US20050209253A1 - Pyrrolopyrimidine and pyrrolopyridine derivatives substituted with cyclic amino group - Google Patents

Pyrrolopyrimidine and pyrrolopyridine derivatives substituted with cyclic amino group Download PDF

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US20050209253A1
US20050209253A1 US10/504,981 US50498105A US2005209253A1 US 20050209253 A1 US20050209253 A1 US 20050209253A1 US 50498105 A US50498105 A US 50498105A US 2005209253 A1 US2005209253 A1 US 2005209253A1
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phenyl
pyrrolo
dimethyl
alkyl
piperidin
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Atsuro Nakazato
Taketoshi Okubo
Dai Nozawa
Mikato Yamaguchi
Tomoko Tamita
Ludo Kennis
Marcel De Bruyn
Jean-Pierre Bongartz
Frans Van Den Keybus
Yves Van Roosbroeck
Marcel Luyckx
Robert Hendrickx
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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Assigned to TAISHO PHARMACEUTICAL CO., LTD. reassignment TAISHO PHARMACEUTICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HENDRICKX, ROBERT J.M., BONGARTZ, JEAN-PIERRE A.M., DE BRUYN, MARCEL F.L., KENNIS, LUDO E.J., LUYCKX, MARCEL G.M., VAN DEN KEYBUS, FRANS M.A., VAN ROOSBROECK, YVES E.M., NAKAZATO, ATSURO, NOZAWA, DAI, OKUBO, TAKATOSHI, TAMITA, TOMOKO, YAMAGUCHI, MIKAKO
Publication of US20050209253A1 publication Critical patent/US20050209253A1/en
Priority to US12/106,873 priority Critical patent/US7932259B2/en
Priority to US12/951,556 priority patent/US8455511B2/en
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Definitions

  • the present invention relates to a therapeutic agent for diseases in which corticotropin releasing factor (CRF) is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastral diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, etc.
  • CCF corticotropin releasing factor
  • CRF is a hormone comprising 41 amino acids (Science, 213, 1394-1397, 1981; and J. Neurosci., 7, 88-100, 1987), and it is suggested that CRF plays a core role in biological reactions against stresses (Cell. Mol. Neurobiol., 14, 579-588, 1994; Endocrinol., 132, 723-728, 1994; and Neuroendocrinol. 61, 445-452, 1995).
  • CRF CRF Releasing Factor: Basic and Clinical Studies of a Neuropeptide, pp. 29-52, 1990.
  • Intraventricular administration of CRF to hypophysectomized rats and normal rats causes an anxiety-like symptom in both types of rats (Pharmacol. Rev., 43, 425-473, 1991; and Brain Res. Rev., 15, 71-100, 1990). That is, there are suggested the participation of CRF in hypothalamus-pituitary-adrenal system and the pathway by which CRF functions as a neurotransmitter in central nervous system.
  • WO02/002549 and WO0/053604 disclose pyrrolopyridine and pyrrolopyrimidine derivatives respectively as CRF receptor antagonists.
  • Bioorganic & Medicinal Chemistry 10 (2002) 175-183 also discloses pyrrolopyrimidine derivatives.
  • An object of the present invention is to provide an antagonist against CRF receptors which is effective as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastral diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, etc.
  • diseases in which CRF is considered to be involved such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastral diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, etc.
  • the present inventors earnestly investigated pyrrolopyrimidine and pyrrolopyridine derivatives substituted with a cyclic amino group that have a high affinity for CRF receptors, whereby the present invention has been accomplished.
  • the present invention is pyrrolopyrimidine and pyrrolopyridine derivatives substituted with a cyclic amino group explained below.
  • a 3- to 8-membered saturated cyclic amine means aziridine, azetidine, pyrrolidine, piperidine, azepane or azocane.
  • C 1-5 alkylene means a straight or branched chain alkylene of 1 to 5 carbon atoms, such as methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene or the like.
  • a 3- to 8-membered saturated cyclic amine bridged with C 1-5 alkylene or C 1-4 alkylene-O—C 1-4 alkylene between any different two carbon atoms of the cyclic amine includes, for example, 8-azabicyclo[3.2.1]oct-8-yl, 9-azabicyclo[3.3.1]non-9-yl, 7-azabicyclo[2.2.1]hept-7-yl, 3-oxa-7-azabicyclo[3.3.1]non-7-yl and 3-oxa-9-azabicyclo[3.3.1]non-9-yl.
  • C 1-5 alkyl means a straight chain or branched chain alkyl group of 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, sec- butyl, pentyl, isopentyl or the like.
  • C 1-5 alkoxy means a straight chain or branched chain alkoxy group of 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy, pentyloxy, isopentyloxy or the like.
  • C 1-5 alkoxy-C 1-5 alkyl means a substituted C 1-5 alkyl group having the above-mentioned C 1-5 alkoxy group as the substituent, such as methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl or the like.
  • hydroxy-C 1-5 alkyl means a substituted C 1-5 alkyl group having hydroxy group, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or the like.
  • cyano-C 1-5 alkyl means a substituted C 1-5 alkyl group having cyano group, such as cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl, 5-cyanopentyl or the like.
  • C 3-8 cycloalkyl means a cyclic alkyl group of 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like.
  • C 3-8 cycloalkyl-C 1-5 alkyl means a substituted C 1-5 alkyl group having the above-mentioned C 3-8 cycloalkyl as the substituent, such as cyclopropylmethyl, cyclopropylethyl, cyclopentylethyl or the like.
  • C 3-8 cycloalkyloxy means a cyclic alkoxy group of 3 to 8 carbon atoms, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or the like.
  • halogen means fluorine, chlorine, bromine or iodine atom.
  • C 3-8 cycloalkyloxy-C 1-5 alkyl means a substituted C 1-5 alkyl group having the above mentioned C 3-8 cycloalkyloxy as the substituent, such as cyclopropyloxymethyl, 2-cyclopropyloxyethyl or the like.
  • C 1-5 alkylthio means a straight chain or branched chain alkylthio group of 1 to 5 carbon atoms, such as methylthio, ethylthio, propylthio or the like.
  • C 1-24 acyl means a straight chain or branched chain, and saturated or unsaturated acyl group of 1 to 24 carbon atoms, such as acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, isobutyryl, 2,2-dimethylpropionyl, octadeca-9,12-dienoyl, eicosa-5,8,11,14-tetraenoyl, docosa-4,7,10,13,16,19-hexaenoyl, eicosa-5,8,11,14,17-pentaenoyl or the like.
  • C 1-10 alkoxycarbonyl means a straight chain or branched chain alkoxycarbonyl group of 2 to 11 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl or the like.
  • aryl means a monocyclic or bicyclic group of 6 to 12 ring carbon atoms having at least one aromatic ring, such as phenyl, naphthyl or the like.
  • aryl-C 1-5 alkyloxycarbonyl means a substituted C 1-5 alkyloxycarbonyl group having the above-mentioned aryl as the substituent, such as benzyloxycarbonyl, phenethyloxycarbonyl or the like.
  • arylcarbonyl means a substituted carbonyl group having the above- mentioned aryl as the substituent, such as benzoyl, naphthalene-1-carbonyl, naphthalene-2-carbonyl or the like.
  • heteroaryl means a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic ring having in its ring 1 to 4 atoms which may be the same or different and are selected from nitrogen, oxygen and sulfur, such as pyridyl, pyrimidinyl, imidazolyl, quinolyl, indolyl, benzofuranyl, quinoxalinyl, benzo[1,2,5]thiadiazolyl, benzo[1,2,5]oxadiazolyl or the like.
  • heteroarylcarbonyl means a substituted carbonyl group having the above-mentioned heteroaryl as the substituent, such as pyridine-2-carbonyl, pyridine-3-carbonyl, pyridine-4-carbonyl, pyrimidine-2-carbonyl, pyrimidine-4-carbonyl, pyrimidine-5-carbonyl or the like.
  • C 2-5 alkenyl means a straight chain or branched chain alkenyl group of 2 to 5 carbon atoms, such as vinyl, isopropenyl, allyl or the like.
  • C 2-5 alkynyl means a straight chain or branched chain alkynyl group of 2 to 5 carbon atoms, such as ethynyl, prop-1-ynyl, prop-2-ynyl or the like.
  • C 1-5 alkysulfinyl means a straight chain or branched chain alkylsulfinyl group of 1 to 5 carbon atoms, such as methanesulfinyl, ethanesulfinyl or the like.
  • C 1-5 alkysulfonyl means a straight chain or branched chain alkylsulfonyl group of 1 to 5 carbon atoms, such as methanesulfonyl, ethanesulfonyl or the like.
  • hydroxy-C 2-5 alkylamino-C 2-5 alkoxy means a substituted C 2-5 alkoxy group having a hydroxy-C 2-5 alkylamino group as the substituent such as 2-(2-hydroxyethylamino)ethoxy or the like.
  • aryl-C 1-5 alkyl means a substituted C 1-5 alkyl group having the above-mentioned aryl as the substituent, such as benzyl, phenethyl, 3-phenylpropyl, naphthalen-1-ylmethyl, naphthalen-2-ylmethyl or the like.
  • heteroaryl-C 1-5 alkyl means a substituted C 1-5 alkyl group having the above-mentioned heteroaryl as the substituent, such as 1H-indol-3-ylmethyl, 1H- imidazol-4-ylmethyl or the like.
  • hydroxycarbonyl-C 1-5 alkyl means a substituted C 1-5 alkyl group having a hydroxycarbonyl group as the substituent, such as hydroxycarbonylmethyl, 2-hydroxycarbonylethyl, 3-hydroxycarbonylpropyl, 4-hydroxycarbonylbutyl or the like.
  • hydroxyphenyl-C 1-5 alkyl means a substituted C 1-5 alkyl group having a hydroxyphenyl group as the substituent, such as 4-hydroxybenzyl, 3-hydroxybenzyl 2-hydroxybenzyl, 2-(4-hydroxyphenyl)ethyl or the like.
  • amino-C 1-5 alkyl means a substituted C 1-5 alkyl group having a amino group as the substituent, such as aminomethyl, 1-aminoethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl or the like.
  • guanidino-C 1-5 alkyl means a substituted C 1-5 alkyl group having a guanidino group as the substituent, such as guanidinomethyl, 1-guanidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 5-guanidinopentyl or the like.
  • mercapto-C 1-5 alkyl means a substituted C 1-5 alkyl group having a mercapto group as the substituent, such as mercaptomethyl, 1-mercaptoethyl, 2-mercaptoethyl, 3-mercaptopropyl, 4-mercaptobutyl, 5-mercaptopentyl or the like.
  • C 1-5 alkylthio-C 1-5 akyl means a substituted C 1-5 alkyl group having the above-mentioned C 1-5 alkylthio group as the substituent, such as methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, 3-methylthiopropyl, 4-methylthiobutyl, 5-methylthiopentyl or the like.
  • aminocarbonyl-C 1-5 alkyl means a substituted C 1-5 alkyl group having an aminocarbonyl group as the substituent, such as aminocarbonylmethyl, 2-aminocarbonylethyl, 3-aminocarbonylpropyl, 4-aminocarbonylbutyl or the like.
  • aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C 1-5 alkyl, C 3-8 cycloalkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-5 alkoxy, C 1-5 alkylthio, C 1-5 alkylsulfinyl, C 1-5 alkylsulfonyl, cyano, nitro, hydroxy, —CO 2 R 19a , —C( ⁇ O)R 19a , —CONR 11b R 12b , —OC( ⁇ O)R 19a , NR 11b CO 2 R 19a , —S(O) r NR 11b R 12b , hydroxy-C 2-5 alkylamino-C 2-5 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy
  • the “pharmaceutically acceptable salts” in the present invention include, for example, salts with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or the like; salts with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2-sulfonic acid or the like; salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc i
  • a compound of the present invention includes any isomers such as diastereomers, enantiomers, geometricisomers and tautomeric forms.
  • a compound represented by formula [I] if the cyclic amino group has one or more chiral carbons and/or if there is an axial chirality between Ar and pyrrolopyrimidine (or pyrrolopyridine) ring, several stereoisomers (diastereomers or enantiomers) can exist.
  • the compound of the present invention includes the individual isomers and the racemic and non-racemic mixtures of the isomers.
  • Y is CR 10
  • More preferable are compounds represented by the formula [III] in which Y is CR 10 ; n is 0; R 1 , R 2 , R 4 and R 5 are hydrogen; R 10 is hydrogen or halogen.
  • Y is CR 10
  • More preferable are compounds represented by the formula [V] in which Y is CR 10 ; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R 1 , R 2 , R 4 and R 5 are hydrogen; R 10 is hydrogen or halogen.
  • Y is CR 10 ; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R 1 , R 2 and R 5 are hydrogen; R 4 is cyano; R 6 is methyl; R 7 and R 8 are the same or different, and independently are hydrogen or C 1-5 alkyl; R 10 is hydrogen or halogen; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, trifluoromethyl, trifluoromethoxy and —N(R 20 )R 21 (wherein R 20 and R 21 are the same or different, and independently are hydrogen or C 1-3 alkyl), wherein a group represented by (CR
  • Especially preferable compounds of the present invention are: 2- ⁇ 1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl ⁇ -ethanol,
  • the compound represented by the formula [I] can be produced, for example, by the process shown in the following reaction scheme 1-4 [in the following reaction scheme, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m, n, X, Y and Ar are as defined above; LG is chloro, bromo, iodo, methanesulfonyloxy, benzenesulfonyloxy, 4-toluenesulfonyloxy or trifluoromethanesulfonyloxy group; Z 1 and Z 2 are the same or different, and independently are chloride or bromide; R a and R b are the same or different, and independently are hydrogen, C 1-5 alkyl, C 3-8 cycloalkyl or C 3-8 cycloalkyl-C 1-5 alkyl; and X a is —(CHR 3 ) n —OH, —(CHR 3 ) n
  • Compound (3) a compound of the present invention, can be obtained by reacting Compound (1) with Compound (2) in an inert solvent in the presence or absence of a base.
  • the base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide and the like; and Grignard reagents such as methylmagnesium bromide and the like.
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene, xylene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like
  • ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like
  • the compound of the present invention can be converted to a salt in an inert solvent with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or the like, with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2-sulfonic acid or the like, with an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, aluminum hydroxide or
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; esters such as ethyl acetate, ethyl formate and the like; ketones such as acetone, methylethylketone and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • Step 2 is acetonitrile; dichloromethane;
  • Compound (4) can be converted to Compound (6) by reacting Compound (4) with Compound (5) in an inert solvent in the presence or absence of a base.
  • the base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide and the like; and Grignard reagents such as methyl magnesium bromide and the like.
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene, xylene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like
  • ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like
  • Compound (6) can be converted to Compound (7) by reacting Compound (6) with malononitrile in an inert solvent in the presence or absence of a base.
  • the base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, potassium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazamide, sodium hexamethyldisilazamide, potassium hexamethyldisilazamide and the like; alkyl lithiums such as methyl lithium, n-butyl lithium, sec-butyl lithium
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like
  • ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like
  • hydrocarbons such as benz
  • Compound (7) can be converted to Compound (8) by acylation of amino group in Compound (7) and followed by formation of pyrimidine ring.
  • the acylation and the formation of pyrimidine ring may occur continuously in one pot.
  • the acylation can be achieved by reacting Compound (7) with an acylating reagent in an inert solvent in the presence or absence of a base or an acid.
  • the following formation of pyrimidine ring can be carried out by heating the acylated compound in an inert solvent in the presence or absence of an acid.
  • the acylating reagent includes, for example, halogenated acyls such as acetyl chloride, acetyl bromide, propionyl chloride, propionyl bromide, butyryl chloride, cyclopropanecarbonyl chloride, benzoyl chloride and the like; acid anhydride such as acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride and the like.
  • halogenated acyls such as acetyl chloride, acetyl bromide, propionyl chloride, propionyl bromide, butyryl chloride, cyclopropanecarbonyl chloride, benzoyl chloride and the like
  • acid anhydride such as acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride and the like.
  • the base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, potassium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazamide, sodium hexamethyldisilazamide, potassium hexamethyldisilazamide and the like; and Grignard reagents such as methyl magnesium bromide and the like.
  • amines such as triethylamine, N,N-diisopropylethylamine, pyridine and the like
  • inorganic bases such as sodium carbonate,
  • the acid includes, for example, organic acids such as formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, trifluoromethanesulfonic acid and the like; inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, nitric acid or the like.
  • organic acids such as formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, trifluoromethanesulfonic acid and the like
  • inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, nitric acid or the like.
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene, xylene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; acetic acid; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like
  • ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the
  • Compound (8) can be converted to Compound (9) by reacting (8) with a halogenating reagent or a sulfonating reagent in the presence or absence of a base in an inert solvent or without any solvent.
  • the halogenating reagent includes, for example, phosphoryl chloride, phosphoryl bromide, phosphorous pentachloride, phosphorous trichloride, phosphorous pentabromide, phosphorous tribromide, thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide and the like.
  • the sulfonating reagent includes, for example, p-toluenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonic anhydride, methansulfonic anhydride, trifluoromethanesulfonic anhydride, N-phenylbis(trifluoromethanesulfonimide) and the like.
  • the base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-diethylaniline and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide and the like; and Grignard reagents such as methyl magnesium bromide and the like.
  • amines such as triethylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-diethylaniline and the like
  • inorganic bases such as sodium carbonate, potassium carbon
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; dichloromethane; chloroform; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like
  • ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the
  • Compound (9) can be converted to Compound (11) by reacting Compound (9) with Compound (10) in the same method as step 1.
  • Compound (11) can be converted to Compound (12) by reduction of Compound (11) with a conventional reducing agent in an inert solvent. Or if necessary, treatment with an acid in the presence or absence of inert solvent after the reduction can provide Compound (12).
  • X a is —CO 2 —(C 1-5 alkyl)
  • the ester group can be converted to a hydroxymethyl group at the same time.
  • the reducing agent includes, for example, lithium borohydride, sodium borohydride, calcium borohydride, lithium triethylborohydride, lithium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, zinc borohydride, borane, lithium trimethoxyborohydride, lithium triacetoxyborohydride, tetramethylammonium borohydride, lithium aluminum hydride, sodium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, diisobutylaluminum hydride, trichlorosilane and the like.
  • the reduction can be also carried out by hydrogenation using a catalyst including palladium, platinum dioxide, Raney nickel or the like.
  • the acid includes, for example, organic acids such as acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid and the like; inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, nitric acid or the like.
  • organic acids such as acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid and the like
  • inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, nitric acid or the like.
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like
  • ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like
  • hydrocarbons such as benz
  • Compoumd (7) can be converted to Compound (13) by reacting Compound (7) with ketones such as acetone and the like; vinyl ethers such as isopropenyl methyl ether and the like in an inert solvent in the presence or absence of an acid, and the following conversion from Compound (13) to Compound (14) can be carried out in the presence of base in an inert solvent.
  • the acid includes, for example, organic acids such as acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid and the like.
  • the base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazamide, sodium hexamethyldisilazamide, potassium hexamethyldisilazamide and the like; alkyl lithiums such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium and the like; and Grignard reagents such as methyl magnesium bro
  • the inert solvent includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; and mixtures of solvents selected from these inert solvents.
  • ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like
  • hydrocarbons such as benzene, toluene and the like
  • amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like
  • Compound (14) can be converted to Compound (15) in the same manner as step 7.
  • Compound (15) can be converted into Compound (16) via the corresponding diazonium compound.
  • the conversion to the diazonium compound can be carried out using, for example, sodium nitrite, potassium nitrite, butylnitrite, tert-butylnitrite, iso-butylnitrite or the like in the presence or absence of an acid in an inert solvent.
  • the acid includes, for example, inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid or the like.
  • the inert solvent includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like
  • hydrocarbons such as benzene, toluene and the like
  • amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like
  • Compound (16) can be converted to Compound (17) in the same manner as step 5.
  • Compound (17) can be obtained from Compound (15) directly by formation of the diazonium compound in the presence of one or more metal salts in an inert solvent.
  • the formation of the diazonium compound can be carried out in the same manner as step 10.
  • the metal salts include, for example, potassium iodide, potassium bromide, sodium iodide, sodium bromide, sodium chloride, copper (I) chloride, copper (II) chloride, copper (I) bromide, copper (II) bromide, copper (I) iodide and the like.
  • the inert solvent includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like
  • hydrocarbons such as benzene, toluene and the like
  • amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like
  • Compound (17) can be converted to Compound (18) in the same manner as step 1.
  • Compound (20) can be converted to Compound (21) by a coupling of Compound (20) with the corresponding carboxylic acid using a conventional coupling reagent in the presence or absence of an additive or a base in an inert solvent or a coupling of Compound (20) with the corresponding acyl halide in the presence or absence of a base in an inert solvent.
  • R 9 has protective groups of an amino group, a hydroxy group, a mercapto goup, a carboxy group, a guanidine group or a phosphoric acid group, those protective groups can be removed by conventional methods for deprotection (ref. Theodora W Greene and Peter G. M.
  • the coupling reagent includes, for example, N,N′-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1,1′-carbonyldiimidazole (CDI), diphenylphosphorylazide (DPPA), diethyl cyanophosphate and the like.
  • the additive includes, for example, 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide, 4-dimethylaminopyridine and the like.
  • the base includes amines such as triethylamine, N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazamide, sodium hexamethyldisilazamide, potassium hexamethyldisilazamide and the like; alkyl lithiums such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium and the like; and Grignard reagents such as methyl magnesium bromide and the
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like
  • ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the
  • the compound of the present invention is useful as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved.
  • the compound of the present invention can be formulated into tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, injections and the like by a conventional preparation technique by adding conventional fillers, binders, disintegrators, pH-adjusting agents, solvents, etc.
  • the compound of the present invention can be administered to an adult patient in a dose of 0.1 to 500 mg per day in one portion or several portions orally or parenterally.
  • the dose can be properly increased or decreased depending on the kind of a disease and the age, body weight and symptom of a patient.
  • Table 1 and Table 2 list the compound obtained in Example 1 and compounds obtained by the similar procedure as in Example 1.
  • the low polar diastereoisomer was optically resolved by high performance liquid chromatography to give each enantiomer.
  • the high polar diastereoisomer was also optically resolved by high performance liquid chromatography to give each enantiomer.
  • CHIRAL PAK AD DICEL CHEMICAL INDUSTRIES, LTD
  • flow rate 5.0 mL/min.
  • Table 1 lists the compounds obtained in Example 2.
  • Lithium diisopropylamide in tetrahydrofuran solution (generated from 2.64M n-butyl lithium in hexane (127 mL), diisopropylamine (40.5 g) and tetrahydrofuran (300 mL)) was added dropwise over 30 minutes, and stirred at room temperature for 1 hour.
  • a saturated NH 4 Cl aqueous solution was added and separated.
  • the aqueous layer was extracted with CHCl 3 .
  • the organic layer was washed with water, dried over anhydrous sodium sulfate and filtered.
  • Table 3 lists the compound obtained in Example 5 and compounds obtained by the similar procedure as in Example 5.
  • Table 3 lists the compound obtained in Example 6 and compounds obtained by the similar procedure as in Example 6.
  • Table 3 lists the compound obtained in Example 7 and compounds obtained by the similar procedure as in Example 7.
  • R 6 R 7 R 8 Ar melting point (° C.) (solvent for crystallization) 1-001 1 CH 3 CH 3 CH 3 142-144 (hexane) 1-002 1 CH 3 CH 3 H 124-126 (hexane) 1-003 1 CH 3 CH 3 CH 3 amorphous 1-004 1 CH 3 CH 3 CH 3 146-148* 2 (EtOAc/EtOH) 1-005 1 CH 3 CH 3 H amorphous 1-006 1 CH 3 CH 3 CH 3 144-146 (hexane) 1-007 1 CH 3 CH 3 H 121-122 (hexane) 1-008 1 CH 3 CH 3 H 141-143* 2 (EtOAc/EtOH) 1-009 1 CH 3 CH 3 CH 3 134-136* 2 (EtOAc/EtOH) 1-010 1 CH 3 CH 3 H 157-159* 2 (EtOAc/EtOH) 1-011 1 CH 3 CH 3 CH 3 amorphous 1-012 1 CH 3 CH 3 H a
  • Monkey amygdala membranes were used as a receptor preparation.
  • 125 I-CRF was used as 125 I-labeled ligand.
  • Binding reaction using the 125 I -labeled ligand was carried out by the following method described in The Journal of Neuroscience, 7, 88 (1987).
  • Monkey amygdala was homogenized in 50 mM Tris-HCl buffer (pH 7.0) containing 10 mM MgCl 2 , 2 mM EDTA and centrifuged at 48,000 ⁇ g for 20 min, and the precipitate was washed once with Tris-HCl buffer. The washed precipitate was suspended in 50 mM Tris-HCl buffer (pH 7.0) containing 10 mM MgCl 2 , 2 mM EDTA, 0.1% bovine serum albumin and 100 kallikrein units/ml aprotinin, to obtain a membrane preparation.
  • the membrane preparation (0.3 mg protein/ml), 125 I-CRF (0.2 nM) and a test drug were reacted at 25° C. for 2 hours.
  • the reaction mixture was filtered by suction through a glass filter (GF/C) treated with 0.3% polyethylene imine, and the glass filter was washed three times with phosphate-buffered saline containing 0.01% Triton X-100. After the washing, the radioactivity of the filter paper was measured in a gamma counter.
  • the amount of 125 I-CRF bound when the reaction was carried out in the presence of 1 ⁇ M CRF was taken as the degree of nonspecific binding of 125 I -CRF, and the difference between the total degree of 125 I -CRF binding and the degree of nonspecific 125 I -CRF binding was taken as the degree of specific 125 I -CRF binding.
  • An inhibition curve was obtained by reacting a definite concentration (0.2 nM) of 125 I-CRF with various concentrations of each test drug under the conditions described above. A concentration of the test drug at which binding of 125 I -CRF is inhibited by 50% (IC 50 ) was determined from the inhibition curve.
  • compounds having a high affinity for CRF receptors have been provided. These compounds are effective against diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastric diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, etc.
  • diseases in which CRF is considered to be involved such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastric diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, etc.

Abstract

An object of the present invention is to provide an antagonist against CRF receptors which is effective as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastric diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, etc. [Solution]
A pyrrolopyrimidine or pyrrolopyridine derivative substituted with a cyclic amino group represented by the following formula [I]:
Figure US20050209253A1-20050922-C00001
 has a high affinity for CRF receptors and is effective against diseases in which CRF is considered to be involved.

Description

    DETAILED DESCRIPTION OF THE INVENTION
  • 1. Technical Field
  • The present invention relates to a therapeutic agent for diseases in which corticotropin releasing factor (CRF) is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastral diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, etc.
  • 2. Description of the Prior Art
  • CRF is a hormone comprising 41 amino acids (Science, 213, 1394-1397, 1981; and J. Neurosci., 7, 88-100, 1987), and it is suggested that CRF plays a core role in biological reactions against stresses (Cell. Mol. Neurobiol., 14, 579-588, 1994; Endocrinol., 132, 723-728, 1994; and Neuroendocrinol. 61, 445-452, 1995). For CRF, there are the following two paths: a path by which CRF acts on peripheral immune system or sympathetic nervous system through hypothalamus-pituitary-adrenal system, and a path by which CRF functions as a neurotransmitter in central nervous system (in Corticotropin Releasing Factor: Basic and Clinical Studies of a Neuropeptide, pp. 29-52, 1990). Intraventricular administration of CRF to hypophysectomized rats and normal rats causes an anxiety-like symptom in both types of rats (Pharmacol. Rev., 43, 425-473, 1991; and Brain Res. Rev., 15, 71-100, 1990). That is, there are suggested the participation of CRF in hypothalamus-pituitary-adrenal system and the pathway by which CRF functions as a neurotransmitter in central nervous system.
  • The review by Owens and Nemeroff in 1991 summarizes diseases in which CRF is involved (Pharmacol. Rev., 43, 425-474, 1991). That is, CRF is involved in depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal diseases, drug dependence, inflammation, immunity-related diseases, etc. It has recently been reported that CRF is involved also in epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, and cephalic external wound (Brain Res. 545, 339-342, 1991; Ann. Neurol. 31, 48-498, 1992; Dev. Brain Res. 91, 245-251, 1996; and Brain Res. 744, 166-170, 1997). Accordingly, antagonists against CRF receptors are useful as therapeutic agents for the diseases described above.
  • WO02/002549 and WO0/053604 disclose pyrrolopyridine and pyrrolopyrimidine derivatives respectively as CRF receptor antagonists. Bioorganic & Medicinal Chemistry 10 (2002) 175-183 also discloses pyrrolopyrimidine derivatives. However, none disclose the compounds provided in the present invention.
    • PROBLEM(S) TO BE SOLVED BY INVENTION
  • An object of the present invention is to provide an antagonist against CRF receptors which is effective as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastral diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, etc.
    • MEANS FOR SOLVING PROBLEM
  • The present inventors earnestly investigated pyrrolopyrimidine and pyrrolopyridine derivatives substituted with a cyclic amino group that have a high affinity for CRF receptors, whereby the present invention has been accomplished.
  • The present invention is pyrrolopyrimidine and pyrrolopyridine derivatives substituted with a cyclic amino group explained below.
  • A pyrrolopyrimidine or pyrrolopyridine derivative substituted with a cyclic amino group represented by the following formula [I]:
    Figure US20050209253A1-20050922-C00002
    (wherein the cyclic amino group is represented by the following formula [II]:
    Figure US20050209253A1-20050922-C00003
      • in which the cyclic amino group is a 3- to 8-membered saturated cyclic amine or a 3- to 8-membered saturated cyclic amine bridged with C1-5alkylene or C1-4alkylene- O—C1-4alkylene between any different two carbon atoms of the cyclic amine, which cyclic amine is substituted with a group represented by —(CR1R2)m—(CHR3)n—X, R4 and R5 independently on the same or different carbon atoms of the cyclic amine;
      • X is cyano, hydroxy or —OR9;
      • Y is N or CR10;
      • R1 is hydrogen, hydroxy, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
      • R2 is hydrogen or C1-5alkyl;
      • R3 is hydrogen, cyano, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
      • m is an integer selected from 0, 1, 2, 3, 4 and 5;
      • n is 0 or 1;
        with the proviso that when X is hydroxy or OR9, and n is 0, then m is an integer selected from 1, 2,3,4 and 5;
      • R4 is hydrogen, hydroxy, hydroxy-C1-5alkyl, cyano, cyano-C1-5alkyl or C1-5alkyl;
      • R5 is hydrogen or C1-5alkyl;
      • R6 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy or —N(R11)R12;
      • R7 and R8 are the same or different, and independently are hydrogen, halogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy, N(R11a)R12a, —CO2R13, cyano, nitro, C1-5alkylthio, trifluoromethyl or trifluoromethoxy; or R7 and R9 are taken together to form —CH2—CH2—CH2—CH2— or —CH═CH—CH═CH—;
      • R9 is C1-24acyl, C1-10alkoxycarbonyl, aryl-C1-5alkyloxycarbonyl, —CO—O—CHR14—OCO—R15, —P(═O)(OR14a)OR15a, —CO—(CH2)p—(CHR16)q—NR17R18, arylcarbonyl or heteroarylcarbonyl, wherein each said acyl, aryl and heteroaryl is unsubstituted or substituted with C1-5alkoxy, and C1-24acyl optionally includes one to six double bonds;
      • R10 is hydrogen, C1-5alkyl, halogen, cyano or —CO2R19;
      • Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C1-5alkyl, C3-8cycloalkyl, C2-5alkenyl, C2-5alkynyl, C1-5alkoxy, C1-5alkylthio, C1-5alkylsulfinyl, C1-5alkylsulfonyl, cyano, nitro, hydroxy, —CO2R19a, —C(═O)R19a, —CONR11bR12b, —OC(═O)R19a, —NR11bCO2R19a, —S(O)rNR11bR12b, hydroxy-C2-5alkylamino-C2-5alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and —N(R20)R21; with the proviso that when X is hydroxy, Y is N, and the cyclic amino group is 5-membered ring, then Ar is aryl or heteroaryl which aryl or heteroaryl is substituted with at least one of substituents which are selected from halogen and trifluoromethyl;
      • R11 and R12 are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
      • R11a and R12a are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
      • R11b and R12b are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
      • R13 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, C1-5alkoxy- C1-5alkyl, C3-8cycloalkyloxy-C1-5alkyl or phenyl;
      • R14 and R15 are the same or different, and independently are hydrogen, C1-5alkyl or aryl-C1-5alkyl;
      • R14a and R15a are the same or different, and independently are hydrogen, C1-5alkyl or aryl-C1-5alkyl;
      • R16 is hydrogen, C1-5alkyl, aryl, heteroaryl, aryl-C1-5alkyl, heteroaryl-C1-5alkyl, hydroxy-C1-5alkyl, hydroxycarbonyl-C1-5alkyl, hydroxyphenyl-C1-5alkyl, C1-5alkoxy- C1-5alkyl, amino-C1-5alkyl, guanidino-C1-5alkyl, mercapto-C1-5alkyl, C1-5alkylthio- C1-5alkyl or aminocarbonyl-C1-5alkyl;
      • R17 and R18 are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, C1-10acyl, C1-10alkoxycarbonyl or aryl-C1-5alkyloxycarbonyl;
      • or R16 and R17 are taken together to form —CH2—, —CH2CH2—, —CH2CH2CH2— or —CH2CH2CH2CH2—;
      • p is an integer selected from 0, 1, 2, 3, 4 and 5;
      • q is 0 or 1;
      • R19 is hydrogen or C1-5alkyl;
      • R19a is hydrogen or C1-5alkyl;
      • r is 1 or 2;
      • R20 and R21 are the same or different, and independently are hydrogen or C1-5alkyl), individual isomers thereof, racemic or non-racemic mixtures of isomers thereof or N-oxide thereof, or pharmaceutically acceptable salts and hydrates thereof.
  • The terms used in the present specification have the following meanings.
  • The term “a 3- to 8-membered saturated cyclic amine” means aziridine, azetidine, pyrrolidine, piperidine, azepane or azocane.
  • The term “C1-5alkylene” means a straight or branched chain alkylene of 1 to 5 carbon atoms, such as methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene or the like.
  • The term “a 3- to 8-membered saturated cyclic amine bridged with C1-5alkylene or C1-4alkylene-O—C1-4alkylene between any different two carbon atoms of the cyclic amine” includes, for example, 8-azabicyclo[3.2.1]oct-8-yl, 9-azabicyclo[3.3.1]non-9-yl, 7-azabicyclo[2.2.1]hept-7-yl, 3-oxa-7-azabicyclo[3.3.1]non-7-yl and 3-oxa-9-azabicyclo[3.3.1]non-9-yl.
  • The term “C1-5alkyl” means a straight chain or branched chain alkyl group of 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, sec- butyl, pentyl, isopentyl or the like.
  • The term “C1-5alkoxy” means a straight chain or branched chain alkoxy group of 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy, pentyloxy, isopentyloxy or the like.
  • The term “C1-5alkoxy-C1-5alkyl” means a substituted C1-5alkyl group having the above-mentioned C1-5alkoxy group as the substituent, such as methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl or the like.
  • The term “hydroxy-C1-5alkyl” means a substituted C1-5alkyl group having hydroxy group, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or the like.
  • The term “cyano-C1-5alkyl” means a substituted C1-5alkyl group having cyano group, such as cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl, 5-cyanopentyl or the like.
  • The term “C3-8cycloalkyl” means a cyclic alkyl group of 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like.
  • The term “C3-8cycloalkyl-C1-5alkyl” means a substituted C1-5alkyl group having the above-mentioned C3-8cycloalkyl as the substituent, such as cyclopropylmethyl, cyclopropylethyl, cyclopentylethyl or the like.
  • The term “C3-8cycloalkyloxy” means a cyclic alkoxy group of 3 to 8 carbon atoms, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or the like.
  • The term “halogen” means fluorine, chlorine, bromine or iodine atom.
  • The term “C3-8cycloalkyloxy-C1-5alkyl” means a substituted C1-5alkyl group having the above mentioned C3-8cycloalkyloxy as the substituent, such as cyclopropyloxymethyl, 2-cyclopropyloxyethyl or the like.
  • The term “C1-5alkylthio” means a straight chain or branched chain alkylthio group of 1 to 5 carbon atoms, such as methylthio, ethylthio, propylthio or the like.
  • The term “C1-24acyl” means a straight chain or branched chain, and saturated or unsaturated acyl group of 1 to 24 carbon atoms, such as acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, isobutyryl, 2,2-dimethylpropionyl, octadeca-9,12-dienoyl, eicosa-5,8,11,14-tetraenoyl, docosa-4,7,10,13,16,19-hexaenoyl, eicosa-5,8,11,14,17-pentaenoyl or the like.
  • The term “C1-10alkoxycarbonyl” means a straight chain or branched chain alkoxycarbonyl group of 2 to 11 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl or the like.
  • The term “aryl” means a monocyclic or bicyclic group of 6 to 12 ring carbon atoms having at least one aromatic ring, such as phenyl, naphthyl or the like.
  • The term “aryl-C1-5alkyloxycarbonyl” means a substituted C1-5alkyloxycarbonyl group having the above-mentioned aryl as the substituent, such as benzyloxycarbonyl, phenethyloxycarbonyl or the like.
  • The term “arylcarbonyl” means a substituted carbonyl group having the above- mentioned aryl as the substituent, such as benzoyl, naphthalene-1-carbonyl, naphthalene-2-carbonyl or the like.
  • The term “heteroaryl” means a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic ring having in its ring 1 to 4 atoms which may be the same or different and are selected from nitrogen, oxygen and sulfur, such as pyridyl, pyrimidinyl, imidazolyl, quinolyl, indolyl, benzofuranyl, quinoxalinyl, benzo[1,2,5]thiadiazolyl, benzo[1,2,5]oxadiazolyl or the like.
  • The term “heteroarylcarbonyl” means a substituted carbonyl group having the above-mentioned heteroaryl as the substituent, such as pyridine-2-carbonyl, pyridine-3-carbonyl, pyridine-4-carbonyl, pyrimidine-2-carbonyl, pyrimidine-4-carbonyl, pyrimidine-5-carbonyl or the like.
  • The term “C2-5alkenyl” means a straight chain or branched chain alkenyl group of 2 to 5 carbon atoms, such as vinyl, isopropenyl, allyl or the like.
  • The term “C2-5alkynyl” means a straight chain or branched chain alkynyl group of 2 to 5 carbon atoms, such as ethynyl, prop-1-ynyl, prop-2-ynyl or the like.
  • The term “C1-5alkysulfinyl” means a straight chain or branched chain alkylsulfinyl group of 1 to 5 carbon atoms, such as methanesulfinyl, ethanesulfinyl or the like.
  • The term “C1-5alkysulfonyl” means a straight chain or branched chain alkylsulfonyl group of 1 to 5 carbon atoms, such as methanesulfonyl, ethanesulfonyl or the like.
  • The term “hydroxy-C2-5alkylamino-C2-5alkoxy” means a substituted C2-5alkoxy group having a hydroxy-C2-5alkylamino group as the substituent such as 2-(2-hydroxyethylamino)ethoxy or the like.
  • The term “aryl-C1-5alkyl” means a substituted C1-5alkyl group having the above-mentioned aryl as the substituent, such as benzyl, phenethyl, 3-phenylpropyl, naphthalen-1-ylmethyl, naphthalen-2-ylmethyl or the like.
  • The term “heteroaryl-C1-5alkyl” means a substituted C1-5alkyl group having the above-mentioned heteroaryl as the substituent, such as 1H-indol-3-ylmethyl, 1H- imidazol-4-ylmethyl or the like.
  • The term “hydroxycarbonyl-C1-5alkyl” means a substituted C1-5alkyl group having a hydroxycarbonyl group as the substituent, such as hydroxycarbonylmethyl, 2-hydroxycarbonylethyl, 3-hydroxycarbonylpropyl, 4-hydroxycarbonylbutyl or the like.
  • The term “hydroxyphenyl-C1-5alkyl” means a substituted C1-5alkyl group having a hydroxyphenyl group as the substituent, such as 4-hydroxybenzyl, 3-hydroxybenzyl 2-hydroxybenzyl, 2-(4-hydroxyphenyl)ethyl or the like.
  • The term “amino-C1-5alkyl” means a substituted C1-5alkyl group having a amino group as the substituent, such as aminomethyl, 1-aminoethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl or the like.
  • The term “guanidino-C1-5alkyl” means a substituted C1-5alkyl group having a guanidino group as the substituent, such as guanidinomethyl, 1-guanidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 5-guanidinopentyl or the like.
  • The term “mercapto-C1-5alkyl” means a substituted C1-5alkyl group having a mercapto group as the substituent, such as mercaptomethyl, 1-mercaptoethyl, 2-mercaptoethyl, 3-mercaptopropyl, 4-mercaptobutyl, 5-mercaptopentyl or the like.
  • The term “C1-5alkylthio-C1-5akyl” means a substituted C1-5alkyl group having the above-mentioned C1-5alkylthio group as the substituent, such as methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, 3-methylthiopropyl, 4-methylthiobutyl, 5-methylthiopentyl or the like.
  • The term “aminocarbonyl-C1-5alkyl” means a substituted C1-5alkyl group having an aminocarbonyl group as the substituent, such as aminocarbonylmethyl, 2-aminocarbonylethyl, 3-aminocarbonylpropyl, 4-aminocarbonylbutyl or the like.
  • The phrase “aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C1-5alkyl, C3-8cycloalkyl, C2-5alkenyl, C2-5alkynyl, C1-5alkoxy, C1-5alkylthio, C1-5alkylsulfinyl, C1-5alkylsulfonyl, cyano, nitro, hydroxy, —CO2R19a, —C(═O)R19a, —CONR11bR12b, —OC(═O)R19a, NR11bCO2R19a, —S(O)rNR11bR12b, hydroxy-C2-5alkylamino-C2-5alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and —N(R20)R21” includes, for example, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,4-dibromophenyl, 2-bromo-4-isoproylphenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-chloro-4-trifluoromethylphenyl, 4-methoxy-2-methylphenyl, 2-chloro-4-trifluoromethoxyphenyl, 4-isopropyl-2-methylthiophenyl, 2,4,6-trimethylphenyl, 4-bromo-2,6-dimethylphenyl, 4-bromo-2,6-diethylphenyl, 4-chloro-2,6-dimethylphenyl, 2,4,6-tribromophenyl, 2,4,5-tribromophenyl, 2,4,6-trichlorophenyl, 2,4,5-trichlorophenyl, 4-bromo-2,6-dichlorophenyl, 6-chloro-2,4-dibromophenyl, 2,4-dibromo-6-fluorophenyl, 2,4-dibromo-6-methylphenyl, 2,4-dibromo-6-methoxyphenyl, 2,4-dibromo-6-methylthiophenyl, 2,6-dibromo-4-isopropylphenyl, 2,6-dibromo-4-trifluoromethylphenyl, 2-bromo-4-trifluoromethylphenyl, 4-bromo-2-chlorophenyl, 2-bromo-4-chlorophenyl, 4-bromo-2-methylphenyl, 4-chloro-2-methylphenyl, 2,4-dimethoxyphenyl, 2,6-dimethyl-4-methoxyphenyl, 4-chloro-2,6-dibromophenyl, 4-bromo-2,6-difluorophenyl, 2,6-dichloro-4-trifluoromethylphenyl, 2,6-dichloro-4-trifluoromethoxyphenyl, 2,6-dibromo-4-trifluoromethoxyphenyl, 2-chloro-4,6-dimethylphenyl, 2-bromo-4,6-dimethoxyphenyl, 2-bromo-4-isopropyl-6-methoxyphenyl, 2,4-dimethoxy-6-methylphenyl, 2,6-dimethyl-4-[2-(2-hydroxyethylamino)ethoxy]phenyl, 6-dimethylamino-4-methylpyridin-3-yl, 2-chloro-6-trifluoromethylpyridin-3-yl, 2-chloro-6-trifluoromethoxypyridin-3-yl, 2-chloro-6-methoxypyridin-3-yl, 6-methoxy-2-trifluoromethylpyridin-3-yl, 2-chloro-6-difluoromethylpyridin-3-yl, 6-methoxy-2-methylpyridin-3-yl, 2,6-dimethoxypyridin-3-yl, 4,6-dimethyl-2-trifluoromethylpyrimidin-5-yl, 2-dimethylamino-6-methylpyridin-3-yl, 6-dimethylamino-2-methylpyridin-3-yl, 2,3-dihydrobenzo[1,4]dioxin-5-yl and benzo[1,3]dioxol-4-yl, 5,7-dimethylbenzo[1,2,5]thiadiazol-4-yl, 5,7-dimethylbenzo[1,2,5]oxadiazol-4-yl, 2-isopropoxy-6-trifluoromethylpyridin-3-yl, 2-methoxy-6-methylpyridin-3-yl, 2,6-dimethylpyridin-3-yl, 2-bromo-6-methoxypyridin-3-yl, 2-chloro-6-dimethylaminopyridin-3-yl, 2,6-dichloropyridin-3-yl, 2,4-dimethyl-6-dimethylaminopyridin-3-yl, 2,4,6-trimethylpyridin-3-yl, 2,4,6-trimethylpyrimidin-5-yl, 4,6-dimethyl-2-dimethylaminopyrimidin-5-yl, 5-iodo-3-methylpyridin-2-yl, 3-methyl-5- methylaminopyridin-2-yl, 3-dimethylamino-5-methylpyridin-2-yl, 5-methyl-3-methylaminopyridin-2-yl, 3-chloro-5-methylpyridin-2-yl, 3-amino-5-methylpyridin-2-yl, 5-methyl-3-nitropyridin-2-yl, 5-diethylamino-3-methylpyridin-2-yl, 5-fluoro-3-methylpyridin-2-yl, 5-chloro-3-methylpyridin-2-yl, 5-dimethylamino-3-methylpyridin-2-yl, 5-amino-3-methylpyridin-2-yl, 3-methyl-5-nitropyridin-2-yl, 3-bromo-5-methylpyridin-2-yl, 4-chloro-2,5-dimethoxyphenyl, 4,5-dimethyl-2-methoxyphenyl, 5-fluoro-2,4-dimethylphenyl, 2,4-dimethoxy-5-methylphenyl, 2-chloro-4-methoxy-5-methylphenyl, 2-chloro-5-fluoro-4-methylphenyl, 2-bromo-4,5-dimethoxyphenyl, 2-bromo-5-fluoro-4-methoxyphenyl, 2-chloro-4,5-dimethoxyphenyl, 2.5-dichloro-4-methoxyphenyl, 2,4-dichloro-5-fluorophenyl, 2-chloro-5-fluoro-4-methoxyphenyl, 2,4,5-trichlorophenyl, 2-chloro-5-fluoro-4-methylphenyl, 5-fluoro-4-methoxy-2-methylphenyl, 4,5-dimethoxy-2-methylphenyl, 5-chloro-4-methoxy-2-methylphenyl, 2,4,5-trimethylphenyl, 6-methoxy-4-methylpyridin-3-yl, 4-methoxy-6-methylpyridin-3-yl, 4,6-dimethylpyridin-3-yl, 2-chloro-4-isopropylphenyl, 2-chloro-4-methylphenyl, 4-amino-2-chlorophenyl, 2-chloro-4-dimethylcarbamoylphenyl, 2-chloro-4-methylcarbamoylphenyl, 4-carbamoyl-2-chlorophenyl, 2-chloro-4-methylsulfonylphenyl, 4-carboxy-2-chlorophenyl, 2-chloro-4-iodophenyl, 2-bromo-4-methylthiophenyl, 2-bromo-4-methylsulfinylphenyl, 2-bromo-4-dimethylaminophenyl, 2-bromo-4-methylsulfonylphenyl, 2-bromo-4-cyclopentylphenyl, 2-bromo-4-tert- butylphenyl, 2-bromo-4-propylphenyl, 2-bromo-4-methylphenyl, 2-bromo-4-trifluoromethoxyphenyl, 2-bromo-4-methoxyphenyl, 2-bromo-4-ethoxyphenyl, 4-isopropyl-2-methylsulfonylphenyl, 4-cyclopentyl-2-methylthiophenyl, 4-butyl-2-methylthiophenyl, 4-methoxy-2-methylthiophenyl, 2-methylthio-4-propylphenyl, 2-dimethylamino-4-isopropylphenyl, 2-iodo-4-isopropylphenyl, 2-fluoro-4-methylphenyl, 2,4-difluorophenyl, 2-chloro-4-methoxyphenyl, 2-chloro-4-hydroxyphenyl, 4-cyano-2-methoxyphenyl, 4-bromo-2-methoxyphenyl, 2-methoxy-4-methylphenyl, 4-chloro-2-methoxyphenyl, 2-hydroxy-4-methylphenyl, 4-fluoro-2-methoxyphenyl, 2-hydroxy-4methylphenyl, 4-cyano-2-methoxyphenyl, 2-chloro-4-methylthiophenyl, 2-methoxy-4-trifluoromethylphenyl, 4-isopropyl-2-methoxyphenyl, 2-chloro-4-cyanophenyl, 2-chloro-4-ethoxycarbonylphenyl, 2-chloro-4-methylaminophenyl, 4-cyano-2-trifluoromethylphenyl, 4-cyano-2-methylphenyl, 2-methyl-4-trifluoromethoxyphenyl, 2-cyano-4-trifluoromethylphenyl, 4-carboxyamino-2-trifluoromethylphenyl, 4-methoxy-2-trifluoromethylphenyl, 4-fluoro-2-methylphenyl, 4-hydroxy-2-methylphenyl, 4-methoxy-2-methoxycarbonylphenyl, 2-ethyl-4-methoxyphenyl, 2-formyl-4-methoxyphenyl, 4-chloro-2-trifluoromethylphenyl, 4-dimethylamino-2-trifluoromethylphenyl, 4-difluoromethoxy-2-methylphenyl, 2-cyano-4-methoxyphenyl, 4-hydroxy-2-trifluoromethylphenyl, 4-isopropyl-2-trifluoromethylphenyl, 4-diethylamino-2-methylphenyl, 4-fluoro-2-trifluoromethylphenyl, 4-propoxy-2-trifluoromethylphenyl, 4-dimethylamino-2-methylthiophenyl, 4-isopropyl-2-isopropylthiophenyl, 2-ethylthio-4-isopropylphenyl, 4-methylamino-2-methylthiophenyl, 2-methylthio-4-propionylphenyl, 4-acetyl-2-methylthiophenyl, 4-cyano-2-methylthiophenyl, 4-methoxy-2-methylthiophenyl, 4-ethyl-2-methylthiophenyl, 4-bromo-2-methylthiophenyl, 4-isopropyl-2-methylsulfinylphenyl, 2,4-dimethylthiophenyl, 4,6-dimethyl-2-isopropylphenyl, 4,6-dimethyl-2-isopropenylphenyl, 2-acetyl-4,6-dimethylphenyl, 2,6-dimethyl-4-trifluoromethylphenyl, 2,6-dimethyl-4-isopropenylphenyl, 4-acetyl-2,6-dimethylphenyl, 2,4,6-triethylphenyl, 4,6-dimethyl-2-methylthiophenyl, 4,6-dimethyl-2-iodophenyl, 2-fluoromethoxy-4,6-dimethylphenyl, 4,6-dimethyl-2-isopropoxyphenyl, 4,6-dimethyl-2-ethoxyphenyl, 2,6-dichloro-4-ethoxyphenyl, 2-bromo-4,6-dimethoxyphenyl, 2-bromo-6-hydroxy-4-methoxyphenyl, 2,6-dibromo-4-ethoxyphenyl, 4-bromo-2-methoxy-6-methylphenyl, 2,6-dibromo-4-methoxyphenyl, 4,6-dibromo-2-trifluoromethoxyphenyl, 2,4-dibromo-6-trifluoromethylphenyl, 4-bromo-2-chloro-6-methylphenyl, 4-chloro-2,6-dimethoxyphenyl, 2,4-dichloro-6-methoxyphenyl, 4,6-dichloro-2-methylthiophenyl, 4,6-dichloro-2-trifluoromethylphenyl, 2,6-dimethoxy-4-ethylphenyl, 4,6-dimethyl-2-methoxyphenyl, 2,6-dimethoxy-4-methylphenyl, 2-chloro-6-methoxy-4-methylphenyl, 4,6-dimethyl-2-ethoxyphenyl, 6-hydroxy-2,4-dimethylphenyl, 4-cyano-2-methoxy-6-methylphenyl, 6-fluoro-2-methoxy-4-methylphenyl, 4-acetyl-2-methoxy-6-methylphenyl, 2-chloro-4,6-dimethoxyphenyl, 2,6-dimethoxy-4-ethoxyphenyl, 2,4,6-trimethoxyphenyl, 4,6-dibromo-2-trifluoromethoxyphenyl, 2-bromo-4-dimethylamino-6-methoxyphenyl, 4-bromo-2-methoxy-6-methylphenyl, 4,6-dimethoxy-2-propoxyphenyl, 4,6-dichloro-2-propoxyphenyl, 2-bromo-6-hydroxy-4-methoxyphenyl, 2,4,6-trifluorophenyl, 2-bromo-6-fluoro-4-methylphenyl, 4-difluoromethoxy-2,6-dimethylphenyl, 2,6-dimethyl-4-ethoxyphenyl, 2,6-dimethyl-4-isopropoxyphenyl, 2,6-dimethyl-4-methylthiophenyl, 2,6-dimethyl-4-methylsulfonylophenyl, 2,6-dimethyl-4-methylsulfinylophenyl, 2,3-dichlorophenyl, 4-methoxy-2,3-dimethylphenyl, 2-chloro-3-fluoro-4-methoxyphenyl, 2,3,4-trichlorophenyl and 4-methoxy-2,5-dimethylphenyl.
  • The “pharmaceutically acceptable salts” in the present invention include, for example, salts with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or the like; salts with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2-sulfonic acid or the like; salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, aluminium ion or the like; salts with amines such as ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, benzathine or the like.
  • A compound of the present invention includes any isomers such as diastereomers, enantiomers, geometricisomers and tautomeric forms. In a compound represented by formula [I], if the cyclic amino group has one or more chiral carbons and/or if there is an axial chirality between Ar and pyrrolopyrimidine (or pyrrolopyridine) ring, several stereoisomers (diastereomers or enantiomers) can exist. The compound of the present invention includes the individual isomers and the racemic and non-racemic mixtures of the isomers.
  • Preferable examples of the compound of the present invention are as follows.
  • That is, preferable are compounds represented by the following formula [III]
    Figure US20050209253A1-20050922-C00004
    (wherein the cyclic amino group is represented by the following formula [IV]:
    Figure US20050209253A1-20050922-C00005
      • in which the cyclic amino group is a 3- to 8-membered saturated cyclic amine or a 3- to 8-membered saturated cyclic amine bridged with C1-5alkylene or C1-4alkylene- O—C1-4alkylene between any different two carbon atoms of the cyclic amine, which cyclic amine is substituted with a group represented by —(CR1R2)m—(CHR3)n—CN, R4 and R5 independently on the same or different carbon atoms of the cyclic amine;
      • Y is N or CR10;
      • R1 is hydrogen, hydroxy, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
      • R2 is hydrogen or C1-5alkyl;
      • R3 is hydrogen, cyano, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
      • m is an integer selected from 0, 1, 2, 3, 4 and 5;
      • n is 0 or 1;
      • R4 is hydrogen, hydroxy, hydroxy-C1-5alkyl, cyano, cyano-C1-5alkyl or C1-5alkyl;
      • R5 is hydrogen or C1-5alkyl;
      • R6 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy or —N(R11)R12;
      • R7 and R9 are the same or different, and independently are hydrogen, halogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy, —N(R11a)R12a, —CO2R13, cyano, nitro, C1-5alkylthio, trifluoromethyl or trifluoromethoxy; or R7 and R8 are taken together to form —CH2—CH2—CH2—CH2— or —CH═CH—CH═CH—;
      • R10 is hydrogen, C1-5alkyl, halogen, cyano or —CO2R19;
      • Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C1-5alkyl, C3-8cycloalkyl, C2-5alkenyl, C2-5alkynyl, C1-5alkoxy, C1-5alkylthio, C1-5alkylsulfinyl, C1-5alkylsulfonyl, cyano, nitro, hydroxy, —CO2R19a—C(═O)R19a, CONR11bR12b, —OC(═O)R19a, —NR11bCO2R19a, —S(O)rNR11bR12b, hydroxy-C2-5alkylamino-C2-5alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and —N(R20)R21;
      • R11 and R12 are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
      • R11a and R12a are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
      • R11b and R12b are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
      • R13 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, C1-5alkoxy- C1-5alkyl, C3-8cycloalkyloxy-C1-5alkyl or phenyl;
      • R19 is hydrogen or C1-5alkyl;
      • R19a is hydrogen or C1-5alkyl;
      • r is 1 or 2;
      • R20 and R21 are the same or different, and independently are hydrogen or C1-5alkyl). More preferable are compounds represented by the formula [III] in which Y is N. More preferable are compounds represented by the formula [III] in which Y is N; n is 0; R1, R2, R4 and R5 are hydrogen. More preferable are compounds represented by the formula [III] in which Y is N; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 0, 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl). More preferable are compounds represented by the formula [III] in which wherein Y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is 0 or 1; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino.
  • Other preferable are compounds represented by the formula [III] in which Y is CR10. More preferable are compounds represented by the formula [III] in which Y is CR10; n is 0; R1, R2, R4 and R5 are hydrogen; R10 is hydrogen or halogen. More preferable are compounds represented by the formula [III] in which Y is CR10; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 0, 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; R10 is hydrogen or halogen; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl. More preferable are compounds represented by the formula [III] in which Y is CR10; the cyclic amino group is a 6-membered saturated cyclic amine; m is 0 or 1; n is 0; R17, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; R10 is hydrogen; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino.
  • Other preferable are compounds represented by the following formula [V]:
    Figure US20050209253A1-20050922-C00006
    (wherein the cyclic amino group is represented by the following formula [VI]:
    Figure US20050209253A1-20050922-C00007
      • in which the cyclic amino group is a 3- to 8-membered saturated cyclic amine or a 3- to 8-membered saturated cyclic amine bridged with C1-5alkylene or C1-4alkylene- O—C1-4alkylene between any different two carbon atoms of the cyclic amine, which cyclic amine is substituted with a group represented by —(CR1R2)m—(CHR3)n—OH, R4 and R5 independently on the same or different carbon atoms of the cyclic amine;
      • Y is N or CR10;
      • R1 is hydrogen, hydroxy, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
      • R2 is hydrogen or C1-5alkyl;
      • R3 is hydrogen, cyano, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
      • m is an integer selected from 0, 1, 2, 3, 4 and 5;
      • n is 0 or 1; with the proviso that when n is 0, m is an integer selected from 1, 2, 3, 4 and 5;
      • R4 is hydrogen, hydroxy, hydroxy-C1-5alkyl, cyano, cyano-C1-5alkyl or C1-5alkyl;
      • R5 is hydrogen or C1-5alkyl;
      • R6 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy or —N(R11)R12;
      • R7 and R8 are the same or different, and independently are hydrogen, halogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy, —N(R11a)R12a, —CO2R13, cyano, nitro, C1-5alkylthio, trifluoromethyl or trifluoromethoxy; or R7 and R8 are taken together to form —CH2—CH2—CH2—CH2— or ——CH═CH—CH═CH—;
      • R10 is hydrogen, C1-5alkyl, halogen, cyano or —CO2R19;
      • Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C1-5alkyl, C3-8cycloalkyl, C2-5alkenyl, C2-5alkynyl, C1-5alkoxy, C1-5alkylthio, C1-5alkylsulfinyl, C1-5alkylsulfonyl, cyano, nitro, hydroxy, —CO2R19a, —C(═O)R19a, —CONR11bR12b, —OC(═O)R19a, —NR11bCO2R19a, —S(O)rNR11bR12b, hydroxy-C2-5alkylamino-C2-5alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and —N(R20)R21; with the proviso that when Y is N, and the cyclic amino group is 5-membered ring, then Ar is aryl or heteroaryl which aryl or heteroaryl is substituted with at least one of substituents which are selected from halogen and trifluoromethyl;
      • R11 and R12 are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
      • R11a and R12a are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
      • R11b and R12b are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
      • R13 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, C1-5alkoxy- C1-5alkyl, C3-8cycloalkyloxy-C1-5alkyl or phenyl;
      • R19 is hydrogen or C1-5alkyl;
      • R19a is hydrogen or C1-5alkyl;
      • r is 1 or 2;
      • R20 and R21 are the same or different, and independently are hydrogen or C1-5alkyl). More preferable are compounds represented by the formula [V] in which Y is N. More preferable are compounds represented by the formula [V] in which Y is N;
    • m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R1, R2, R4 and R5 are hydrogen. More preferable are compounds represented by the formula [V] in which Y is N; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; Ar. is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl); with the proviso that when the cyclic amino group is 5-membered ring, Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with at least one of substituents which are selected from halogen and trifluoromethyl. More preferable are compounds represented by the formula [V] in which Y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino.
  • Other preferable are compounds represented by the formula [V] in which Y is N; m is 1; n is 0; R1 is C1-5alkyl or hydroxy-C1-5alkyl; R2, R4 and R5 are hydrogen. More preferable are compounds represented by the formula [V] in which Y is N; m is 1; n is 0; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; R1 is C1-5alkyl or hydroxy-C1-5alkyl; R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl). More preferable are compounds represented by the formula [V] in which Y is N; m is 1; n is 0; the cyclic amino group is a 6-membered saturated cyclic amine; R1 is C1-5alkyl or hydroxy-C1-5alkyl; R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino.
  • Other preferable are compounds represented by the formula [V] in which Y is N; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R1, R2 and R5 are hydrogen; R4 is cyano, wherein a group represented by —(CR1R2)m—(CHR3)n—OH and R4 are substituted on the same carbon atom of the cyclic amine. More preferable are compounds represented by the formula [V] in which Y is N; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2 and R5 are hydrogen; R4 is cyano; R6 is methyl; R7 and R5 are the same or different, and independently are hydrogen or C1-5alkyl; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl), wherein a group represented by —(CR1R2)m—(CHR3)n—OH and R4 are substituted on the same carbon atom of the cyclic amine. More preferable are compounds represented by the formula [V] in which Y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2 and R5 are hydrogen; R4 is cyano; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino, wherein a group represented by —(CR1R2)m—(CHR3)n—OH and R4 are substituted on the same carbon atom of the cyclic amine.
  • Other preferable are compounds represented by the formula [V] in which wherein Y is CR10. More preferable are compounds represented by the formula [V] in which Y is CR10; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R1, R2, R4 and R5 are hydrogen; R10 is hydrogen or halogen. More preferable are compounds represented by the formula [V] in which Y is CR10; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; R10 is hydrogen or halogen; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl). More preferable are compounds represented by the formula [V] in which Y is CR10; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; R10 is hydrogen; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino.
  • Other preferable are compounds represented by the formula [V] in which Y is CR10; m is 1; n is 0; R1 is C1-5alkyl or hydroxy-C1-5alkyl; R2, R4 and R5 are hydrogen; R10 is hydrogen or halogen. More preferable are compounds represented by the formula [V] in which Y is CR10; m is 1; n is 0; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; R1 is C1-5alkyl or hydroxy-C1-5alkyl; R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; R10 is hydrogen or halogen; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl). More preferable are compounds represented by the formula [V] in which Y is CR10; m is 1; n is 0; the cyclic amino group is a 6-membered saturated cyclic amine; R1 is C1-5alkyl or hydroxy- C1-5alkyl; R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; R10 is hydrogen; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino.
  • Other preferable are compounds represented by the formula [V] in which Y is CR10; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R1, R2 and R5 are hydrogen; R4 is cyano; R10 is hydrogen or halogen, wherein a group represented by —(CR1R2)m (CHR3)—OH and R4 are substituted on the same carbon atom of the cyclic amine. More preferable are compounds represented by the formula [V] in which Y is CR10; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2 and R5 are hydrogen; R4 is cyano; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; R10 is hydrogen or halogen; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl), wherein a group represented by (CR1R2)m—(CHR3)n—OH and R4 are substituted on the same carbon atom of the cyclic amine. More preferable are compounds represented by the formula [V] in which Y is CR10; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2 and R5 are hydrogen; R4 is cyano; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; R10 is hydrogen; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino, wherein a group represented by —(CR1R2)m—(CHR3)n—OH and R4 are substituted on the same carbon atom of the cyclic amine.
  • Other preferable are compounds represented by the following formula [VII]:
    Figure US20050209253A1-20050922-C00008
    (wherein the cyclic amino group is represented by the following formula [VIII]:
    Figure US20050209253A1-20050922-C00009
      • in which the cyclic amino group is a 3- to 8-membered saturated cyclic amine or a 3- to 8-membered saturated cyclic amine bridged with C1-5alkylene or C1-4alkylene- O—C1-4alkylene between any different two carbon atoms of the cyclic amine, which cyclic amine is substituted with a group represented by —(CR1R2)m—(CHR3)n—OR9, R4 and R5 independently on the same or different carbon atoms of the cyclic amine;
      • Y is N or CR10;
      • R1 is hydrogen, hydroxy, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
      • R2 is hydrogen or C1-5alkyl;
      • R3 is hydrogen, cyano, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
      • m is an integer selected from 0, 1, 2, 3, 4 and 5;
      • n is 0 or 1;
        with the proviso that when n is 0, m is an integer selected from 1, 2, 3, 4 and 5;
      • R4 is hydrogen, hydroxy, hydroxy-C1-5alkyl, cyano, cyano-C1-5alkyl or C1-5alkyl;
      • R5 is hydrogen or C1-5alkyl;
      • R6 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy or —N(R11)R12;
      • R7 and R8 are the same or different, and independently are hydrogen, halogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy, N(R11a)R12a, —CO2R13, cyano, nitro, C1-5alkylthio, trifluoromethyl or trifluoromethoxy; or R7 and R8 are taken together to form —CH2—CH2—CH2—CH2— or —CH═CH—CH═CH—;
      • R9 is C1-24acyl, Cl1-10alkoxycarbonyl, aryl-C1-5alkyloxycarbonyl, —CO—O—CHR14O—CO—R15, —P(═O)(OR14a)OR15a, —CO—(CH2)p—(CHR16)q—NR17R18, arylcarbonyl or heteroarylcarbonyl, wherein each said acyl, aryl and heteroaryl is unsubstituted or substituted with C1-5alkoxy, and C1-24acyl optionally includes one to six double bonds;
      • R10 is hydrogen, C1-5alkyl, halogen, cyano or —CO2R19;
      • Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C1-5alkyl, C3-8cycloalkyl, C2-5alkenyl, C2-5alkynyl, C1-5alkoxy, C1-5alkylthio, C1-5alkylsulfinyl, C1-5alkylsulfonyl, cyano, nitro, hydroxy, —CO2R19a, C(═O)R19a, CONR11bR12b, —OC(═O)R19a, —NR11bCO2R19a, —S(O)rNR11bR12b, hydroxy-C2-5alkylamino-C2-5alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and —N(R20)R21;
      • R11 and R12 are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
      • R11a and R12a are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
      • R11b and R12b are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
      • R13 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, C1-5alkoxy- C1-5alkyl, C3-8cycloalkyloxy-C1-5alkyl or phenyl;
      • R14 and R15 are the same or different, and independently are hydrogen, C1-5alkyl or aryl-C1-5alkyl;
      • R14a and R15a are the same or different, and independently are hydrogen, C1-5alkyl or aryl-C1-5alkyl;
      • R16 is hydrogen, C1-5alkyl, aryl, heteroaryl, aryl-C1-5alkyl, heteroaryl-C1-5alkyl, hydroxy-C1-5alkyl, hydroxycarbonyl-C1-5alkyl, hydroxyphenyl-C1-5alkyl, C1-5alkoxy- C1-5alkyl, amino-C1-5alkyl, guanidino-C1-5alkyl, mercapto-C1-5alkyl, C1-5alkylthio- C1-5alkyl or aminocarbonyl-C1-5alkyl;
      • R17 and R18 are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, C1-10acyl, C1-10alkoxycarbonyl and aryl-C1-5alkyloxycarbonyl, or R16 and R17 are taken together to form —CH2—, —CH2CH2—, —CH2CH2CH2— or —CH2CH2CH2CH2—;
      • p is an integer selected from 0, 1, 2, 3, 4 and 5;
      • q is 0 or 1;
      • R19 is hydrogen or C1-5alkyl;
      • R19a is hydrogen or C1-5alkyl;
      • r is 1 or 2;
      • R20 and R21 are the same or different, and independently are hydrogen or C1-5alkyl). More preferable are compounds represented by the formula [VII] in which Y is N. More preferable are compounds represented by the formula [VII] in which Y is N; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R1, R2, R4 and R5 are hydrogen. More preferable are compounds represented by the formula [VII] in which the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; Y is N; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R3 are the same or different, and independently are hydrogen or C1-5alkyl; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl). More preferable are compounds represented by the formula [VII] in which the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; Y is N; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino.
  • Other preferable are compounds represented by the formula [VII] in which Y is CR10. More preferable are compounds represented by the formula [VII] in which Y is CR10; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R1, R2, R4 and R5 are hydrogen. More preferable are compounds represented by the formula [VII] in which Y is CR10; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; R10 is hydrogen or halogen; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl). More preferable are compounds represented by the formula [VII] in which Y is CR10; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; R10 is hydrogen; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino.
  • Especially preferable compounds of the present invention are: 2-{1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-ethanol,
    Figure US20050209253A1-20050922-C00010
    • 2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-ethanol,
      Figure US20050209253A1-20050922-C00011
    • 2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-ethanol,
      Figure US20050209253A1-20050922-C00012
    • 2-{1-[7-(4-bromo-2,6-diethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-ethanol,
      Figure US20050209253A1-20050922-C00013
    • 2-{1-[2,5-dimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-ethanol,
      Figure US20050209253A1-20050922-C00014
    • 3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00015
    • 3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00016
    • {1-[7-(2,4-dibromo-6-methoxy-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-methanol,
      Figure US20050209253A1-20050922-C00017
    • {1-[7-(2,4-dibromo-6-methylsulfanyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-methanol,
      Figure US20050209253A1-20050922-C00018
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-methanol,
      Figure US20050209253A1-20050922-C00019
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-methanol,
      Figure US20050209253A1-20050922-C00020
    • {1-[2,5-dimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-methanol,
      Figure US20050209253A1-20050922-C00021
    • 2-{1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-ethanol,
      Figure US20050209253A1-20050922-C00022
    • 2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-ethanol,
      Figure US20050209253A1-20050922-C00023
    • 2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-ethanol,
      Figure US20050209253A1-20050922-C00024
    • 2-{1-[2,5-dimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- piperidin-3-yl}-ethanol,
      Figure US20050209253A1-20050922-C00025
    • {1-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00026
    • {1-[2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00027
    • {1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00028
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00029
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00030
    • {1-[2-methyl-9-(2,4,6-trimethyl-phenyl)-9H-1,3,9-triaza-fluoren-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00031
    • {1-[7-(4-bromo-2,6-diethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00032
    • {1-[7-(4-bromo-2,6-diethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00033
    • {1-[2,5,6-trimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00034
    • {1-[2,5-dimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00035
    • {1-[7-(4-bromo-2,6-dichloro-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00036
    • {1-[7-(4-bromo-2,6-dichloro-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00037
    • {1-[7-(2,6-dibromo-4-isopropyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00038
    • {1-[7-(2,6-dibromo-4-isopropyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00039
    • {1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00040
    • {1-[7-(4-chloro-2,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00041
    • 2-{1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00042
    • 2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00043
    • 2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00044
    • 2-{1-[2,5,6-trimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00045
    • 2-{1-[2,5-dimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00046
    • 3-{1-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00047
    • 3-{1-[2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00048
    • 3-{1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00049
    • 3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00050
    • 3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00051
    • 3-{1-[2,5-dimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00052
    • 3-{1-[7-(4-bromo-2,6-dichloro-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00053
    • 3-{1-[7-(4-bromo-2,6-dichloro-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00054
    • {1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-yl}-methanol,
      Figure US20050209253A1-20050922-C00055
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-yl}-methanol,
      Figure US20050209253A1-20050922-C00056
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-yl}-methanol,
      Figure US20050209253A1-20050922-C00057
    • 1-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethane-1,2-diol,
      Figure US20050209253A1-20050922-C00058
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-2-yl}-methanol
      Figure US20050209253A1-20050922-C00059
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-2-yl}-methanol,
      Figure US20050209253A1-20050922-C00060
    • 2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-ethanol,
      Figure US20050209253A1-20050922-C00061
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-azepan-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00062
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-azepan-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00063
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00064
    • 1-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00065
    • 1-[2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00066
    • 1-[7-(2,4-dibromo-6-methylsulfanyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00067
    • 1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00068
    • 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00069
    • 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00070
    • 1-[7-(4-isopropyl-2-methylsulfanyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00071
    • 1-[7-(4-isopropyl-2-methylsulfanyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00072
    • 1-[7-(2-bromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00073
    • 1-[7-(4-bromo-2,6-diethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00074
    • 1-[7-(4-bromo-2,6-diethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00075
    • {1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00076
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00077
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00078
    • 3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-propionitrile,
      Figure US20050209253A1-20050922-C00079
    • 3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-propionitrile,
      Figure US20050209253A1-20050922-C00080
    • 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00081
    • 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00082
    • {1-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00083
    • {1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00084
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00085
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00086
    • {1-[7-(4-bromo-2,6-diethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00087
    • {1-[7-(4-bromo-2,6-diethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00088
    • {1-[2,5,6-trimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00089
    • {1-[2,5-dimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00090
    • {1-[7-(4-bromo-2,6-dichloro-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00091
    • {1-[7-(4-bromo-2,6-dichloro-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00092
    • {1-[7-(2,6-dibromo-4-isopropyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00093
    • {1-[7-(2,6-dibromo-4-isopropyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00094
    • {1-[7-(4-methoxy-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00095
    • {1-[7-(4-methoxy-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00096
    • {1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00097
    • {1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00098
    • 8-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-8-aza-bicyclo[3.2.1]octane-3-carbonitrile,
      Figure US20050209253A1-20050922-C00099
    • 8-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-8-aza-bicyclo[3.2.1]octane-3-carbonitrile,
      Figure US20050209253A1-20050922-C00100
    • 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00101
    • 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00102
    • 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-azepane-4-carbonitrile,
      Figure US20050209253A1-20050922-C00103
    • 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-azepane-4-carbonitrile,
      Figure US20050209253A1-20050922-C00104
    • 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-hydroxymethyl-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00105
    • {1-[7-(4-isopropyl-2-methylsulfanyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00106
    • {1-[7-(2-bromo-4-isopropyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00107
    • {1-[7-(2,4-dibromo-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00108
    • {1-[7-(2,6-dibromo-4-chloro-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00109
    • 2-{1-[7-(2,6-dibromo-4-chloro-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00110
    • 1-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propane-1,3-diol,
      Figure US20050209253A1-20050922-C00111
    • {1-[7-(2,6-dibromo-4-chloro-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00112
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00113
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00114
    • {1-[2,5-dimethyl-7-(2,4,6-trichloro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00115
    • {1-[7-(2,6-dichloro-4-trifluoromethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00116
    • 3-{1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00117
    • 1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00118
    • {1-[7-(2,6-Dichloro-4-trifluoromethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00119
    • 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-azetidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00120
    • 1-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00121
    • 1-{1-[7-(4-isopropyl-2-methylsulfanyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00122
    • 1-{1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00123
    • 1-{1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00124
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-methyl-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00125
    • {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-methyl-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00126
    • {8-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-8-aza-bicyclo[3.2.1]oct-3-yl}-methanol,
      Figure US20050209253A1-20050922-C00127
    • {8-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-8-aza-bicyclo [3.2.1]oct-3-yl}-methanol,
      Figure US20050209253A1-20050922-C00128
    • {8-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-8-aza-bicyclo [3.2.1]oct-3-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00129
    • {8-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-8-aza-bicyclo[3.2.1]oct-3-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00130
    • 2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-malononitrile,
      Figure US20050209253A1-20050922-C00131
    • 2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-malononitrile,
      Figure US20050209253A1-20050922-C00132
    • 2-{1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-3-yl}-ethanol,
      Figure US20050209253A1-20050922-C00133
    • 2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dim ethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-3-yl}-ethanol,
      Figure US20050209253A1-20050922-C00134
    • {1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00135
    • {1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00136
    • 2{-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00137
    • 2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00138
    • 3-{1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00139
    • 3-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00140
    • 1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00141
    • 1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00142
    • {1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-3-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00143
    • 1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00144
    • 1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00145
    • {1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00146
    • 2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-3-yl}-ethanol,
      Figure US20050209253A1-20050922-C00147
    • {1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00148
    • {1-[1-(4-chloro-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00149
    • {1-[1-(4-chloro-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00150
    • 2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00151
    • 2-{1-[1-(4-chloro-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00152
    • 2-{1-[1-(4-chloro-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00153
    • 3-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00154
    • 3-{1-[1-(4-chloro-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00155
    • 3-{1-[1-(4-chloro-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00156
    • 1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-3-carbonitrile,
      Figure US20050209253A1-20050922-C00157
    • 1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00158
    • 1-[1-(4-chloro-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00159
    • 1-[1-(4-chloro-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00160
    • {1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00161
    • {1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00162
    • {1-[1-(4-chloro-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00163
    • {1-[1-(2,6-dibromo-4-isopropyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00164
    • {1-[1-(2,6-dibromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00165
    • {1-[2,3,6-trimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00166
    • {1-[3,6-dimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00167
    • {1-[1-(4-bromo-2,6-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00168
    • {1-[1-(4-bromo-2,6-dichloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00169
    • {1-[2,3,6-trimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00170
    • {1-[3,6-dimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00171
    • {1-[1-(2,6-dibromo-4-chloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00172
    • {1-[1-(2,6-dibromo-4-chloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00173
    • {1-[1-(4-methoxy-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00174
    • {1-[1-(4-methoxy-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00175
    • {1-[1-(2-bromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00176
    • {1-[1-(4-isopropyl-2-methylsulfanyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00177
    • {1-[1-(2,4-dibromo-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00178
    • {1-[1-(2-bromo-4-trifluoromethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00179
    • {1-[2,3,6-trimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00180
    • {1-[3,6-dimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
      Figure US20050209253A1-20050922-C00181
    • 2-{1-[1-(2,6-dibromo-4-isopropyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00182
    • 2-{1-[1-(2,6-dibromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00183
    • 2-{1-[2,3,6-trimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl-ethanol,
      Figure US20050209253A1-20050922-C00184
    • 2-{1-[3,6-dimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl]-ethanol,
      Figure US20050209253A1-20050922-C00185
    • 2-{1-[1-(4-bromo-2,6-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00186
    • 2-{1-[1-(4-bromo-2,6-dichloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00187
    • 2-{1-[2,3,6-trimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00188
    • 2-{1-[3,6-dimethyl-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00189
    • 2-{1-[1-(2,6-dibromo-4-chloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00190
    • 2-{1-[1-(2,6-dibromo-4-chloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00191
    • 2-{1-[1-(4-methoxy-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00192
    • 2-{1-[1-(4-methoxy-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00193
    • 2-{1-[1-(2-bromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00194
    • 2-{1-[1-(4-isopropyl-2-methylsulfanyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00195
    • 2-{1-[1-(2,4-dibromo-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00196
    • 2-{1-[2,3,6-trimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00197
    • 2-{1-[3,6-dimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00198
    • 2-{1-[5-bromo-1-(4-chloro-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
      Figure US20050209253A1-20050922-C00199
    • 3-{1-[1-(2,6-dibromo-4-isopropyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00200
    • 3-{1-[1-(2,6-dibromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00201
    • 3-{1-[2,3,6-trimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00202
    • 3-{1-[3,6-dimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00203
    • 3-{1-[1-(4-bromo-2,6-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00204
    • 3-{1-[1-(4-bromo-2,6-dichloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00205
    • 3-{1-[2,3,6-trimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00206
    • 3-{1-[3,6-dimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00207
    • 3-{1-[1-(2,6-dibromo-4-chloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00208
    • 3-{1-[1-(2,6-dibromo-4-chloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00209
    • 3-{1-[1-(4-methoxy-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00210
    • 3-{1-[1-(4-methoxy-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00211
    • 3-{1-[1-(4-isopropyl-2-methylsulfanyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00212
    • 3-{1-[2,3,6-trimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00213
    • 3-{1-[3,6-dimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
      Figure US20050209253A1-20050922-C00214
    • 1-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethane-1,2-diol,
      Figure US20050209253A1-20050922-C00215
    • 1-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethane-1,2-diol,
      Figure US20050209253A1-20050922-C00216
    • 1-1{1-[1-(4-bromo-2,6-dimethyl-phenyl)-23,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propane-1,3-diol,
      Figure US20050209253A1-20050922-C00217
    • 1-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propane-1,3-diol,
      Figure US20050209253A1-20050922-C00218
    • 1-[1-(2,6-dibromo-4-isopropyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00219
    • 1-[1-(2,6-dibromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00220
    • 1-[2,3,6-trimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00221
    • 1-[3,6-dimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00222
    • 1-[1-(4-bromo-2,6-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00223
    • 1-[1-(4-bromo-2,6-dichloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00224
    • 1-[2,3,6-trimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00225
    • 1-[3,6-dimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00226
    • 1-[1-(2,6-dibromo-4-chloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00227
    • 1-[1-(2,6-dibromo-4-chloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00228
    • 1-[1-(4-methoxy-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00229
    • 1-[1-(4-methoxy-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00230
    • 1-[1-(2-bromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00231
    • 1-[1-(4-isopropyl-2-methylsulfanyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00232
    • 1-[1-(2,4-dibromo-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00233
    • 1-[1-(2-bromo-4-trifluoromethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00234
    • 1-[2,3,6-trimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00235
    • 1-[3,6-dimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
      Figure US20050209253A1-20050922-C00236
    • {1-[1-(4-chloro-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00237
    • {1-[1-(2,6-dibromo-4-isopropyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00238
    • {1-[1-(2,6-dibromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00239
    • {1-[2,3,6-trimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00240
    • {1-[3,6-dimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00241
    • {1-[1-(4-bromo-2,6-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00242
    • {1-[1-(4-bromo-2,6-dichloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00243
    • {1-[2,3,6-trimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00244
    • {1-[3,6-dimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00245
    • {1-[1-(2,6-dibromo-4-chloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00246
    • {1-[1-(2,6-dibromo-4-chloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00247
    • {1-[1-(4-methoxy-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00248
    • {1-[1-(4-methoxy-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00249
    • {1-[1-(2-bromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00250
    • {1-[1-(4-isopropyl-2-methylsulfanyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00251
    • {1-[1-(2,4-dibromo-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00252
    • {1-[1-(2-bromo-4-trifluoromethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00253
    • {1-[3,6-dimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
      Figure US20050209253A1-20050922-C00254
    • carbonic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester ethyl ester,
      Figure US20050209253A1-20050922-C00255
    • pyridine-2-carboxylic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester,
      Figure US20050209253A1-20050922-C00256
    • methoxy-acetic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester,
      Figure US20050209253A1-20050922-C00257
    • methoxy-acetic acid 1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-ylmethyl ester,
      Figure US20050209253A1-20050922-C00258
    • carbonic acid benzyl ester 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester,
      Figure US20050209253A1-20050922-C00259
    • decanoic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester,
      Figure US20050209253A1-20050922-C00260
    • 3-diethylamino-propionic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester,
      Figure US20050209253A1-20050922-C00261
    • and phosphoric acid mono-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl}ester.
      Figure US20050209253A1-20050922-C00262
  • The compound represented by the formula [I] can be produced, for example, by the process shown in the following reaction scheme 1-4 [in the following reaction scheme, R1, R2, R3, R4, R5, R6, R7, R8, m, n, X, Y and Ar are as defined above; LG is chloro, bromo, iodo, methanesulfonyloxy, benzenesulfonyloxy, 4-toluenesulfonyloxy or trifluoromethanesulfonyloxy group; Z1 and Z2 are the same or different, and independently are chloride or bromide; Ra and Rb are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl; and Xa is —(CHR3)n—OH, —(CHR3)n—CN or —CO2—(C1-5alkyl)].
    Figure US20050209253A1-20050922-C00263
    Step 1:
  • Compound (3), a compound of the present invention, can be obtained by reacting Compound (1) with Compound (2) in an inert solvent in the presence or absence of a base. Herein, the base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide and the like; and Grignard reagents such as methylmagnesium bromide and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene, xylene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • The compound of the present invention can be converted to a salt in an inert solvent with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or the like, with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2-sulfonic acid or the like, with an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, aluminum hydroxide or the like or with an organic base such as ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, benzathine or the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; esters such as ethyl acetate, ethyl formate and the like; ketones such as acetone, methylethylketone and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
    Figure US20050209253A1-20050922-C00264
    Step 2:
  • Compound (4) can be converted to Compound (6) by reacting Compound (4) with Compound (5) in an inert solvent in the presence or absence of a base. Herein, the base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide and the like; and Grignard reagents such as methyl magnesium bromide and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene, xylene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • Step 3:
  • Compound (6) can be converted to Compound (7) by reacting Compound (6) with malononitrile in an inert solvent in the presence or absence of a base. Herein, the base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, potassium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazamide, sodium hexamethyldisilazamide, potassium hexamethyldisilazamide and the like; alkyl lithiums such as methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium and phenyl lithium; and Grignard reagents such as methyl magnesium bromide and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • Step 4:
  • Compound (7) can be converted to Compound (8) by acylation of amino group in Compound (7) and followed by formation of pyrimidine ring. The acylation and the formation of pyrimidine ring may occur continuously in one pot. The acylation can be achieved by reacting Compound (7) with an acylating reagent in an inert solvent in the presence or absence of a base or an acid. The following formation of pyrimidine ring can be carried out by heating the acylated compound in an inert solvent in the presence or absence of an acid. Herein, the acylating reagent includes, for example, halogenated acyls such as acetyl chloride, acetyl bromide, propionyl chloride, propionyl bromide, butyryl chloride, cyclopropanecarbonyl chloride, benzoyl chloride and the like; acid anhydride such as acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride and the like. The base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, potassium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazamide, sodium hexamethyldisilazamide, potassium hexamethyldisilazamide and the like; and Grignard reagents such as methyl magnesium bromide and the like. The acid includes, for example, organic acids such as formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, trifluoromethanesulfonic acid and the like; inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, nitric acid or the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene, xylene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; acetic acid; water; and mixtures of solvents selected from these inert solvents.
  • Step 5
  • Compound (8) can be converted to Compound (9) by reacting (8) with a halogenating reagent or a sulfonating reagent in the presence or absence of a base in an inert solvent or without any solvent. Herein, the halogenating reagent includes, for example, phosphoryl chloride, phosphoryl bromide, phosphorous pentachloride, phosphorous trichloride, phosphorous pentabromide, phosphorous tribromide, thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide and the like. The sulfonating reagent includes, for example, p-toluenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonic anhydride, methansulfonic anhydride, trifluoromethanesulfonic anhydride, N-phenylbis(trifluoromethanesulfonimide) and the like. The base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-diethylaniline and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide and the like; and Grignard reagents such as methyl magnesium bromide and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; dichloromethane; chloroform; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • Step 6
  • Compound (9) can be converted to Compound (11) by reacting Compound (9) with Compound (10) in the same method as step 1.
  • Step 7
  • Compound (11) can be converted to Compound (12) by reduction of Compound (11) with a conventional reducing agent in an inert solvent. Or if necessary, treatment with an acid in the presence or absence of inert solvent after the reduction can provide Compound (12). When Xa is —CO2—(C1-5alkyl), the ester group can be converted to a hydroxymethyl group at the same time. Herein, the reducing agent includes, for example, lithium borohydride, sodium borohydride, calcium borohydride, lithium triethylborohydride, lithium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, zinc borohydride, borane, lithium trimethoxyborohydride, lithium triacetoxyborohydride, tetramethylammonium borohydride, lithium aluminum hydride, sodium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, diisobutylaluminum hydride, trichlorosilane and the like. The reduction can be also carried out by hydrogenation using a catalyst including palladium, platinum dioxide, Raney nickel or the like. The acid includes, for example, organic acids such as acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid and the like; inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, nitric acid or the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
    Figure US20050209253A1-20050922-C00265
    Step 8
  • Compoumd (7) can be converted to Compound (13) by reacting Compound (7) with ketones such as acetone and the like; vinyl ethers such as isopropenyl methyl ether and the like in an inert solvent in the presence or absence of an acid, and the following conversion from Compound (13) to Compound (14) can be carried out in the presence of base in an inert solvent. Herein, the acid includes, for example, organic acids such as acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid and the like. The base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazamide, sodium hexamethyldisilazamide, potassium hexamethyldisilazamide and the like; alkyl lithiums such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium and the like; and Grignard reagents such as methyl magnesium bromide and the like. The inert solvent includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; and mixtures of solvents selected from these inert solvents.
  • Step 9
  • Compound (14) can be converted to Compound (15) in the same manner as step 7.
  • Step 10
  • Compound (15) can be converted into Compound (16) via the corresponding diazonium compound. The conversion to the diazonium compound can be carried out using, for example, sodium nitrite, potassium nitrite, butylnitrite, tert-butylnitrite, iso-butylnitrite or the like in the presence or absence of an acid in an inert solvent. The acid includes, for example, inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid or the like. The inert solvent includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • Step 11
  • Compound (16) can be converted to Compound (17) in the same manner as step 5.
  • Step 12
  • When LG is chloride, bromide or iodide, Compound (17) can be obtained from Compound (15) directly by formation of the diazonium compound in the presence of one or more metal salts in an inert solvent. The formation of the diazonium compound can be carried out in the same manner as step 10. The metal salts include, for example, potassium iodide, potassium bromide, sodium iodide, sodium bromide, sodium chloride, copper (I) chloride, copper (II) chloride, copper (I) bromide, copper (II) bromide, copper (I) iodide and the like. The inert solvent includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • Step 13
  • Compound (17) can be converted to Compound (18) in the same manner as step 1.
  • Step 14
  • When Xa is —CO2—(C1-5alkyl), the ester group can be converted to hydroxymethyl group in the same manner as step 7.
    Figure US20050209253A1-20050922-C00266
    Step 15
  • Compound (20) can be converted to Compound (21) by a coupling of Compound (20) with the corresponding carboxylic acid using a conventional coupling reagent in the presence or absence of an additive or a base in an inert solvent or a coupling of Compound (20) with the corresponding acyl halide in the presence or absence of a base in an inert solvent. When R9 has protective groups of an amino group, a hydroxy group, a mercapto goup, a carboxy group, a guanidine group or a phosphoric acid group, those protective groups can be removed by conventional methods for deprotection (ref. Theodora W Greene and Peter G. M. Wuts “Protective Groups in Organic Synthesis”; Wiley-Interscience) after the above coupling. Herein, the coupling reagent includes, for example, N,N′-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1,1′-carbonyldiimidazole (CDI), diphenylphosphorylazide (DPPA), diethyl cyanophosphate and the like. The additive includes, for example, 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide, 4-dimethylaminopyridine and the like. The base includes amines such as triethylamine, N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazamide, sodium hexamethyldisilazamide, potassium hexamethyldisilazamide and the like; alkyl lithiums such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium and the like; and Grignard reagents such as methyl magnesium bromide and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and mixtures of solvents selected from these inert solvents.
  • The compound of the present invention is useful as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved. For this purpose, the compound of the present invention can be formulated into tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, injections and the like by a conventional preparation technique by adding conventional fillers, binders, disintegrators, pH-adjusting agents, solvents, etc.
  • The compound of the present invention can be administered to an adult patient in a dose of 0.1 to 500 mg per day in one portion or several portions orally or parenterally. The dose can be properly increased or decreased depending on the kind of a disease and the age, body weight and symptom of a patient.
    • ENBODIMENTS OF THE INVENTION
  • The present invention is concretely explained with reference to the following examples and test example, but is not limited thereto.
    • Example 1 Synthesis of 2-{1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}ethanol hydrochloride (compound 1-074)
  • Figure US20050209253A1-20050922-C00267
  • (1) A mixture of 7-(4-bromo-2,6-dimethylphenyl)-4-chloro-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (6.0 g), 4-(2-hydroxyethyl)piperidine (3.2 g), N,N-diisopropylethylamine (3.2 g) in ethanol (15 mL) was heated at reflux for 5.5 hours. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogencarbonate, and then extracted with ethyl acetate three times. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by a silica gel column chromatography (silica gel: Wako Gel (C200); eluent: hexane/ethyl acetate=2:1) to obtain 2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol as a white solid (6.41 g).
  • (2) To a suspension of 2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol (6.41 g) in ethanol (51 mL) was added 4 M HCl in ethyl acetate (4.2 mL) under ice-cooling. After removing the solvent, ethyl acetate (26 mL) was added to the residue. The mixture was stirred overnight to afford a white crystal. The crystal was collected by filtration to give the title compound (6.1 g).
  • m.p. 187-189° C.
  • Table 1 and Table 2 list the compound obtained in Example 1 and compounds obtained by the similar procedure as in Example 1.
    • Example 2 Synthesis of optically active 1-[7-(2-bromo-4-trifluoromethylphenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]piperidine-3-carbonitrile (compound 1-134, 1-135, 1-136 and 1-137)
  • Figure US20050209253A1-20050922-C00268
  • A mixture of 7-(2-bromo-4-trifluoromethylphenyl)-4-chloro-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine (400 mg), piperidine-3-carbonitrile (290 mg), N,N-diisopropylethylamine (309 mg) in ethanol (2 mL) was heated at reflux for 6 days. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=5:1) to obtain two diastereoisomers (low polar diastereoisomer: 62 mg and high polar diastereoisomer: 36 mg) of 1-[7-(2-bromo-4-trifuoromethylphenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl]piperidine-3-carbonitrile.
  • Low Polar Diastereoisomer:
  • Rf value 0.64 (developing solvent: hexane/ethyl acetate=1:1, TLC plate Silica gel 60 F254 (Merck))
  • 1H NMR (300 MHz) δ 1.68-1.83 (1H, m), 1.85-2.07 (3H, m), 2.08 (3H, s), 2.40 (3H, s), 2.51 (3H, s), 3.04-3.16 (1H, m), 3.26-3.62 (3H, m), 3.81-3.95 (1H, m), 7.43 (1H, d, J=8.2 Hz), 7.74 (1H, d, J=8.2 Hz), 8.02 (1H, s)
  • High Polar Diastereoisomer:
  • Rf value 0.56 (developing solvent: hexane/ethyl acetate=1:1, TLC plate Silica gel 60 F254 (Merck))
  • 1H NMR (300 MHz) δ 1.65-1.83 (1H, m), 1.82-2.16 (6H, m), 2.40 (3H, s), 2.51 (3H, s), 3.04-3.17 (1H, m), 3.28-3.63 (3H, m), 3.85-3.98 (1H, m), 7.47 (1H, d, J=8.6 Hz), 7.74 (1H, d, J=8.6 Hz), 8.02 (1H, s)
  • The low polar diastereoisomer was optically resolved by high performance liquid chromatography to give each enantiomer.
  • Compound 1-134:
  • 1H NMR (300 MHz) δ 1.68-1.83 (1H, m), 1.85-2.07 (3H, m), 2.08 (3H, s), 2.40 (3H, s), 2.51 (3H, s), 3.04-3.16 (1H, m), 3.26-3.62 (3H, m), 3.81-3.95 (1H, m), 7.43 (1H, d, J=8.2 Hz), 7.74 (1H, d, J=8.2 Hz), 8.02 (1H, s)
  • HPLC retention time: 20.0 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 2.0 cm I.D.×25 cm, mobile phase: hexane−IPA=4:1, flow rate: 5.0 mL/min.)
  • Compound 1-135:
  • 1H NMR (300 MHz) δ 1.68-1.83 (1H, m), 1.85-2.07 (3H, m), 2.08 (3H, s), 2.40 (3H, s), 2.51 (3H, s), 3.04-3.16 (1H, m), 3.26-3.62 (3H, m), 3.81-3.95 (1H, m), 7.43 (1H, d, J=8.2 Hz), 7.74 (1H, d, J=8.2 Hz), 8.02 (1H, s)
  • HPLC retention time: 23.0 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 2.0 cm I.D.×25 cm, mobile phase: hexane−IPA=4:1, flow rate: 5.0 mL/min.)
  • The high polar diastereoisomer was also optically resolved by high performance liquid chromatography to give each enantiomer.
  • Compound 1-136:
  • 1H NMR (300 MHz) δ 1.65-1.83 (1H, m), 1.82-2.16 (6H, m), 2.40 (3H, s), 2.51 (3H, s), 3.04-3.17 (1H, m), 3.28-3.63 (3H, m), 3.85-3.98 (1H, m), 7.47 (1H, d, J=8.6 Hz), 7.74 (1H, d, J=8.6 Hz), 8.02 (1H, s)
  • HPLC retention time: 21.4 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 2.0 cm I.D.×25 cm, mobile phase: hexane−IPA=4:1, flow rate: 5.0 mL/min.)
  • Compound 1-137:
  • 1H NMR (300 MHz) δ 1.65-1.83 (1H, m), 1.82-2.16 (6H, m), 2.40 (3H, s), 2.51 (3H, s), 3.04-3.17 (1H, m), 3.28-3.63 (3H, m), 3.85-3.98 (1H, m), 7.47 (1H, d, J=8.6 Hz), 7.74 (1H, d, J=8.6 Hz), 8.02 (1H, s)
  • HPLC retention time: 32.8 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 2.0 cm I.D.×25 cm, mobile phase: hexane−IPA=4:1, flow rate: 5.0 mL/min.).
  • Table 1 lists the compounds obtained in Example 2.
    • Example 3 Synthesis of {1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl} methanol hydrochloride (1-054)
  • Figure US20050209253A1-20050922-C00269
  • (1) To a solution of 4-bromo-2,6-dimethylaniline (100.0 g) in tetrahydrofuran (400 mL) was added triethylamine (60.7 g) and 2-bromopropionyl bromide (129.5 g) under ice-cooling. The mixture was stirred at room temperature for 1 hour and cooled in an ice-cooling bath. To the reaction mixture was added a sodium hydrogencarbonate aqueous solution and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with water and diethyl ether, and dried to give 2-bromo-N-(4-bromo-2,6-dimethylphenyl)propionamide (151.2 g).
  • m.p. 187-189° C.
    Figure US20050209253A1-20050922-C00270
  • (2) To a suspension of NaH (17.2 g) in tetrahydrofuran (500 mL) was added a solution of malononitrile (28.4 g) in tetrahydrofuran (100 mL) under ice-cooling and the mixture was stirred at room temperature for 1 hour. 2-Bromo-N-(4-bromo-2,6-dimethylphenyl)propionamide (120 g) was added and the mixture was heated at reflux for 1 hour. With ice-cooling, an ammonium chloride aqueous solution was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a solid. The solid was washed with a mixture of diisopropylether and ethyl acetate and filtered, dried to give 2-amino-1-(4-bromo-2,6-dimethylphenyl)-4-methyl-5-oxo-4,5-dihydro-1H-pyrrole-3-carbonitrile (110.1 g).
  • m.p. 175-177° C.
    Figure US20050209253A1-20050922-C00271
  • (3) To a suspension of 2-amino-1-(4-bromo-2,6-dimethylphenyl)-4-methyl-5-oxo-4,5-dihydro-1H-pyrrole-3-carbonitrile (100 g) in acetic acid (100 mL) was added acetic anhydride (38.3 g) and the mixture was heated at reflux for 8 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure, and water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropylether to give 7-(4-bromo-2,6-dimethylphenyl)-4-hydroxy-2,5-dimethyl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one (56.6 g).
  • m.p. 271-273° C.
    Figure US20050209253A1-20050922-C00272
  • (4) To a suspension of 7-(4-bromo-2,6-dimethylphenyl)-4-hydroxy-2,5-dimethyl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one (10.0 g) in phosphoryl chloride (25.7 mL) was added N,N-dimethylaniline (2.6 mL) and the mixture was heated at 120° C. for 6 hours. After cooling to room temperature the mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with a sodium hydrogencarbonate aqueous solution and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a solid. The solid was washed with diisopropylether to afford 7-(4-bromo-2,6-dimethylphenyl)-4-chloro-2,5-dimethyl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one (8.0 g)
  • m.p. 148-150° C.
    Figure US20050209253A1-20050922-C00273
  • (5) A suspension of 7-(4-bromo-2,6-dimethylphenyl)-4-chloro-2,5-dimethyl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one (7.5 g), ethyl isonipecotate (4.7 g), N,N-diisopropylethylamine (3.8 g) in ethanol (35 mL) was heated at reflux for 12 hours. The reaction mixture was stirred at room temperature to afford a solid. The solid was collected by filtration and washed with cold ethanol to give 1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidine-4-carboxylic acid ethyl ester (7.7 g).
  • m.p. 159-161° C.
    Figure US20050209253A1-20050922-C00274
  • (6) To a solution of lithium borohydride (2.61 g) in tetrahydrofuran (60 mL) was added a solution of 1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidine-4-carboxylic acid ethyl ester (6.0 g) in a mixture of tetrahydrofuran (60 mL) and methanol (3 mL) dropwise over 10 minutes under ice-cooling. The reaction mixture was warmed up to room temperature and stirred for 3 hours. After cooling with an ice-bath, 6 M HCl aqueous solution (30 mL) was added and stirred at room temperature for 1 hour. The solution was made to alkaline (pH=9) with 6 M NaOH aqueous solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=1:1) to give {1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}methanol (4.6 g).
  • (7) To a suspension of {1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}methanol (0.71 g) in water (7 mL) was added concentrated HCl aqueous solution (0.15 mL) under ice-cooling. The mixture was stirred at room temperature for 5 minutes, cooled with an ice-bath again, and stirred for 15 minutes in an ice-cooling bath. The precipitate was collected by filtration, washed with water and dried to give the title compound (0.73 g).
    • Example 4 Synthesis of {1-[1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-4-yl}methanol hydrochloride (2-019)
  • Figure US20050209253A1-20050922-C00275
  • (1) To a solution of 2-amino-1-(4-chloro-2,6-dimethylphenyl)-4-methyl-5-oxo-4,5-dihydro-1H-pyrrole-3-carbonitrile (44.1 g), which was obtained in the same method as example 3, in tetrahydrofuran (220 mL) was added isopropenyl methyl ether (46.2 g) and p-toluenesulfonic acid (608 mg). The mixture was heated at reflux for 1 hour. After removing the solvent under reduced pressure, the residue was dissolved in tetrahydrofuran (500 mL) and cooled in an ice-NaCl bath. Lithium diisopropylamide in tetrahydrofuran solution (generated from 2.64M n-butyl lithium in hexane (127 mL), diisopropylamine (40.5 g) and tetrahydrofuran (300 mL)) was added dropwise over 30 minutes, and stirred at room temperature for 1 hour. To the reaction mixture a saturated NH4Cl aqueous solution was added and separated. The aqueous layer was extracted with CHCl3. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=1:1) to give 4-amino-1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (35.8 g) as an amorphous.
  • MS (ES, Pos.): 316 (M+1)+, 318 (M+3)+, 338 (M+Na)+, 340 (M+Na+2)+
    Figure US20050209253A1-20050922-C00276
  • (2) To a suspension of lithium borohydride (11.6 g) in tetrahydrofuran (50 mL) was added a solution of 4-amino-1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (33.7 g) in tetrahydrofuran (100 mL) was added. The mixture was stirred at reflux for 1 hour. After cooling with ice-cooling bath, a 6M HCl aqueous solution was added slowly. The solution was made to alkaline (pH=9) with 4 M NaOH aqueous solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=3:1) to give 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-ylamine (17.9 g) as a solid.
  • m.p. 190-192° C.
    Figure US20050209253A1-20050922-C00277
  • (3) With ice-cooling, to a suspension of 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-ylamine (17.9 g) in a mixure of 1,4-dioxane (45 mL) and water (45 mL) was added dropwise a mixture of concentrated H2SO4 (17.8 mL) and water (90 mL) and then a solution of NaNO2 (6.2 g) in water (62 mL). The mixture was stirred at room temperature for 20 minutes, and heated at 100° C. for 1.5 hours. After cooling in an ice-cooling bath, the reaction mixture was poured into a cold saturated NaHCO3 aqueous solution and extracted with CHCl3. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a solid. The solid was washed with a mixture of ethyl acetate and diisopropylether (1:5) to give 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-ol (14.4 g).
  • m.p. 260° C. (decomp.)
    Figure US20050209253A1-20050922-C00278
  • (4) To a mixture of 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-ol (14.4 g) and triethylamine (9.7 g) in CHCl3 (100 mL) was added trifluoromethansulfonic anhydride (9.7 mL) in an ice-cooling bath. After stirring for 10 miniutes, water was added and extracted with CHCl3. The organic layer was washed with water and brine successively, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude trifluoromethanesulfonic acid 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl ester (20.7 g).
  • A mixture of the crude trifluoromethanesulfonic acid 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl ester (20.5 g), ethyl isonipecotate (74.4 g) and N,N-diisopropylethylamine (12.2 g) was heated at 150-170° C. for 1 hour. To the reaction mixture, water was added and extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=5:1) to give 1-[1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidine-4-carboxylic acid ethyl ester (16.6 g) as a pale yellow solid.
  • m.p. 140-142° C.
    Figure US20050209253A1-20050922-C00279
  • (5) To a suspension of lithium borohydride (4.11 g) in tetrahydrofuran (50 mL) was added a solution of 1-[1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidine-4-carboxylic acid ethyl ester (16.6 g) in a mixture of tertrahydrofuran (80 mL) and methanol (7.7 mL) in an ice-cooling bath. The mixture was stirred at room temperature for 2 hours. After cooling with an ice-cooling bath, water was added and the mixture was poured slowly into a 3M HCl aqueous solution. The solution was made to alkaline (pH=8) with 4 M NaOH aqueous solution to give a solid. The solid was collected by filtration and washed with water and diethylether. The solid was recrystallized from a mixture of ethanol and ethyl acetate to give {1-[1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-4-yl}methanol (9.1 g).
  • (6) In the same method as example 1-(2), the title compound (8.0 g) was obtained from {1-[1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2.3-b]pyridin-4-yl]piperidin-4-yl} methanol (9.1 g).
    • Example 5 Synthesis of carbonic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester ethyl ester (3-001)
  • Figure US20050209253A1-20050922-C00280
  • {1-[7-(4-Bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}methanol (1.15 g) synthesized in the similar manner as example 1 in tetrahydrofuran (25 mL) was stirred, then NaH (60% in paraffin, 0.10 g) was added and the mixture was heated at reflux for 3 hours. After cooling to 0° C., ethyl chloroformate (0.28 g) in a small amount of tetrahydrofuran was added and the reaction mixture was allowed to reach room temperature and evaporated. The residue was purified over a silica gel on a glass filter (eluent: CH2Cl2/CH3CN=95:5 then 90:10) to give the title product (366 mg).
  • Table 3 lists the compound obtained in Example 5 and compounds obtained by the similar procedure as in Example 5.
    • Example 6 Synthesis of decanoic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester (3-009)
  • Figure US20050209253A1-20050922-C00281
  • Under nitrogen atmosphere, {1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl} methanol (1.15 g) synthesized in the similar manner as example 1 in tetrahydrofuran (25 mL) was stirred, then NaH (60% in paraffin, 0.10 g) was added and the mixture was heated at reflux overnight, giving mixture (I). Decanoic acid (0.45 g) in tetrahydrofuran (25 mL) was stirred, then 1,1′-carbonyldiimidazole (0.42 g) was added and the mixture was stirred overnight at room temperature, giving mixture (II). The mixture (II) was added dropwise to the mixture (I) at 0-5° C. and the resulting reaction mixture was allowed to reach room temperature. The solvent was evaporated and the residue was purified over a silica gel on a glass filter (eluent: CH2Cl2/CH3CN=100:0, 95:5 then 90:10) to give the title product (888 mg).
  • Table 3 lists the compound obtained in Example 6 and compounds obtained by the similar procedure as in Example 6.
    • Example 7 Synthesis of eicosa-5,8,11,14-tetraenoic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester (3-020)
  • Figure US20050209253A1-20050922-C00282
  • Under nitrogen atmosphere, to a solution of 1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}methanol (606 mg) in CH2Cl2 (20 ml) was added arachidonic acid (500 mg), 4-dimethylaminopyridine (33 mg) and N,N′-dicyclohexylcarbodiimide (565 mg). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=7:1) to give the title compound (990 mg) as an oil.
  • Table 3 lists the compound obtained in Example 7 and compounds obtained by the similar procedure as in Example 7.
    • Example 8 Synthesis of (S)-2-tert-butoxycarbonylamino-3-(1H-indol-3-yl)-propionic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester (3-014) and (S)-2-amino-3-(1H-indol-3-yl)-propionic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester (3-016)
  • Figure US20050209253A1-20050922-C00283
  • (1) A solution of N-(tert-butoxycarbonyl)-L-tryptophan (510 mg) and 1,1′-carbonyldiimidazole (330 mg) in acetonitrile (10 mL) was stirred at room temperature overnight. The solvent is evaporated and the residue is redissolved in toluene (5 mL). Sequentially {1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}methanol (594 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (40 μL) were added and stirred at room temperature for 2 days. After evaporation of the solvent the residue was extracted with ethylacetate and dilute NaHCO3 solution. After the usual work-up the residue of the extract was purified over silica gel (eluent: CH2Cl2/MeOH=95:5) to give the title product 3-014 (578 mg).
    Figure US20050209253A1-20050922-C00284
  • (2) To a solution of 3-014 (1.16 g) in CH2Cl2 (200 mL) a 6M solution of HCl in isopropanol (2.7 mL) was added and stirred at room temperature for 2 days. After evaporation, the residue is purified by reversed-phase chromatography (BDS RP18, 8 μm particle size, 200 g, ID 5 cm column, eluent: (0.5% NH4Ac/CH3CN: 9:1 (v/v))/CH3CN 85/15 to 1/9 gradient). After partial evaporation of the aqueous fractions a fine precipitate of pure compound is formed and recuperated, yielding the tiltle compound 3-016 (139 mg). The aqueous filtrate was extracted with CH2Cl2 and the organic extract was washed with dilute ammonia. After the usual work-up of the organic extract some more product 3-016 was recuperated (304 mg).
    • Example 9 Synthesis of phosphoric acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester diethyl ester (3-017)
  • Figure US20050209253A1-20050922-C00285
  • Under nitrogen atmosphere, to a solution of {1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}methanol (0.50 g) and 4-dimethylaminopyridine (0.55 g) in CH2Cl2 (50 mL) at 0° C. diethyl chlorophosphate (0.38 g) was added dropwise and the reaction is slowly heated up to room temperature. The reaction mixture is poured on ice-water and extracted with CH2Cl2. After the usual work-up the residue is purified over silica gel on a glass filter (eluent: CH2Cl2/MeOH=98:2) yielding product 3-017 (0.31 g).
    • Example 10 Synthesis of phosphoric acid mono-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl}ester (3-018)
  • Figure US20050209253A1-20050922-C00286
  • {1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}methyl diphenoxyphosphate ester (1.8 g), which was produced in a similar way as in example 9, was dissolved in 50% NaOH (1 mL) and dioxane (50 mL) and stirred at 60° C. for several hours until completion of the hydrolysis. The solution was treated with water (25 mL), acidified with HCl until pH=2 and extracted five times with portions CH2Cl2, using NaCl to improve the phase separation. After the usual work-up the residue is purified over silica gel on a glass filter (eluent: CH2Cl2/MeOH=9:1 to pure MeOH) yielding the title product 3-018 (0.38 g).
    TABLE 1*1
    Figure US20050209253A1-20050922-C00287
    Com. No. Ex. No.
    Figure US20050209253A1-20050922-C00288
         		R6 R7 R8 —Ar melting point (° C.) (solvent for crystallization)
    1-001 1
    Figure US20050209253A1-20050922-C00289
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00290
         		142-144 (hexane)
    1-002 1
    Figure US20050209253A1-20050922-C00291
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00292
         		124-126 (hexane)
    1-003 1
    Figure US20050209253A1-20050922-C00293
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00294
         		amorphous
    1-004 1
    Figure US20050209253A1-20050922-C00295
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00296
         		146-148*2(EtOAc/EtOH)
    1-005 1
    Figure US20050209253A1-20050922-C00297
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00298
         		amorphous
    1-006 1
    Figure US20050209253A1-20050922-C00299
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00300
         		144-146 (hexane)
    1-007 1
    Figure US20050209253A1-20050922-C00301
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00302
         		121-122 (hexane)
    1-008 1
    Figure US20050209253A1-20050922-C00303
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00304
         		141-143*2(EtOAc/EtOH)
    1-009 1
    Figure US20050209253A1-20050922-C00305
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00306
         		134-136*2(EtOAc/EtOH)
    1-010 1
    Figure US20050209253A1-20050922-C00307
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00308
         		157-159*2(EtOAc/EtOH)
    1-011 1
    Figure US20050209253A1-20050922-C00309
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00310
         		amorphous
    1-012 1
    Figure US20050209253A1-20050922-C00311
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00312
         		amorphous
    1-013 1
    Figure US20050209253A1-20050922-C00313
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00314
         		amorphous*3
    1-014 1
    Figure US20050209253A1-20050922-C00315
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00316
         		amorphous*3
    1-015 1
    Figure US20050209253A1-20050922-C00317
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00318
         		amorphous
    1-016 1
    Figure US20050209253A1-20050922-C00319
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00320
         		amorphous
    1-017 1
    Figure US20050209253A1-20050922-C00321
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00322
         		144-146*2*4(EtOAc/EtOH)
    1-018 1
    Figure US20050209253A1-20050922-C00323
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00324
         		131-133*2*4(EtOAc/EtOH)
    1-019 1
    Figure US20050209253A1-20050922-C00325
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00326
         		amorphous
    1-020 1
    Figure US20050209253A1-20050922-C00327
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00328
         		152-154*2*4(EtOAc/EtOH)
    1-021 1
    Figure US20050209253A1-20050922-C00329
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00330
         		145-147*2*4(EtOAc)
    1-022 1
    Figure US20050209253A1-20050922-C00331
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00332
         		amorphous*3
    1-023 1
    Figure US20050209253A1-20050922-C00333
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00334
         		amorphous
    1-024 1
    Figure US20050209253A1-20050922-C00335
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00336
         		amorphous
    1-025 1
    Figure US20050209253A1-20050922-C00337
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00338
         		amorphous
    1-026 1
    Figure US20050209253A1-20050922-C00339
         		CH3 CH2CH3 CH2CH3
    Figure US20050209253A1-20050922-C00340
         		amorphous
    1-027 1
    Figure US20050209253A1-20050922-C00341
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00342
         		amorphous*3
    1-028 1
    Figure US20050209253A1-20050922-C00343
         		CH3 —(CH2)4—
    Figure US20050209253A1-20050922-C00344
         		amorphous
    1-029 1
    Figure US20050209253A1-20050922-C00345
         		CH3 —CH═CH—CH═CH—
    Figure US20050209253A1-20050922-C00346
         		amorphous
    1-030 1
    Figure US20050209253A1-20050922-C00347
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00348
         		amorphous
    1-031 1
    Figure US20050209253A1-20050922-C00349
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00350
         		amorphous
    1-032 1
    Figure US20050209253A1-20050922-C00351
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00352
         		159-161*2(EtOAc/EtOH)
    1-033 1
    Figure US20050209253A1-20050922-C00353
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00354
         		163-164*2(EtOAc/EtOH)
    1-034 1
    Figure US20050209253A1-20050922-C00355
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00356
         		160-162*2(EtOAc/EtOH)
    1-035 1
    Figure US20050209253A1-20050922-C00357
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00358
         		157-159*2(EtOAc/EtOH)
    1-036 1
    Figure US20050209253A1-20050922-C00359
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00360
         		amorphous
    1-037 1
    Figure US20050209253A1-20050922-C00361
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00362
         		amorphous
    1-038 1
    Figure US20050209253A1-20050922-C00363
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00364
         		159-161 (IPE)
    1-039 1
    Figure US20050209253A1-20050922-C00365
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00366
         		amorphous
    1-040 1
    Figure US20050209253A1-20050922-C00367
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00368
         		amorphous
    1-041 1
    Figure US20050209253A1-20050922-C00369
         		CH3 CH2CH3 CH2CH3
    Figure US20050209253A1-20050922-C00370
         		amorphous
    1-042 1
    Figure US20050209253A1-20050922-C00371
         		CH3 —(CH2)4—
    Figure US20050209253A1-20050922-C00372
         		134-136*5
    1-043 1
    Figure US20050209253A1-20050922-C00373
         		CH3 —CH═CH—CH═CH—
    Figure US20050209253A1-20050922-C00374
         		amorphous
    1-044 1
    Figure US20050209253A1-20050922-C00375
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00376
         		amorphous
    1-045 1
    Figure US20050209253A1-20050922-C00377
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00378
         		amorphous
    1-046 1
    Figure US20050209253A1-20050922-C00379
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00380
         		172-174*2(EtOAc/EtOH)
    1-047 1
    Figure US20050209253A1-20050922-C00381
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00382
         		150-152*2(EtOAc/EtOH)
    1-048 1
    Figure US20050209253A1-20050922-C00383
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00384
         		177-179*2(EtOAc/EtOH)
    1-049 1
    Figure US20050209253A1-20050922-C00385
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00386
         		156-158*2(EtOAc/EtOH)
    1-050 1
    Figure US20050209253A1-20050922-C00387
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00388
         		170-172 (hexane)
    1-051 1
    Figure US20050209253A1-20050922-C00389
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00390
         		178-180 (hexane)
    1-052 1
    Figure US20050209253A1-20050922-C00391
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00392
         		157-159 (IPE/hexane)
    1-053 1
    Figure US20050209253A1-20050922-C00393
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00394
         		167-169*2(EtOAc)
    1-054 1
    Figure US20050209253A1-20050922-C00395
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00396
         		173-175*2(EtOH)
    1-055 1
    Figure US20050209253A1-20050922-C00397
         		CH3 —(CH2)4—
    Figure US20050209253A1-20050922-C00398
         		177-179 (IPE)
    1-056 1
    Figure US20050209253A1-20050922-C00399
         		CH3 —CH═CH—CH═CH—
    Figure US20050209253A1-20050922-C00400
         		amorphous
    1-057 1
    Figure US20050209253A1-20050922-C00401
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00402
         		amorphous
    1-058 1
    Figure US20050209253A1-20050922-C00403
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00404
         		166-168*2(EtOAc)
    1-059 1
    Figure US20050209253A1-20050922-C00405
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00406
         		155-157*2(EtOAc)
    1-060 1
    Figure US20050209253A1-20050922-C00407
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00408
         		176-178*2(EtOAc)
    1-061 1
    Figure US20050209253A1-20050922-C00409
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00410
         		164-166*2(EtOAc)
    1-062 1
    Figure US20050209253A1-20050922-C00411
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00412
         		170-172*2(EtOAc)
    1-063 1
    Figure US20050209253A1-20050922-C00413
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00414
         		amorphous*2
    1-064 1
    Figure US20050209253A1-20050922-C00415
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00416
         		164-166*2(EtOAc)
    1-065 1
    Figure US20050209253A1-20050922-C00417
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00418
         		188-190*2(EtOAc)
    1-066 1
    Figure US20050209253A1-20050922-C00419
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00420
         		184-186*2(EtOAc)
    1-067 1
    Figure US20050209253A1-20050922-C00421
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00422
         		179-181*2(EtOAc)
    1-068 1
    Figure US20050209253A1-20050922-C00423
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00424
         		178-180*2(EtOAc)
    1-069 1
    Figure US20050209253A1-20050922-C00425
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00426
         		197-199*2(EtOAc/EtOH)
    1-070 1
    Figure US20050209253A1-20050922-C00427
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00428
         		155-157*2(EtOAc)
    1-071 1
    Figure US20050209253A1-20050922-C00429
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00430
         		167-169*2(EtOAc/EtOH)
    1-072 1
    Figure US20050209253A1-20050922-C00431
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00432
         		220-222 (hexane)
    1-073 1
    Figure US20050209253A1-20050922-C00433
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00434
         		212-214*2(EtOAc)
    1-074 1
    Figure US20050209253A1-20050922-C00435
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00436
         		187-189*2(EtOAc)
    1-075 1
    Figure US20050209253A1-20050922-C00437
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00438
         		180-182*2(hexane)
    1-076 1
    Figure US20050209253A1-20050922-C00439
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00440
         		188-190*2(IPE)
    1-077 1
    Figure US20050209253A1-20050922-C00441
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00442
         		179-181*2(EtOAc/EtOH)
    1-078 1
    Figure US20050209253A1-20050922-C00443
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00444
         		194-196*2(EtOAc/EtOH)
    1-079 1
    Figure US20050209253A1-20050922-C00445
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00446
         		199-201*2(EtOAc/EtOH)
    1-080 1
    Figure US20050209253A1-20050922-C00447
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00448
         		193-195*2(EtOAc/EtOH)
    1-081 1
    Figure US20050209253A1-20050922-C00449
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00450
         		164-166*2(EtOAc/EtOH)
    1-082 1
    Figure US20050209253A1-20050922-C00451
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00452
         		177-179*2(EtOAc/EtOH)
    1-083 1
    Figure US20050209253A1-20050922-C00453
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00454
         		170-172*2(EtOAc/EtOH)
    1-084 1
    Figure US20050209253A1-20050922-C00455
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00456
         		162-164*2(EtOAc)
    1-085 1
    Figure US20050209253A1-20050922-C00457
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00458
         		168-170*2(EtOAc)
    1-086 1
    Figure US20050209253A1-20050922-C00459
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00460
         		187-189*2(EtOAc/EtOH)
    1-087 1
    Figure US20050209253A1-20050922-C00461
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00462
         		183-184 (hexane)
    1-088 1
    Figure US20050209253A1-20050922-C00463
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00464
         		165-167 (hexane)
    1-089 1
    Figure US20050209253A1-20050922-C00465
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00466
         		191-193 (IPA)
    1-090 1
    Figure US20050209253A1-20050922-C00467
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00468
         		189-191*2(THF/EtOAc)
    1-091 1
    Figure US20050209253A1-20050922-C00469
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00470
         		202-204*2(EtOAc/EtOH)
    1-092 1
    Figure US20050209253A1-20050922-C00471
         		CH3 CH2CH3 CH2CH3
    Figure US20050209253A1-20050922-C00472
         		amorphous
    1-093 1
    Figure US20050209253A1-20050922-C00473
         		CH3 —(CH2)4—
    Figure US20050209253A1-20050922-C00474
         		177-179 (IPE)
    1-094 1
    Figure US20050209253A1-20050922-C00475
         		CH3 —CH═CH—CH═CH—
    Figure US20050209253A1-20050922-C00476
         		amorphous
    1-095 1
    Figure US20050209253A1-20050922-C00477
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00478
         		175-177*2(hexane)
    1-096 1
    Figure US20050209253A1-20050922-C00479
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00480
         		174-176*2(EtOAc)
    1-097 1
    Figure US20050209253A1-20050922-C00481
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00482
         		207-209*2(EtOAc/EtOH)
    1-098 1
    Figure US20050209253A1-20050922-C00483
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00484
         		205-207*2(EtOAc/EtOH)
    1-099 1
    Figure US20050209253A1-20050922-C00485
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00486
         		195-197*2(EtOAc/EtOH)
    1-100 1
    Figure US20050209253A1-20050922-C00487
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00488
         		192-194*2(EtOAc/EtOH)
    1-101 1
    Figure US20050209253A1-20050922-C00489
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00490
         		175-177*2(EtOAc)
    1-102 1
    Figure US20050209253A1-20050922-C00491
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00492
         		158-160*2(EtOAc/EtOH)
    1-103 1
    Figure US20050209253A1-20050922-C00493
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00494
         		amorphous
    1-104 1
    Figure US20050209253A1-20050922-C00495
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00496
         		amorphous
    1-105 1
    Figure US20050209253A1-20050922-C00497
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00498
         		amorphous
    1-106 1
    Figure US20050209253A1-20050922-C00499
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00500
         		amorphous
    1-107 1
    Figure US20050209253A1-20050922-C00501
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00502
         		amorphous
    1-108 1
    Figure US20050209253A1-20050922-C00503
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00504
         		206-208 (IPE)
    1-109 1
    Figure US20050209253A1-20050922-C00505
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00506
         		161-163 (IPE)
    1-110 1
    Figure US20050209253A1-20050922-C00507
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00508
         		amorphous
    1-111 1
    Figure US20050209253A1-20050922-C00509
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00510
         		141-143 (IPE)
    1-112 1
    Figure US20050209253A1-20050922-C00511
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00512
         		184-186*2(EtOH)
    1-113 1
    Figure US20050209253A1-20050922-C00513
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00514
         		181-182 (IPE)
    1-114 1
    Figure US20050209253A1-20050922-C00515
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00516
         		amorphous
    1-115 1
    Figure US20050209253A1-20050922-C00517
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00518
         		167-169*2*4(EtOAc)
    1-116 1
    Figure US20050209253A1-20050922-C00519
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00520
         		amorphous*2*4
    1-117 1
    Figure US20050209253A1-20050922-C00521
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00522
         		148-150*2*4(EtOAc)
    1-118 1
    Figure US20050209253A1-20050922-C00523
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00524
         		amorphous*2*4
    1-119 1
    Figure US20050209253A1-20050922-C00525
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00526
         		214-216*2(EtOAc)
    1-120 1
    Figure US20050209253A1-20050922-C00527
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00528
         		153-155*2(EtOH/EtOAc)
    1-121 1
    Figure US20050209253A1-20050922-C00529
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00530
         		214-215*2(EtOAc)
    1-122 1
    Figure US20050209253A1-20050922-C00531
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00532
         		148-150*2(EtOH/EtOAc)
    1-123 1
    Figure US20050209253A1-20050922-C00533
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00534
         		170-172*2(EtOAc)
    1-124 1
    Figure US20050209253A1-20050922-C00535
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00536
         		 91-93*2(EtOH/EtOAc)
    1-125 1
    Figure US20050209253A1-20050922-C00537
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00538
         		amorphous
    1-126 1
    Figure US20050209253A1-20050922-C00539
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00540
         		amorphous
    1-127 1
    Figure US20050209253A1-20050922-C00541
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00542
         		amorphous
    1-128 1
    Figure US20050209253A1-20050922-C00543
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00544
         		amorphous
    1-129 1
    Figure US20050209253A1-20050922-C00545
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00546
         		amorphous
    1-130 1
    Figure US20050209253A1-20050922-C00547
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00548
         		amorphous
    1-131 1
    Figure US20050209253A1-20050922-C00549
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00550
         		amorphous
    1-132 1
    Figure US20050209253A1-20050922-C00551
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00552
         		amorphous*3
    1-133 1
    Figure US20050209253A1-20050922-C00553
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00554
         		amorphous
    1-134 1
    Figure US20050209253A1-20050922-C00555
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00556
         		amorphous*4
    1-135 1
    Figure US20050209253A1-20050922-C00557
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00558
         		amorphous*4
    1-136 1
    Figure US20050209253A1-20050922-C00559
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00560
         		amorphous*4
    1-137 1
    Figure US20050209253A1-20050922-C00561
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00562
         		amorphous*4
    1-138 1
    Figure US20050209253A1-20050922-C00563
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00564
         		amorphous
    1-139 1
    Figure US20050209253A1-20050922-C00565
         		CH3 —(CH2)4—
    Figure US20050209253A1-20050922-C00566
         		173-175*5
    1-140 1
    Figure US20050209253A1-20050922-C00567
         		CH3 —CH═CH—CH═CH—
    Figure US20050209253A1-20050922-C00568
         		amorphous
    1-141 1
    Figure US20050209253A1-20050922-C00569
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00570
         		amorphous
    1-142 1
    Figure US20050209253A1-20050922-C00571
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00572
         		amorphous
    1-143 1
    Figure US20050209253A1-20050922-C00573
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00574
         		amorphous
    1-144 1
    Figure US20050209253A1-20050922-C00575
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00576
         		amorphous
    1-145 1
    Figure US20050209253A1-20050922-C00577
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00578
         		147-149 (hexane)
    1-146 1
    Figure US20050209253A1-20050922-C00579
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00580
         		amorphous
    1-147 1
    Figure US20050209253A1-20050922-C00581
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00582
         		amorphous
    1-148 1
    Figure US20050209253A1-20050922-C00583
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00584
         		195-197*2(EtOAc)
    1-149 1
    Figure US20050209253A1-20050922-C00585
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00586
         		amorphous*2
    1-150 1
    Figure US20050209253A1-20050922-C00587
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00588
         		164-166*2(EtOAc)
    1-151 1
    Figure US20050209253A1-20050922-C00589
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00590
         		168-170*2(EtOAc)
    1-152 1
    Figure US20050209253A1-20050922-C00591
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00592
         		145-147*2(EtOAc/IPE)
    1-153 1
    Figure US20050209253A1-20050922-C00593
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00594
         		182-184 (hexane)
    1-154 1
    Figure US20050209253A1-20050922-C00595
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00596
         		166-168*2(IPE)
    1-155 1
    Figure US20050209253A1-20050922-C00597
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00598
         		145-146*2(EtOAc)
    1-156 1
    Figure US20050209253A1-20050922-C00599
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00600
         		164-166*2(EtOAc/IPE)
    1-157 1
    Figure US20050209253A1-20050922-C00601
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00602
         		174-176*2(EtOAc/IPE)
    1-158 1
    Figure US20050209253A1-20050922-C00603
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00604
         		194-196*2(EtOAc)
    1-159 1
    Figure US20050209253A1-20050922-C00605
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00606
         		199-201*2(EtOAc)
    1-160 1
    Figure US20050209253A1-20050922-C00607
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00608
         		162-164*2(EtOAc)
    1-161 1
    Figure US20050209253A1-20050922-C00609
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00610
         		170-172*2(EtOAc)
    1-162 1
    Figure US20050209253A1-20050922-C00611
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00612
         		164-166*2(EtOAc)
    1-163 1
    Figure US20050209253A1-20050922-C00613
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00614
         		152-154*2(EtOAc)
    1-164 1
    Figure US20050209253A1-20050922-C00615
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00616
         		158-160*2(EtOAc)
    1-165 1
    Figure US20050209253A1-20050922-C00617
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00618
         		139-141*2(EtOAc/EtOH)
    1-166 1
    Figure US20050209253A1-20050922-C00619
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00620
         		140-141*2(EtOAc)
    1-167 1
    Figure US20050209253A1-20050922-C00621
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00622
         		137-139*2(EtOAc)
    1-168 1
    Figure US20050209253A1-20050922-C00623
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00624
         		amorphous*2
    1-169 1
    Figure US20050209253A1-20050922-C00625
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00626
         		219-221 (IPE)
    1-170 1
    Figure US20050209253A1-20050922-C00627
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00628
         		179-181 (IPE)
    1-171 1
    Figure US20050209253A1-20050922-C00629
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00630
         		amorphous
    1-172 1
    Figure US20050209253A1-20050922-C00631
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00632
         		269-270 (IPE)
    1-173 1
    Figure US20050209253A1-20050922-C00633
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00634
         		236-238 (IPE)
    1-174 1
    Figure US20050209253A1-20050922-C00635
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00636
         		amorphous
    1-175 1
    Figure US20050209253A1-20050922-C00637
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00638
         		196-198 (IPE)
    1-176 1
    Figure US20050209253A1-20050922-C00639
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00640
         		153-155*2(EtOAc)
    1-177 1
    Figure US20050209253A1-20050922-C00641
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00642
         		205-207*2(EtOAc/EtOH)
    1-178 1
    Figure US20050209253A1-20050922-C00643
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00644
         		182-184*2(EtOAc)
    1-179 1
    Figure US20050209253A1-20050922-C00645
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00646
         		amorphous*2
    1-180 1
    Figure US20050209253A1-20050922-C00647
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00648
         		215-217 (hexane)
    1-181 1
    Figure US20050209253A1-20050922-C00649
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00650
         		150-152*2(EtOAc/EtOH)
    1-182 1
    Figure US20050209253A1-20050922-C00651
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00652
         		121-123*2(EtOAc/EtOH)
    1-183 1
    Figure US20050209253A1-20050922-C00653
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00654
         		125-127*2(EtOAc)
    1-184 1
    Figure US20050209253A1-20050922-C00655
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00656
         		161-163*2(EtOAc/EtOH)
    1-185 1
    Figure US20050209253A1-20050922-C00657
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00658
         		149-151*2(EtOAc/EtOH)
    1-186 1
    Figure US20050209253A1-20050922-C00659
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00660
         		152-154*2(EtOAc/EtOH)
    1-187 1
    Figure US20050209253A1-20050922-C00661
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00662
         		170-172*2(EtOAc/EtOH)
    1-188 1
    Figure US20050209253A1-20050922-C00663
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00664
         		158-160*2(EtOAc)
    1-189 1
    Figure US20050209253A1-20050922-C00665
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00666
         		173-175*2(EtOAc/EtOH)
    1-190 1
    Figure US20050209253A1-20050922-C00667
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00668
         		155-157*2(EtOAc/EtOH)
    1-191 1
    Figure US20050209253A1-20050922-C00669
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00670
         		146-148*2(EtOAc/EtOH)
    1-192 1
    Figure US20050209253A1-20050922-C00671
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00672
         		150-152*2(EtOAc/EtOH)
    1-193 1
    Figure US20050209253A1-20050922-C00673
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00674
         		158-160*2(EtOAc/EtOH)
    1-194 1
    Figure US20050209253A1-20050922-C00675
         		CH3 CH2CH3 CH2CH3
    Figure US20050209253A1-20050922-C00676
         		amorphous
    1-195 1
    Figure US20050209253A1-20050922-C00677
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00678
         		177-179*2(EtOAc/EtOH)
    1-196 1
    Figure US20050209253A1-20050922-C00679
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00680
         		154-156*2(EtOAc/EtOH)
    1-197 1
    Figure US20050209253A1-20050922-C00681
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00682
         		153-155*2(EtOAc)
    1-198 1
    Figure US20050209253A1-20050922-C00683
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00684
         		128-130*2(EtOAc/EtOH)
    1-199 1
    Figure US20050209253A1-20050922-C00685
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00686
         		140-142*2(EtOAc)
    1-200 1
    Figure US20050209253A1-20050922-C00687
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00688
         		149-151*2(EtOAc/EtOH)
    1-201 1
    Figure US20050209253A1-20050922-C00689
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00690
         		168-170*2(EtOAc/EtOH)
    1-202 1
    Figure US20050209253A1-20050922-C00691
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00692
         		152-154*2(EtOAc/EtOH)
    1-203 1
    Figure US20050209253A1-20050922-C00693
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00694
         		153-155*2(EtOAc/EtOH)
    1-204 1
    Figure US20050209253A1-20050922-C00695
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00696
         		157-159*2(EtOAc/EtOH)
    1-205 1
    Figure US20050209253A1-20050922-C00697
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00698
         		179-181*2(EtOAc/EtOH)
    1-206 1
    Figure US20050209253A1-20050922-C00699
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00700
         		170-172*2(EtOAc/EtOH)
    1-207 1
    Figure US20050209253A1-20050922-C00701
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00702
         		184-186*2(EtOAc)
    1-208 1
    Figure US20050209253A1-20050922-C00703
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00704
         		172-174*2(EtOAc/EtOH)
    1-209 1
    Figure US20050209253A1-20050922-C00705
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00706
         		amorphous
    1-210 1
    Figure US20050209253A1-20050922-C00707
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00708
         		amorphous
    1-211 1
    Figure US20050209253A1-20050922-C00709
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00710
         		193-195*2(EtOAc)
    1-212 1
    Figure US20050209253A1-20050922-C00711
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00712
         		164-166*2(EtOAc/EtOH)
    1-213 1
    Figure US20050209253A1-20050922-C00713
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00714
         		163-165 (IPE)
    1-214 1
    Figure US20050209253A1-20050922-C00715
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00716
         		182-184 (IPE)
    1-215 1
    Figure US20050209253A1-20050922-C00717
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00718
         		180-182 (EtOAc/EtOH)
    1-216 1
    Figure US20050209253A1-20050922-C00719
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00720
         		153-155 (IPE)
    1-217 1
    Figure US20050209253A1-20050922-C00721
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00722
         		177-179*2(EtOAc)
    1-218 1
    Figure US20050209253A1-20050922-C00723
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00724
         		162-164*2(EtOAc/EtOH)
    1-219 1
    Figure US20050209253A1-20050922-C00725
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00726
         		151-153*2(EtOAc/EtOH)
    1-220 1
    Figure US20050209253A1-20050922-C00727
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00728
         		138-140*2(EtOAc/EtOH)
    1-221 1
    Figure US20050209253A1-20050922-C00729
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00730
         		164-166*2(EtOAc/EtOH)
    1-222 1
    Figure US20050209253A1-20050922-C00731
         		CH3 CH2CH3 CH2CH3
    Figure US20050209253A1-20050922-C00732
         		amorphous
    1-223 1
    Figure US20050209253A1-20050922-C00733
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00734
         		129-131*2(EtOAc/IPE)
    1-224 1
    Figure US20050209253A1-20050922-C00735
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00736
         		138-140*2(EtOAc/EtOH)
    1-225 1
    Figure US20050209253A1-20050922-C00737
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00738
         		131-133*2(EtOAc)
    1-226 1
    Figure US20050209253A1-20050922-C00739
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00740
         		205-207*2(EtOAc)
    1-227 1
    Figure US20050209253A1-20050922-C00741
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00742
         		180-182*2(EtOAc)
    1-228 1
    Figure US20050209253A1-20050922-C00743
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00744
         		165-167*2(EtOAc/EtOH)
    1-229 1
    Figure US20050209253A1-20050922-C00745
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00746
         		185-187*2(IPE)
    1-230 1
    Figure US20050209253A1-20050922-C00747
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00748
         		130-132*2(EtOAc/EtOH)
    1-231 1
    Figure US20050209253A1-20050922-C00749
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00750
         		131-133*2(EtOH)
    1-232 1
    Figure US20050209253A1-20050922-C00751
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00752
         		146-148*2(EtOAc/EtOH)
    1-233 1
    Figure US20050209253A1-20050922-C00753
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00754
         		160-162*2(EtOAc/EtOH)
    1-234 1
    Figure US20050209253A1-20050922-C00755
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00756
         		193-195*2(EtOAc/EtOH)
    1-235 1
    Figure US20050209253A1-20050922-C00757
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00758
         		190-192*2(EtOAc/EtOH)
    1-236 1
    Figure US20050209253A1-20050922-C00759
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00760
         		180-182*2(EtOAc/EtOH)
    1-237 1
    Figure US20050209253A1-20050922-C00761
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00762
         		159-161*2(EtOAc/EtOH)
    1-238 1
    Figure US20050209253A1-20050922-C00763
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00764
         		amorphous*4
    1-239 1
    Figure US20050209253A1-20050922-C00765
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00766
         		amorphous*4
    1-240 1
    Figure US20050209253A1-20050922-C00767
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00768
         		amorphous*4
    1-241 1
    Figure US20050209253A1-20050922-C00769
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00770
         		amorphous*4
    1-242 1
    Figure US20050209253A1-20050922-C00771
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00772
         		185-187*2(EtOH)
    1-243 1
    Figure US20050209253A1-20050922-C00773
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00774
         		186-188*2(EtOAc/EtOH)
    1-244 1
    Figure US20050209253A1-20050922-C00775
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00776
         		174-176*2(EtOAc/EtOH)
    1-245 1
    Figure US20050209253A1-20050922-C00777
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00778
         		165-167*2(EtOAc/EtOH)
    1-246 1
    Figure US20050209253A1-20050922-C00779
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00780
         		172-174*2(EtOAc/EtOH)
    1-247 1
    Figure US20050209253A1-20050922-C00781
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00782
         		155-157*2(EtOAc/EtOH)
    1-248 1
    Figure US20050209253A1-20050922-C00783
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00784
         		139-141*2(EtOAc/EtOH)
    1-249 1
    Figure US20050209253A1-20050922-C00785
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00786
         		176-178*2(EtOAc/IPE)
    1-250 1
    Figure US20050209253A1-20050922-C00787
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00788
         		147-149*2(EtOAc)
    1-251 1
    Figure US20050209253A1-20050922-C00789
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00790
         		170-172*2(EtOAc)
    1-252 1
    Figure US20050209253A1-20050922-C00791
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00792
         		193-195 (EtOAc/IPE)
    1-253 1
    Figure US20050209253A1-20050922-C00793
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00794
         		200-202 (IPE)
    1-254 1
    Figure US20050209253A1-20050922-C00795
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00796
         		155-157*2(EtOAc/EtOH)
    1-255 1
    Figure US20050209253A1-20050922-C00797
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00798
         		222-224 (IPE)
    1-256 1
    Figure US20050209253A1-20050922-C00799
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00800
         		193-195 (IPE)
    1-257 1
    Figure US20050209253A1-20050922-C00801
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00802
         		199-201*2(EtOAc/EtOH)
    1-258 1
    Figure US20050209253A1-20050922-C00803
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00804
         		166-168*2(EtOAc/EtOH)
    1-259 1
    Figure US20050209253A1-20050922-C00805
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00806
         		165-167*2(EtOAc/EtOH)
    1-260 1
    Figure US20050209253A1-20050922-C00807
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00808
         		167-169*2(EtOAc)
    1-261 1
    Figure US20050209253A1-20050922-C00809
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00810
         		187-189*2(EtOAc/EtOH)
    1-262 1
    Figure US20050209253A1-20050922-C00811
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00812
         		185-187*2(EtOAc/IPE)
    1-263 1
    Figure US20050209253A1-20050922-C00813
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00814
         		141-143*2(EtOAc)
    1-264 1
    Figure US20050209253A1-20050922-C00815
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00816
         		179-181 (IPE)
    1-265 1
    Figure US20050209253A1-20050922-C00817
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00818
         		218-220*2(EtOAc/EtOH)
    1-266 1
    Figure US20050209253A1-20050922-C00819
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00820
         		166-168*2(EtOAc/EtOH)
    1-267 1
    Figure US20050209253A1-20050922-C00821
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00822
         		amorphous*2
    1-268 1
    Figure US20050209253A1-20050922-C00823
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00824
         		158-160*2(EtOAc/EtOH)
    1-269 1
    Figure US20050209253A1-20050922-C00825
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00826
         		160-162*2(EtOAc/EtOH)
    1-270 1
    Figure US20050209253A1-20050922-C00827
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00828
         		162-164 (EtOAc/IPE)
    1-271 1
    Figure US20050209253A1-20050922-C00829
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00830
         		133-136*2(EtOAc/EtOH)
    1-272 1
    Figure US20050209253A1-20050922-C00831
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00832
         		229-231 (CH3CN)
    1-273 1
    Figure US20050209253A1-20050922-C00833
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00834
         		208-210 (CH3CN)
    1-274 1
    Figure US20050209253A1-20050922-C00835
         		CH3 CH3 OH
    Figure US20050209253A1-20050922-C00836
         		196-198 (EtOH)
    1-275 1
    Figure US20050209253A1-20050922-C00837
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00838
         		129-131*2(EtOAc)
    1-276 1
    Figure US20050209253A1-20050922-C00839
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00840
         		166-168*2*4(EtOAc/EtOH)
    1-277 1
    Figure US20050209253A1-20050922-C00841
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00842
         		131-133*2*4(EtOAc/EtOH)
    1-278 1
    Figure US20050209253A1-20050922-C00843
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00844
         		158-160*2*4(EtOAc/EtOH)
    1-279 1
    Figure US20050209253A1-20050922-C00845
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00846
         		129-131*2*4(EtOAc/EtOH)
    1-280 1
    Figure US20050209253A1-20050922-C00847
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00848
         		144-146*2*4(EtOAc/EtOH)
    1-281 1
    Figure US20050209253A1-20050922-C00849
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00850
         		170-173*2*4(EtOAc/EtOH)
    1-282 1
    Figure US20050209253A1-20050922-C00851
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00852
         		152-155*2*4(EtOAc/EtOH)
    1-283 1
    Figure US20050209253A1-20050922-C00853
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00854
         		184-185*2*4(EtOAc/EtOH)
    1-284 1
    Figure US20050209253A1-20050922-C00855
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00856
         		122-124*2*4(EtOAc/EtOH)
    1-285 1
    Figure US20050209253A1-20050922-C00857
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00858
         		150-152*2(EtOAc/EtOH)
    1-286 1
    Figure US20050209253A1-20050922-C00859
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00860
         		165-167*2(EtOAc/EtOH)
    1-287 1
    Figure US20050209253A1-20050922-C00861
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00862
         		182-184*2(EtOAc/EtOH)
    1-288 1
    Figure US20050209253A1-20050922-C00863
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00864
         		172-174*2(EtOAc/EtOH)
    1-289 1
    Figure US20050209253A1-20050922-C00865
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00866
         		162-165*2(EtOAc/EtOH)
    1-290 1
    Figure US20050209253A1-20050922-C00867
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00868
         		149-151*2(EtOAc/EtOH)
    1-291 1
    Figure US20050209253A1-20050922-C00869
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00870
         		232-234*2(EtOAc/EtOH)
    1-292 1
    Figure US20050209253A1-20050922-C00871
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00872
         		164-166*2(EtOAc/EtOH)
    1-293 1
    Figure US20050209253A1-20050922-C00873
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00874
         		192-194*2(EtOAc/EtOH)
    1-294 1
    Figure US20050209253A1-20050922-C00875
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00876
         		153-155*2(EtOAc/EtOH)
    1-295 1
    Figure US20050209253A1-20050922-C00877
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00878
         		162-164*2(EtOAc)
    1-296 1
    Figure US20050209253A1-20050922-C00879
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00880
         		204-206*2(EtOAc/EtOH)
    1-297 1
    Figure US20050209253A1-20050922-C00881
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00882
         		145-147 (EtOAc/IPE)
    1-298 1
    Figure US20050209253A1-20050922-C00883
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00884
         		195-196 (EtOAc/IPE)
    1-299 1
    Figure US20050209253A1-20050922-C00885
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00886
         		202-203 (EtOAc/IPE)
    1-300 1
    Figure US20050209253A1-20050922-C00887
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00888
         		202-203 (EtOAc/IPE)
    1-301 1
    Figure US20050209253A1-20050922-C00889
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00890
         		181-183 (EtOAc/IPE)
    1-302 1
    Figure US20050209253A1-20050922-C00891
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00892
         		203-205*4(IPE)
    1-303 1
    Figure US20050209253A1-20050922-C00893
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00894
         		156-158*4(IPE)
    1-304 1
    Figure US20050209253A1-20050922-C00895
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00896
         		212-213*4(IPE)
    1-305 1
    Figure US20050209253A1-20050922-C00897
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00898
         		164-166*4(IPE)
    1-306 1
    Figure US20050209253A1-20050922-C00899
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00900
         		188-190 (IPE)*4
    1-307 1
    Figure US20050209253A1-20050922-C00901
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00902
         		191-192 (IPE)*4
    1-308 1
    Figure US20050209253A1-20050922-C00903
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00904
         		188-189 (IPE)*4
    1-309 1
    Figure US20050209253A1-20050922-C00905
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00906
         		190-191 (IPE)*4
    1-310 1
    Figure US20050209253A1-20050922-C00907
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00908
         		200-202 (IPE)
    1-311 1
    Figure US20050209253A1-20050922-C00909
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00910
         		131-133 (IPE)
    1-312 1
    Figure US20050209253A1-20050922-C00911
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00912
         		223-224 (IPE)
    1-313 1
    Figure US20050209253A1-20050922-C00913
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00914
         		184-186 (IPE)
    1-314 1
    Figure US20050209253A1-20050922-C00915
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00916
         		215-216 (IPE)
    1-315 1
    Figure US20050209253A1-20050922-C00917
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00918
         		214-215 (IPE)
    1-316 1
    Figure US20050209253A1-20050922-C00919
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00920
         		amorphous
    1-317 1
    Figure US20050209253A1-20050922-C00921
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00922
         		151-153 (EtOAc)
    1-318 1
    Figure US20050209253A1-20050922-C00923
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00924
         		149-151(IPE)
    1-319 1
    Figure US20050209253A1-20050922-C00925
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00926
         		240-242*2(EtOAc/EtOH)
    1-320 1
    Figure US20050209253A1-20050922-C00927
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00928
         		216-218*2(EtOAc/EtOH)
    1-321 1
    Figure US20050209253A1-20050922-C00929
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00930
         		180-183*2(EtOAc/EtOH)
    1-322 1
    Figure US20050209253A1-20050922-C00931
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00932
         		214-216*2(EtOAc/EtOH)
    1-323 1
    Figure US20050209253A1-20050922-C00933
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00934
         		198-200*2(EtOAc/EtOH)
    1-324 1
    Figure US20050209253A1-20050922-C00935
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00936
         		291-293*2(EtOAc/EtOH)
    1-325 1
    Figure US20050209253A1-20050922-C00937
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00938
         		amorphous
    1-326 1
    Figure US20050209253A1-20050922-C00939
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00940
         		183-186*2(EtOAc/EtOH)
    1-327 1
    Figure US20050209253A1-20050922-C00941
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00942
         		154-156*2(EtOAc/EtOH)
    1-328 1
    Figure US20050209253A1-20050922-C00943
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00944
         		192-194*2(No solvent)
    1-329 1
    Figure US20050209253A1-20050922-C00945
         		CH3 H H
    Figure US20050209253A1-20050922-C00946
         		156-158*2*5
    1-330 1
    Figure US20050209253A1-20050922-C00947
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00948
         		159-161*2(IPE)
    1-331 1
    Figure US20050209253A1-20050922-C00949
         		CH3 CH3 OH
    Figure US20050209253A1-20050922-C00950
         		242-244*5
    1-332 1
    Figure US20050209253A1-20050922-C00951
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00952
         		217-219*2(EtOAc/EtOH)
    1-333 1
    Figure US20050209253A1-20050922-C00953
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00954
         		204-206*2(EtOAc/EtOH)
    1-334 1
    Figure US20050209253A1-20050922-C00955
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00956
         		143-145*2(EtOAc/EtOH)
    1-335 1
    Figure US20050209253A1-20050922-C00957
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00958
         		172-174*2(EtOAc/EtOH)
    1-336 1
    Figure US20050209253A1-20050922-C00959
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00960
         		168-170 (IPE/hexane)
    1-337 1
    Figure US20050209253A1-20050922-C00961
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00962
         		164-166 (IPE)
    1-338 1
    Figure US20050209253A1-20050922-C00963
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00964
         		amorphous
    1-339 1
    Figure US20050209253A1-20050922-C00965
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00966
         		amorphous
    1-340 1
    Figure US20050209253A1-20050922-C00967
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00968
         		148-150 (IPE)
    1-341 1
    Figure US20050209253A1-20050922-C00969
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00970
         		183-185 (IPE)
    1-342 1
    Figure US20050209253A1-20050922-C00971
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00972
         		221-223 (EtOAc)
    1-343 1
    Figure US20050209253A1-20050922-C00973
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00974
         		205-206 (EtOAc)
    1-344 1
    Figure US20050209253A1-20050922-C00975
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00976
         		203-204 (EtOAc)
    1-345 1
    Figure US20050209253A1-20050922-C00977
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00978
         		196-198 (EtOAc)
    1-346 1
    Figure US20050209253A1-20050922-C00979
         		CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00980
         		234-236 (EtOAc)
    1-347 1
    Figure US20050209253A1-20050922-C00981
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00982
         		202-236 (EtOAc)
    1-348 1
    Figure US20050209253A1-20050922-C00983
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00984
         		187-188 (EtOAc)
    1-349 1
    Figure US20050209253A1-20050922-C00985
         		CH3 CH3 H
    Figure US20050209253A1-20050922-C00986
         		200-201 (EtOAc)

    *1: Com. No. = compound number, Ex. No. = example number, solvent for crystallization; EtOAc = ethyl acetate, EtOH = ethanol, IPE = diisopropylether, THF = tetrahydrofuran, IPA = isopropyl alcohol, ACE = acetone, CH3CN = acetonitrile
  • Analytical data of non-crystal compounds, diastereoisomers and optically active compounds are described below.
  • 1-003:
  • MS (ES, Pos.): 589 (M+1)+, 591 (M+3)+, 593 (M+5)+, 611 (M+Na)+, 613 (M+Na+2)+, 615 (M+Na+4)+; HPLC retention time: 4.84 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-005:
  • MS (ES, Pos.): 457 (M+1)+, 459 (M+3)+, 479 (M+Na)+, 481 (M+Na+2)+; HPLC retention time: 9.47 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-011:
  • MS (ES, Pos.): 393 (M+1)+, 415 (M+Na)+; HPLC retention time: 4.16 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-012:
  • MS (ES, Pos.): 379 (M+1)+, 401 (M+Na)+; HPLC retention time: 3.8 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-013:
  • MS (ES, Pos.): 523 (M+1)+, 525 (M+3)+, 527 (M+5)+, 545 (M+Na)+, 547 (M+Na+2)+, 549 (M+Na+4)+; HPLC retention time: 3.14 and 3.27 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-014:
  • MS (ES, Pos.): 539 (M+1)+, 541 (M+3)+, 543 (M+5)+, 561 (M+Na)+, 563 (M+Na+2)+, 565 (M+Na+4)+; HPLC retention time: 3.57 and 3.69 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-015:
  • MS (ES, Pos.): 575 (M+1)+, 577 (M+3)+, 579 (M+5)+; HPLC retention time: 4.05 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-016:
  • MS (ES, Pos.): 457 (M+1)+, 459 (M+3)+, 479 (M+Na)+, 481 (M+Na+2)+; HPLC retention time: 4.60 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-017 (the Enantiomer of 1-018):
  • HPLC retention time: 10.0 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=20:1, flow rate: 1.0 mL/min.)
  • 1-018 (the Enantiomer of 1-017):
  • HPLC retention time: 11.4 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=20:1, flow rate: 1.0 mL/min.)
  • 1-019:
  • MS (ES, Pos.): 443 (M+1)+, 466 (M+Na)+; HPLC retention time: 4.27 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-020 (the Enantiomer of 1-021):
  • HPLC retention time: 9.1 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=20:1, flow rate: 1.0 mL/min.)
  • 1-021 (the Enantiomer of 1-020):
  • HPLC retention time: 11.0 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=20:1, flow rate: 1.0 mL/min.)
  • 1-022:
  • MS (ES, Pos.): 439 (M+1)+, 461 (M+Na)+; HPLC retention time: 4.27 and 4.56 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-023:
  • MS (ES, Pos.): 425 (M+1)+, 447 (M+Na)+; HPLC retention time: 4.16 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-024:
  • MS (ES, Pos.): 497 (M+1)+, 499 (M+3)+, 519 (M+Na)+, 521 (M+Na+2)+; HPLC retention time: 3.72 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-025:
  • MS (ES, Pos.): 483 (M+1)+, 485 (M+3)+, 505 (M+Na)+, 507 (M+Na+2)+; HPLC retention time: 3.66 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-026:
  • MS (ES, Pos.): 421 (M+1)+; HPLC retention time: 5.20 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-027:
  • MS (ES, Pos.): 409 (M+1)+, 431 (M+Na)+; HPLC retention time: 2.70 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 m/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-028:
  • MS (ES, Pos.): 419 (M+1)+; HPLC retention time: 5.45 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-029:
  • MS (ES, Pos.): 415 (M+1)+; HPLC retention time: 5.27 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-030:
  • MS (ES, Pos.): 485 (M+1)+, 487 (M+3)+, 507 (M+Na)+, 509 (M+Na+2)+; HPLC retention time: 8.57 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-031:
  • MS (ES, Pos.): 471 (M+1)+, 473 (M+3)+, 493 (M+Na)+, 495 (M+Na+2)+; HPLC retention time: 7.71 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-036:
  • MS (ES, Pos.): 407 (M+1)+, 429 (M+Na)+; HPLC retention time: 4.32 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 m/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-037:
  • MS (ES, Pos.): 415 (M+Na)+; HPLC retention time: 3.98 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-039:
  • MS (ES, Pos.): 471 (M+1)+, 473 (M+3)+, 493 (M+Na)+, 495 (M+Na+2)+; HPLC retention time: 4.91 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-040:
  • MS (ES, Pos.): 479 (M+Na)+, 481 (M+Na+2)+; HPLC retention time: 4.46 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-041:
  • MS (ES, Pos.): 435 (M+1)+; HPLC retention time: 5.56 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-043:
  • MS (ES, Pos.): 429 (M+1)+; HPLC retention time: 5.47 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-044:
  • MS (ES, Pos.): 499 (M+1)+, 501 (M+3)+; HPLC retention time: 6.66 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-045:
  • MS (ES, Pos.): 485 (M+1)+, 487 (M+3)+, 507 (M+Na)+, 509 (M+Na+2)+; HPLC retention time: 6.89 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-056:
  • MS (ES, Pos.): 415 (M+1)+; HPLC retention time: 4.45 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-057:
  • MS (ES, Pos.): 485 (M+1)+, 487 (M+3)+; HPLC retention time: 7.54 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-063:
  • MS (ES, Pos.): 571 (M+Na)+, 573 (M+Na+2)+, 575 (M+Na+4)+; HPLC retention time: 5.20 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-092:
  • MS (ES, Pos.): 449 (M+1)+; HPLC retention time: 6.24 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-094:
  • MS (ES, Pos.): 443 (M+1)+; HPLC retention time: 6.22 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-103:
  • MS (ES, Pos.): 589 (M+1)+, 591 (M+3)+, 593 (M+5), 611 (M+Na)+, 613 (M+Na+2)+, 615 (M+Na+4)+; HPLC retention time: 5.01 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-104:
  • MS (ES, Pos.): 471 (M+1)+, 473 (M+3)+, 493 (M+Na)+, 495 (M+Na+2)+; HPLC retention time: 6.69 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-105:
  • MS (ES, Pos.): 457 (M+1)+, 459 (M+3)+, 479 (M+Na)+, 481 (M+Na+2)+; HPLC retention time: 6.01 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-106:
  • MS (ES, Pos.): 499 (M+1)+, 501 (M+3)+, 521 (M+Na)+, 523 (M+Na+2)+; HPLC retention time: 8.06 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-107:
  • MS (ES, Pos.): 485 (M+1)+, 487 (M+3)+, 507 (M+Na)+, 509 (M+Na+2)+; HPLC retention time: 10.24 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-110:
  • MS (ES, Pos.): 501 (M+1)+, 503 (M+3)+, 523 (M+Na)+, 525 (M+Na+2)+; HPLC retention time: 4.61 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-114:
  • MS (ES, Pos.): 613 (M+Na)+, 615 (M+Na+2)+, 617 (M+Na+4)+; HPLC retention time: 2.57 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-115:
  • HPLC retention time: 10.6 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=20:1, flow rate: 1.0 mL/min.)
  • 1-116:
  • MS (ES, Pos.): 451 (M+Na)+, 453 (M+Na+2)+; HPLC retention time: 11.5 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=20:1, flow rate: 1.0 mL/min.)
  • 1-117:
  • HPLC retention time: 9.3 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=20:1, flow rate: 1.0 mL/min.)
  • 1-118:
  • MS (ES, Pos.): 429 (M+1)+, 431 (M+3)+; HPLC retention time: 12.1 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=20:1, flow rate: 1.0 mL/min.)
  • 1-125:
  • MS (ES, Pos.): 388 (M+1)+, 410 (M+Na)+; HPLC retention time: 4.20 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-126:
  • MS (ES, Pos.): 396 (M+Na)+; HPLC retention time: 4.40 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-127 (a Diastereoisomer of 1-128):
  • Rf value 0.55 (developing solvent: hexane/EtOAc=1:1, TLC plate Silica gel 60 F254 (Merck)); 1H NMR (300 MHz, CDCl3) δ 1.64-1.82 (1H, m), 1.83-2.03 (2H, m), 2.05-2.18 (1H, m), 2.34 (3H, s), 2.46 (3H, m), 2.53 (3H, s), 2.99-3.12 (1H, m), 3.31-3.70 (3H, m), 3.90-4.02 (1H, m), 6.63 (1H, s), 7.30 (1H, d, J=2.0 Hz), 7.62 (1H, d, J=2.0 Hz); MS (ES, Pos.): 556 (M+Na)+, 558 (M+Na+2), 560 (M+Na+4)+
  • 1-128 (a Diastereoisomer of 1-127):
  • Rf value 0.48 (developing solvent: hexane/EtOAc=1:1, TLC plate Silica gel 60 F 254 (Merck)); 1H NMR (300 MHz, CDCl3) δ 1.62-1.81 (1H, m), 1.89-2.03 (2H, m), 2.05-2.19 (1H, m), 2.35 (3H, s), 2.46 (3H, d, J=1.2 Hz), 2.53 (3H, s), 3.01-3.13 (1H, m), 3.34-3.70 (3H, m), 3.91-4.02 (1H, m), 6.63 (1H, s), 7.30 (1H, d, J=2.0 Hz), 7.62 (1H, d, J=2.0 Hz); MS (ES, Pos.): 534 (M+1)+, 536 (M+3)+, 538 (M+5)+, 556 (M+Na)+, 558 (M+Na+2), 560 (M+Na+4)+
  • 1-129:
  • MS (ES, Pos.): 570 (M+1)+, 572 (M+3)+, 574 (M+5)+; HPLC retention time: 4.46 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-130:
  • MS (ES, Pos.): 452 (M+1)+, 454 (M+3)+, 474 (M+Na)+, 476 (M+Na+2)+; HPLC retention time: 5.36 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-131:
  • MS (ES, Pos.): 460 (M+Na)+, 462 (M+Na+2)+; HPLC retention time: 4.87 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-132:
  • MS (ES, Pos.): 456 (M+Na)+; HPLC retention time: 5.12 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-133:
  • MS (ES, Pos.): 442 (M+Na)+; HPLC retention time: 4.64 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-138:
  • MS (ES, Pos.): 500 (M+Na)+, 502 (M+Na+2)+; HPLC retention time: 4.05 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-140:
  • MS (ES, Pos.): 410 (M+1)+; HPLC retention time: 5.85 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-141:
  • MS (ES, Pos.): 480 (M+1)+, 482 (M+3)+, 502 (M+Na)+, 504 (M+Na+2)+; HPLC retention time: 7.51 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-142:
  • MS (ES, Pos.): 466 (M+1)+, 468 (M+3)+, 488 (M+Na)+, 490 (M+Na+2)+; HPLC retention time: 9.01 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-143:
  • MS (ES, Pos.): 584 (M+1)+, 586 (M+3)+, 588 (M+5)+, 606 (M+Na)+, 608 (M+Na+2)+, 610 (M+Na+4)+; HPLC retention time: 4.48 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-144:
  • MS (ES, Pos.): 466 (M+1)+, 468 (M+3)+, 488 (M+Na)+, 490 (M+Na+2)+; HPLC retention time: 5.92 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-146:
  • MS (ES, Pos.): 516 (M+Na)+, 518 (M+Na+2)+; HPLC retention time: 8.63 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-147:
  • MS (ES, Pos.): 480 (M+1)+, 482 (M+3)+, 502 (M+Na)+, 504 (M+Na+2)+; HPLC retention time: 3.44 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-149:
  • MS (ES, Pos.): 466 (M+1)+, 468 (M+3)+, 488 (M+Na)+, 490 (M+Na+2)+
  • 1-168:
  • MS (ES, Pos.): 444 (M+1)+, 466 (M+Na)+; HPLC retention time: 4.11 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-171:
  • MS (ES, Pos.): 596 (M+1)+, 598 (M+3)+, 600 (M+5)+, 618 (M+Na)+, 620 (M+Na+2)+, 622 (M+Na+4)+; HPLC retention time: 5.87 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-174:
  • MS (ES, Pos.): 506 (M+1)+, 508 (M+3)+, 528 (M+Na)+, 530 (M+Na+2)+; HPLC retention time: 5.83 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-179:
  • MS (ES, Pos.): 474 (M+Na)+, 476 (M+Na+2)+; HPLC retention time: 5.74 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-194:
  • MS (ES, Pos.): 421 (M+1)+; HPLC retention time: 5.08 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-209:
  • MS (ES, Pos.): 496 (M+1)+
  • 1-210:
  • MS (ES, Pos.): 482 (M+1)+
  • 1-222:
  • MS (ES, Pos.): 421 (M+1)+; HPLC retention time: 7.13 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-238:
  • MS (ES, Pos.): 575 (M+1)+, 577 (M+3)+, 579 (M+5)+
  • HPLC retention time: 8.6 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=20:1, flow rate: 1.0 mL/min.)
  • 1-239:
  • MS (ES, Pos.): 575 (M+1)+, 577 (M+3)+, 579 (M+5)+
  • HPLC retention time: 9.6 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=20:1, flow rate: 1.0 mL/min.)
  • 1-240:
  • MS (ES, Pos.): 570 (M+1)+, 572 (M+3)+, 574 (M+5)+
  • HPLC retention time: 13.0 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=100:1, flow rate: 1.0 mL/min.)
  • 1-241:
  • MS (ES, Pos.): 570 (M+1)+, 572 (M+3)+, 574 (M+5)+
  • HPLC retention time: 11.9 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=100:1, flow rate: 1.0 mL/min.)
  • 1-267:
  • MS (ES, Pos.): 438 (M+1)+, 440 (M+3)+, 460 (M+Na)+, 462 (M+Na+2)+; HPLC retention time: 4.43 min. (Capcell Pak UG120, 4.6 mm×150 mm, Shiseido); Flow rate: 1.0 ml/min; Mobile phase: acetonitrile/0.05M ammonium acetate aqueous solution (80:20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
  • 1-276 (the Enantiomer of 1-278):
  • [α]D 29=+7.41 (c 1.00, CH3OH)
  • 1-277 (the Enantiomer of 1-279):
  • HPLC retention time: 6.0 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=8:1, flow rate: 1.0 mL/min.)
  • 1-278 (the enantiomer of 1-276):
  • [α]D 29=−5.90 (c 1.01, CH3OH)
  • 1-279 (the Enantiomer of 1-277):
  • HPLC retention time: 5.5 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=8:1, flow rate: 1.0 mL/min.)
  • 1-280:
  • [α]D 29=−9.30 (c 0.41, CH3OH)
  • 1-281:
  • [α]D 28=−11.2 (c 0.41, CH3OH)
  • 1-282:
  • [α]D 28=−18.0 (c 0.41, CH3OH)
  • 1-283:
  • [α]D 22=−6.6 (c 0.40, CH3OH)
  • 1-284:
  • [α]D 28=−5.5 (c 0.40, CH3OH)
  • 1-302 (the Enantiomer of 1-304):
  • HPLC retention time: 8.4 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=8:1, flow rate: 1.0 mL/min.)
  • 1-303 (the Enantiomer of 1-305):
  • HPLC retention time: 9.2 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=8:1, flow rate: 1.0 mL/min.)
  • 1-304 (the Enantiomer of 1-302):
  • HPLC retention time: 8.9 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=8:1, flow rate: 1.0 mL/min.)
  • 1-305 (the Enantiomer of 1-303):
  • HPLC retention time: 10.6 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), 0.46 cm I.D.×25 cm, mobile phase: hexane/IPA=8:1, flow rate: 1.0 mL/min.)
  • 1-306 (the Enantiomer of 1-308):
  • [α]D 28=+5.38 (c 0.81, CH3OH)
  • 1-307 (the Enantiomer of 1-309):
  • HPLC retention time: 16.6 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), (0.46 cm I.D.×25 cm)×2, mobile phase: hexane/IPA=8:1, flow rate: 1.0 mL/min.)
  • 1-308 (the Enantiomer of 1-306):
  • [α]D 29=−7.69 (c 0.80, CH3OH)
  • 1-309 (the Enantiomer of 1-307):
  • HPLC retention time: 17.4 min. (CHIRAL PAK AD (DAICEL CHEMICAL INDUSTRIES, LTD), (0.46 cm I.D.×25 cm)×2, mobile phase: hexane/IPA=8:1, flow rate: 1.0 mL/min.)
  • 1-316:
  • MS (ES, Pos.): 451 (M+1)+; HPLC retention time: 6.26 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 1-325:
  • MS (ES, Pos.): 449 (M+1)+; HPLC retention time: 5.78 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 1-338:
  • MS (ES, Pos.): 360 (M+1)+; HPLC retention time: 6.19 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 1-339:
  • MS (ES, Pos.): 424 (M+1)+, 426 (M+3)+; HPLC retention time: 5.93 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
    • *2: HCl salt
    • *3: a mixture of diastereomers
    • *4: optically active compound
  • *5: Crystallized on standing from the compound purified (silica gel column chromatography) and dried.
    TABLE 2*1
    Figure US20050209253A1-20050922-C00987
    Com. No. Ex. No.
    Figure US20050209253A1-20050922-C00988
         		R10 R6 R7 R8 —Ar melting point (° C.) (solvent for crystallization)
    2-001 1
    Figure US20050209253A1-20050922-C00989
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00990
         		amorphous
    2-002 1
    Figure US20050209253A1-20050922-C00991
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00992
         		amorphous
    2-003 1
    Figure US20050209253A1-20050922-C00993
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C00994
         		119-121*2(IPE)
    2-004 1
    Figure US20050209253A1-20050922-C00995
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C00996
         		200-202*2(EtOAc)
    2-005 1
    Figure US20050209253A1-20050922-C00997
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C00998
         		204-206*2(ACE)
    2-006 1
    Figure US20050209253A1-20050922-C00999
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01000
         		228-230*2(EtOAc)
    2-007 1
    Figure US20050209253A1-20050922-C01001
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01002
         		218-220*2(ACE)
    2-008 1
    Figure US20050209253A1-20050922-C01003
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01004
         		179-181*2(EtOAc/EtOH)
    2-009 1
    Figure US20050209253A1-20050922-C01005
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01006
         		204-206*2(ACE)
    2-010 1
    Figure US20050209253A1-20050922-C01007
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01008
         		146-148*2(EtOAc/EtOH)
    2-011 1
    Figure US20050209253A1-20050922-C01009
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01010
         		108-110*2(IPE)
    2-012 1
    Figure US20050209253A1-20050922-C01011
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01012
         		amorphous
    2-013 1
    Figure US20050209253A1-20050922-C01013
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01014
         		163-165*2(EtOAc/EtOH)
    2-014 1
    Figure US20050209253A1-20050922-C01015
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01016
         		179-181*2(ACE)
    2-015 1
    Figure US20050209253A1-20050922-C01017
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01018
         		149-151*2(EtOAc)
    2-016 1
    Figure US20050209253A1-20050922-C01019
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01020
         		125-127*2(MeOH/IPE)
    2-017 1
    Figure US20050209253A1-20050922-C01021
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01022
         		172-174*2(ACE/IPE)
    2-018 1
    Figure US20050209253A1-20050922-C01023
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01024
         		133-135*2(MeOH)
    2-019 1
    Figure US20050209253A1-20050922-C01025
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01026
         		207-209*2(ACE)
    2-020 1
    Figure US20050209253A1-20050922-C01027
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01028
         		130-132*2(MeOH/IPE)
    2-021 1
    Figure US20050209253A1-20050922-C01029
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01030
         		124-126*2(MeOH)
    2-022 1
    Figure US20050209253A1-20050922-C01031
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01032
         		110-112*2(IPE)
    2-023 1
    Figure US20050209253A1-20050922-C01033
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01034
         		132-134*2(MeOH/IPE)
    2-024 1
    Figure US20050209253A1-20050922-C01035
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01036
         		130-132*2(MeOH)
    2-025 1
    Figure US20050209253A1-20050922-C01037
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01038
         		200-202*2(IPA)
    2-026 1
    Figure US20050209253A1-20050922-C01039
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01040
         		122-124*2(MeOH)
    2-027 1
    Figure US20050209253A1-20050922-C01041
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01042
         		198-200*2(MeOH/IPE)
    2-028 1
    Figure US20050209253A1-20050922-C01043
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01044
         		124-126*2(MeOH)
    2-029 1
    Figure US20050209253A1-20050922-C01045
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01046
         		184-186*2(Et2O)
    2-030 1
    Figure US20050209253A1-20050922-C01047
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01048
         		138-140*2(MeOH)
    2-031 1
    Figure US20050209253A1-20050922-C01049
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01050
         		157-159*2(ACE)
    2-032 1
    Figure US20050209253A1-20050922-C01051
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01052
         		154-156*2(EtOH)
    2-033 1
    Figure US20050209253A1-20050922-C01053
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01054
         		167-169*2(MeOH)
    2-034 1
    Figure US20050209253A1-20050922-C01055
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01056
         		amorphous*2
    2-035 1
    Figure US20050209253A1-20050922-C01057
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01058
         		223-225*2(ACE)
    2-036 1
    Figure US20050209253A1-20050922-C01059
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01060
         		236-238*2(CH3CN)
    2-037 1
    Figure US20050209253A1-20050922-C01061
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01062
         		228-230*2(ACE)
    2-038 1
    Figure US20050209253A1-20050922-C01063
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01064
         		230-232*2(CH3CN)
    2-039 1
    Figure US20050209253A1-20050922-C01065
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01066
         		218-220*2(ACE)
    2-040 1
    Figure US20050209253A1-20050922-C01067
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01068
         		232-234*2(ACE)
    2-041 1
    Figure US20050209253A1-20050922-C01069
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01070
         		amorphous*2
    2-042 1
    Figure US20050209253A1-20050922-C01071
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01072
         		241-243*2(CH3CN)
    2-043 1
    Figure US20050209253A1-20050922-C01073
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01074
         		218-220*2(ACE)
    2-044 1
    Figure US20050209253A1-20050922-C01075
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01076
         		182-184*2(CH3CN)
    2-045 1
    Figure US20050209253A1-20050922-C01077
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01078
         		amorphous*2
    2-046 1
    Figure US20050209253A1-20050922-C01079
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01080
         		amorphous*2
    2-047 1
    Figure US20050209253A1-20050922-C01081
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01082
         		198-200*2(CH3CN)
    2-048 1
    Figure US20050209253A1-20050922-C01083
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01084
         		amorphous*2
    2-049 1
    Figure US20050209253A1-20050922-C01085
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01086
         		amorphous*2
    2-050 1
    Figure US20050209253A1-20050922-C01087
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01088
         		amorphous*2
    2-051 1
    Figure US20050209253A1-20050922-C01089
         		CO2Et CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01090
         		169-171 (IPE)
    2-052 1
    Figure US20050209253A1-20050922-C01091
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01092
         		amorphous*2
    2-053 1
    Figure US20050209253A1-20050922-C01093
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01094
         		amorphous*2
    2-054 1
    Figure US20050209253A1-20050922-C01095
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01096
         		amorphous*2
    2-055 1
    Figure US20050209253A1-20050922-C01097
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01098
         		215-217*2(CH3CN)
    2-056 1
    Figure US20050209253A1-20050922-C01099
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01100
         		amorphous*2
    2-057 1
    Figure US20050209253A1-20050922-C01101
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01102
         		amorphous*2
    2-058 1
    Figure US20050209253A1-20050922-C01103
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01104
         		amorphous*2
    2-059 1
    Figure US20050209253A1-20050922-C01105
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01106
         		amorphous*2
    2-060 1
    Figure US20050209253A1-20050922-C01107
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01108
         		amorphous*2
    2-061 1
    Figure US20050209253A1-20050922-C01109
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01110
         		210-212*2(CH3CN)
    2-062 1
    Figure US20050209253A1-20050922-C01111
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01112
         		amorphous*2
    2-063 1
    Figure US20050209253A1-20050922-C01113
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01114
         		amorphous*2
    2-064 1
    Figure US20050209253A1-20050922-C01115
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01116
         		amorphous*2
    2-065 1
    Figure US20050209253A1-20050922-C01117
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01118
         		amorphous*2
    2-066 1
    Figure US20050209253A1-20050922-C01119
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01120
         		amorphous*2
    2-067 1
    Figure US20050209253A1-20050922-C01121
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01122
         		113-115*2(IPE)
    2-068 1
    Figure US20050209253A1-20050922-C01123
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01124
         		amorphous*2
    2-069 1
    Figure US20050209253A1-20050922-C01125
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01126
         		amorphous*2
    2-070 1
    Figure US20050209253A1-20050922-C01127
         		Br CH3 CH3 H
    Figure US20050209253A1-20050922-C01128
         		216-218*2(EtOAc/EtOH)
    2-071 1
    Figure US20050209253A1-20050922-C01129
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01130
         		127-129*2(MeOH)
    2-072 1
    Figure US20050209253A1-20050922-C01131
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01132
         		amorphous*2
    2-073 1
    Figure US20050209253A1-20050922-C01133
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01134
         		amorphous*2
    2-074 1
    Figure US20050209253A1-20050922-C01135
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01136
         		215-217*2(CH3CN)
    2-075 1
    Figure US20050209253A1-20050922-C01137
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01138
         		202-204*2(ACE)
    2-076 1
    Figure US20050209253A1-20050922-C01139
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01140
         		197-199*2(CH3CN)
    2-077 1
    Figure US20050209253A1-20050922-C01141
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01142
         		amorphous*2
    2-078 1
    Figure US20050209253A1-20050922-C01143
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01144
         		amorphous*2
    2-079 1
    Figure US20050209253A1-20050922-C01145
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01146
         		amorphous*2
    2-080 1
    Figure US20050209253A1-20050922-C01147
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01148
         		212-214*2(CH3CN)
    2-081 1
    Figure US20050209253A1-20050922-C01149
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01150
         		amorphous*2
    2-082 1
    Figure US20050209253A1-20050922-C01151
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01152
         		178-180*2(CH3CN)
    2-083 1
    Figure US20050209253A1-20050922-C01153
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01154
         		amorphous*2
    2-084 1
    Figure US20050209253A1-20050922-C01155
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01156
         		amorphous*2
    2-085 1
    Figure US20050209253A1-20050922-C01157
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01158
         		201-203*2(CH3CN)
    2-086 1
    Figure US20050209253A1-20050922-C01159
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01160
         		192-194*2(IPE)
    2-087 1
    Figure US20050209253A1-20050922-C01161
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01162
         		amorphous*2
    2-088 1
    Figure US20050209253A1-20050922-C01163
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01164
         		amorphous*2
    2-089 1
    Figure US20050209253A1-20050922-C01165
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01166
         		153-155*2(Et2O)
    2-090 1
    Figure US20050209253A1-20050922-C01167
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01168
         		215-217*2(CH3CN)
    2-091 1
    Figure US20050209253A1-20050922-C01169
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01170
         		208-210*2(IPE)
    2-092 1
    Figure US20050209253A1-20050922-C01171
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01172
         		207-209*2(CH3CN)
    2-093 1
    Figure US20050209253A1-20050922-C01173
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01174
         		130-132*2(MeOH)
    2-094 1
    Figure US20050209253A1-20050922-C01175
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01176
         		amorphous*2
    2-095 1
    Figure US20050209253A1-20050922-C01177
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01178
         		236-238*2(ACE)
    2-096 1
    Figure US20050209253A1-20050922-C01179
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01180
         		226-238*2(Et2O)
    2-097 1
    Figure US20050209253A1-20050922-C01181
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01182
         		amorphous*2
    2-098 1
    Figure US20050209253A1-20050922-C01183
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01184
         		225-227*2(Et2O)
    2-099 1
    Figure US20050209253A1-20050922-C01185
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01186
         		amorphous
    2-100 1
    Figure US20050209253A1-20050922-C01187
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01188
         		amorphous*2
    2-101 1
    Figure US20050209253A1-20050922-C01189
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01190
         		amorphous*2
    2-102 1
    Figure US20050209253A1-20050922-C01191
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01192
         		amorphous*2
    2-103 1
    Figure US20050209253A1-20050922-C01193
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01194
         		amorphous*2
    2-104 1
    Figure US20050209253A1-20050922-C01195
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01196
         		amorphous*2
    2-105 1
    Figure US20050209253A1-20050922-C01197
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01198
         		amorphous*2
    2-106 1
    Figure US20050209253A1-20050922-C01199
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01200
         		amorphous*2
    2-107 1
    Figure US20050209253A1-20050922-C01201
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01202
         		amorphous*2
    2-108 1
    Figure US20050209253A1-20050922-C01203
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01204
         		amorphous*2
    2-109 1
    Figure US20050209253A1-20050922-C01205
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01206
         		amorphous*2
    2-110 1
    Figure US20050209253A1-20050922-C01207
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01208
         		amorphous*2
    2-111 1
    Figure US20050209253A1-20050922-C01209
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01210
         		amorphous*2
    2-112 1
    Figure US20050209253A1-20050922-C01211
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01212
         		amorphous*2
    2-113 1
    Figure US20050209253A1-20050922-C01213
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01214
         		amorphous*2
    2-114 1
    Figure US20050209253A1-20050922-C01215
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01216
         		amorphous*2
    2-115 1
    Figure US20050209253A1-20050922-C01217
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01218
         		217-219*2(ACE)
    2-116 1
    Figure US20050209253A1-20050922-C01219
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01220
         		amorphous*2
    2-117 1
    Figure US20050209253A1-20050922-C01221
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01222
         		amorphous*2
    2-118 1
    Figure US20050209253A1-20050922-C01223
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01224
         		amorphous*2
    2-119 1
    Figure US20050209253A1-20050922-C01225
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01226
         		amorphous*2
    2-120 1
    Figure US20050209253A1-20050922-C01227
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01228
         		amorphous*2
    2-121 1
    Figure US20050209253A1-20050922-C01229
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01230
         		amorphous*2
    2-122 1
    Figure US20050209253A1-20050922-C01231
         		H CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01232
         		amorphous*2
    2-123 1
    Figure US20050209253A1-20050922-C01233
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01234
         		amorphous*2
    2-124 1
    Figure US20050209253A1-20050922-C01235
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01236
         		amorphous*2
    2-125 1
    Figure US20050209253A1-20050922-C01237
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01238
         		amorphous*2
    2-126 1
    Figure US20050209253A1-20050922-C01239
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01240
         		amorphous*2
    2-127 1
    Figure US20050209253A1-20050922-C01241
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01242
         		212-214*2(IPE)
    2-128 1
    Figure US20050209253A1-20050922-C01243
         		H CH3 CH3 H
    Figure US20050209253A1-20050922-C01244
         		amorphous*2
    2-129 1
    Figure US20050209253A1-20050922-C01245
         		CO2Et CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01246
         		176-178 (IPE)

    *1: Com. No. = compound number, Ex. No. = example number, solvent for crystallization; ACE = acetone, EtOAc = ethyl acetate, EtOH = ethanol, Et2O = diethylether, IPA = isopropyl alcohol, IPE = diisopropyl ether, MeOH = methanol, CH3CN = acetonitrile
  • Analytical data of non-crystal compounds are described below.
  • 2-001:
  • MS (ES, Pos.): 418 (M+1)+, 420 (M+3)+, 422 (M+5)+
  • 2-002:
  • MS (ES, Pos.): 432 (M+1)+, 434 (M+3)+, 436 (M+5)+
  • 2-012:
  • MS (ES, Pos.): 427 (M+1)+
  • 2-034:
  • MS (ES, Pos.): 534 (M+1)+, 536 (M+3)+, 538 (M+5)+; HPLC retention time: 6.55 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-041:
  • MS (ES, Pos.): 540 (M+1)+, 542 (M+3)+, 544 (M+5)+; HPLC retention time: 6.60 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acelonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-045:
  • MS (ES, Pos.): 456 (M+1)+, 458 (M+3)+; HPLC retention time: 6.72 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-046:
  • MS (ES, Pos.): 424 (M+1)+; HPLC retention time: 6.61 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-048:
  • MS (ES, Pos.): 482 (M+1)+, 484 (M+3)+; HPLC retention time: 5.67 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-049:
  • MS (ES, Pos.): 584 (M+1)+, 586 (M+3)+, 588 (M+5)+; HPLC retention time: 6.73 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-050:
  • MS (ES, Pos.): 570 (M+1)+, 572 (M+3)+, 574 (M+5)+; HPLC retention time: 6.90 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-052:
  • MS (ES, Pos.): 562 (M+1)+, 564 (M+3)+, 562 (M+5)+; HPLC retention time: 6.81 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-053:
  • MS (ES, Pos.): 548 (M+1)+, 550 (M+3)+, 552 (M+5)+; HPLC retention time: 6.72 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-054:
  • MS (ES, Pos.): 598 (M+1)+, 600 (M+3)+, 602 (M+5)+; HPLC retention time: 6.47 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-056:
  • MS (ES, Pos.): 510 (M+1)+, 512 (M+3)+, 514 (M+5)+; HPLC retention time: 6.42 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-057:
  • MS (ES, Pos.): 496 (M+1)+, 498 (M+3)+, 500 (M+5)+; HPLC retention time: 6.55 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-058:
  • MS (ES, Pos.): 466 (M+1)+, 468 (M+3)+, 470 (M+5)+; HPLC retention time: 6.82 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-059:
  • MS (ES, Pos.): 452 (M+1)+, 454 (M+3)+, 456 (M+5)+; HPLC retention time: 6.23 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-060:
  • MS (ES, Pos.): 554 (M+1)+, 556 (M+3)+, 558 (M+5)+; HPLC retention time: 6.43 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-062:
  • MS (ES, Pos.): 422 (M+1)+; HPLC retention time: 6.29 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-063:
  • MS (ES, Pos.): 408 (M+1)+; HPLC retention time: 5.94 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-064:
  • MS (ES, Pos.): 470 (M+1)+, 472 (M+3)+, HPLC retention time: 6.92 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 m/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-065:
  • MS (ES, Pos.): 438 (M+1)+; HPLC retention time: 6.40 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-066:
  • MS (ES, Pos.): 506 (M+1)+, 508 (M+3)+, 510 (M+5)+; HPLC retention time: 6.31 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-068:
  • MS (ES, Pos.): 598 (M+1)+, 600 (M+3)+, 602 (M+5)+; HPLC retention time: 7.11 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-069:
  • MS (ES, Pos.): 584 (M+1)+, 586 (M+3)+, 588 (M+5)+; HPLC retention time: 7.11 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-072:
  • MS (ES, Pos.): 562 (M+1)+, 564 (M+3)+, 566 (M+5)+; HPLC retention time: 6.63 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-073:
  • MS (ES, Pos.): 612 (M+1)+, 614 (M+3)+, 616 (M+5)+; HPLC retention time: 6.61 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-077:
  • MS (ES, Pos.): 480 (M+1)+, 482 (M+3)+, 484 (M+5)+; HPLC retention time: 6.54 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-078:
  • MS (ES, Pos.): 466 (M+1)+, 468 (M+3)+, 470 (M+5)+; HPLC retention time: 5.95 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-079:
  • MS (ES, Pos.): 568 (M+1)+, 570 (M+3)+, 572 (M+5)+; HPLC retention time: 6.97 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-081:
  • MS (ES, Pos.): 436 (M+1)+; HPLC retention time: 6.49 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-083:
  • MS (ES, Pos.): 484 (M+1)+, 486 (M+3)+; HPLC retention time: 7.09 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-084:
  • MS (ES, Pos.): 452 (M+1)+; HPLC retention time: 6.55 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-087:
  • MS (ES, Pos.): 612 (M+1)+, 614 (M+3)+, 616 (M+5)+; HPLC retention time: 7.24 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-088:
  • MS (ES, Pos.): 598 (M+1)+, 600 (M+3)+, 602 (M+5)+; HPLC retention time: 7.21 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-094:
  • MS (ES, Pos.): 529 (M+1)+, 531 (M+3)+, 533 (M+5)+; HPLC retention time: 6.40 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-097:
  • MS (ES, Pos.): 491 (M+1)+, 493 (M+3)+, 495 (M+5)+; HPLC retention time: 6.78 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 [un, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-099:
  • MS (ES, Pos.): 447 (M+1)+, 449 (M+3)+, 451 (M+5)+; HPLC retention time: 6.73 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-100:
  • MS (ES, Pos.): 433 (M+1)+, 435 (M+3)+, 437 (M+5)+; HPLC retention time: 5.70 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-101:
  • MS (ES, Pos.): 535 (M+1)+, 537 (M+3)+, 539 (M+5)+; HPLC retention time: 6.72 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-102:
  • MS (ES, Pos.): 521 (M+1)+, 523 (M+3)+, 525 (M+5)+; HPLC retention time: 6.27 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-103:
  • MS (ES, Pos.): 403 (M+1); HPLC retention time: 6.24 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-104:
  • MS (ES, Pos.): 389 (M+1)+; HPLC retention time: 5.89 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% Ato 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-105:
  • MS (ES, Pos.): 451 (M+1)+, 453 (M+3)+, HPLC retention time: 6.87 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 m/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-106:
  • MS (ES, Pos.): 419 (M+1)+; HPLC retention time: 6.33 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-107:
  • MS (ES, Pos.): 487 (M+1)+, 489 (M+3)+, 491 (M+5)+; HPLC retention time: 6.20 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-108:
  • MS (ES, Pos.): 477 (M+1)+, 479 (M+3)+, 481 (M+5)+; HPLC retention time: 6.21 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acelonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-109:
  • MS (ES, Pos.): 579 (M+1)+, 581 (M+3)+, 583 (M+5)+; HPLC retention time: 7.00 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-110:
  • MS (ES, Pos.): 565 (M+1)+, 567 (M+3)+, 569 (M+5)+; HPLC retention time: 7.00 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-111:
  • MS (ES, Pos.): 421 (M+1)+, 423 (M+3)+; HPLC retention time: 6.84 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-112:
  • MS (ES, Pos.): 557 (M+1)+, 559 (M+3)+, 561 (M+5)+; HPLC retention time: 6.54 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-113:
  • MS (ES, Pos.): 543 (M+1)+, 545 (M+3)+, 547 (M+5)+; HPLC retention time: 6.69 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-114:
  • MS (ES, Pos.): 593 (M+1)+, 595 (M+3)+, 597 (M+5)+; HPLC retention time: 6.84 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-116:
  • MS (ES, Pos.): 505 (M+1)+, 507 (M+3)+, 509 (M+5)+; HPLC retention time: 6.37 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-117:
  • MS (ES, Pos.): 491 (M+1)+, 493 (M+3)+, 495 (M+5)+; HPLC retention time: 6.52 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-118:
  • MS (ES, Pos.): 461 (M+1)+, 463 (M+3)+, 465 (M+5)+; HPLC retention time: 6.34 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-119:
  • MS (ES, Pos.): 447 (M+1)+, 449 (M+3)+, 451 (M+5)+; HPLC retention time: 5.79 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-120:
  • MS (ES, Pos.): 549 (M+1)+, 551 (M+3)+, 553 (M+5)+; HPLC retention time: 6.77 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-121:
  • MS (ES, Pos.): 535 (M+1)+, 537 (M+3)+, 539 (M+5)+; HPLC retention time: 5.83 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 m/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-122:
  • MS (ES, Pos.): 417 (M+1)+; HPLC retention time: 6.49 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-123:
  • MS (ES, Pos.): 403 (M+1)+; HPLC retention time: 5.96 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-124:
  • MS (ES, Pos.): 465 (M+1)+, 467 (M+3)+, HPLC retention time: 6.87 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-125:
  • MS (ES, Pos.): 433 (M+1)+; HPLC retention time: 6.38 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-126:
  • MS (ES, Pos.): 501 (M+1)+, 503 (M+3)+, 505 (M+5)+; HPLC retention time: 6.26 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 2-128:
  • MS (ES, Pos.): 579 (M+1)+, 581 (M+3)+, 583 (M+5)+; HPLC retention time: 6.10 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • *2: HCl salt
    TABLE 3*1
    Figure US20050209253A1-20050922-C01247
    Com. No. Ex. No.
    Figure US20050209253A1-20050922-C01248
         		Y R6 R7 R8 —Ar melting point (° C.) (solvent for crystallization)
    3-001 5
    Figure US20050209253A1-20050922-C01249
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01250
         		151-153 (No solvent)
    3-002 5
    Figure US20050209253A1-20050922-C01251
         		CH CH3 CH3 H
    Figure US20050209253A1-20050922-C01252
         		amorphous
    3-003 6
    Figure US20050209253A1-20050922-C01253
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01254
         		142-144 (IPE)
    3-004 6
    Figure US20050209253A1-20050922-C01255
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01256
         		143-145 (IPE)
    3-005 6
    Figure US20050209253A1-20050922-C01257
         		CH CH3 CH3 H
    Figure US20050209253A1-20050922-C01258
         		amorphous
    3-006 6
    Figure US20050209253A1-20050922-C01259
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01260
         		131-133 (hexane)
    3-007 6
    Figure US20050209253A1-20050922-C01261
         		CH CH3 CH3 H
    Figure US20050209253A1-20050922-C01262
         		amorphous
    3-008 5
    Figure US20050209253A1-20050922-C01263
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01264
         		amorphous
    3-009 6
    Figure US20050209253A1-20050922-C01265
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01266
         		amorphous
    3-010 6
    Figure US20050209253A1-20050922-C01267
         		CH CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01268
         		oil
    3-011 6
    Figure US20050209253A1-20050922-C01269
         		CH CH3 CH3 H
    Figure US20050209253A1-20050922-C01270
         		oil
    3-012 5
    Figure US20050209253A1-20050922-C01271
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01272
         		110-112 (No solvent)
    3-013 5
    Figure US20050209253A1-20050922-C01273
         		N CH3 CH3 CH3
    Figure US20050209253A1-20050922-C01274
         		amorphous
    3-014 8
    Figure US20050209253A1-20050922-C01275
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01276
         		205-507*2(No solvent)
    3-015 7
    Figure US20050209253A1-20050922-C01277
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01278
         		amorphous
    3-016 8
    Figure US20050209253A1-20050922-C01279
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01280
         		amorphous*2
    3-017 9
    Figure US20050209253A1-20050922-C01281
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01282
         		 94-96 (No solvent)
    3-018 10
    Figure US20050209253A1-20050922-C01283
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01284
         		215-217*3(No solvent)
    3-019 7
    Figure US20050209253A1-20050922-C01285
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01286
         		amorphous
    3-020 7
    Figure US20050209253A1-20050922-C01287
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01288
         		amorphous
    3-021 7
    Figure US20050209253A1-20050922-C01289
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01290
         		amorphous
    3-022 7
    Figure US20050209253A1-20050922-C01291
         		N CH3 CH3 H
    Figure US20050209253A1-20050922-C01292
         		amorphous

    *1: Com. No. = compound number, Ex. No. = example number, solvent for crystallization; IPE = diisopropyl ether
  • Analytical data of non-crystal compounds are described below.
  • 3-002:
  • MS (ES, Pos.): 514 (M+1)+, 516 (M+3)+; HPLC Retention time: 6.77 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 3-005:
  • MS (ES, Pos.): 547 (M+1)+, 549 (M+3)+; HPLC Retention time: 7.06 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 3-007:
  • MS (ES, Pos.): 514 (M+1)+, 516 (M+3)+; HPLC Retention time: 7.01 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 3-008:
  • MS (ES, Pos.): 577 (M+1)+, 579 (M+3)+; HPLC Retention time: 10.89 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.2 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 30% A, 50% B and 20% C to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 3-009:
  • MS (ES, Pos.): 597 (M+1)+, 599 (M+3)+; HPLC Retention time: 13.94 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.2 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 30% A, 50% B and 20% C to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 3-010:
  • MS No spectrum (decomposition in LC-MS); 1H NMR (360 MHz, DMSO-D6) δ ppm 0.83 (3H, t, J=6.4 Hz), 1.24 (12H, br.s), 1.52 (4H, m), 1.79 (9H, m), 1.93 (3H, s), 2.29 (3H, s), 2.32 (2H, t, J=7.1 Hz), 2.39 (3H, s), 2.68 (2H, t, J=11.3 Hz), 3.46 (2H, d, J=11.7 Hz,), 4.00 (2H, d, J=5.9 Hz), 6.45 (1H, s), 7.47 (2H, s)
  • 3-011:
  • MS (ES, Pos.): 596 (M+1)+, 598 (M+3)+; HPLC Retention time: 6.45 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 3-013:
  • MS (ES, Pos.): 617 (M+1)+, 619 (M+3)+, 621 (M+5)+; HPLC Retention time: 6.65 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 3-015:
  • MS (ES, Pos.): 570 (M+1)+, 572 (M+3)+; HPLC Retention time: 7.05 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 m/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 3-016:
  • MS (ES, Pos.): 629 (M+1)+, 631 (M+3)+; HPLC Retention time: 6.86 min. (Xterra MS C18 (Waters, Milford, Mass.) 3.5 μm, 4.6×100 mm); Flow rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 50% B and 50% C in 6.5 min., to 100% B in 1 min, 100% B for 1 min. and reequilibrate with 100% A for 1.5 min)
  • 3-019:
  • MS (ES, Pos.): 705 (M+1)+, 707 (M+3)+; 1H NMR (300 MHz, CDCl3) δ ppm 0.89 (3H, t, J=6.7 Hz), 1.17-1.40 (4H, m), 1.42-1.72 (4H, m), 1.81-1.93 (3H, m), 1.92 (6H, s), 2.00-2.07 (4H, m), 2.34 (2H, t, J=7.5 Hz), 2.44 (3H, d, J=1.1 Hz), 2.51 (3H, s), 2.74-2.81 (2H, m), 2.90-3.04 (2H, m), 4.03 (2H, d, J=6.4 Hz,), 4.10-4.19 (2H, m), 5.28-5.42 (4H, m), 6.57 (1H, m), 7.30 (2H, s)
  • 3-020:
  • MS (ES, Pos.): 729 (M+1)+, 731 (M+3)+; 1H NMR (300 MHz, CDCl3) δ ppm 0.89 (3H, t, J=6.7 Hz), 1.20-1.40 (6H, m), 1.41-1.53 (2H, m), 1.65-1.80 (2H, m), 1.81-2.00 (3H, m), 1.92 (6H, s), 2.02-2.19 (4H, m), 2.36 (2H, t, J=7.5 Hz), 2.44 (3H, d, J=1.0 Hz), 2.51 (3H, s), 2.77-2.90 (6H, m), 2.92-3.05 (2H, m), 4.03 (2H, d, J=6.4 Hz,), 4.05-4.19 (2H, m), 5.28-5.47 (8H, m), 6.57 (1H, m), 7.30 (2H, s)
  • 3-021:
  • MS (ES, Pos.): 753 (M+1)+, 754 (M+3)+; 1H NMR (500 MHz, CDCl3) δ ppm 0.97 (3H, t, J=7.3 Hz), 1.15-1.40 (1H, m), 1.45-1.55 (2H, m), 1.84-2.00 (3H, m), 1.92 (6H, s), 2.04-2.11 (2H, m), 2.38-2.44 (4H, m), 2.43 (3H, d, J=1.2 Hz), 2.50 (3H, s), 2.77-2.90 (10H, m), 2.94-3.02 (2H, m), 4.04 (2H, d, J=6.7 Hz,), 4.09-4.16 (2H, m), 5.27-5.46 (12H, m), 6.57 (1H, m), 7.30 (2H, s)
  • 3-022:
  • MS (ES, Pos.): 727 (M+1)+, 729 (M+3)+; 1H NMR (500 MHz, CDCl3) δ ppm 0.97 (3H, t, J=7.3 Hz), 1.15-1.40 (1H, m), 1.45-1.55 (2H, m), 1.65-1.80 (2H, m), 1.84-1.98 (2H, m), 1.92 (6H, s), 2.03-2.17 (4H, m), 2.36 (2H, t, J=7.3 Hz), 2.43 (3H, d, J=1.2 Hz), 2.50 (3H, s), 2.77-2.91 (8H, m), 2.94-3.02 (2H, m), 4.04 (2H, d, J=6.7 Hz,), 4.09-4.16 (2H, m), 5.28-5.44 (10H, m), 6.57 (1H, m), 7.30 (2H, s)
    • *2: optically active compound
    • *3: 1 Na salt
    Test Example [CRF Receptor Binding Test]
  • Monkey amygdala membranes were used as a receptor preparation.
  • 125I-CRF was used as 125I-labeled ligand.
  • Binding reaction using the 125I -labeled ligand was carried out by the following method described in The Journal of Neuroscience, 7, 88 (1987).
  • Preparation of Receptor Membranes:
  • Monkey amygdala was homogenized in 50 mM Tris-HCl buffer (pH 7.0) containing 10 mM MgCl2, 2 mM EDTA and centrifuged at 48,000×g for 20 min, and the precipitate was washed once with Tris-HCl buffer. The washed precipitate was suspended in 50 mM Tris-HCl buffer (pH 7.0) containing 10 mM MgCl2, 2 mM EDTA, 0.1% bovine serum albumin and 100 kallikrein units/ml aprotinin, to obtain a membrane preparation.
  • CRF Receptor Binding Test:
  • The membrane preparation (0.3 mg protein/ml), 125I-CRF (0.2 nM) and a test drug were reacted at 25° C. for 2 hours. After completion of the reaction, the reaction mixture was filtered by suction through a glass filter (GF/C) treated with 0.3% polyethylene imine, and the glass filter was washed three times with phosphate-buffered saline containing 0.01% Triton X-100. After the washing, the radioactivity of the filter paper was measured in a gamma counter.
  • The amount of 125I-CRF bound when the reaction was carried out in the presence of 1 μM CRF was taken as the degree of nonspecific binding of 125I -CRF, and the difference between the total degree of 125I -CRF binding and the degree of nonspecific 125I -CRF binding was taken as the degree of specific 125I -CRF binding. An inhibition curve was obtained by reacting a definite concentration (0.2 nM) of 125I-CRF with various concentrations of each test drug under the conditions described above. A concentration of the test drug at which binding of 125I -CRF is inhibited by 50% (IC50) was determined from the inhibition curve.
  • As a result, it was found that compounds 1-003, 1-004, 1-005, 1-007, 1-008, 1-009, 1-010, 1-013, 1-014, 1-016, 1-018, 1-019, 1-021, 1-032, 1-038, 1-039, 1-040, 1-046, 1-050, 1-051, 1-052, 1-053, 1-054, 1-056, 1-057, 1-058, 1-059, 1-060, 1-061, 1-062, 1-063, 1-064, 1-067, 1-068, 1-072, 1-073, 1-074, 1-077, 1-078, 1-087, 1-088, 1-089, 1-090, 1-091, 1-097, 1-098, 1-099, 1-103, 1-104, 1-105, 1-112, 1-117, 1-118, 1-120, 1-121, 1-122, 1-123, 1-125, 1-126, 1-127, 1-128, 1-129, 1-130, 1-131, 1-132, 1-133, 1-135, 1-141, 1-142, 1-143, 1-144, 1-145, 1-148, 1-149, 1-150, 1-151, 1-152, 1-153, 1-154, 1-155, 1-156, 1-157, 1-158, 1-159, 1-160, 1-161, 1-162, 1-163, 1-164, 1-165, 1-166, 1-167, 1-172, 1-173, 1-176, 1-177, 1-178, 1-179, 1-181, 1-183, 1-184, 1-188, 1-195, 1-208, 1-213, 1-235, 1-236, 1-237, 1-243, 1-245, 1-251, 1-257, 1-262, 1-264, 1-278, 1-280, 1-283, 1-284, 1-285, 1-286, 1-287, 1-288, 1-302, 1-304, 1-306, 1-308, 1-319, 1-320, 1-332, 1-333, 1-336, 1-337, 2-002, 2-003, 2-004, 2-005, 2-006, 2-007, 2-008, 2-009, 2-010, 2-011, 2-012, 2-013, 2-014, 2-015, 2-016, 2-017, 2-018, 2-019, 2-020, 2-021, 2-022, 2-023, 2-024, 2-025, 2-026, 2-027, 2-028, 2-029, 2-030, 2-031, 2-032, 2-033, 2-034, 2-035, 2-036, 2-037, 2-038, 2-039, 2-040, 2-041, 2-042, 2-043, 2-044, 2-045, 2-046, 2-047, 2-048, 2-049, 2-050, 2-052, 2-053, 2-054, 2-055, 2-056, 2-057, 2-058, 2-059, 2-060, 2-061, 2-062, 2-063, 2-064, 2-065, 2-066, 2-068, 2-069, 2-070, 2-071, 2-072, 2-073, 2-074, 2-075, 2-076, 2-077, 2-078, 2-079, 2-080, 2-081, 2-082, 2-084, 2-087, 2-088, 2-089, 2-090, 2-091, 2-092, 2-093, 2-094, 2-095, 2-096, 2-097, 2-098, 2-099, 2-100, 2-101, 2-102, 2-103, 2-104, 2-105, 2-106, 2-107, 2-108, 2-109, 2-110, 2-111, 2-112, 2-113, 2-114, 2-115, 2-116, 2-117, 2-118, 2-119, 2-120, 2-121, 2-122, 2-123, 2-124, 2-125, 2-126, 2-127, 2-128, 3-001, 3-004, 3-006, 3-007, 3-008, 3-009, 3-015 and 3-018 can be exemplified as typical compounds having an IC50 value of 50 nM or less.
    • EFFECT OF THE INVENTION
  • According to the present invention, compounds having a high affinity for CRF receptors have been provided. These compounds are effective against diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastric diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, etc.

Claims (43)

1. A pyrrolopyrimidine or pyrrolopyridine derivative substituted with a cyclic amino group represented by the following formula [I]:
Figure US20050209253A1-20050922-C01293
(wherein the cyclic amino group is represented by the following formula [II]:
Figure US20050209253A1-20050922-C01294
in which the cyclic amino group is a 3- to 8-membered saturated cyclic amine or a 3- to 8-membered saturated cyclic amine bridged with C1-5alkylene or C1-4alkylene-O—C1-4alkylene between any different two carbon atoms of the cyclic amine, which cyclic amine is substituted with a group represented by —(CR1R2)m—(CHR3)n—X, R4 and R5 independently on the same or different carbon atoms of the cyclic amine;
X is cyano, hydroxy or —OR9;
Y is N or CR10;
R1 is hydrogen, hydroxy, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
R2 is hydrogen or C1-5alkyl;
R3 is hydrogen, cyano, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
m is an integer selected from 0, 1, 2, 3, 4 and 5;
n is 0 or 1;
with the proviso that when X is hydroxy or OR9, and n is 0, then m is an integer selected from 1, 2, 3, 4 and 5;
R4 is hydrogen, hydroxy, hydroxy-C1-5alkyl, cyano, cyano-C1-5alkyl or C1-5alkyl;
R5 is hydrogen or C1-5alkyl;
R6 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy or —N(R11)R12;
R7 and R8 are the same or different, and independently are hydrogen, halogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy, —N(R11a)R12a, —CO2R13, cyano, nitro, C1-5alkylthio, trifluoromethyl or trifluoromethoxy; or R7 and R8 are taken together to form —CH2—CH2—CH2—CH2— or —CH═CH—CH═CH—;
R9 is C1-24acyl, C1-10alkoxycarbonyl, aryl-C1-5alkyloxycarbonyl, —CO—O—CHR14—O—CO—R15, —P(═O)(OR14a)OR15a, —CO—(CH2)p—(CHR16)q—NR17R18, arylcarbonyl or heteroarylcarbonyl, wherein each said acyl, aryl and heteroaryl is unsubstituted or substituted with C1-5alkoxy, and C1-24acyl optionally includes one to six double bonds;
R10 is hydrogen, C1-5alkyl, halogen, cyano or —CO2R19;
Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C1-5alkyl, C3-8cycloalkyl, C2-5alkenyl, C2-5alkynyl, C1-5alkoxy, C1-5alkylthio, C1-5alkylsulfinyl, C1-5alkylsulfonyl, cyano, nitro, hydroxy, —CO2R19a, C(═O)R19a, CONR11bR12b, —OC(═O)R19a, —NR11bCO2R19b, —S(O)rNR11bR12b, hydroxy-C2-5alkylamino-C2-5alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and —N(R20)R21; with the proviso that when X is hydroxy, Y is N, and the cyclic amino group is 5-membered ring, then Ar is aryl or heteroaryl which aryl or heteroaryl is substituted with at least one of substituents which are selected from halogen and trifluoromethyl;
R11 and R12 are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
R11a and R12a are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
R11b and R12b are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
R13 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, C1-5alkoxy-C1-5alkyl, C3-8cycloalkyloxy-C1-5alkyl or phenyl;
R14 and R15 are the same or different, and independently are hydrogen, C1-5alkyl or aryl-C1-5alkyl;
R14a and R15a are the same or different, and independently are hydrogen, C1-5alkyl or aryl-C1-5alkyl;
R16 is hydrogen, C1-5alkyl, aryl, heteroaryl, aryl-C1-5alkyl, heteroaryl-C1-5alkyl, hydroxy-C1-5alkyl, hydroxycarbonyl-C1-5alkyl, hydroxyphenyl-C1-5alkyl, C1-5alkoxy-C1-5alkyl, amino-C1-5alkyl, guanidino-C1-5alkyl, mercapto-C1-5alkyl, C1-5alkylthio-C1-5alkyl or aminocarbonyl-C1-5alkyl;
R17 and R18 are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, C1-10acyl, C1-10alkoxycarbonyl or aryl-C1-5alkyloxycarbonyl;
or R16 and R17 are taken together to form —CH2—, —CH2CH2—, —CH2CH2CH2— or —CH2CH2CH2CH2—;
p is an integer selected from 0, 1, 2, 3, 4 and 5;
q is 0 or 1;
R19 is hydrogen or C1-5alkyl;
R19a is hydrogen or C1-5alkyl;
r is 1 or 2;
R20 and R21 are the same or different, and independently are hydrogen or C1-5alkyl), individual isomers thereof, racemic or non-racemic mixtures of isomers thereof or N-oxide thereof, or pharmaceutically acceptable salts and hydrates thereof.
2. The pyrrolopyrimidine or pyrrolopyridine derivative substituted with the cyclic amino group according to claim 1, which is a compound represented by the following formula [III]:
Figure US20050209253A1-20050922-C01295
(wherein the cyclic amino group is represented by the following formula [IV]:
Figure US20050209253A1-20050922-C01296
in which the cyclic amino group is a 3- to 8-membered saturated cyclic amine or a 3- to 8-membered saturated cyclic amine bridged with C1-5alkylene or C1-4alkylene-O—C1-4alkylene between any different two carbon atoms of the cyclic amine, which cyclic amine is substituted with a group represented by —(CR1R2)m—(CHR3)n—CN, R4 and R5 independently on the same or different carbon atoms of the cyclic amine;
Y is N or CR10;
R1 is hydrogen, hydroxy, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
R2 is hydrogen or C1-5alkyl;
R3 is hydrogen, cyano, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
m is an integer selected from 0, 1, 2, 3, 4 and 5;
n is 0 or 1;
R4 is hydrogen, hydroxy, hydroxy-C1-5alkyl, cyano, cyano-C1-5alkyl or C1-5alkyl;
R5 is hydrogen or C1-5alkyl;
R6 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy or —N(R11)R12;
R7 and R8 are the same or different, and independently are hydrogen, halogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy, —N(R11a)R12a, —CO2R13, cyano, nitro, C1-5alkylthio, trifluoromethyl or trifluoromethoxy; or R7 and R8 are taken together to form —CH2—CH2—CH2—CH2— or —CH═CH—CH═CH—;
R10 is hydrogen, C1-5alkyl, halogen, cyano or —CO2R19;
Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C1-5alkyl, C3-8cycloalkyl, C2-5alkenyl, C2-5alkynyl, C1-5alkoxy, C1-5alkylthio, C1-5alkylsulfinyl C1-5alkylsulfonyl, cyano, nitro, hydroxy, —CO2R19a, —C(═O)R19a, —CONR11bR12b, —OC(═O)R19a, —NR11bCO2R19a, S(O)rNR11bR12b, hydroxy-C2-5alkylamino-C2-5alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and —N(R20)R21;
R11 and R12 are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
R11 and R12 are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
R11b and R12b are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-15alkyl;
R13 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, C1-5alkoxy-C1-5alkyl, C3-8cycloalkyloxy-C1-5alkyl or phenyl;
R19 is hydrogen or C1-5alkyl;
R19a is hydrogen or C1-5alkyl;
r is 1 or 2;
R20 and R21 are the same or different, and independently are hydrogen or C1-5alkyl), individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
3. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 2 represented by formula [III], wherein Y is N; the cyclic amino group, m, n, R1, R2, R3, R4, R5, R6, R7, R8 and Ar are as defined in claim 2; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
4. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 2 represented by formula [III], wherein Y is N; n is 0; R1, R2, R4 and R5 are hydrogen; the cyclic amino group, m, R6, R7, R8 and Ar are as defined in claim 2; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
5. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 2 represented by formula [III], wherein Y is N; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 0, 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl); individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
6. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 2 represented by formula [III], wherein Y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is 0 or 1; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
7. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 2 represented by formula [III], wherein Y is CR10; the cyclic amino group, m, n, R1, R2, R3, R4, R5, R6, R7 R8, R10 and Ar are as defined in claim 2; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
8. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 2 represented by formula [III], wherein Y is CR10; n is 0; R1, R2, R4 and R5 are hydrogen; R10 is hydrogen or halogen; the cyclic amino group, m, R6, R7, R8 and Ar are as defined in claim 2; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
9. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 2 represented by formula [III], wherein Y is CR10; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 0, 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; R10 is hydrogen or halogen; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl); individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
10. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 2 represented by formula [III], wherein Y is CR10; the cyclic amino group is a 6-membered saturated cyclic amine; m is 0 or 1; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; R10 is hydrogen; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
11. The pyrrolopyrimidine or pyrrolopyridine derivative substituted with the cyclic amino group according to claim 1, which is a compound represented by the following formula [V]:
Figure US20050209253A1-20050922-C01297
(wherein the cyclic amino group is represented by the following formula [VI]:
Figure US20050209253A1-20050922-C01298
in which the cyclic amino group is a 3- to 8-membered saturated cyclic amine or a 3- to 8-membered saturated cyclic amine bridged with C1-5alkylene or C1-4alkylene-O—C1-4alkylene between any different two carbon atoms of the cyclic amine, which cyclic amine is substituted with a group represented by —(CR1R2)m—(CHR3)n—OH, R4 and R5 independently on the same or different carbon atoms of the cyclic amine;
Y is N or CR10;
R1 is hydrogen, hydroxy, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
R2 is hydrogen or C1-5alkyl;
R3 is hydrogen, cyano, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
m is an integer selected from 0, 1, 2, 3, 4 and 5;
n is 0 or 1;
with the proviso that when n is 0, m is an integer selected from 1, 2, 3, 4 and 5;
R4 is hydrogen, hydroxy, hydroxy-C1-5alkyl, cyano, cyano-C1-5alkyl or C1-5alkyl;
R5 is hydrogen or C1-5alkyl;
R6 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy or —N(R11)R12;
R7 and R8 are the same or different, and independently are hydrogen, halogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy, —N(R11a)R12a, —CO2R13, cyano, nitro, C1-5alkylthio, trifluoromethyl or trifluoromethoxy; or R7 and R8 are taken together to form —CH2—CH2—CH2—CH2— or —CH═CH—CH═CH—;
R10 is hydrogen, C1-5alkyl, halogen, cyano or —CO2R19;
Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C1-5alkyl, C3-8cycloalkyl, C2-5alkenyl, C2-5alkynyl, C1-5alkoxy, C1-5alkylthio, C1-5alkylsulfinyl, C1-5alkylsulfonyl, cyano, nitro, hydroxy, —CO2R19a, C(═O)R19a, CONR11bR12b —OC(═O)R19a, —NR11bCO2R19a, —S(O)rNR11bR12b, hydroxy-C2-5alkylamino-C2-5alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and —N(R20)R21; with the proviso that when Y is N, and the cyclic amino group is 5-membered ring, then Ar is aryl or heteroaryl which aryl or heteroaryl is substituted with at least one of substituents which are selected from halogen and trifluoromethyl;
R11 and R12 are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
R11a and R12a are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
R11b and R12b are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
R13 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, C1-5alkoxy-C1-5alkyl, C3-8cycloalkyloxy-C1-5alkyl or phenyl;
R19 is hydrogen or C1-5alkyl;
R19a is hydrogen or C1-5alkyl;
r is 1 or 2;
R20 and R21 are the same or different, and independently are hydrogen or C1-5alkyl), individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
12. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is N; the cyclic amino group, m, n, R1, R2, R3, R4, R5, R6, R7, R8 and Ar are as defined in claim 11; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
13. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is N; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R1, R2, R4 and R5 are hydrogen; the cyclic amino group, R6, R7, R8 and Ar are as defined in claim 11; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
14. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is N; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20 R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl); with the proviso that when the cyclic amino group is 5-membered ring, Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with at least one of substituents which are selected from halogen and trifluoromethyl; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
15. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
16. The pyrrolopyrimidine derivatives substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is N; m is 1; n is 0; R1 is C1-5alkyl or hydroxy-C1-5alkyl; R2, R4 and R5 are hydrogen; the cyclic amino group, R6, R7, R8 and Ar are as defined in claim 11; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
17. The pyrrolopyrimidine derivatives substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is N; m is 1; n is 0; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; R1 is C1-5alkyl or hydroxy-C1-5alkyl; R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl); individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
18. The pyrrolopyrimidine derivatives substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is N; m is 1; n is 0; the cyclic amino group is a 6-membered saturated cyclic amine; R1 is C1-5alkyl or hydroxy-C1-5alkyl; R2, R4 and R5 are hydrogen; R6 is methyl; R7 and RB are the same or different, and independently are hydrogen or methyl; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
19. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is N; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R1, R2 and R5 are hydrogen; R4 is cyano; the cyclic amino group, R6, R7, R8 and Ar are as defined in claim 11, wherein a group represented by —(CR1R2)m—(CHR3)n—OH and R4 are substituted on the same carbon atom of the cyclic amine; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
20. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is N; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2 and R5 are hydrogen; R4 is cyano; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl), wherein a group represented by —(CR1R2)m—(CHR3)n—OH and R4 are substituted on the same carbon atom of the cyclic amine; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
21. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2 and R5 are hydrogen; R4 is cyano; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino, wherein a group represented by —(CR1R2)m, —(CHR3)n—OH and R4 are substituted on the same carbon atom of the cyclic amine; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
22. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is CR10; the cyclic amino group, m, n, R1, R2, R3, R4, R5, R6, R7, R8, R10 and Ar are as defined in claim 11; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
23. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is CR10; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R1, R2, R4 and R5 are hydrogen; R10 is hydrogen or halogen; the cyclic amino group, R6, R7, R9 and Ar are as defined in claim 11; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof or pharmaceutically acceptable salts and hydrates thereof.
24. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is CR10; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; R10 is hydrogen or halogen; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl); individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
25. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is CR10; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3;
n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; R10 is hydrogen; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
26. The pyrrolopyridine derivatives substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is CR10; m is 1; n is 0; R1 is C1-5alkyl or hydroxy-C1-5alkyl; R2, R4 and R5 are hydrogen; R10 is hydrogen or halogen; the cyclic amino group, R6, R7, R8 and Ar are as defined in claim 11; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
27. The pyrrolopyridine derivatives substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is CR10; m is 1; n is 0; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; R1 is C1-5alkyl or hydroxy-C1-5alkyl; R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; R10 is hydrogen or halogen; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl); individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
28. The pyrrolopyridine derivatives substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is CR10; m is 1; n is 0; the cyclic amino group is a 6-membered saturated cyclic amine; R1 is C1-5alkyl or hydroxy-C1-5alkyl; R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; R10 is hydrogen; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
29. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is CR10; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R1, R2 and R5 are hydrogen; R4 is cyano; R10 is hydrogen or halogen; the cyclic amino group, R6, R7, R8 and Ar are as defined in claim 11, wherein a group represented by —(CR1R2)m—(CHR3)n—OH and R4 are substituted on the same carbon atom of the cyclic amine; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
30. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is CR10; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2 and R5 are hydrogen; R4 is cyano; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; R10 is hydrogen or halogen; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl), wherein a group represented by (CR1R2)m—(CHR3)n—OH and R4 are substituted on the same carbon atom of the cyclic amine; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
31. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 11 represented by formula [V], wherein Y is CR10; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2 and R5 are hydrogen; R4 is cyano; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; R10 is hydrogen; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino, wherein a group represented by —(CR1R2)m—(CHR3)n—OH and R4 are substituted on the same carbon atom of the cyclic amine; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
32. The pyrrolopyrimidine or pyrrolopyridine derivative substituted with the cyclic amino group according to claim 1, which is a compound represented by the following formula [VII]:
Figure US20050209253A1-20050922-C01299
(wherein the cyclic amino group is represented by the following formula [VIII]:
Figure US20050209253A1-20050922-C01300
in which the cyclic amino group is a 3- to 8-membered saturated cyclic amine or a 3- to 8-membered saturated cyclic amine bridged with C1-5alkylene or C1-4alkylene-O—C1-4alkylene between any different two carbon atoms of the cyclic amine, which cyclic amine is substituted with a group represented by —(CR1R2)m—(CHR3)n—OR9, R4 and R5 independently on the same or different carbon atoms of the cyclic amine;
Y is N or CR10;
R1 is hydrogen, hydroxy, C1-5alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
R2 is hydrogen or C1-5alkyl;
R3 is hydrogen, cyano, C105alkyl, C1-5alkoxy-C1-5alkyl or hydroxy-C1-5alkyl;
m is an integer selected from 0, 1, 2, 3, 4 and 5;
n is 0 or 1;
with the proviso that when n is 0, m is an integer selected from 1, 2, 3, 4 and 5;
R4 is hydrogen, hydroxy, hydroxy-C1-5alkyl, cyano, cyano-C1-5alkyl or C1-5alkyl;
R5 is hydrogen or C1-5alkyl;
R6 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy or —N(R11)R12;
R7 and R8 are the same or different, and independently are hydrogen, halogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, hydroxy, C1-5alkoxy, C3-8cycloalkyloxy —N(R11a)R12a, —CO2R13, cyano, nitro, C1-5alkylthio, trifluoromethyl or trifluoromethoxy; or R7 and R8 are taken together to form —CH2—CH2—CH2—CH2— or —CH═CH—CH═CH—;
R9 is C1-24acyl, C1-10alkoxycarbonyl, aryl-C1-5alkyloxycarbonyl, —CO—O—CHR14—O—CO—R15, P(═O)(OR14a)OR15a, —CO—(CH2)p—(CHR16)q—NR17R18, arylcarbonyl or heteroarylcarbonyl, wherein each said acyl, aryl and heteroaryl is unsubstituted or substituted with C1-5alkoxy, and C1-24acyl optionally includes one to six double bonds;
R10 is hydrogen, C1-5alkyl, halogen, cyano or —CO2R19;
Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C1-5alkyl, C3-8cycloalkyl, C2-5alkenyl, C2-5alkynyl, C1-5alkoxy, C1-5alkylthio, C1-5alkylsulfinyl, C1-5alkylsulfonyl, cyano, nitro, hydroxy, —CO2R19a, —C(═O)R19a, —CONR11bR12b, —OC(═O)R19a, —NR11bCO2R19a, —S(O)rNR11bR12b, hydroxy-C2-5alkylamino-C2-5alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and —N(R20)R21;
R11 and R12 are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
R11a and R12a are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
R11b and R12b are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl or C3-8cycloalkyl-C1-5alkyl;
R13 is hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, C1-5alkoxy-C1-5alkyl, C3-8cycloalkyloxy-C1-5alkyl or phenyl;
R14 and R15 are the same or different, and independently are hydrogen, C1-5alkyl or aryl-C1-5alkyl;
R14a and R15a are the same or different, and independently are hydrogen, C1-5alkyl or aryl-C1-5alkyl;
R16 is hydrogen, C1-5alkyl, aryl, heteroaryl, aryl-C1-5alkyl, heteroaryl-C1-5alkyl, hydroxy-C1-5alkyl, hydroxycarbonyl-C1-5alkyl, hydroxyphenyl-C1-5alkyl, C1-5alkoxy-C1-5alkyl, amino-C1-5alkyl, guanidino-C1-5alkyl, mercapto-C1-5alkyl, C1-5alkylthio-C1-5alkyl or aminocarbonyl-C1-5alkyl;
R17 and R18 are the same or different, and independently are hydrogen, C1-5alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-5alkyl, C1-10acyl, C1-10alkoxycarbonyl and aryl-C1-5alkyloxycarbonyl,
or R16 and R17 are taken together to form —CH2—, —CH2CH2—, —CH2CH2CH2— or —CH2CH2CH2CH2—;
p is an integer selected from 0, 1, 2, 3, 4 and 5;
q is 0 or 1;
R19 is hydrogen or C1-5alkyl;
R19a is hydrogen or C1-5alkyl;
r is 1 or 2;
R20 and R21 are the same or different, and independently are hydrogen or C1-5alkyl), individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
33. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 32 represented by the formula [VII], wherein Y is N; the cyclic amino group, m, n, R1, R2, R3, R4, R5, R6, R7, R8, R9 and Ar are as defined in claim 32; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
34. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 32 represented by formula [VII], wherein Y is N; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R1, R2, R4 and R5 are hydrogen; the cyclic amino group, R6, R7, R8, R9 and Ar are as defined in claim 32; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
35. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 32 represented by the formula [VII], wherein the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; Y is N; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl); R9 is as defined in claim 32; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
36. The pyrrolopyrimidine derivative substituted with the cyclic amino group according to claim 32 represented by the formula [VII], wherein the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0;
Y is N; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or methyl; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino; R9 is as defined in claim 32; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
37. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 32 represented by formula [VII], wherein Y is CR10; the cyclic amino group, m, n, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and Ar are as defined in claim 32; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
38. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 32 represented by formula [VII], wherein Y is CR10; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; R1, R2, R4 and R5 are hydrogen; the cyclic amino group, R6, R7, R8, R9, R10 and Ar are as defined in claim 32; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
39. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 32 represented by formula [VII], wherein Y is CR10; the cyclic amino group is a 4- to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R8 are the same or different, and independently are hydrogen or C1-5alkyl; R10 is hydrogen or halogen; Ar is phenyl or pyridyl which phenyl or pyridyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and —N(R20)R21 (wherein R20 and R21 are the same or different, and independently are hydrogen or C1-3alkyl); R9 is as defined in claim 32; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
40. The pyrrolopyridine derivative substituted with the cyclic amino group according to claim 32 represented by formula [VII], wherein Y is CR10; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; R1, R2, R4 and R5 are hydrogen; R6 is methyl; R7 and R9 are the same or different, and independently are hydrogen or methyl; R10 is hydrogen; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of chloro, bromo, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino; R9 is as defined in claim 32; individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
41. Compounds represented by formula [I] according to claim 1, which compounds are selected from the group consisting of
2-{1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-ethanol,
2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-ethanol,
2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-ethanol,
2-{1-[7-(4-bromo-2,6-diethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-ethanol,
2-{1-[2,5-dimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-ethanol,
3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-pro pan-1-ol,
3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-propan-1-ol,
{1-[7-(2,4-dibromo-6-methoxy-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-methanol,
{1-[7-(2,4-dibromo-6-methylsulfanyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-methanol,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-methanol,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-methanol,
{1-[2,5-dimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-methanol,
2-{1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-ethanol,
2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-y}}-ethanol,
2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-ethanol,
2-{1-[2,5-dimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo-2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-ethanol,
{1-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[2-methyl-9-(2,4,6-trimethyl-phenyl)-9H-1,3,9-triaza-fluoren-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(4-bromo-2,6-diethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(4-bromo-2,6-diethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[2,5,6-trimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[2,5-dimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(4-bromo-2,6-dichloro-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(4-bromo-2,6-dichloro-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(2,6-dibromo-4-isopropyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(2,6-dibromo-4-isopropyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
2-{1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[2,5,6-trimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[2,5-dimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
3-{1-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[2,5-dimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[7-(4-bromo-2,6-dichloro-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[7-(4-bromo-2,6-dichloro-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
{1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-yl}-methanol,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-yl}-methanol,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-yl}-methanol,
1-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethane-1,2-diol,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-2-yl}-methanol,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-2-yl}-methanol,
2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-ethanol,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-azepan-4-yl}-methanol,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-azepan-4-yl}-methanol,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-2-yl}-acetonitrile,
1-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
1-[2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
1-[7-(2,4-dibromo-6-methylsulfanyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
1-[7-(4-isopropyl-2-methylsulfanyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
1-[7-(4-isopropyl-2-methylsulfanyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
1-[7-(2-bromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
1-[7-(4-bromo-2,6-diethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
1-[7-(4-bromo-2,6-diethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-3-carbonitrile,
{1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-acetonitrile,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-acetonitrile,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-acetonitrile,
3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-propionitrile,
3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-3-yl}-propionitrile,
1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-4-carbonitrile,
1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-4-carbonitrile,
{1-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[7-(2,6-dibromo-4-trifluoromethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[7-(4-bromo-2,6-diethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[7-(4-bromo-2,6-diethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[2,5,6-trimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[2,5-dimethyl-7-(2,4,6-tribromo-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[7-(4-bromo-2,6-dichloro-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[7-(4-bromo-2,6-dichloro-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[7-(2,6-dibromo-4-isopropyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[7-(2,6-dibromo-4-isopropyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[7-(4-methoxy-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[7-(4-methoxy-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
8-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-8-aza-bicyclo[3.2.1]octane-3-carbonitrile,
8-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-8-aza-bicyclo[3.2.1]octane-3-carbonitrile,
1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidine-3-carbonitrile,
1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidine-3-carbonitrile,
1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-azepane-4-carbonitrile,
1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-azepane-4-carbonitrile,
1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-hydroxymethyl-piperidine-3-carbonitrile,
{1-[7-(4-isopropyl-2-methylsulfanyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(2-bromo-4-isopropyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(2,4-dibromo-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(2,6-dibromo-4-chloro-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
2-{1-[7-(2,6-dibromo-4-chloro-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
1-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propane-1,3-diol,
{1-[7-(2,6-dibromo-4-chloro-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-acetonitrile,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-acetonitrile,
{1-[2,5-dimethyl-7-(2,4,6-trichloro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
{1-[7-(2,6-dichloro-4-trifluoromethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol,
3-{1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propan-1-ol,
1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidine-4-carbonitrile,
{1-[7-(2,6-Dichloro-4-trifluoromethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-acetonitrile,
1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-azetidine-3-carbonitrile,
1-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
1-{1-[7-(4-isopropyl-2-methylsulfanyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
1-{1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
1-{1-[7-(4-chloro-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-methyl-piperidin-4-yl}-methanol,
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-methyl-piperidin-4-yl}-methanol,
{8-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-8-aza-bicyclo[3.2.1]oct-3-yl}-methanol,
{8-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-8-aza-bicyclo[3.2.1]oct-3-yl}-methanol,
{8-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-8-aza-bicyclo[3.2.1]oct-3-yl}-acetonitrile,
{8-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-8-aza-bicyclo[3.2.1]oct-3-yl}-acetonitrile,
2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-malononitrile,
2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-malononitrile,
2-{1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-3-yl}-ethanol,
2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-3-yl}-ethanol,
{1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
2-{1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
3-{1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-3-carbonitrile,
1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-3-carbonitrile,
{1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-3-yl}-acetonitrile,
1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
{1-[1-(2,4-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-3-yl}-ethanol,
{1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[1-(4-chloro-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[1-(4-chloro-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[1-(4-chloro-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[1-(4-chloro-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
3-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[1-(4-chloro-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[1-(4-chloro-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-3-carbonitrile,
1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[1-(4-chloro-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[1-(4-chloro-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
{1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(4-chloro-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(2,6-dibromo-4-isopropyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[1-(2,6-dibromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[2,3,6-trimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[3,6-dimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[1-(4-bromo-2,6-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[1-(4-bromo-2,6-dichloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[2,3,6-trimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[3,6-dimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[1-(2,6-dibromo-4-chloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[1-(2,6-dibromo-4-chloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[1-(4-methoxy-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[1-(4-methoxy-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[1-(2-bromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[1-(4-isopropyl-2-methylsulfanyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[1-(2,4-dibromo-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[1-(2-bromo-4-trifluoromethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[2,3,6-trimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
{1-[3,6-dimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-methanol,
2-{1-[1-(2,6-dibromo-4-isopropyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[1-(2,6-dibromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[2,3,6-trimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[3,6-dimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[1-(4-bromo-2,6-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[1-(4-bromo-2,6-dichloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[2,3,6-trimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[3,6-dimethyl-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[1-(2,6-dibromo-4-chloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[1-(2,6-dibromo-4-chloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[1-(4-methoxy-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[1-(4-methoxy-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[1-(2-bromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[1-(4-isopropyl-2-methylsulfanyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[1-(2,4-dibromo-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[2,3,6-trimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[3,6-dimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
2-{1-[5-bromo-1-(4-chloro-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethanol,
3-{1-[1-(2,6-dibromo-4-isopropyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[1-(2,6-dibromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[2,3,6-trimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[3,6-dimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[1-(4-bromo-2,6-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[1-(4-bromo-2,6-dichloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[2,3,6-trimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[3,6-dimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[1-(2,6-dibromo-4-chloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[1-(2,6-dibromo-4-chloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[1-(4-methoxy-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-pro pan-1-ol,
3-{1-[1-(4-methoxy-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[1-(4-isopropyl-2-methylsulfanyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[2,3,6-trimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
3-{1-[3,6-dimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propan-1-ol,
1-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethane-1,2-diol,
1-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethane-1,2-diol,
1-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propane-1,3-diol,
1-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-propane-1,3-diol, 1-[1-(2,6-dibromo-4-isopropyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[1-(2,6-dibromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[2,3,6-trimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[3,6-dimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[1-(4-bromo-2,6-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[1-(4-bromo-2,6-dichloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[2,3,6-trimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[3,6-dimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[1-(2,6-dibromo-4-chloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[1-(2,6-dibromo-4-chloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[1-(4-methoxy-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[1-(4-methoxy-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[1-(2-bromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[1-(4-isopropyl-2-methylsulfanyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[1-(2,4-dibromo-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[1-(2-bromo-4-trifluoromethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[2,3,6-trimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
1-[3,6-dimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidine-4-carbonitrile,
{1-[1-(4-chloro-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(2,6-dibromo-4-isopropyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(2,6-dibromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[2,3,6-trimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[3,6-dimethyl-1-(2,4,6-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(4-bromo-2,6-dichloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(4-bromo-2,6-dichloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[2,3,6-trimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[3,6-dimethyl-1-(2,4,6-trichloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(2,6-dibromo-4-chloro-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(2,6-dibromo-4-chloro-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(4-methoxy-2,6-dimethyl-phenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(4-methoxy-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(2-bromo-4-isopropyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(4-isopropyl-2-methylsulfanyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(2,4-dibromo-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[1-(2-bromo-4-trifluoromethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
{1-[3,6-dimethyl-1-(2,4,5-tribromo-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetonitrile,
carbonic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester ethyl ester,
pyridine-2-carboxylic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester,
methoxy-acetic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester,
methoxy-acetic acid 1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-ylmethyl ester,
carbonic acid benzyl ester 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester,
decanoic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester,
3-diethylamino-propionic acid 1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl ester
and phosphoric acid mono-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-ylmethyl} ester,
individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
42. An antagonist for CRF receptors, comprising a pyrrolopyrimidine or pyrrolopyridine derivative substituted with a cyclic amino group, a pharmaceutically acceptable salt thereof or its hydrate according to any one of claims 1 to 41, as an active ingredient.
43. Use of a pyrrolopyrimidine or pyrrolopyridine derivative substituted with a cyclic amino group, a pharmaceutically acceptable salt thereof or its hydrate according to any one of claim 1 to 41, for the manufacture of an antagonist for CRF receptors.
US10/504,981 2002-12-26 2003-12-24 Pyrrolopyrimidine and pyrrolopyridine derivatives substituted with cyclic amino group Abandoned US20050209253A1 (en)

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