Table 3
Figure imgf000139_0001
w ff2 W3 W W5 W6
C N C H C H C H C H
C C H N C H C H C H
C C H C H N C H C H
N C 0 C H C H C H C H
N C H C H C 0 C H C H
C N C H C H C H N
C N C H N C H C H
C C H N C H N C H
C N N C H C H C H
C C H N N C H C H
N N C H C H C H C 0
C N C H C H N C H Table 4
Figure imgf000140_0001
w1 W2 W3 W4 W5 W6 W7 W8 W9
C H C H C H C C H C H C H C H C
C CM e NH c C H C H C H C H C
C C e NM e c C H C H C H C H C
C C H N H C C H C H C H C H C
C C H S C C H C H C H C H C
N C H N C C H C H C H C H C
C C H 0 C C H C H C H C H C
C C H C H c C H C H C H C H N
C N NH C C H C H C H C H C
C N NM e c C H C H C H C H C
N N N c C H C H C H C H C
N C H N c N C H N C H C
C C H N N C H C H C H N C
C C H N N C H C H N N C
C CM e S C N C C F 3 N * N
C CM e S C N CM e N — N
C C H S C N C H N — N
* • covalent bond 2
O
2
O O
O
O μ- (
O C
O
Figure imgf000141_0001
w1 W2 W3 W4 W3 W6 W: * W9
NM e c N C C H C H C H C H c
N H C N c C H CM e CM e C H C
NM e C N c C H CM e CM e C H C
N H C N c C H C P h C H C H C
NM e C N c C H C P h C H C H C
NM e C N c C H C H C P h C H C
N C 0 c C H C H C H C H C
N C 0 c C H C P h C H C H C
N C 0 c C H C H C P h C H C
N C 0 c C H CM e C H C H C
N C 0 c C H C H CM e C H C
N C s c C H C H C H C H C
N C s c C H C P h C H C H C
N C s c C H C H C P h C H C
N C s c C H CM e C H C H C
N C s c C H C H CM e C H C
C H C C H c C H C H C H C H N
N H C N c N C H N C H C
NM e C N c N C H N C H C
N C C H c N C H C H C H N
N C C H c N N C H C H N
S C CM e N N C C F3 N _ * C
S C CM e N N CM e N — C
S C C H N N C H N — C
* ; covalent bond
Table 6
Figure imgf000143_0001
w W2 W3 W * W5 W6 W7 W8 ψ
C H2 C H C H C C C H C H C H C
C H C H C H 2 C C C H C H C H C
NM e C H C H C C C H C H C H C
C H C H NM e C C C H C H C H C
S C H C H c C C H C H C H C
C H C H S C C C H C H C H C
O C H C H C C C H C H C H C
C H C H 0 C C C H C H C H C
NH C N C C C H C H C H C
NM e C N C C C H C H C H C
N C NM e C C C H C H C H C
N C 0 C C C H C H C H C
0 C N c C C H C H C H C
N C S C C C H C H C H C
S C N C C C H C H C H C
C H C H C H C C C H C H C H N
C H C H C H N C C H C H C H C
NH C H N C C N C H N C
C H C H N N C C H C H N C
C H C H N N C C H N N C 02
PC PC
O O H PH
22
20
02
O O
02 i-l—i
20
PH
00
Figure imgf000144_0001
w W2 W3 W4 Wδ w,: W: Ws w9
C H CM e N N CM e C C H N C
C H C H N N C H C N N C
C H CM e N N CM e C N N C
C H C P h N N CM e C C H N C
C H C P h N N CM e C N N C
Tab le 8
Figure imgf000146_0001
w w2 W 3 W 4 w s ff 6 W7 W s
C C H C H C H C H C H C H C H
C C H C H C H, C H C H C H N
C C H C H C H N C H C H C H
C C H C H N C H C H C H C H
C C H C H C H C H C H N C H
C C H C H C H C H N C H C H
C C H N C H C H C H C H C H
C N C H C H C H C H C H C H
C C H C H C H 0 C H 2 C H 2 0
C C H C H C H 0 C H C H 0
C N N C H C H C H C H C H
C C H C H C H C H N N C H
C C H C H N • N C H C H C H
C C H C H C H N C H C H N
C C H C H C H C H N C H N
C C H C H C H N C H N C H
C C H C H C H C H C H N N
C C H C H C H N N C H C H
C N C H N N C H C H N
N C H C H S C H C H C H C H
C C H C H C H S C H C H N H
C C H C H C H S C H C H N M
C C H C H C H N H C H C H S w1 w2 W3 W W5 W" W" c C H C H C H NM e C H C H s
N C 0 C H C H C H C H C H C H
N C H C H C 0 C H C H C H C H
C C H C H C H N H C 0 C H C H
C C H C H C H NM e C 0 C H C H
C C H C H C H C H C H C 0 N H
C C H C H C H C H C H C 0 NM e
C C H C H C H N H C H C H C 0
C C H C H C H NM e C H C H C 0
C C H C H C H C 0 C H C H N H
C C H C H C H C 0 C H C H NM e
C C H NH C 0 C H C H C H C H
C C H NM e C 0 C H C H C H C H
C C H C H C H C 0 N H C H C H
C C H C H C H C 0 NM e C H C H
C C H C H C H C H C H N H C 0
C C H C H C H C H C H NM e C 0
C C 0 NH C H C H C H C H C H
C C 0 NM e C H C H C H C H C H
C NH C 0 C H C H C H C H C H
C NM e C 0 C H C H C H C H C H
C C H C H C H C H N H C 0 C H
C C H C H C H C H NM e C 0 C H
C C H C H C H C H C 0 N H C H
C C H C H C H C H C 0 NM e C H
C N NH C 0 C H C H C H C H
C N NM e C 0 C H C H C H C H
C C H C H C H C H N N H C 0
C C H C H C H C H N NM e C 0
C C H C H C H C 0 N H N C H
C C H C H C H C 0 NM e N C H
220
O OO
020
PH H
2 O0
022 H
202
000
PH PH PH
220
PH
Figure imgf000148_0001
w1 W2 w3 W4 W3 wp W7
N c C H N N C H N C H
S c C H N H C H C H C H C H s c C H NM e C H C H C H C H
N H c C H S C H C H C H C H
NM e c C H S C H C H C H C H
C H c C H C H N H C H C H S
C H c C H C H NM e C H C H S
C H c C H C H S C H C H N H
C H c C H C H S C H C H NM e
S c CM e N H C H C H C H C H
S c CM e NM e C H C H C H C H
C H C C 0 N H C H C H C H C H
C H C C 0 NM e C H C H C H C H
C H c C H C H N H C 0 C H C H
C H c C H C H NM e C 0 C H C H
C H c C H C H C H C H C 0 N H
C H c C H C H C H C H C 0 NM e
NH c C H C 0 C H C H C H C H
NM e C C H C 0 C H C H C H C H
C 0 C C H N H C H C H C H C H
C 0 C C H NM e C H C H C H C H
C 0 N C H C H C H C H C H C H
C H C NH C 0 C H C H C H C H
C H C NM e C 0 C H C H C H C H
C H C C H C H C 0 NH C H C H
C H C C H C H C 0 NM e C H C H
C H C C H C H C H C H N H C 0
C H C C H C H C H C H NM e C 0
C H N C 0 C H C H C H C H C H
C H c C H C H C H C 0 N H C H
C H c C H C H C H C 0 NM e C H
C H c C H C H C I N H C 0 C H
C H C C H C H C H NM e C 0 C H
C 0 N N C H C H C H C H C H
C H c C H C H C H N N H C 0
C H C C H C H C H N NM e C 0
C H C C H C H C 0 N H N C H
H 3 N 9 N N 0 3 H 3 H 3 3 H 3
Figure imgf000150_0001
P irεθ/66dT/XDd 188S9/66 OΛV As evident from the following test results, the compound [i] or its pharmaceutically acceptable salt of the present invention has a hypoglycemic activity, and can be used alone or in a mixture with a known pharmaceutically acceptable binder, excipient, lubricant or disintegrator, for preventing or treating diabetes mellitus of mammals including humans, mice, rats, rabbits, dogs, monkeys, cows, horses, pigs and the like. The compound [i] or its pharmaceutically acceptable salt of the present invention can also be used in combination with various oral hypoglycemic agents such as insulin preparations, sulfonylureas, insulin sensitizers, α- glucosidase inhibitors and biguanides, and aldose- reductase inhibitors, to obtain effects of treating diabetes.
The active ingredient may be formulated into various suitable formulations depending upon the manner of administration. The compound [i] or its pharmaceutically acceptable salt of the present invention is preferably administered orally in the form of powders, granules, tablets or capsules formulated by mixing the compound of the present invention with a suitable pharmaceutically acceptable binder (such as hydroxypropyl cellulose, syrup, gum arabic, gelacin, sorbitol, tragacanth gum, polyvinyl pyrrolidone or CMC-Ca), an excipient (such as lactose, sugar, corn starch, calcium phosphate, sorbicol, glycine or microcrystal cellulose powder) , a lubricant (such as magnesium stearate, talc, polyethylene glycol or silica) , a disintegrator (such as potato starch) or the like.
However, the pharmaceutical composition of the present invention is not limited to such oral administration and it is applicable for parenteral administration.
For example, it may be administered in the form of e.g. a suppository formulated by using oily base material such as cacao butter, polyethylene glycol, lanolin or fatty acid triglyceride, a transdermal therapeutic base formulated by using liquid paraffin, white vaseline, a higher alcohol, Macrogol ointment, hydrophilic ointment or hydro-gel base material, an injection formulation formulated by using one or more materials selected from the group consisting of polyethylene glycol, hydro-gel base material, distilled water, distilled water for injection and an excipient such as lactose or corn starch, or a formulation for administration through mucous membranes such as an ocular mucous membrane, a nasal mucous membrane and an oral mucous membrane. The daily dose of the compound of the present invention is from about 0.05 to about 50 mg, preferably from about 0.10 to about 10 mg per kg weight of a patient, and it is administered from once to three times per day. The dose may of course be varied depending upon the age, the weight or the condition of illness of a patient .
BEST MODE FOR CARRYING OUT THE INVENTION
Now, the present invention will be described in further detail with reference to Synthesis Examples of the compounds of the present invention, Test Examples for the pharmaceutical activities and Formulation Examples.
However, it should be understood that the present invention is by no means restricted to such specific
Examples . REFERENCE EXAMPLE 1
Synthesis of methyl ( S ) -2-benzyloxycarbonylamino-3-tert- butoxycarbonylamino Orooionate (Compound (1) )
50 mc? of an ether solution having 2.82 g (8.34 mmol) of (S) -2-benzyloxycarbonylamino-3-tert- butoxycarbonylamino propionate synthesized by a method as described in J. Med. Chem., 1987, 30, 1458-1463, was cooled to 0°C, diazo ethane was added thereto until the solution turned yellow, the solvent was distilled off, and 2.94 g (8.34 mmol) of Compound (1) as colorless oil was quantitatively obtained.
'H-NMR(CDC13, rt, 60 MHz) δ 7.03-7.37 (5H, m) 5.78 (IH, br s) 5.12 (2H, s) 4.83 (IH. br s) 4,40 (IH, br s) 3.76 (3H. s) 3.55 (2H, s) 1.42 (9H, s) FAB-MS m/z (M+H)+ 353
REFERENCE EXAMPLE 2
Synthesis of methyl ( 5 ) -2-amino-3-tert- butoxycarbonylamino oroDionate (Compound (2))
294 mg of 10% Pd-C was added to 15 mf of a methanol solution having 2.94 g (8.34 mmol) of the Compound (1) synthesized in Reference Example 1, followed by stirring for 17 hours at room temperature. The reaction solution was subjected to filtration, the solvent was distilled off, and a colorless oily substance was obtained. The residue was purified by column chromatography (CHC13: MeOH=20:l), and 2.14 g of Compound (2) as pale yellow oil was quantitatively obtained.
Η-NMR(CDC13, rt, 60 MHz) δ 5.18 (IH, br s) 5.30 (IH, br s) 4.78 (2H, br s) 5.25 (IH, m) 4.02 (IH, br s) 3.48 (3H, s) 1.42 (9H, s) FAB-MS m/z (M+H)+ 353
REFERENCE EXAMPLE 3,
Synthesis of 8-benzyl-2 , 4-dioxo-l .3.8- triazaspiro[4.5]decane (Compound (3)) 98.6 g (1.03 mol) of ammonium carbonate and 16.8 g (0.342 mol) of sodium cyanide were added to 1.5 t of 50% ethanol-water solution having 64.8 g (0.342 mol) of 1- benzyl-4-piperidone, followed by stirring for 3.5 hours at 68°C, in the same manner as in USP 3,330,836. The reaction mixture was concentrated under reduced pressure followed by cooling, a resulting solid was collected by filtration, and was washed with 200 m of 50% ethanol- water, 200 mc? of water and 100 M of diethylether . The obtained solid was dried at 50°C under reduced pressure for 6.5 hours, and 79.3 g (0.306 mol) of Compound (3) as colorless solid was obtained with an yield of 89%.
mp 278.0-278.1 °C
Η-NMR((CD3)2S0, rt, 400 MHz) δ 10.62 (IH, s) 8.43 (IH, s) 7.22-7.34 (5H.m) 3.48 (2H, s) 2.68
(2H, m) 2.28 (2H, m) 1.S2 (2H, m) 1.52 (2H, m)
EI-MS m/z (M)+ 259
REFERENCE EXAMPLE 4
Synthesis of 4-amino-l-benzyloioeridine-4-carboxylic acid (Compound (4))
58.8 g (0.227 mol) of the Compound (3) was dissolved in 1.2 t of 1M sodium hydroxide aqueous solution, followed by reflux under heating for 33 hours. The reaction solution was cooled to room temperature, and then it was neutralized with 3M hydrochloric acid, acidified with 25 mf of concentrated hydrochloric acid, and alkalified with 50 mf of concentrated aqueous ammonia. The obtained solid was collected by filtration, washed with 100 mf? of water and 100 mi of diethylether , and dried under reduced pressure at 60°C for 9.5 hours, and 51.0 g (0.218 mol) of Compound (4) as colorless solid was obtained with an yield of 96%. mp 246. 2-246. 6 °C Η-NMR(CD3C02D. rt , 400 MHz) δ 7. 55 (2H, m) 7. 46 (3H. m) 4. 38 (2H, s) 3. 8 (2H, m) 3. 6 (2H, m) 2. 45 (4H, m) FD-MS ra/z (M+H) + 235
REFERENCE EXAMPLE 5
Synthesis of 1 -benzvl-4- ( tert- butoxycarbonyl ) aminooiperidine-4-carboxylic acid (Compound ( 5 ) )
45.3 g (0.448 mol) of triethylamine was added to 1.5 I of 67% tetrahydrofuran-water suspension having 50.0 g (0.213 mol) of the Compound (4). 70.0 g (0.321 mol) of di-tert-butyl dicarbonate was dropwise added to the suspension, followed by stirring for 21.5 hours at 47°C. 20.0 g (0.092 mol) of di-tert-butyl dicarbonate was further added thereto followed by stirring for 23 hours, 10.0 g (0.046 mol) of di-tert-butyl dicarbonate and 6.5 g (0.064 mol) of triethylamine were added thereto followed by stirring for 62 hours, and the mixture was cooled to room temperature. The solvent was evaporated to dryness, 40 ml of methanol and 100 mf of diisopropylether were added thereto for solidification. The solid was collected by filtration, washed with 100 mf? of diisopropylether, and dried under reduced pressure at
50°C for 10 hours, and 59.1 g (0.177 mol) of Compound (5) as colorless powder was obtained with an yield of 83%. mp 304. 3-309. 8 °C (decomp. )
Η-XMR ( (CD3) ,S0, rt , 400 MHz) δ 7. 24-7. 32 (5H, m) 7. 01 (IH, br s) 3. 48 (2H, br s) 2. 53 (2H. m)
2. 23 (2H, m) 1. 85-1. 92 (4H. m) 1. 37 (9H. s)
FAB-MS m/z (M+H) + 335
REFERENCE EXAMPLE 6
Synthesis of 4- ( tert-butoxycarbonyl ) aminopiperidine-4- carboxylic acid (Compound (6)) 20.0 g (59.8 mmol) of the Compound (5) was dissolved in 3 I of 67% tetrahydrofuran-water and 6.0 g (59.5 mmol) of triethylamine, and 4.6 g of 10% palladium-carbon was added thereto followed by stirring under hydrogen atmosphere at room temperature for 46 hours. The
® catalyst was removed by Celite filtration, followed by washing with a mixed solution of 1.5 f of 67% tetrahydrofuran-water and 10 mi of triethylamine, and then with a mixed solution of 1 f of 50% methanol-water and 10 ml of triethylamine, the solvent was removed to dryness, and 13.7 g (56.1 mmol) of Compound (6) as pale gray solid was obtained with an yield of 94%.
mp 262.8-263.7 °C lH-NMR(CD3C0,D, rt, 400 MHz) δ 3.3-3.5 (4H, ra) 2.3-2.5 (4H. m) 1.45 (9H. s) El-MS m/z (M)+ 244 REFERENCE EXAMPLE 7
Synthesis of l-benzyloxycarbonyl-4- ( tert- butoxycarbonyl) aminooiperidine-4-carboxylic acid (Compound (7) ) 15.0 g (61.4 mmol) of the Compound (6) was dissolved in 62 ml of 1M sodium hydroxide aqueous solution, and 80 ml of an ethyl ether solution having 10.8 g (63.0 mmol) of benzyl chloroformate and 64 ml of 1M sodium hydroxide aqueous solution were simultaneously dropwise added thereto at a temperature ranging from -2 to 5°C over a period of 1 hour, followed by stirring at a temperature ranging from -2 to 0°C for 3 hours and 45 minutes. The reaction solution was washed with ether, 30 ml of 1M citric acid aqueous solution was added to the aqueous layer under cooling to adjust pH to be about 4, extractions with ethyl acetate were conducted (200 ml x 2 ) , and the organic layer was dried over sodium sulfate. The drying agent was removed by filtration, the solvent was distilled off, the obtained crude product was recrystallized (benzene-hexane), and 16. 9g (44.7 mmol) of Compound (7) as colorless crystals was obtained with an yield of 73%.
mp 92.0-93.7 °C Η-NMR(CDC13, rt, 400 MHz) δ 7.29-7.38 (5H, m) 6.1 (IH, br s) 5.13 (2H, s) 3.94 (2H. m) 3.23 (2H, m) 1.98-2.05 (4H, m) 1.41 (9H, s) EI-MS m/z (M) τ 321
REFERENCE EXAMPLE 8
Synthesis of ethyl l-benzyloxycarbonyl-4- ( tert- butoxycarbonyl) amino-4-oioeridyl acetate (Compound (9) 1.9 ml (13.6 mmol) of triethylamine was added to 10 ml of tetrahydrofuran solution having 4.97 g (13.1 mmol) of the Compound (7), and 1 ml of tetrahydrofuran solution having 1.24 g (13.1 mmol) of methyl chloroformate was dropwise added thereto at a temperature ranging from -17 to -11°C. The reaction solution was stirred for 45 minutes under cooling, a precipitated solid was separated therefrom by filtration, and was washed with 4 ml of tetrahydrofuran. Diazomethane (4.3 equivalent as p-toluenesulfonyl-N- methyl-N-nitrosamide which is a precursor) with a nitrogen current, were introduced to the filtrate, and the solvent was distilled off. The obtained crude product was purified by column chromatography (ethyl acetate-hexane=2 : 3 ) , and 1.89 g (4.70 mmol) of diazoketone was obtained with an yield of 36%. 2.24 g (5.72 mmol) of methyl l-benzyloxycarbonyl-4- ( tert- butoxycarbonyl) aminopiperidine-4-carboxylic acid (Compound (8)) was also obtained with an yield of 44%. Methyl l-benzyloxycarbonyl-4- ( tert- butoxycarbonyl ) aminopiperidine-4-carboxylic acid (Compound (8) ) mp 122.9-123.1 °C Η-NMR(CDC13, rt, 400 MHz) δ 7.30-7.36 (5H, m) 5.13 (2H. s) 4.73 (IH, s) 3.87-3.91 (2H, m) 3.73 (3H, s) 3.22-3.27 (2H, m) 2.02-2.09 (2H, m) 1.93-1.96 (2H, m) 1.43 (9H, s) FD-MS m/z (M+H)+ 393
2.8 ml (20 mmol) of triethylamine was added to 50 ml of a methanol solution having 3.70 g (9.19 mmol) of diazoketone, and 422 mg (1.85 mmol) of silver benzoate was added thereto, followed by stirring under shading at room temperature overnight. 344 mg (1.50 mmol) of silver benzoate was further added thereto, followed by stirring at room temperature overnight. The reaction solution was
© subjected to Celite.1 filtration, the solvent was distilled off, the obtained crude product was purified by column chromatography (ethyl acetate-hexane=2 : 3 ) , and
2.78 g (6.84 mmol) of Compound (9) as colorless amorphous was obtained with an yield of 74%.
Η-NMR(CDC13. rt, 400 MHz) δ 7.30-7.36 (5H, m) 5.12 (2H. s) 4.51 (IH. s) 3.88 (2H. m) 3.68 (3H, s) 3.15 (2H, m) 2.76 (2H. s) 2.20 (2H, m) 1.6 (2H, m) 1.43 (9H, s)
FD-MS m/z (M+H)+ 407 REFERENCE EXAMPLE 9
Synthesis of methyl 4-amino-l-benzyloxycarbonyl-4- piperidyl acetate (Compound (10))
859 mg (2.11 mmol) of the Compound (9) was dissolved in 2 ml of 4M hydrochloric acid-dioxane, followed by stirring for 6 hours at room temperature. The solvent was distilled off, the obtained crude product was dissolved in 10 ml of ethyl acetate and washed with saturated aqueous sodium bicarbonate, the organic layer was dried over sodium sulfate, the drying agent was removed by filtration, the solvent was removed, and 599 mg (1.96 mmol) of Compound (10) as yellow amorphous was obtained with an yield of 93%.
Η-NMR(CDC13, rt, 400 MHz) δ 7.29-7.36 (5H. m) 5.12 (2H, s) 3.72 (3H. s) 3.7 (2H, m) 3.6 (2H, m) 2.77 (2H, s) 1.95 (2H, m) 1.8 (2H, m) FAB-MS m/z (M+H)+ 307
REFERENCE EXAMPLE 10
Synthesis of ethyl ( l-benzyloxycarbonyl-4- phenoxycarbonylamino-4-oiperidyl) acetate (Compound (ID) 31 μ^ (0.2481 mmol) of phenyl chloroformate and 35 \ιl (0.2481 mmol) of Et3N were added to 2 ml of a THF solution having 76 mg (0.2481 mmol) of the Compound (10) under cooling with ice, followed by stirring for 1 hour at the same temperature. The reaction solution was subjected to filtration, the solvent was distilled off, and (104 mg) of the crude product of Compound (11) was obtained.
'H-NMR (400 MHz, CDC13) δ 7.40-7.15 (10H, m) 5.42 (IH, s) 5.13 (2H, s) 3.89(2H, br s) 3.72 (3H, s) 3.19 (2H, t. 12.0 Hz) 2.79 (2H, s)2.27 (2H, s) 1.60 (2H, br s)
REFERENCE EXAMPLE 11
Synthesis of l-benzγloxycarbonyl-4-oiperidone (Compound (12))
500 ml of a tetrahydrofuran solution having 143 ml (1.00 mol) of benzyl chloroformate and 127 g (1.20 mol) of sodium carbonate was added to 1,000 ml of 50% tetrahydrofuran-wate-r solution having 154 g (1.00 mol) of 4-piperidone hydrochloride*H20 under cooling with ice, followed by stirring for 16 hours at room temperature. The reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. 500 ml of ethyl acetate was added to residue, the organic layer was separated therefrom, and the aqueous layer was extracted with 200 ml of ethyl acetate. The collected organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, the obtained residue was purified by column chromatography (30% ethyl acetate-hexane) , and 230 g (0.986 mol) of Compound (12) as pale yellow oil was obtained with an yield of 99%.
'H-NMR(CDC13> rt, 400 MHz) δ 7.31-7.39 (5H.m) 5.18 (2H, s) 3.80 (4H, m) 2.46 (4H, m) EI-MS m/z (M)+ 233
REFERENCE EXAMPLE 12 Synthesis of l-benzyloxycarbonyl-4-methylenepioeridine (Compound (13) )
37.8 g (0.337 mol) of potassium tert-butoxide was added to 500 ml of diethyl ether suspension having 110 g (0.308 mol) of triphenylphosphonium bromide under cooling with ice, followed by stirring for 1 hour under cooling with ice, and 200 ml of a diethyl ether solution having 71.9 g (0.308 mol) of the Compound (12) was added thereto followed by stirring for 2 hours under cooling with ice. The reaction mixture was diluted with 1,400 ml of hexane followed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 250 ml of 25% diethyl ether-hexane solution, and 100 g of silica gel was added thereto, followed by stirring for 1 hour at room temperature, which was then subjected to filtration. Silica gel was washed with 25% diethyl ether-hexane solution, the collected filtrate was concentrated under reduced pressure, and 64.4 g (0.278 mol) of Compound (13) as pale yellow oil was obtained with an yield of 90%.
,H-NMR(CDC13, rt. 400 MHz) δ 7.31-7.37 (5H, m) 5.15 (2H, s) 4.76 (2H, s) 3.51 (4H. m) 2.20 (4H, brs) EI-MS m/z (M)+ 231
REFERENCE EXAMPLE 13 Synthesis of 7-benzyloxycarbonγl-2-oxo-l .7- diazaspiro[3.5]nonane (Compound (14))
20 ml of a dichloromethane solution having 2.80 ml (32.2 mmol) of chlorosulfonylisocyanate was added to 40 ml of a dichloromethane solution having 6.18 g (26.7 mmol) of the Compound (13) under cooling with ice, followed by stirring for 14 hours at room temperature. The reaction mixture was diluted with 120 ml of diethyl ether, followed by cooling with ice. 120 ml of an aqueous solution having 16.0 g (64.5 mol) of sodium thiosulfate-5H20 and 30 ml of 10% potassium hydroxide aqueous solution were dropwise added thereto, followed by stirring for 3 hours under cooling with ice. The organic layer was separated therefrom, the aqueous layer was extracted with ethyl acetate (30 ml x 2 ) , and the collected organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, followed by dissolution in hot ethyl acetate. Hexane was added thereto followed by cooling, the resulting solid was collected by filtration, the obtained solid was dried under reduced pressure at 50°C for 5 hours, and 5.46 g (19.9 mmol) of Compound (14) as pale yellow powder was obtained with an yield of 74%.
m.p. : 93.6 - 95.2 °C Η-NMR(CDC13, rt, 400 MHz) δ 7.31-7.38 (5H, m) 6.26 (IH, s) 5.13 (2H, s) 3.73 (2H. dt) 3.33 (2H, ddd) 2.74 (2H, m) 1.79 (4H, brs) EI-MS m/z (M)+ 274
REFERENCE EXAMPLE 14 Synthesis of methyl 4-amino-l-benzyloxycarbonyl-4- piperidyl acetate (Compound (10))
15 ml of sulfuric acid was added to 200 ml of a methanol solution having 44.7 g (0.986 mol) of the Compound (14) under cooling with ice, followed by stirring for 17.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure, 300 ml of ethyl acetate was added thereto to dissolve the residue, and 250 ml of saturated sodium hydrogencarbonate aqueous solution was added thereto. The organic layer was separated therefrom, and the aqueous layer was extracted with 200 ml of ethyl acetate. The collected organic layer was washed with saturated sodium chloride solution, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and 44.9 g (0.146 mol) of Compound (10) as pale yellow amorphous was obtained with an yield of 90%.
Η-NMR(CDC13. rt, 400 MHz) δ 7.30-7.39 (5H, m) 5.12 (2H, s) 3.72 (2H, m) 3.69 (3H, s) 3.39
(2H, m) 2.41 (2H, s) 1.55 (4H, m)
EI-MS m/z (M)+ 306
REFERENCE EXAMPLE 15
Synthesis of 2- (2.4-dinitrophenoxy) ethanol (Compound
(15))
3.57 g (13.9 mmol) of tetraethylammonium iodide was added to a mixture having 5.34 g (29.0 mmol) of 2,4- dinitrophenol and 3,88 g (44.0 mmol) of 1 , 3-dioxolan-2- on, followed by stirring for 2.5 hours at 140°C. After the completion of the reaction, extraction with chloroform from water was conducted, the obtained crude product was recrystallized from ethanol, and 3.13 g (13.7 mmol) of Compound (15) as pale yellow crystals was obtained with an yield of 47%.
Η-NMR(CDC13, rt, 400 MHz) δ 8.77 (IH, d) 8.52 (IH, dd) 7.57 (IH, d) 4.42 (2H, t) 3.98 (2H, t) FAB-MS m/z (M+H)+ 229 mp 100-102 °C
REFERENCE EXAMPLE 16
Synthesis of 6-chloro-2-methylthio-4- (2- phenoxyethoχy)oγrimidine (Compound (16))
6 ml of an acetonitrile solution having 1.58 g (11.4 mmol) of 2-phenoxyethanol was dropwise added to 10 ml of an acetonitrile suspension having 507 mg (12.7 mmol) of sodium hydride (60%) under cooling with ice, followed by stirring for 1 hour, and 5 ml of an acetonitrile solution having 2.02 g (10.4 mmol) of 4,6- dichloro-2-methylthiopyrimidine was dropwise added thereto under cooling with ice, followed by stirring for 30 minutes. The temperature was raised to room temperature, and the mixture was stirred overnight. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, extraction with ethyl acetate was conducted, the obtained crude product was recrystallized from methanol-water , and 3.09 g (10.4 mmol) of Compound (16) as pale yellow crystals was quantitatively obtained.
'H-NMR(CDC13, rt, 400 MHz) δ 7.28-7.32 (2H, m) 6.98 (IH, m) 6.92 (2H, m) 6.48 (IH, s) 4.72- 4.74 (2H, m) 4.29 (2H, t) 2.55 (3H. s) EI-MS m/z (M)+ 296 mp 80-86 °C REFERENCE EXAMPLE 17
Synthesis of 6-chloro-2-methylsulfonyl-4- (2- ohenoxγethoxy)pyrimidine (Compound (17))
28 mg (0.084 mmol) of sodium tungstate*2H20 was added to 3 ml of an acetic acid solution having 1.50 g
(5.05 mmol) of the Compound (16) synthesized in Reference Example 16, and 1.23 g (12.7 mmol) of aqueous hydrogen peroxide was dropwise added thereto, followed by stirring for 2.5 hours at room temperature. Water was added to the reaction solution, extraction with ethyl acetate was conducted, the obtained crude product was purified by column chromatography (ethyl acetate-hexane=l : 2 ) , and 1.13 g (3.44 mmol) of Compound (17) as colorless amorphous was obtained with an yield of 68%.
Η-NMR(CDC13, rt, 400 MHz) δ 7.28-7.33 (2H, m) 6.99 (IH, s) 6.97-7.01 (IH, m) 6.91-6.94 (2H, m) 4.86-4.89 (2H. m) 4.32-4.35 (2H, m) 3.55 (3H, s) EI-MS m/z (M)+ 328
REFERENCE EXAMPLE 18
Synthesis of 2-azide-4-chloro-6- (2-phenoxyethoxγ) - pyrimidine (Compound (18))
63 mg (0.9680 mmol) of sodium azide was added to 2 ml of a DMF solution having 138 mg (0.4840 mmol) of 2 , 6- dichloro-4- (2-phenoxyethoxy) -pyrimidine (Compound (22)), followed by stirring for 3 hours and 30 minutes at 50°C. The reaction solution was diluted with ethyl acetate and washed with water. The solvent was distilled off, and
956 mg of a residue was obtained, which was then purified by column chromatography (hexane : ethyl acetate=4 : 1) , and 129.6 mg (0.4443 mmol) of Compound (18) as colorless oil was obtained with an yield of 92%. REFERENCE EXAMPLE 19
Synthesis of 2-amino-4-chloro-6- (2-ohenoxyethoxγ) - pyrimidine (Compound (19)) 10% Pd-C was added to 5 ml of a methanol solution having 91 mg (0.3120 mmol) of the Compound (18), followed by stirring for 35 minutes at room temperature. The reaction solution was subjected to filtration, the solvent was distilled off, and 956 mg of a residue was obtained, which was then purified by column chromatography (chloroform:methanol=5 : 1) , and 73.0 mg (0.4443 mmol) of Compound (19) as colorless oil was obtained with an yield of 88%.
'H-NMR (400 MHz, CDC13) δ 7.28 (2H, m) 6.95 (3H, d. J=8.4 Hz) 6.01 (2H, d, J=8.0 Hz) 5.89 (IH, s) 4.40 (2H, ra) 4.20 (2H, d, J=3.6 Hz)
REFERENCE EXAMPLE 20 Synthesis of 2.6-dichloro-4- (2- phenylethylamino) pyrimidine (Compound (20)) and 4,6- dichloro-2- (2-phenylethγlamino) pyrimidine (Compound (2D) 2 ml of a DMF solution having 712.3 mg (5.89 mmol) of 2-phenylethylamine was dropwise added to 3 ml of a DMF solution having 1.00 g (5.47 mmol) of 2,4,6- trichloropyrimidine, and 1 m( (7.17 mmol) of triethylamine was added thereto, followed by stirring for 3 hours at room temperature. 5 ml of saturated aqueous ammonium chloride solution and 3 ml of water were added to the reaction solution, extraction with 40 ml of ethyl acetate was conducted three times, and the organic layer was dried over sodium sulfate. The drying agent was removed by filtration, the solvent was distilled off, the obtained crude product was purified by column chromatography (ethyl acetate-hexane=l : 7) , and 963 mg (66%) of Compound (20) as colorless solid and 468 mg (32%) of Compound (21) as colorless solid were obtained.
Compound (20) 'H-NMR(CDC13, rt, 60 MHz) δ 2.89 (t, 2H, NHCH2CH,Ph) , 3.66 (t, 2H, NHCH,CH,Ph) , 5.4 (br, IH, NH), 6.20 (s, IH, 5-H of pyrimidine), 7.25 (s, 5H, arom H of Ph) MS (FAB) m/z 268 (M)+ mp 108-110 °C Rf 0.32 (AcOEt-hexane = 1 : 2)
Compound (21)
Η-NMR(CDC13, rt, 60 MHz) δ 2.94 (t, 2H, NHCH2CH,Ph) , 3.70 (t, 2H, NHCH,CH,Ph) , 5.6 (br, IH, NH), 6.62 (s, IH. 5-H of pyrimidine), 7.29 (s. 5H, arom H of Ph)
MS (FAB) m/z 268 (M+H)τ mp 126-128 °C
Rf 0.61 (AcOEt-hexane = 1 : 2)
REFERENCE EXAMPLE 21
Synthesis of 2 , 6-dichloro-4- (2-ohenoxyethoxγ) pyrimidine (Compound (22))
2.38 g (60% dispersion in mineral oil, 59.5 mmol) of sodium hydride was added to 200 ml of a THF solution having 7.72 g (55.9 mmol) of 2-phenoxyethanol at room temperature, followed by stirring for 30 minutes. The reaction solution was cooled to -78°C, 10.54 g (53.3 mmol) of 2 , 4 , 6-trichloropyrimidine was added thereto, and the temperature was gradually raised to room temperature over a period of 3 hours. 100 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, extraction with 300 ml of ethyl acetate was conducted, and the organic layer was dried over magnesium sulfate. The drying agent was removed by filtration, the solvent was distilled off, the obtained crude product was purified by recrystallization (ether- hexane) , and 5.89 g (39%) of Compound (22) as colorless crystals was obtained.
mp 50-52 °C 170
The following compounds were synthesized in the same manner as in Reference Example 21.
Figure imgf000172_0001
compound No. R5 properties
23 θ(CH2)20 colorless crystals Cl
24
Figure imgf000172_0002
colorless crystals
25 $K)(CH2)30 colorless crystals
26
Figure imgf000172_0003
colorless crystals
28 MeO-^^CH2)40 colorless oil
29 ^-(C 2)40 colorless oil
30 O CH2 ) 3 0 colorless oil
31 Q)-(CH2)20 Pale yellow crystals
32 Qr 20 colorless oil
33 i colorless oil
Compound (23) m.p. 61-63°C FAB-MS (m/z) (M+H)+ 319
Compound (24) m.p. 39-4 TO
FAB-MS (M/Z) (M+H)+ 31 Compound (25) m.p. 40-42cC FAB-MS (m/z) (M+H)+ 299 Compound (26) m.p. 48-51 °C
FD-MS (m/z) (M)+ 312
Compound (28) FAB-MS (m/z) (M+H)+ 327
Compound (29) FAB-MS (m/z) (M+H)+ 297
Compound (30) FAB-MS (m/z) (M+H)+ 283
Compound (31) m.p. 101-103°C
FAB-MS (m/z) (M+H)+ 269
Compound (32)
FAB-MS (m/z) (M+H)+ 255
Compound (33) FAB-MS (ra/z) (M+H)+ 241 SYNTHESIS EXAMPLE 1
Synthesis of methyl (R -3- (4-chloro-6- (2- ohenoxyethoxy) oyrimidin-2-yl ) amino-4-tert- butoxycarbonylamino butyrate (Compound (34)) To 9 ml of a DMI solution having 269 mg (0.943 mmol) of the Compound (22) synthesized in Reference Example 21, 329 mg (1.42 mmol) of methyl 3-amino-4- ( tert- butoxycarbonylamino)butyrate synthesized by a method as described in J. Med. Chem., 1987, 30, 1458-1463 and then 493 ]il (2.83 mmol) of diisopropylethylamine were added, followed by stirring for 17.5 hours at 60°C. The reaction solution was diluted with EtOAc, washed with saturated aqueous ammonium chloride solution, and dried over magnesium sulfate followed by filtration. The solvent was distilled off, and pale yellow oil was obtained. The residue was purified by column chromatography (Hexane:EtOAc=4 : 1) and 389 mg (0.808 mmol) of Compound (34) as colorless oil was obtained with an yield of 86%.
lH-NMR(CD30D, rt, 400 MHz) δ 7.27-7.31 (2H, m) 6.92-6.99 (3H, m) 6.11 (IH. s) 5.88 (IH. br s) 4.97 (IH, m) 4.64 (2H, m) 4.45 (IH. m) 4.26 (2H, ra) 3.68 (3H. s) 3.40 (2H, m) 2.65 (2H, m) 1.42 (9H. s) FAB-MS m/z (M+H)+ 481 Compounds (35) to (49) were synthesized in the same manner as in Synthesis Example 1.
Figure imgf000175_0001
compound No. R5 m properties
35 5HCH2)2NH 0 pale brown amorphous
36 @ (CH2)20 0 colorless oil
37 < -0(CH2)20 colorless oil Cl
38 CH^O(CH2)20 colorless oil
39 0O(CH2)3O colorless oil
40 colorless oil
42 colorless oil
43
Figure imgf000175_0002
colorless oil
44 "(CH2>3° colorless oil
45
Figure imgf000175_0003
colorless oil
46 ^CH20 colorless oil
47 0° colorless oil
Figure imgf000175_0004
compound No. m properties
48 0 pal 2 yellow amorphous
49 1 pal( 3 yellow amorphous Compound (35) - MR(CDC13, rt, 400 MHz) δ 1.42 (s, 9H, t-Cjy. 2.87 (t, 2H, J= 7.1 Hz, NHCH H2Ph). 3.55 (br, 2H, NHCH,CH2Ph), 3.62 (br, 2H, CH HBOC) , 3.74 (s, 3H, C0,CH3) . 4.65 (br, IH, NH). 5.0 (br, IH, CH(C0,Me)CH2NHB0C) , 5.1 (br, IH. NH), 5.75 (s, IH, 5-H of pyrimidine), 5.8 (br, IH, NH), 7.19-7.21 (m, 3H, ortho and para H of Ph) , 7.30-7.34 (m, 2H, meta H of Ph) MS (FAB) m/z 450 (M+H)-
Compound (36)
Η-NMR(CDC13, rt, 400 MHz) δ 7.23-7.31 (2H, ra) 6.91-6.99 (3H, m) 6.27 (lH.br s) 6.15 (IH. s) 5.04 (IH, br s) 4.61 (2H, ra) 4.25 (2H, m) 3.76 (3H, s) 3.65 (IH, m) 1.42 (9H, s) FAB-MS m/z (M+H)+467
Compound (37) -NMR(CDC13, rt, 400 MHz) δ 7.19-7.34 (2H, ra) 6.90-6.97 (2H, m) 6.10 (IH, s) 5.88 (IH. br s) 5.08 (IH, br s) 4.68 (2H. m) 4.45 (IH, m) 4.33 (IH, s) 3.67 (3H, s) 3.40 (2H, dd, J=6.S, 12.6 Hz) 2.65 (2H, m) 1.41 (9H, s) FAB-MS m/z (M+H)+ 515
Compound (38) -NMR(CDC13, rt, 60 MHz) δ 7.25 (2H,d, J=8.4 Hz) 6.85 (2H,d, J=S.4 Hz) 6.09UH. s) 6.03 (IH, s) 5.20 (IH, br s) 4.60 (3H, ra) 4.24 (2H, m) 3.68 (3H, s) 3.37 (2H, dd, J=6.0. 12.0 Hz) 2.65 (2H. d, J=6.6 Hz) 1.38 (9H, s)
FAB-MS m/z (M+H)+ 515 Compound (39)
Η-NMR(CDC13, rt, 400 MHz) δ 7.25-7.31 (2H, m) 6.89-6.96 (3H. m) 6.04 (IH, s) 5.82 (IH, br s) 4.95 (IH, br s) 4.45 (3H. m) 4.09 (2H, ra) 3.67 (3H. s) 3.38 (2H. m) 2.63 (2H, ddd, J=5.S, 16.1. 22.0 Hz) 2.21 (2H, dd, J=5.S, 11.6 Hz) 1.41 (9H, s) FAB-MS ra/z (M+H)+ 479
Compound (40) Η-NMR(CDC13, rt, 400 MHz) δ 7.11 (2H, d, J=8.6 Hz) 6.83 (2H. d, J=8.6 Hz) 6.0K1H. s) 5.70 (IH, br s) 4.98 (IH, br s) 4.41 (IH, m) 4.26 (2H, m) 3.79 (3H, s) 3.68 (3H, s) 3.38 (2H, ra) 2.68 (2H, dd, J=7.5, 15.0 Hz) 2.62 (2H, m) 2.00 (2H, m) 1.41 (9H. s) FAB-MS m/z (M+H)+ 509
Compound (42) Η-NMR(CDC13, rt, 400 MHz) δ 7.09 (2H,d, J=8.4 Hz) 6.82 (2H,d. J=8.4 Hz) 6.10 (IH, br s) 6.00 (IH, s) 5.13 (IH, br s) 4.42 (IH, m) 4.25 (2H, br s) 3.77 (3H, s) 3.66. (3H, s) 3.39 (2H. m) 2.64 (4H, ra) 1.72 (4H. s) 1.41 (9H, s) FAB-MS ra/z (M+H)+ 522
Compound (43)
Η-NMR(CDC13, rt, 60 MHz) δ 7.22 (5H, s) 6.03 (IH, s) 5.18 (IH, br s) 4.29 (5H, m) 3.64 (3H, s) 3.37 (2H, ra) 2.70 (2H, m) 1.70 (4H, m) 1.37 (9H, s)
FAB-MS m/z (M+H)+ 493 Compound (44) -NMR(CDC13, rt. 400 MHz) δ 7.19-7.31 (5H, m) 6.06 (IH, s) 5.74 (IH, m) 4.89 (IH. br s) 4.41 (IH, m) 4.27 (2H, m) 3.68 (3H, s) 3.37 (2H, m) 2.74 (2H, m) 2.62 (2H, m) 2.05 (2H. m) 1.41 (9H, s) FAB-MS m/z (M+H)+ 479
Compound (45) Η-NMR(CDC13, rt, 400 MHz) δ 7.21-7.33 (5H, m) 6.04 (IH, s) 5.76 (IH, br d, J=7.9 Hz) 4.90 (IH, br s) 4.48 (2H, br s) 4.42 (IH, ra) 3.66 (3H, s) 3.38 (2H, dd, J=6.0, 12.0 Hz) 2.66 (IH, dd, J=5.7, 16.0 Hz) 2.60 (IH, dd, J=6.2, 16.0 Hz) 1.41 (9H, s) FAB-MS m/z (M+H)+ 465
Compound (46) lH-NMR(CDCl3, rt, 400 MHz) δ 7.31-7.39 (5H, m) 6.11 (IH, s) 5.78 (IH, br s) 5.33 (2H. s)
4.80 (IH, br s) 4.44 (IH, dd, J=5.9, 14.5 Hz) 3.69 (3H, s) 3.36 (2H, br s) 2.61 (2H. ra) 1.42 (9H, s)
Compound (47) 'H-NMR(CDC13, rt, 400 MHz) δ 7.38-7.43 (2H, ra) 7.28 (IH, ra) 7.11 (IH, d, J=7.7 Hz) 6.02 (IH. s) 5.88 (IH, br s) 4.42 (IH. br s) 3.66 (3H. s) 3.27 (2H. br s) 2.55 (2H, br s) 1.42 (9H, s) Compound (48) -NMR(CDC13, rt, 400 MHz) δ 1.43 (s, 9H, t-CJk), 2.85 (t. 2H, J= 7.1 Hz. NHCH,CH_,Ph). 3.6 (m, 2H+2H, NHCH,CH,Ph and CH.NHB0C) , 3.75 (s, 3H, C02CH3). 4.68 (br, IH, NH), 4.96 (br, IH, CH(C02Me)CH.\"HBOC) , 5.15 (br. IH. NH) . 5.81 (s, IH, 5-H of pyrimidine). 5.87 (br, IH, NH). 7.20-7.23 (ra. 3H. ortho and para H of Ph) , 7.28-7.32 (ra. 2H, meta H of Ph) MS (FAB) m/z 450 (M+H)+
Compound (49)
Η-NMR(CDC13, rt, 400 MHz) δ 1.43 (s, 9H, t-C,H9), 2.5-2.6 (m, IH, CHH'COΗ), 2.7-2.8 (ra. IH.
CHH1C02H), 2.87 (t, 2H, J= 7.0 Hz, NHCH2CH,Ph), 3.36 (ra, 2H, CH,
NHB0C), 3.6 (m, 2H, NHCH,CH,Ph). 3.67 (s. 3H. C02CH3), 4.3-4.4 (br, IH, CH(CH2C02Me)-CH2NHB0C), 4.9 (br, IH, NH), 5.0 (br, IH, NH) , 5.7
(br, IH, NH), 5.73 (s, IH, 5-H of pyrimidine). 7.20-7.23 (m, 3H, ortho and para H of Ph) , 7.30 (m, 2H, meta H of Ph)
MS (FAB) m/z 464 (M+H)+
SYNTHESIS EXAMPLE 2
Synthesis of (R) -3- (4-chloro-6- (2- phenoxyethoxy)pyrimidin-2-yl ) amino-4- ert- butoxycarbonylamino butyrate (Compound (50))
4 ml of 1M NaOH aqueous solution was added to 8 ml of a methanol solution having 199 mg (0.414mmol) of the Compound (34) synthesized in Synthesis Example 1, followed by stirring for 16 hours at room temperature. The reaction solution was acidified by 10% aqueous citric acid solution, and diluted with EtOAc . The organic layer was dried over magnesium sulfate followed by filtration, the solvent was distilled off, and colorless oil was obtained. The residue was purified by column chromatography (Hexane : EtOAc=2 : 1) , and 164 mg (0.350 mmol) of Compound (50) as colorless oil was obtained with an yield of 85% .
Η-NMR(CDC13, rt, 400 MHz) δ 7.26-7.31 (2H, ra) 6.92-6.99 (3H, ra) 6.10 (IH. d, J=5.7 Hz) 5.09 (IH, br s) 4.69 (2H, br s) 4.46 (2H. br s) 4.28 (2H, m) 3.51 (2H, m) 2.71QH. m) 1.42 (9H. s) FAB-MS m/z (M+H)+ 467
Compounds (51) to (65) were synthesized in the same manner as in Synthesis Example 2.
Figure imgf000181_0001
compound No. R5 R5' m properties
51 ^HCH2)2 H ci 0 pale brown solid
52 "0(CH2)20 ci 0 colorless oil
53 -0(CH2)20 ci 1 colorless oil
Cl
54 <Q >(CH2)20 H 1 colorless oil
Cl
55 C ^ -0(CH2)2θ Cl 1 colorless amorphous
56 ^0(CH2)30 Cl 1 colorless oil
57 Cl 1 colorless oil
59
Figure imgf000181_0002
Cl 1 colorless oil
60 <QHCH2)4O CI 1 colorless oil
61 $HCH2)3° ci 1 colorless oil
62
Figure imgf000181_0003
Cl 1 colorless oil
63 ^ H20 Cl 1 colorless oil
Figure imgf000181_0004
compound No. m properties
64 0 pale yellow amorphous 65 1 colorless solid Compound (51) -NMR(CDC13, rt, 400 MHz) δ 1.46 (s, 9H, t-Cjjg , 2.S8 (t, 2H, J= 6.8 Hz. NHCH.,CH2Ph ) . 3.5- 3.9 (br, 2H+2H. NHCH,CH2Ph . CH2NHBOC), 4.66 (br, IH. CH(C0,Me)CH, NHBOC), 5.43 (br, IH, NH), 5.73 (s, IH. 5-H of pyrimidine). 5-6 (br, 1HX2, NH x2), 7.19-7.33 (m. 5H, arom H of Ph) , 8.3 (br, IH, C02H) MS (FAB) m/z 436 (M+H)+
Compound (52)
Η-NMR(CDC13, rt, 400 MHz) δ 9.55 (IH, br s) 7.56 (IH. br s) 7.23-7.27 (2H, m) 6.88-6.95 (3H, m) 6.11 (IH, s) 5.35 (IH, br s) 4.67 (2H, m) 4.23 (2H, m) 3.65 (2H, s) 1.37 (9H, s) FAB-MS m/z (M+H)+ 453
Compound (53) -NMR(CDC13, rt, 400 MHz) δ 7.19-7.37 (2H, m) 6.90-6.97 (2H, m) 6.09 (IH. s) 5.17 (IH, br s) 4.74 (2H, br s) 4.46 (IH. br s) 4.34 (2H, s) 3.54 (IH, m) 3.45 (IH, m) 2.70 (2H, d, J=4.9 Hz) 1.42 (9H, s) FAB-MS m/z (M+H)+ 501
Compound (54) Η-NMR(CDC13, rt. 400 MHz) δ 8.27 (IH, br s) 7.86 (IH. br s) 7.37-7.19 (2H, m) 6.99-6.90 (2H, m) 6.09 (IH, d, J=6.2 Hz) 5.29 (IH, br s) 4.78 (IH, br s) 4.73 (IH. br s) 4.45 (IH, br s) 4.36 (IH, m) 4.30 (IH, ra) 3.56 (IH. dd, J=7.5, 12.4 Hz) 3.44 (2H. m: 2.69 (IH, dd, J=5.3. 16.3 Hz) 2.63 (IH, dd, J=4.4. 16.1 Hz) 1.40 (9H. s) FAB-MS m/z (M+H)÷ 467
Compound (55) -NMR(CDC13, rt. 60 MHz) δ 7.72 (IH, br s) 7.27 (2H. d, J=9.0 Hz) 6.85 (2H, d, J=9.0 Hz) ; 6.11 (IH, s) 5.16 (IH, br s) 4.63 (2H, m) 4.26 (3H, ra) 3.48 (2H. m) 2.72 (2H, m) 1.39 (9H, s)
Compound (56) -NMR(CDC13, rt, 400 MHz) δ 7.26-7.30 (3H, m) 7.21 (IH, br s) 6.89-6.96 (2H, m) 6.03 (IH. s) 5.12 (IH, br s) 4.51 (2H. br s) 4.42 (IH, br s) 4.09 (2H. m) 3.46 (2H, br s) 2.68 (2H, dd, J=5.8, 11.6) 2.22 (2H. m) 1.40 (9H, ' s)
Compound (57) -NMR(CDC13, rt, 400 MHz) δ 7.24 (IH, br s) 7.10 (2H. d, J=8.6 Hz) 6.83 (2H. d, J=8.6 Hz.) 6.03 (IH, s) 5.16 (IH, ra) 4.39 (IH, m) 4.31 (2H. br s) 3.78 (3H. s) 3.47 (2H, m) 2.68 (2H, m) 2.00 (2H. m) 1.41 (9H. s) FAB-MS m/z (M+H)+ 496
Compound (59) Η-NMR(CDC13, rt, 400 MHz) δ 10.9 (IH, br s) 7.26 (IH. br s) 7.09 (2H.d, J=8.6 Hz) 6.82 (2H.d. J=8.6 Hz) 5.99 (IH, s) 5.24 (IH, br s) 5.13 (IH, br s) 4.42 (IH, m) 4.30 (2H, br s) 3.71 (3H. s) 3.47 (2H. m) 2.68 (2H, d, J=4.δ Hz) 2.60 (2H. m)l. 72 (4H, br s) 1.40 (9H, s)
FAB-MS m/z (M+H) + 509
Compound (60)
Η-NMR(CDC13, rt, 400 MHz) δ 9.49 (IH, br s) 7.23 (5H, s) 6.01 (IH, s) 5.24 (IH, br s) 4.29
(5H, m) 3.46 (2H, m) 2.61 (2H, ra) 1.71 (4H, m) 1.40 (9H, s)
Compound (61)
Η-NMR(CDC13, rt, 400 MHz) δ 7.29-7.20 (5H, m) 6.04 (IH, s) 5.09 (IH, s) 4.38 (IH, m) 4.32 (2H, m) 3.49 (2H, m) 2.72 (4H, ra) 2.05 (2H, m) 2.74 (2H, m) 1.41 (9H, s)
Compound (62)
Η-NMR(CDC13, rt, 400 MHz) δ 7.27 (5H, ra) 6.00 (IH, s) 5.20 (IH, br s) 4.52 (IH, br s) 4.46
(2H, br s) 3.48 (IH, m) 3.30 (2H, dd, J=6.8, 13.5 Hz) 2.68 (2H, s) 1.39 (9H, s)
Compound (63) Η-NMR(CDC13, rt, 400 MHz) δ 7.30-7.38 (5H, m) 7.18 (IH. br s) 6.09 (IH, s) 5.35 (2H. br s) 5.04 (IH, br s) 4.45 (IH, br s) 3.46 (2H, m) 2.66 (2H, d, J=4.9 Hz) 1.41 (9H, s) Compound (64) -NMR(CDC13. rt. 400 MHz) δ 1.45 (s, 9H, t-Cϋ9), 2.88 (t, 2H, J= 7.1 Hz, NHCH,CH,Ph). 3.52- 3.63 (br, 2H+2H, NHCH2CH,Ph , CH2NHB0C), 4.75 (br, IH, CH(C0H)CH, NHBOC), 5.03 (br, 3H, NHx3). 5.92 (s. IH, 5-H of pyrimidine),
7.18-7.22 (m, IH, para H of Ph) . 7.26-7.32 (m, 4H, ortho and meta
H of Ph)
MS (FAB) m/z 436 (M+H)+
Compound (65)
Η-NMR(CD30D+CDC13. rt, 400 MHz) δ 1.40 (s. 9H, t-Cjy, 2-5 (br, 2H, CH2C02H) , 2.87 (t. 2H, J= 7.0 Hz, NHCH2CH2Ph), 3.2-3.3 (br, 2H. CH,NHB0C), 3.60 (m. 2H, NHCH CH2Ph), 3.7 (br, IH, NH), 4.4 (br, IH, CH(CH,C02H)CH,NHB0C) , 5.5- 5.6 (br, IH, NH) , 5.8 (s, IH, 5-H of pyrimidine), 7.20-7.23 (ra. 3H, ortho and para H of Ph) . 7.27-7.31 (ra, 2H, meta H of Ph) MS (FAB) m/z 450 (M+H)+
SYNTHESIS EXAMPLE 3 Synthesis of (S) -2- (4-chloro-6- (2- phenylethylamino)pyrimidin-2-yl) amino-3-amino-prooionic acid trifluoroacetate (Compound (66) )
35 mg (0.080 mmol) of the Compound (51) was dissolved in 1 ml of trifluoroacetatic acid, followed by stirring for 7.5 hours at room temperature. The solvent was distilled off, and 48 mg of a Compound (66) as brown amorphous was quantitatively obtained. -NMR(CD30D. rt, 400 MHz) δ 2.87 (t, 2H, J= 7.3 Hz, NHCH,CH2Ph) , 3.46-3.64 (br, 2H+2H. CH,Ph , CH2.\H2), 4.76 (ra. IH, CH(C02H)CH,NH) , 6.01 (s, IH. 5-H of pyrimidine), 7.17-7.30 (m, 5H, arom H of Ph) MS (FAB) m/z 336 (M+H)+
Compounds (67) to (80) were synthesized in the same manner as in Synthesis Example 3. Data of the isolated compounds are shown below. Compounds of which the data are not shown, were used for the following reaction without being isolated.
Figure imgf000186_0001
compoun d No. R5 m properties
67 "0(CH2)20 i colorless oil
68 <Q-0(CH2)20 i colorless oil Cl
69 C ^-0(CH2)20 i colorless oil
70 ^0(CH2)30 l colorless oil
71 i colorless oil
73
Figure imgf000186_0002
' colorless oil
74 < HCH2)4O i colorless oil
75 @iCH2)30 i colorless oil
76 CH 2 ) 2 0 l colorless oil
77 <^CH20 1 colorless oil
78 ° 1 colorless oil
Figure imgf000187_0001
compound No. m properties
79 0 brown amorphous 80 1 pale yellow amorphous
Compound (79) Η-NMR(CD30D, rt, 400 MHz) δ 2.87 (t, 2H, J= 7.3 Hz, NHCH2CH2Ph), 3.3-3.4 (br, NH2), 3.51- 3.66 (br, 2H+2H, NHCH2CHPh , CH2NH2), 4.85 (dd. IH, 3JHH = 5.0,
8.5 Hz, CH(C02H)CH2NH2). 6.12 (s, IH, 5-H of pyrimidine) . 7.16-7.20 (m, IH, para H of Ph) , 7.24-7.29 (m, 4H, ortho and meta H of Ph) MS (FAB) m/z 336 (M+H)+
Compound (80) -NMR(CD30D, rt, 400 MHz) δ 2.78 (ra. 2H, CH2C02H) , 2.94 (m, 2H, NHCH2CH2Ph). 3.29-3.35 (m,
2H, CH,NHB0C, NH), 3.62-3.67 (m. 2H, NHCHH'CHPh) , 3.83 (m. 2H.
NHCHHlCH2Ph) , 4.89 (m, IH, CH(CH2C0H)CH,NHB0C) , 5.17 (s, 2H, NH2) , 6.21 (s, IH, 5-H of pyrimidine), 7.19-7.29 (m. 5H+1H. arom H of Ph.
NH), 8.33 (br, IH, C02H)
MS (FAB) m/z 350 (M+H)+
SYNTHESIS EXAMPLE 4 Synthesis of (R) -3- (4-chloro-6- (2- phenoxyethoxy)oyrimidin-2-yl) amino-4- trimethylammonium lactate inner salt (Compound (81)) 3 mf of TEA was added to 160 mg (0.343 mmol) of the Compound (50) synthesized in Synthesis Example 2, followed by stirring for 10 minutes at room temperature. The solvent was distilled off from the reaction solution, and 287 mg of the residue was obtained, to which 3 ml of 10% NaOH aqueous solution and 146 \ιl (1.54 mmol) of Me2SO, were added, followed by stirring for 16 hours at room temperature. The solvent was distilled off, the residue was purified by column chromatography (CHCl3:MeOH:NH3aq=5: 1:0.1) , and 72 mg (0.176 mmol) of
Compound (81) as colorless oil was obtained with an yield of 52%.
Η-NMR(CD30D, rt, 400 MHz) δ 7.25-7.29 (2H, m) 6.93 (3H, dd, J=7.3, 14.6 Hz) 6.18 (IH, s) 4.72 (IH, br s) 4.60 (2H, br s) 4.28 (2H. br s) 3.69 (IH, br s) 3.60 (IH, d, J=12.3 Hz) 3.21 (9H, s) 2.54 (2H, d, J=5.5 Hz) FD-MS m/z (M+H)+ 409
Compounds (82) to (92) were synthesized in the same manner as in Synthesis Example 4.
Figure imgf000189_0001
compound No. R5 m properties
82 θ(CH2)20 colorless oil Cl
83 CI- -0(CH2)20 colorless solid
84 @°(CH2>3° colorless solid
85 MeO-^^ CH2)30 colorless oil
87 I colorless solid
88 l colorless solid
89
Figure imgf000189_0002
l colorless solid
90 -(CH2)2O l colorless solid
91
Figure imgf000189_0003
1 colorless oil
92 Oo 1 colorless solid
Compound (82) -NMR(CD30D, rt. 400 MHz) δ 7.33-7.35 (IH, m) 7.24-7.28 (IH, m) 7.10 (lH.br s) 6.91-6.95 (IH, m) 6.12 (IH, s) 4.80 (2H, br s) 4.68 (IH, br s) 4.37 (2H, br s) 3.70 (2H, s) 3.25 (911, s) 2.6K2H. d, J=6.2 Hz) FD-MS m/z (M+H)÷ 443
Compound (83) -NMR(CD30D, rt. 400 MHz) δ 7.25 (2H, d. J=8.4 Hz) 6.93 (2H, d, J=8.4 Hz) 6.19 (IH, s) 4.63
(2H, br s) 4.28 (2H, br s) 3.79 (IH. br s) 3.65 (2H. m) 3.26 (9H, s) 2.64 (2H, d, J=6.2 Hz) FAB-MS m/z (M+H)+ 443
Compound (84) -NMR(CD30D, rt, 400 MHz) δ 7.24-7.28 (2H, m) 6.89-6.93 (3H, m) 6.15 (IH, s) 4.49 (2H. br s) 4.10 (2H, br s) 3.82 (IH. br s) 3.71 (3H, s) 3.25 (9H, s) 2.65
(2H, m) 2.20 (2H, m) FAB-MS m/z (M+H)+ 421
Compound (85) -NMR(CD30D, rt, 400 MHz) δ 7.09 (2H, br s) 6.84 (2H, d, J=S.4 Hz) 6.12 (IH, s) 4.37 (IH, br s) 4.24 (IH, br s) 3.75 (3H. s) 3.66 (IH, br s) 3.65 (2H, m) 3.20 (9H, s) 2.67 (2H, br s) 2.50 (2H, J=5.5 Hz) 2.00 (2H, br s) FAB-MS m/z (M+H)+ 438
Compound (87) m.p. 101-106°C Η-NMR(CD30D, rt, 400 MHz) δ 7.08 (2H, d, J=8.5 Hz) 6.81 (2H, d, J=8.5 Hz) 6.12 (IH, s) 4.38 (IH, br s) 4.30 (2H, br s) 3.75 (3H, s) 3.61 (IH, br d, J=13.4 Hz ) 3.24 (9H, s) 2.61 (4H, m) 1.79 (4H. br s) FAB-MS m/z (M+H)+ 451
Compound (88) -NMR(CD30D, rt, 400 MHz) δ 7.13-7.27 (5H, s) 6.13 (IH, s) 4.31 (4H, br s) 3.81 (IH, br s
3.69 (IH, s) 3.63 (IH, d, J=13.5 Hz) 3.25 (9H, s) 2.64 (2H, m) 1.74 (4H, br s)
Compound (89) -NMR(CD30D, rt, 400 MHz) δ 7.29-7.15 (5H, m) 6.14 (IH, s) 4.27 (2H, br s) 3.79 (IH. br s) 3.62 (2H, d, J=13.6 Hz) 3.14 (9H. s) 2.74 (2H, br s) 2.59 (2H. d,
J=5.6 Hz) 2.
05 (2H, br s)
FAB-MS m/z (M+H)+ 407
Compound (90) m.p. 121-127°C Η-NMR(CD30D, rt, 400 MHz) δ 7.19-7.28 (5H, m) 6.09 (IH, s) 4.63 (IH, br s) 4.49 (2H, br s) 3.79 (IH, br s) 3.62 (IH, d, J = 12.4 Hz) 3.35 (IH, s) 3.24 (9H. s)
3.03 (2H, b r s) 2.63 (2H, d, J=6.4 Hz)
FAB-MS m/z (M+H)+ 393
Compound (91)
Η-NMR(CD30D, rt, 400 MHz) δ 7.32 (5H, m) 6.21 (IH, s) 5.41 (2H, m) 3.58 (2H, m) 3.23 (3H. br s) 3
.10 (6H, br s) 2.58 (2H, br s) FAB-MS m/z (M+H)+ 379
Compound (92) -NMR(CD30D, rt, 400 MHz) δ 7. 13-7. 48 (5H, m) 6. 34 (IH. s) 4. 52 ( IH. br s) 3. 59 (2H. m)
3. 22 (3H, br s) 2. 69 (6H, br s) 2. 50 (2H. m)
FAB-MS m/z (M+H) + 365
SYNTHESIS EXAMPLE 5
Synthesis of methyl (R) -3- (4-chloro-6- (2- phenoxyethoxy)pyrimidin-2-yl) amino-4-amino-butyric a i trifluoroacetate (Compound (93)) 1 ml of a TFA solution having 47 mg (0.0977 mmol) of the Compound (34) synthesized in Synthesis Example 1 was stirred for 15 minutes at room temperature. The solvent was distilled off from the reaction solution, and 55 mg of Compound (93) as colorless oil was obtained.
'H-NMR(CDC13, rt, 400 MHz) δ'8.56 (IH, br s) 8.01 (2H, br s) 7.26-7.30 (2H, m) 6.89-6.99 (3H, m) 6.23 (IH, s) 4.76 (IH, br s) 4.68 (IH, br s) 4.28 (2H, s) 3.66 (3H, s) 3.43 (2H, br s) 2.79 (2H, s) FAB-MS m/z (M+H)+ 381
Compounds (94) to (101) were synthesized in the same manner as in Synthesis Example 5. 191
Figure imgf000193_0001
compound No. R5 R5' m properties
94 0O(CH2)2O Cl 0 colorless oil
95 >-0(CH2)20 Cl 1 colorless oil Cl
96 < -0(CH2)20 H 1 colorless oil Cl
97 Cl 1 colorless oil
Figure imgf000193_0002
98 MeO-Q>-(CH2)3θ Cl 1 colorless oil
100
Figure imgf000193_0003
Cl 1 colorless oil
101 iCH2)40 Cl 1 colorless oil
Compound (94) -NMR(CDCl3, rt, 400 MHz) δ 7.76 (2H, br s) 7.26-7.31 (2H, ra) 6.99 (IH, dd, J=7.3, 14.6Hz)
6.88 (2H, d, J=7.9 Hz) 6.41 (IH, s) 5.02 (IH, ra) 4.70 2H, m) 4.29
(2H, ra) 3.79 (3H, s) 3.66 (IH, m) 3.53 (2H. s)
FAB-MS m/z (M+H)+ 367
Compound (95) 'H-NMR(CDC13, rt, 400 MHz) δ 8.41 (2H, s) 7.17-7.34 (2H, m) 6.88-6.96 (2H. ra) 6.03 (IH. s)
4.67 (2H, m) 4.31 (2H, s) 3.62 (3H, s) 3.46 (IH, ra) 2.88 (IH. m) 2.79 (IH, ra) FAB-MS m/z (M+H)+ 415
Compound (96) -NMR(CDC13, rt, 400 MHz) δ 8.15 (IH, m) 7.35 (IH, dd, J=1.3, 7.8 Hz) 7.28 (IH. dd, J=7.S, 15.6 Hz) 6.95 (2H, dd, J=7.1, 14.2 Hz) 6.57 (IH, m) 4.48 (2H, s) 4.40 (IH, brs) 3.69 (3H, s) 3.37 (IH, s) 2.91 (IH, m)
Compound (97) Η-NMR(CDC13, rt, 400 MHz) δ 7.22 (2H, d, J=8.8 Hz) 6.84 (2H, d, J=8.8 Hz) 6.02 (IH, s) 4.59 (3H, m) 4.21 (2H, m) 3.62 (3H, s) 3.27 (2H, m) 2.76 (2H, m)
Compound (98) -NMR(CDC13, rt, 400 MHz) δ 9.04 (IH, br s) 7.72 (2H. br s) 7.09 (2H, d. J=8.6 Hz) 6.84 (2H. d, J=8.6 Hz) 6.30 (IH, s) 4.78 (IH, br s) 4.45 (IH, br s) 4.40 (IH, br s) 3.79 (3H, s) 3.48 (3H, s) 2.81 (2H, d, J=3.3 Hz) 2.68 (2H, m) 2.06 (2H, m) FAB-MS m/z (M+H)+ 409
Compound (100) 'H-NMR(CDC13, rt, 400 MHz) δ 8.36 (2H, br s) 7.91 (IH. br s) 7.10 (2H, d, J=6.2 Hz) 6.82 (2H,d, J=7.3 Hz) 6.02 (IH, s) 4.81 (2H, br s) 4.38 (211, br s) 3.78 (3H, s) 3.63 (3
H, s) 3.06 (IH, br s) 2.85 (IH, br s) 2.60 (2H, s) 1.73 (4H. s) FAB-MS m/z (M+H)+ 422 Compound (101) 'H- MR CDCl,, rt, 400 MHz) δ 7.17-7.30 (5H, s) 6.63 (IH, br s) 6.06 (IH, s) 4.61 (IH. br s) 4.46 (IH, br s) 4.24 (3H, m) 3.63 (3H, s) 3.15 (2H, br s) 2.66 (2H. m) 1.74 (4H, m)
SYNTHESIS EXAMPLE 6
Synthesis of methyl (S) -2- (4-chloro-2- (2- phenylethylamino) oyrimidin-6-yl ) amino-3-amino-prooionic acid trif luoroacetate (Compound (102))
From 46 mg (0.10 mmol) of the Compound (48), 56 mg of Compound (102) as brown solid was quantitatively obtained in the same manner as in Synthesis example 5. -NMR(CD30D+CDC13, rt, 400 MHz) δ 2.87 (t, 2H,J= 7.5 Hz, NHCH,CH,Ph) , 3.45-3.55 (ra. 2H, CH ΗBOC) .
3.59 (m, 2H, NHCHgCH. h) , 3.74 (s. 3H, C02CH3), 4.0 (br, 2H. NHx2).
4.86 (dd, 1H,J= 8.2. 4.9 Hz, CH(C0Me)CH,NHB0C) , 6.13 (s, IH, 5-H of pyrimidine), 7.22-7.23 (ra, 3H, ortho and para H of Ph), 7.28- 7.32 (m, 2H, meta H of Ph)
MS (FAB) m/z 350 (M+H)+
SYNTHESIS EXAMPLE 7
Synthesis of methyl (R) -3- (4- (3- (4- methoxyphenyl ) oropoxy) yrimidin-2-yl ) amino-4-tert- butoxycarbonylamino butyrate (Compound (103))
11 mg of 10% Pd-C was added to 5 m of a methanol solution having 106 mg (0.208 mmol) of the Compound (40), followed by stirring for 52 hours at room temperature under hydrogen atmosphere. The reaction solution was subjected to filtration, the solvent was distilled off, , the residue was purified by thin layer chromatography (Hexane:EtOAc=l:D, and 36 mg (0.0748 mmol) of Compound (103) as colorless oil was obtained with an yield of 36%.
Η-NMR(CDC13, rt, 400 MHz) δ 7.99 (IH, d, J=5.7 Hz) 7.12 (2H, d, J=8.8 Hz) 6.84 (2H, d, J=8.8 Hz) 6.03 (IH, d, J=5.7 Hz) 5.65 (lH.br s) 5.02 (IH. s) 4.42 (IH, m) 4.26 (2H, m) 3.79 (3H, s) 3.67 (3H, s) 3.39 (2H, dd, J=5.9,
11.8 Hz ) 2.69 (2H, m) 2.60 (2H, dd, J=6.4, 9.3 Hz ) 2.01 (2H, m) 1.41 (9H, s)s FAB-MS m/z (M+H)+ 474
Compounds (108)' and (109) were synthesized in the same manner as in Synthesis Example 7.
Figure imgf000196_0001
compound No. R5 properties
108 < -0(CH2)20 colorless oil Cl 109 3 0(CH2)30 colorless oil Compound (108) Η-NMR (CDC13.- rt, 400 MHz)
3 8.03 (IH, d, J=5.5 Hz) 7.22-7.34 (2H. m) 7.90 (IH. d. J=S.2 Hz) 6.90-6.94 (IH. m) 6.15 (IH. d, J=5.5 Hz) 4.97 (IH. m) 4.71 (2H. br s) 4.36 (2H, t. J=4.2 Hz) 3.70 (IH. m) 3.58 (IH, d. J=13.5 Hz) 3.20 (9H, s) 2.52 (2H, m) FAB-MS (m/z) (M+H)+ 409
Compound (109) -NMR (CDCI3. rt, 400 MHz)
0 8.07 (IH, br s) 7.41 (2H, br s) 7.26 (IH, s) 6.92 (2H, s) 6.25 (IH, br s) 4.57 (2H, br s) 4.13 (2H, br s) 3.87 (IH, br s) 3.69 (2H, s) 3.26 (9H, s) 2.75 (2H. s) 2.25 (2H. br s) FAB-MS (m/z) (M+H)+ 389
SYNTHESIS EXAMPLE 8
Synthesis of methyl 2- (4- (2 , 6-dichloropyrimidin-4- yl) amino-l-benzyloxycarbonyl-pioeridin-4-yl ) acetate (Compound (104)) and methyl 2- (4- (4 , 6-dichlorooyrimidin- 2-yl ) amino-l-benzyloxycarbonyl-oiperidin-4-yl ) acetate (Compound (105))
17.4 g (56.70 mmol) of the Compound (10) and 19.8 ml (113.4 mmol) of diisopropylethylamine were added to 25 ml of a DMPU solution having 10.4 g (56.60 mmol) of 2,4,6- trichloropyrimidine, followed by stirring for 5 hours at 100°C. The reaction solution was diluted with ethyl acetate, and washed with 1M hydrochloric acid, saturated aqueous ammonium chloride and saturated aqueous sodium chloride solution. The solvent was distilled off, 33.7 g of a residue was obtained, which was then purified by column chromatography (hexane : ethyl acetate=4 : 1) . The obtained crude product was washed with hexane and ethyl acetate, and 9.25 g (20.40 mmol) of Compound (104) as pale yellow powder was obtained with an yield of 36%. Further, 3.69g (8.142 mmol) of Compound (105) as pale yellow powder was also obtained with an yield of 14%.
Compound (104) m.p. 153-158°C -NMR (CDC13. rt, 400 MHz)
$ 7.21-7.34 (5H, m),7.07 (IH, s),6.62 (IH, s),5.12 (2H, s),3.90 (2H, br s),3.58 (3H, s),3.19 (2H, br s).2.99 (2H, m).2.49 (2H, br s) , 1.69 (2H, m)
Compound (105) m.p. 105-109°C -NMR (CDCI3. rt, 400 MHz) δ 7.20-7.35, (5H, m),6.62 (IH, s).5.69 (IH. s),5.13 (2H, s) .3.91 (211. br s),3.60 (3H, s),3.18 (2H, ra),2.97 (2H, s),2.43 (2H. d, J=13.7
Hz), 1.70 (2H, m)
SYNTHESIS EXAMPLE 9
Synthesis of 2- (4- ( 6-chIoro-2- ( 2-phenoxyethoxy) pyrimidin- 4-yl) amino-l-benzyloxycarbonyl-oiperidin-4-yl) acetate (Compound (106) )
2 ml of an acetonitrile solution having 71 mg (0.5163 mmol) of 2-phenoxyethanol was added to 2 ml of an acetonitrile solution having 22 mg (0.5593 mmol) of NaH, followed by stirring for 15 minutes at room temperature, and 2 ml of an acetonitrile solution having 195 mg (0.4303 mmol) of the Compound (104) was added thereto, followed by stirring for 19 hours at the same temperature. The reaction solution was diluted with ethyl acetate, and washed with water. The solvent was distilled off, 177 mg of a residue was obtained, which was then purified by column chromatography (hexane : ethyl acetate=2 : 1) , and 41.4 mg (0.07652 mmol) of Compound (106) as colorless oil was obtained with an yield of 18%. -NMR (CDC13. rt, 400 MHz) δ 7.23-7.36 (7H, m) 6.89-7.00 (3H. m) 6.11 (IH, s) 5.50 (IH. s) 5.11 (2H, s) 4.57 (2H, m) 4.25 (2H, m) 3.83 (2H. b s) 3.14 (2H, t. J=11.5 Hz) 3.03 (IH, br s) 2.91 (IH, br s) 2.47 (IH, br s) 2.38 (IH. br s) 1.67 (2H, m)
FAB-MS (m/z) (M+H)+ 541
SYNTHESIS EXAMPLE 10
Synthesis of methyl 2- (4- (4-chloro-6- (2- phenoxyethoxy) oyrimidin-2-yl ) amino-1-benzyloxycarbonyl- pioeridin-4-yl ) acetate (Compound (107))
2 ml of an acetonitrile solution having 57 mg (0.4104 mmol) of 2-phenoxyethanol was added to 2 ml of an acetonitrile solution having 18 mg (0.4446 mmol) of NaH, followed by stirring for 15 minutes at room temperature, and 2 ml of an acetonitrile solution having 155 mg (0.3420 mmol) of the Compound (105) was added thereto, followed by stirring for 16 hours and 30 minutes at the same temperature. The reaction solution was diluted with ethyl acetate, and washed with water. The solvent was distilled off, 219 mg of a residue was obtained, which was then purified by thin layer chromatography
(hexane:ethyl acetate=l : 1) , and 41.4 mg (0.07652 mmol) of Compound (107) as colorless oil was obtained with an yield of 25%. -NMR (CDC13, rt, 400 MHz) δ 7.26-7.36 (7H, m) 6.,90-6.99 (3H, m) 6.14 (IH. s) 5.20 (IH. br s) 5.12 (2H, s) 4.59 (2H. m) 4.26 (2H, t, J=4.8 Hz) 3.93 (2H. br s) 3.59 (3H, s) 3.19 (2H. ra) 2.96 (2H, s) 2.43 (2H, t, J=13.5 Hz) 1.69 (2H, t, J=10.8 Hz) FAB-MS (m/z) (M+H)+ 555
SYNTHESIS EXAMPLE 11
Synthesis of 2- (4- (4-chloro-6- (2 -phenoxyethoxy) oyrimidin- 2-yl) amino-l-benzyloxy-carbonylpiperidin-4-yl ) acetic acid (110)
To an ice-cooled suspension of sodium hydride (60% oil dispersion, 111 mg, 2.33 mmol) in acetonitrile (30 ml) , 2-phenoxyethanol (359 \ιl , 2.79 mmol) was added. The reaction mixture was stirred for 40 minutes, and then the Compound (105) (1.03 g, 2.33 mmol) was added therein at 0°C. The reaction mixture was allowed to warm to room temperature, and stirred over 10 hours. After cooling to 0°C, saturated aqueous ammonium chloride (20 ml ) , water (10 ml) and ethyl acetate (10 ml) was added therein. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 ml) . The combined organic phase was washed with brine and dried over magnesium sulfate. After filtration, the solvent was removed under reduced pressure, and the remaining oil was dissolved in methanol (4 m . 1 M aqueous sodium hydroxide (4 ml) was added into the solution, and then the mixture was stirred for 14 hours at room temperature. The reaction mixture was acidified with 10% aqueous citric acid, and diluted with ethyl acetate (30 ml) . The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, 25% methanol-chloroform) to give Compound (110) (802 mg, 1.48 mmol) as a colorless powder in 63% yield.
mp 157. 1 - 157. 8°C -NMR ( (CD3) 2S0, rt , 400 MHz δ 12. 02 ( IH, s) 7. 54 ( IH, brs) 7. 25-7. 41 (5H. m) 6. 91-6. 97 (2H. m) 6. 22 (IH, s) 5. 06 (2H. s) 4. 56-4. 61 (2H, m) 4. 26-4. 31 (2H. m) 3. 72 (2H, brd, J = 14. 4 Hz) 3. 12 (2H. brs) 2. 83 (2H. s) 2. 40 (2H. d. J = 14. 4 Hz) 1. 57-1. 67 (2H, m) EI-MS m/z 539 (M-H) +
SYNTHESIS EXAMPLE 12
Synthesis of 2- (4- (4- (2-phenoxγethoxy) oyrimidin-2- yl) amino-1 , l-dimethyloiperidin-4-yl acetate inner salt (111)
To a solution of the Compound (110) (301 mg, 0.556 mmol) in methanol (20 mO , 10% palladium-carbon (32.1 mg) was added. Under hydrogen atmosphere, the reaction mixture was stirred for 14 hours at room temperature, which was subjected to filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (20 ml) , and 10% palladium-carbon (32.1 mg) was added • therein . Under hydrogen atmosphere, the reaction mixture was stirred for 8 hours at room temperature, and then filtered. The solvent was removed under reduced pressure, and the obtained crude product was dissolved in 10% aqueous sodium hydroxide (5 mO , and dimethyl sulfate (260 ιl , 2.75 mmol) was added therein. The mixture was stirred for 3 hours at room temperature, neutralized with 1 M hydrochloric acid, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform-methanol- ammonium hydroxide, 3/1/0.1) to give Compound (111) (181 mg, 0.452 mmol) as a colorless powder in 81% yield. mp 232.0 - 233.1°C -NMR ((CD3)2S0, rt, 400 MHz) δ 8.05 (IH, d, J = 5.6 Hz) 7.30 (2H, brt, J = 8.0 Hz) 6.92-7.00 (3H, ra) 6.09 (IH, d. J = 5.6 Hz) 4.51-4.55 (2H, m) 4.26-4.30 (2H, m) 3.2S-3.47 (6H, m) 3.21 (3H, s) 3.15 (3H. s) 2.94-3.16 (2H. m) 2.35
(2H, s)
FAB-MS m/z 401 (M+H)+
TEST EXAMPLE 1: CTP-inhibitory activity 1 Isolation of mitochondria
Male ddy mice (6-week-old) were used. The mice were fasted for over night. They were injected intraperitoneally with a bolus injection of 150 mg/kg of streptozotocin (STZ; Sigma) dissolved in 3mM citrate buffer (pH 4.5). Mice with blood glucose level >300 mg/df were used. In case of using rats, SD rats (6-week- old) having a normal blood glucose level were used after fasted for overnight.
Hepatic mitochondria were isolated by a modification of the procedure of McGarry et al . (J. Biol. Chem., vol. 253, 4128-4236). Briefly, mouse liver was homogenized with 0.25M sucrose (25 ml buffer/10 g tissue), and centrifuged at 600 x g. The supernatant was centrifuged at 7,700 x g, the obtained pellet was resuspended in 0.25M sucrose and was centrifuged at 7,700 x g again. The obtained pellet was resuspended in 0.15M KCl-5mM Tris-HCl (pH 7.2) to obtain a preparation of isolated mitochondria. All the operations were carried out at 4°C. The preparation of isolated mitochondria obtained in the above-mentioned manner was used for experiments as CPT- enzyme . Measurement of CPT activity
CPT activity was measured by a modification of the 5, 5-L-dithiobis-L2-nitrobenzoil acid (DTNB) method (Diabetes research strategy, 342-343) as follows. The reaction of DTNB with free CoA which was generated when CPT was reacted with palmitoyl-CoA and carnitine, was measured by changes of absorption (412 run) . Assay was conducted in 50mM Tris-HCl buffer (pH 7.4) containing the mitochondria suspension, the test compound having various concentrations, 0. ImM DTNB, 12.5 mg/ml of bovine serum albumin, 5mM MgCl2, 0.5mM EDTA and 0. ImM palmitoyl-CoA. The reaction was initiated by adding a substrate; L- carnitine (final concentration: 1.6mM) at 25°C, and the reaction rate in one minute was measured. Standard blank contained all the above compounds except L-carnitine. The test compound was dissolved in dimethyl sulfoxide (DMSO) so that the final concentration of DMSO in the reaction solution did not exceed 1%.
Test results are shown in Table 10. Table 10
Compound No. Concentration (μM) Inhibitory ratio (%)
81 30 35.6
34 30 53.4
103 30 41.4
87 30 35.7
TEST EXAMPLE 2: CPT inhibitory activity 2
Isolation of rat hepatic mitochondria Rat hepatic mitochondria were isolated by a modification of the procedure of McGarry et al. (J. Biol.
Chem., vol. 253, 4128-4136, 1978).
Rat liver was minced with scissors and homogenized with 10 volumes of 0.25M sucrose. The homogenate was centrifuged for 15 minutes at 600 x g. The supernatant was centrifuged for 15 minutes at 7,700 x g, the obtained pellet was resuspended to the original volume of 0.25M sucrose, and was centrifuged for 15 minutes at 7,700 x g again. The obtained pellet was resuspended in 150mM KC1- 5mM Tris-HCl (pH 7.2), to obtain a preparation of isolated mitochondria. All the operations were carried out at 4°C.
Measurement of CPT I-activity
CPT I-activity was measured by a modification of the procedure of McGarry et al. (Biochem. J., vol. 214, 21-28,
1983) . Namely, CPT I-activity was measured from rate of formation of palmitoyl carnitine when CPT I was reacted with palmitoyl-CoA and carnitine. The reaction was initiated by the addition of 10 \ιl of mitochondria suspension (0.02-0.05 mg protein/10 ul) to a mixture having 80 \xl of an incubation buffer (131.25mM Tris-HCl, 0.3ImM reduced glutathione, 5mM ATP, 5mM MgCl2, 18.75mM KC1, 2.5mM KCN, 0.005% rotenone, 1.25% BSA (FFA free), 62.5μM palmitoyl-CoA, 250μM L-carnitine) and 1 \ιl of the test compound having various concentrations and 10 xl of L- [methyl- C]carnitme (0.2 μCi) added thereto. Incubation was carried out at 30°C for 10 minutes, and the reaction was terminated with 100 ιl of 1.2M HC1. One hundred \ιl of butanol was added to the reaction mixture, followed by shaking vigorously, which was then centrifuged. Fifty \ιl of the butanol layer was transferred to another tube containing 50 ul of water- saturated butanol, followed by shaking vigorously again, which was then centrifuged. Twenty ul of the. butanol phase was used for measurement of radioactivity in liquid scintillation counter. The test compound was dissolved in dimethyl sulfoxide (DMSO) so that the final concentration of DMSO in the reaction solution did not exceed 1%. The effect of the inhibitory activity was evaluated as the concentration of test compounds required for 50% inhibition of enzyme activity (IC50) . TEST EXAMPLE 3: Hypoglycemic activity
Male ddY mice (5-week-old) were purchased from Nippon SLC. They were allowed free access to foods and water for at least one week for preliminarily breeding. Mice with a blood glucose level of higher than 300 mg/d after 150 mg/kg of streptozotocine was intraperitoneally administered after fasted for overnight, were used as diabetic models.
The diabetic model mice were fasted for overnight, olive oil was given by oral administration, and immediately after the administration, the test compound was administered in mice. Blood was collected from the orbital vein plexus before and 6 hours after the administration of the test compound, and the blood glucose level was measured.
Each test compound suspended in 0.5% carboxy-methyl cellulose (CMC) -saline was orally administered in mice. For measurement of the blood glucose level, 20 ιl of blood collected from the orbital vein plexus was diluted in 60 units heparin sodium-solution and was centrifuged. The glucose concentration in the supernatant was measured by glucose oxidase method. The hypoglycemic activity was expressed by reducing rate of blood glucose relative to the control . FORMULATION EXAMPLE 1
Tablets
The compound of the present invention 1.0 g
Lactose 5.0 g
Crystal cellulose powder 8.0 g
Corn starch 3.0 g Hydroxypropyl cellulose 1.0 g
CMC-Ca 1.5 g
Magnesium stearate 0.5 g
Total 20.0 g
The above components were mixed by a usual method and then tabletted to produce 100 tablets each containing
10 mg of the active ingredient. FORMULATION EXAMPLE 2 Capsules
The compound of the present invention 1.0 g
Lactose 3.5 g
Crystal cellulose powder 10.0 g
Magnesium stearate 0.5 g
Total 15.0 g
The above components were mixed by a usual method and then packed in No. 4 gelatin capsules to obtain 100 capsules each containing 10 mg of the active ingredient. FORMULATION EXAMPLE 3
Soft capsules
The compound of the present invention 1.00 g
PEG 400 3.89 g
Saturated fatty acid triglyceride 15.00 g
Peppermint oil 0.01 g
Polysorbate 80 0.10 g
Total 20.00 g The above compounds were mixed and packed in No . 3 soft gelatin capsules by a usual method to obtain 100 soft capsules each containing 10 mg of the active ingredient. FORMULATION EXAMPLE 4
Ointment
The compound of the present invention 1.0 g
Liquid paraffin 10.0 g
Cetanol 20.0 g
White vaseline 68.4 g
Ethylparaben 0.1 g
^-menthol 0.5 g
Total ' 100.0 g The above components were mixed by a usual method to obtain a 1% (10%) ointment. FORMULATION EXAMPLE 5
Suppository
The compound of the present invention 1.0 g Witepsol H15* 46.9 g
Witepsol 35* 52.0 g
Polysorbate 80 0.1 g
Total 100.0 g
* : Trademark for triglyceride compound The above components were melt-mixed by a usual method and poured into suppository containers, followed by cooling for solidification to obtain 100 suppositories of 1 g each containing 10 mg of the active ingredient. FORMULATION EXAMPLE 6
Granules
The compound of the present invention 1 . 0 g
Lactose 6 . 0 g
Crystal cellulose powder 6 . 5 g
Corn starch 5 . 0 g Hydroxypropyl cellulose 1 . 0 g Magnesium stearate 0 . 5 g Total 20.0 g
The above components were granulated by a usual method and packaged to obtain 100 packages each containing 200 mg of the granules so that each package contains 10 mg of the active ingredient. INDUSTRIAL APPLICABILITY
Since the compound of the present invention has a hypoglycemic effect and a CPT inhibitory activity and has less toxicity, it is useful for preventing or treating diabetic complications such as diabetic eye diseases, diabetic neuropathy, diabetic nephropathy and diabetic gangrene .

Claims

CLAIMS 1. A 6-membered heterocyclic-compound or its salt represented by the formula [I] :
Figure imgf000211_0001
[wherein A is
Figure imgf000211_0002
1 2 {wherein each of m, n, n and n which are independent of one another, is 0, 1, 2 or 3 , R' is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a sulfonic acid group, a sulfonamide- group, P02H ,
6 6
P03H2 , . a 5-tetrazolyl group , C (0) OR (R is a hydrogen
7 7' 7 7' atom or a C1_1 alkyl group), C(0)NRR (each of R and R which are independent of each other, is a hydrogen atom
S 3 . or a C1_1 alkyl group) , OR (R is a hydrogen atom, a C. -
9 9' 9 alkyl group or a phenyl group) or NR R (each of R and
9'
R which are independent of each other, is a hydrogen atom, a Cχ_7 alkyl group or a phenyl group) , R' is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a guanidyl group, an amidino ID :o' iO :c group, NR R (each of R and R which are independent of each other, is a hydrogen atom, a C,_7 alkyl group, a
C,_7 aliphatic acyl group, a C,_10 aromatic acyl group or a
+ 11 11' 11" 11 II' protecting group) or N R R R (each of R , R and R x which are independent of one another, is a C1_1 alkyl group) , each of R and R which are independent of each other, is a Cχ_7 alkyl group, R-" is a hydrogen atom, a C1-7 alkyl group, a Cχ_7 aliphatic acyl group, a C6_10 aromatic acyl group or a protecting group}; D is a covalent bond, -CH2-, -0-, -S-, -S(O)-, -S(0)2-, -NR12-, -C(0)-NR12-, -NR12-C(0)- or
12 12' , „ 12 12'
-NR -C(0)-NR - (each of R and R which are independent of each other, is a hydrogen atom or a C1_7 alkyl group) ;
1 2 3 4 5 each of X , X , X , X and X which are independent of
5 5 . one another, is a nitrogen atom or CR {R is a hydrogen atom, a halogen atom or -E-G (E is
1 13 13' 2 14 14' 3
-L -(CR R )k-L -(CR R )rL - (k is from 1 to 10, 1 is
13 13 ' 14 14 ' from 0 to 10, and each of R , R , R and R which are independent of one another, is a hydrogen atom, a halogen atom, a hydroxyl group, a C17 alkyl group or a C17 alkoxy
1 2 3 . group, each of L , L and L which are independent of one another, is a covalent bond, -0-, -S-, -S(O)-, -S(0)„-, -C(0)-, -C≡C-, -CR15=CRlD -, -NR15-, -NRl3-C(0) -, -C(0)-NR15- or -NR -C(0)-NR - (each of R 3 and R which are independent of each other, is a hydrogen atom, a C1 7 alkyl group or a C6_1 aromatic group) ) , and G is a hydrogen atom, a C1.12 heteroaromatic group (said heteroaromatic group may contain at most 5 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms as constituents for the ring) , a C1_6 heteroalicyclic group (said heteroalicyclic group may contain at most 3 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms as constituents for the ring) , a C3_10 cycloalkyl group, a C,_7 cycloalkenyl group or a C6_14 aromatic group (said C1_12 heteroaromatic group, C1_6 heteroalicyclic group, C3_10 cycloalkyl group, C, . cycloalkenyl group and C6_1 aromatic group may contain at most 5 substituents in total (said substituent is a hydrogen atom, a Cχ_7 alkyl group, a C,_7 cycloalkyl group, a C3_7 cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a C1_7 alkoxy group, a Cχ_7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group,, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C1_3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C,_7 alkylsilyloxy group, phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (each of said phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl may be substituted with at most 5 of Cχ_7 alkyl groups, C3_7 cycloalkyl groups, C1 3 alkoxy groups, C._. alkylthio groups, hydroxyl groups, halogen atoms, nitro groups and dimethylamino groups))))}, provided that at least one of X" to X is a nitrogen atom] . 2. The 6-membered heterocyclic-compound or its salt according to Claim 1, wherein among groups of G, the C3_10 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo [2.2. ljheptyl, bicyclo [3.1. ljheptyl, bicyclo [2.2.2 ] octyl or adamantyl, the C3_7 cycloalkenyl group is cyclohexenyl, cyclopentadienyl, 2-bicyclo [2.2. l]heptenyl or 2,5- bicyclo [2.2. ljheptadienyl, the C6_14 aromatic group is phenyl, naphthyl, indenyl, indanyl or fluorenyl, the C1 heteroaromatic group is furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, furazanyl, pyrazolyl, oxopyrazolyl, imidazolyl, oxoimidazolyl, triazolyl, oxotriazolyl, tetrazolyl, pyranyl, pyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrimidinyl, pyrimidinonyl , pyrazinyl, triazinyl, tetrazinyl, indolyl, quinolyl, quinolonyl, benzofuranyl, benzothienyl, isoquinolyl, isoquinolonyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzimidazolyl , benzotriazolyl, benzopyranyl, indolizinyl, purinyl, phthalazinyl, oxophthalazinyl , naphthylidinyl , quinoxalinyl, quinazolinyl , cinnolinyl, benzodioxolyl, benzodioxanyl , oxonaphthalenyl , dihydrobenzofuranyl, benzothiazinyl, pteridinyl, pyrazolo [1 , 5-a] pyrimidinyl, pyrazolofl, 5-c] [1, 2 , 4 ] triadinyl , thiazolo [3 , 2- b]triazolyl, benzopyrano [2 , 3-b] pyridyl, 5H- oxobenzopyrano[2, 3-b] pyridyl, xanthenyl, phenoxathiinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or thianthrenyl, or the Cχ_, heteroalicyclic group is piperidyl, pyrrolidinyl, imidazolidinyl, pyrazoridinyl, morpholinyl or tetrahydrofuranyl, and the above-described C3_10 cycloalkyl group, C3_7 cycloalkenyl group, C,_14 aromatic group, C1_12 heteroaromatic group or Cχ_6 heteroalicyclic group may contain at most 5 substituents in total (said substituent is a hydrogen atom, a C1_7 alkyl group, a C3 7 cycloalkyl group, a C, cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a C17 alkoxy group, a Cχ_7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C1 3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C1_7 alkylsilyloxy group, phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (each of said phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl may be substituted by at most 5 of Cχ_7 alkyl groups, C,_7 cycloalkyl groups, C1 3 alkoxy groups, C. , alkylthio groups, hydroxyl groups, halogen atoms, nitro groups and dimethylamino groups)).
3. The 6-membered heterocyclic-compound or its salt according to Claim 2, wherein G is a hydrogen atom,
Figure imgf000216_0001
Figure imgf000217_0001
a b
[wherein each of R and R which are independent of each other, is a hydrogen atom, a C1-7 alkyl group, a C3_7 cycloalkyl group, a C3_7 cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a C,_7 alkoxy group, a C._7 alkylthio group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a Cχ_3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C1_7 alkylsilyloxy group, phenyl, α -naphthyl, β - naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (each of said phenyl, a -naphthyl, β -naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl may be substituted with at most 5 of Cχ_7 alkyl groups, C3 7 cycloalkyl groups, C1_3 alkoxy groups, C1_3 alkylthio groups, hydroxyl groups, fluorine atoms, chlorine atoms, bromine atoms, nitro groups and dimethylamino groups); c and R is a hydrogen atom, a C1 7 alkyl group, a C3 7 cycloalkyl group or a hydroxymethyl group] .
4. The 6-membered heterocyclic-compound or its salts according to Claim 3, wherein G is a hydrogen atom,
Figure imgf000218_0001
Figure imgf000219_0001
[wherein each of R* and R^ which are independent of each other, is a hydrogen atom, a C17 alkyl group, a C3_7 cycloalkyl group, a C,_7 cycloalkenyl group (said alkyl group,, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a C1-7 alkoxy group, a C17 alkylthio group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C^ alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C1_7 alkylsilyloxy group, phenyl, α -naphthyl, β - naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (each of said phenyl, α-naphthyl, β -naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl may be substituted with at most 5 of C1 7 alkyl groups, C3_7 cycloalkyl groups, C:_3 alkoxy groups, C1_3 alkylthio groups, hydroxyl groups, fluorine atoms, chlorine atoms, bromine atoms, nitro groups and dimethylamino groups); c and R is a hydrogen atom, a C1 7 alkyl group, a C3_7 cycloalkyl group or a hydroxymethyl group] .
5. The 6-membered heterocyclic-compound or its salts according to Claim 4, wherein R is a sulfonic acid
6 5 group, P03H2, a 5-tetrazolyl group or C(0)0R (R is a
2 . hydrogen atom or a Cχ_7 alkyl group) ; R is a guanidyl
. , . 10 10' , r 10 , 10' group, an amidmo group, NR R (each of R and R which are independent of each other, is a hydrogen atom
,, + 11 11' 11" , 11 11' or a C1-7 alkyl group) or N R R R (each of R , R and R which are independent of one another, is a C1 7 alkyl
4 group) ; R is a hydrogen atom or a C1-7 alkyl group; D is -0-, -NR - or -C(0)-NR - (R is a hydrogen atom or a C^,
13 13 ' 1 14 ' alkyl group) ; each of R , R , R and R which are independent of one another, is a hydrogen atom, a C1 7
1 2 alkyl group or a Cχ_7 alkoxy group, and each of L , L and L which are independent of one another, is a covalent bond, -0-, -C(0)-, -CR15=CR15 -, -NR15- , -NR15-C(0)- or
-C(0)-NR - (each of R and R which are independent of each other, is a hydrogen atom or a C1 7 alkyl group) .
6. The 6-membered heterocyclic-compound or its salt according to Claim 5, wherein E is
R15 R15
-0-(CH2)k-0- , _o-(CH2)k_N_ , _N-(CH2)k-0- ,
_
Figure imgf000221_0001
.15 R1 > R ,1153 9 R 15'
-N-(CH2)k-N-c- , -N-(CH2)k-£-N_ (CH2)k-0-
R15 R 50 o R15
_(CH2)k-N_ , _(CH2)k-N_έ_ , _(CH2)k-έ-N_ ,
O O R15
_(CH2)k- , -c-(CH2)k-o— . -C-(CH2)k-N_
R15° R150 R15' R15θ
.N-c-(CH2)k-0- , — N-c-(CH2)k-N_ , — N-C-.(CH2)κ- ,
Figure imgf000221_0002
H H O R 5 R 15
— C=C-C-N-(CH2)k-o— , — 0-(CH2)k- , _N-(CH2)k-
Figure imgf000221_0003
15 15 '
[wherein k is from 1 to 10, and each of R and R which are independent of each other, is a hydrogen atom or a Cχ_7 alkyl group] .
7. The 6-membered heterocyclic-compound or its salts
1 3 5 according to Claim 6, wherein each of X , X and X which are independent of one another, is a nitrogen atom or CH,
2 4 and each of X and X which are independent of each
5 other, is CR .
8. The 6-membered heterocyclic-compound or its salts according to Claim 7, wherein E is
R15 R15
— O-(CH2)k-0- , -0-(CH2)k-N— , _N-(CH2)k-o- ,
R15 R1ff R15
-N-(CH2)k-N_ , _(CH2)k-0- , -(CH2)k-N_ ,
R15 — O-(CH2)k_ , _N-(CH2)k- or -(CH2)k-
[wherein k is from 1 to 10, and each of R and R which are independent of each other, is a hydrogen atom or a
C1-7 alkyl group] .
9. The 6-membered heterocyclic-compound or its salts
1 2 according to Claim 8, wherein each of m, n, n and n which are independent of one another, is 0 or 1, R is
6 6 2
C(0)OR (R is a hydrogen atom or a Cχ_η alkyl group), R
10 10' _ 10 10' is NR R (each of R and R which are independent of each other, is a hydrogen atom or a C1 7 alkyl group) or
+ 11 11' 11" 11 11' 11"
N R R R (each of R , R and R which are independent of one another, is a C._7 alkyl group), D is
4 . 5 5 .
-0- or -NH- , and X is CR (R is a hydrogen atom or a halogen atom) .
10. A hypoglycemic agent which contains the 6-membered heterocyclic-compound or its salts as defined in Claim 1.
11. A carnitine-palmitoyl transferase intibitor v/hich contains the 6-membered heterocyclic-compound or its salts as defined in Claim 1.
12. A pharmaceutical agent for preventing or treating diabetes mellitus and diabetic complications, which contains the 6-membered heterocyclic-compound or its salts as defined in Claim 1.
PCT/JP1999/003214 1998-06-19 1999-06-16 Heterocyclic compounds as hypoglycemic agents WO1999065881A1 (en)

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US7378436B2 (en) 2003-06-17 2008-05-27 Pfizer Inc. Compounds
WO2005003103A3 (en) * 2003-06-30 2005-11-03 Astrazeneca Ab 2, 4, 6-tri-substituted 6-membered heterocycles and their use in the treatment of neurodegenerative diseases
WO2005003103A2 (en) * 2003-06-30 2005-01-13 Astrazeneca Ab 2, 4, 6-tri-substituted 6-membered heterocycles and their use in the treatment of neurodegenerative diseases
US7498351B2 (en) 2003-10-31 2009-03-03 Janssen Pharmaceutica N.V. 4-((Phenoxyalkyl)thio)-phenoxyacetic acids and analogs
US7015329B2 (en) 2003-10-31 2006-03-21 Janssen Pharmaceutica N. V. 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs
US7645776B2 (en) 2005-12-01 2010-01-12 Hoffmann-La Roche Inc. Heteroaryl substituted piperidine derivatives which are L-CPT1 inhibitors
WO2007063012A1 (en) * 2005-12-01 2007-06-07 F. Hoffmann-La Roche Ag Heteroaryl substituted piperidine derivatives as l-cpt1 inhibitors
AU2006319247B2 (en) * 2005-12-01 2010-03-11 F. Hoffmann-La Roche Ag Heteroaryl substituted piperidine derivatives as L-CPT1 inhibitors
US8410150B2 (en) 2007-03-09 2013-04-02 University Health Network Inhibitors of carnitine palmitoyltransferase and treating cancer
US8680282B2 (en) 2007-08-01 2014-03-25 University Health Network Cyclic inhibitors of carnitine palmitoyltransferase and treating cancer
US8431575B2 (en) 2010-02-18 2013-04-30 Transtech Pharma, Inc. Phenyl-heteroaryl derivatives and methods of use thereof
US8741900B2 (en) 2010-02-18 2014-06-03 Transtech Pharma, Llc Phenyl-heteroaryl derivatives and methods of use thereof
US9045461B2 (en) 2010-02-18 2015-06-02 Transtech Pharma, Llc Phenyl-heteroaryl derivatives and methods of use thereof
CN115650903A (en) * 2022-10-31 2023-01-31 苏州天马医药集团天吉生物制药有限公司 Preparation method of initial amino acid Boc-Pip (Fmoc) -OH

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