US20110098280A1 - 2,4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders - Google Patents

2,4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders Download PDF

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US20110098280A1
US20110098280A1 US12/984,519 US98451911A US2011098280A1 US 20110098280 A1 US20110098280 A1 US 20110098280A1 US 98451911 A US98451911 A US 98451911A US 2011098280 A1 US2011098280 A1 US 2011098280A1
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Carlos Garcia-Echeverria
Takanori Kanazawa
Eiji Kawahara
Keiichi Masuya
Naoko Matsuura
Takahiro Miyake
Osamu Ohmori
Ichiro Umemura
Ruo Steensma
Greg Chopiuk
Jiqing Jiang
Yongqin Wan
Qiang Ding
Qiong Zhang
Nathanael Schiander Gray
Donald Karanewsky
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IRM LLC
Novartis AG
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Novartis AG
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Priority to GB0322370A priority patent/GB0322370D0/en
Priority to PCT/EP2004/009099 priority patent/WO2005016894A1/en
Priority to US56836706A priority
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Priority to US12/984,519 priority patent/US20110098280A1/en
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Assigned to NOVARTIS AG, IRM LLC reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHOPIUK, GREG, DING, QIANG, GRAY, NATHANAEL SCHIANDER, JIANG, JIQING, KARANEWSKY, DONALD, STEENSMA, RUO, WAN, YONGQIN, ZHANG, QIONG, KAWAHARA, EIJI, MATSUURA, NAOKO, MIYAKE, TAKAHIRO, OHMORI, OSAMU, UMEMURA, ICHIRO, KANAZAWA, TAKANORI, MASUYA, KEIICHI, GARCIA-ECHEVERRIA, CARLOS
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46Two or more oxygen, sulfur or nitrogen atoms
    • C07D239/48Two nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C04CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04BLIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/622Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/626Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
    • C04B35/63Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
    • C04B35/632Organic additives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Abstract

Novel pyrimidine derivatives of formula I
Figure US20110098280A1-20110428-C00001
to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.

Description

  • This application is a continuation of U.S. application Ser. No. 10/568,367, filed Aug. 18, 2006, which is a 371 U.S. national phase application of international application number PCT/EP2004/009099 filed Aug. 13, 2004, which application claims priority to GB application no. 0322370.8 filed Sep. 24, 2003 and GB application no. 0319227.5 filed Aug. 15, 2003, each of which is incorporated herein by reference in its entirety and for all purposes.
  • The present invention relates to the use novel pyrimidine derivatives, the certain novel pyrimidine derivatives, to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.
  • More particularly the present invention provides in a first aspect, the use of a compound of formula I
  • Figure US20110098280A1-20110428-C00002
  • wherein
    • R is selected from C6-10aryl, C5-10heteroaryl, C3-12cycloalkyl and C3-10heterocycloalkyl;
    • each of R0, R1, R2, and R3 independently is hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkinyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C8alkyl, C5-C10arylC1-C8alkyl, hydroxyC1-C8alkyl, C1-C8alkoxyC1-C8alkyl, aminoC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1, 2 or 3 hetero atoms selected from N, O and S, hydroxy, C1-C8alkoxy, hydroxyC1-C8alkoxy, C1-C8alkoxyC1-C8alkoxy, haloC1-C8alkoxy, unsubstituted or substituted C5-C10arylC1-C8alkoxy, unsubstituted or substituted heterocyclyloxy, or unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, C1-C8alkylthio, C1-C8alkylsulfinyl, C1-C8alkylsulfonyl, C5-C10arylsulfonyl, halogen, carboxy, C1-C8alkoxycarbonyl, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl, cyano, nitro, —S(O)0-2NR12R13, —S(O)0-2R13, —NR12S(O)0-2R13, —C(O)NR12R13, —C(O)R13 and —C(O)OR13; wherein R12 is selected from hydrogen and C1-6alkyl; and R13 is selected from hydrogen, C1-6alkyl and C3-12cycloalkyl; or R0 and R1, R1 and R2, and/or R2 and R3 form, together with the carbon atoms to which they are attached, a 5 or 6 membered carbocyclic or heterocyclic ring comprising 0, 1, 2 or 3 heteroatoms selected from N, O and S;
    • R4 is hydrogen or C1-C8alkyl;
    • each of R5 and R6 independently is hydrogen, C1-C8alkyl, C1-C8alkoxyC1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, halogen, carboxy, C1-C8alkoxycarbonyl, unsubstituted or substituted carbamoyl, cyano, or nitro;
    • R is unsubstituted or substituted by R7, R8, R9, R10, and R′10;
    • R7, R3, R9, R10, or R′10 is a substituent independently selected from hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkinyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C8alkyl, C5-C10arylC1-C8alkyl, hydroxyC1-C8alkyl, C1-C8alkoxyC1-C8alkyl, aminoC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1, 2 or 3 hetero atoms selected from N, O and S, hydroxy, C1-C8alkoxy, hydroxyC1-C8alkoxy, C1-C8alkoxyC1-C8alkoxy, haloC1-C8alkoxy, unsubstituted or substituted aminoC1-C8alkoxy, unsubstituted or substituted C5-C10arylC1-C8alkoxy, unsubstituted or substituted heterocyclyloxy, or unsubstituted or substituted heterocyclylC1-C8alkyl, unsubstituted or substituted heterocyclylC1-C8alkoxy, unsubstituted or substituted amino, C1-C8alkylthio, C1-C8alkylsulfinyl, C1-C8alkylsulfonyl, C5-C10arylsulfonyl, heterocyclosulfonyl, halogen, carboxy, C1-C8alkylcarbonyl, C1-C8alkoxycarbonyl, unsubstituted or substituted carbamoyl, unsubstituted or substituted sulfamoyl, cyano, nitro, —S(O)0-2NR12R13, —S(O)0-2R12, —C(O)R11, —OXR11, —NR12XR11, —NR12XNR12R13, —OXNR12R13, —OXR12 and —XR11;
    • or two adjacent substituents on R may form together with the carbon atoms to which they are attached, a unsubstituted or substituted 5 or 6 membered carbocyclic or heterocyclic ring comprising 0, 1, 2 or 3 heteroatoms selected from N, O and S;
    • X is a bond or C1-6alkylene; and
    • R11 is independently selected from C6-10aryl, C5-10heteroaryl, C3-12cycloalkyl and C3-10heterocycloalkyl;
    • and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R11 is optionally substituted by 1 to 3 radicals independently selected from C1-6alkyl, C3-10heterocycloalkyl-C0-4alkyl optionally substituted with C1-6alkyl, —C(O)R12, —C(O)NR12R13, —XNR12R13, —NR12XNR12R13 and —NR12C(O)R13; wherein X is a bond or C1-6alkylene; R12 and R13 are independently selected from hydrogen and C1-6alkyl;
      and salts thereof in the treatment of a disease associated to tyrosine kinase activity of anaplastic lymphoma kinase (ALK) or for the manufacture of pharmaceutical compositions for use in the treatment of said diseases, as well as use in the treatment of said diseases, to methods of use of such pyrimidine derivatives in the treatment of said diseases, and to pharmaceutical compositions comprising such pyrimidine derivatives for the treatment of said diseases.
  • The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:
  • Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
  • Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration. The compounds may thus be present as mixtures of isomers or as pure isomers, preferably as enantiomer-pure diastereomers.
  • The invention relates also to possible tautomers of the compounds of formula I.
  • C1-C8alkyl denotes a an alkyl radical having from 1 up to 8, especially up to 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching; preferably, C1-C8alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl; especially methyl, propyl or tert-butyl.
  • C2-C8alkenyl denotes a an alkenyl radical having from 2 up to 8, especially up to 5 carbon atoms, the radicals in question being either linear or branched with single or multiple branching; preferably, C2-C8alkenyl is pentenyl, such as 3-methyl-2-buten-2-yl, butenyl, such as 1- or 2-butenyl or 2-buten-2-yl, propenyl, such as 1-propenyl or allyl, or vinyl.
  • C2-C8alkinyl denotes a an alkinyl radical having from 2 up to 8, especially up to 5 carbon atoms, the radicals in question being either linear or branched; preferably, C2-C8alkinyl is propinyl, such as 1-propinyl or propargyl, or acetylenyl.
  • C3-C8cycloalkyl denotes a cycloalkyl radical having from 3 up to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl.
  • C1-C8alkoxy is especially methoxy, ethoxy, isopropyloxy, or tert-butoxy.
  • HydroxyC1-C8alkyl is especially hydroxymethyl, 2-hydroxyethyl or 2-hydroxy-2-propyl.
  • HydroxyC1-C8alkoxy is especially 2-hydroxyethoxy or 3-hydroxypropoxy.
  • C1-C8alkoxyC1-C8alkoxy is especially 2-methoxyethoxy.
  • C1-C8alkoxyC1-C8alkyl is especially methoxymethyl, 2-methoxyethyl or 2-ethoxyethyl.
  • Halogen is preferably fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.
  • HaloC1-C8alkyl is preferably chloroC1-C8alkyl or fluoroC1-C8alkyl, especially trifluoromethyl or pentafluoroethyl.
  • HaloC1-C8alkoxy is preferably chloroC1-C8alkoxy or fluoroC1-C8alkoxy, especially trifluoromethoxy.
  • C1-C8alkoxycarbonyl is especially tert-butoxycarbonyl, iso-propoxycarbonyl, methoxycarbonyl or ethoxycarbonyl.
  • Unsubstituted or substituted carbamoyl is carbamoyl substituted by one or two substituents selected from hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkinyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C8alkyl, C5-C10arylC1-C8alkyl, hydroxyC1-C8alkyl, C1-C8alkoxyC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, or aminoC1-C8alkyl, or carbamoyl wherein the substituents and the nitrogen atom of the carbamoyl group represent a 5 or 6 membered heterocyclyl further comprising 0, 1 or 2 hetero atoms selected from N, O and S; and is preferably carbamoyl, methylcarbamoyl, dimethylcarbamoyl, propylcarbamoyl, hydroxyethyl-methyl-carbamoyl, di(hydroxyethyl)carbamoyl, dimethylaminoethylcarbamoyl, or pyrrolidinocarbonyl, piperidinocarbonyl, N-methylpiperazinocarbonyl or morpholinocarbonyl, especially carbamoyl or dimethylcarbamoyl.
  • Unsubstituted or substituted sulfamoyl is sulfamoyl substituted by one or two substituents selected from hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkinyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C8alkyl, C5-C10arylC1-C8alkyl, hydroxyC1-C8alkyl, C1-C8alkoxyC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, or aminoC1-C8alkyl, or sulfamoyl wherein the substituents and the nitrogen atom of the sulfamoyl group represent a 5 or 6 membered heterocyclyl further comprising 0, 1 or 2 hetero atoms selected from N, O and S; and is preferably sulfamoyl, methylsulfamoyl, propylsulfamoyl, cyclopropylmethyl-sulfamoyl, 2,2,2-trifluoroethylsulfamoyl, dimethylaminoethylsulfamoyl, dimethylsulfamoyl, hydroxyethyl-methyl-sulfamoyl, di(hydroxyethyl)sulfamoyl, or pyrrolidinosulfonyl, piperidinosulfonyl, N-methylpiperazinosulfonyl or morpholinosulfonyl, especially sulfamoyl or methylsulfamoyl.
  • Unsubstituted or substituted amino is amino substituted by one or two substituents selected from hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkinyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C8alkyl, C5-C10arylC1-C8alkyl, hydroxyC1-C8alkyl, C1-C8alkoxyC1-C8alkyl, haloC1-C8alkyl, unsubstituted or substituted C5-C10aryl, aminoC1-C8alkyl, acyl, e.g. formyl, C1-C8alkylcarbonyl, C5-C10arylcarbonyl, C1-C8alkylsulfonyl or C5-C10arylsulfonyl, and is preferably amino, methylamino, dimethylamino, propylamino, benzylamino, hydroxyethyl-methyl-amino, di(hydroxyethyl)amino, dimethylaminoethylamino, acetylamino, acetyl-methyl-amino, benzoylamino, methylsulfonylamino or phenylsulfonylamino, especially amino or dimethylamino.
  • AminoC1-C8alkyl is especially aminoethyl, methylaminoethyl, dimethylaminoethyl or dimethylaminopropyl.
  • Unsubstituted or substituted C5-C10aryl is, for example, phenyl, indenyl, indanyl, naphthyl, or 1,2,3,4-tetrahydronaphthalenyl, optionally substituted by C1-C8alkyl, C1-C8alkoxyC1-C8alkyl, haloC1-C8alkyl, hydroxy, C1-C8alkoxy, methylenedioxy, amino, substituted amino, halogen, carboxy, C1-C8alkoxycarbonyl, carbamoyl, sulfamoyl, cyano or nitro; preferably phenyl, tolyl, trifluoromethylphenyl, methoxyphenyl, dimethoxyphenyl, methylenedioxyphenyl, chlorophenyl or bromophenyl, whereby the substituents may be in ortho, meta or para position, preferably meta or para.
  • C5-C10aryloxy is especially phenoxy or methoxyphenoxy, e.g. p-methoxyphenoxy.
  • C5-C10arylC1-C8alkyl is especially benzyl or 2-phenylethyl.
  • C5-C10arylC1-C8alkoxy is especially benzyloxy or 2-phenylethoxy.
  • Unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1, 2 or 3 hetero atoms selected from N, O and S may be unsaturated, partially unsaturated or saturated, and further condensed to a benzo group or a 5 or 6 membered heterocyclyl group, and may be bound through a hetero or a carbon atom, and is, for example, pyrrolyl, indolyl, pyrrolidinyl, imidazolyl, benzimidazolyl, pyrazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyridyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, piperidyl, pyrimidinyl, pyrazinyl, piperazinyl, purinyl, tetrazinyl, oxazolyl, isoxalyl, morpholinyl, thiazolyl, benzothiazolyl, oxadiazolyl, and benzoxadiazolyl. Substituents considered are C1-C8alkyl, hydroxyC1-C8alkyl, C1-C8alkoxyC1-C8alkyl, C1-C8alkoxyC1-C8alkoxy, haloC1-C8alkyl, hydroxy, amino, substituted amino, C1-C8alkoxy, halogen, carboxy, C1-C8alkylcarbonyl, C1-C8alkoxycarbonyl, carbamoyl, C1-C8alkylcarbamoyl, cyano, oxo, or unsubstituted or substituted 5 or 6 membered heterocyclyl as defined in this paragraph. 5 or 6 membered heterocyclyl preferably comprises 1 or 2 hetero atoms selected from N, O and S, and is especially indolyl, pyrrolidinyl, pyrrolidonyl, imidazolyl, N-methylimidazolyl, benzimidazolyl, S,S-dioxoisothiazolidinyl, piperidyl, 4-acetylaminopiperidyl, 4-methylcarbamoylpiperidyl, 4-piperidinopiperidyl, 4-cyanopiperidyl, piperazinyl, N-methylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, morpholinyl, 1-aza-2,2-dioxo-2-thiacyclohexyl, or sulfolanyl.
  • In unsubstituted or substituted heterocyclyloxy, heterocyclyl has the meaning as defined above, and is especially N-methyl-4-piperidyloxy. In unsubstituted or substituted heterocyclylC1-C8alkoxy, heterocyclyl has the meaning as defined above, and is especially 2-pyrrolidinoethoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 1-methyl-piperidin-3-ylmethoxy, 3-(N-methylpiperazino)propoxy or 2-(1-imidazolyl)ethoxy.
  • In a 5 or 6 membered carbocyclic or heterocyclic ring comprising 0, 1, 2 or 3 heteroatoms selected from N, O and S, and formed by two adjacent substituents together with the benzene ring, the ring may be further substituted, e.g. by C1-C8alkyl, C1-C8alkoxy, haloC1-C8alkyl, hydroxy, amino, substituted amino, C1-C8alkoxy, halogen, carboxy, C1-C8alkoxycarbonyl, carbamoyl, cyano, or oxo. The two adjacent substituents forming such a ring are preferably propylene, butylene, 1-aza-2-propylidene, 3-aza-1-propylidene, 1,2-diaza-2-propylidene, 2,3-diaza-1-propylidene, 1-oxapropylene, 1-oxapropylidene, methylenedioxy, difluoromethylene-dioxy, 2-aza-1-oxopropylene, 2-aza-2-methyl-1-oxopropylene, 1-aza-2-oxopropylene, 2-aza-1,1-dioxo-1-thiapropylene or the corresponding butylene derivatives forming a 6 membered ring.
  • Salts are especially the pharmaceutically acceptable salts of compounds of formula I.
  • Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
  • For isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
  • In view of the close relationship between the novel compounds in free form and those in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the novel compounds, any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
  • The compounds of formula I have valuable pharmacological properties, as described hereinbefore and hereinafter.
  • In formula I the following significances are preferred independently, collectively or in any combination or sub-combination. R is C6-10aryl, C5-10heteroaryl, C3-12cycloalkyl or C3-10heterocycloalkyl, preferably R is
  • Figure US20110098280A1-20110428-C00003
  • wherein R7, R8, R9, R10, or R′10 are as defined above;
  • In each of the following significances A, D or E is C or N but A, D and E may not all be N, preferably A, D or E is C:
    • (a) each of R0 or R2 independently is hydrogen, C1-C8alkyl, e.g. methyl, ethyl or isopropyl, hydroxyC1-C8alkyl, e.g. hydroxyethyl or hydroxybutyl, haloC1-C8alkyl, e.g. trifluoromethyl, unsubstituted or substituted C5-C10aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, C1-C8alkoxy, e.g. methoxy, ethoxy or isopropoxy, haloC1-C8alkoxy, e.g. trifluoromethoxy, C5-C10aryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, C1-C8alkylsulfonyl, e.g. methylsulfonyl, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morpholinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably hydrogen, piperazino, N-methylpiperazino or 1-methyl-4-piperidyloxy, —S(O)0-2NR12R13, —S(O)0-2R13, —NR12S(O)0-2R13, —C(O)NR12R13, and —C(O)OR13 in particular hydrogen;
    • (b) R1 is hydrogen, C1-C8alkyl, e.g. methyl, ethyl or isopropyl, hydroxyC1-C8alkyl, e.g. hydroxyethyl or hydroxybutyl, haloC1-C8alkyl, e.g. trifluoromethyl, unsubstituted or substituted C5-C10aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, C1-C8alkoxy, e.g. methoxy, ethoxy or isopropoxy, haloC1-C8alkoxy, e.g. trifluoromethoxy, C5-C10aryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, C1-C8alkylsulfonyl, e.g. methylsulfonyl, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morpholinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably hydrogen, piperazino, N-methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3-morpholinopropoxy or 2-morpholinoethoxy, in particular hydrogen;
    • (c) R3 is hydrogen, C1-C8alkyl, e.g. methyl or ethyl, hydroxyC1-C8alkyl, e.g. hydroxyethyl or hydroxybutyl, haloC1-C8alkyl, e.g. trifluoromethyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O and S, e.g. 2-pyrrolidonyl or S,S-dioxoisothiazolidinyl, C1-C8alkoxy, e.g. methoxy, substituted amino, e.g. acetylamino, acetyl-methyl-amino, benzoylamino, methylsulfonylamino or phenylsulfonylamino, C1-C8alkylsulfonyl, e.g. methylsulfonyl, propyl-sulfonyl, cyclohexyl-sulfonyl, isopropyl-sulfonyl, C5-C10arylsulfonyl, e.g. phenylsulfonyl, halogen, e.g. fluoro or chloro, carboxy, substituted or unsubstituted carbamoyl, e.g. carbamoyl, methylcarbamoyl, ethyl-amino-carbonyl or dimethylcarbamoyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl, isobutylsulfamoyl, cyclopropylmethyl-sulfamoyl, 2,2,2-trifluoroethylsulfamoyl, dimethylsulfamoyl or morpholinosulfonyl dimethyl-sulfamoyl, ethyl-sulfamoyl, 1-ethyl-propyl-sulfamoyl, cyclopentyl-sulfamoyl, cyclobutyl-sulfamoyl; preferably sulfamoyl, methylsulfamoyl or propylsulfamoyl;
    • (d) each pair of adjacent substituents R0 and R1, or R1 and R2, or R2 and R3 are —CH2—NH—CO—, —CH2—CH2—NH—CO—, —CH2—CO—NH—, —CH2—CH2—CO—NH—, —CH2—NH—SO2—, —CH2—CH2—NH—SO2—, —CH2—SO2—NH—, —CH2—CH2—SO2—NH—, —CH2—CH2—SO2—, —CH2—CH2—CH2—SO2—, —O—CH2—O—, or —O—CF2—O—, and such pairs wherein hydrogen in NH is replaced by C1-C8alkyl; preferably the pair of adjacent substituents R0 and R1, or R1 and R2 being —O—CH2—O—, and the pair of adjacent substituents R2 and R3 being —CH2—NH—CO— or —CH2—NH—SO2—.
    • (e) R4 is hydrogen or C1-C8alkyl, e.g. methyl; preferably hydrogen;
    • (f) R5 is hydrogen; C1-C8alkyl, e.g. methyl or ethyl, halogen, e.g. chloro or bromo, haloC1-C8alkyl, e.g. trifluoromethyl, cyano or nitro; preferably hydrogen, methyl, ethyl, chloro, bromo, trifluoromethyl or nitro; in particular chloro or bromo;
    • (g) R6 is hydrogen;
    • (h) each of R7 and R9 independently is hydrogen, C1-C8alkyl, e.g. methyl, ethyl or isopropyl, hydroxyC1-C8alkyl, e.g. hydroxyethyl or hydroxybutyl, C1-C8alkylcarbonyl, e.g methyl carbonyl, aminoalkoxy, e.g diethylaminoethoxy, haloC1-C8alkyl, e.g. trifluoromethyl, unsubstituted or substituted C5-C10aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, C1-C8alkoxy, e.g. methoxy, ethoxy or isopropoxy, haloC1-C8alkoxy, e.g. trifluoromethoxy, C5-C10aryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, C1-C8alkylsulfonyl, e.g. methylsulfonyl, heterocyclosulfonyl, e.g piperazinylsulfonyl, heterocyclocarbonyl, e.g. methylpiperazinylcarbonyl, cyano, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morpholinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, methoxyphenyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 2-(1-imidazolyl)ethoxy, dimethylamino, fluoro, morpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl;
    • (i) R8 is hydrogen, C1-C8alkyl, e.g. methyl, ethyl or isopropyl, hydroxyC1-C8alkyl, e.g. hydroxyethyl or hydroxybutyl, haloC1-C8alkyl, e.g. trifluoromethyl, C5-C10aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, heterocyclylalkyl, e.g. methylpiperazinoethyl, heterocyclylcarbonyl, e.g. piperazinocarbonyl, heterocyclyl C1-C8alkylamino, e.g. pyridylethyl(methyl)amino, C1-C8alkoxy, e.g. methoxy, ethoxy or isopropoxy, haloC1-C8alkoxy, e.g. trifluoromethoxy, C5-C10aryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino or dimethylamino, C1-C8alkylamino-C1-C8alkylamino, e.g. dimethylamino-propylamino, C1-C8alkylsulfonyl, e.g. methylsulfonyl, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morpholinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl, cyano, or nitro; preferably hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoromethoxy, phenoxy, 1-methyl-4-piperidyloxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-(N-methylpiperazino)-propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro;
    • (j) R10 is hydrogen, C1-C8alkyl, e.g. methyl, ethyl or butyl, hydroxy, cyano, hydroxyC1-C8alkyl, e.g. hydroxyethyl or hydroxybutyl, haloC1-C8alkyl, e.g. trifluoromethyl, C1-C8alkoxy, e.g. methoxy or ethoxy, cycloalkylalkoxy, aryloxy, haloC1-C8alkoxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, e.g. 2-(1-imidazolyl)ethoxy, unsubstituted or substituted amino, e.g. methylamino or dimethylamino, halogen, e.g. fluoro or chloro; carboxy, carbamoyl, or unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably methyl, butyl, methoxy, ethoxy, 2-(1-imidazolyl)ethoxy, methylamino, dimethylamino or fluoro; and
    • (k) each pair of adjacent substituents R7 and R8, or R8 and R9 or R9 and R10, are —NH—CH═CH—, —CH═CH—NH—, —NH—N═CH—, —CH═N—NH—, —CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—, —CH2—CH2—O—, —CH2C(CH3)2O—, —CH═C(CH3)O—, —OCH2CH2O—, -(Morpholinopropyl)N—CH═CH—, —CH═CH—O—, —O—CH2—O—, or —O—CF2—O—; preferably the pair of adjacent substituents R7 and R8 or R8 and R9 being —O—CH2—O— or the pair of adjacent substituents R9 and R10 being —NH—CH═CH—, —CH═N—NH—, —CH2—CH2—CH2—, —CH2—CH2—CH2—CH2— or —O—CF2—O—.
    • (l) or R7, R8, R9, R10 and R′10 are ethoxy, ethyl, propyl, methyl, t-butyl, trifluoromethyl, nitrile, cyclobutyloxy, 2,2,2-trifluoroethoxy, methoxy, isobutyloxy, t-butyloxy, isopropyloxy, methyl-amino-carbonyl, cyclopropyl-methoxy, dimethylamino-propyl-amino, methoxy-ethoxy, —XR11, —C(O)R11 and —OXR11; wherein X is a bond, methylene or ethylene; R11 is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, azepanyl and 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl; wherein R11 is optionally substituted by 1 to 3 radicals independently selected from methyl, isopropyl, acetyl, acetyl-methyl-amino, 3-dimethylamino-2,2-dimethyl-propylamino, ethyl-methyl-amino-ethoxy, diethyl-amino-ethoxy, amino-carbonyl, ethyl, 2-oxo-pyrrolidin-1-yl, pyrrolidinyl, pyrrolidinyl-methyl, piperidinyl optionally substituted with methyl or ethyl, morpholino, dimethylamino, dimethylamino-propyl-amino, methyl-amino and ethyl-amino.
  • More preferred are the following meanings, independently, collectively or in any combination or sub-combination:
    • (a′) each of R0 or R2 independently is hydrogen, C1-C8alkyl, e.g. methyl, ethyl or isopropyl, haloC1-C8alkyl, e.g. trifluoromethyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, C1-C8alkoxy, e.g. methoxy, ethoxy or isopropoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, halogen, e.g. fluoro or chloro; preferably hydrogen, piperazino, N-methylpiperazino or 1-methyl-4-piperidyloxy, in particular hydrogen;
    • (b′) R1 is hydrogen, C1-C8alkyl, e.g. methyl, ethyl or isopropyl, haloC1-C8alkyl, e.g. trifluoromethyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, C1-C8alkoxy, e.g. methoxy, ethoxy or isopropoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, halogen, e.g. fluoro or chloro; preferably hydrogen, piperazino, N-methylpiperazino, morpholino, 1-methyl-4-piperidinyloxy, 3-morpholinopropoxy or 2-morpholinoethoxy, in particular hydrogen;
    • (c′) R3 is hydrogen, C1-C8alkyl, e.g. methyl or ethyl, haloC1-C8alkyl, e.g. trifluoromethyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O and S, e.g. 2-pyrrolidonyl or S,S-dioxoisothiazolidinyl, C1-C8alkoxy, e.g. methoxy, substituted amino, e.g. acetylamino, acetyl-methyl-amino, benzoylamino, methylsulfonylamino or phenylsulfonylamino, C1-C8alkylsulfonyl, e.g. methylsulfonyl, C5-C10arylsulfonyl, e.g. phenylsulfonyl, halogen, e.g. fluoro or chloro, carboxy, substituted or unsubstituted carbamoyl, e.g. carbamoyl, methylcarbamoyl or dimethylcarbamoyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl, isobutylsulfamoyl, cyclopropylmethyl-sulfamoyl, 2,2,2-trifluoroethylsulfamoyl, dimethylsulfamoyl or morpholinosulfonyl; preferably sulfamoyl, methylsulfamoyl or propylsulfamoyl;
    • (d′) each pair of adjacent substituents R0 and R1, or R1 and R2, or R2 and R3 are —CH2—NH—CO—, —CH2—NH—SO2—, —CH2—CH2—SO2—, —O—CH2—O—, or —O—CF2—O—, and such pairs wherein hydrogen in NH is replaced by C1-C8alkyl; preferably the pair of adjacent substituents R0 and R1, or R1 and R2 being —O—CH2—O—, and the pair of adjacent substituents R2 and R3 being —CH2—NH—CO— or —CH2—NH—SO2—.
    • (e′) R4 is hydrogen;
    • (f′) R5 is hydrogen, halogen, e.g. chloro or bromo, haloC1-C8alkyl, e.g. trifluoromethyl, or nitro; preferably hydrogen, chloro, bromo, trifluoromethyl or nitro; in particular chloro or bromo;
    • (g′) R6 is hydrogen;
    • (h′) each of R7 and R9 independently is hydrogen, C1-C8alkyl, e.g. methyl, ethyl or isopropyl, haloC1-C8alkyl, e.g. trifluoromethyl, unsubstituted or substituted C5-C10aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, C1-C8alkoxy, e.g. methoxy, ethoxy or isopropoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino, dimethylamino or acetylamino, halogen, e.g. fluoro or chloro, unsubstituted or substituted carbamoyl, e.g. cyclohexylcarbamoyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl or morpholinocarbonyl, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl; preferably hydrogen, methyl, isopropyl, trifluoromethyl, phenyl, o-, m- or p-methoxyphenyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, isopropoxy, phenoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 2-(1-imidazolyl)ethoxy, dimethylamino, fluoro, morpholinocarbonyl, piperidinocarbonyl, piperazinocarbonyl or cyclohexylcarbamoyl;
    • (i′) R8 is hydrogen, C1-C8alkyl, e.g. methyl, ethyl or isopropyl, haloC1-C8alkyl, e.g. trifluoromethyl, C5-C10aryl, e.g. phenyl or methoxyphenyl, unsubstituted or substituted 5 or 6 membered heterocyclyl comprising 1 or 2 hetero atoms selected from N, O and S, e.g. morpholino, piperidino, piperazino or N-methylpiperazino, C1-C8alkoxy, e.g. methoxy, ethoxy or isopropoxy, haloC1-C8alkoxy, e.g. trifluoromethoxy, C5-C10aryloxy, e.g. phenoxy, unsubstituted or substituted heterocyclyloxy, e.g. 1-methyl-4-piperidyloxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, e.g. 2-(1-imidazolyl)ethoxy, 3-morpholinopropoxy or 2-morpholinoethoxy, unsubstituted or substituted amino, e.g. methylamino or dimethylamino, halogen, e.g. fluoro or chloro, unsubstituted or substituted sulfamoyl, e.g. sulfamoyl, methylsulfamoyl or dimethylsulfamoyl, or nitro; preferably hydrogen, methyl, piperidino, piperazino, N-methylpiperazino, morpholino, methoxy, ethoxy, trifluoromethoxy, phenoxy, 1-methyl-4-piperidyloxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-(N-methylpiperazino)-propoxy, methylamino, fluoro, chloro, sulfamoyl or nitro;
    • (j′) R10 is C1-C8alkyl, e.g. methyl, ethyl or butyl, haloC1-C8alkyl, e.g. trifluoromethyl, C1-C8alkoxy, e.g. methoxy or ethoxy, unsubstituted or substituted heterocyclylC1-C8alkoxy, e.g. 2-(1-imidazolyl)ethoxy, unsubstituted or substituted amino, e.g. methylamino or dimethylamino, halogen, e.g. fluoro or chloro; preferably methyl, butyl, methoxy, ethoxy, 2-(1-imidazolyl)ethoxy, methylamino, dimethylamino or fluoro; and
    • (k′) each pair of adjacent substituents R7 and R8, or R8 and R9 or R9 and R10, are —NH—CH═CH—, —CH═CH—NH—, —NH—N═CH—, —CH═N—NH—, —CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—, —O—CH2—O—, or —O—CF2—O—; preferably the pair of adjacent substituents R7 and R8 or R8 and R9 being —O—CH2—O— or the pair of adjacent substituents R9 and R10 being —NH—CH═CH—, —CH═N—NH—, —CH2—CH2—CH2—, —CH2—CH2—CH2—CH2— or —O—CF2—O—.
    • Most preferred as compounds of the formula I are those wherein the substituents have the meaning given in the Examples.
  • In another embodiment of the invention the invention provides a compound of formula I′ with the proviso that this does not include any of the compounds of examples 1 to 52 inclusive.
  • Figure US20110098280A1-20110428-C00004
      • in which:
      • n′ is selected from 1, 2 and 3;
      • R′1 is selected from C6-10aryl, C5-10heteroaryl, C3-12cycloalkyl and C3-10heterocycloalkyl;
      • wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R′1 is optionally substituted by 1 to 3 radicals independently selected from C1-6alkyl, C1-6alkoxy, alkoxy-substituted-C1-6alkyl, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, —C(O)NR′5R′6, —S(O)0-2NR′5R′6, —S(O)0-2R′5, —C(O)R′4, —OXR′4, —NR′5XNR′5R′, —OXNR′5R′6, —OXOR′5 and —XR′4;
      • wherein X′ is a bond or C1-6alkylene; R′5 is selected from hydrogen and C1-6alkyl; R′6 is selected from hydrogen, C1-6alkyl and C3-12cycloalkyl-C1-4alkyl; and R′4 is independently selected from C6-10aryl, C5-10heteroaryl, C3-12cycloalkyl and C3-10heterocycloalkyl;
      • and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R′4 is optionally substituted by 1 to 3 radicals independently selected from C1-6alkyl, C3-10heterocycloalkyl-C0-4alkyl optionally substituted with C1-6alkyl, —C(O)NR′5R′6, —XNR′5R′6, —NR′5XNR′5R′6 and —NR′5C(O)R′6; wherein X is a bond or C1-6alkylene; R′5 and R′6 are independently selected from hydrogen and C1-6alkyl;
      • R′2 is selected from hydrogen and halo, cyano, C1-6alkyl, halo-substituted-C1-6alkyl;
      • R′3 is selected from halo, —S(O)0-2NR′5R′6, —S(O)0-2R′6, —NR′5S(O)0-2R′6, —C(O)NR′5R′6, —C(O)R′6 and —C(O)OR′6; wherein R′5 is selected from hydrogen and C1-6alkyl; and R′6 is selected from hydrogen, C1-6alkyl and C3-12cycloalkyl;
      • and the pharmaceutically acceptable salts, hydrates, solvates, isomers and prodrugs thereof.
  • Preferably a compound of formula I′ in which:
      • n′ is selected from 1 and 2;
      • R′1 is selected from C6-10aryl and C5-10heteroaryl; wherein any aryl or heteroaryl of R1 is optionally substituted by 1 to 3 radicals independently selected from C1-6alkyl, C1-6alkoxy, —C(O)NR′5R′6, —OX′R′4, —C(O)R′4, —NR′5X′NR′5R′6, —OX′NR′5R′6, —OX′OR′5 and —X′R′4; wherein X′ is a bond or C1-6alkylene; R′5 is selected from hydrogen and C1-6alkyl; R′6 is selected from hydrogen, C1-6alkyl and C3-12cycloalkyl-C1-4alkyl; and R′4 is C3-10heterocycloalkyl optionally substituted by 1 to 3 radicals independently selected from C1-6alkyl, halo-substituted-C1-6alkyl, C3-10heterocycloalkyl-C0-4alkyl optionally substituted with C1-6alkyl, —C(O)NR′5R′6, —X′NR′5R′6, —NR′5X′NR′5R′6 and —NR′5C(O)R′6; wherein X′ is a bond or C1-6alkylene; R′5 and R′6 are independently selected from hydrogen and C1-6alkyl;
      • R′2 is selected from hydrogen and halo;
      • R′3 is selected from halo, —S(O)0-2NR′5R′6, —S(O)0-2R′6, —NR′5S(O)0-2R′6, —C(O)NR′5R′6 and —C(O)OR′6; wherein R′5 is selected from hydrogen and C1-6alkyl; and R′6 is selected from hydrogen, C1-6alkyl and C3-12cycloalkyl.
  • more preferably a compound of formula I′ in which R′1 is selected from phenyl, pyridinyl, pyrazolyl and pyrimidinyl; wherein any aryl or heteroaryl of R′1 is optionally substituted by 1 to 3 radicals independently selected from ethoxy, ethyl, propyl, methyl, t-butyl, trifluoromethyl, nitrile, cyclobutyloxy, 2,2,2-trifluoroethoxy, methoxy, isobutyloxy, t-butyloxy, isopropyloxy, methyl-amino-carbonyl, cyclopropyl-methoxy, dimethylamino-propyl-amino, methoxy-ethoxy, —X′R′4, —C(O)R′4 and —OX′R′4; wherein X′ is a bond, methylene or ethylene; R′4 is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, azepanyl and 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl; wherein R′4 is optionally substituted by 1 to 3 radicals independently selected from methyl, isopropyl, acetyl, acetyl-methyl-amino, 3-dimethylamino-2,2-dimethyl-propylamino, ethyl-methyl-amino-ethoxy, diethyl-amino-ethoxy, amino-carbonyl, ethyl, 2-oxo-pyrrolidin-1-yl, pyrrolidinyl, pyrrolidinyl-methyl, piperidinyl optionally substituted with methyl or ethyl, morpholino, dimethylamino, dimethylamino-propyl-amino, methyl-amino and ethyl-amino.
  • Even more preferably a compound of formula I′ in which R′2 is selected from hydrogen and halo; and R′3 is selected from halo, dimethyl-sulfamoyl, isobutyl-sulfamoyl, methyl-sulfamoyl, ethyl-sulfamoyl, propyl-sulfonyl, ethyl-amino-carbonyl, 1-ethyl-propyl-sulfamoyl, cyclopentyl-sulfamoyl, isopropyl-sulfamoyl, cyclohexyl-sulfonyl, cyclopropyl-methyl-sulfamoyl, cyclobutyl-sulfamoyl, isopropyl-sulfonyl,
  • Most preferably a compound of example 53
  • In a yet further embodiment of the invention the present invention also provides a process for the production of a compound of formula I, comprising reacting a compound of formula II
  • Figure US20110098280A1-20110428-C00005
  • wherein R0, R1, R2, R3, R4, R5, and R6 are as defined above, and Y is a leaving group, preferably halogen such as bromide, iodine, or in particular chloride;
    with a compound of formula III
  • Figure US20110098280A1-20110428-C00006
  • wherein R7, R8, R9 and R10 are as defined above; and, if desired, converting a compound of formula I, wherein the substituents have the meaning as defined above, into another compound of formula I as defined;
    and recovering the resulting compound of formula I in free from or as a salt, and, when required, converting the compound of formula I obtained in free form into the desired salt, or an obtained salt into the free form.
  • The reaction can be carried out in a manner known per se, the reaction conditions being dependent especially on the reactivity of the leaving group Y and the reactivity of the amino group in the aniline of formula III, usually in the presence of a suitable solvent or diluent or of a mixture thereof and, if necessary, in the presence of an acid or a base, with cooling or, preferably, with heating, for example in a temperature range from approximately −30° C. to approximately +150° C., especially approximately from 0° C. to +100° C., preferably from room temperature (approx. +20° C.) to +80° C., in an open or closed reaction vessel and/or in the atmosphere of an inert gas, for example nitrogen. Alternatively, the reaction can proceed in the presence of a suitable catalyst (for example, palladium di-benzyl-acetone), in the presence of a base (for example, caesium carbonate) and in the presence of a suitable reaction facilitator (for example, xanthphos).
  • If one or more other functional groups, for example carboxy, hydroxy or amino, are or need to be protected in a compound of formula II or III, because they should not take part in the reaction, these are such groups as are usually used in the synthesis of peptide compounds, cephalosporins and penicillins, as well as nucleic acid derivatives and sugars.
  • The protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as substitution reaction or solvolysis. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove.
  • Salts of a compound of formula I with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of formula I may thus be obtained by treatment with an acid or with a suitable anion exchange reagent.
  • Salts can usually be converted to compounds in free form, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • Stereoisomeric mixtures, e.g. mixtures of diastereomers, can be separated into their corresponding isomers in a manner known per se by means of suitable separation methods. Diastereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This separation may take place either at the level of a starting compound or in a compound of formula I itself. Enantiomers may be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands.
  • It should be emphasized that reactions analogous to the conversions mentioned in this chapter may also take place at the level of appropriate intermediates.
  • The compounds of formula I, including their salts, are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization (present as solvates).
  • The compound of formula II used as starting materials may be obtained by reacting a compound of formula IV
  • Figure US20110098280A1-20110428-C00007
  • with a compound of formula V
  • Figure US20110098280A1-20110428-C00008
  • wherein R1, R2, R3, R4, R5 and R6 are as defined above, and Y1 and Y2 are identical or different leaving groups as defined above for Y. The reaction conditions are those mentioned above for the reaction of a compound of formula II with a compound of formula III.
  • The compounds of formula IV and V are known or may be produced in accordance with known procedures.
  • The compounds of formula I and their pharmaceutically acceptable salts exhibit valuable pharmacological properties when tested in vitro in cell-free kinase assays and in cellular assays, and are therefore useful as pharmaceuticals. In particular, the compounds of the invention are inhibitors of Focal Adhesion Kinase, and are useful as pharmaceuticals to treat conditions caused by a malfunction of signal cascades connected with Focal Adhesion Kinase, in particular tumors as described hereinbelow.
  • Focal Adhesion Kinase (FAK) is a key enzyme in the integrin-mediated outside-in signal cascade (D. Schlaepfer et al., Prog Biophys Mol Biol 1999, 71, 435-478). Interaction between cells and extracellular matrix (ECM) proteins is transduced as intracellular signals important for growth, survival and migration through cell surface receptors, integrins. FAK plays an essential role in these integrin-mediated outside-in signal cascades. The trigger in the signal transduction cascade is the autophosphorylation of Y397. Phosphorylated Y397 is a SH2 docking site for Src family tyrosine kinases. The bound c-Src kinase phosphorylates other tyrosine residues in FAK. Among them, phosphorylated Y925 becomes a binding site for the SH2 site of Grb2 small adaptor protein. This direct binding of Grb2 to FAK is one of the key steps for the activation of down stream targets such as the Ras-ERK2/MAP kinase cascade.
  • The inhibition of endogenous FAK signalling results in reduced motility and in some cases induces cell death. On the other hand, enhancing FAK signalling by exogenous expression increases cell motility and transmitting a cell survival signal from ECM. In addition FAK is overexpressed in invasive and metastatic epithelial, mesenchymal, thyroid and prostate cancers. Consequently, an inhibitor of FAK is likely to be a drug for anti-tumor growth and metastasis. The compounds of the invention are thus indicated, for example, to prevent and/or treat a vertebrate and more particularly a mammal, affected by a neoplastic disease, in particular breast tumor, cancer of the bowel (colon and rectum), stomach cancer and cancer of the ovary and prostate, non-small cell lung cancer, small cell lung cancer, cancer of liver, melanoma, bladder tumor and cancer of head and neck.
  • The relation between FAK inhibition and immuno-system is described e.g. in G. A. van Seventer et al., Eur. J. Immunol. 2001, 31, 1417-1427. Therefore, the compounds of the invention are, for example, useful to prevent and/or treat a vertebrate and more particularly a mammal, affected by immune system disorders, diseases or disorders mediated by T lymphocytes, B lymphocytes, mast cells and/or eosinophils e.g. acute or chronic rejection of organ or tissue allo- or xenografts, atherosclerosis, vascular occlusion due to vascular injury such as angioplasty, restenosis, hypertension, heart failure, chronic obstructive pulmonary disease, CNS disease such as Alzheimer disease or amyotrophic lateral sclerosis, cancer, infectious disease such as AIDS, septic shock or adult respiratory distress syndrome, ischemia/reperfusion injury e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, or traumatic shock. The agent of the invention are also useful in the treatment and/or prevention of acute or chronic inflammatory diseases or disorders or autoimmune diseases e.g. rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, diabetes (type I and II) and the disorders associated with therewith, respiratory diseases such as asthma or inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of immunologically-mediated disorders or illnesses, inflammatory and hyperproliferative skin diseases (such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis), inflammatory eye diseases, e.g. Sjoegren's syndrome, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis.
  • Compounds of the invention are active in a FAK assay system as described in the Examples, and show an inhibition IC50 in the range of 1 nM to 100 nM. Particularly active are the compounds Example No. 3-12 and No. 3-17 described hereinbelow showing IC50 vales in the range of 1 to 5 nM.
  • Some of the compounds of the invention exhibit also ZAP-70 (zeta chain-associated protein of 70 kD) protein tyrosine kinase inhibiting activity. ZAP-70 protein tyrosine kinase interaction of the agents of the invention may be demonstrated by their ability to prevent phosphorylation of e.g. LAT-11 (linker for activation of T cell) by human ZAP-70 protein tyrosine kinase in aqueous solution, as described in the Examples. The compounds of the invention are thus also indicated for the prevention or treatment of disorders or diseases where ZAP-70 inhibition play a role.
  • Compounds of the invention are active in a ZAP-70 assay system as described in the Examples, and show an inhibition IC50 in the range of 1 μM to 10 μM, e.g. the compounds Example No. 2 and No. 3-2 described hereinbelow.
  • Compounds of the present invention are also good inhibitors of the IGF-IR (insulin like growth factor receptor 1) and are therefore useful in the treatment of IGF-1R mediated diseases for example such diseases include proliferative diseases, such as tumours, like for example breast, renal, prostate, colorectal, thyroid, ovarian, pancreas, neuronal, lung, uterine and gastro-intestinal tumours as well as osteosarcomas and melanomas. The efficacy of the compounds of the invention as inhibitors of IGF-IR tyrosine kinase activity can be demonstrated using a cellular “Capture ELISA”. In this assay the activity of the compounds of the invention against Insulin-like growth factor I (IGF-I) induced autophosphorylation of the IGF-IR is determined.
  • The compounds of formula I and their pharmaceutically acceptable salts exhibit valuable pharmacological properties when tested in vitro in cell-free kinase assays and in cellular assays, and are therefore useful as pharmaceuticals. In particular, the compounds of the invention are inhibitors of Anaplastic Lymphoma Kinase (ALK), and are useful as pharmaceuticals to treat conditions caused by a malfunction of signal cascades connected with Anaplastic Lymphoma Kinase, in particular tumors as described hereinbelow.
  • ALK-mediated signaling could play a role in the development and/or progression of a number of common solid tumors (Pulford, K., et al., J. Cell. Physiol. 2004 June; 199(3):330-58). The compounds of the present invention also exhibit powerful inhibition of the tyrosine kinase activity of anaplastic lymphoma kinase (ALK) and its fusion proteins, particularly the fusion protein of NPM-ALK. This protein tyrosine kinase results from a gene fusion of nucleophosmin (NPM) and the anaplastic lymphoma kinase (ALK), rendering the protein tyrosine kinase activity of ALK ligand-independent. NPM-ALK plays a key role in signal transmission in a number of hematopoetic and other human cells leading to hematological and neoplastic diseases, for example in anaplastic large-cell lymphoma (ALCL) and non-Hodgkin's lymphomas (NHL), specifically in ALK+NHL or Alkomas, in inflammatory myofibroblastic tumors (IMT) and neuroblastomas. (Duyster J et al. 2001 Oncogene 20, 5623-5637). NPM-ALK has been shown to be a potent oncogene in vitro, being able to transform various cell lines and primary hematopoetic cells. Furthermore, NPM-ALK transduced bone marrow cells are able to induce a lymphoma-like disease after transplantation into irradiated recipient mice. Signaling pathways activated by NPM-ALK include ras, PLC and PI3K pathways and, in addition, STAT5 has been shown to be phosphorylated by NPM-ALK. In addition to NPM-ALK, other gene fusions have been identified in human hematological and neoplastic diseases; mainly TPM3-ALK (a fusion of nonmuscle tropomyosin 3 with ALK). Further, the ALK fusion protein CLTC-ALK, is associated with diseases that include classical T cell or null ALCL, ALK+ DLBCL and inflammatory myofibroblastic tumors. CLTCL-ALK is also thought to play a role in the pathogenesis of large B-cell lymphomas.
  • Further, the ALK fusion protein CLTC-ALK is associated with diseases that include classical T cell or null ALCL, ALK+ DLBCL and inflammatory myofibroblastic tumors. CLTCL-ALK is also thought to play a role in the pathogenesis of large B-cell lymphomas.
  • Aberrant activity of ALK is involved in the development of brain tumors and overexpression of ALK has been reported in neuroblastomas and several cell lines derived from neural tissue. ALK-mediated signaling could play a role in the development and/or progression of a number of common solid tumors (Pulford, K., et al., J. Cell. Physiol. 2004 June; 199(3):330-58).
  • The inhibition of ALK tyrosine kinase activity can be demonstrated using known methods, for example using the recombinant kinase domain of the ALK in analogy to the VEGF-R kinase assay described in J. Wood et al. Cancer Res. 60, 2178-2189 (2000). In vitro enzyme assays using GST-ALK protein tyrosine kinase are performed in 96-well plates as a filter binding assay in 20 mM Tris.HCl, pH=7.5, 3 mM MgCl2, 10 mM MnCl2, 1 mM DTT, 0.1 μCi/assay (=30 μl) [γ-33P]-ATP, 2 μM ATP, 3 μg/ml poly(Glu, Tyr 4:1) Poly-EY (Sigma P-0275), 1% DMSO, 25 ng ALK enzyme. Assays are incubated for 10 min at ambient temperature. Reactions are terminated by adding 50 μl of 125 mM EDTA, and the reaction mixture is transferred onto a MAIP Multiscreen plate (Millipore, Bedford, Mass., USA), previously wet with methanol, and rehydrated for 5 min with H2O. Following washing (0.5% H3PO4), plates are counted in a liquid scintillation counter. IC50 values are calculated by linear regression analysis of the percentage inhibition. Compared with the control without inhibitor, the compounds of formula I inhibit the enzyme activity by 50% (IC50), for example in a concentration of from 0.001 to 0.5 μM, especially from 0.01 to 0.1 μM.
  • The compounds of formula I potently inhibit the growth of human NPM-ALK overexpressing murine BaF3 cells (DSMZ Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH, Braunschweig, Germany). The expression of NPM-ALK is achieved by transfecting the BaF3 cell line with an expression vector pCIneo™ (Promega Corp., Madison Wis., USA) coding for NPM-ALK and subsequent selection of G418 resistant cells. Non-transfected BaF3 cells depend on IL-3 for cell survival. In contrast NPM-ALK expressing BaF3 cells (named BaF3-NPM-ALK hereinafter) can proliferate in the absence of IL-3 because they obtain proliferative signal through NPM-ALK kinase. Putative inhibitors of the NPM-ALK kinase therefore abolish the growth signal and result in antiproliferative activity. The antiproliferative activity of putative inhibitors of the NPM-ALK kinase can however be overcome by addition of IL-3 which provides growth signals through an NPM-ALK independent mechanism. [For an analogous cell system using FLT3 kinase see E Weisberg et al. Cancer Cell; 1, 433-443 (2002)]. The inhibitory activity of the compounds of formula I is determined, briefly, as follows: BaF3-NPM-ALK cells (15,000/microtitre plate well) are transferred to 96-well microtitre plates. The test compounds [dissolved in dimethyl sulfoxide (DMSO)] are added in a series of concentrations (dilution series) in such a manner that the final concentration of DMSO is not greater than 1% (v/v). After the addition, the plates are incubated for two days during which the control cultures without test compound are able to undergo two cell-division cycles. The growth of the BaF3-NPM-ALK cells is measured by means of Yopro™ staining [T Idziorek et al. J. Immunol. Methods; 185: 249-258 (1995)]: 25 μl of lysis buffer consisting of 20 mM sodium citrate, pH 4.0, 26.8 mM sodium chloride, 0.4% NP40, 20 mM EDTA and 20 mM is added to each well. Cell lysis is completed within 60 min at room temperature and total amount of Yopro bound to DNA is determined by measurement using the Cytofluor II 96-well reader (PerSeptive Biosystems) with the following settings: Excitation (nm) 485/20 and Emission (nm) 530/25.
  • IC50 values are determined by a computer-aided system using the formula:

  • IC50=[(ABStest−ABSstart)/(ABScontrol−ABSstart)]×100. (ABS=absorption)
  • The IC50 value in those experiments is given as that concentration of the test compound in question that results in a cell count that is 50% lower than that obtained using the control without inhibitor. The compounds of formula I exhibit inhibitory activity with an IC50 in the range from approximately 0.01 to 1 μM.
  • The antiproliferative action of the compounds of formula I can also be determined in the human KARPAS-299 lymphoma cell line (DSMZ Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH, Braunschweig, Germany) [described in W G Dirks et al. Int. J. Cancer 100, 49-56 (2002)] using the same methodology described above for the BaF3-NPM-ALK cell line. The compounds of formula I exhibit inhibitory activity with an IC50 in the range from approximately 0.01 to 1 μM.
  • The action of the compounds of formula I on autophosphorylation of the ALK can be determined in the human KARPAS-299 lymphoma cell line by means of an immunoblot as described in W G Dirks et al. Int. J. Cancer 100, 49-56 (2002). In that test the compounds of formula I exhibit an IC50 of approximately from 0.001 to 1 μM.
  • Among the compounds of formula I, 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide is an especially potent ALK inhibitor, in that this compound inhibits the growth of the BaF3-NPM-ALK cells with an IC50 of 97 nM. Further specifically preferred compounds that inhibit the tyrosine kinase activity of anaplastic lymphoma kinase (ALK) are the compounds described hereinafter in the examples 7A and 7B, as well as 7-2, 7-15, 19-5, 21-1, 26-3 and 28-5, respectively, all of which are having an IC50 within the range from <0.5 to 200 nM.
  • For the above uses in the treatment of neoplastic diseases and immune system disorders the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.1 to about 100 mg/kg body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 2000 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form.
  • The compounds of the invention may be administered by any conventional route, in particular parenterally, for example in the form of injectable solutions or suspensions, enterally, preferably orally, for example in the form of tablets or capsules, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form. Pharmaceutical compositions comprising a compound of the invention in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. Unit dosage forms for oral administration contain, for example, from about 0.1 mg to about 500 mg of active substance. Topical administration is e.g. to the skin. A further form of topical administration is to the eye.
  • The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.
  • Preference is given to the use of solutions of the active ingredient, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized compositions comprising the active ingredient alone or together with a carrier, for example mannitol, can be made up before use. The pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes. The said solutions or suspensions may comprise viscosity-increasing agents, typically sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, e.g. Tween 80® (polyoxyethylene(20)sorbitan mono-oleate).
  • Suspensions in oil comprise as the oil component the vegetable, synthetic, or semi-synthetic oils customary for injection purposes. In respect of such, special mention may be made of liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, β-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a monovalent or polyvalent, for example a mono-, di- or trivalent, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol. As fatty acid esters, therefore, the following are mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, “Labrafil M 2375” (polyoxyethylene glycerol), “Labrafil M 1944 CS” (unsaturated polyglycolized glycerides prepared by alcoholysis of apricot kernel oil and consisting of glycerides and polyethylene glycol ester), “Labrasol” (saturated polyglycolized glycerides prepared by alcoholysis of TCM and consisting of glycerides and polyethylene glycol ester; all available from Gattefossé, France), and/or “Miglyol 812” (triglyceride of saturated fatty acids of chain length C8 to C12 from Hüls AG, Germany), but especially vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.
  • The manufacture of injectable preparations is usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.
  • Pharmaceutical compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, if desired granulating a resulting mixture, and processing the mixture or granules, if desired or necessary, by the inclusion of additional excipients, to form tablets or tablet cores.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Tablet cores can be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • Pharmaceutical compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. The hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • Pharmaceutical compositions suitable for rectal administration are, for example, suppositories that consist of a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers, are especially suitable. The active ingredient, optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents.
  • Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
  • Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.
  • The compounds of the invention may be administered as the sole active ingredient or together with other drugs useful against neoplastic diseases or useful in immunomodulating regimens. For example, the agents of the invention may be used in accordance with the invention in combination with pharmaceutical compositions effective in various diseases as described above, e.g. with cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine, cisplatinum, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituxan, doxorubicine, gefitinib, or imatinib; or also with cyclosporins, rapamycins, ascomycins or their immunosuppressive analogs, e.g. cyclosporin A, cyclosporin G, FK-506, sirolimus or everolimus, corticosteroids, e.g. prednisone, cyclophosphamide, azathioprene, methotrexate, gold salts, sulfasalazine, antimalarials, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolate, mofetil, 15-deoxyspergualine, immuno-suppressive monoclonal antibodies, e.g. monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4, CD7, CD25, CD28, CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154, ICOS, LFA-1, VLA-4 or their ligands, or other immunomodulatory compounds, e.g. CTLA4Ig.
  • In accordance with the foregoing, the present invention also provides:
  • (1) A compound of the invention for use as a pharmaceutical;
    (2) a compound of the invention for use as a 5-Chloro-N*2*-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-N*4*-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine, for example for use in any of the particular indications hereinbefore set forth;
    (3) a pharmaceutical composition, e.g. for use in any of the indications herein before set forth, comprising a compound of the invention as active ingredient together with one or more pharmaceutically acceptable diluents or carriers;
    (4) a method for the treatment of any particular indication set forth hereinbefore in a subject in need thereof which comprises administering an effective amount of a compound of the invention or a pharmaceutical composition comprising same;
    (5) the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which FAK and/or ALK and/or ZAP-70 and/or IGF-I activation plays a role or is implicated, preferably ALK;
    (6) the method as defined above under (4) comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of a compound of the invention and one or more further drug substances, said further drug substance being useful in any of the particular indications set forth hereinbefore;
    (7) a combination comprising a therapeutically effective amount of a compound of the invention and one or more further drug substances, said further drug substance being useful in any of the particular indications set forth hereinbefore;
    (8) use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease which responds to inhibition of the anaplastic lymphoma kinase;
    (9) the use according to (8), wherein the disease to be treated is selected from lymphoma, anaplastic large-cell lymphoma, non-Hodgkin's lymphomas, inflammatory myofibroblastic tumors and neuroblastomas; (10) the use according to (8) or (9), wherein the compound is 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide or 5-Chloro-N*2*-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-N*4*-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine or a pharmaceutically acceptable salt thereof, or any of the compounds described hereinafter in the examples or a pharmaceutically acceptable salt of any one of these;
    (11) a method for the treatment of a disease which responds to inhibition of the anaplastic lymphoma kinase, especially a disease selected from anaplastic large-cell lymphoma, non-Hodgkin's lymphomas, inflammatory myofibroblastic tumors and neuroblastomas, comprising administering an effective amount of a compound of the invention, especially 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide or 5-Chloro-N*2*-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-N*4*-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine or a pharmaceutically acceptable salt thereof.
  • Additionally preferred a compound according to the present invention that is useful as herein before described is a compound specifically mentioned in the examples.
  • Additional specifically preferred compounds according to the present invention that are useful either as FAK inhibitor, as ALK inhibitor or for inhibition of both and which may be prepared essentially according to the methods described hereinbefore are the following:
    • 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide,
    • N2-(4-[1,4]Bipiperidinyl-1′-yl-2-methoxy-phenyl)-5-chloro-N4-[2-(propane-1-sulfonyl)-phenyl]-pyrimidine-2,4-diamine,
    • 2-{5-Chloro-2-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-N-isopropyl-benzenesulfonamide,
    • 2-[5-Bromo-2-(2-methoxy-5-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide
    • 2-{2-[5-(1-Acetyl-piperidin-4-yloxy)-2-methoxy-phenylamino]-5-bromo-pyrimidin-4-ylamino}-N-methyl-benzenesulfonamide,
    • N-[5-Bromo-2-(2,5-dimethoxy-phenylamino)-pyrimidin-4-yl]-N-(4-morpholin-4-yl-phenyl)-methanesulfonamide,
    • 5-Bromo-N-4-(4-fluoro-phenyl)-N*2*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine,
    • 2-[5-Chloro-2-(2-methoxy-4-piperazin-1-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide,
    • 2-[5-Bromo-2-(5-fluoro-2-methoxy-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide,
    • 2-[5-Chloro-2-(5-fluoro-2-methoxy-phenylamino)-pyrimidin-4-ylamino]-N-isobutyl-benzenesulfonamide, and
    • 2-{5-Chloro-2-[2-methoxy-5-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-ylamino}-N-methyl-benzenesulfonamide,
    • 5-Chloro-N*2*-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-N*4*-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine.
  • The invention also provides a compound of formula 2-{5-Chloro-2-[4-(3-methylamino-pyrrolidin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-N-isopropyl-benzenesulfonamide
  • The invention also provides a compound of formula 5-Chloro-N*2*-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-N*4*-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine
  • The following Examples serve to illustrate the invention without limiting the invention in its scope.
  • EXAMPLES Abbreviations
  • AcOH=acetic acid, ALK=anaplastic lymphoma kinase, ATP=adenosine 5′-triphosphate, brine=saturated sodium chloride solution, BSA=bovine serum albumin, DIAD=diisopropyl azodicarboxylate, DIPCDI=N,N′-diisopropylcarbodiimid, DMAP=4-dimethylaminopyridine, DMF=N,N-dimethylformamide, DTT=1,4-dithio-D,L-threitol, EDTA=ethylene diamine tetraacetic acid, Et=ethyl, EtOAc=ethyl acetate, EtOH=ethanol, Eu-PT66=LANCE™ europium-W1024-labelled anti-phosphotyrosine antibody (Perkin Elmer), FAK=Focal Adhesion Kinase, FRET=fluorescence resonance energy transfer, HEPES=N-2-hydroxyethyl-piperazine-N′-2-ethanesulfonic acid, HOAt=1-hydroxy-7-azabenzotriazole, Me=methyl, RT-PCR=reverse transcription polymerase chain reaction, SA-(SL)APC=Streptavidin conjugated to SuperLight™ allophycocyanin (Perkin Elmer), subst.=substituted, TBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethylammonium tetrafluoroborate, THF=tetrahydrofuran.
  • Example 1 2-[2-(2,5-Dimethoxy-phenylamino)-5-nitro-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide
  • Figure US20110098280A1-20110428-C00009
  • To a solution of 2-(2-chloro-5-nitro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (100 mg, 0.29 mmol) in EtOH (3 mL), 2,5-dimethoxyaniline (49 mg, 0.32 mmol) is added at room temperature. The mixture is heated at 78° C. for 5 h. The solvent is evaporated, and the mixture is purified by reverse phase HPLC to give the title product in.
  • Rf=0.47 (n-hexane:ethyl acetate=1:1). 1H-NMR (400 MHz, CDCl3), δ (ppm): 2.36 (d, 3H), 3.57 (s, 3H), 3.73 (s, 3H), 6.72 (d, 1H), 6.99 (d, 1H), 7.17 (s, 1H), 7.35 (t, 1H), 7.4-7.6 (m, 1H), 7.63 (d, 1H), 7.81 (d, 1H), 8.0-8.2 (m, 1H), 9.13 (s, 1H), 9.41 (br.s, 1H), 11.0 (s, 1H).
  • Preparation of 2-(2-chloro-5-nitro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide
  • 2,4-Dichloro-5-nitro-pyrimidine (1.94 g, 10 mmol) and 2-amino-N-methyl-benzenesulfonamide (1.86 g, 10 mmol) are dissolved in CHCl3 (30 mL). The reaction mixture is heated at 61° C. for 2 h. The solvent is evaporated and the residue is washed with ether to give the title product.
  • Rf=0.5 (n-hexane:ethyl acetate=1:1). 1H-NMR (400 MHz, CDCl3), δ (ppm): 2.67 (d, 3H), 4.6-4.7 (m, 2H), 7.41 (dd, 1H), 7.7 (dd, 1H), 8.04 (d, 1H), 8.15 (d, 1H), 9.21 (s, 1H), 11.2 (s, 1H).
  • Example 2 2-[5-Bromo-2-(2,4-dimethoxy-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide
  • Figure US20110098280A1-20110428-C00010
  • To a solution of 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (300 mg, 0.79 mmol), 2,4-dimethoxyaniline (181.5 mg, 1.18 mmol) in ethanol (3 mL), 1 N hydrochloric acid (0.03 mL) is added and stirred under reflux condition for 5 hours. The reaction mixture is cooled to room temperature, poured into water and extracted twice with ethyl acetate. The organic layer is successively washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 1:1) to afford the title compound.
  • 1H-NMR (CDCl3), δ (ppm): 8.95 (s, 1H), 8.44 (d, 1H), 8.20 (s, 1H), 7.98 (dd, 1H), 7.58 (ddd, 1H), 7.22-7.32 (m, 1H), 6.51 (d, 1H), 6.40 (d, 1H), 4.56-4.48 (m, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 2.64 (d, 3H). Rf (n-hexane:ethyl acetate=1:1): 0.31.
  • Preparation of 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide
  • A solution of 5-bromo-2,4-dichloropyrimidine (684 mg, 3.0 mmol) and 2-amino-N-methyl-benzenesulfonamide (559 mg, 3.0 mmol) in N,N-dimethylformamide (10 mL) containing potassium carbonate (830 mg, 6.0 mmol) is stirred at room temperature for 23 hours. Saturated aqueous ammonium chloride is added and the mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane-ethyl acetate gradient) to afford the title compound as a slightly yellow solid.
  • 1H-NMR (CDCl3), δ (ppm): 2.67 (d, 3H), 4.79 (q, 1H), 7.26 (s, 1H), 7.29 (ddd, 1H), 7.66 (ddd, 1H), 7.95 (dd, 1H), 8.37 (s, 1H), 8.48 (d, 1H), 9.52 (s, 1H). Rf (n-hexane:ethyl acetate=10:3): 0.33.
  • Example 3
  • The following 2-[5-bromo-2-(subst. phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzene-sulfonamides are prepared from 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide and the corresponding aniline following the procedure of Example 2:
  • Figure US20110098280A1-20110428-C00011
    Rf (solvent)
    ExplNo. Rx or MS 1H-NMR (400 MHz), δ (ppm)
    3-1
    Figure US20110098280A1-20110428-C00012
    0.48 (n-hexane: AcOEt = 1:1) CDCl3: 2.64 (d, 3H), 4.48-4.40 (m, 1H), 6.78 (d, 1H), 6.87 (bs, 1H), 6.99 (dd, 1H), 6.82 (s, 1H), 7.54 (ddd, 1H), 7.79 (d, 1H), 7.97 (dd, 1H), 8.28 (s, 1H), 8.32 (dd, 1H), 9.07 (s, 1H)
    3-2
    Figure US20110098280A1-20110428-C00013
    0.58 (n-hexane: AcOEt = 1:1) CDCl3: 2.25 (s, 3H), 2.33 (s, 3H), 2.63 (d, 3H), 4.53- 4.45 (m, 1H), 6.61 (bs, 1H), 6.99 (dd, 1H), 7.04 (s, 1H), 7.18 (ddd, 1H), 7.43 (ddd, 1H), 7.56 (d, 1H), 7.92 (dd, 1H), 8.19 (s, 1H), 8.41 (dd, 1H), 9.08 (s, 1H)
    3-3
    Figure US20110098280A1-20110428-C00014
    0.36 (n-hexane: AcOEt = 1:1) CDCl3: 2.23 (s, 3H), 2.62 (d, 3H), 3.69 (s, 3H), 4.53- 4.44 (m, 1H), 6.62 (dd, 1H), 6.69 (bs, 1H), 7.10 (d, 1H), 7.19 (dd, 1H), 7.48 (d, 1H), 7.51 (dd, 1H), 7.93 (dd, 1H), 8.22 (s, 1H), 8.44 (dd, 1H), 9.09 (s1, 1H)
    3-4
    Figure US20110098280A1-20110428-C00015
    0.41 (n-hexane: AcOEt = 1:1) CDCl3: 2.32 (s, 3H), 2.63 (d, 3H), 4.45-4.44 (m, 1H), 6.85 (d, 1H), 6.91 (d, 1H), 7.00 (bs, 1H), 7.28-7.24 (m, 1H), 7.57 (dd, 1H), 7.99 (dd, 1H), 8.25 (s, 1H), 8.39 (d, 1H), 9.00 (bs, 1H)
    3-5
    Figure US20110098280A1-20110428-C00016
    0.39 (n-hexane: AcOEt = 1:1) CDCl3: 2.33 (s, 3H), 2.63 (d, 3H), 3.87 (s, 3H), 4.46- 4.44 (m, 1H), 6.66 (d, 1H), 6.71 (s, 1H), 7.48 (bs, 1H), 7.63-7.59 (m, 1H), 7.97 (dd, 1H), 8.05 (d, 1H), 8.23 (s, 1H), 8.44 (d, 1H), 8.92 (bs, 1H)
    3-6
    Figure US20110098280A1-20110428-C00017
    0.27 (n-hexane: AcOEt = 3:1) CDCl3: 2.63 (d, 3H), 3.90 (s, 3H), 4.45-4.40 (m, 1H), 6.90-6.86 (m, 2H), 7.00-6.96 (m, 1H), 7.23-7.17 (m, 3H), 7.45 (dd, 1H), 7.50-7.60 (m, 2H), 7.97 (dd, 1H), 8.22 (d, 1H), 8.26 (s, 1H), 8.43 (d, 1H), 8.94 (bs, 1H)
    3-7
    Figure US20110098280A1-20110428-C00018
    0.34 (n-hexane: AcOEt = 3:1) CDCl3: 2.30 (s, 3H), 2.63 (d, 3H), 4.44-4.43 (m, 1H), 6.68 (bs, 1H), 7.00-6.68 (m, 1H), 7.23-7.17 (m, 2H), 7.46-7.43 (m, 1H), 7.76 (d, 1H), 7.93 (dd, 1H), 8.22 (s, 1H), 8.40 (d, 1H), 9.01 (bs, 1H)
    3-8
    Figure US20110098280A1-20110428-C00019
    0.12 (n-hexane: AcOEt = 3:1) CDCl3: 2.62 (d, 3H), 2.81 (s, 3H), 4.07-3.98 (m, 1H), 4.52-4.45 (m, 1H), 6.37 (bs, 1H), 6.77-6.73 (m, 2H), 7.12 (dd, 1H), 7.24-7.20 (m, 1H), 7.30-7.27 (m, 1H), 7.35 (dd, 1H), 7.88 (dd, 1H), 8.18 (s, 1H), 8.41 (d, 1H), 9.19 (bs, 1H)
    3-9
    Figure US20110098280A1-20110428-C00020
    0.28 (n-hexane: AcOEt = 3:1) CDCl3: 2.62 (d, 3H), 3.94 (s, 3H), 4.49-4.43 (m, 1H), 6.99-6.90 (m, 3H), 7.18-7.23 (m, 1H), 7.31-7.24 (m, 3H), 7.63 (bs, 1H), 7.93-7.86 (m, 1H), 8.28-8.23 (m, 1H), 8.28 (s, 1H), 8.45 (bs, 1H), 8.89 (bs, 1H)
    3-10
    Figure US20110098280A1-20110428-C00021
    0.23 (n-hexane: AcOEt = 3:1) CDCl3: 0.91 (t, 3H), 1.37 (dd, 2H), 1.64-1.55 (m, 2H), 2.64-2.60 (m, 2H), 4.45-4.40 (m, 1H), 6.69 (bs, 1H), 7.23-7.10 (m, 1H), 7.46-7.38 (m, 1H), 7.73 (d 1H), 7.92 (d, 1H), 8.21 (s, 1H), 8.38-8.46 (m, 1H), 9.09 (bs, 1H)
    3-11
    Figure US20110098280A1-20110428-C00022
    0.12 (n-hexane: AcOEt = 3:1) CDCl3: 2.63 (d, 3H), 4.15-4.10 (m, 1H), 6.58 (bs, 1H), 7.31-7.10 (m, 4H), 7.53-7.49 (m, 1H), 7.71 (d 1H), 7.95 (d, 1H), 8.30-8.23 (m, 1H), 8.26 (s, 1H), 8.45 (d, 1H), 9.03 (bs, 1H)
    3-12
    Figure US20110098280A1-20110428-C00023
    0.4 (n-hexane: AcOEt = 3:1) CDCl3: 2.09 (dd, 2H), 2.63 (d, 3H), 2.85 (t, 2H), 2.96 (t, 2H), 4.46-4.43 (m, 2H), 6.73 (bs, 1H), 6.99 (d, 1H), 7.09 (dd, 1H), 7.25-7.20 (m, 1H), 7.52 (dd, 1H), 7.74 (d 1H), 7.92 (dd, 1H), 8.22 (s, 1H), 8.42 (d, 1H), 9.02 (bs, 1H)
    3-13
    Figure US20110098280A1-20110428-C00024
    0.33 (AcOEt) CDCl3: 2.63 (d, 3H), 4.63-4.64 (m, 1H), 7.11 (d, 2H), 7.18 (dd, 1H), 7.42-7.34 (m, 1H), 7.58-7.55 (m, 1H), 7.96 (d, 1H), 8.07 (s, 1H), 8.19-8.10 (m, 1H), 8.24 (s, 1H), 9.15 (s, 1H), 11.6-11.4 (m, 1H)
    3-14
    Figure US20110098280A1-20110428-C00025
    0.28 (n-hexane: AcOEt = 3:1) CDCl3: 2.63 (d, 3H), 3.88 (s, 3H), 3.89 (s, 3H), 4.47- 4.41 (m, 1H), 6.60 (d, 1H), 6.92 (dd,1H), 7.64 (dd, 1H), 7.66-7.61 (m, 1H), 7.89 (d, 1H), 7.98 (dd, 1H), 8.26 (s, 1H), 8.43 (d, 1H), 8.95 (s, 1H)
    3-15
    Figure US20110098280A1-20110428-C00026
    0.30 (n-hexane: AcOEt = 3:1) CDCl3: 2.63 (d, 3H), 3.66 (s, 3H), 3.85 (s, 3H), 4.45- 4.44 (m, 1H), 6.48 (dd, 1H), 6.79 (d, 1H), 7.64 (dd, 1H), 7.97 (dd, 2H), 8.26 (s, 1H), 8.44 (d, 1H), 8.96 (s, 1H)
    3-16
    Figure US20110098280A1-20110428-C00027
    0.22 (n-hexane: AcOEt = 3:1) CDCl3: 2.17 (s, 3H), 2.22 (s, 3H), 2.64 (s, 3H), 2.63 (d, 3H), 4.46-4.44 (m, 1H), 6.57 (bs, 1H), 7.00 (s, 1H), 7.17 (dd, 1H), 7.44-7.40 (m, 1H), 7.44 (s, 1H), 7.93 (dd, 1H), 8.19 (s, 1H), 8.43 (d, 1H), 9.06 (s, 1H)
    3-17
    Figure US20110098280A1-20110428-C00028
    0.46 (AcOEt) CDCl3: 2.22 (s, 3H), 2.63 (d, 3H), 3.68 (s, 3H), 3.89 (s, 3H), 4.52-4.47 (m, 1H), 6.51 (s, 1H), 6.74 (s, 1H), 7.12 (s, 1H), 7.16-7.12 (m, 1H), 7.40 (dd, 1H), 7.91 (dd, 1H), 8.19 (s, 1H), 8.42 (d, 1H), 9.12 (s, 1H)
    3-18
    Figure US20110098280A1-20110428-C00029
    0.35 (n-hexane: AcOEt = 3:1) CDCl3: 1.16 (d, 6H), 2.25 (s, 3H), 2.62 (d, 3H), 2.77 (t, 1H), 4.49-4.48 (m, 1H), 7.00 (s, 1H), 7.15 (d, 1H), 7.41- 7.37 (m, 1H), 7.49 (d, 2H), 7.54 (dd, 1H), 7.92 (dd, 1H), 8.21 (s, 1H), 8.32 (d, 1H), 9.02 (s, 1H)
    3-19
    Figure US20110098280A1-20110428-C00030
    0.23 (n-hexane: AcOEt = 1:1) CDCl3: 2.63 (d, 3H), 3.13-3.10 (m, 4H), 3.87 (s, 3H), 3.89-3.86 (m, 4H), 4.97-4.93 (m, 1H), 6.41 (dd, 1H), 6.52 (d, 1H), 7.24-7.22 (m, 1H), 7.32 (s, 1H), 7.57 (dd, 1H), 7.96 (dd, 1H), 8.01 (d, 1H), 8.14 (s, 1H), 8.44 (d, 1H), 8.98 (s, 1H)
    3-20
    Figure US20110098280A1-20110428-C00031
    0.36 (n-hexane: AcOEt = 1:1) CDCl3: 2.22 (s, 3H), 2.64 (d, 3H), 3.00-3.2.97 (m, 4H), 3.76-3.74 (m, 4H), 4.54-4.50 (m, 1H), 6.64 (d, 1H), 6.66 (dd, 1H), 7.11 (d, 1H), 7.18 (dd, 1H), 7.37 (d, 1H), 7.46 (dd, 1H), 7.93 (dd, 1H), 8.22 (s, 1H), 8.42 (d, 1H), 9.09 (s, 1H)
    3-21
    Figure US20110098280A1-20110428-C00032
    3-22
    Figure US20110098280A1-20110428-C00033
    0.27 (AcOEt) CDCl3: 2.33 (s, 3H), 2.65 (d, 3H), 3.60-3.45 (m, 8H), 4.53-4.49 (m, 1H), 6.74 (s, 1H), 7.11 (d, 1H), 7.22- 7.18 (m, 1H), 7.58-7.54 (m 1H), 7.94 (dd, 1H), 8.00 (d, 1H), 8.22 (s, 1H), 8.37 (d, 1H), 9.13 (s, 1H)
    3-23
    Figure US20110098280A1-20110428-C00034
    0.38 (AcOEt) CDCl3: 1.24-1.08 (m, 2H), 1.46-1.32 (m, 2H), 1.76- 1.67 (m, 2H), 1.98-1.90 (m, 2H), 2.33 (s, 3H), 2.64 (d, 3H), 3.95-3.90 (m, 1H), 4.49-4.47 (m, 1H), 5.89- 5.80 (m, 1H), 6.66 (s, 1H), 7.15 (dd, 1H), 7.48-7.31 (m, 2H), 7.91 (dd, 1H), 8.12 (s, 1H), 8.23 (s, 1H), 8.41 (d, 1H), 9.18 (s, 1H)
    3-24
    Figure US20110098280A1-20110428-C00035
    0.11 (AcOEt) CDCl3: 2.35 (s, 3H), 2.71 (s, 3H), 3.07-2.73 (m, 2H), 3.86-3.31 (m, 6H), 6.85 (s, 1H), 7.10 (d, 1H), 7.24- 7.19 (m, 1H), 7.52-7.48 (m, 1H), 7.66-7.59 (m, 2H), 7.93 (d, 1H), 8.06 (s, 1H), 8.27-8.21 (m, 1H), 8.23 (s, 1H), 9.11 (s, 1H)
    3-25
    Figure US20110098280A1-20110428-C00036
    0.5 (n-hexane: AcOEt = 1:1) CDCl3: 2.52 (d, 3H), 2.62 (s, 3H), 4.36-4.32 (m, 1H), 6.74 (s, 1H), 6.87 (d, 2H), 7.00-6.91 (m, 2H), 7.00- 6.97 (m, 2H), 7.38 (dd, 2H), 7.86 (dd, 1H), 7.98 (s, 1H), 8.23 (s, 1H), 8.28 (d, 1H), 9.04 (s, 1H)
    3-26
    Figure US20110098280A1-20110428-C00037
    0.45 (n-hexane: AcOEt = 1:1) CDCl3: 1.62-1.34 (m, 6H), 2.13 (s, 3H), 2.56 (d, 3H), 3.01-2.87 (m, 4H), 4.54-4.38 (m, 1H), 6.59 (s, 1H), 6.69-6.59 (m, 1H), 7.02 (d, 1H), 7.10-7.07 (m, 1H), 7.37 (dd, 1H), 7.84 (dd, 1H), 8.15 (s, 1H), 8.34 (d, 1H), 9.01 (s, 1H)
    3-27
    Figure US20110098280A1-20110428-C00038
    0.45 (n-hexane: AcOEt = 1:1) CDCl3: 2.32 (s, 3H), 2.58 (d, 3H), 3.75 (s, 3H), 4.37- 4.44 (m, 1H), 6.77-6.73 (m, 1H), 6.89-6.82 (m 1H), 6.97-6.91 (m, 2H), 6.96 (d, 1H), 7.20 (dd, 1H), 7.25- 7.24 (m, 1H), 7.33-7.29 (m, 1H)
    3-28
    Figure US20110098280A1-20110428-C00039
    0.35 (n-hexane: AcOEt = 1:1) CDCl3: 2.34 (s, 3H), 2.64 (d, 3H), 3.81 (s, 3H), 4.57- 4.50 (m, 1H), 6.76 (bs, 1H), 6.91-6.84 (m, 41H), 7.04 (d, 1H), 7.83 (dd, 1H), 8.06 (d, 1H), 8.19 (dd, 1H), 8.23 (s, 1H), 9.00 (s, 1H)
    3-29
    Figure US20110098280A1-20110428-C00040
    0.45 (n-hexane: AcOEt = 1:1) CDCl3: 1.50 (t, 3H), 2.62 (d, 3H), 4.17 (dd, 2H), 4.51- 4.44 (m, 1H), 6.95-6.89 (m, 2H), 6.94 (d, 1H), 7.16 (dd, 1H), 7.31-7.23 (m, 5H), 7.67 (s, 1H), 7.11 (dd, 1H), 7.23 (d, 2H), 7.65 (s, 1H), 7.88 (dd, 1H), 8.28-8.23 (m, 1H), 8.28 (s, 1H), 8.43 (s, 1H), 8.89 (s, 1H)
    3-30
    Figure US20110098280A1-20110428-C00041
    0.45 (n-hexane: AcOEt = 1:1) CDCl3: 1.49 (t, 3H), 2.63 (d, 3H), 3.85 (s, 3H), 4.16 (dd, 2H), 4.55-4.48 (m, 1H), 6.81 (dd, 1H), 6.95-6.91 (m, 3H), 7.11 (dd, 1H), 7.23 (d, 2H), 7.65 (s, 1H), 7.90- 7.88 (m, 1H), 8.28-8.26 (m, 1H), 8.27 (s, 1H), 8.39 (s, 1H), 8.90 (s, 1H)
    3-31
    Figure US20110098280A1-20110428-C00042
    0.29 (n-hexane: AcOEt = 1:1) 1H-NMR: (CDCl3) 1.83-1.72 (4H, m), 2.63 (3H, d), 2.66-2.62 (2H, m), 2.80 (2H, t), 4.41-4.44 (1H, m), 6.64 (1H, br.s), 6.92 (1H, d), 7.09 (1H, dd), 7.18 (1H, dd), 7.45 (1H, dd), 7.59 (1H, dd), 7.92 (1H, d), 8.20 (1H, s), 8.42 (1H, d), 9.08 (1H, br.s).
    3-32
    Figure US20110098280A1-20110428-C00043
    0.3 (n-hexane: AcOEt = 1:1) DMSO-d6: 2.43 (s, 3H), 2.80-2.82 (m, 4H), 3.61-3.64 (m, 4H), 3.75 (s, 3H), 6.62 (dd, 1H), 6.93 (d, 1H), 7.46 (d, 1H), 7.54 (dd, 1H), 7.77 (dd, 2H), 8.14 (bs, 1H), 8.32 (s, 1H), 8.38-8.30 (m, 1H), 9.14 (bs, 1H)
    3-33
    Figure US20110098280A1-20110428-C00044
    0.61 (MeOH: CH2Cl2 = 1:1) DMSO-d6: 1.59-1.68 (m, 2H), 1.88-1.98 (m, 2H), 2.13- 2.25 (m, 2H), 2.19 (s, 3H), 2.43 (s, 3H), 2.60-2.70 (m, 2H), 3.75 (s, 3H), 4.32-4.40 (m, 1H), 6.51 (dd, 1H), 6.64 (d, 1H), 7.20 (dd, 1H), 7.39 (d, 1H), 7.75 (dd, 1H), 7.70-7.78 (s, 1H), 8.22 (s, 1H), 8.26 (s, 1H), 8.38- 8.41 (m, 1H), 9.22 (s, 1H)
    3-34
    Figure US20110098280A1-20110428-C00045
    0.17 (AcOEt) CDCl3: 2.11 (s, 3H), 2.68 (d, 3H), 2.76-2.83 (m, 2H), 2.89-2.97 (m, 2H), 3.47-3.55 (m, 2H), 3.58-3.66 (m, 2H), 3.86 (s, 3H), 4.70-4.78 (m, 1H), 6.53 (dd, 1H), 6.81 (d, 1H), 7.23 (dd, 1H), 7.54-7.62 (m, 2H), 7.97 (dd, 1H), 8.02-8.03 (m, 1H), 8.29 (s, 1H), 8.40 (d, 1H), 8.99 (bs, 1H)
    3-35
    Figure US20110098280A1-20110428-C00046
    0.22 (AcOEt only) DMSO-d6: 2.40-2.48 (m, 7H), 2.63 (t, 2H), 3.50-3.58 (m, 4H), 3.77 (s, 3H), 3.91 (t, 2H), 6.60 (dd, 1H), 6.93 (d, 1H), 7.28 (dd, 1H), 7.56 (d, 1H), 7.60 (dd, 1H), 7.75- 7.80 (m, 1H), 7.80 (dd, 1H), 8.10 (s, 1H), 8.35 (s, 1H), 8.40 (d, 1H), 9.21 (s, 1H)
    3-36
    Figure US20110098280A1-20110428-C00047
    0.4 (n-hexane: AcOEt = 1:1) DMSO-d6: 2.43 (s, 3H), 7.03-7.08 (m, 1H), 7.21- 7.23 (m, 1H), 7.25-7.36 (m, 1H), 7.47-7.57 (m, 2H), 7.74-7.77 (m, 2H), 8.28 (s, 1H), 8.35 (d, 1H), 9.09 (s, 1H), 9.24 (s, 1H)
    3-37
    Figure US20110098280A1-20110428-C00048
    0.4 (n-hexane: AcOEt = 1:1) CDCl3: 2.64 (d, 3H), 4.53-4.54 (m, 1H), 6.88-6.93 (m, 1H), 7.14-7.28 (m, 3H), 7.54-7.58 (m, 1H), 7.95- 7.98 (m, 1H), 8.16-8.21 (m, 1H), 8.24 (s, 1H), 8.33- 8.36 (m, 1H), 9.05 (s, 1H)
    3-38
    Figure US20110098280A1-20110428-C00049
    0.42 (n-hexane: AcOEt = 1:1) CDCl3: 2.64 (d, 3H), 4.46-4.47 (m, 1H), 6.63-6.68 (m, 1H), 7.30-7.32 (m, 2H), 7.55 (s, 1H), 7.64-7.68 (m, 1H), 7.97-7.99 (m, 1H), 8.20-8.39 (m, 3H), 9.03 (s, 1H)
    3-39
    Figure US20110098280A1-20110428-C00050
    562, 564 [M + 1]+ CDCl3: 2.37 (s, 3H), 2.58-2.64 (m, 7H), 3.15- 3.18 (m, 4H), 3.87 (s, 3H), 4.60-4.65 (m, 1H), 6.43 (dd, 1H), 6.44-6.54 (m, 1H), 7.22 (d, 1H), 7.30 (s, 1H), 7.57 (dd, 1H), 7.94-7.99 (m, 2H), 8.18 (s, 1H), 8.45 (d, 1H), 8.95 (s, 1H)
    3-40
    Figure US20110098280A1-20110428-C00051
    572, 574 [M + 1]+ DMSO-d6: 1.79-1.88 (m, 2H), 1.98-2.02 (m, 2H), 2.43 (s, 3H), 3.02-3.08 (m, 3H), 3.28-3.39 (m, 2H), 3.76 (s, 3H), 6.47 (dd, 1H), 6.65 (d, 1H), 7.22 (dd, 1H), 7.39 (d, 1H), 7.45-7.50 (m, 1H), 7.74-7.77 (m, 2H), 8.18 (s, 1H), 8.22 (s, 1H), 8.41-8.44 (m, 1H), 9.21 (bs, 1H)
    3-41
    Figure US20110098280A1-20110428-C00052
    565, 567 [M + 1]+ DMSO-d6: 2.44 (d, 3H), 2.69-2.71 (m, 4H), 3.49- 3.52 (m, 4H), 3.76 (s, 3H), 6.45 (dd, 1H), 6.62 (d, 1H), 7.23 (ddd, 1H), 7.38 (d, 1H), 7.46-7.50 (m, 1H), 7.72- 7.77 (m, 2H), 8.19 (s, 1H), 8.22 (s, 1H), 8.42-8.45 (m, 1H), 9.22 (s, 1H)
    3-42
    Figure US20110098280A1-20110428-C00053
    595, 597 [M + 1]+ DMSO-d6: 2.44 (s, 3H), 3.31 (s, 6H), 3.48-3.53 (m, 8H), 3.72 (s, 3H), 6.24 (dd, 1H), 6.37 (d, 1H), 7.18-7.21 (m, 2H), 7.40-7.55 (m, 1H), 7.72-7.76 (m, 2H), 8.17- 8.19 (m, 2H), 8.40-8.50 (m, 1H), 9.23 (s, 1H)
    3-43
    Figure US20110098280A1-20110428-C00054
    590, 592 [M + 1]+ DMSO-d6: 1.64-1.71 (m, 2H), 1.75-1.82 (m, 2H), 2.21- 2.28 (m, 1H), 2.43 (d, 3H), 2.62-2.67 (m, 2H), 3.68- 3.74 (m, 2H), 3.76 (s, 3H), 6.45 (dd, 1H), 6.63 (d, 1H), 6.75-6.81 (m, 1H), 7.20 (ddd, 1H), 7.25-7.30 (m, 1H), 7.35 (d, 1H), 7.45-7.52 (m, 1H), 7.70-7.77 (m, 2H), 8.18 (s, 1H), 8.21 (s, 1H), 8.40-8.47 (m, 1H), 9.22 (s, 1H)
    3-44
    Figure US20110098280A1-20110428-C00055
    597, 599 [M + 1]+ DMSO-d6: 2.44 (s, 3H), 3.12-3.17 (m, 4H), 3.68- 3.85 (m, 4H), 3.79 (s, 3H), 6.55 (dd, 1H), 6.71 (d, 1H), 7.19-7.25 (m, 1H), 7.43 (d, 1H), 7.46-7.53 (m, 1H), 7.73-7.78 (m, 2H), 8.19-8.22 (m, 1H), 8.22 (s, 1H), 8.38-8.45 (m, 1H), 9.20 (bs, 1H)
    3-45
    Figure US20110098280A1-20110428-C00056
    600, 602 [M + 1]+ DMSO-d6: 1.85-1.95 (m, 2H), 2.19 (t, 2H), 2.25- 2.35 (m, 4H), 2.43 (s, 3H), 3.52-3.64 (m, 4H), 4.19 (t, 2H), 6.65 (d, 1H), 7.05 (dd, 1H), 7.20 (d, 1H), 7.23 (ddd, 1H), 7.27 (d, 1H), 7.40-7.46 (m, 1H), 7.42 (d, 1H), 7.70- 7.75 (m, 1H), 7.76 (dd, 1H), 8.32 (s, 1H), 8.45 (d, 1H), 9.22 (s, 1H), 9.23 (s, 1H)
    3-46
    Figure US20110098280A1-20110428-C00057
    590, 592 [M + 1]+ DMSO-d6: 2.05 (s, 3H), 2.44 (s, 3H), 3.08-3.17 (m, 4H), 3.55-3.63 (m, 4H), 3.77 (s, 3H), 6.48 (dd, 1H), 6.67 (d, 1H), 7.23 (dd, 1H), 7.41 (d, 1H), 7.45-7.52 (m, 1H), 7.76 (dd, 1H), 7.72-7.78 (m, 1H), 8.19 (s, 1H), 8.22 (s, 1H), 8.40-8.47 (m, 1H), 9.22 (bs, 1H)
    3-47
    Figure US20110098280A1-20110428-C00058
    548, 550 [M + 1]+ DMSO-d6: 2.43 (s, 3H), 2.82-2.87 (m, 4H), 2.99- 3.15 (m, 4H), 3.76 (s, 3H), 6.43 (dd, 1H), 6.61 (d, 1H), 7.22 (dd, 1H), 7.36 (d, 1H), 7.43-7.51 (m, 1H), 7.75 (dd, 1H), 8.17 (s, 1H), 8.21 (s, 1H), 8.38-8.45 (m, 1H), 9.12- 9.28 (m, 1H)
    3-48
    Figure US20110098280A1-20110428-C00059
    MS 530, 532 CDCl3: 2.65 (d, 3H), 3.96 (s, 3H), 4.40-4.48 (m, 1H), 6.85-6.88 (m, 2H), 7.22 (d, 1H), 7.25-7.31 (m, 1H), 7.56-7.65 (m, 3H), 7.79 (s, 1H), 8.00 (dd, 1H), 8.29 (s, 1H), 8.39 (dd, 1H), 9.00 (s, 1H).
    3-49
    Figure US20110098280A1-20110428-C00060
    Rf (AcOEt: MeOH = 9:1) 0.20 CDCl3: 2.18-2.50 (m, 4H), 2.28 (s, 3H), 2.65 (d, 3H), 3.10-3.75 (m, 4H), 3.93 (s, 3H), 4.50-4.61 (m, 1H), 6.89 (d, 1H), 7.06 (dd, 1H), 7.59-7.67 (m, 2H), 7.93- 7.97 (m, 1H), 8.26 (s, 1H), 8.37-8.43 (m, 2H), 9.02 (s, 1H).
    3-50
    Figure US20110098280A1-20110428-C00061
    Rf 0.4 (Hexane/Ac OEt = 1/1) CDCl3: 2.63 (d, 3H), 3.90 (s, 3H), 4.00 (s, 3H), 4.39- 4.47 (m, 1H), 6.23 (d, 1H), 7.00 (s, 1H), 7.22-7.25 (m, 1H), 7.57 (dd, 1H), 7.96 (dd, 1H), 8.22 (s, 1H), 8.25 (d, 1H), 8.37 (d, 1H), 8.96 (s, 1H)
    3-51
    Figure US20110098280A1-20110428-C00062
    MS 535, 537 CDCl3: 1.17 (t, 3H), 1.71-1.79 (m, 1H), 2.28 (s, 3H), 2.62 (d, 3H), 3.41 (q, 2H), 3.46 (t, 2H), 3.79 (q, 2H), 4.41-4.48 (m, 1H), 6.43 (s, 1H), 6.10-6.18 (m, 2H), 7.15 (dd, 1H), 7.33 (d, 1H), 7.35-7.42 (m, 1H), 7.90 (dd, 1H), 8.16 (s, 1H), 8.45 (d, 1H), 9.07 (s, 1H).
    3-52
    Figure US20110098280A1-20110428-C00063
    Rf CDCl3: 2.66 (d, 3H), 3.91 (s, 3H), 4.41-4.47 (m, 1H), 6.80 (d, 1H), 6.92 (dd, 1H), 7.26-7.35 (m, 1H), 7.54 (s, 1H), 7.76 (dd, 1H), 8.00 (dd, 1H), 8.27-8.32 (m, 2H), 8.38 (dd, 1H), 8.97 (s, 1H).
    3-53
    Figure US20110098280A1-20110428-C00064
    MS 491, 493 CDCl3: 2.26 (s, 3H), 2.62 (d, 3H), 2.68 (s, 6H), 4.72 (q, 1H), 6.78 (s, 1H), 6.89 (d, 1H), 7.12 (d, 1H), 7.15 (d, 1H), 7.40-7.47 (m, 2H), 7.91 (dd, 1H), 8.40 (s, 1H), 8.41 (dd, 1H), 9.11 (s, 1H).
    3-54
    Figure US20110098280A1-20110428-C00065
    MS 525, 527 CDCl3: 2.04 (s, 3H), 2.65 (d, 3H), 4.42-4.48 (m, 1H), 6.79 (s, 1H), 6.96-7.00 (m, 2H), 7.28-7.34 (m, 4H), 7.87-7.91 (m, 1H), 8.18 (s, 1H), 8.23-8.26 (m, 2H), 8.53 (d, 2H), 9.07 (s, 1H).
    3-55
    Figure US20110098280A1-20110428-C00066
    Rf (Hexane: AcOEt = 3:1 0.19 CDCl3: 1.34 (t, 3H), 1.44 (t, 3H), 2.63 (d, 3H), 3.81 (q, 2H), 4.06 (q, 2H), 4.46 (q, 1H), 6.43 (dd, 1H), 6.76 (d, 1H), 7.63-7.69 (m, 2H), 7.94 (d, 1H), 7.98 (dd, 1H), 8.42 (d, 1H), 8.93 (s, 1H).
    3-56
    Figure US20110098280A1-20110428-C00067
    MS 570, 572 CDCl3: 2.63 (d, 3H), 3.85 (s, 3H), 3.93 (s, 3H), 4.52 (q, 1H), 6.78-6.83 (m, 2H), 6.93 (d, 2H), 6390-7.02 (m, 1H), 7.11-7.15 (m, 1H), 7.21-7.27 (m, 1H), 7.61 (s, 1H), 7.87-7.92 (m, 1H), 8.26 (s, 1H), 8.20-8.30 (m, 1H), 8.38-8.41 (m, 1H), 8.92 (s, 1H).
    3-57
    Figure US20110098280A1-20110428-C00068
    Rf (Hexane:Ac OEt = 3:1) 0.16 CDCl3: 1.44 (t, 3H), 2.65 (d, 3H), 2.79-2.89 (m, 4H), 3.65-3.74 (m, 4H), 4.07 (q, 2H), 4.52 (q, 4H), 6.48 (dd, 1H), 6.80 (d, 1H), 7.20-7.25 (m, 1H), 7.55-7.67 (m, 2H), 7.92-7.98 (m, 2H), 8.29 (s, 1H), 8.43 (d, 1H), 8.95 (s, 1H).
    3-58
    Figure US20110098280A1-20110428-C00069
    Rf 0.17 (Hexane/Ac OEt = 1/1) CDCl3: 1.46 (t, 3H), 2.63 (d, 3H), 3.08-3.13 (m, 4H), 3.83-3.90 (m, 4H), 4.09 (q, 2H), 4.46 (q, 1H), 6.39 (dd, 1H), 6.51 (d, 1H), 7.21-7.28 (m, 1H), 7.37 (s, 1H), 7.58 (dd, 1H), 7.97 (dd, 1H), 8.03 (d, 1H), 8.21 (s, 1H), 8.46 (d, 1H), 8.94 (s, 1H).
    3-59
    Figure US20110098280A1-20110428-C00070
    MS 538, 540 CDCl3: 2.63 (d, 3H), 3.44 (s, 3H), 3.65 (s, 3H), 3.69- 3.73 (m, 2H), 4.10-4.15 (m, 2H), 4.40 (q, 1H), 6.45 (dd, 1H), 6.85 (d, 1H), 7.19-7.25 (m, 1H), 7.61 (dd, 1H), 7.88 (s, 1H), 7.93-7.97 (m, 2H), 8.27 (s, 1H), 8.46 (d, 1H), 8.95 (s, 1H).
    3-60
    Figure US20110098280A1-20110428-C00071
    Rf (AcOEt) 0.54 CDCl3: 2.63 (d, 3H), 3.67 (s, 3H), 4.18 (t, 2H), 4.38- 4.49 (m, 3H), 6.46 (dd, 1H), 6.81 (d, 1H), 7.60-7.69 (m, 2H), 7.92-7.99 (m, 2H), 8.27 (s, 1H), 8.49 (d, 1H), 9.00 (s, 1H).
    3-61
    Figure US20110098280A1-20110428-C00072
    Rf (Hexane: AcOEt = 2:1) 0.46 CDCl3: 1.44 (t, 3H), 2.63 (d, 3H), 3.64 (s, 3H), 4.07 (q, 2H), 4.47 (q, 1H), 6.45 (dd, 1H), 6.78 (d, 1H), 7.21- 7.28 (m, 1H), 7.40-7.48 (m, 2H), 7.93-7.99 (m, 2H), 8.26 (s, 1H), 8.44 (d, 1H), 8.96 (s, 1H).
    3-62
    Figure US20110098280A1-20110428-C00073
    Rf (Hexane:Ac OEt = 3:1) 0.31 CDCl3: 1.36 (d, 6H), 2.63 (d, 3H), 3.63 (s, 3H), 4.41- 4.52 (m, 2H), 6.45 (dd, 1H), 6.81 (d, 1H), 7.21-7.26 (m, 1H), 7.59-7.68 (m, 2H), 7.91-7.98 (m, 2H), 8.26 (s, 1H), 8.45 (d, 1H), 8.96 (s, 1H).
    3-63
    Figure US20110098280A1-20110428-C00074
    Rf (Hexane: AcOEt = 3:1) 0.40 CDCl3: 1.07 (t, 3H), 1.84 (m, 2H), 6.63 (d, 3H), 3.64 (s, 3H), 3.96 (t, 2H), 4.40-4.49 (m, 1H), 6.46 (dd, 1H), 6.79 (d, 1H), 7.20-7.27 (m, 1H), 7.58-7.66 (m, 2H), 7.94-7.97 (m, 2H), 8.26 (s, 1H), 8.45 (d, 1H), 8.97 (s, 1H).
    3-64
    Figure US20110098280A1-20110428-C00075
    Rf (Hexane:Ac OEt = 3:1) 0.19 CDCl3: 2.62 (d, 3H), 6.68 (s, 6H), 3.84 (s, 3H), 4.41- 4.48 (m, 1H), 6.36 (dd, 1H), 6.80 (d, 1H), 7.17-7.24 (m, 1H), 7.51-7.62 (m, 2H), 7.83 (s, 1H), 7.95 (dd, 1H), 8.27 (s, 1H), 8.3*9-8.45 (m, 1H), 8.91 (s, 1H).
    3-65
    Figure US20110098280A1-20110428-C00076
    Rf (Hexane:Ac OEt = 1:1) 0.12 CDCl3: 2.66 (d, 3H), 3.97 (s, 3H), 4.47-4.55 (m, 1H), 6.96-7.10 (m, 3H), 7.21-7.24 (m, 1H), 7.66 (s, 1H), 7.93 (dd, 1H), 8.25 (d, 1H), 8.31 (s, 1H), 8.47 (d, 2H), 8.59 (s, 1H), 8.96 (s, 1H).
    3-66
    Figure US20110098280A1-20110428-C00077
    MS 541, 543 CDCl3: 2.65 (d, 3H), 3.96 (s, 3H), 4.61-4.71 (m, 1H), 6.89-7.05 (m, 3H), 7.16 (dd, 1H), 7.15-7.23 (m, 1H), 7.60 (d, 1H), 7.65 (s, 1H), 7.89 (d, 1H), 8.21 (d, 1H), 8.28 (d, 1H), 8.51 (br. s, 2H), 8.57 (s, 1H), 8.93 (s, 1H).
    3-67
    Figure US20110098280A1-20110428-C00078
    MS 541, 543 CDCl3: 2.65 (d, 3H), 3.96 (s, 3H), 4.51 (q, 1H), 6.90- 7.06 (m, 3H), 7.11-7.16 (m, 1H), 7.38 (d, 1H), 7.50- 7.61 (m, 2H), 7.62-7.67 (m, 1H), 7.89 (dd, 1H), 8.29 (s, 1H), 8.34 (d, 1H), 8.53 (d, 1H), 8.79 (br.s, 1H), 8.94 (s, 1H).
    3-68
    Figure US20110098280A1-20110428-C00079
    LC-MS 590 CDCl3: 1.45-1.59 (m, 2H), 1.70-1.78 (m, 1H), 1.82- 1.90 (m, 1H), 2.38-2.50 (m, 1H), 2.43 (s, 3H), 2.62- 2.77 (m, 2H), 3.56-3.70 (m, 2H), 3.76 (s, 3H), 6.46 (dd, 1H), 6.63 (d, 1H), 6.82-6.88 (br, 1H), 7.22 (dd, 1H), 7.31-7.40 (m, 2H), 7.43-7.51 (m, 1H), 7.50-7.80 (m, 2H), 8.14-8.20 (br, 1H), 8.21 (s, 1H), 8.39-8.48 (m, 1H), 9.16-9.26 (br, 1H)
    3-69
    Figure US20110098280A1-20110428-C00080
    0.34 (CH2Cl2:M eOH = 9:1) CDCl3: 1.58-1.82 (br, 7H), 1.88-2.03 (br, 3H), 2.44- 2.45 (m,5H), 3.42-3.52 (m, 3H), 3.75 (s, 3H), 6.66 (dd, 1H), 6.92 (d, 1H), 7.28 (dd, 1H), 7.44 (br, 1H), 7.51 (dd, 1H), 7.79-7.81 (m, 2H), 8.18 (s, 1H), 8.32 (s, 1H), 8.35-8.37 (m, 1H), 9.17 (s, 1H)
    3-70
    Figure US20110098280A1-20110428-C00081
    Ms: 607, 609 DMSO-d6: 1.84-1.92 (m, 2H), 2.34-2.41 (m, 4H), 2.41- 2.45 (m, 3H), 2.44 (t, 2H), 3.58 (t, 4H), 3.75 (s, 3H), 4.02 (t, 2H), 6.48 (dd, 1H), 6.63 (d, 1H), 7.21 (dd, 1H), 7.41 (d, 1H), 7.46 (dd, 1H), 7.72-7.78 (m, 1H), 7.76 (dd, 1H), 8.22 (s, 1H), 8.25 (s, 1H), 8.40 (d, 1H), 9.22 (s, 1H)
    3-71
    Figure US20110098280A1-20110428-C00082
    Ms: 591, 593 DMSO-d6: 1.84-1.92 (m, 2H), 2.14 (s, 3H), 2.35-2.4 (m, 4H), 2.43 (t, 2H), 2.44 (d, 3H), 3.58 (t, 4H), 4.01 (t, 2H), 6.77 (dd, 1H), 6.82 (d, 1H), 7.17 (dd, 1H), 7.20 (d, 1H), 7.3-7.39 (m, 1H, 7.71-7.77 (m, 2H), 8.2 (s, 1H), 8.35-8.44 (m, 1H), 8.71 (s, 1H), 9.27 (s, 1H)
    3-72
    Figure US20110098280A1-20110428-C00083
    Ms: 620, 622 DMSO-d6: 1.82-1.9 (m, 2H), 2.13-2.17 (m, 3H), 2.25-2.47 (m, 13H), 3.75 (s, 3H), 4.01 (t, 2H), 6.47 (dd, 1H), 6.63 (d, 1H), 7.19-7.24 (m, 1H), 7.41 (d, 1H), 7.43-7.5 (m, 1H), 7.70-7.79 (m, 2H), 8.22 (s, 1H), 8.25 (brs, 1H), 8.37-8.44 (m, 1H), 9.22 (s, 1H)
    3-73
    Figure US20110098280A1-20110428-C00084
    Ms: 607, 609 DMSO-d6: 1.78 (t, 2H), 2.32-2.36 (m, 4H9, 2.35-2.38 (m, 3H), 3.54-3.59 (m, 4H), 3.74 (t, 3H), 3.78 (s, 3H), 6.38-6.42 (m, 1H), 6.85 (d, 1H), 6.86-6.95 (m, 1H), 7.33-7.43 (m, 2H), 7.63-7.68 (m, 1H), 7.85-8.15 (m, 3H), 8.64-8.8 (m, 1H).
    3-74
    Figure US20110098280A1-20110428-C00085
    Ms: 605, 607 DMSO-d6: 1.47-1.67 (m, 2H), 1.84-2.01 (m, 2H), 2.03 (s, 3H), 2.41-2.46 (m, 3H), 3.23-3.39 (m, 2H), 3.65- 3.73 (m, 1H), 3.81 (s, 3H), 3.8-3.88 (m, 1H), 4.58-4.65 (m, 1H), 6.55 (dd, 1H), 6.68 (d, 1H), 7.2-7.26 (m, 1H), 7.43 (d, 1H), 7.42-7.51 (m, 1H), 7.7-7.8 (m, 2H), 8.23 (s, 1H), 8.26 (brs, 1H), 8.37-8.44 (m, 1H), 9.22 (brs, 1H)
    3-75
    Figure US20110098280A1-20110428-C00086
    Ms: 605, 607 DMSO-d6: 1.38-1.6 (m, 2H), 1.74-1.9 (m, 2H), 2.0 (s, 3H), 2.42-2.47 (m, 3H), 3.12-3.3 (m, 2H), 3.55-3.65 (m, 1H), 3.7-3.8 (m, 1H), 3.78 (s, 3H), 4.27-4.34 (m, 1H), 6.65 (dd, 1H), 6.94 (d, 1H), 7.24-7.3 (m, 1H), 7.53-7.63 (m, 2H), 7.74-7.83 (m, 2H), 8.09 (brs, 1H), 8.35 (s, 1H), 8.38 (d, 1H), 9.19 (brs, 1H)
    3-76
    Figure US20110098280A1-20110428-C00087
    Ms: 577, 579 DMSO-d6: 1.51-1.61 (m, 2H), 1.79-1.87 (m, 2H), 2.03-2.11 (m, 2H), 2.14 (s, 3H), 2.42-2.47 (m, 3H), 2.52-2.6 (m, 2H), 3.77 (s, 3H), 4.02-4.09 (m, 1H), 6.6 (dd, 1H), 6.92 (d, 1H), 7.24-7.3 (m, 1H), 7.52-7.6 (m, 2H), 7.74-7.82 (m, 2H), 8.08 (brs, 1H), 8.34 (s, 1H), 8.4 (d, 1H), 9.2 (brs, 1H)
    3-77
    Figure US20110098280A1-20110428-C00088
    Rf: 0.4 (n-hexane: AcOEt = 7:3) DMSO-d6: 2.41-2.45 (m, 3H), 6.89-6.96 (m, 1H), 6.69 (bs, 1H), 7.24-7.33 (m, 2H), 7.51-7.57 (m, 1H), 7.63-7.7 (m, 1H), 7.73-7.78 (m, 1H), 7.79 (dd, 1H), 8.37 (s, 1H), 8.41 (d, 1H), 9.21 (brs, 1H), 9.24 (brs, 1H)
    3-78
    Figure US20110098280A1-20110428-C00089
    Ms: 563, 565 DMSO-d6: 1.33-1.43 (m, 2H), 1.79-1.86 (m, 2H), 2.43-2.46 (m, 3H), 2.46-2.53 (m, 2H), 2.87-2.94 (m, 2H), 3.77 (s, 3H), 4.07-4.14 (m, 1H), 6.59 (dd, 1H), 6.91 (d, 1H), 7.23-7.28 (m, 1H), 7.53-7.59 (m, 2H), 7.79 (dd, 1H), 8.03 (brs, 1H), 8.32 (s, 1H), 8.38 (d, 1H), 8.7-9.5 (brs, 1H)
    3-79
    Figure US20110098280A1-20110428-C00090
    Ms: 563, 565 DMSO-d6: 1.41-1.51 (m, 2H), 1.88-1.95 (m, 2H), 2.41-2.45 (m, 3H), 2.54-2.63 (m, 2H), 2.92-3.0 (m, 2H), 3.75 (s, 3H), 4.35-4.43 (m, 1H), 6.50 (dd, 1H), 6.63 (d, 1H), 7.18-7.23 (m, 1H), 7.40 (d, 1H), 7.42- 7.48 (m, 1H), 7.75 (dd, 1H), 8.21 (s, 1H), 8.22-8.25 (m, 1H), 8.37-8.42 (m, 1H), 8.9-9.5 (brs, 1H)
    3-80
    Figure US20110098280A1-20110428-C00091
    Ms: 482, 484 DMSO-d6: 2.4-2.46 (m, 3H), 3.79 (s, 3H), 6.72 (ddd, 1H), 6.99 (dd, 1H), 7.21-7.26 (m, 1H), 7.47-7.53 (m, 1H), 7.59-7.64 (m, 1H), 7.76 (dd, 1H), 8.25 (s, 1H), 8.29-8.37 (m, 2H), 8.8-9.6 (m, 1H)
    3-81
    Figure US20110098280A1-20110428-C00092
    Ms: 482, 484 DMSO-d6: 2.41-2.49 (m, 3H), 3.82 (s, 3H), 6.80 (ddd, 1H), 7.01 (dd, 1H), 7.3-7.35 (m, 1H), 7.56-7.63 (m, 1H), 7.7-7.8 (m, 1H), 7.82 (dd, 1H), 7.85 (dd, 1H), 8.16 (s, 1H), 8.35 (dd, 1H), 9.18 (brs, 1H)
    3-82
    Figure US20110098280A1-20110428-C00093
    Ms: 563, 565 DMSO-d6: 1.73-1.82 (m, 1H), 2.23-2.34 (m, 4H), 2.34-2.42 (m, 3H), 2.42-2.46 (m, 3H), 2.59 (dd, 1H), 2.62-2.68 (m, 1H), 2.80 (dd, 1H), 3.75 (s, 1H), 4.85- 4.91 (m, 1H), 6.42 (dd, 1H), 6.57 (d, 1H), 7.19-7.24 (m, 1H), 7.41 (d, 1H), 7.43-7.51 (m, 1H), 7.68-7.79 (m, 2H), 8.22 (s, 1H), 8.23 (s, 1H), 8.37-8.43 (m, 1H), 9.21 (brs, 1H).
    3-83
    Figure US20110098280A1-20110428-C00094
    MS 544, 546 2.36 (s, 3H), 2.65 (d, 3H), 3.93 (s, 3H), 4.46-4.51 (m, 1H), 6.75-6.80 (m, 2H), 6.97-7.04 (m, 2h), 7.25-7.30 (m, 1H), 7.56-7.66 (m, 2H), 7.98 (dd, 1H), 8.29 (s, 1H), 8.36-8.44 (m, 2H), 9.01 (s, 1H).
    3-84
    Figure US20110098280A1-20110428-C00095
    MS 562, 564 CDCl3: 2.32 (s, 3H), 2.39-2.47 (m, 4H), 2.64 (d, 3H), 2.89-2.97 (m, 4H), 3.85 (s, 3H), 4.54-4.52 (m, 1H), 6.52 (dd, 1H), 6.79 (d, 1H), 7.22 (m, 1H), 7.52-7.64 (m, 2H), 7.94-7.99 (m, 2H), 8.28 (s, 1H), 8.42 (d, 1H), 8.93 (s, 1H).
  • Example 4 2-[5-Bromo-2-(subst. phenylamino)-pyrimidin-4-ylamino]-N-propyl-benzene-sulfonamides
  • These compounds are prepared in analogy to Example 2 using 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-propyl-benzenesulfonamide and the corresponding aniline to give compounds No. 4-1 to 4-31 having the substituent Rx as listed under Example 3 for compounds No. 3-1 to 3-31.
  • Preparation of 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-propyl-benzenesulfonamide
  • To a solution of 5-bromo-2,4-dichloropyrimidine (90 μL, 0.70 mmol) and 2-amino-N-propyl-benzenesulfonamide (100 mg, 0.47 mmol), sodium hydride (54.2 mg, 0.56 mmol) in DMSO (1.0 mL) is added and the resulting solution is stirred at 80° C. for 3.0 h. The mixture is poured into water and extracted with ethyl acetate three times. The organic layer is washed with water and then brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1) to afford the title compound as a slightly yellow solid.
  • 1H-NMR (δ, ppm): 0.89 (t, 3H), 1.41 (q, 2H), 3.56 (t, 2H), 4.92 (br.s, 2H), 6.71 (dd, 1H), 6.77 (dd, 1H), 7.33 (dd, 1H), 7.54 (dd, 1H), 8.79 (s, 1H)
  • Rf (hexane:ethyl acetate=1:1): 0.64.
  • Example 5 2-[5-Trifluoromethyl-2-(subst. phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamides
  • These compounds are prepared in analogy to Example 2 using 2-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide and the corresponding aniline to give compounds No. 5-1 to 5-31 having the substituent Rx as listed under Example 3 for compounds No. 3-1 to 3-31.
  • Preparation of 2-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide
  • To a solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (386 mg, 1.79 mmol) in acetonitrile (10 mL), 2-amino-N-methyl-benzenesulfonamide (333 mg, 1.79 mmol) and 1,8-diaza[5.4.0]-bicyclo-7-undecene (280 μL, 1.88 mmol) are added successively at ambient temperature. After stirring for 15 h at room temperature, dichloromethane (30 mL) is added to the mixture, and the solution is washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The resulting solid is purified by flash chromatography.
  • 1H NMR (CDCl3) δ: 3.73 (s, 3H), 6.67-6.69 (m, 1H), 6.72-6.73 (m, 1H), 7.27-7.31 (m, 1H), 7.78 (dd, 1H), 8.60 (s, 1H). Rf (hexane:ethyl acetate=1:1): 0.28.
  • Example 6 2-[5-Bromo-2-(2,3-[difluoromethylenedioxy]phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide
  • Figure US20110098280A1-20110428-C00096
  • This compound is obtained as a side product formed by N-demethylation on reaction of 2-(5-bromo-2-chloropyrimidin-4-ylamino)-N-methyl-benzenesulfonamide with 2,3-(difluoromethylene-dioxy)aniline following the procedure of Example 2. It may also be prepared by reaction of 2-(5-bromo-2-chloropyrimidin-4-ylamino)benzenesulfonamide with 2,3-(difluoromethylenedioxy)-aniline.
  • Rf (n-hexane:ethyl acetate=1:1): 0.46.
  • 1H-NMR: (CDCl3) 4.83 (bs, 2H), 6.77 (dd, 1H), 6.86 (s, 1H), 6.97 (dd, 1H), 7.31-7.24 (m, 1H), 7.57 (dd, 1H), 7.81 (d, 1H), 8.02 (dd, 1H), 8.28 (d, 1H), 8.29 (s, 1H), 8.88 (s, 1H).
  • Preparation of 2-(5-bromo-2-chloropyrimidin-4-ylamino)benzenesulfonamide: To a solution of 5-bromo-2,4-dichloropyrimidine (300 mg, 1.32 mmol) and 2-amino-benzenesulfonamide (340 mg, 1.97 mmol) in 2-propanol (3 mL), concentrated hydrochloric acid (0.06 mL) is added and the mixture is stirred at 90° C. for 4.5 hours. The mixture is poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate three times. The organic layer is washed with water, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by column chromatography (hexane:ethyl acetate=2:1) to afford the title compound.
  • Rf (hexane:ethyl acetate=1:1): 0.55. 1H-NMR (400 MHz, CDCl3) δ: 4.78 (br.s, 2H), 7.22 (dd, 1H), 7.61 (ddd, 1H), 7.95 (dd, 1H), 8.35 (s, 1H), 8.35 (d, 1H), 9.18 (s, 1H).
  • Example 7A 2-[5-Chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide
  • Figure US20110098280A1-20110428-C00097
  • To a suspension of 2-(2,5-dichloro-pyrimidin-4-yl-amino)-N-methyl-benzamide (5.05 g, 17.0 mmol) in 90 mL of 2-methoxyethanol are added 2-methoxy-4-morpholinoaniline dihydrochloride (4.56 g, 16.2 mmol) and 17.0 mL of 1N ethanolic solution of hydrogen chloride (17.0 mmol). After the reaction mixture is stirred at 110° C. for 4 hours and cooled to room temperature, the mixture is neutralized with 1N aqueous NaOH solution and extracted with EtOAc (100 mL×3). The organic layer is washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting black solid is washed with EtOH (90 mL), then purified with silica gel column chromatography (CH2Cl2 to CH2Cl2:AcOEt=1:2) to give 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a pale yellow solid.
  • 1H-NMR (400 MHz, DMSO-d6, δ): 2.80 (d, 3H, J=4.52 Hz), 3.10-3.20 (m, 4H), 3.78 (s, 3H), 3.70-3.80 (m, 4H), 6.49 (dd, 1H, J=8.56, 2.52 Hz), 6.66 (d, 1H, J=2.52 Hz), 7.08 (dd, 1H, J=8.04, 8.04 Hz), 7.44 (d, 1H, J=8.56 Hz), 7.71 (dd, 1H, J=8.04, 1.48 Hz), 8.10 (s, 1H), 8.13 (s, 1H), 8.59 (d, 1H, J=8.04 Hz) 8.68-8.75 (m, 1H), 11.59 (S, 1H). MS m/z 469, 471 (M+1)+.
  • The following 2-[5-Chloro-2-(substituted phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide are prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and the corresponding aniline following the procedure of Example 7A.
  • Figure US20110098280A1-20110428-C00098
    Expl Rf (solvent)
    No. Rx or MS NMR (400 MHz), δ (ppm)
    7-1
    Figure US20110098280A1-20110428-C00099
    MS: m/z 550, 552 (M + 1) DMSO-d6: 1.44-1.33 (m, 2H), 1.64-1.45 (m, 6H), 1.73-1.89 (m, 2H), 2.34-2.44 (m, 1H), 2.43-2.55 (m, 4H), 2.65 (t, 2H), 2.80 (d, 3H), 3.75 (s, 3H), 3.72-3.75 (m, 2H), 6.48 (dd, 1H), 6.62 (d, 1H), 7.06 (dd, 1H), 7.32 (dd, 1H), 7.39 (d, 1H), 7.71 (dd, 1H), 8.09 (s, 1H), 8.60 (d, 1H), 8.70 (d, 1H), 11.58 (s, 1H)
    7-2
    Figure US20110098280A1-20110428-C00100
    0.3 (MeOH:AcOEt = 5:95) CDCl3: 1.70-1.97 (m, 4H), 2.62-2.79 (m, 1H), 3.04 (d, 3H), 3.02-3.18 (m, 2H), 3.23-3.33 (m, 2H), 3.88 (s, 3H), 5.39-5.47 (m, 1H), 6.15-6.24 (m, 1H), 6.55-6.62 (m, 2H), 6.74-6.82 (m, 1H), 7.09 (dd, 1H), 7.23-7.32 (m, 1H), 7.46-7.52 (m, 2H), 8.09 (s, 1H), 8.15 (d, 1H), 8.68 (d, 1H) 11.0 (bs, 1H)
    7-3
    Figure US20110098280A1-20110428-C00101
    MS (ESI) mz/ 482, 484 (M + 1)+ DMSO-d6: 2.24 (s, 3H), 2.45-2.55 (m, 4H), 2.80 (d, 3H, J = 4.52 Hz), 3.12-3.17 (m, 4H), 3.76 (s, 3H), 6.48 (dd, 1H, J = 8.56, 2.52 Hz), 6.63 (d, 1H, J = 2.52 Hz), 7.05-7.10 (m, 1H), 7.27-7.35 (m, 1H), 7.40 (d, 1H, J = 8.56 Hz), 7.69-7.72 (m, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.55-8.65 (m, 1H), 8.67-8.75 (m, 1H), 11.59 (s, 1H)
    7-4
    Figure US20110098280A1-20110428-C00102
    0.46 (MeOH:CH2Cl2 = 1:4) DMSO-d6: 2.48-2.55 (m, 4H), 2.71 (t, 2H), 2.80 (d, 3H), 3.58-3.61 (m, 4H), 3.76 (s, 3H), 4.11 (t, 2H), 6.52 (dd, 1H), 6.66 (d, 1H), 7.06 (dd, 1H), 7.32 (dd, 1H), 7.46 (d, 1H), 7.71 (dd, 1H), 8.11 (s, 1H), 8.19 (s, 1H), 8.54-8.60 (m, 1H), 8.60-8.75 (m, 1H), 11.6 (s, 1H)
    7-5
    Figure US20110098280A1-20110428-C00103
    mz/ 497, 499 (M + 1)+ DMSO-d6: 1.60-1.70 (m, 2H), 1.90-1.98 (m, 2H), 2.13-2.25 (m, 2H), 2.19 (s, 3H), 2.60-2.67 (m, 2H), 2.80 (d, 3H, J = 4.52 Hz), 3.75 (s, 3H), 4.30-4.40 (m, 1H), 6.54 (dd, 1H, J = 8.56, 2.0 Hz), 6.65 (d, 1H, J = 2.0 Hz), 7.04-7.09 (m, 1H), 7.25-7.35 (m, 1H), 7.43 (d, 1H, J = 8.56 Hz), 7.68-7.73 (m, 1H), 8.10 (s, 1H), 8.18 (s, 1H) 8.52-8.59 (m, 1H), 8.68-8.75 (m, 1H), 11.57 (s, 1H)
    7-6
    Figure US20110098280A1-20110428-C00104
    0.25 (n-hexane:AcOEt = 1:2) CDCl3: 2.95 (m, 4H), 3.03 (d, 3H), 3.75 (m, 4H), 3.86 (s, 3H), 6.21-6.19 (br, 1H), 6.49 (dd, 1H), 6.80 (d, 1H), 7.09-7.05 (m, 1H), 7.50 (dd, 1H), 8.08 (d, 1H), 8.13 (s, 1H), 8.68 (d, 1H), 11.07 (s, 1H)
    7-7
    Figure US20110098280A1-20110428-C00105
    MS m/z 510 512 (M + 1) DMSO-d6: 2.06 (s, 3H), 2.80 (d, 3H), 3.11 (t, 2H), 3.16 (t, 2H), 3.60 (dd, 4H), 3.77 (s, 3H), 6.51 (dd, 1H), 6.68 (d, 1H), 7.08 (dd, 1H), 7.33 (dd, 1H), 7.46 (d, 1H), 7.71 (d, 1H), 8.10 (s, 1H), 8.12 (s, 1H), 8.59-8.61 (m, 1H), 8.70-8.71 (m, 1H), 11.59 (s, 1H)
    7-8
    Figure US20110098280A1-20110428-C00106
    0.48 (MeOH:AcOEt = 5:95) CDCl3: 1.46 (d, 1H), 1.68-1.82 (m, 2H), 2.02-2.09 (m, 2H), 2.83-2.96 (m, 2H), 3.03 (d, 3H), 3.44-3.53 (m, 2H), 3.82-3.92 (m, 1H), 3.87 (s, 3H), 6.15-6.23 (m, 1H), 6.51 (d, 1H), 6.56 (bs, 1H), 7.07 (dd, 1H), 7.48 (d, 2H), 8.08 (s, 1H), 8.08-8.10 (m, 1H), 8.69 (d, 1H), 11.0 (bs, 1H)
    7-9
    Figure US20110098280A1-20110428-C00107
    0.4 (n-hexane:AcOEt = 1:1) CDCl3: 1.22 (t, 3H), 1.73-1.85 (m, 2H), 2.00-2.09 (m, 2H), 2.81-2.90 (m, 2H), 3.03 (d, 3H), 3.41-3.56 (m, 3H), 3.56 (dd, 2H), 3.58-3.62 (m, 2H), 3.64-3.68 (m, 2H), 3.86 (s, 3H), 6.15-6.24 (m, 1H), 6.50 (dd, 1H), 6.56 (d, 1H), 7.07 (dd, 1H), 7.24-7.30 (m, 1H), 7.45-7.52 (m, 2H), 8.08 (s, 1H), 8.06-8.08 (m, 1H), 8.69 (d, 1H), 11.0 (bs, 1H)
    7-10
    Figure US20110098280A1-20110428-C00108
    0.4 (n-hexane:AcOEt = 1:1) CDCl3: 1.73-1.85 (m, 2H), 2.01-2.10 (m, 2H), 2.82-2.90 (m, 2H), 3.03 (d, 3H), 3.41 (s, 3H), 3.45-3.51 (m, 2H), 3.56-3.58 (m, 2H), 3.65-3.68 (m, 2H), 3.86 (s, 3H), 6.14-6.22 (m, 1H), 6.50 (dd, 1H), 6.56 (d, 1H), 7.07 (dd, 1H), 7.23-7.30 (m, 1H), 7.44-7.52 (m, 2H), 8.08 (s, 1H), 8.06-8.08 (m, 1H), 8.69 (d, 1H), 11.0 (bs, 1H)
    7-11
    Figure US20110098280A1-20110428-C00109
    0.54 (MeOH:CH2Cl2 = 1:4) DMSO-d6: 1.78-1.89 (m, 1H), 2.13-2.22 (m, 1H), 2.22 (s, 6H), 2.77-2.87 (m, 1H), 2.79 (d, 3H), 3.04-3.10 (m, 1H), 3.23-3.50 (m, 3H), 3.75 (s, 3H), 6.11 (dd, 1H), 6.22 (d, 1H), 7.05 (dd1H), 7.21-7.32 (m, 1H), 7.26 (d, 1H), 7.70 (d, 1H), 8.06 (s, 1H), 8.08 (s, 1H), 8.57-8.66 (m, 1H), 8.66-8.73 (m, 1H), 11.6 (s, 1H)
    7-12
    Figure US20110098280A1-20110428-C00110
    0.27 (MeOH:CH2Cl2 = 1:1) DMSO-d6: 1.77-1.87 (m, 1H), 2.09-2.18 (m, 1H), 2.35 (s, 3H), 2.79 (d, 1H), 3.02-3.07 (m, 1H), 3.23-3.50 (m, 4H), 3.74 (s, 3H), 6.09 (dd, 1H), 6.20 (d, 1H), 7.04 (dd, H), 7.22-7.32 (m, 1H), 7.26 (d, 1H), 7.70 (d, 1H), 8.05 (s, 1H), 8.08 (s, 1H), 8.57-8.67 (m, 1H), 8.67-8.73 (m, 1H), 11.6 (s, 1H)
    7-13
    Figure US20110098280A1-20110428-C00111
    0.23 (MeOH:AcOEt = 5:95) CDCl3: 1.62-1.74 (m, 3H), 1.76-1.85 (m, 2H), 2.00-2.09 (m, 2H), 2.20-2.31 (m, 1H), 2.64-2.69 (m, 2H), 2.79 (d, 3H), 3.56-4.04 (m, 2H), 4.04 (s, 3H), 6.49 (dd, 1H), 6.63 (d, 1H), 6.78 (bs, 1H), 7.07 (dd, 1H), 7.28-7.38 (m, 1H), 7.39 (d, 1H), 7.71 (d, 1H), 8.09-8.11 (m, 2H), 8.09 (s, 1H), 8.60 (d, 1H), 8.71 (d, 1H), 11.6 (bs, 1H)
    7-14
    Figure US20110098280A1-20110428-C00112
    0.30 (MeOH:CH2Cl2 = 4:1) DMSO-d6: 1.61-1.46 (m, 2H), 1.92-1.82 (m, 2H), 2.14 (s, 3H), 2.41-2.23 (m, 5H, 2.60-2.45 (m, 4H), 2.67 (t, 2H), 2.79 (d, 3H), 3.75 (s, 3H), 3.71-3.75 (m, 2H), 6.48 (dd, 1H), 6.63 (d, 1H), 7.10-7.03 (m, 1H), 7.34-7.27 (m, 1H), 7.43-7.35 (m, 1H), 7.71 (dd, 1H), 8.09 (s, 1H), 8.11 (bs, 1H), 8.65-8.56 (m, 1H), 8.75-8.67 (m, 1H), 11.6 (s, 1H)
    7-15
    Figure US20110098280A1-20110428-C00113
    MS (ESI) mz/ 524, 526 (M + 1)+ DMSO-d6: 2.19-2.37 (m, 4H), 2.65-2.85 (m, 3H), 2.80 (d, 3H, J = 4.5 Hz), 3.15-3.21 (m, 1H), 3.48-3.59 (m, 2H), 3.61-3.67 (m, 1H), 3.72-3.81 (m, 1H), 3.76 (s, 3H), 6.47 (dd, 1H, J = 8.6, 2.5 Hz), 6.65 (d, 1H, J = 2.5 Hz), 7.04-7.10 (m, 1H), 7.28-7.35 (m, 1H), 7.42 (d, 1H, J = 8.6 Hz), 7.69-7.74 (m, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.55-8.63 (m, 1H), 8.68-8.73 (m, 1H), 11.60 (s, 1H)
    7-16
    Figure US20110098280A1-20110428-C00114
    MS (ESI) mz/ 524, 526 (M + 1)+ DMSO-d6: 2.19-2.37 (m, 4H), 2.65-2.85 (m, 3H), 2.80 (d, 3H, J = 4.5 Hz), 3.15-3.21 (m, 1H), 3.48-3.59 (m, 2H), 3.61-3.67 (m, 1H), 3.72-3.81 (m, 1H), 3.76 (s, 3H), 6.47 (dd, 1H, J = 8.6, 2.5 Hz), 6.65 (d, 1H, J = 2.5 Hz), 7.04-7.10 (m, 1H), 7.28-7.35 (m, 1H), 7.42 (d, 1H, J = 8.6 Hz), 7.69-7.74 (m, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.55-8.63 (m, 1H), 8.68-8.73 (m, 1H), 11.60 (s, 1H)
    7-17
    Figure US20110098280A1-20110428-C00115
    MS 510 DMSO-d6: 0.98 (t, 3H), 1.81-1.71 (m, 3H), 1.95-1.84 (m, 3H), 2.68-2.63 (m, 1H), 2.80 (d, 3H), 3.12-3.08 (m, 4H), 3.28 (d, 2H), 3.76 (s, 3H), 6.50 (dd, 1H), 6.64 (d, 1H), 6.86 (bs, 1H), 7.07 (dd, 1H), 7.46-7.19 (m, 3H), 7.71 (d, 1H), 8.09 (s, 1H), 8.15-8.10 (m, 1H), 8.66-8.58 (m, 1H), 8.77-8.70 (m, 1H), 11.6 (s, 1H)
    7-18
    Figure US20110098280A1-20110428-C00116
    MS 510 DMSO-d6: 0.98 (t, 3H), 1.81-1.71 (m, 3H), 1.95-1.84 (m, 3H), 2.68-2.63 (m, 1H), 2.80 (d, 3H), 3.12-3.08 (m, 4H), 3.28 (d, 2H), 3.76 (s, 3H), 6.50 (dd, 1H), 6.64 (d, 1H), 6.86 (bs, 1H), 7.07 (dd, 1H), 7.46-7.19 (m, 3H), 7.71 (d, 1H), 8.09 (s, 1H), 8.15-8.10 (m, 1H), 8.66-8.58 (m, 1H), 8.77-8.70 (m, 1H), 11.6 (s, 1H)
    7-19
    Figure US20110098280A1-20110428-C00117
    0.16 (CH2Cl2:MeOH = 9:1) 1.40-1.53 (m, 2H), 1.72-1.80 (m, 2H), 2.18 (s, 3H), 2.19-2.44 (m, 5H), 2.80 (d, 3H), 3.46 (m, 2H), 3.74 (s, 3H), 6.65 (dd, 1H), 6.91 (d, 1H), 7.07-7.10 (m, 1H), 7.36-7.40 (m, 1H), 7.45-7.49 (m, 1H), 7.73 (dd, 1H), 8.12 (s, 1H), 8.18 (s, 1H), 8.61 (d, 1H), 8.72-8.77 (m, 1H), 11.68 (s, 1H)
    7-20
    Figure US20110098280A1-20110428-C00118
    Ms: 511 1.25-1.37 (m, 2H), 1.62-1.79 (m, 3H), 1.81-1.9 (m, 2H), 2.16 (s, 3H), 2.75-2.85 (m, 5H), 3.76 (s, 3H), 3.8-3.88 (m, 2H), 6.45-6.55 (m, 1H), 6.6-6.67 (m, 1H), 7.02-7.12 (m, 1H), 7.25-7.35 (m, 1H), 7.4-7.5 (m, 1H), 7.67-7.78 (m, 1H), 8.1 (s, 1H), 8.19 (brs, 1H) 8.5-8.62 (m, 1H), 8.66-8.8 (m, 1H), 11.6 (s, 1H)
    7-21
    Figure US20110098280A1-20110428-C00119
    Ms: 526 2.17 (s, 3H), 2.29-2.39 (m, 3H), 2.45-2.56 (m, 4H), 2.7 (t, 2H), 3.76 (s, 3H), 4.09 (t, 2H), 6.52 (dd, 1H), 6.66 (d, 1H), 7.06 (dd, 1H), 7.31 (dd, 1H), 7.45 (d, 1H), 7.71 (dd, 1H), 8.1 (s, 1H), 8.19 (s, 1H), 8.5-8.6 (m, 1H), 8.67-8.75 (m, 1H), 11.6 (s, 1H)
    7-22
    Figure US20110098280A1-20110428-C00120
    Ms: 482 2.24 (s, 3H), 2.42-2.5 (m, 4H), 2.8 (d, 3H), 2.94-3.0 (m, 4H), 3.74 (s, 3H), 6.65 (dd, 1H), 6.93 (d, 1H), 7.07-7.14 (m, 1H), 7.34-7.4 (m, 1H), 7.45 (d, 1H), 7.73 (dd, 1H), 8.14 (s, 1H), 8.18 (s, 1H), 8.61 (dd, 1H), 8.7-8.77 (m, 1H), 11.7 (s, 1H)
    7-23
    Figure US20110098280A1-20110428-C00121
    Ms: 482 1.67-1.76 (m, 1H), 2.0-2.1 (m, 1H), 2.25-2.31 (m, 3H), 2.8 (d, 3H), 2.85-2.91 (m, 1H), 3.04-3.12 (m, 1H), 3.14-3.3 (m, 3H), 3.7 (s, 3H), 6.26 (dd, 1H), 6.91 (d, 1H), 7.01-7.04 (m, 1H), 7.07 (dd, 1H), 7.32 (dd, 1H), 7.72 (d, 1H), 8.14 (s, 1H), 8.17 (s, 1H), 8.63 (d, 1H), 8.7-8.78 (m, 1H), 11.6 (s, 1H)
    7-24
    Figure US20110098280A1-20110428-C00122
    Ms: 550 1.35-1.57 (m, 8H), 1.7-1.78 (m, 2H), 2.81 (d, 3H), 3.46-3.52 (m, 2H), 3.74 (s, 3H), 6.65 (dd, 1H), 6.91 (d, 1H), 7.05-7.12 (m, 1H), 7.34-7.42 (m, 1H), 7.46 (d, 1H), 7.73 (dd, 1H), 8.11 (s, 1H), 8.18 (s, 1H), 8.62 (dd, 1H), 8.71-8.78 (m, 1H), 11.7 (s, 1H)
    7-25
    Figure US20110098280A1-20110428-C00123
    536 [M + 1]+ DMSO-d6: 1.48-1.58 (m, 2H), 1.65-1.72 (m, 4H), 1.90-1.97 (m, 2H), 2.07-2.14 (m, 1H), 2.49-2.55 (m, 4H), 2.70-2.77 (m, 2H), 2.79 (d, 3H), 3.60-3.65 (m, 2H), 3.75 (s, 3H), 6.48 (dd, 1H), 6.63 (d, 1H), 7.03-7.09 (m, 1H), 7.28-7.34 (m, 1H), 7.39 (d, 1H), 7.71 (dd, 1H), 8.09 (s, 1H), 8.11 (s, 1H), 8.55-8.65 (m, 1H), 8.69-8.73 (m, 1H), 11.59 (s, 1H)
    7-26
    Figure US20110098280A1-20110428-C00124
    468 [M + 1]+ DMSO-d6: 2.80 (d, 3H), 2.84-2.89 (m, 4H), 3.04-3.08 (m, 4H), 3.76 (s, 3H), 6.47 (dd, 1H), 6.62 (dd, 1H), 7.04-7.10 (m, 1H), 7.28-7.35 (m, 1H), 7.40 (d, 1H), 7.69-7.73 (m, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.55-8.63 (m, 1H), 8.68-8.73 (m, 1H), 11.59 (s, 1H) (an aliphatic NH is hidden)
    7-27
    Figure US20110098280A1-20110428-C00125
    393 [M + 1]+ DMSO-d6: 2.80 (d, 3H), 6.64-6.67 (m, 1H), 7.01-7.08 (m, 2H), 7.15 (d, 1H), 7.24-7.29 (m, 2H), 7.44 (d, 1H), 7.69-7.73 (m, 1H), 8.20 (s, 1H), 8.65-8.73 (m, 2H), 9.15 (s, 1H), 11.06 (s, 1H), 11.63 (s, 1H)
    7-28
    Figure US20110098280A1-20110428-C00126
    407 [M + 1]+ DMSO-d6: 2.81 (d, 3H), 3.79 (s, 3H), 6.67 (d, 1H), 7.05-7.10 (m, 1H), 7.12 (d, 1H), 7.17 (d, 1H), 7.23 (d, 1H), 7.25-7.30 (m, 1H), 7.50 (d, 1H), 7.70-7.73 (m, 1H), 8.20 (s, 1H), 8.67 (d, 1H), 8.70-8.75 (m, 1H), 9.17 (s, 1H), 11.64 (s, 1H)
    7-29
    Figure US20110098280A1-20110428-C00127
    492 [M + 1]+ DMSO-d6: 2.80 (d, 3H), 2.91-2.99 (m, 4H), 3.65-3.81 (m, 2H), 3.82-3.95 (m, 2H), 4.12 (s, 3H), 6.58 (d, 1H), 6.90 (d, 1H), 7.05-7.09 (m, 1H), 7.14 (d, 1H), 7.22-7.28 (m, 1H), 7.30 (d, 1H), 7.70 (dd, 1H), 8.16 (s, 1H), 8.63-8.67 (m, 1H), 8.68-8.72 (m, 1H), 9.06 (s, 1H), 11.64 (s, 1H)
    7-30
    Figure US20110098280A1-20110428-C00128
    MS m/z 510 DMSO-d6: 2.02 (s, 3H), 2.80 (d, 3H), 2.82-2.92 (m, 2H), 2.92-3.01 (m, 2H), 3.44-3.53 (m, 4H), 3.76 (s, 3H), 6.68 (dd, 1H), 6.95 (d, 1H), 7.09 (dd, 1H), 7.35-7.40 (m, 1H), 7.50 (brs, 1H), 7.73 (d, 1H), 8.15 (s, 1H), 8.19 (s, 1H), 8.59 (d, 1H), 8.69-8.76 (m, 1H), 11.66 (s, 1H).
  • The following 2-[5-Bromo-2-(substituted phenylamino)-pyrimidin-4-ylamino]-N-ethyl-benzamide are prepared from 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-ethyl-benzamide and the corresponding aniline following the procedure of Example 7A
  • Figure US20110098280A1-20110428-C00129
    Expl Rf (solvent)
    No. Rx or MS NMR
    8-1
    Figure US20110098280A1-20110428-C00130
    0.27 (n-hexane:AcOEt = 1:2) DMSO-d6: 2.80 (d, 3H), 2.88 (t, 4H), 3.65 (m, 4H), 3.75 (s, 3H), 6.64 (dd, 1H), 6.94 (d, 1H), 7.11-7.08 (m, 1H), 7.38-7.34 (m, 1H), 7.47-7.46 (m, 1H), 7.70 (dd, 1H), 8.11 (s, 1H), 8.26 (s, 1H), 8.51-8.49 (m, 1H), 8.72-8.71 (m, 1H), 11.41 (s, 1H)
    8-2
    Figure US20110098280A1-20110428-C00131
    mz/ 513, 515 (M + 1) DMSO-d6: 2.79 (d, 3H, J = 4.04 Hz), 3.10-3.20 (m, 4H), 3.77 (s, 3H), 3.70-3.80 (m, 4H), 6.45-6.55 (m, 1H), 6.63-6.69 (m, 1H), 7.05-7.10 (m, 1H), 7.28-7.34 (m, 1H), 7.40-7.45 (m, 1H), 7.65-7.70 (m, 1H), 8.13 (s, 1H), 8.16 (s, 1H), 8.50-8.56 (m, 1H) 8.65-8.72 (m, 1H), 11.40 (s, 1H)
    8-3
    Figure US20110098280A1-20110428-C00132
    0.48 (n-Hexane:AcOEt = 4:1) DMSO-d6: 2.80 (d, 3H), 3.83 (s, 3H), 4.11 (t, 2H), 6.82 (ddd, 1H), 7.03 (dd, 1H), 7.15 (dd, 1H), 7.44 (dd, 1H), 7.73 (d, 1H), 7.93 (dd, 1H), 8.13 (s, 1H), 8.33 (s, 1H), 8.50 (d, 1H), 8.70-8.77 (m, 1H), 11.3 (s, 1H).
    8-4
    Figure US20110098280A1-20110428-C00133
    MS 446, 448 2.79 (d, 3H), 3.79 (s, 3H), 6.75 (ddd, 1H), 7.0 (dd, 1H), 7.05-7.12 (m, 1H), 7.3-7.36 (m, 1H), 7.62 (dd, 1H), 7.69 (dd, 1H), 8.2 (s, 1H), 8.29 (s, 1H), 8.45 (d, 1H), 8.66-8.73 (m, 1H), 11.4 (brs, 1H).
  • The following 2-[5-Chloro-2-(substituted phenylamino)-pyrimidin-4-ylamino]-N-ethyl-benzamide are prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide and the corresponding aniline following the procedure of Example 7A
  • Figure US20110098280A1-20110428-C00134
    Expl Rf (solvent)
    No. Rx or MS NMR (400 MHz), δ (ppm)
    9-1
    Figure US20110098280A1-20110428-C00135
    0.35 (n-hexane:AcOEt = 1:2) CDCl3: 1.27 (t, 3H), 3.10-3.15 (m, 4H), 3.47-3.58 (m, 2H), 3.85-3.93 (m, 4H), 3.89 (s, 3H), 6.08-6.17 (m, 1H), 6.48 (dd, 1H), 6.53 (d, 1H), 7.05-7.11 (m, 1H), 7.42-7.53 (m, 2H), 8.08 (s, 1H), 8.12 (d, 1H), 8.67 (d, 1H), 10.94 (brs, 1H).
    9-2
    Figure US20110098280A1-20110428-C00136
    MS (ESI) mz/ 497, 499 (M + 1)+ CDCl3: 1.26 (t, 3H, J = 7.56 Hz), 2.37 (s, 3H), 2.57-2.62 (m, 4H), 3.15-3.20 (m, 4H), 3.49 (dq, 2H, J = 7.56, 1.52 Hz), 3.87 (s, 3H), 6.11-6.16 (m, 1H), 6.49 (dd, 1H, J = 8.56, 2.52 Hz), 6.55 (d, 1H, J = 2.52 Hz), 7.05-7.10 (m, 1H), 7.23 (s, 1H), 7.41-7.50 (m, 2H), 8.07 (s, 1H), 8.08 (d, 1H, J = 8.56 Hz), 8.65-8.69 (m, 1H), 10.93 (s, 1H)
    9-3
    Figure US20110098280A1-20110428-C00137
    mz/ 564, 566 (M + 1)+ DMSO-d6: 1.26 (t, 3H, J = 7.56 Hz), 1.40-1.50 (m, 2H), 1.56-1.64 (m, 4H), 1.67-1.82 (m, 2H), 1.88-1.97 (m, 2H), 2.33-2.44 (m, 1H), 2.52-2.57 (m, 4H), 2.63-2.73 (m, 2H), 3.51 (dq, 2H, J = 7.56, 1.52 Hz), 3.62-3.69 (m, 2H), 3.86 (s, 3H), 6.10-6.15 (m, 1H), 6.49 (dd, 1H, J = 8.56, 2.52 Hz), 6.55 (d, 1H, J = 2.52 Hz), 7.05-7.10 (m, 1H), 7.23 (s, 1H), 7.43-7.50 (m, 2H) 8.05-8.11 (m, 1H), 8.07 (s, 1H), 8.65-8.69 (m, 1H), 10.91 (s, 1H)
    9-4
    Figure US20110098280A1-20110428-C00138
    0.39 (MeOH:CH2Cl2 = 1:4) DMSO-d6: 1.19 (t, 3H), 1.52-1.68 (m, 2H), 1.71-1.79 (m, 4H), 1.92-2.05 (m, 2H), 2.12-2.23 (m, 1H), 2.76-2.85 (m, 2H), 3.65-3.73 (m, 2H), 3.82 (s, 3H), 6.54 (dd, 1H), 6.69 (d, 1H), 7.13 (m, 1H), 7.45 (d, 1H), 7.79 (dd, 1H), 8.15 (s, 1H), 8.15-8.18 (m, 1H), 8.60-8.68 (m, 1H), 8.74-8.83 (m, 1H).
    9-5
    Figure US20110098280A1-20110428-C00139
    Rf (Hexane:AcOEt = 1:2): 0.30 CDCl3: 1.27 (t, 3H), 3.08-3.14 (m, 4H), 3.52 (q, 2H), 3.71-3.90 (m, 7H), 6.05-6.18 (m, 1H), 6.47 (dd, 1H), 6.53 (dd, 1H), 7.08 (dd, 1H), 7.41-7.53 (m, 2H), 8.08 (s, 1H), 8.12 (d, 1H), 8.67 (d, 1H), 10.94 (s, 1H).
    9-6
    Figure US20110098280A1-20110428-C00140
    Rf (AcOEt:MeOH = 4:1) 0.050 DMSO: 1.11 (t, 3H), 1.60-1.69 (m, 1H), 1.88-1.96 (m, 2H), 2.19 (s, 3H), 2.55-2.68 (m, 2H), 3.30-3.45 (m, 2H), 3.75 (s, 3H), 4.33-4.43 (m, 1H), 6.54 (dd, 1H), 6.65 (d, 1H), 7.07 (dd, 1H), 7.30 (dd, 1H), 7.43 (d, 1H), 7.71 (dd, 1H), 8.11 (s, 1H), 8.20 (s, 1H), 8.54 (br.d, 1H), 8.75 (dd, 1H), 11.49 (s, 1H).
    9-7
    Figure US20110098280A1-20110428-C00141
    0.44 (CH2Cl2:MeOH = 8:2) CDCl3: 1.34 (t, 3H), 1.62-1.68 (m, 2H), 1.93-2.18 (m, 8H), 2.37-2.40 (br, 2H), 2.74-2.86 (br, 3H), 3.20-3.23 (m, 2H), 3.34 (br, 2H), 3.53 (q, 2H), 3.85 (s, 3H), 6.47 (dd, 1H), 6.76 (d, 1H), 7.04-7.08 (m, 1H), 7.30 (dd, 1H), 7.53 (s, 1H), 8.00 (d, 1H), 8.13-8.17 (m, 1H), 8.22 (d, 1H), 8.42-8.53 (br, 1H), 10.91 (s, 1H), 11.59-11.75 (br, 1H)
  • The following 2-[5-Chloro-2-(substituted phenylamino)-pyrimidin-4-ylamino]-6,N-dimethyl-benzamide are prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-6,N-dimethyl-benzamide and the corresponding aniline following the procedure of Example 7A
  • Figure US20110098280A1-20110428-C00142
    Expl
    No. Rx Identification
    10-1
    Figure US20110098280A1-20110428-C00143
    NMR (400 MHz, DMSO-d6, δ): 1.58-1.68(m, 2H), 1.87-1.96(m, 2H), 2.13-2.22(m, 2H), 2.18(s, 3H), 2.18(s, 3H), 2.29(s, 3H), 2.57- 2.65(m, 2H), 2.76(d, 3H), 3.75(s, 3H), 4.29-4.37(m, 1H), 6.45(dd, 1H), 6.61(d, 1H), 6.98(d, 1H), 7.18(dd, 1H), 7.47(d, 1H), 7.89(d, 1H), 8.02(s, 1H), 8.07(s, 1H), 8.37- 8.43(m, 1H), 8.49(s, 1H). Rf: 0.39 (MeOH: CH2Cl2 = 1:4).
    10-2
    Figure US20110098280A1-20110428-C00144
    NMR (400MHz, DMSO-d6, δ): 1.35-1.42 (m, 2H), 1.45-1.60 (m, 6H), 1.75-1.85 (m, 2H), 2.29 (s, 3H), 2.30-2.35 (m, 1H), 2.43-2.50 (m, 4H), 2.57-2.66 (m, 2H), 2.76 (d, 3H, J = 5.0 Hz), 3.65-3.74 (m, 2H), 3.76 (s, 3H), 6.40 (dd, 1H, J = 9.0, 2.0 Hz), 6.59 (d, 1H, J = 2.0 Hz), 6.98 (d, 1H, J = 7.6 Hz), 7.20 (dd, 1H, J = 7.6, 7.6 Hz), 7.43 (d, 1H, J = 9.0 Hz), 7.91-7.94 (m, 1H), 7.93 (s, 1H), 8.06 (s, 1H), 8.36-8.42 (m, 1H) 8.47 (s, 1H). MS (ESI) m/z 564, 566 (M + 1)+
    10-3
    Figure US20110098280A1-20110428-C00145
    DMSO-d6: 2.29(s, 3H), 2.77(d, 3H), 3.07-3.11(m, 4H), 3.73- 3.76(m, 4H), 3.77(s, 3H), 6.41(dd, 1H), 6.63(d, 1H), 7.00(d, 1H), 7.21(dd, 1H), 7.49(d, 1H), 7.93(d, 1H), 7.96(s, 1H), 8.07(s, 1H), 8.37-8.42(m, 1H), 8.49(s, 1H). MS m/z 483 [M + 1]+
  • The following 2-[5-Chloro-2-(substituted phenylamino)-pyrimidin-4-ylamino]-5-fluoro-N-methyl-benzamide are prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-fluoro-N-methyl-benzamide and the corresponding aniline following the procedure of Example 7A
  • Figure US20110098280A1-20110428-C00146
    Expl No. Rx Identification
    11-1
    Figure US20110098280A1-20110428-C00147
    NMR (400 MHz, DMSO-d6, δ): 2.79 (d, 3 H), 3.10-3.15 (m, 4 H), 3.74-3.78 (m, 7 H), 6.50 (dd, 1 H), 6.66 (d, 1 H), 7.13-7.20 (m, 1 H), 7.41 (d, 1 H), 7.57 (dd, 1 H), 8.09 (s, 1 H), 8.14 (s, 1 H), 8.55-8.65 (m, 1 H), 8.75-8.82 (m, 1 H), 11.39 (s, 1 H). MS (ESI): m/z 487, 489 (M + 1).
    11-2
    Figure US20110098280A1-20110428-C00148
    NMR (400 MHz, DMSO-d6, δ): 1.68-1.33 (m, 8 H), 1.93-1.73 (m, 2 H), 2.35-2.60 (m, 1 H), 2.62-2.74 (m, 2 H), 2.67 (t, 2 H), 2.74 (d, 3 H), 3.25-3.38 (m, 4 H), 3.76 (s, 3 H), 3.83-3.71 (m, 2 H), 6.48 (dd, 1 H), 6.49 (dd, 1 H), 6.63 (d, 1 H), 7.15 (dd, 1 H), 7.36 (d, 1 H), 7.57 (dd, 1 H), 8.09 (s, 1 H), 8.12 (s, 1 H), 8.65- 8.55 (m, 1 H), 8.78 (d, 1 H), 11.39 (s, 1 H) MS (ESI): m/z 568, 570 (M + 1)
    11-3
    Figure US20110098280A1-20110428-C00149
    DMSO-d6: 2.80 (d, 3 H), 3.79 (s, 3 H), 6.64 (d, 1 H), 7.05-7.20 (m, 3 H), 7.23 (d, 1 H), 7.42-7.49 (d, 1 H), 7.57 (dd, 1 H), 8.20 (s, 1 H), 8.62-8.69 (m, 1 H), 8.75-8.82 (m, 1 H), 9.17 (s, 1 H), 11.43 (s, 1 H). MS m/z 425 [M + 1]+
    11-4
    Figure US20110098280A1-20110428-C00150
    DMSO-d6: 2.06 (s, 3 H), 2.79 (d, 3 H), 3.10-3.14 (m, 2 H), 3.15- 3.19 (m, 2 H), 3.55-3.62 (m, 4 H), 3.77 (s, 3 H), 6.52 (dd, 1 H), 6.69 (d, 1 H), 7.15-7.23 (m, 1 H), 7.43 (d, 1 H), 7.58 (dd, 1 H), 8.10 (s, 1 H), 8.14 (s, 1 H), 8.56-8.65 (m, 1 H), 8.75-8.81 (m, 1 H), 11.39 (s, 1 H). MS m/z 528 [M + 1]+
  • 12-1 Preparation of 7-[5-Chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-2-methyl-2,3-dihydro-isoindol-1-one Synthetic procedure for 7-(2,5-Dichloro-pyrimidin-4-ylamino)-2-methyl-2,3-dihydro-isoindol-1-one
  • N-Methyl-7-nitro-2,3-dihydroisoindole-1-one. At room temperature, a solution of methyl 2-bromomethyl-6-nitrobenzoate (1.26 g, 4.63 mmol) in THF (13 mL) is treated with 2M soln. of methylamine in THF (14 mL), stirred for 5 h, diluted with EtOAc (100 mL), washed with sat. aqueous solution of NaHCO3 (15 mL) and brine (15 mL), dried (MgSO4), and evaporated. A flash chromatography (30 g of silica gel; CH2Cl2/EtOAc 1:1) gives N-Methyl-7-nirto-2,3-dihydroisoindole-1-one (0.561 g, 2.92 mmol) in 63%. Yellow solid. Rf (CH2Cl2/EtOAc 1:1) 0.46.
  • 1H-NMR (400 MHz, CDCl3) 3.21 (s), 4.44 (s), 7.63-7.69 (m, 2H), 7.70-7.75 (m, 1H).
  • 7-Amino-N-methyl-2,3-dihydroisoindole-1-one. At room temperature, a solution of N-Methyl-7-nirto-2,3-dihydroisoindole-1-one (561.0 mg, 2.92 mmol) in EtOAc (8.4 mL) is treated with SnCl2.2H2O (2.68 g), stirred at 80° C. under reflux for 5 h, and treated with 30 mL of 5N NaOH at 0° C. After the both layers are separated, the aqueous layer is extracted with EtOAc (2×8 mL), the combined extracts are washed with brine (5 mL), dried (MgSO4), and evaporated to give 7-Amino-N-methyl-2,3-dihydroisoindole-1-one (455.9 g, 2.81 mmol) in 96%. Yellow solid.
  • Rf (CH2Cl2/EtOAc 1:1) 0.53. 1H-NMR (400 MHz, CDCl3) 3.12 (s), 4.28 (s), 5.20 (br. s), 6.56 (d, J=8.0), 6.68 (d, J=8.0), 7.21 (dd, J=8.0, 8.0).
  • 7-(4-Amino-2,5-dichloropyrimidin-4-yl)amino-N-methyl-2,3-dihydroisoindole-1-one. At 0° C., a solution of 7-Amino-N-methyl-2,3-dihydroisoindole-1-one (232.6 mg, 1.43 mmol) in DMF (2.0 mL) is treated with 60% NaH (89.8 mg), stirred at the same temperature for 1.5 h, treated with a solution of 2,4,5-trichlropyrimidine (0.557 g) in DMF (3.5 mL), stirred for 1 h, and warmed to room temperature. After furthermore stirring for 13 h, the mixture is treated with sat. aqueous NH4Cl (6 mL), and the resulting brown precipitates are collected by a filtration, followed by washing with H2O, hexane, and CH3CN to give 7-(4-Amino-2,5-dichloropyrimidin-4-yl)amino-N-methyl-2,3-dihydroisoindole-1-one (130.2 g, 0.416 mmol) in 26%. Brown solid. Rf (CH2Cl2/EtOAc 1:1) 0.50. 1H-NMR (400 MHz, CDCl3): 3.22 (s), 4.43 (s), 7.15 (d, J=8.0), 7.59 (dd, J=8.0, 8.0), 8.24 (s), 8.71 (d, J=8.0), 11.05 (br. s).
  • Figure US20110098280A1-20110428-C00151
  • The following 7-[5-Chloro-2-(substituted phenylamino)-pyrimidin-4-ylamino]-2-methyl-2,3-dihydro-isoindol-1-one are prepared from 7-(2,5-Dichloro-pyrimidin-4-ylamino)-2-methyl-2,3-dihydro-isoindol-1-one and the corresponding aniline following the procedure of Example 7A.
  • 7-[5-Chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-2-methyl-2,3-dihydro-isoindol-1-one
  • Figure US20110098280A1-20110428-C00152
  • 1H-NMR (400 MHz, DMSO-d6, δ): 3.07 (s, 3H), 3.13-3.17 (m, 4H), 3.75 (s, 3H), 3.34-3.78 (m, 4H), 4.46 (s, 2H), 6.54 (dd, 1H, J=8.6, 2.5 Hz), 6.67 (d, 1H, J=2.5 Hz), 7.15 (d, 1H, J=7.6 Hz), 7.25-7.34 (m, 1H) 7.36 (d, 1H, J=8.6 Hz), 8.13 (s, 1H), 8.36 (s, 1H), 8.37-8.50 (m, 1H) 10.57 (s, 1H). MS (ESI) m/z 481. 483 (M+1)+
  • The following 7-(5-Chloro-2-(subst. phenylamino)-pyrimidin-4-ylamino)-2-methyl-2,3-dihydro-isoindol-1-ones are prepared from 7-(2,5-Dichloro-pyrimidin-4-ylamino)-2-methyl-2,3-dihydro-isoindol-1-one and the corresponding aniline following the procedure of Example 2:
  • Figure US20110098280A1-20110428-C00153
    Expl Mass
    No. Rx (m/z) NMR (400 MHz) δ (ppm)
    12-2
    Figure US20110098280A1-20110428-C00154
    494 [M + 1]+ DMSO-d6: 2.24 (s, 3 H), 2.45-2.50 (m, 4 H), 3.07 (s, 3 H), 3.15-3.19 (m, 4 H), 3.74 (s, 3 H), 4.46 (s, 2 H), 6.52 (dd, 1 H), 6.66 (d, 1 H), 7.15 (d, 1 H), 7.25-7.36 (m, 2 H), 8.12 (s, 1 H), 8.35 (s, 1 H), 8.35-8.45 (m, 1 H), 10.57 (s, 1 H)
    12-3
    Figure US20110098280A1-20110428-C00155
    495 [M + 1]+ DMSO-d6: 1.48-1.57 (m, 2 H), 1.83-1.88 (m, 2 H), 2.83- 2.90 (m, 2 H), 3.07 (s, 3 H), 3.51-3.60 (m, 2 H), 3.61- 3.70 (m, 2 H), 3.73 (s, 3 H), 4.46 (s, 2 H), 4.69 (d, 1 H), 6.52 (dd, 1 H), 6.64 (d, 1 H), 7.14 (d, 1 H), 7.25-7.35 (m, 2 H), 8.12 (s, 1 H), 8.33 (s, 1 H), 8.35-8.45 (m, 1 H), 10.57 (s, 1 H)
    12-4
    Figure US20110098280A1-20110428-C00156
    577 [M + 1]+ DMSO-d6: 1.48-1.59 (m, 2 H), 1.83-1.88 (m, 2 H), 2.14 (s, 3 H), 2.25-2.39 (m, 4 H), 2.42-2.60 (m, 5 H), 2.66- 2.73 (m, 2 H), 3.07 (s, 3 H), 3.73-3.77 (m, 2 H), 3.74 (s, 3 H), 4.46 (s, 2 H), 6.52 (dd, 1 H), 6.64 (d, 1 H), 7.14 (d, 1 H), 7.25-7.34 (m, 2 H), 8.12 (s, 1 H), 8.34 (s, 1 H), 8.35- 8.45 (m, 1 H), 10.57 (s, 1 H)
    12-5
    Figure US20110098280A1-20110428-C00157
    562 [M + 1]+ DMSO-d6: 1.35-1.65 (m, 8 H), 1.73-1.85 (m, 2 H), 2.40- 2.59 (m, 7 H), 3.08 (s, 3 H), 3.52-3.61 (m, 2 H), 3.73 (s, 3 H), 4.47 (s, 2 H), 6.72 (dd, 1 H), 6.94 (d, 1 H), 7.17 (d, 1 H), 7.34-7.39 (m, 2 H), 8.21 (s, 1 H), 8.37 (s, 1 H), 8.45- 8.53 (m, 1 H), 10.64 (s, 1 H)
    12-6
    Figure US20110098280A1-20110428-C00158
    MS m/z 536 DMSO-d6: 2.19-2.42 (m, 4 H), 2.65-2.89 (m, 3 H), 3.07 (s, 3 H), 3.11-3.30 (m, 1 H), 3.48-3.61 (m, 2 H), 3.62- 3.71 (m, 1 H), 3.75 (s, 3 H), 3.75-3.83 (m, 2 H), 4.47 (s, 2 H), 6.48-6.52 (m, 1 H), 6.66 (d, 1 H), 7.15 (d, 1 H), 7.26-7.37 (m, 2 H), 8.13 (s, 1 H), 8.35 (s, 1 H), 8.42 (brs, 1 H), 10.57 (s, 1 H).
  • The following 7-(5-Chloro-2-(subst. phenylamino)-pyrimidin-4-ylamino)-2-ethyl-2,3-dihydroisoindol-1-ones are prepared from 7-(2,5-Dichloro-pyrimidin-4-ylamino)-2-ethyl-2,3-dihydro-isoindol-1-one and the corresponding aniline following the procedure of Example 2:
  • Figure US20110098280A1-20110428-C00159
    Expl Mass
    No. Rx (m/z) NMR (400 MHz) δ (ppm)
    13-1
    Figure US20110098280A1-20110428-C00160
    508 [M + 1]+ DMSO-d6: 1.19 (t, 3 H), 2.24 (s, 3 H), 2.47-2.51 (m, 4 H), 3.15-3.21 (m, 4 H), 3.54 (q, 2 H), 3.74 (s, 3 H), 4.48 (s, 2 H), 6.54 (dd, 1 H), 6.65 (d, 1 H), 7.15 (d, 1 H), 7.26- 7.36 (m, 2 H), 8.12 (s, 1 H), 8.34 (s, 1 H), 8.37-8.48 (m, 1 H), 10.58 (s, 1 H)
  • Example 7B 2-[5-Chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (alternative synthesis to Example 7A)
  • To a suspension of 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-benzoic acid (5.5 g, 12.1 mmol) in 100 mL of THF are added Et3N (2.06 mL, 14.8 mmol) and isobutyl chloroformate (1.7 mL, 12.8 mmol) at −5° C. After stirring at the same temperature for 30 min, the reaction mixture is further stirred at room temperature for 1 hour and then H2O is added to the reaction mixture. The resulting precipitate is collected by filtration, washed with H2O, and dried under reduced pressure to give an intermediate (4.80 g) (10.96 mmol, 91%) as yellow solid.
  • NMR (400 MHz, DMSO-d6, δ): 3.10-3.20 (m, 4H), 3.70-3.80 (m, 4H), 3.93 (s, 3H), 6.53 (dd, 1H, J=9.08, 2.0 Hz), 6.70 (d, 1H, J=2.0 Hz), 7.49-7.54 (m, 1H), 7.67 (d, 1H, J=8.56 Hz), 7.89 (s, 1H), 7.85-7.95 (m, 1H), 8.23 (d, 1H, J=9.08 Hz), 8.26 (d, 1H, J=8.56 Hz), 12.60 (s, 1H).
  • To a 1M solution of methylamine in THF (560 μL, 0.56 mmol) is added 82 mg of the obtained intermediate (0.187 mmol) followed by 1M solution of NaHMDS in THF (560 μl, 0.56 mmol) dropwise. After the reaction mixture is stirred for 10 minutes, 5 mL of H2O is added and extraction is performed with AcOEt. The organic layer is washed with brine, dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (Hexane:AcOEt=1:1 to AcOEt) to give the title compound as a pale yellow solid. Data are given in Example 7A.
  • By repeating the procedures described above using appropriate starting materials and conditions the following compounds are obtained as identified below.
  • Figure US20110098280A1-20110428-C00161
    Expl Rf (solvent)
    No. Ry or MS NMR (400 MHz), δ (ppm)
    14-1
    Figure US20110098280A1-20110428-C00162
    0.10 (n-hexane: AcOEt = 1:1) CDCl3: 3.02-3.19 (m, 10 H), 3.83-3.91 (m, 4 H), 3.87 (s, 3 H), 6.45 (dd, 1 H), 6.52 (d, 1 H), 7.09-7.14 (m, 1 H), 7.29 (m, 1 H), 7.31 (dd, 1 H), 7.38-7.45 (m, 1 H), 8.06 (s, 1 H), 8.14 (d, 1 H), 8.39 (d, 1 H), 8.97 (s, 1 H).
    14-2
    Figure US20110098280A1-20110428-C00163
    0.36 (n-hexane: AcOEt = 1:2) CDCl3: 1.27 (d, 6 H), 3.09-3.16 (m, 4 H), 3.81-3.92 (m, 4 H), 3.89 (s, 3 H), 4.26-4.37 (m, 1 H), 5.93-5.98 (m, 1 H), 6.48 (dd, 1 H), 6.53 (d, 1 H), 7.05-7.11 (m, 1 H), 7.42-7.49 (m, 2 H), 8.08 (s, 1 H), 8.12 (d, 1 H), 8.65 (d, 1 H), 10.88 (br. s, 1 H).
    14-3
    Figure US20110098280A1-20110428-C00164
    505 [M + 1]+ DMSO-d6: 2.79 (d, 3 H), 3.09-3.14 (m, 4 H), 3.74- 3.77 (m, 4 H), 3.75 (s, 3 H), 6.49 (dd, 1 H), 6.65 (d, 1 H), 7.30 (d, 1 H), 7.84 (dd, 1 H), 8.12 (s, 1 H), 8.40 (s, 1 H), 8.65-8.79 (m, 2 H), 11.39 (s, 1 H)
    14-4
    Figure US20110098280A1-20110428-C00165
    466 [M + 1]+ DMS0-d6: 2.70-2.75 (m, 2 H), 3.04-3.09 (m, 2 H), 3.12- 3.18 (m, 4 H), 3.74-3.80 (m, 4 H), 3.75 (s, 3 H), 6.54 (dd, 1 H), 6.67 (d, 1 H), 7.14 (d, 1 H), 7.34 (d, 1 H), 7.37- 7.44 (m, 1 H), 8.17 (s, 1 H), 8.35-8.50 (m, 1 H), 8.44 (s, 1 H), 10.59 (s, 1 H)
    14-5
    Figure US20110098280A1-20110428-C00166
    Rf (Hexane: AcOEt = 1:2): 0.31 DMSO: 1.18 (t, 3 H), 3.11-3.21 (4, 4 H), 3.30-3.60 (m, 2 H), 3.71-3.85 (m, 7 H), 6.50-6.58 (m, 1 H), 6.71 (d, 1 H), 7.17-7.26 (m, 1 H), 7.46 (d, 1 H), 7.64 (dd, 1 H), 8.14 (s, 1 H), 8.19 (s, 1 H), 8.57-8.68 (m, 1 H), 8.80- 8.87 (m, 1 H), 11.36 (s, 1 H).
    14-6
    Figure US20110098280A1-20110428-C00167
    Rf (Hexane: AcOEt = 1:1): 0.051 DMSO: 1.71-1.92 (m, 2 H), 1.92-2.06 (m, 2 H), 3.08- 3.14 (m, 4 H), 3.48-3.57 (m, 2 H), 3.63-3.75 (m, 2 H), 3.84-3.90 (m, 7 H), 6.47 (dd, 1 H), 6.53 (d, 1 H), 7.09 (ddd, 1 H), 7.25-7.29 (m, 1 H), 7.38-7.44 (m, 1 H), 8.06 (s, 1 H), 8.15 (d, 1 H), 8.45 (dd, 1 H), 9.60 (s, 1 H).
    14-7
    Figure US20110098280A1-20110428-C00168
    1H-NMR (400MHz, δ ppm, CDCl3): 3.04-3.10 (m, 4 H), 3.10-3.16 (m, 4 H), 3.63-3.68 (m, 4 H), 3.85-3.90 (m, 7 H), 6.46 (dd, 1 H), 6.53 (d, 1 H), 7.20-7.25 (m, 1 H), 7.33 (brs, 1 H), 7.56-7.62 (m, 1 H), 7.85 (dd, 1 H), 8.03 (d, 1 H), 8.12 (s, 1 H), 8.57-8.61 (m, 1 H), 9.30 (s, 1 H).
  • The following 2-(5-Chloro-2-(subst. phenylamino)-pyrimidin-4-ylamino)-N-methyl-5-pyrrolidin-1-yl-benzamides are prepared from 2-(5-Chloro-2-methyl-pyrimidin-4-ylamino)-N-methyl-5-pyrrolidin-1-yl-benzamide and the corresponding aniline following the procedure of Example 2:
  • Figure US20110098280A1-20110428-C00169
    Expl Mass
    No. Rx (m/z) NMR (400 MHz) δ (ppm)
    15-1
    Figure US20110098280A1-20110428-C00170
    551 [M + 1]+ DMSO-d6: 1.94-1.99 (m, 4 H), 2.23 (s, 3 H), 2.43- 2.48 (m, 4 H), 2.78 (d, 3 H), 3.11-3.17 (m, 4 H), 3.22- 3.29 (m, 4 H), 3.76 (s, 3 H), 6.46 (dd, 1 H), 6.48-6.53 (m, 1 H), 6.63 (d, 1 H), 6.79 (d, 1 H), 7.44 (d, 1 H), 7.89 (s, 1 H), 7.99 (s, 1 H), 8.24 (d, 1 H), 8.60 (d, 1 H), 10.88 (s, 1 H)
    15-2
    Figure US20110098280A1-20110428-C00171
    566 [M + 1]+ DMSO-d6: 1.60-1.70 (m, 2 H), 1.90-2.00 (m, 6 H), 2.12- 2.20 (m, 2 H), 2.18 (s, 3 H), 2.60-2.65 (m, 2 H), 2.78 (d, 3 H), 3.22-3.28 (m, 4 H), 3.75 (s, 3 H), 4.25-4.37 (m, 1 H), 6.49-6.55 (m, 2 H), 6.62 (d, 1 H), 6.80 (d, 1 H), 7.53 (d, 1 H), 7.90 (s, 1 H), 8.00 (s, 1 H), 8.24 (d, 1 H), 8.58- 8.63 (m, 1 H), 10.88 (s, 1 H)
    15-3
    Figure US20110098280A1-20110428-C00172
    538 [M + 1]+ DMSO-d6: 1.94-1.99 (m, 4 H), 2.78 (d, 3 H), 3.09- 3.15 (m, 4 H), 3.22-3.27 (m, 4 H), 3.73-3.77 (m, 4 H), 3.76 (s, 3 H), 6.47 (dd, 1 H), 6.47-6.53 (m, 1 H), 6.65 (d, 1 H), 6.79 (d, 1 H), 7.47 (d, 1 H), 7.90 (s, 1 H), 7.99 (s, 1 H), 8.24 (d, 1 H), 8.60 (d, 1 H), 10.88 (s, 1 H)
  • The following 2-[5-Chloro-2-(4-fluoro-2-methoxy-phenylamino)-pyrimidin-4-ylamino]-5-subst.-N-methyl-benzamide are prepared from the corresponding aniline following the procedure of Example 2
  • Figure US20110098280A1-20110428-C00173
    Expl Mass
    No. Ry (m/z) NMR (400 MHz) δ (ppm)
    16-1
    Figure US20110098280A1-20110428-C00174
    487 [M + 1]+ DMSO-d6: 2.79 (d, 3 H), 3.11-3.15 (m, 4 H), 3.74-3.81 (m, 4 H), 3.81 (s, 3 H), 6.76 (ddd, 1 H), 6.95-7.05 (m, 2 H), 7.21 (d, 1 H), 7.72 (dd, 1 H), 8.08 (s, 1 H), 8.09 (s, 1 H), 8.33 (d, 1 H), 8.63-8.73 (m, 1 H), 11.17 (s, 1 H)
    16-2
    Figure US20110098280A1-20110428-C00175
    500 [M + 1]+ DMSO-d6: 2.24 (s, 3 H), 2.45-2.52 (m, 4 H), 2.79 (d, 3 H), 3.13-3.18 (m, 4 H), 3.81 (s, 3 H), 6.75 (ddd, 1 H), 6.94- 7.02 (m, 2 H), 7.20 (d, 1 H), 7.73 (dd, 1 H), 8.03-8.11 (m, 2 H), 8.30 (d, 1 H), 8.60-8.70 (m, 1 H), 11.14 (s, 1 H)
    16-3
    Figure US20110098280A1-20110428-C00176
    432 [M + 1]+ DMSO-d6: 2.79 (d, 3 H), 3.80-3.81 (m, 6 H), 6.75 (ddd, 1 H), 6.90-7.02 (m, 2 H), 7.27 (d, 1 H), 7.67 (dd, 1 H), 8.10 (s, 1 H), 8.16 (s, 1 H), 8.39 (d, 1 H), 8.70-8.76 (m, 1 H), 11.20 (s, 1 H)
    16-4
    Figure US20110098280A1-20110428-C00177
    568 [M + 1]+ DMSO-d6: 1.35-1.62 (m, 8 H), 1.78-1.85 (m, 2 H), 2.30-2.40 (m, 1 H), 2.41-2.52 (m, 4 H), 2.60-2.70 (m, 2 H), 2.78 (d, 3 H), 3.70- 3.80 (m, 2 H), 3.81 (s, 3 H), 6.75 (ddd, 1 H), 6.95-7.02 (m, 2 H), 7.20 (d, 1 H), 7.72 (dd, 1 H), 8.05-8.08 (m, 2 H), 8.28 (d, 1 H), 8.63-8.69 (m, 1 H), 11.12 (s, 1 H)
  • Example 16B
  • Figure US20110098280A1-20110428-C00178
  • CDCl3: 3.01-3.10 (m, 4H), 3.63-3.68 (m, 4H), 3.89 (s, 3H), 6.59 (ddd, 1H), 6.66 (dd, 1H), 7.20-7.26 (m, 1H), 7.36 (s, 1H), 7.57-7.63 (m, 1H), 7.84 (dd, 1H), 8.09-8.14 (m, 1H), 8.14 (s, 1H), 8.53 (d, 1H), 9.30 (s, 1H).
  • Example 16C
  • Figure US20110098280A1-20110428-C00179
  • CDCl3: 3.56-3.65 (m, 2H), 3.88 (s, 3H), 5.11-5.19 (m, 1H), 6.50-6.56 (m, 1H), 6.61-6.66 (m, 1H), 7.25-7.29 (m, 1H), 7.38 (brs, 1H), 7.58-7.62 (m, 1H), 7.97 (dd, 1H), 8.02-8.10 (m, 1H), 8.15 (s, 1H), 8.41 (dd, 1H), 8.81 (s, 1H).
  • The following 2-(5-Chloro-2-(subst. phenylamino)-pyrimidin-4-ylamino)-5-fluoro-N-methyl-benzamide are prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-fluoro-N-methyl-benzamide and the corresponding aniline following the procedure of Example 2:
  • Figure US20110098280A1-20110428-C00180
    Expl Mass
    No. Rx (m/z) NMR (400 MHz) δ (ppm)
    18-1
    Figure US20110098280A1-20110428-C00181
    595 [M + 1]+ DMSO-d6: 2.06 (s, 3 H), 2.78 (d, 3 H), 3.05-3.18 (m, 8 H), 3.53-3.64 (m, 4 H), 3.68-3.77 (m, 4 H), 3.77 (s, 3 H), 6.51 (dd, 1 H), 6.69 (d, 1 H), 6.88 (br.d, 1 H), 7.20 (d, 1 H), 7.43 (d, 1 H), 7.99-8.03 (m, 2 H), 8.34 (br.d, 1 H), 8.63-8.71 (m, 1 H), 11.15 (s, 1 H).
  • The following 2-[5-chloro-2-(subst. phenylamino)-pyrimidin-4-ylamino]-N-isopropyl-benzene-sulfonamides are prepared from 2-(5-chloro-2-chloro-pyrimidin-4-ylamino)-N-isopropyl-benzenesulfonamide and the corresponding aniline following the procedure of Example 7A
  • Figure US20110098280A1-20110428-C00182
    Expl Rf (solvent)
    No. Rx Or MS NMR (400 MHz), δ (ppm)
    19-1 
    Figure US20110098280A1-20110428-C00183
    0.39 (MeOH: CH2Cl2 = 1:4) DMSO-d6: 0.94 (d, 6 H), 1.75-1.84 (m, 1 H), 2.07- 2.16 (m, 1 H), 2.33 (s, 3 H), 2.98-3.04 (m, 1 H), 3.22- 3.36 (m, 5 H), 3.42-3.47 (m, 1 H), 3.74 (s, 3 H), 6.05 (dd, 1 H), 6.18 (d, 1 H), 7.18 (dd, 1 H), 7.25 (d, 1 H), 7.35- 7.45 (m, 1 H), 7.77-7.82 (m, 1 H), 7.70-8.10 (m, 1 H), 8.09-8.17 (m, 2 H), 8.45-8.63 (m, 1 H), 9.34 (s, 1 H)
    19-2 
    Figure US20110098280A1-20110428-C00184
    0.40 (n-hexane: AcOEt = 1:1) CDCl3: 1.00 (d, 6 H), 1.13 (t, 3 H), 1.83-1.92 (m, 1 H), 2.23-2.30 (m, 1 H), 2.70-2.78 (m, 2 H), 3.08-3.13 (m, 1 H), 3.27-3.54 (m, 5 H), 3.85 (s, 3 H), 4.33 (d, 1 H), 6.05 (d, 1 H), 6.13 (s, 1 H), 7.13 (bs, 1 H), 7.18-7.22 (m, 1 H), 7.52-7.56 (m, 1 H), 7.83-7.86 (m, 1 H), 7.95-7.98 (m, 1 H), 8.09 (s, 1 H), 8.47-8.49 (m, 1 H), 8.89 (s, 1 H)
    19-3 
    Figure US20110098280A1-20110428-C00185
    0.30 (n-hexane: AcOEt = 1:1) CDCl3: 0.93 (d, 6 H), 1.05-1.09 (m, 1 H), 1.48-1.99 (m, 6 H), 2.16 (s, 3 H), 2.61-2.67 (m, 1 H), 2.80-2.83 (m, 1 H), 3.75 (s, 3 H), 3.80-3.89 (m, 2 H), 6.44-6.47 (m, 1 H), 6.62-6.63 (m, 1 H), 7.18-7.22 (m, 1 H), 7.42-7.46 (m, 1 H), 7.80-7.89 (m, 2 H), 8.17 (s, 1 H), 8.23 (s, 1 H), 8.42-8.44 (m, 1 H), 8.89 (s, 1 H)
    19-4 
    Figure US20110098280A1-20110428-C00186
    0.69 (MeOH: CH2Cl2 = 1:3) DMSO-d6: 0.94 (d, 6 H), 1.45-1.57 (m, 2 H), 1.80- 1.88 (m, 2 H), 2.14 (s, 3 H), 2.25-2.35 (m, 4 H), 2.45- 2.55 (m, 4 H), 2.62-2.70 (m, 2 H), 3.28-3.37 (m, 1 H), 3.68-3.74 (m, 2 H), 3.75 (s, 3 H), 6.44 (dd, 1 H, J = 8.82, 2.0 Hz), 6.61 (d, 1 H, J = 2.0 Hz), 7.21 (dd, 1 H), 7.37 (d, 1 H), 7.45 (dd, 1 H), 7.81 (dd, 1 H, J = 1.82, 1.52 Hz), 7.84- 7.92 (m, 1 H), 8.12-8.20 (m, 1 H), 8.16 (s, 1 H), 8.43- 8.51 (m, 1 H), 9.31 (s, 1 H)
    19-5 
    Figure US20110098280A1-20110428-C00187
    0.35 (n-hexane: AcOEt = 1:1) CDCl3: 0.93 (d, 6 H), 2.23 (s, 3 H), 2.45-2.48 (m, 4 H), 3.12-3.15 (m, 4 H), 3.75 (s, 3 H), 6.42-6.45 (m, 1 H), 6.63 (s, 1 H), 7.19-7.23 (m, 1 H), 7.38-7.47 (m, 2 H), 7.80- 7.89 (m, 2 H), 8.16 (s, 1 H), 8.46-8.48 (m, 1 H), 9.34 (s, 1 H)
    19-6 
    Figure US20110098280A1-20110428-C00188
    0.45 (n-hexane: AcOEt = 1:1) CDCl3: 0.99 (d, 6 H), 3.40-3.49 (m, 1 H), 3.88 (s, 3 H), 4.29-4.31 (d, 1 H), 6.51-6.56 (m, 1 H), 6.62-6.65 (m, 1 H), 7.24-7.28 (m, 1 H), 7.37 (s, 1 H), 7.56-7.60 (m, 1 H), 7.98-8.15 (m, 3 H), 8.34-8.37 (m, 1 H), 8.89 (s, 1 H)
    19-7 
    Figure US20110098280A1-20110428-C00189
    0.28 (n-hexane: AcOEt = 1:1) DMSO-d6: 0.93 (d, 6 H), 1.59-1.67 (m, 2 H), 1.90- 1.93 (m, 2 H), 2.10-2.24 (m, 5 H), 2.60-2.67 (m, 2 H), 3.74 (s, 3 H), 4.33-4.37 (m, 1 H), 6.47-6.50 (m, 1 H), 6.63 (d, 1 H), 7.18-7.22 (m, 1 H), 7.41-7.45 (m, 2 H), 7.79-7.87 (m, 2 H), 8.16 (s, 1 H), 8.21 (s, 1 H), 8.41- 8.43 (m, 1 H), 9.29 (s, 1 H)
    19-8 
    Figure US20110098280A1-20110428-C00190
    0.25 (n-hexane: AcOEt = 1:1) DMSO-d6: 0.93 (d, 6 H), 3.09-3.12 (m, 4 H), 3.74- 3.76 (m, 7 H), 6.43-6.46 (m, 1 H), 6.64 (s, 1 H), 7.19- 7.23 (m, 1 H), 7.41-7.48 (m, 2 H), 7.80 (d, 1 H), 7.82 (d, 1 H), 8.17 (s, 1 H), 8.46-8.48 (m, 1 H), 9.31 (s, 1 H)
    19-9 
    Figure US20110098280A1-20110428-C00191
    0.56 (MeOH: CH2Cl2 = 1:4) DMSO-d6: 0.93 (d, 6 H), 1.89-1.90 (m, 1 H), 2.30 (bs, 6 H), 3.13-3.50 (m, 6 H), 3.74 (s, 3 H), 6.10 (d, 1 H), 6.22 (s, 1 H), 7.16-7.20 (m, 1 H), 7.25-7.27 (m, 1 H), 7.40 (bs, 1 H), 7.79-7.81 (m, 1 H), 7.86-7.88 (m, 1 H), 8.12 (s, 1 H), 8.15 (s, 1 H), 8.51 (s, 1 H), 9.34 (s, 1 H)
    19-10
    Figure US20110098280A1-20110428-C00192
    0.45 (MeOH: CH2Cl2 = 1:4) CDCl3: 0.99 (d, 12 H), 2.27 (s, 2 H), 2.31 (s, 6 H), 2.96 (s, 2 H), 3.39-3.48 (m, 1 H), 3.83 (s, 3 H), 4.30 (d, 1 H), 6.09- 6.12 (m, 1 H), 6.19 (d, 1 H), 7.11 (s, 1 H), 7.19-7.23 (m, 1 H), 7.51-7.57 (m, 1 H), 7.76-7.79 (m, 1 H), 7.95 (d, 1 H), 8.09 (s, 1 H), 8.46-8.49 (m, 1 H), 8.88 (s, 1 H)
    19-11
    Figure US20110098280A1-20110428-C00193
    0.30 (n-hexane: AcOEt = 1:1) DMS0-d6: 0.93 (d, 6 H), 2.96-2.99 (m, 4 H), 3.74- 3.76 (m, 7 H), 6.67-6.72 (m, 1 H), 7.21-7.25 (m, 1 H), 7.31-7.34 (m, 1 H), 7.44-7.48 (m, 1 H), 7.80-7.83 (m, 1 H), 7.88 (d, 1 H), 8.21 (s, 1 H), 8.42 (d, 1 H), 8.58 (s, 1 H), 9.30 (s, 1 H)
    19-12
    Figure US20110098280A1-20110428-C00194
    0.42 (MeOH: CH2Cl2 = 1:4) DMSO-d6: 0.94 (d, 6 H), 1.68-1.76 (m, 1 H), 1.99- 2.07 (m, 1 H), 2.29 (s, 3 H), 3.05-3.49 (m, 6 H), 3.75 (s, 3 H), 6.36-6.40 (m, 1 H), 7.10-7.37 (m, 3 H), 7.70- 7.80 (m, 1 H), 8.08-8.39 (m, 3 H), 9.24 (s, 1 H)
    19-13
    Figure US20110098280A1-20110428-C00195
    0.50 (MeOH: CH2Cl2 = 1:4) CDCl3: 1.01 (d, 6 H), 1.94-1.96 (m, 1 H), 2.01 (s, 3 H), 2.29-2.37 (m, 1 H), 3.19-3.58 (m, 5 H), 3.86 (s, 3 H), 4.42 (d, 1 H), 4.59-4.63 (m, 1 H), 5.70 (d, 1 H), 6.05- 6.08 (m, 1 H), 6.15-6.16 (m, 1 H), 7.17-7.24 (m, 2 H), 7.53-7.57 (m, 1 H), 7.90 (d, 1 H), 7.91-7.98 (m, 1 H), 8.09 (s, 1 H), 8.47 (d, 1 H), 8.91 (s, 1 H)
    19-14
    Figure US20110098280A1-20110428-C00196
    0.53 (MeOH: CH2Cl2 = 1:4) CDCl3: 1.00 (d, 6 H), 2.04 (s, 3 H), 2.05-2.29 (m, 2 H), 2.96 (s, 3 H), 3.19-3.54 (m, 5 H), 3.86 (s, 3 H), 4.57- 4.63 (m, 1 H), 5.39-5.46 (m, 1 H), 6.07-6.09 (m, 1 H), 6.16 (d, 1 H), 7.18-7.26 (m, 2 H), 7.53-7.57 (m, 1 H), 7.89-7.98 (m, 2 H), 8.08 (s, 1 H), 8.47 (d, 1 H), 8.94 (d, 1 H)
    19-15
    Figure US20110098280A1-20110428-C00197
    0.56 (MeOH: CH2Cl2 = 1:4) DMSO-d6: 0.93 (d, 6 H), 1.48-1.56 (m, 2 H), 1.65- 1.75 (m, 4 H), 1.90-1.93 (m, 2 H), 2.05-2.15 (m, 1 H), 2.45-2.55 (m, 5 H), 2.69-2.75 (m, 2 H), 3.61 (d, 2 H), 3.74 (s, 1 H), 6.42-6.51 (m, 1 H), 6.61 (d, 1 H), 7.18- 7.22 (m, 1 H), 7.37 (d, 1 H), 7.43-7.47 (m, 1 H), 7.80 (d, 1 H), 7.81-7.89 (m, 1 H), 8.16 (d, 1 H), 8.46-8.48 (m, 1 H), 9.31 (s, 1 H)
    19-16
    Figure US20110098280A1-20110428-C00198
    0.56 (MeOH: CH2Cl2 = 1:4) DMSO-d6: 0.92 (d, 6 H), 1.65-1.75 (m, 4 H), 1.88- 2.00 (m, 4 H), 2.39-2.43 (m, 2 H), 2.60-2.65 (m, 2 H), 3.03-3.07 (m, 1 H), 3.03-3.40 (m, 2 H), 3.70 (s, 3 H), 3.77-3.78 (m, 1 H), 6.09 (d, 1 H), 6.23 (s, 1 H), 7.13- 7.17 (m, 1 H), 7.23-7.25 (m, 1 H), 7.30-7.42 (m, 1 H), 7.78 (d, 1 H), 7.86 (d, 1 H), 8.10 (s, 1 H), 8.13 (s, 1 H), 8.40-8.50 (m, 1 H), 9.31 (s, 1 H)
    19-17
    Figure US20110098280A1-20110428-C00199
    0.23 (n-hexane: AcOEt = 1:1) DMSO-d6: 0.93 (d, 6 H), 1.24-1.57 (m, 4 H), 1.69- 1.78 (m, 2 H), 1.98-2.04 (m, 1 H), 2.15-2.33 (m, 5 H), 2.70-2.80 (m, 1 H), 3.74 (s, 3 H), 3.91-3.94 (m, 1 H), 4.05-4.09 (m, 1 H), 6.46-6.49 (m, 1 H), 6.63 (d, 1 H), 7.18-7.22 (m, 1 H), 7.42-7.46 (m, 2 H), 7.80 (d, 1 H), 7.89 (d, 1 H), 8.17 (s, 1 H), 8.25 (s, 1 H), 8.42-8.44 (m, 1 H), 9.31 (s, 1 H)
    19-18
    Figure US20110098280A1-20110428-C00200
    0.48 (n-hexane: AcOEt = 1:1) DMSO-d6: 0.93 (d, 6 H), 1.03 (t, 3 H), 1.13 (t, 3 H), 1.42- 1.81 (m, 4 H), 2.57-2.83 (m, 4 H), 3.17-3.41 (m, 4 H), 3.65-3.75 (m, 1 H), 3.80 (s, 3 H), 4.21 (bs, 1 H), 6.42- 6.47 (m, 2 H), 6.51 (d, 1 H), 6.63 (d, 1 H), 7.18-7.22 (m, 1 H), 7.38-7.47 (m, 2 H), 7.80-7.82 (m, 1 H), 7.89 (d, 1 H), 8.16 (s, 1 H), 8.47-8.49 (m, 1 H), 9.31 (s, 1 H)
    19-19
    Figure US20110098280A1-20110428-C00201
    0.44 (CH2Cl2: MeOH = 9:1) CDCl3: 1.45-1.62 (m, 2 H), 1.72-1.78 (m, 1 H), 1.82- 1.90 (m, 1 H), 2.40-2.46 (m, 1 H), 2.61-2.75 (m, 2 H), 3.75-3.70 (m, 2 H), 3.76 (s, 3 H), 6.45 (dd, 1 H), 6.62 (d, 1 H), 6.85 (s, 1 H), 7.19-7.23 (m, 1 H), 7.36-7.48 (m, 3 H), 7.80-7.82 (m, 1 H), 7.85-7.93 (br, 1 H), 8.16 (s, 2 H), 8.43-8.52 (m, 1 H), 9.31 (s, 1 H)
    19-20
    Figure US20110098280A1-20110428-C00202
    Ms: 547 DMSO-d6: 0.94 (d, 6 H), 1.73-1.82 (m, 1 H), 2.23-2.33 (m, 4 H), 2.34-2.41 (m, 1 H), 2.54-2.62 (m, 1 H), 2.62- 2.69 (m, 1 H), 2.77-2.82 (m, 1 H), 3.25-3.35 (m, 1 H), 3.74 (s, 3 H), 4.85-4.92 (m, 1 H), 6.4 (dd, 1 H), 6.57 (d, 1 H), 7.16-7.24 (m, 1 H), 7.38-7.51 (m, 1 H), 7.81 (d, 1 H), 7.82-7.94 (m, 1 H), 8.16 (s, 1 H), 8.22 (brs, 1 H), 8.38-8.48 (m, 1 H), 9.3 (brs, 1 H)
    19-21
    Figure US20110098280A1-20110428-C00203
    Ms: 579 DMSO-d6: 0.92 (d, 6 H), 1.61-1.71 (m, 2 H), 1.86-1.96 (m, 2 H), 2.12-2.22 (m, 5 H), 2.57-2.64 (m, 2 H), 3.2-3.4 (m, 1 H), 3.77 (s, 3 H), 4.27-4.35 (m, 1 H), 6.86 (dd, 1 H), 7.19-7.27 (m, 1 H), 7.39-7.46 (m, 1 H), 7.81 (dd, 1 H), 7.84-7.92 (m, 1 H), 8.21 (s, 1 H), 8.36-8.42 (m, 1 H), 8.62 (s, 1 H), 9.28 (s, 1 H)
    19-22
    Figure US20110098280A1-20110428-C00204
    Ms: 549 DMS0-d6: 0.90 (s, 6 H), 0.94 (d, 6 H), 2.9 (d, 2 H), 3.24 (d, 2 H), 3.25-3.35 (m, 1 H), 3.27-3.36 (m, 1 H), 3.68 (s, 3 H), 4.58 (t, 1 H), 5.3 (t, 1 H), 6.16 (dd, 1 H), 6.39 (d, 1 H), 7.13 (d, 1 H), 7.15-7.21 (m, 1 H), 7.35- 7.45 (m, 1 H), 7.8 (dd, 1 H), 7.83-7.92 (m, 1 H), 8.09 (s, 1 H), 8.11 (s, 1 H), 8.45-8.57 (m, 1 H), 9.33 (s, 1 H)
    19-23
    Figure US20110098280A1-20110428-C00205
    Rf: 0.51 (n-hexane: AcOEt = 1:1) DMSO-d6: 0.94 (d, 6 H), 1.22 (s, 6 H), 3.25-3.35 (m, 1 H), 3.36 (d, 2 H), 3.68 (s, 3 H), 4.73-4.79 (brs, 1 H), 4.81 (t, 1 H), 6.29 (dd, 1 H), 6.44 (d, 1 H), 7.14-7.22 (m, 2 H), 7.38-7.46 (m, 1 H), 7.8 (dd, 1 H), 7.85-7.9 (m, 1 H), 8.1 (s, 1 H), 8.13 (s, 1 H), 8.45-8.55 (m, 1 H), 9.32 (s, 1 H)
    19-24
    Figure US20110098280A1-20110428-C00206
    Ms: 577 DMSO-d6: 0.93 (d, 6 H), 0.96 (s, 6 H), 2.22 (s, 6 H), 3.25-3.35 (m, 1 H), 3.7 (s, 3 H), 3.75 (s, 3 H), 6.46 (dd, 1 H), 6.62 (d, 1 H), 7.16-7.23 (m, 1 H), 7.38-7.47 (m, 1 H), 7.81 (dd, 1 H), 7.85-7.9 (m, 1 H), 8.17 (s, 1 H), 8.23 (s, 1 H), 8.38-8.48 (m, 1 H), 9.31 (s, 1 H)
    19-25
    Figure US20110098280A1-20110428-C00207
    Ms: 521 DMSO-d6: 0.94 (d, 6 H), 3.12 (t, 4 H), 3.25-3.35 (m, 1 H), 3.75 (t, 4 H), 6.73 (dd, 1 H), 6.85 (dd, 1 H), 7.16- 7.24 (m, 1 H), 7.25-7.32 (m, 1 H), 7.38-7.47 (m, 1 H), 7.8 (dd, 1 H), 7.88 (d, 1 H), 8.18 (s, 1 H), 8.42-8.52 (m, 1 H), 8.86 (s, 1 H), 9.36 (s, 1 H)
    19-26
    Figure US20110098280A1-20110428-C00208
    Ms: 565 DMSO-d6: 0.93 (d, 6 H), 2.4-2.56 (m, 4 H), 2.69 (t, 2 H), 3.25-3.38 (m, 1 H), 3.59 (t, 4 H), 4.11 (t, 1 H), 6.75 (dd, 1 H), 6.93 (dd, 1 H), 7.16-7.23 (m, 1 H), 7.3-7.4 (m, 1 H), 7.4-7.38 (m, 1 H), 7.8 (dd, 1 H), 7.88 (d, 1 H), 8.19 (s, 1 H), 8.36-8.5 (m, 1 H), 8.92 (s, 1 H), 9.34 (s, 1 H)
    19-27
    Figure US20110098280A1-20110428-C00209
    Ms: 614 DMSO-d6: 0.93 (d, 6 H), 1.3-1.62 (m, 8 H), 1.75-1.85 (m, sH), 2.26-2.4 (m, 1 H), 2.4-2.58 (m, 4 H), 3.28-3.38 (m, 1 H), 3.68-3.78 (m, 5 H), 6.42 (dd, 1 H), 6.64 (d, 1 H), 7.18-7.24 (m, 1 H), 7.42-7.5 (m, 2 H), 7.77 (d, 1 H), 7.82 (dd, 1 H), 8.13 (s, 1 H), 8.17 (s, 1 H), 8.4-8.5 (m, 1 H), 9.36 (s, 1 H)
    19-28
    Figure US20110098280A1-20110428-C00210
    Rf: 0.5 (MeOH: CH2Cl2 = 3:7) DMSO-d6: 0.93 (d, 6 H), 1.6-1.7 (m, 2 H), 1.88-1.98 (m, 2 H), 2.17-2.35 (m, 5 H), 2.6-2.73 (m, 2 H), 3.25-3.4 (m, 1 H), 4.34-4.44 (m, 1 H), 6.75 (dd, 1 H), 6.93 (dd, 1 H), 7.16-7.23 (m, 1 H), 7.29-7.36 (m, 1 H), 7.37-7.47 (m, 1 H), 7.8 (dd, 1 H), 7.89 (d, 1 H), 8.19 (s, 1 H), 8.36- 8.46 (m, 1 H), 8.92 (s, 1 H), 9.31 (s, 1 H)
    19-29
    Figure US20110098280A1-20110428-C00211
    Ms: 577 DMSO-d6: 0.93 (d, 6 H), 2.45-2.55 (m, 4 H), 2.7 (t, 2 H), 3.25-3.35 (m, 1 H), 3.59 (t, 3 H), 3.76 (s, 3 H), 4.1 (t, 1 H), 6.48 (dd, 1 H), 6.65 (d, 1 H), 7.18-7.24 (m, 1 H), 7.4-7.5 (m, 2 H), 7.82 (dd, 1 H), 7.88 (d, 1 H), 8.17 (s, 1 H), 8.24 (s, 1 H), 8.4-8.48 (m, 1 H), 9.31 (s, 1 H)
    19-30
    Figure US20110098280A1-20110428-C00212
    Ms: 590 DMSO-d6: 0.93 (d, 6 H), 2.15 (s, 3 H), 2.2-2.4 (m, 4 H), 2.4-2.6 (m, 4 H), 2.69 (t, 2 H), 3.25-3.35 (m, 1 H), 3.75 (s, 3 H), 4.08 (t, 2 H), 6.47 (dd, 1 H), 6.64 (d, 1 H), 7.18- 7.24 (m, 1 H), 7.41-7.49 (m, 2 H), 7.81 (dd, 1 H), 7.86- 7.91 (m, 1 H), 8.17 (s, 1 H), 8.24 (s, 1 H), 8.39-8.46 (m, 1 H), 9.31 (s, 1 H)
    19-31
    Figure US20110098280A1-20110428-C00213
    Ms: 588 DMSO-d6: 0.94 (d, 6 H), 2.19-2.36 (m, 4 H), 2.66-2.85 (m, 3 H), 3.15-3.21 (m, 1 H), 3.73-3.8 (m, 5 H), 6.43 (dd, 1 H), 6.63 (d, 1 H), 7.18-7.25 (m, 1 H), 7.4 (d, 1 H), 7.43-7.5 (m, 1 H), 7.81 (dd, 1 H), 7.89 (d, 1 H), 8.16 (s, 1 H), 8.17 (s, 1 H), 8.42-8.52 (m, 1 H), 9.32 (s, 1 H)
    19-32
    Figure US20110098280A1-20110428-C00214
    Ms: 560 CDCl3: 1.01 (s, 6 H), 1.45-1.56 (m, 2 H), 2.03-2.11 (m, 2 H), 2.11-2.2 (m, 2 H), 2.31 (s, 3 H), 2.78-2.87 (m, 2 H), 3.22-3.31 (m, 1 H), 3.39-3.5 (m, 1 H), 3.82 (s, 3 H), 4.5- 4.6 (m, 1 H), 6.13 (dd, 1 H), 6.21 (d, 1 H), 7.16 (s, 1 H), 7.18-7.24 (m, 1 H), 7.5-7.57 (m, 1 H), 7.82 (d, 1 H), 7.97 (dd, 1 H), 8.16 (s, 1 H), 8.08 (s, 1 H), 8.46 (d, 1 H), 8.92 (s, 1 H)
  • The following 2-[5-chloro-2-(subst. phenylamino)-pyrimidin-4-ylamino]-N-methyl-benzene-sulfonamides are prepared from 2-(5-chloro-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide and the corresponding aniline following the procedure of Example A
  • Figure US20110098280A1-20110428-C00215
    Rf (solvent)
    ExplNo. Rx or MS NMR (400 MHz), δ (ppm)
    20-1
    Figure US20110098280A1-20110428-C00216
    0.50 (AcOEt) CDCl3: 2.63(d, 3H), 3.14(t, 4H), 3.87-3.90(m, 7H), 4.64(m,1H), 6.45(dd, 1H), 6.55(d, 1H), 7.23-7.26(m, 1H), 7.51-7.55(m, 1H), 7.91(d, 1H), 7.95(dd, 1H), 8.06(s, 1H), 8.47(d, 1H), 9.26(s, 1H)
    20-2
    Figure US20110098280A1-20110428-C00217
    m/z 546, 548 (M + 1) DMSO-d6: 2.06 (s, 3H), 2.43 (s, 3H), 3.10 (m, 2H), 3.16 (m, 2H), 3.59-3.62 (m, 4H), 3.77 (s, 3H), 6.49 (dd, 1H), 6.68 (d, 1H), 7.21-7.25 (m, 1H), 7.42 (d, 1H), 7.49 (dd, 1H), 7.75-7.77 (m, 1H), 7.78(s, 1H), 8.16(s, 1H), 8.21 (s, 1H), 8.50(d, 1H), 9.35 (s, 1H)
    20-3
    Figure US20110098280A1-20110428-C00218
    0.27 (n-hexane: AcOEt = 3:1) CDCl3: 2.65(d, 3H), 4.45-4.49(m, 1H), 6.99-7.04(m, 1H), 7.17-7.28(m, 4H), 7.56-7.60(m, 1H), 7.96- 7.98(m, 1H), 8.18(s, 1H), 8.31-8.34(m, 1H), 8.41- 8.44(m, 1H), 9.14(s, 1H)
    20-4
    Figure US20110098280A1-20110428-C00219
    0.27 (n-hexane: AcOEt = 3:1) CDCl3: 2.65(d, 3H), 4.54-4.58(m, 1H), 6.53(dd, 1H), 6.98-7.02(m, 1H), 7.11 -7.15(m, 2H), 7.24-7.28(m, 1H), 7.35(bs, 1H), 7.57-7.61(m, 1H), 7.95-7.98(m, 1H), 8.16(s, 1H), 8.29-8.32(m, 1H), 8.42-8.46(m, 1H), 9.14(s, 1H)
    20-5
    Figure US20110098280A1-20110428-C00220
    0.46 (MeOH: CH2Cl2 = 1:4) CDCl3: 1.95-2.00(m, 5H), 2.29-2.37(m, 1H), 2.62(d, 3H), 3.20-3.78(m, 4H), 3.86(s, 3H), 4.60-4.64(m, 2H), 5.68-5.69(m, 1H), 6.09-6.16(m, 2H), 7.15(bs, 1H), 7.19-7.23(m, 1H), 7.54-7.58(m, 1H), 7.88-7.95(m, 2H), 8.06(s, 1H), 8.55-8.57(m, 1H), 9.08(s, 1H)
    20-6
    Figure US20110098280A1-20110428-C00221
    518 [M + 1]+ DMSO-d6: 2.23(s, 3H), 2.43(s, 3H), 2.45-2.50(m, 4H), 3.12-3.17(m, 4H), 3.76(s, 3H), 6.45(dd, 1H), 6.63(d, 1H), 7.22(dd, 1H), 7.37(d, 1H), 7.45-7.50(m, 1H), 7.74-7.78(m, 1H), 7.76(d, 1H), 8.15(s, 1H), 8.19(s, 1H), 8.46-8.53(m, 1H), 9.35(bs, 1H)
    20-7
    Figure US20110098280A1-20110428-C00222
    504 [M + 1]+ DMSO-d6: 2.43(s, 3H), 2.80-2.89(m, 4H), 2.99- 3.07(m, 4H), 3.76(s, 3H), 6.44(dd, 1H), 6.61(d, 1H), 7.18-7.24(m, 1H), 7.37(d, 1H), 7.44-7.50(m, 1H), 7.76(dd, 1H), 8.15(s, 1H), 8.18(s, 1H), 8.45-8.55(m, 1H), 9.20-9.45(m, 1H)
    20-8
    Figure US20110098280A1-20110428-C00223
    586 [M + 1]+ DMSO-d6: 1.35-1.43(m, 2H), 1.45-1.61(m, 6H), 1.75- 1.85(m, 2H), 2.30-2.40(m, 1H), 2.43(d, 3H), 2.42- 2.55(m, 4H), 2.60-2.70(m, 2H), 3.68-3.77(m, 2H), 3.75(s, 3H), 6.45(dd, 1H), 6.62(d, 1H), 7.21(dd, 1H), 7.36(d, 1H), 7.43-7.51(m, 1H), 7.73-7.81(m, 1H), 7.75(dd, 1H), 8.15(s, 1H), 8.17(s, 1H), 8.45-8.52(m, 1H), 9.34(bs, 1H)
    20-9
    Figure US20110098280A1-20110428-C00224
    569 [M + 1]+ DMSO-d6: 1.85-1.95(m, 2H), 2.15(s, 3H), 2.18(t, 2H), 2.22-2.40(m, 8H), 2.43(s, 3H), 4.17(t, 2H), 6.65(d, 1H), 7.06(dd, 1H), 7.20(d, 1H), 7.22(ddd, 1H), 7.25(d, 1H), 7.39-7.47(m, 2H), 7.72-7.82(m, 1H), 7.77(dd, 1H), 8.26(s, 1H), 8.52(d, 1H), 9.22(s, 1H), 9.36(s, 1H)
    20-10
    Figure US20110098280A1-20110428-C00225
    556 [M + 1]+ DMSO-d6: 1.85-1.95(m, 2H), 2.19(t, 2H), 2.25- 2.35(m, 4H), 2.43(s, 3H), 3.55-3.60(m, 4H), 4.19(t, 2H), 6.66(d, 1H), 7.06(dd, 1H), 7.17-7.24(m, 1H), 7.21(d, 1H), 7.27(d, 1H), 7.39-7.45(m, 1H), 7.44(d, 1H), 7.70-7.80(m, 1H), 7.76(dd, 1H), 8.26(s, 1H), 8.52(d, 1H), 9.21(s, 1H), 9.36(s, 1H)
    20-11
    Figure US20110098280A1-20110428-C00226
    Rf (Hexane: AcOEt = 1:1) 0.29 DMSO-d6: 2.64 (d, 3H), 2.87-2.96 (m, 4H), 3.65-3.74 (m, 4H), 3.86 (s, 3H), 4.41-4.51 (m, 1H), 6.50 (dd, 1H), 6.81 (d, 1H), 7.55-7.64 (m, 2H), 7.96 (d, 1H), 8.01 (s, 1H), 8.19 (s, 1H), 8.49 (d, 1H), 9.07 (s, 1H).
    20-12
    Figure US20110098280A1-20110428-C00227
    MS 535 DMSO-d6: 2.64 (d, 3H), 3.05 (bs, 4H), 3.59 (bs, 3H), 3.87(bs, 3H), 3.89 (bs, 4H), 4.52-4.48 (m, 1H), 6.57(bs, 1H), 7.25-7.20(m, 1H), 7.44-7.32 (m, 1H), 7.63-7.52 (m, 1H), 7.94(bs, 1H), 8.06 (d, 1H), 8.25(s, 1H), 8.48(d, 1H), 9.06(bs, 1H)
    20-13
    Figure US20110098280A1-20110428-C00228
    MS 548 DMSO-d6: 2.17 (bs, 3H), 2.63 (d, 3H), 2.68 (bs, 4H), 3.10(bs, 4H), 3.57 (s, 3H), 4.54-4.46 (m, 1H), 6.59(bs, 1H), 7.27-7.18(m, 1H), 7.37 (bs, 1H), 7.62- 7.55 (m, 1H), 7.94(bs, 1H), 7.95 (d, 1H), 8.16(s, 1H), 8.48(d, 1H), 9.04(bs, 1H)
    20-14
    Figure US20110098280A1-20110428-C00229
    MS 546 DMSO-d6: 1.06 (t, 3H), 1.86 (dd, 2H), 2.37 (s, 3H), 2.62-2.59 (m, 4H), 2.64(d, 3H), 4.00-3.97 (m, 4H), 4.62-4.54 (m, 1H), 6.44 (dd, 1H), 6.54(d, 1H), 7.27- 7.22(m, 1H), 7.34(bs, 1H), 7.58-7.54(m, 1H), 7.95(dd, 1H), 8.02(d, 1H), 8.11(s, 1H), 8.53(d, 1H), 9.07(bs, 1H)
    20-15
    Figure US20110098280A1-20110428-C00230
    LC-MS 545 DMSO-d6: 1.46-1.62 (m, 2H), 1.72-1.79 (m, 1H), 1.82-1.90 (m, 1H), 2.38-2.46 (m, 1H), 2.43 (s, 3H), 2.62-2.76 (m, 2H), 3.59-3.69 (m, 2H), 3.43 (s, 3H), 6.47 (dd, 1H), 6.63 (d, 1H), 6.82-6.89 (br, 1H), 7.21 (dd, 1H), 7.32-7.41 (m, 2H), 7.44-7.52 (m, 1H), 7.71- 7.82 (m, 2H), 8.15 (s, 1H), 8.15-8.20 (br, 1H), 8.44- 8.53 (m, 1H), 9.28-9.38 (m, 1H)
    20-16
    Figure US20110098280A1-20110428-C00231
    0.24 (CH2Cl2: MeOH = 8:2) DMSO-d6: 1.47-1.55 (m, 2H), 1.80-1.91 (m, 2H), 2.16 (s, 3H), 2.25-2.41 (m, 5H), 2.42-2.48 (m, 3H), 2.61- 2.73 (m, 2H), 3.68-3.79 (m, 5H), 6.45 (dd, 1H), 6.62 (d, 1H), 7.21 (dd, 1H), 7.34 (d, 1H), 7.45-7.49 (m, 1H), 7.73-7.80 (m, 2H), 8.15 (s, 1H), 8.20 (s, 1H), 8.45-8.54 (m, 1H), 9.34 (s, 1H)
    20-17
    Figure US20110098280A1-20110428-C00232
    LC-MS 518 DMSO-d6: 1.76-1.84 (m, 1H), 2.08-2.16 (m, 1H), 2.33 (s, 3H), 2.42 (s, 3H), 3.00-3.03 (m, 1H), 3.23-3.27 (m, 3H), 3.42-3.46 (m, 1H), 3.74 (s, 3H), 6.06 (dd, 1H), 6.18- 6.20 (m, 1H), 7.17-7.23 (m, 1H), 7.38-7.48 (br, 1H), 7.72-7.77 (m, 1H), 8.12 (s, 1H), 8.17-8.21 (br, 1H), 8.46-8.58 (br, 1H), 9.30-9.40 (br, 1H)
    20-18
    Figure US20110098280A1-20110428-C00233
    LC-MS 601 DMSO-d6: 1.36-1.49 (m, 2H), 1.69-1.76 (m, 2H), 2.13 (s, 3H), 2.15-2.23 (m, 1H), 2.24-2.36 (br, 4H), 2.39- 2.48 (m, 5H), 2.43 (s, 3H), 3.27-3.40 (m, 2H), 3.74 (s, 3H), 6.62 (dd, 1H), 6.90 (d, 1H), 7.22-7.26 (m, 1H), 7.41-7.46 (m, 1H), 7.49-7.53 (m, 1H), 7.55-7.86 (br, 1H), 7.77 (dd, 1H), 8.16 (s, 1H), 8.25 (s, 1H), 8.42 (d, 1H), 9.28 (s, 1H)
    20-19
    Figure US20110098280A1-20110428-C00234
    LC-MS 519 DMSO-d6: 1.37-1.46 (m, 2H), 1.69-1.75 (m, 2H), 2.43 (s, 3H), 2.53-2.61 (m, 2H), 3.18-3.26 (m, 2H), 3.40- 3.74 (m, 2H), 4.62 (d, 1H), 6.62 (dd, 1H), 6.90 (d, 1H), 7.22-7.26 (m, 1H), 7.42-7.46 (br, 1H), 7.48-7.55 (m, 1H), 7.77-7.80 (m, 2H), 8.13-8.18 (br, 1H), 8.25 (s, 1H), 8.40-8.45 (m, 1H), 9.25-9.30 (m, 1H)
    20-20
    Figure US20110098280A1-20110428-C00235
    LC-MS 532 DMSO-d6: 1.66-1.76 (m, 1H), 2.00-2.07 (m, 1H), 2.14 (s, 6H), 2.43 (s, 3H), 2.68-2.76 (m, 1H), 2.87-2.91 (m, 1H), 2.99-3.10 (m, 2H), 3.24-3.28 (m, 1H), 3.71 (s, 3H), 6.25 (dd, 1H), 6.90 (d, 1H), 7.00-7.03 (m, 1H), 7.21-7.24 (m, 1H), 7.40-7.45 (m, 1H), 7.78-7.83 (m, 2H), 8.19 (s, 1H), 8.24 (s, 1H), 8.46 (d, 1H), 9.27-9.36 (br, 1H)
    20-21
    Figure US20110098280A1-20110428-C00236
    MS: 549 DMSO-d6: 2.37-2.47 (m, 4H), 2.48-2.53 (m, 3H), 2.64 (t, 2H), 3.57 (t, 3H), 3.77 (s, 3H), 3.92 (t, 2H), 6.61 (dd, 1H), 6.93 (d, 1H), 7.28 (dd, 1H), 7.56-7.63 (m, 2H), 7.75-7.85 (m, 2H), 7.74-7.84 (m, 2H), 8.14 (s, 1H), 8.29 (s, 1H) 8.46 (d, 1H), 9.33(s, 1H)
    20-22
    Figure US20110098280A1-20110428-C00237
    Ms: 562 DMSO-d6: 2.20 (s, 3H), 2.3-2.5 (m, 11H), 2.64 (t, 2H), 3.77 (s, 3H), 3.91 (t, 2H), 6.61(dd, 1H), 6.94 (d, 1H), 7.25-7.31(m, 1H), 7.57 (d, 1H), 7.58-7.64 (m, 1H), 7.74-7.84 (m, 2H), 8.12 (brs, 1H), 8.28 (s, 1H) 8.46 (d, 1H), 9.33(brs, 1H)
    20-23
    Figure US20110098280A1-20110428-C00238
    Ms: 438 DMSO-d6: 2.42-2.45 (m, 3H), 3.83 (s, 2H), 6.8 (ddd, 1H), 7.02 (dd, 1H), 7.3-7.36 (m, 1H), 7.58-7.64 (m, 1H), 7.74-7.8 (m, 1H), 7.82 (dd, 1H), 7.85 (dd, 1H), 8.18 (brs, 1H), 8.31 (s, 1H), 8.41 (d, 1H), 9.3 (brs, 1H)
    20-24
    Figure US20110098280A1-20110428-C00239
    Ms: 438 DMSO-d6: 2.41-2.45 (m, 3H), 3.79 (s, 2H), 6.74 (ddd, 1H), 7.0 (dd, 1H), 7.22-7.28 (m, 1H), 7.49-7.55 (m, 1H), 7.6 (dd, 1H), 7.75-7.8 (m, 2H), 8.21 (s, 1H), 8.37 (brs, 1H), 8.39-8.45 (m, 1H), 9.34 (brs, 1H)
    20-25
    Figure US20110098280A1-20110428-C00240
    Ms: 547 DMSO-d6: 1.24-1.38 (m, 2H), 1.64-1.8 (m, 3H), 1.83- 1.92 (m, 2H), 2.16 (s, 3H), 2.41-2.45(m, 3H), 2.76- 2.83 (m, 2H), 3.75 (s, 3H), 3.84 (d, 2H), 6.48 (dd, 1H), 6.64 (d, 1H), 7.2-7.25 (m, 1H), 7.41 (d, 1H), 7.43-7.5 (m, 1H), 7.74-7.8 (m, 2H), 8.16 (s, 1H), 8.26 (brs, 1H) 8.44-8.5 (m, 1H), 9.34 (brs, 1H)
    20-26
    Figure US20110098280A1-20110428-C00241
    Ms: 547 DMSO-d6: 1.18-1.3 (m, 2H), 1.56-1.7 (m, 3H), 1.8- 1.88 (m, 2H), 2.15 (s, 3H), 2.41-2.45(m, 3H), 2.73-2.8 (m, 2H), 3.75 (s, 3H), 3.65 (d, 2H), 3.77 (s, 3H), 6.57 (dd, 1H), 6.93 (d, 1H), 7.25 (dd, 1H), 7.51 -7.6 (m, 2H), 7.7-7.9 (m, 2H), 8.09 (brs, 1H), 8.28 (s, 1H), 8.45 (d, 1H), 9.31 (brs, 1H)
    20-27
    Figure US20110098280A1-20110428-C00242
    Ms: 533 DMSO-d6: 1.62-1.72 (m, 2H), 1.9-1.99 (m, 2H), 2.3- 2.35 (m, 5H), 2.41-2.45(m, 3H), 2.64-2.74 (m, 2H), 3.75 (s, 3H), 4.35-4.43 (m, 1H), 6.52 (dd, 1H), 6.65 (d, 1H), 7.19-7.25 (m, 1H), 7.41 (d, 1H), 7.43-7.49 (m, 1H), 7.74-7.8 (m, 2H), 8.16 (s, 1H), 8.27 (brs, 1H), 8.42-8.5 (m, 1H), 9.34 (brs, 1H)
    20-28
    Figure US20110098280A1-20110428-C00243
    Ms: 547 DMSO-d6: 0.96-1.2 (m, 2H), 1.75-1.9 (m, 1H), 2.2-2.3 (m, 1H), 2.35-2.45 (m, 1H), 2.41-2.45(m, 2H), 2.43(d, 3H), 2.6-3.0 (m, 3H), 3.76 (s, 3H), 4.85-5.0 (m, 1H), 6.43-6.49 (m, 1H), 6.57-6.64 (m, 1H), 7.18-7.25 (m, 1H), 7.39-7.52 (m, 2H), 7.73-7.83 (m, 2H), 8.17 (s, 1H), 8.27 (brs, 1H), 8.44-8.51 (m, 1H), 9.35 (brs, 1H)
    20-29
    Figure US20110098280A1-20110428-C00244
    Ms: 519 DMSO-d6: 1.74-1.83 (m, 1H), 2.23-2.31 (m, 1H), 2.28 (s, 3H), 2.35-2.4 (m, 1H), 2.41-2.45(m, 3H), 2.58-2.63 (m, 1H), 2.63-2.7 (m, 1H), 2.78-2.83 (m, 1H), 3.75 (s, 3H), 4.86-4.92 (m, 1H), 6.43 (dd, 1H), 6.58 (d, 1H), 7.19-7.25 (m, 1H), 7.41 (d, 1H), 7.44-7.51 (m, 1H), 7.73-7.83 (m, 2H), 8.16 (s, 1H), 8.26 (brs, 1H), 8.43- 8.52 (m, 1H), 9.34 (brs, 1H)
    20-30
    Figure US20110098280A1-20110428-C00245
    Ms: 533 DMSO-d6: 1.04 (t, 3H), 1.74-1.82 (m, 1H), 2.23-2.33 (m, 1H), 2.47-2.5(m, 6H), 2.62-2.72 (m, 2H), 2.8-2.87 (m, 1H), 3.75 (s, 3H), 4.86-4.92 (m, 1H), 6.44 (dd, 1H), 6.59 (d, 1H), 7.19-7.25 (m, 1H), 7.41 (d, 1H), 7.44-7.51 (m, 1H), 7.73-7.8 (m, 2H), 8.16 (s, 1H), 8.26 (brs, 1H), 8.44-8.51 (m, 1H), 9.34 (brs, 1H)
    20-31
    Figure US20110098280A1-20110428-C00246
    Ms: 518 DMSO-d6: 2.23(s, 3H), 2.38-2.47 (m, 7H), 2.87-2.93 (m, 4H), 3.75 (s, 3H), 6.63 (dd, 1H), 6.93 (d, 1H), 7.22-7.28 (m, 1H), 7.42 (d, 1H), 7.48-7.54 (m, 1H), 7.76-7.84 (m, 1H), 8.2 (s, 1H), 8.25(s, 1H), 8.43 (dd, 1H) 9.29 (s, 1H)
    20-32
    Figure US20110098280A1-20110428-C00247
    Ms: 586 DMSO-d6: 1.35-1.55 (m, 8H), 1.66-1.75 (m, 2H), 2.23(s, 3H), 2.41-2.45 (m, 3H), 3.74 (s, 3H), 6.63 (dd, 1H), 6.91 (d, 1H), 7.21-7.28 (m, 1H), 7.44 (d, 1H), 7.48-7.54 (m, 1H), 7.76-7.87 (m, 1H), 8.16 (s, 1H), 8.25 (s, 1H), 8.43 (dd, 1H) 9.29 (s, 1H)
    20-33
    Figure US20110098280A1-20110428-C00248
    Ms: 518 DMSO-d6: 1.62-1.71 (m, 1H), 1.95-2.04 (m, 1H), 2.23-2.27 (m, 3H), 2.39-2.43 (m, 3H), 2.93-3.1 (m, 2H), 3.13-3.26 (m, 2H), 3.71 (s, 3H), 6.19 (dd, 1H), 6.88 (d, 1H), 7.07-7.13 (m, 1H), 7.13-7.2 (m, 1H), 7.4- 7.48 (m, 1H), 7.75 (dd, 1H), 8.06 (brs, 1H), 8.18 (s, 1H), 8.4 (d, 1H)
    20-34
    Figure US20110098280A1-20110428-C00249
    Ms: 546 DMSO-d6: 2.02 (m, 1H), 2.42-2.46 (m, 3H), 2.71-2.91 (m, 4H), 3.44-3.51 (m, 4H), 3.76 (s, 3H), 6.66 (dd, 1H), 6.94 (d, 1H), 7.21-7.27 (m, 1H), 7.75-7.85 (m, 2H), 8.19 (s, 1H), 8.26 (s, 1H), 8.41 (d, 1H), 9.28 (brs, 1H).
    20-35
    Figure US20110098280A1-20110428-C00250
    MS (ESI) 464 (M + H) HPLC Retention time (min) 2.68
  • The following 2-[5-chloro-2-(subst. phenylamino)-pyrimidin-4-ylamino]-N-sec-butyl-benzene-sulfonamides are prepared from 2-(5-chloro-2-chloro-pyrimidin-4-ylamino)-N-sec-butyl-benzenesulfonamide and the corresponding aniline following the procedure of Example 7A
  • Figure US20110098280A1-20110428-C00251
    Rf (solvent)
    ExplNo. Rx or MS NMR (400 MHz), δ (ppm)
    21-1
    Figure US20110098280A1-20110428-C00252
    0.35 (n-hexane: AcOEt = 1:1) CDCl3: 0.62(t, 3H), 0.88(d, 3H), 1.22-1.29(m, 2H), 2.23(s,3H), 2.45-2.47(m, 4H), 3.05-3.14(m, 5H), 3.75 (s, 3H), 6.40-6.43(m, 1H), 6.62(s, 1H), 7.18-7.22(m, 1H), 7.39-7.47(m, 2H), 7.80-7.82(m, 1H), 8.15- 8.16(m, 2H), 8.44-8.46(m, 1H), 9.32(s, 1H)
    21-2
    Figure US20110098280A1-20110428-C00253
    0.30 (n-hexane: AcOEt = 3:1) DMSO-d6: 0.62(t, 3H), 0.87(d, 3H), 1.17-1.26(m, 2H), 3.03-3.10(m, 1H), 3.79(s, 3H), 6.66-6.71(m, 1H), 6.96-7.00(m, 1H), 7.21-7.25(m, 1H), 7.47-7.51(m, 1H), 7.60-7.64(m, 1H), 7.79-7.83(m, 2H), 8.21(s, 1H), 8.31(s, 1H), 8.35-8.37(m, 1H), 9.29(s, 1H)
    21-3
    Figure US20110098280A1-20110428-C00254
    0.30 (n-hexane: AcOEt = 1:1) DMSO-d6: 0.61(t, 3H), 0.87(d, 3H), 1.21-1.29(m, 2H), 1.58-1.67(m, 2H), 1.86-1.93(m, 2H), 2.14-2.20(m, 5H), 2.59-2.67(m, 2H), 3.06-3.08(m, 1H), 3.74(s, 3H), 4.32-4.36(m, 1H), 6.46-6.48(m, 1H), 6.63(d, 1H), 7.17-7.21(m, 1H), 7.40-7.50(m, 2H), 7.79-7.81(m, 2H), 8.16(s, 1H), 8.21(bs, 1H), 8.35-8.42(m, 1H), 9.29(s, 1H)
    21-4
    Figure US20110098280A1-20110428-C00255
    0.30 (n-hexane: AcOEt = 1:1) DMSO-d6: 0.61(t, 3H), 0.87(d, 3H), 1.22-1.29(m, 2H), 2.43-2.47(m, 2H), 2.61-2.63(m, 1H), 2.68-2.70(m, 2H), 3.04-3.11(m, 1H), 3.56-3.60(m, 5H), 3.75(s, 3H), 3.93-3.96(m, 1H), 4.08-4.11(m, 2H), 6.45-6.47(m, 1H), 6.64(d, 1H), 7.18-7.22(m, 1H), 7.43-7.46(m, 2H), 7.80-7.82(m, 2H), 8.17(s, 1H), 8.21(s, 1H), 8.42- 8.44(m, 1H), 9.31(s, 1H)
  • The following 2-[5-chloro-2-(subst. phenylamino)-pyrimidin-4-ylamino]-N-iso-butyl-benzene-sulfonamides are prepared from 2-(5-chloro-2-chloro-pyrimidin-4-ylamino)-N-sec-butyl-benzenesulfonamide and the corresponding aniline following the procedure of Example 7A
  • Figure US20110098280A1-20110428-C00256
    Rf (solvent)
    ExplNo. Rx or MS NMR (400 MHz), δ (ppm)
    22-1
    Figure US20110098280A1-20110428-C00257
    0.30 (n-hexane: AcOEt = 3:1) DMSO-d6: 0.69(d, 6H), 1.52-1.59(m, 1H), 2.57- 2.58(m, 2H), 3.82(s, 3H), 6.75-6.80(m, 1H), 6.99- 7.02(m, 1H), 7.29-7.33(m, 1H), 7.56-7.60(m, 1H), 7.82-7.93(m, 3H), 8.14(bs, 1H), 8.31(s, 1H), 8.33(s, 1H), 9.23(s, 1 H)
    22-2
    Figure US20110098280A1-20110428-C00258
    0.30 (n-hexane: AcOEt = 3:1) CDCl3: 0.74(d, 6H), 1.57-1.64(m, 1 H), 2.72- 2.76(m, 2H), 3.88(s, 3H), 4.55-4.56(m, 1H), 6.52-6.57 (m, 1H), 6.62-6.65(m, 1H), 7.24-7.28(m, 2H), 7.36(bs, 1H), 7.56-7.60(m, 1H), 7.95-8.08(m, 1H), 8.10- 8.14(m, 2H), 8.36-8.39(m, 1H), 8.98(bs, 1H)
    22-3
    Figure US20110098280A1-20110428-C00259
    0.54 (AcOEt) DMSO-d6: 0.73(d, 6H), 1.55-1.62(m, 1H), 2.56- 2.59(m, 2H), 3.10-3.12(m, 4H), 3.74-3.76(m, 7H), 6.43-6.46(m, 1H), 6.65(d, 1H), 7.20-7.24(m, 1H), 7.40-7.48(m, 2H), 7.76-7.78(m, 1H), 7.90-7.95(m, 1H), 8.16(s, 1H), 8.17(s, 1H), 8.43-8.45(m, 1H), 9.32(s, 1H)
  • The following 2-[5-chloro-2-(subst. phenylamino)-pyrimidin-4-ylamino]-N-(1-ethyl-propyl)-benzenesulfonamides are prepared from 2-(5-chloro-2-chloro-pyrimidin-4-ylamino)-N-(1-ethyl-propyl)-benzenesulfonamide and the corresponding aniline following the procedure of Example 7A
  • Figure US20110098280A1-20110428-C00260
    Rf (solvent)
    ExplNo. Rx or MS NMR (400 MHz), δ (ppm)
    23-1
    Figure US20110098280A1-20110428-C00261
    0.46 (MeOH: CH2Cl2 = 3:7) DMSO-d6: 0.58(t, 6H), 1.14-1.34(m, 4H), 1.58- 1.68(m, 2H), 1.87-1.96(m, 2H), 2.12-2.22(m, 2H), 2.18(s, 3H), 2.57-2.65(m, 2H), 2.86-2.96(m, 1H), 3.75(s, 3H), 4.30-4.39(m, 1H), 6.46(dd, 1H), 6.63(d, 1H), 7.19(dd, 1H), 7.39-7.48(m, 2H), 7.75-7.84(m, 2H), 8.18(s, 1H), 8.20 (s, 1H), 8.39(m, 1H), 9.33(bs, 1H)
    23-2
    Figure US20110098280A1-20110428-C00262
    0.35 (n-hexane: AcOEt = 1:1) CDCl3: 0.59(t, 6H), 1.14-1.34(m, 4H), 2.23(s, 3H), 2.45-2.47(m, 4H), 2.90-2.95(m, 1H), 3.11-3.14(m, 4H), 3.76 (s, 3H), 6.39-6.42(m, 1H), 6.62(s, 1H), 7.18- 7.22(m, 1H), 7.41-7.46(m, 2H), 7.76-7.82(m, 2H), 8.12(s, 1H), 8.16(s, 1H), 8.43-8.44(m, 1H), 9.35(s, 1H)
    23-3
    Figure US20110098280A1-20110428-C00263
    0.41 (MeOH: CH2Cl2 = 1:4) DMSO-d6: 0.59(t, 6H), 1.16-1.35(m, 4H), 1.75- 1.89(m, 1H), 2.08-2.15(m, 1H), 2.32(s, 3H), 2.90- 3.02(m, 2H), 3.21-3.45(m, 4H), 3.73(s, 3H), 6.02(dd, 1H), 6.18(d, 1H), 7.16(dd, 1H), 7.27(d, 1H), 7.35- 7.45(m, 1H), 7.77-7.82(m, 2H), 8.10 (s, 1H) 8.12 (s, 1H), 8.45-8.55(m, 1H), 9.38(s, 1H)
    23-4
    Figure US20110098280A1-20110428-C00264
    0.41 (MeOH: CH2Cl2 = 1:4) DMSO-d6: 0.60(t, 6H), 1.04(t, 3H), 1.17-1.35(m, 4H), 1.76-1.83(m, 1H), 2.10-2.15(m, 1H), 2.56-2.64(m, 2H), 2.91-3.01(m, 2H), 3.21-3.47(m, 4H), 3.74(s, 3H), 6.02(dd, 1H), 6.18(d, 1H), 7.14-7.17(m, 1H), 7.28(d, 1H), 7.35-7.45(m, 1H), 7.77-7.82(m, 2H), 8.11 (s, 1H) 8.12 (s, 1H), 8.45-8.55(m, 1H), 9.38(s, 1H)
    23-5
    Figure US20110098280A1-20110428-C00265
    0.25 (n-hexane: AcOEt = 1:1) DMSO-d6: 0.58(t, 6H), 1.06-2.16(m, 11H), 2.16(s, 3H), 2.62-2.67(m, 1H), 2.81-2.94(m, 2H), 3.75(s, 3H), 3.80-3.89(m, 2H), 6.41-6.44(m, 1H), 6.62(d, 1H), 7.17-7.21(m, 1H), 7.42-7.47(m, 2H), 7.77-7.82(m, 2H), 8.18(s, 1H), 8.19(s, 1H), 8.35-8.42(m, 1H), 9.35(s, 1H)
    23-6
    Figure US20110098280A1-20110428-C00266
    Ms: 561 DMSO-d6: 0.59 (t, 6H), 1.14-1.38 (m, 4H), 2.87-2.98 (m, 1H), 3.1 (t, 4H), 3.72-3.79 (m, 7H), 6.42 (dd, 1H), 6.64 (d, 1H), 7.18-7.24 (m, 1H), 7.42-7.5 (m, 2H), 7.77 (d, 1H), 7.81 (dd, 1H), 8.13 (s, 1H), 8.17 (s, 1H), 8.4-8.5 (m, 1H), 9.36 (s, 1H)
    23-7
    Figure US20110098280A1-20110428-C00267
    MS: 575 DMSO-d6: 0.58 (t, 6H), 1.13-1.37 (m, 4H), 1.72-1.82 (m, 1H), 2.21-2.31 (m, 4H), 2.32-2.4 (m, 1H), 2.54- 2.61 (m, 1H), 2.62-2.68 (m, 1H), 2.75-2.82 (m, 1H), 2.87-2.97 (m, 1H), 3.75 (s, 3H), 4.84-4.91 (m, 1H), 6.37 (dd, 1H), 6.56 (d, 1H), 7.14-7.24 (m, 1H), 7.38- 7.52 (m, 2H), 7.72-7.86 (m, 1H), 8.12-8.25 (m, 2H), 8.34-8.45 (m, 1H), 9.33 (brs, 1H)
    23-8
    Figure US20110098280A1-20110428-C00268
    Ms: 605 DMSO-d6: 0.58 (t, 6H), 1.14-1.36 (m, 4H), 2.43-2.53 (m, 4H), 2.69 (t, 2H), 2.89-2.95 (m, 1H), 3.59 (t, 4H), 3.76 (s, 3H), 4.09 (t, 1H), 6.45 (dd, 1H), 6.64 (d, 1H), 7.17-7.23 (m, 1H), 7.41-7.52 (m, 2H), 7.78 (d, 1H), 7.81 (dd, 1H), 8.18 (s, 1H), 8.19 (s, 1H), 8.36-8.46 (m, 1H), 9.35 (s, 1H)
    23-9
    Figure US20110098280A1-20110428-C00269
    Ms: 618 DMSO-d6: 0.58 (t, 6H), 1.14-1.37 (m, 4H), 2.15 (s, 1H), 2.25-2.4 (m, 4H), 2.45-2.55 (m, 4H), 2.68 (t, 2H), 2.88-2.97 (m, 1H), 3.76 (s, 3H), 4.07 (t, 1H), 6.44 (dd, 1H), 6.64 (d, 1H), 7.15-7.23 (m, 1H), 7.41-7.51 (m, 2H), 7.7-7.84 (m, 2H), 8.12-8.22 (m, 1H), 8.34-8.44 (m, 1H), 9.34 (s, 1H)
  • The following 2-[5-chloro-2-(subst. phenylamino)-pyrimidin-4-ylamino]-N-iso-butyl-benzene-sulfonamides are prepared from 2-(5-chloro-2-chloro-pyrimidin-4-ylamino)-N-cyclobutyl-benzenesulfonamide and the corresponding aniline following the procedure of Example 7A
  • Figure US20110098280A1-20110428-C00270
    Rf (solvent)
    ExplNo. Rx or MS NMR (400 MHz), δ (ppm)
    24-1
    Figure US20110098280A1-20110428-C00271
    0.35 (n-hexane: AcOEt = 1:1) DMSO-d6: 1.37-1.48(m, 2H), 1.69-1.91(m, 4H), 3.09- 3.12(m, 4H), 3.63-3.74(m, 1H), 3.76(s, 3H), 6.43- 6.45(m, 1H), 6.63(d, 1H), 7.18-7.22(m, 1H), 7.41- 7.47(m, 2H), 7.76-7.78(m, 1H), 8.17-8.24(m, 3H), 8.46(d, 1H), 9.33(s, 1H)
    24-2
    Figure US20110098280A1-20110428-C00272
    0.46 (MeOH: CH2Cl2 = 3:7) DMSO-d6: 1.37-1.93(m, 10H), 2.18(s, 3H), 2.59- 2.62(m, 1H), 3.60-3.74(m, 1H), 3.77(s, 3H), 4.32- 4.36(m, 1H), 6.46-6.49(m, 1H), 6.62(d, 1H), 7.16- 7.20(m, 1H), 7.41-7.44(m, 2H), 7.75-7.77(m, 1H), 8.16(s, 1H), 8.22(bs, 1H), 8.40-8.42(m, 1H), 9.30(bs, 1H)
    24-3
    Figure US20110098280A1-20110428-C00273
    0.46 (MeOH: CH2Cl2 = 1:4) CDCl3: 1.45-1.75(m, 5H), 1.94-2.06(m, 6H), 2.29- 2.37(m, 1H), 3.21-3.56(m, 4H), 3.72-3.81(m, 1H), 3.86(s, 3H), 4.55-4.65(m, 1H), 4.90(d, 1H), 5.72(d, 1H), 6.07(bs, 1H), 6.15(bs, 1H), 7.18-7.22(m, 2H), 7.52-7.56(m, 1H), 7.89-7.94(m, 2H), 8.08(s, 1H), 8.50(d, 1H), 9.00(s, 1H)
  • Figure US20110098280A1-20110428-C00274
    Expl
    No. Rx Ms NMR (400 MHz), δ (ppm)
    25-1
    Figure US20110098280A1-20110428-C00275
    Ms: 559 DMSO-d6: 1.2-1.38 (m, 4H), 1.4-1.65 (m, 4H), 3.11 (t, 4H), 3.42-3.5 (m, 1H), 3.7-3.8 (m, 7H), 6.44 (dd, 1H), 6.64 (d, 1H), 7.18-7.26 (m, 1H), 7.38-7.5 (m, 2H), 7.81 (d, 1H), 7.88-7.96 (m, 1H), 8.16 (s, 1H), 8.17 (s, 1H), 8.4-8.5 (m, 1H), 9.34 (s, 1H)
    25-2
    Figure US20110098280A1-20110428-C00276
    Ms: 587 DMSO-d6: 1.2-1.38 (m, 4H), 1.42-1.6 (m, 6H), 1.88- 1.98 (m, 2H), 2.1-2.25 (m, 5H), 2.55-2.65 (m, 2H), 3.4-3.5 (m, 1H), 3.74 (s, 3H), 4.3-4.4 (m, 1H), 6.48 (dd, 1H), 6.63 (d, 1H), 7.18- 7.24 (m, 1H), 7.38-7.47 (m, 1H), 7.77-7.82 (m, 1H), 7.88-7.96 (m, 1H), 8.17 (s, 1H), 8.22 (s, 1H), 8.36-8.46 (m, 1H), 9.31 (s, 1H)
  • The following 5-Chloro-N2-(substituted phenyl)-N4-[2-(propane-1-sulfonyl)-phenyl]-pyrimidine-2,4-diamine are prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-1-sulfonyl)-phenyl]-amine and the corresponding aniline following the procedure of Example 7A
  • Figure US20110098280A1-20110428-C00277
    Rf (solvent),
    ExplNo. Rx MS or Mp NMR (400 MHz), δ (ppm)
    26-1
    Figure US20110098280A1-20110428-C00278
    0.58 (AcOEt) CDCl3: 0.97(t, 3H), 1.72-1.82(m, 2H), 3.08-3.14(m, 6H), 3.87-3.89(m, 7H), 6.46(dd, 1H), 6.53(d, 1H), 7.24- 7.28(m, 1H), 7.30(s, 1H), 7.60-7.64(m, 1H), 7.94(dd, 1H), 8.05(d, 1H), 8.15(s, 1H), 8.59(d, 1H), 9.40(s, 1H)
    26-2
    Figure US20110098280A1-20110428-C00279
    0.57 (MeOH: AcOEt = 1:4) CDCl3: 0.98(t, 3H), 1.85-1.68(m, 2H), 2.15(s, 3H), 3.16-3.07(m, 6H), 3.67-3.62(m, 2H), 3.81-3.78(m, 2H), 3.89(s, 3H), 6.47(d, 1H), 6.55(d, 1H), 7.36- 7.33(m, 1H), 7.62(dd, 1H), 7.95(dd, 1H), 8.08(d, 1H), 8.15(s, 1H), 8.58(d, 1H), 9.41(s, 1H)
    26-3
    Figure US20110098280A1-20110428-C00280
    0.13 (MeOH: AcOEt = 1:4) CDCl3: 0.97(t, 3H), 1.43-1.52(m, 2H), 1.52-1.67(m, 4H), 1.69-1.72(m, 4H), 1.90-1.98(m, 2H), 2.34- 2.46(m, 1H), 2.51-2.59(m, 4H), 2.64-2.74(m, 2H), 3.11(dd, 2H), 3.64-3.73(m, 2H), 3.87(s, 3H), 6.47(dd, 1H), 6.56(d, 1H), 7.24-7.33(m, 1H), 7.62(dd, 1H), 7.94(dd, 1H), 8.00(d, 1H), 8.14(s, 1H), 8.59(d, 1H), 9.39(bs, 1H).
    26-4
    Figure US20110098280A1-20110428-C00281
    0.22 (AcOEt) CDCl3: 0.97(t, 3H), 1.45(d, 1H), 1.68-1.82(m, 4H), 2.0- 2.1(m, 2H), 2.91(ddd, 2H), 3.10(ddd, 2H), 3.46-3.51 (m, 2H), 3.84-3.92(m, 1H), 3.88 (s, 1H), 6.48(dd, 1H), 6.57(d, 1H), 7.23-7.32 (m, 1 H), 7.62(dd, 1H), 7.94(dd, 1H), 8.02 (dd, 1H), 8.14(s, 1H), 8.59(d, 1H), 9.39(bs, 1H)
    26-5
    Figure US20110098280A1-20110428-C00282
    0.1  (AcOEt) CDCl3: 0.97(t, 3H), 1.71-1.82(m, 2H), 1.86-1.98(m, 2H), 2.01-2.08(m, 2H), 2.25-2.37(m, 1H), 2.75(ddd, 2H), 3.10(ddd, 2H), 3.63-3.66(m, 2H), 3.88(s, 3H), 5.25-5.40(m, 1H), 5.40-5.58 (m, 1H), 6.48(dd, 1H), 6.57(d, 1H), 7.22-7.34 (m, 1H), 7.62(ddd, 1H), 7.93 (d, 1H), 7.94 (dd, 1H), 8.02 (d, 1H), 8.14(s, 1H), 8.59(d, 1H), 9.40(m, 1H)
    26-6
    Figure US20110098280A1-20110428-C00283
    MS 587 CDCl3: 0.97 (t, 3H), 1.77 (ddd, 2H), 2.00-1.85 (m, 4H), 2.27-2.18(m, 1H), 2.72(ddd, 2H) 3.12-3.08 (m, 2H), 3.69-3.61 (m, 2H), 3.58-3.46(m, 1H), 3.64 (t, 2H), 3.80(t, 2H), 3.88(s, 3H), 5.56-5.46 (m, 1H), 6.47(dd, 1H), 6.55(d, 1H), 7.32-7.23 (m, 1H), 7.30(bs, 1H), 7.64-7.60(m, 1H), 7.94(dd, 1H), 8.02(d, 1H), 8.14(s, 1H), 8.59(d, 1H), 9.40(s, 1H)
    26-7
    Figure US20110098280A1-20110428-C00284
    MS 587 CDCl3: 0.98 (t, 3H), 1.46(bs, 6H) 1.82-1.73 (m, 2H), 2.17(s, 3H), 3.58-3.46(m, 1H), 2.95-2.84 (m, 2H), 3.12-3.08 (m, 2H), 3.90(s, 3H), 6.48(dd, 1H), 6.52(d, 1H), 7.30-7.22 (m, 1H), 7.31(bs, 1H), 7.66-7.60(m, 1H), 7.95(dd, 1H), 8.06(d, 1H), 8.15(s, 1H), 8.59(d, 1H), 9.43(s, 1H)
    26-8
    Figure US20110098280A1-20110428-C00285
    MS 573 CDCl3: 0.97 (t, 3H), 1.19(t, 3H), 1.77 (ddd, 2H), 2.41(m, 2H), 3.18-3.09(m, 6H), 3.68-3.64 (m, 2H), 3.85-3.78 (m, 2H), 3.89(s, 3H), 6.47(dd, 1H), 6.55(d, 1H), 7.29-7.25 (m, 1H), 7.34(bs, 1H), 7.64-7.60(m, 1H), 7.95(dd, 1H), 8.07(d, 1H), 8.15(s, 1H), 8.58(d, 1H), 9.41(s, 1H)
    26-9
    Figure US20110098280A1-20110428-C00286
    MS 587 CDCl3: 0.97 (t, 3H), 1.17(d, 3H) 1.76 (ddd, 2H), 2.88- 2.81(m, 2H), 3.18-3.05(m, 6H), 3.74-3.67 (m, 2H), 3.86-3.78 (m, 2H), 3.89(s, 3H), 6.47(dd, 1H), 6.55(d, 1H), 7.29-7.20(m, 1H), 7.34(bs, 1H), 7.64-7.60(m, 1H), 7.95(dd, 1H), 8.07(d, 1H), 8.15(s, 1H), 8.58(d, 1H), 9.41(s, 1H)
    26-10
    Figure US20110098280A1-20110428-C00287
    MS 517 CDCl3: 0.97 (t, 3H), 1.76 (ddd, 2H), 2.86(d, 3H), 3.14- 3.08(m, 2H), 3.13(t, 4H), 3.55(t, 4H), 3.89(s, 3H), 4.48-4.39 (m, 1H), 6.46(dd, 1H), 6.55(d, 1H), 7.29- 7.21 (m, 1H), 7.34(bs, 1H), 7.64-7.60(m, 1H), 7.95(dd, 1H), 8.06(d, 1H), 8.15(s, 1H), 8.58(d, 1H), 9.41(s, 1H)
    26-11
    Figure US20110098280A1-20110428-C00288
    MS 587 CDCl3: 0.98 (t, 3H), 1.51 (s, 6H), 1.82-1.72 (m, 1H), 2.13 (s, 3H), 3.12-3.08 (m, 2H), 3.26(s, 2H), 3.44 (t, 2H), 3.74(t, 2H), 3.88(s, 3H), 5.56-5.46 (m, 1H), 6.45(dd, 1H), 6.51(d, 1H), 7.00(bs, 1H), 7.62-7.58 (m, 1H), 7.64-7.60(m, 1H), 7.93(d, 1H), 7.96(dd, 1H), 8.13(s, 1H), 8.62(d, 1H), 9.42(s, 1H)
    26-12
    Figure US20110098280A1-20110428-C00289
    MS 559 CDCl3: 0.98(t, 3H), 1.81-1.71(m, 3H), 1.95-1.84(m, 3H), 2.68-2.63(m, 1H), 3.12-3.08(m, 4H), 3.28(d, 2H), 3.89(s, 3H), 5.45-5.38(m, 1H), 6.53(dd, 1H), 6.59(d, 1H), 6.71-6.62(m, 1H), 7.28-7.21(m, 1H), 7.35(bs, 1H), 7.65-7.61(m, 1H), 7.95(dd, 1H), 8.08(d, 1H), 8.15(s, 1H), 8.58(d, 1H), 9.41(s, 1H)
    26-13
    Figure US20110098280A1-20110428-C00290
    MS 559 CDCl3: 0.98 (t, 3H), 1.81-1.71 (m, 3H), 1.95-1.84 (m, 3H), 2.68-2.63(m, 1H), 3.12-3.08 (m, 4H), 3.28(d, 2H), 3.89(s, 3H), 5.45-5.38 (m, 1H), 6.53(dd, 1H), 6.59(d, 1H), 6.71-6.62 (m, 1H), 7.28-7.21 (m, 1H), 7.35(bs, 1H), 7.65-7.61(m, 1H), 7.95(dd, 1H), 8.08(d, 1H), 8.15(s, 1H), 8.58(d, 1H), 9.41(s, 1H)
    26-14
    Figure US20110098280A1-20110428-C00291
    MS 559 CDCl3: 0.98 (t, 3H), 1.85-1.74 (m, 3H), 2.00-1.86 (m, 3H), 2.70-2.51(m, 1H), 3.13-3.08 (m, 4H), 3.29-3.27 (m, 2H), 3.89(s, 3H), 5.46-5.37 (m, 1H), 6.53(dd, 1H), 6.59(d, 1H), 6.69-6.56 (m, 1H), 7.29-7.19 (m, 1H), 7.34(bs, 1H), 7.65-7.61(m, 1H), 7.95(dd, 1H), 8.08(d, 1H), 8.15(s, 1H), 8.58(d, 1H), 9.41(s, 1H)
    26-15
    Figure US20110098280A1-20110428-C00292
    MS 559 CDCl3: 0.99(t, 3H), 1.79-1.72 (m, 2H), 2.92 (t, 2H), 2.98(t, 2H), 3.16-3.12 (m, 2H), 3.53(t, 2H), 3.67(t, 2H), 3.87(s, 3H), 6.54(dd, 1H), 6.82 (d, 1H), 7.29-7.19 (m, 1H), 7.56(bs, 1H), 7.67-7.62(m, 1H), 7.96(dd, 1H), 8.07(d, 1H), 8.21(s, 1H), 8.59(dd, 1H), 9.46(s, 1H)
    26-16
    Figure US20110098280A1-20110428-C00293
    MS 561 CDCl3: 0.98 (t, 3H), 1.81-1.72 (m, 2H), 2.49 (t, 4H), 2.66 (t, 2H), 3.12-3.08(m, 2H), 3.18 (t, 2H), 3.74(t, 4H), 3.86(s, 3H), 6.53(dd, 1H), 6.20(dd, 1H), 6.26 (d, 1H), 7.13(bs, 1H), 7.25-7.21 (m, 1H), 7.62-7.57(m, 1H), 7.87(dd, 1H), 7.93(dd, 1H), 8.12(s, 1H), 8.62(d, 1H), 9.40(s, 1H)
    26-17
    Figure US20110098280A1-20110428-C00294
    MS 518 CDCl3: 0.98 (t, 3H), 1.78-1.73 (m, 2H), 2.49 (t, 4H), 2.66 (t, 2H), 2.94-2.92 (m, 4H), 3.15-3.11(m, 2H), 3.76-3.73(m, 4H), 3.88(s, 3H), 6.52(dd, 1H), 6.82(d, 1H), 7.28-7.24 (m, 1H), 7.57(bs, 1H), 7.25-7.21 (m, 1H), 7.68-7.63(m, 1H), 7.95(dd, 1H), 8.02(d, 1H), 8.20(s, 1H), 8.56(d, 1H), 9.41(s, 1H)
    26-18
    Figure US20110098280A1-20110428-C00295
    MS 559 CDCl3: 0.97 (t, 3H), 1.81-1.72 (m, 2H), 2.08-2.00 (m, 2H), 2.49 (t, 4H), 2.66 (t, 2H), 2.40 (t, 2H), 3.59 (t, 2H), 3.69(t, 2H), 3.87(s, 3H), 6.41 (dd, 1H), 6.51(d, 1H), 7.29-7.25 (m, 2H), 7.65-7.60(m, 1H), 7.95(dd, 1H), 8.05(d, 1H), 8.15(s, 1H), 8.56(d, 1H), 9.41(s, 1H)
    26-19
    Figure US20110098280A1-20110428-C00296
    MS 587 CDCl3: 0.98 (t, 3H), 1.82-1.73 (m, 2H), 2.14 (s, 3H), 3.12-3.08 (m, 2H), 3.55-3.45(m, 2H), 3.66-3.56 (m, 4H), 3.79-3.68 (m, 2H), 3.95(s, 3H), 6.95(dd, 1H), 7.03 (d, 1H), 7.32-7.28(m, 1H), 7.69-7.64 (m, 1H), 7.71(s, 1H), 7.97(dd, 1H), 8.22(s, 1H), 8.39(d, 1H), 8.52(d, 1H), 9.46(s, 1H)
    26-20
    Figure US20110098280A1-20110428-C00297
    MS 546 CDCl3: 0.97 (t, 3H), 1.82-1.73 (m, 2H), 3.12-3.08 (m, 2H), 3.80-3.58(m, 8H), 3.94(s, 3H), 6.94(dd, 1H), 7.02 (d, 1H), 7.32-7.28(m, 1H), 7.69-7.64 (m, 1H), 7.32- 7.28(m, 1H), 7.97(dd, 1H), 8.21 (s, 1H), 8.34(d, 1H), 8.52(d, 1H), 9.45(s, 1H)
    26-21
    Figure US20110098280A1-20110428-C00298
    MS 615 CDCl3: 0.97 (t, 3H), 1.82-1.72 (m, 2H), 2.71 (t, 3H), 3.05 (s, 2H), 3.10 (m, 2H), 3.18 (t, 4H), 3.88(s, 3H), 4.17-4.08 (m, 1H), 6.47 (dd, 1H), 6.54 (d, 1H), 6.99- 6.89(m, 1H), 7.28-7.24 (m, 1H), 7.31(bs, 1H), 7.65- 7.60 (m, 1H), 7.32-7.28(m, 1H), 7.95(dd, 1H), 8.05 (d, 1H), 8.15(s, 1H), 8.59(d, 1H), 9.41(s, 1H)
    26-22
    Figure US20110098280A1-20110428-C00299
    MS 530 CDCl3: 0.98 (t, 3H), 1.80-1.74 (m, 2H), 3.12-3.08 (m, 2H), 3.45-3.42 (m, 2H), 3.55-3.53 (m, 2H), 3.87 (s, 2H), 3.89(s,3H), 5.98-5.89 (m, 1H), 6.44 (dd, 1H), 6.50(d, 1H), 7.35-7.19 (m, 2H), 7.62-7.58(m, 1H), 7.95(dd, 1H), 8.09 (d, 1H), 8.15(s, 1H), 8.57(d, 1H), 9.43(s, 1H)
    26-23
    Figure US20110098280A1-20110428-C00300
    MS 558 CDCl3: 0.97 (t, 3H), 1.10 (s, 3H), 1.12 (s, 3H), 1.80- 1.74(m, 2H), 2.80-2.63 (m, 5H), 3.12-3.08 (m, 2H), 3.19-3.17 (m, 4H), 3.87(s, 3H), 6.48 (dd, 1H), 6.56(d, 1H), 7.30-7.23 (m, 2H), 7.62-7.58(m, 1H), 7.94(dd, 1H), 8.00 (d, 1H), 8.14(s, 1H), 8.59(d, 1H), 9.40(s, 1H)
    26-24
    Figure US20110098280A1-20110428-C00301
    MS 544 CDCl3: 0.98 (t, 3H), 1.81-1.72 (m, 2H), 2.03-1.91 (m, 1H), 2.28-2.19 (m, 1H), 2.33 (s, 6H), 2.92-2.84 (m, 1H), 3.12-3.08 (m, 2H), 3.17(t, 1H), 3.35(ddd, 1H), 3.51-3.42 (m, 2H), 3.87 (s, 3H), 6.11 (dd, 1H), 6.14 (d, 1H), 7.09 (s, 1H), 7.26-7.20(m, 1H), 7.60-7.56 (m, 1H), 7.85(d, 1H), 7.92(dd, 1H), 8.11(s, 1H), 8.38(d, 1H), 9.41(s, 1 H)
    26-25
    Figure US20110098280A1-20110428-C00302
    MS 530 CDCl3: 0.98 (t, 3H), 1.82-1.71 (m, 2H), 1.96-1.86 (m, 1H), 2.33-2.20 (m, 1H), 2.51 (s, 1H), 3.17-3.08 (m, 3H), 3.35-3.30 (m, 1H), 3.54-3.30 (m, 3H), 3.87 (s, 3H), 6.12 (dd, 1H), 6.16 (d, 1H), 7.09 (s, 1H), 7.32- 7.21(m, 1H), 7.58 (dd, 1H), 7.85(d, 1H), 7.92(dd, 1H), 8.11(s, 1H), 8.64(d, 1H), 9.40(s, 1H)
    26-26
    Figure US20110098280A1-20110428-C00303
    MS 546 CDCl3: 0.98 (t, 3H), 1.83-1.71 (m, 2H), 1.98-1.81 (m, 2H), 2.16-2.02(m, 2H), 2.53-2.28 (m, 5H), 2.87-2.72 (m, 2H), 3.12-3.08 (m, 2H), 3.88 (s, 3H), 4.32 (bs, 3H), 6.44 (dd, 1H), 6.53(d, 1H), 7.32-7.25(m, 2H), 7.63-7.59 (m, 2H), 7.94(dd, 1H), 8.04 (d, 1H), 8.15(s, 1H), 8.57(d, 1H), 9.42(s, 1H)
    26-27
    Figure US20110098280A1-20110428-C00304
    MS 545 CDCl3: 0.97 (t, 3H), 1.38-1.30 (m, 1H), 1.49-1.40 (m, 2H), 1.70-1.62 (m, 1H), 1.83-1.72 (m, 2H), 1.89 (d, 2H), 2.74-2.10 (m, 2H), 3.12-3.08 (m, 2H), 3.57 (d, 2H), 3.63 (d, 2H), 3.90 (s, 3H), 6.50 (d, 1H), 6.58 (s, 1H), 7.34-7.24 (m, 2H), 7.64-7.60(m, 1H), 7.94(dd, 1H), 8.02 (d, 1H), 8.14(s, 1H), 8.60(dd, 1H), 9.40(s, 1H)
    26-28
    Figure US20110098280A1-20110428-C00305
    MS 517 CDCl3: 0.97 (t, 3H), 1.88-1.65 (m, 3H), 2.05-1.97 (m, 2H), 2.21-2.08 (m, 1H), 2.67-2.55 (m, 4H), 2.78- 2.71(m, 2H), 3.12-3.08 (m, 2H), 3.61 (d, 2H), 3.87 (s, 3H), 6.47 (dd, 1H), 6.56 (d, 1H), 7.28-7.23 (m, 2H), 7.64-7.60(m, 1H), 7.94(dd, 1H), 7.99 (d, 1H), 8.13(s, 1H), 8.60(dd, 1H), 9.39(s, 1H)
    26-29
    Figure US20110098280A1-20110428-C00306
    MS 585 CDCl3: 0.97 (t, 3H), 1.89-1.65 (m, 8H), 2.03 (d, 2H), 2.20-2.10 (m, 1H), 2.68-2.58 (m, 4H), 2.78-2.72 (m, 2H), 3.12-3.08 (m, 2H), 3.61(d, 2H), 3.87(s, 3H), 6.47 (dd, 1H), 6.56(d, 1H), 7.30-7.23 (m, 2H), 7.64-7.60(m, 1H), 7.94(dd, 1H), 7.99 (dd, 1H), 8.13(s, 1H), 8.60(dd, 1H), 9.39 (s, 1H)
    26-30
    Figure US20110098280A1-20110428-C00307
    MS 451, 453 0.97 (t, 3H), 1.71-1.82 (m, 2H), 3.06-3.14 (m, 2H), 3.89 (s, 1H), 6.60 (ddd, 1H), 6.66 (dd, 1H), 7.25-7.30 (m, 1H), 7.35 (br.s, 1H), 7.63 (dd, 1H), 7.95 (dd, 1H), 8.09-8.18 (m, 1H), 8.17 (s, 1H), 8.52 (dd, 1H), 9.42 (s, 1H).
    26-31
    Figure US20110098280A1-20110428-C00308
    MS 647, 649 0.98 (t, 3H), 1.71-1.83 (m, 2H), 2.18 (s, 3H), 2.47-2.64 (m, 4H), 2.72-2.84 (m, 2H), 3.08-3.15 (m, 2H), 3.42- 3.54 (m, 2H), 3.58-3.69 (m, 2H), 3.84 (s, 3H), 3.94- 4.03 (m, 2H), 6.45-6.51 (m, 1H), 6.78 (d, 1H), 7.22- 7.27 (m, 1H), 7.60 (s, 1H), 7.67-7.74 (m, 1H), 7.93- 7.97 (m, 1H), 7.73 (d, 1H), 8.02 (s, 1H), 8.54 (d, 1H), 9.33 (s, 1H).
    26-32
    Figure US20110098280A1-20110428-C00309
    m.p. 139.4 400 MHz, CDCl3, δ (ppm): 0.98(t; 3H), 1.55-1.90 (m; 6H), 2.38 (s; 3H), 2.45-2.80 (m; 6H), 3.13 (m; 2H), 3.47 (m; 2H), 3.84 (s; 3H), 6.54 (dd; 1H), 6.79 (d; 1H), 7.23 (dd; 1H); 7.51 (s; 1H), 7.64 (dd: 1H), 7.92 (d; 1H), 8.00 (s; 1H), 8.19 (s; 1H), 8.57 (d; 1H), 9.41 (s; 1H).
    26-33
    Figure US20110098280A1-20110428-C00310
    m.p. 163.4 400 MHz, CDCl3, δ (ppm): 0.98 (t; 3H), 1.50-1.90 (m; 6H), 2.24 (bs; 1H), 2.45-2.65 (m; 6H), 3.12 (m; 2H), 3.45 (m; 2H), 3.77 (m; 4H9, 3.85(s; 3H), 6.55(dd; 1H); 6.79 (d; 1H), 7.24 (dd; 1H). 7.52 (s; 1H), 7.64 (dd; 1H), 7.93 (d; 1H), 8.01 (s; 1H), 8.20 (s; 1H9, 9.42 (s; 1H).
    26-34
    Figure US20110098280A1-20110428-C00311
    m.p. 232.9 400 MHz, CDCl3, δ (ppm): 1.00 (s; 3H), 1.78 (m; 2H), 2.83 (s; 3H), 3.03 (m; 2H), 3.12 (m; 2H), 3.38-3.60 (m; 8H), 3.88 (s; 3H), 6.56 (m; 1H), 6.82 (d; 1H), 7.29 (m; 1H), 7.60 (s; 1H), 7.64 (m; 1H), 7.95 (d; 1H), 8.12 (s; 1H), 8.20 (s; 1H), 8.59 (d; 1H), 9.50 (s; 1H).
    26-35
    Figure US20110098280A1-20110428-C00312
    m.p. 197.3 400 MHz, CDCl3, δ (ppm): 0.99 (t; 3H), 1.43 (m; 1H), 1.63 (m; 2H), 1.77 (m; 2H), 1.90 (m; 2H), 2.70 (m; 2H), 3.13 (m; 2H), 3.28 (m; 2H), 3.75 (s; 1H), 3.84 (s; 3H), 6.55 (m; 1H), 6.80 (d; 1H), 7.24 (m; 1H), 7.53 (s; 1H), 7.64 (s; 1H), 7.93 (d; 1H), 8.02 (s; 1H), 8.20 (s; 1H), 8.58 (d; 1H), 9.41 (s; 1H).
    26-36
    Figure US20110098280A1-20110428-C00313
    m.p. 147.6 400 MHz, CDCl3, δ (ppm): 1.00 (t; 3H), 1.78 (m; 2H), 3.12 (m; 2H), 3.56 (m; 1H), 3.87 (s; 3H), 6.53 (dd; 1H), 6.80 (d; 1H), 7.30 (dd; 1H), 7.52 (s; 1H), 7.64 (m; 1H), 7.95 (dd; 1H), 8.08 (s; 1H), 8.20 (s; 1H), 8.60 (d; 1H), 9.48(s; 1H).
    26-37
    Figure US20110098280A1-20110428-C00314
    m.p. 143.2 500 MHz, CDCl3, δ (ppm): 0.96 (t; 3H), 1.70 (m; 2H), 2.11 (m; 1H), 2.39 (m; 1H), 2.75 (s; 3H), 3.02 (m; 1H), 3.22 (m; 2H), 3.43 (d; 2H), 3.82 (s; 3H), 3.86 (m; 1H), 6.40 (dd; 1H), 6.94 (d; 1H), 7.34 (ddd; 1H), 7.47 (s; 1H), 7.63 (ddd; 1H), 7.93 (dd; 1H), 8.18 (s; 1H), 8.51 (d; 1H).
    26-38
    Figure US20110098280A1-20110428-C00315
    m.p. 133.5 400 MHz, CDCl3, δ (ppm): 1.00 (t; 3H), 1.70-1.95 (m; 6H), 2.63 (s; 1H), 2.92 (s; 1H), 3.00-3.25 (m; 5H), 3.89 (s; 3H), 5.42 (s; 1H), 6.70 (s; 1H), 6.83 (m; 2H), 7.25 (m; 1H), 7.55 (s; 1H), 7.63 (m; 1H9, 8.95 (m; 1H), 8.15 (s; 1H), 8.23 (s; 1H), 8.54 (d; 1H), 9.45 (s; 1H).
    26-39
    Figure US20110098280A1-20110428-C00316
    m.p. 188.8 400 MHz, CDCl3, δ (ppm): 0.99 (t; 3H), 1.70-1.90 (m; 3H), 2.08 (m; 1H), 2.28 (s; 6H9, 2.83 (s; 1H), 3.00- 3.23 (m; 4H9, 3.37 (m; 1H), 3.83 (s; 3H), 6.19 (dd; 1H), 6.83 (d; 1H), 7.23 (dd; 1H), 7.50 (s; 1H), 7.59 (m; 2H), 7.93 (d; 1H), 8.19 (s; 1H), 8.60 (d; 1H), 9.42 (s; 1H).
  • The following 5-Chloro-N2-(substituted phenyl)-N4-[2-ethanesulfonyl-phenyl]-pyrimidine-2,4-diamine are prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-ethanesulfonyl-phenyl]-amine and the corresponding aniline following the procedure of Example 7A
  • Figure US20110098280A1-20110428-C00317
    Expl Rf (solvent) NMR (400 MHz), δ (ppm) or
    No. Rx or MS Retention time min. (HPLC)
    27-1
    Figure US20110098280A1-20110428-C00318
    0.53 (AcOEt) CDCl3: 1.28(t, 3H), 3.12-3.19(m, 6H), 3.87-3.89(m, 7H), 6.45(dd, 1H), 6.53(d, 1H), 7.24-7.28(m, 1H), 7.31(s, 1H), 7.60-7.64(m, 1H), 7.95(dd, 1H), 8.04(d, 1H), 8.14(s, 1H), 8.58(d, 1H), 9.39(s, 1H)
    27-2
    Figure US20110098280A1-20110428-C00319
    585 (M + H) 2.38
    27-3
    Figure US20110098280A1-20110428-C00320
    486 (M + H) 3.07
    27-4
    Figure US20110098280A1-20110428-C00321
    587 (M + H) 2.29
    27-5
    Figure US20110098280A1-20110428-C00322
    545 (M + H) 2.59
    27-6
    Figure US20110098280A1-20110428-C00323
    545 (M + H) 2.45
    27-7
    Figure US20110098280A1-20110428-C00324
    531 (M + H) 2.25
    27-8
    Figure US20110098280A1-20110428-C00325
    545 (M + H) 2.45
    27-9
    Figure US20110098280A1-20110428-C00326
    600 (M + H) 2.17
    HPLC condition
    Column: YMC CombiScreen ODS-A (5 um, 12 nm), 50 x 4.6 mm I.D.
    Flow rate: 2.0 ml/min
    Eluent: A) TFA/water (0.1/100), B) TFA/acetonitrile (0.1/100)
    Gradient: 5-100% B (0-5 min)
    Detection: UV at 215 nm
  • The following 5-Chloro-N2-(substituted phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine are prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine and the corresponding aniline following the procedure of Example 7A
  • Figure US20110098280A1-20110428-C00327
    Expl Rf (solvent) NMR (400 MHz), δ (ppm) or
    No. Rx or MS Retention time min. (HPLC)
    28-1
    Figure US20110098280A1-20110428-C00328
    0.2 (AcOEt) CDCl3: 1.31 (d, 6H), 1.85-1.73 (m, 1H), 1.86-1.98 (m, 3H), 2.62-2.70 (m, 1H), 3.11-3.13 (m, 2H), 3.21-8.28 (m, 1H), 3.28 (m, 2H), 3.88 8 s, 3H), 5.41 (brs, 1H), 6.53 (d, 1H), 6.59 (d, 1H), 6.64 (brs, 1H), 7.28-7.34 (m, 1H), 7.34 (s, 1H), 7.60-7.67 (m, 1H), 7.91 (dd, 1H), 8.08 (d, 1H), 8.13 (s, 1H), 8.60 (d, 1H), 9.55 (s, 1H).
    28-2
    Figure US20110098280A1-20110428-C00329
    MS m/z 561, 563 (M + 1). CDCl3: 1.31 (d, 6H), 2.64 (t, 2H), 2.68-2.77 (m, 4H), 3.19 (t, 4H), 3.17-3.28 (m, 1H), 3.68 (t, 2H), 3.88 (s, 3H), 6.48 (dd, 1H), 6.55 (d, 1H), 7.23-7.32 (m, 1H), 7.62 (ddd, 1H), 7.91 (dd, 1H), 8.04 (dd, 1H), 8.12 (s, 1H), 8.60 (d, 1H), 9.54 (bs, 1H)
    28-3
    Figure US20110098280A1-20110428-C00330
    0.55 (AcOEt) CDCl3: 1.31 (d, 6H), 3.12-3.14 (m, 4H), 3.21-3.27 (m, 1H), 3.87-3.89 (m, 7H), 6.46 (dd, 1H), 6.53 (d, 1H), 7.23- 7.27 (m, 1H), 7.30 (s, 1H), 7.59-7.64 (m, 1H), 7.91 (dd, 1H), 8.05 (d, 1H), 8.14 (s, 1H), 8.60 (d, 1H), 9.55 (s, 1H)
    28-4
    Figure US20110098280A1-20110428-C00331
    0.37 (AcOEt) CDCl3: 1.32 (d, 6H), 3.21-3.27 (m, 1H), 4.00 (s, 1H), 7.11 (dd, 1H), 7.26-7.27 (m, 1H), 7.29-7.33 (m, 1H), 7.64 (s, 1H), 7.66-7.71 (m, 1H), 7.95 (dd, 1H), 8.10 (s, 1H), 8.21 (s, 1H), 8.46 (d, 1H), 8.50 (s, 1H), 8.54 (d, H), 9.59 (s, 1H)
    28-5
    Figure US20110098280A1-20110428-C00332
    0.03 (AcOEt) CDCl3: 1.31 (d, 6H), 1.67-1.77 (m, 2H), 1.95-2.05 (m, 2H), 2.39-2.48 (m, 1H), 2.48-2.61 (m, 2H), 2.63- 2.78 (m, 8H), 3.24 (sept, 1H), 3.71-3.63 (m, 2H), 3.87 (s, 3H), 6.47 (dd, 1H), 6.55 (d, 1H), 7.21-7.28 (m, 1H), 7.61 (ddd, 1H), 7.91 (dd, 1H), 8.00 (dd, 1H), 8.12 (s, 1H), 8.60 (d, 1H), 9.53 (bs, 1H)
    28-6
    Figure US20110098280A1-20110428-C00333
    502 (M + H) 2.84
    28-7
    Figure US20110098280A1-20110428-C00334
    478 (M + H) 4.53
    28-8
    Figure US20110098280A1-20110428-C00335
    MS 599 CDCl3: 1.31 (d, 6H), 1.51-1.42 (m, 2H), 1.67-1.53 (m, 4H), 1.81-1.68 (m, 2H), 1.96-1.89 (m, 2H), 2.47- 2.36 (m, 1H), 2.57-2.54 (m, 4H), 2.69 (dd, 2H) 3.24 (sept, 1H), 3.67 (d, 1H), 3.87 (s, 1H), 6.48 (dd, 1H), 6.56 (d, 1H), 7.31-7.21 (m, 1H), 7.63-7.59 (m, 1H), 8.00 (d, 1H), 8.12 (s, 1H), 8.60 (d, 1H), 9.55 (s, 1H)
    28-9
    Figure US20110098280A1-20110428-C00336
    MS 585 CDCl3: 1.26 (t, 3H), 1.31 (d, 6H), 1.74-1.68 (m, 2H), 1.85-1.76 (m, 4H), 2.08-1.98 (m, 2H), 2.19-2.10 (m, 2H), 2.67-2.58 (m, 4H), 2.79-2.72 (m, 2H), 3.24 (sept, 1H) 3.61 (d, 2H), 3.87 (s, 3H), 6.48 (dd, 1H), 6.56 (d, 1H), 7.29-7.22 (m, 1H), 7.62 (dd, 1H), 7.90 (dd, 1H), 7.99 (d, 1H), 8.12 (s, 1H), 8.60 (d, 1H), 9.53 (s, 1H)
    28-10
    Figure US20110098280A1-20110428-C00337
    MS 559 CDCl3: 1.31 (d, 6H), 1.59-1.37 (m, 2H), 1.81-1.69 (m, 1H), 1.87 (d, 2H), 2.73-2.67 (m, 2H), 3.28-3.21 (m, 1H), 3.37 (s, 3H), 3.61 (d, 1H), 3.87 (s, 3H), 6.49 (dd, 1H), 6.57 (s, 1H), 7.31-7.21 (m, 1H), 7.64-7.60 (m, 1H), 7.91 (dd, 1H), 8.00 (d, 1H), 8.60 (d, 1H) 9.53 (s, 1H)
    28-11
    Figure US20110098280A1-20110428-C00338
    MS 558 CDCl3: 1.31 (d, 6H), 2.15 (s, 3H), 3.12 (ddd, 4H), 3.24 (sept, 1H), 3.64 (t, 2H), 3.80 (t, 2H), 3.89 (s, 3H), 6.47 (dd, 1H), 6.55 (d, 1H), 7.29-7.24 (m, 1H), 7.33 (bs, 1H), 7.62 (m, 1H), 7.92 (dd, 1H), 8.08 (d, 1H), 8.14 (s, 1H), 8.60 (d, 1H) 9.55 (s, 1H)
    28-12
    Figure US20110098280A1-20110428-C00339
    MS 544 CDCl3: 1.16, (t, 3H), 1.31 (d, 6H), 2.56-2.44 (b, 2H), 2.71-2.60 (m, 4H), 3.28-3.17 (m, 5H), 3.88 (s, 3H), 6.48 (dd, 1H), 6.58 (d, 1H), 7.30-7.22 (m, 1H), 7.63- 7.58 (m, 1H), 7.90 (dd, 1H), 8.01 (d, 1H), 8.12 (s, 1H), 8.60 (d, 1H) 9.54 (s, 1H)
    28-13
    Figure US20110098280A1-20110428-C00340
    MS 601 CDCl3: 1.31 (d, 6H, J = 6.55), 1.75-1.63 (m, 2H), 2.00- 1.91 (m, 2H), 2.37-2.27 (m, 1H), 2.60 (t, 4H, J = 4.79), 2.74-2.59 (m, 2H), 3.24 (sept, 1H), 3.66 (d, 2H, J = 12.1), 3.75 (t, 4H, J = 4.53), 3.88 (s, 3H), 6.48 (dd, 1H, J = 2.52, 8.56), 6.56 (d, 1H, J = 2.52), 7.33-7.22 (m, 1H), 7.64-7.59 (m, 1H), 7.91 (dd, 1H, J = 8.05, 1.51), 8.01 (d, 1H, J = 8.56), 8.12 (s, 1H), 8.61 (d, 1H, J = 7.55) 9.54 (s, 1H)
    28-14
    Figure US20110098280A1-20110428-C00341
    MS 559 CDCl3: 1.11 (d, 6H, J = 6.55), 1.31 (d, 6H, J = 7.05), 2.82-2.68 (m, 5H), 3.20-3.17 (m, 4H), 3.28-3.17 (m, 1H), 3.87 (s, 3H), 6.48 (dd, 1H, J = 2.52, 8.56), 6.56 (d, 1H, J = 2.52), 7.33-7.24 (m, 1H), 7.62-7.58 (m, 1H), 7.90 (dd, 1H, J = ), 8.01 (d, 1H, J = 8.56), 8.12 (s, 1H), 8.60 (d, 1H, J = 8.56) 9.54 (s, 1H)
    28-15
    Figure US20110098280A1-20110428-C00342
    MS 559 CDCl3: 1.31 (d, 6H, J = 7.05), 1.97-1.85 (m, 2H), 2.17- 1.98 (m, 2H), 2.35-2.25 (m, 1H), 2.75 (m, 2H), 3.24 (sept, 1H), 3.65 (d, 2H), 3.88 (s, 3H), 5.30 (bs, 1H), 5.48 (bs, 1H), 6.48 (dd, 1H, J = 2.51, 8.56), 6.56 (d, 1H, J = 2.52), 7.33-7.21 (m, 1H), 7.62 (m, 1H), 7.91 (dd, 1H, J = 1.51, 8.06), 8.03 (dd, 1H, J = 3.02, 8.56), 8.13 (s, 1H), 8.60 (d, 1H, J = 8.57), 9.54 (s, 1H)
    28-16
    Figure US20110098280A1-20110428-C00343
    MS 532 CDCl3: 1.31 (d, 6H, J = 7.06), 1.46-1.43 (m, 1H), 1.79- 1.68 (m, 2H), 2.08-1.99 (m, 2H), 2.99-2.88 (m, 2H), 3.24 (sept, 1H), 3.51-3.45 (m, 2H), 3.91-3.80 (m, 1H), 3.88 (s, 3H), 6.49 (dd, 1H, J = 2.52, 8.56), 6.57 (d, 1H, J = 2.52), 7.34-7.23 (m, 1H), 7.64-7.60 (m, 1H), 7.91 (dd, 1H, J = 1.51, 8.06), 8.02 (dd, 1H, J = 3.02, 9.06), 8.13 (s, 1H), 8.60 (d, 1H, J = 8.06) 9.53 (s, 1H)
    28-17
    Figure US20110098280A1-20110428-C00344
    MS 532 CDCl3: 1.31 (d, 6H, J = 6.96), 2.18-2.12 (m, 2H), 3.24 (sept, 1H), 3.37-3.32 (m, 2H), 3.39 (s, 3H), 3.43 (d, 1H, J = 8.56), 3.51 (dd, 1H, J = 5.04, 10.6), 3.87 (s, 3H), 4.17-4.09 (m, 1H) 6.13 (dd, 1H, J = 2.51, 8.56), 6.16 (d, 1H, J = 2.52), 7.09 (bs, 1H), 7.31-7.21 (m, 1H), 7.60-7.56 (m, 1H), 7.85 (d, 1H, J = 8.56), 7.89 (dd, 1H, J = 1.51, 8.06), 8.10 (s, 1H), 8.65 (d, 1H, J = 9.06) 9.54 (s, 1H)
    28-18
    Figure US20110098280A1-20110428-C00345
    MS 546 CDCl3: 1.31 (d, 6H, J = 7.05), 1.82-1.70 (m, 2H), 2.08- 1.99 (m, 2H), 2.96-2.87 (m, 2H), 3.24 (sept, 1H), 3.41- 3.33 (m, 1H), 3.40 (s, 3H), 3.51-3.42 (m, 2H), 3.87 (s, 3H), 6.49 (dd, 1H, J = 2.52, 9.07), 6.57 (d, 1H, J = 2.52), 7.32-7.22 (m, 1H), 7.64-7.60 (m, 1H), 7.91 (dd, 1H,), 8.00 (dd, 1H, J = 3.02, 9.06), 8.12 (s, 1H), 8.60 (d, 1H, J = 8.56) 9.53 (s, 1H)
    28-19
    Figure US20110098280A1-20110428-C00346
    0.33 (AcOEt) CDCl3: 1.31 (d, 6H, J = 7.05), 1.82-1.70 (m, 2H), 2.08- 1.99 (m, 2H), 2.96-2.87 (m, 2H), 3.24 (sept, 1H), 3.41- 3.33 (m, 1H), 3.40 (s, 3H), 3.51-3.42 (m, 2H), 3.87 (s, 3H), 6.49 (dd, 1H, J = 2.52, 9.07), 6.57 (d, 1H, J = 2.52), 7.32-7.22 (m, 1H), 7.62 (m, 1H), 7.91 (dd, 1H,), 8.00 (dd, 1H, J = 3.02, 9.06), 8.12 (s, 1H), 8.60 (d, 1H, J = 8.56) 9.53 (s, 1H)
    28-20
    Figure US20110098280A1-20110428-C00347
    MS 544 CDCl3: 1.31 (d, 6H), 1.66-1.53 (m, 2H), 2.10-2.01 (m, 2H), 2.51 (s, 3H), 2.70-2.13 (m, 1H), 2.83-2.74 (m, 2H), 3.24 (Sept, 1H), 3.63-3.55 (m, 2H), 3.87 (s, 3H), 4.34- 4.25 (m, 1H), 6.48 (dd, 1H), 6.56 (d, 1H), 7.34-7.24 (m, 1H), 7.64-7.60 (m, 1H), 7.90 (dd, 1H), 8.00 (d, 1H), 8.12 (s, 1H), 8.60 (dd, 1H), 9.53 (s, 1H)
    28-21
    Figure US20110098280A1-20110428-C00348
    MS 531 CDCl3: 1.30 (s, 3H), 1.32 (s, 3H), 2.33-2.22 (m, 1H), 2.54 (s, 3H), 3.37-3.20 (m, 3H), 3.57-3.44 (m, 3H), 3.86 (s, 3H), 6.12 (dd, 1H), 6.16 (d, 1H), 7.14-7.08 (m, 1H), 7.30-7.20 (m, 1H), 7.65-7.58 (m, 1H), 7.93-7.87 (m, 1H,), 8.10 (s, 1H), 8.64 (d, 1H) 9.54 (s, 1H)
    28-22
    Figure US20110098280A1-20110428-C00349
    MS 545 CDCl3: 1.30 (s, 3H), 1.32 (s, 3H), 2.03-1.89 (m, 1H), 2.30-2.18 (m, 1H), 2.34 (s, 6H), 2.96-2.83 (m, 1H), 3.29-3.16 (m, 2H), 3.40-3.34 (m, 1H), 3.53-3.43 (m, 2H), 3.87 (s, 3H), 6.11 (dd, 1H,) 6.13 (dd, 1H), 7.08 (bs, 1H), 7.31-7.21 (m, 1H), 7.60-7.56 (m, 1H), 7.85 (d, 1H), 7.89 (dd, 1H), 8.10 (s, 1H), 8.66 (d, 1H) 9.54 (s, 1H)
    28-23
    Figure US20110098280A1-20110428-C00350
    MS 545 CDCl3: 1.31 (s, 3H), 1.32 (s, 3H), 3.05 (s, 3H), 3.24 (sept, 1H), 3.50-3.43 (m, 4H), 3.85 (s, 2H), 3.89 (s, 3H), 6.11 (dd, 1H,) 6.43 (dd, 1H), 6.50 (d, 1H), 7.31- 7.28 (m, 1H), 7.64-7.60 (m, 1H), 7.92 (dd, 1H), 8.09 (d, 1H), 8.13 (s, 1H), 8.58 (d, 1H) 9.55 (s, 1H)
    28-24
    Figure US20110098280A1-20110428-C00351
    0.05 (AcOEt/ MeOH = 4/1) CDCl3: 1.30 (s, 3H), 1.32 (s, 3H), 1.92-1.83 (m, 1H), 2.17-1.95 (m, 1H), 2.43-2.27 (m, 2H), 2.79-2.71 (m, 4H), 3.15-2.97 (m, 4H), 3.23-3.16 (m, 4H), 3.24 (sept, 1H), 3.87 (s, 3H), 6.11 (dd, 1H,) 6.47 (dd, 1H), 6.55 (d, 1H), 7.33-7.23 (m, 1H), 7.63-7.59 (m, 1H), 7.95 (dd, 1H), 8.01 (dd, 1H), 8.12 (s, 1H), 8.60 (d, 1H) 9.54 (s, 1H)
    28-25
    Figure US20110098280A1-20110428-C00352
    MS 600 CDCl3: 1.30 (s, 3H), 1.32 (s, 3H), 1.80-1.70 (m, 2H), 2.01-1.93 (m, 2H), 2.49-2.28 (m, 12H), 2.76- 2.62 (m, 4H), 3.04-2.96 (m, 4H), 3.16-3.05 (m, 2H), 3.24 (sept, 1H), 3.72-3.63 (m, 2H), 3.87 (s, 3H), 6.48 (dd, 1H), 6.55 (d, 1H), 7.31-7.23 (m, 1H), 7.66- 7.589 (m, 1H), 7.91 (dd, 1H), 8.01 (d, 1H), 8.12 (s, 1H), 8.60 (d, 1H) 9.53 (s, 1H)
    28-26
    Figure US20110098280A1-20110428-C00353
    MS 573 CDCl3: 1.30 (s, 3H), 1.32 (s, 3H), 2.59-2.43 (m, 4H), 2.78-2.73 (m, 1H), 3.00-2.86 (m, 2H), 3.38-3.20 (m, 3H), 3.54-2.45 (m, 1H), 3.73 (dd, 1H), 3.84-3.77 (m, 1H), 3.94-3.87 (m, 1H), 3.88 (s, 3H), 6.46 (dd, 1H), 6.53 (d, 1H), 7.32-7.23 (m, 1H), 7.31 (bs, 1H), 7.63-7.52 (m, 1H), 7.91 (dd, 1H), 8.04 (d, 1H), 8.13 (s, 1H), 8.60 (d, 1H) 9.54 (s, 1H)
    28-27
    Figure US20110098280A1-20110428-C00354
    MS 559 CDCl3: 1.30 (s, 3H), 1.32 (s, 3H), 1.82-1.73 (m, 1H), 1.97-1.84 (m, 3H), 2.73-2.51 (m, 1H), 3.12 (t, 2H), 3.31-3.20 (m, 3H), 3.90 (s, 3H), 5.46-5.37 (m, 1H), 6.53 (dd, 1H), 6.59 (d, 1H), 6.68-6.62 (m, 1H), 7.28- 7.21 (m, 1H), 7.33 (bs, 1H), 7.65-7.61 (m, 1H), 7.92 (dd, 1H), 8.08 (d, 1H), 8.14 (s, 1H), 8.60 (d, 1H), 9.55 (s, 1H)
    28-28
    Figure US20110098280A1-20110428-C00355
    MS 559 CDCl3: 1.30 (s, 3H), 1.32 (s, 3H), 1.82-1.73 (m, 1H), 1.97-1.84 (m, 3H), 2.73-2.51 (m, 1H), 3.12 (t, 2H), 3.31-3.20 (m, 3H), 3.90 (s, 3H), 5.46-5.37 (m, 1H), 6.53 (dd, 1H), 6.59 (d, 1H), 6.68-6.62 (m, 1H), 7.28- 7.21 (m, 1H), 7.33 (bs, 1H), 7.65-7.61 (m, 1H), 7.92 (dd, 1H), 8.08 (d, 1H), 8.14 (s, 1H), 8.60 (d, 1H), 9.55 (s, 1H)
    28-29
    Figure US20110098280A1-20110428-C00356
    MS 413 CDCl3: 1.31 (s, 3H), 1.33 (s, 3H), 2.92 (t, 4H), 3.28 (sept, 1H) 3.73 (t, 4H), 3.87 (s, 3H), 6.51 (dd, 1H), 6.82 (d, 1H), 7.32-7.23 (m, 1H), 7.57 (bs, 1H), 7.70- 7.64 (m, 1H), 7.92 (dd, 1H), 8.01 (bs, 1H), 8.12 (s, 1H), 8.60 (d, 1H), 9.53 (s, 1H)
    28-30
    Figure US20110098280A1-20110428-C00357
    MS 493 CDCl3: 1.30 (s, 3H), 1.33 (s, 3H), 3.25 (sept, 1H) 3.60 (bs, 3H), 3.89 (s, 3H), 6.59 (s, 1H), 7.27-7.18 (m, 1H), 7.61 (dd, 1H), 7.83 (bs, 1H), 7.90 (dd, 1H), 8.15 (s, 1H), 8.55 (d, 1H), 9.55 (s, 1H)
    28-31
    Figure US20110098280A1-20110428-C00358
    MS 445 CDCl3: 1.31 (d, 6H), 1.59-1.37 (m, 2H), 1.81-1.69 (m, 1H), 1.87 (d, 2H), 2.73-2.67 (m, 2H), 3.28-3.21 (m, 1H), 3.37 (s, 3H), 3.61 (d, 1H), 3.87 (s, 3H), 6.49 (dd, 1H), 7.025 (bs, 1H), 7.28-7.23 (m, 1H), 7.64-7.59 (m, 1H), 7.93-7.89 (m, 2H), 8.15 (s, 1H), 8.57 (dd, 1H) 9.56 (s, 1H)
  • Figure US20110098280A1-20110428-C00359
    HPLC
    Expl Retention Mass (ESI)
    No. Rx time (min) m/z
    29-1
    Figure US20110098280A1-20110428-C00360
    3.30 546 (M + H)
    29-2
    Figure US20110098280A1-20110428-C00361
    2.82 627 (M + H)
    29-3
    Figure US20110098280A1-20110428-C00362
    3.07 587 (M + H)
  • Figure US20110098280A1-20110428-C00363
    HPLC
    Expl Retention Mass (ESI)
    No. Rx time (min) m/z
    30-1
    Figure US20110098280A1-20110428-C00364
    2.82 516 (M + H)
    30-2
    Figure US20110098280A1-20110428-C00365
    2.65 557 (M + H)
    30-3
    Figure US20110098280A1-20110428-C00366
    2.50 557 (M + H)
    30-4
    Figure US20110098280A1-20110428-C00367
    3.10 498 (M + H)
    30-5
    Figure US20110098280A1-20110428-C00368
    2.30 543 (M + H)
    30-6
    Figure US20110098280A1-20110428-C00369
    2.52 557 (M + H)
    30-7
    Figure US20110098280A1-20110428-C00370
    2.23 612 (M + H)
  • Figure US20110098280A1-20110428-C00371
    HPLC
    Expl Retention Mass (ESI)
    No. Rx time (min) m/z
    31-1
    Figure US20110098280A1-20110428-C00372
    3.15 423 (M + H)
    31-2
    Figure US20110098280A1-20110428-C00373
    2.62 490 (M + H)
  • Figure US20110098280A1-20110428-C00374
    Expl
    No. Rx MS NMR (400 MHz) in CDCl3, δ (ppm)
    32-1
    Figure US20110098280A1-20110428-C00375
    585.3 1.03 (s, 3H), 1.04 (s, 3H), 2.15 (s, 3H), 2.32 (sept, 1H) 3.00 (d, 2H) 3.10 (t, 2H), 3.13 (t, 2H), 3.64 (t, 2H), 3.79 (t, 2H), 3.89 (s, 3H), 6.45 (dd, 1H), 6.55 (d, 1H), 7.34-7.26 (m, 1H), 7.52 (bs, 1H), 7.64-7.60 (m, 1H), 7.97 (dd, 1H), 8.07 (d, 1H), 8.15 (s, 1H), 8.54 (d, 1H), 9.32 (s, 1H)
    32-2
    Figure US20110098280A1-20110428-C00376
    532   (M + H) 3.17
  • Figure US20110098280A1-20110428-C00377
    Expl
    No. Rx MS NMR (400 MHz) in CDCl3, δ (ppm)
    33-1
    Figure US20110098280A1-20110428-C00378
    585.3 1.66-1.52 (m, 2H), 1.92-1.73 (m, 4H), 2.12-2.03 (m, 2H), 2.15 (s, 3H), 3.00 (d, 2H) 3.11 (t, 2H), 3.14 (t, 2H), 3.58-3.46 (m, 1H), 3.64 (t, 2H), 3.80 (t, 2H), 3.89 (s, 3H), 6.48 (dd, 1H), 6.55 (d, 1H), 7.30-7.24 (m, 1H), 7.52 (bs, 1H), 7.63-7.58 (m, 1H), 7.94 (dd, 1H), 8.08 (d, 1H), 8.14 (s, 1H), 8.60 (d, 1H), 9.54 (s, 1H)
    33-2
    Figure US20110098280A1-20110428-C00379
    544   (M + H) 3.15
  • Figure US20110098280A1-20110428-C00380
    HPLC
    Expl Retention Mass (ESI)
    No. Rx time (min) m/z
    34-1
    Figure US20110098280A1-20110428-C00381
    3.15 532 (M + H)
    34-2
    Figure US20110098280A1-20110428-C00382
    3.34 558 (M + H)
    34-3
    Figure US20110098280A1-20110428-C00383
    3.35 546 (M + H)
    34-4
    Figure US20110098280A1-20110428-C00384
    3.32 546 (M + H)
    34-5
    Figure US20110098280A1-20110428-C00385
    3.09 566 (M + H)
    34-6
    Figure US20110098280A1-20110428-C00386
    2.87 552 (M + H)
    Ex
    No MS NMR (400 MHz), CDCl3, δ ppm
    34-7
    Figure US20110098280A1-20110428-C00387
    MS 435, 436 1.05 (t, 3H), 1.69-1.78 (m, 2H), 2.86-2.95 (m, 1H), 3.16-3.25 (m, 1H), 6.57-6.68 (m, 2H), 7.17 (dd, 1H), 7.35-7.39 (m, 1H), 7.50 (dd, 1H), 8.13 (s, 1H), 8.16-8.21 (m, 1H), 8.48 (d, 1H), 10.14 (s, 1H)
    34-8
    Figure US20110098280A1-20110428-C00388
    MS 549, 551 0.94 (t, 3H), 1.69-1.80 (m, 2H), 2.38 (s, 3H), 2.55-2.64 (m, 4H), 3.02-3.08 (m, 2H), 3.22-3.29 (m, 4H), 3.88 (s, 3H), 6.55 (ddd, 1H), 6.60-6.66 (m, 1H), 7.13-7.18 (m, 1H), 7.34 (br.s, 1H), 7.44 (d, 1H), 8.10 (s, 1H), 8.10-8.23 (m, 2H), 8.88 (s, 1H).
  • Figure US20110098280A1-20110428-C00389
    35-1
    Figure US20110098280A1-20110428-C00390
    567 [M + 1]+ DMSO-d6: 2.24 (s, 3H), 2.45-2.50 (m, 4H), 2.78 (d, 3H), 3.10-3.17 (m, 8H), 3.74-3.79 (m, 7H), 6.49 (dd, 1H), 6.66 (d, 1H), 6.85-6.89 (m, 1H), 7.18 (d, 1H), 7.40 (d, 1H), 7.98-8.02 (m, 2H), 8.29 (br.d, 1H), 8.60-8.66 (m, 1H), 11.17 (s, 1H).
    35-2
    Figure US20110098280A1-20110428-C00391
    505 [M + 1]+ DMSO-d6: 2.24 (s, 3H), 2.46-2.50 (m, 4H), 2.79 (d, 3H), 3.13-3.17 (m, 4H), 3.78 (s, 3H), 6.69 (d, 1H), 6.87 (dd, 1H), 7.07-7.17 (m, 2H), 7.19-7.23 (m, 2H), 7.54 (d, 1H), 8.13 (s, 1H), 8.45 (s, 1H), 8.65-8.75 (m, 1H), 9.04 (s, 1H), 11.19 (s, 1H)
  • Example 36 Intermediates for Left Anilines 36-1 Preparation of 2-amino-N-methyl-benzamide
  • Figure US20110098280A1-20110428-C00392
  • To a suspension of 16.3 g (100 mmol) of isatoic anhydride in 100 mL of H2O is added portionwise 100 mL of 2N methylamine-tetrahydrofuran solution (200 mmol) at room temperature. The reaction mixture is stirred for 1 hour and then extracted with AcOEt. The organic layer is washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to give 13.79 g of desired product, 2-amino-N-methyl-benzamide (92 mmol, 92%) as colorless solid.
  • NMR (400 MHz, CDCl3, δ): 2.97 (d, 3H, J=4.52 Hz), 5.49 (bs, 1H), 6.07 (bs, 1H), 6.64 (ddd, 1H, J=8.04, 7.56, 1.0 Hz), 6.68 (dd, 1H, J=8.32, 1.0 Hz), 7.20 (ddd, 1H, J=8.32, 7.56, 1.52 Hz), 7.29 (dd, 1H, J=8.04, 1.52 Hz).
  • 36-2 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide
  • Figure US20110098280A1-20110428-C00393
  • To a solution of 15.0 g (99.8 mmol) of 2-amino-N-methyl-benzamide in DMF (300 mL) are added 2,4,5-trichloropyrimidine (23.8 g, 130 mmol) and potassium carbonate (17.9 g, 130 mmol). The reaction mixture is stirred at 75° C. for 5 hours, cooled to room temperature, and then poured into H2O (600 mL). The resulting precipitate is collected by a filtration followed by washing with 50% aqueous CH3CN (200 mL) and dried under reduced pressure (40° C., 10 hours) to give desired 2-(2,5-dichloro-pyrimidin-4-yl-amino)-N-methyl-benzamide as ivory solid (26.4 g, 88.9 mmol, 89%).
  • NMR (400 MHz, DMSO-d6, δ): 2.81 (d, 3H, J=4.52 Hz), 7.22 (dd, 1H, J=8.56, 8.04 Hz), 7.60 (ddd, 1H, J=8.56, 8.56, 1.0 Hz), 7.81 (dd, 1H, J=8.04, 1.0 Hz), 8.48 (s, 1H), 8.52 (d, 1H, J=8.56 Hz) 8.80-8.90 (m, 1H), 12.18 (s, 1H).
  • According the manner described above, the following compounds are prepared.
  • 36-3 2-(5-Bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzamide
  • Figure US20110098280A1-20110428-C00394
  • NMR (400 MHz, DMSO-d6, δ): 2.81 (d, 3H), 7.23 (ddd, 1H, J=7.54, 7.54, 1.0 Hz), 7.59 (ddd, 1H, J=7.93, 8.06, 1.52 Hz), 7.79 (dd, 1H, J=7.8, 1.52 Hz), 8.47 (dd, 1H J=8.06, 1.0 Hz), 8.55 (s, 1H), 8.81-8.87 (m, 1H), 12.0 (brs, 1H). Rf: 0.46 (n-Hexane:AcOEt=7:3).
  • 36-4 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide
  • Figure US20110098280A1-20110428-C00395
  • NMR (400 MHz, CDCl3, δ): 1.28 (t, d=7.04, 3H), 3.48-3.57 (m, 2H), 6.22 (br. s, 1H), 7.11-7.17 (m, 1H), 7.51 (dd, J=1.0, 8.04, 1H), 7.53-7.61 (m, 1H), 8.22 (s, 1H), 8.69-8.74 (m, 1H), 11.66 (br. s, 1H). Rf: 0.60 (Hexane:AcOEt=1:1).
  • 36-5 Preparation of 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide
  • Figure US20110098280A1-20110428-C00396
  • A suspension of 5-bromo-2,4-dichloropyrimidine (684 mg, 3.0 mmol) and 2-amino-N-methyl-benzenesulfonamide (559 mg, 3.0 mmol) in N,N-dimethylformamide (10 mL) containing potassium carbonate (830 mg, 6.0 mmol) is stirred at room temperature for 23 hours. Saturated aqueous ammonium chloride is added and the mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane-ethyl acetate gradient) to afford the title compound as a slightly yellow solid.
  • 1H-NMR (CDCl3), δ (ppm): 2.67 (d, 3H), 4.79 (q, 1H), 7.26 (s, 1H), 7.29 (ddd, 1H), 7.66 (ddd, 1H), 7.95 (dd, 1H), 8.37 (s, 1H), 8.48 (d, 1H), 9.52 (s, 1H). Rf (n-hexane:ethyl acetate=10:3): 0.33.
  • According to the manner described above, the following compound is prepared.
  • 36-6 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide
  • Figure US20110098280A1-20110428-C00397
  • 1H-NMR (400 MHz, CDCl3, δ); 2.67 (d, 3H), 4.97-5.04 (m, 1H), 7.29 (ddd, 1H, J=7.54, 7.54, 1.0 Hz), 7.66 (ddd, 1H, J=7.93, 8.08, 1.48 Hz), 7.94 (dd, 1H, J=8.04, 1.52 Hz), 8.24 (s, 1H), 8.51 (dd, 1H J=8.06, 1.0 Hz), 9.64 (brs, 1H). Rf: 0.45 (n-Hexane:AcOEt=4:1).
  • 36-7 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-isopropyl-benzenesulfonamide
  • Figure US20110098280A1-20110428-C00398
  • To a solution of 2-amino-N-isopropyl-benzenesulfonamide (16.1 g, 75.1 mmol) in DMI (150 mL) is added sodium hydride (6.6 g, 165.3 mmol) portionwise at 0° C. After the mixture is stirred at room temperature for one hour, 2,4,5-trichloropyrimidine (20.7 g, 112.7 mmol) is added at 0° C. After further stirring at room temperature for 5 hrs, water is added and the mixture is extracted with AcOEt three times. Organic layer is washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by silica gel column chromatography (Hexane to Hexane:AcOEt=4:1) to afford the title compound as pale brown solid (10.2 g, 38%).
  • 1H-NMR (400 MHz, CDCl3, δ); 1.06 (d, 6H), 3.43-3.53 (m, 1H), 4.38 (d, 1H), 7.29 (dd, 1H), 7.66 (dd, 1H), 7.98 (d, 1H), 8.29 (s, 1H), 8.51 (d, 1H), 9.51 (brs, 1H). Rf: 0.45 (n-Hexane:AcOEt=4:1)
  • The following compounds are prepared in the same manner described above.
  • Figure US20110098280A1-20110428-C00399
    Expl Rf (solvent)
    No. Rz or MS NMR (400 MHz), δ (ppm)
    36-8
    Figure US20110098280A1-20110428-C00400
    0.45 (n-Hexane: AcOEt = 4:1) DMSO-d6; 0.63 (t, 6H), 0.86 (d, 3H), 1.21-1.31 (m, 2H), 3.02-3.12 (m, 1H), 7.37 (dd, 1H), 7.71 (d, 1H), 7.85 (d, 1H), 7.89 (d, 1H), 8.20 (d, 1H), 8.56 (s, 1H), 9.51 (brs, 1H)
    36-9
    Figure US20110098280A1-20110428-C00401
    0.46 (n-Hexane: AcOEt = 7:3) CDCl3; 0.70 (t, 6H), 1.23-1.45 (m, 4H), 3.03-3.13 (m, 1H), 4.27 (d, 1H), 7.27 (dd, 1H), 7.65 (dd, 1H), 7.98 (d, 1H), 8.29 (s, 1H), 8.52 (d, 1H), 9.59 (brs, 1H)
  • 36-10 Preparation of 2-(2-chloro-5-nitro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide
  • Figure US20110098280A1-20110428-C00402
  • 2,4-Dichloro-5-nitro-pyrimidine (1.94 g, 10 mmol) and 2-amino-N-methyl-benzenesulfonamide (1.86 g, 10 mmol) are dissolved in CHCl3 (30 mL). The reaction mixture is heated at 61° C. for 2 h. The solvent is evaporated and the residue is washed with ether to give the title product.
  • Rf=0.5 (n-hexane:ethyl acetate=1:1). 1H-NMR (400 MHz, CDCl3), δ (ppm): 2.67 (d, 3H), 4.6-4.7 (m, 2H), 7.41 (t, 1H), 7.7 (t, 1H), 8.04 (d, 1H), 8.15 (d, 1H), 9.21 (s, 1H), 11.2 (s, 1H).
  • 36-11 Preparation of (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-1-sulfonyl)-phenyl]-amine
  • Figure US20110098280A1-20110428-C00403
  • To a solution of 2-(Propane-1-sulfonyl)-phenylamine (3.69 g, 18.5 mmol) of N,N-dimethylformamide (40 mL), sodium hydride (1.48 g, 37 mmol) is added portionwise at 0° C. After stirring, 2,4,5-trichloropyrimidine (2.1 mL, 18.5 mmol) is added. The mixture is stirred at 0° C. for 30 minutes and is further stirred at room temperature for 7 hrs. After adding saturated aqueous ammonium chloride, the mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane-ethyl acetate gradient) to afford the title compound as colorless solids.
  • 1H-NMR (CDCl3), δ (ppm): 0.99 (t, 3H), 1.77 (d, 2H), 3.07-3.11 (m, 2H), 7.26 (s, 1H), 7.32 (ddd, 1H), 7.73 (ddd, 1H), 7.95 (dd, 1H), 8.31 (s, 1H), 8.61 (dd, 1H), 9.94 (bs, 1H). Rf (n-hexane:ethyl acetate=3:1): 0.63
  • According to the manner described above, the following compounds are prepared.
  • Figure US20110098280A1-20110428-C00404
    Expl
    No. Rx Identification
    36-12
    Figure US20110098280A1-20110428-C00405
    1H-NMR (CDCl3), δ (ppm): 1.35 (d, 6H), 3.18-3.24 (m, 1H), 7.30-7.34 (m, 1H), 7.70-7.75 (m, 1H), 7.92 (dd, 1H), 8.30 (s, 1H), 8.63 (d, 1H), 10.06 (s, 1H). Rf 0.70: (AcOEt)
    36-13
    Figure US20110098280A1-20110428-C00406
    NMR (400 MHz) in CDCl3, δ (ppm): 1.29 (t, 3H), 3.15 (q, 1H), 7.31-7.35 (m, 1H), 7.71-7.75 (m, 1H), 7.96 (dd, 1H), 8.31 (s, 1H), 8.60 (d, 1H), 9.92 (s, 1H). Rf: 0.67 (AcOEt).
    36-14
    Figure US20110098280A1-20110428-C00407
    1.01-1.06 (m, 2H), 1.32-1.37 (m, 2H), 2.49-2.55 (m, 1H), 7.29-7.33 (m, 1H), 7.69-7.73 (m, 1H), 7.91 (dd, 1H), 8.31 (s, 1H), 8.58 (d, 1H), 9.90 (s, 1H). Rf 0.69 (AcOEt)
    36-15
    Figure US20110098280A1-20110428-C00408
    0.99 (t, 6H), 1.72-1.90 (m, 4H), 2.76-2.82 (m, 1H), 7.26-7.34 (m, 1H), 7.69-7.74 (m, 1H), 7.92 (dd, 1H), 8.30 (s, 1H), 8.62 (d, 1H), 10.02 (s, 1H). Rf: 0.73 (AcOEt)
  • Example 36-16 Synthesis of Substituted Amines which are Commercially not Available Preparation of 3-amino-4′-methoxy-4-methylbiphenyl
  • To a solution of 4-methoxyphenyl-boronic acid (500 mg, 3.29 mmol) in toluene (5.2 mL) and ethanol (1.3 mL), potassium carbonate (910 mg, 6.58 mmol), tetrakis(triphenylphosphine)-palladium (228.1 mg, 0.099 mmol) and 4-bromo-1-methyl-2-nitrobenzene (711 mg, 3.29 mmol) are added and stirred at 100° C. for 7 hours. The mixture is poured into water and extracted with ethyl acetate two times. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1) to afford the 4′-methoxy-4-methyl-3-nitro-biphenyl as a yellow solid.
  • 1H-NMR (δ, ppm): 2.62 (s, 3H), 3.86 (s, 3H), 7.02-6.98 (m, 2H), 7.37 (d, 1H), 7.54 (dd, 2H), 7.68 (dd, 1H), 8.18 (d, 1H). Rf (hexane:ethyl acetate=3:1): 0.40.
  • A suspension of 4′-methoxy-4-methyl-3-nitrobiphenyl (630 mg, 2.95 mmol) and 10% palladium on charcoal (63 mg, 0.059 mmol) in methanol (6 mL) is stirred under hydrogen atmosphere for 12 hours. Palladium catalyst is removed by filtration and the resulting solution is evaporated in vacuo to afford the title compound.
  • 1H-NMR (δ, ppm): 2.20 (s, 3H), 3.84 (s, 3H), 6.87 (d, 1H), 6.89 (dd, 1H), 6.95 (d, 2H), 7.09 (d, 1H), 7.48 (d, 2H). Rf (n-hexane:ethyl acetate=1:1): 0.50.
  • Preparation of 4-(3-amino-4-methylbenzoyl)-piperazine-1-carboxylic acid tert-butyl ester
  • To a solution of 4-methyl-3-nitro-benzoic acid (300 mg, 2.76 mmol), N-butoxycarbonyl-piperazine (340 mg, 1.83 mmol) in DMF (3.0 mL), triethylamine (300 μL, 3.59 mmol), TBTU (800 mg, 2.49 mmol) and HOAt (270.5 mg, 1.99 mmol) are added and stirred at room temperature for 24 hours. The mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1) to afford 4-(4-methyl-3-nitrobenzoyl)-piperazine-1-carboxylic acid tert-butyl ester as a colorless solid.
  • 1H-NMR (δ, ppm): 1.47 (s, 9H), 2.64 (s, 3H), 3.28-3.88 (m, 8H), 7.42 (d, 1H), 7.56 (dd, 1H), 8.03 (d, 1H). Rf (hexane:ethyl acetate=10:1): 0.13.
  • The title compound is obtained by reduction with hydrogen over 10% palladium on charcoal in methanol solution.
  • Preparation of 4-(3-amino-4-methylphenyl)-morpholine
  • To a solution of 4-bromo-1-methyl-2-nitrobenzene (225 mg, 1.04 mmol), morpholine (125 μL, 1.25 mmol), and cesium carbonate (474.4 mg, 1.46 mmol) in toluene, palladium diacetate (31.2 mg, 0.139 mmol) and 2-(di-t-butylphosphino)biphenyl (125 mg, 0.403 mmol) are added and stirred at 100° C. for 5 hours. After cooling, the mixture is filtered to remove insoluble material. The filtrate is poured into water and extracted with ethyl acetate twice. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1) to afford 4-(4-methyl-3-nitrophenyl)-morpholine as a yellow solid.
  • 1H-NMR (δ, ppm): 2.50 (s, 3H), 3.17-3.19 (m, 4H), 3.86-3.88 (m, 4H), 7.04 (dd, 1H), 7.21 (d, 1H), 7.47 (d, 1H). Rf (hexane:ethyl acetate=5:1): 0.20.
  • The title compound is obtained by reduction with hydrogen over 10% palladium on charcoal in methanol solution.
  • Example 37 Synthesis of Substituted Amines which are Commercially not Available 37-1 Preparation of 1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-ol
  • Figure US20110098280A1-20110428-C00409
  • To a suspension of piperidin-4-ol (2.79 g, 28 mmol) and potassium carbonate (3.88 g, 28 mmol) in N,N-dimethylformamide (40 mL), 4-Fluoro-2-methoxy-1-nitro-benzene (4.0 g, 23 mmol) is added and stirred at room temperature for 24 hours. The mixture is poured into water and the precipitate is collected by a filtration. The resulting solid is dried in vacuo at 50° C. to afford 1-(3-methoxy-4-nitro-phenyl)-piperidin-4-ol (5.23 g) as yellow solids in 89% yield.
  • 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.54 (d, 1H), 1.62-1.71 (m, 2H), 1.98-2.04 (m, 2H), 3.22 (ddd, 4H), 3.73-3.80 (m, 2H), 3.95 (s, 3H), 3.98-4.02 (m, 1H), 6.33 (d, 1H), 6.43 (dd, 1H), 8.00 (d, 1H).
  • By repeating the procedures described above using appropriate starting materials and conditions the following compounds are obtained.
  • Ex-No Rx Identification
    37-2
    Figure US20110098280A1-20110428-C00410
    1H-NMR (400 MHz, CDCl3, δ, ppm): 1.53-1.72 (m, 2H), 1.80-1.83 (m, 4H), 1.99-2.04 (m, 2H), 2.24-2.31 (m, 1H), 2.54-2.67 (m, 4H), 3.03 (dt, 2H), 3.84-3.89 (m, 2H), 3.95 (s, 3H), 6.31 (d, 1H), 6.42 (dd, 1H), 8.01 (d, 1H). Rf 0.54 (AcOEt)
    37-3
    Figure US20110098280A1-20110428-C00411
    1H-NMR (400 MHz, CDCl3, δ, ppm): 1.81-1.91 (m, 2H), 1.99-2.04 (m, 2H), 2.38-2.48 (m, 1H), 3.03 (ddd, 2H), 3.91-3.96 (m, 2H), 3.95 (s, 3H), 5.22-5.41 (m, 1H), 5.40-5.53 (m, 1H), 6.36 (d, 1H), 6.43 (dd, 1H), 8.00 (d, 1H). Rf 0.15 (AcOEt)
    37-4
    Figure US20110098280A1-20110428-C00412
    1H-NMR (400 MHz, CDCl3, δ, ppm): 1.15 (t, 3H), 1.88-1.96 (m, 1H), 2.22-2.30 (m, 1H), 2.68-2.77 (m, 2H), 3.15-3.18 (m, 1H), 3.38-3.44 (m, 1H), 3.52-3.62 (m, 2H), 3.93 (s, 3H), 5.92 (d, 1H), 6.07-6.10 (m, 1H), 8.00-8.02 (m, 1H). Rf 0.65 (n- hexane:AcOEt = 1:1).
    37-5
    Figure US20110098280A1-20110428-C00413
    1H-NMR (400 MHz, CDCl3, δ, ppm): 2.36 (s, 3H), 2.52-2.57 (m, 4H), 3.40-3.43 (m, 4H), 3.95 (s, 3H), 6.32 (d, 1H, J = 2.52 Hz), 6.43 (dd, 1H, J = 9.56, 2.52 Hz), 7.99 (d, 1H, J = 9.08 Hz). Rf 0.60 (MeOH:CH2Cl2 = 4:1).
    37-6
    Figure US20110098280A1-20110428-C00414
    1H-NMR (400 MHz, CDCl3, δ, ppm): 1.10-1.19 (m, 1H), 1.59-2.18 (m, 6H), 2.28 (s, 3H), 2.71-2.74 (m, 1H), 2.88-2.91 (m, 1H), 3.86-3.95 (m, 5H), 6.47-6.52 (m, 2H), 7.97-8.00 (m, 1H). Rf 0.65 (n- hexane:AcOEt = 1:1)
    37-7
    Figure US20110098280A1-20110428-C00415
    1H-NMR (400 MHz, CDCl3, δ, ppm): 4.08 (s, 3H), 7.30 (dd, 1H), 7.58 (d, 1H), 8.05 (d, 1H), 8.15 (s, 1H), 8.67 (s, 1H). Rf: 0.42 (AcOEt)
    37-8
    Figure US20110098280A1-20110428-C00416
    1H-NMR (400 MHz, CDCl3, δ, ppm): 1.40-1.50 (m, 2H), 1.55-1.69 (m, 6H), 1.90-1.96 (m, 2H), 2.45-2.53 (m, 5H), 2.90-2.99 (m, 2H), 3.90-4.00 (m, 2H), 3.94 (s, 3H), 6.30 (d, 1H, J =, 2.5 Hz), 6.41 (dd, 1H, J = 9.0, 2.5 Hz), 7.99 (d, 1H, J = 9.0 Hz)
    37-9
    Figure US20110098280A1-20110428-C00417
    1H-NMR (400 MHz, DMSO-d6, δ, ppm): 1.95-1.82 (m, 2H), 2.15-2.06 (m, 1H), 2.30 (s, 3H), 3.17 (dd, 1H), 3.32-3.23 (m, 1H), 3.56-3.34 (m, 3H), 3.96 (s, 1H), 6.09 (d, 1H), 6.21 (dd, 1H), 7.91 (d, 1H)
    37-10
    Figure US20110098280A1-20110428-C00418
    1H-NMR (400 MHz, CDCl3, δ, ppm): 2.30-2.48 (m, 3H), 2.59-2.66 (m, 1H), 2.70-2.76 (m, 1H), 2.85-2.92 (m, 1H), 3.09-3.17 (m, 1H), 3.30-3.34 (m, 1H), 3.52-3.58 (m, 1H), 3.68-3.84 (m, 3H), 3.87-3.91 (m, 1H), 3.96 (s, 3H), 6.32 (d, 1H, J = 2.5 Hz), 6.42 (dd, 1H, J = 9.6, 2.5 Hz), 8.00 (d, 1H, J = 9.6 Hz)
    37-11
    Figure US20110098280A1-20110428-C00419
    1H-NMR (400 MHz, DMSO-d6, CDCl3, δ, ppm): 1.90-1.79 (m, 1H), 2.25-2.15 (m, 1H), 2.21 (s, 3H), 2.87-2.77 (m, 1H), 3.16 (dd, 1H), 3.42-3.32 (m, 1H), 3.59-3.52 (m, 1H), 3.67-3.61 (m, 1H), 3.91 (s, 3H), 6.13 (d, 1H), 6.24 (dd, 1H) ), 7.91 (dd, 1H)
    37-12
    Figure US20110098280A1-20110428-C00420
    1H-NMR (400 MHz, CDCl3): 1.43-1.00 (m, 2H), 1.95-1.81 (m, 2H), 2.94-2.17 (m, 2H), 2.96 (s, 3H), 3.27 (d, 2H), 3.35 (s, 3H), 3.97-3.90 (m, 2H), 3.95 (s, 3H), 6.30 (d, 1H), 6.42 (dd, 1H) 8.00 (d, 1H). Rf: 0.25 (AcOEt)
    37-13
    Figure US20110098280A1-20110428-C00421
    1H-NMR (400 MHz, CDCl3): 1.14 (t, 3H), 2.48 (dd, 2H), 2.59 (t, 4H), 3.42 (t, 4H), 3.95 (s, 3H), 6.32 (d, 1H), 6.43 (dd, 1H) 8.01 (d, 1H). Rf 0.15 (AcOEt)
    37-14
    Figure US20110098280A1-20110428-C00422
    1H-NMR (400 MHz, CDCl3): 1.02-0.89 (m, 2H), 2.01-1.94 (m, 2H), 2.52-2.38 (m, 1H), 2.65-2.53 (m, 4H), 3.04-2.94 (m, 2H), 3.79-3.69 (m, 4H), 3.97-3.88 (m, 2H), 3.95 (s, 3H), 6.32 (d, 1H), 6.42 (dd, 1H), 8.00 (d, 1H). . Rf 0.10 (AcOEt)
    37-15
    Figure US20110098280A1-20110428-C00423
    1H-NMR (400 MHz, CDCl3): 1.08 (s, 3H), 1.09 (s, 3H), 2.66 (t, 4H), 2.74 (sept, 1H), 3.41 (t, 4H), 3.95 (s, 3H), 6.32 (d, 1H), 6.42 (dd, 1H) 8.00 (d, 1H). Rf 0.15 (AcOEt)
    37-16
    Figure US20110098280A1-20110428-C00424
    1H-NMR (400 MHz, CDCl3): 1.91-1.81 (m, 2H), 2.06-1.97 (m, 2H), 2.48-2.40 (m, 1H), 3.07-2.98 (m, 2H), 3.97-3.93 (m, 2H), 3.93 (s, 3H), 5.37-5.30 (m, 1H), 5.55-5.43 (m, 1H), 6.33 (d, 1H), 6.43 (dd, 1H) 8.00 (d, 1H). Rf 0.10 (AcOEt)
    37-17
    Figure US20110098280A1-20110428-C00425
    1H-NMR (400 MHz, CDCl3): 2.18-2.07 (m, 1H), 2.30-2.22 (m, 1H), 3.38 (s, 3H), 3.56-3.44 (m, 4H), 3.95 (s, 3H), 4.13 (ddd, 1H), 5.96 (d, 1H), 6.12 (dd, 1H) 8.03 (d, 1H). Rf 0.30 (AcOEt)
    37-18
    Figure US20110098280A1-20110428-C00426
    1H-NMR (400 MHz, CDCl3): 1.46 (s, 9H), 1.81-1.68 (m, 4H), 2.73 (bs, 3H), 3.07-2.97 (m, 2H), 3.95 (s, 3H), 4.03-3.94 (m, 2H), 6.32 (d, 1H), 6.43 (dd, 1H) 8.00 (d, 1H). Rf 0.55 (Hexane:AcOEt)
    37-19
    Figure US20110098280A1-20110428-C00427
    1H-NMR (400 MHz, CDCl3): 3.60-3.57 (m, 2H), 3.68-3.65 (m, 2H), 3.97 (s, 3H), 4.07 (s, 2H), 6.17 (bs, 1H), 6.26 (d, 1H), 6.39 (dd, 1H), 8.04 (d, 1H). Rf 0.85 (AcOEt)
    37-20
    Figure US20110098280A1-20110428-C00428
    1H-NMR (400 MHz, CDCl3): 3.08 (s, 3H), 3.54 (dd, 2H), 3.67 (dd, 2H), 3.96 (s, 3H), 4.05 (s, 2H), 6.25 (d, 1H), 6.38 (dd, 1H) 8.03 (d, 1H). Rf 0.30 (AcOEt)
    37-21
    Figure US20110098280A1-20110428-C00429
    1H-NMR (400 MHz, CDCl3): 1.73-1.55 (m, 2H), 1.99-1.91 (m, 2H), 2.09 (s, 3H), 2.61-2.49 (m, 5H), 3.47 (t, 2H), 3.63 (t, 2H), 3.99-3.89 (m, 3H), 3.95 (s, 3H), 6.32 (d, 1H), 6.42 (dd, 1H) 8.01 (d, 1H). Rf 0.10 (AcOEt:MeOH = 4:1)
    37-22
    Figure US20110098280A1-20110428-C00430
    1H-NMR (400 MHz, CDCl3): 3.90 (s, 3H), 3.98 (s, 3H), 3.98 (s, 3H), 6.56 (s, 1H), 7.59 (s, 1H). Rf 0.605 (AcOEt)
    37-23
    Figure US20110098280A1-20110428-C00431
    1H-NMR (400 MHz, CDCl3): 3.25-3.22 (m, 4H), 3.90-3.87 (m, 4H), 3.95 (s, 3H), 6.48 (s, 1H), 7.57 (s, 1H). Rf 0.060 (Hexane:AcOEt = 5:1)
    37-24
    Figure US20110098280A1-20110428-C00432
    1H-NMR (400 MHz, CDCl3): 2.37 (s, 3H), 2.61 (bs, 4H), 3.27 (bs, 4H), 3.88 (s, 3H), 3.95 (s, 3H), 6.48 (s, 1H), 7.56 (s, 1H). Rf 0.10 (AcOEt:MeOH = 5:1)
    37-25
    Figure US20110098280A1-20110428-C00433
    1H-NMR (400 MHz, CDCl3): 1.09 (t, 3H), 1.89 (dd, 2H), 2.36 (s, 3H), 2.55 (t, 4H), 3.39 (t, 4H), 4.03 (t, 2H), 6.32 (d, 1H), 6.42 (dd, 1H), 7.98 (d, 1H). Rf 0.12 (AcOEt:MeOH = 9:1)
    37-26
    Figure US20110098280A1-20110428-C00434
    1H-NMR (400 MHz, CDCl3): 1.36 (s, 3H), 1.38 (s, 3H), 2.10 (s, 2H), 2.17 (s, 3H), 3.27-2.96 (m, 2H), 3.71 (d, 2H), 3.96 (s, 3H), 6.33 (d, 1H), 6.43 (dd, 1H), 8.02 (d, 1H). Rf 0.10 (AcOEt)
    37-27
    Figure US20110098280A1-20110428-C00435
    1H-NMR (400 MHz, CDCl3): 1.16 (s, 3H), 1.18 (s, 3H), 2.50 (dd, 2H), 3.02-2.47 (m, 2H), 3.69 (dd, 2H), 3.96 (s, 3H), 6.31 (d, 1H), 6.43 (dd, 1H), 8.00 (d, 1H). Rf 0.070 (AcOEt)
    37-28
    Figure US20110098280A1-20110428-C00436
    1H-NMR (400 MHz, CDCl3): 1.16 (d, 3H), 2.57 (dd, 1H), 3.00-2.89 (m, 4H), 3.18-3.11 (m, 1H), 3.75-3.68 (m, 2H), 3.96 (s, 3H), 6.31 (d, 1H), 6.43 (dd, 1H), 8.01 (d, 1H). Rf 0.070 (AcOEt)
    37-29
    Figure US20110098280A1-20110428-C00437
    1H-NMR (400 MHz, CDCl3): 1.18 (t, 3H), 2.40 (dd, 2H), 3.47-3.38 (m, 4H), 3.71-3.63 (m, 2H), 3.85-3.79 (m, 2H), 3.96 (s, 3H), 6.32 (d, 1H), 6.42 (dd, 1H), 8.01 (d, 1H). Rf 0.20 (AcOEt)
    37-30
    Figure US20110098280A1-20110428-C00438
    1H-NMR (400 MHz, CDCl3): 1.16 (s, 3H), 1.18 (s, 3H), 2.82 (sept, 1H), 3.50-3.37 (m, 4H), 3.77-3.65 (m, 2H), 3.86-3.78 (m, 2H), 3.96 (s, 3H), 6.33 (d, 1H), 6.43 (dd, 1H), 8.01 (d, 1H). Rf 0.48 (AcOEt)
    37-31
    Figure US20110098280A1-20110428-C00439
    1H-NMR (400 MHz, CDCl3): 2.86 (d, 3H), 3.48-3.45 (m, 4H), 3.61-3.58 (m, 4H), 3.96 (s, 3H), 4.48-4.37 (m, 1H), 6.29 (d, 1H), 6.40 (dd, 1H), 8.01 (d, 1H). Rf 0.20 (AcOEt)
    37-32
    Figure US20110098280A1-20110428-C00440
    1H-NMR (400 MHz, CDCl3): 1.72-1.60 (m, 2H), 2.06-1.97 (m, 2H), 3.25-3.17 (d, 3H), 3.78-3.70 (m, 2H), 3.95 (s, 3H), 4.04-3.99 (m, 1H), 6.33 (d, 1H), 6.43 (dd, 1H), 8.00 (d, 1H). Rf 0.20 (AcOEt)
    37-33
    Figure US20110098280A1-20110428-C00441
    1H-NMR (400 MHz, CDCl3): 1.53 (s, 6H), 2.14 (s, 3H), 3.50 (s, 2H), 3.61-3.58 (m, 2H), 3.97-3.81 (m, 2H), 3.97 (s, 3H), 6.10 (d, 1H), 6.26 (dd, 1H), 8.05 (d, 1H). Rf 0.030 (AcOEt)
    37-34
    Figure US20110098280A1-20110428-C00442
    1H-NMR (400 MHz, CDCl3): 2.54-2.23 (m, 4H), 2.67 (t, 2H), 3.29-3.23 (m, 2H), 3.74 (t, 4H), 3.94 (s, 3H), 6.07 (d, 1H), 6.16 (dd, 1H), 8.00 (d, 1H). Rf 0.15 (AcOEt)
    37-35
    Figure US20110098280A1-20110428-C00443
    1H-NMR (400 MHz, CDCl3): 2.10-2.02 (m, 2H), 2.41 (t, 2H), 3.56 (dd, 2H), 3.71 (t, 2H), 3.95 (s, 3H), 4.19 (t, 2H), 6.49 (dd, 1H), 6.55 (d, 1H), 7.99 (d, 1H). Rf 0.10 (AcOEt)
    37-36
    Figure US20110098280A1-20110428-C00444
    1H-NMR (400 MHz, CDCl3): 2.14 (s, 3H), 3.87-3.34 (m, 8H), 3.99 (s, 3H), 7.01 (dd, 1H), 7.16 (d, 1H), 7.88 (d, 1H). Rf 0.25 (AcOEt)
    37-37
    Figure US20110098280A1-20110428-C00445
    1H-NMR (400 MHz, CDCl3): 3.49-3.37 (m, 2H), 3.88-3.55 (m, 6H), 3.99 (s, 3H), 7.00 (dd, 1H), 7.16 (d, 1H), 7.87 (d, 1H). Rf 0.50 (AcOEt)
    37-38
    Figure US20110098280A1-20110428-C00446
    1H-NMR (400 MHz, CDCl3): 1.17 (s, 3H), 1.19 (s, 3H), 2.69 (t, 4H), 3.06 (s, 2H), 3.42 (t, 4H), 3.96 (s, 3H), 4.13 (sept, 1H), 6.34 (d, 1H), 6.44 (dd, 1H), 6.90-6.79 (m, 1H), 8.00 (d, 1H). Rf 0.20 (AcOEt)
    37-39
    Figure US20110098280A1-20110428-C00447
    1H-NMR (400 MHz, CDCl3): 1.44-1.34 (m, 2H), 1.84-1.77 (m, 1H), 1.94-1.85 (m, 2H), 3.04-2.94 (m, 2H), 3.55 (t, 2H), 3.96-3.57 (m, 2H), 3.95 (s, 3H), 6.31 (d, 1H), 6.42 (dd, 1H), 8.00 (d, 1H). Rf 0.30 (AcOEt)
    37-40
    Figure US20110098280A1-20110428-C00448
    1H-NMR (400 MHz, CDCl3): 1.44-1.34 (m, 2H), 1.84-1.77 (m, 1H), 1.94-1.85 (m, 2H), 3.04-2.94 (m, 2H), 3.55 (t, 2H), 3.96-3.57 (m, 2H), 3.95 (s, 3H), 6.31 (d, 1H), 6.42 (dd, 1H), 8.04 (d, 1H). Rf 0.45 (AcOEt)
    37-41
    Figure US20110098280A1-20110428-C00449
    1H-NMR (400 MHz, CDCl3): 4.05 (s, 3H), 7.07 (d, 1H), 7.08 (d, 1H), 7.27-7.26 (m, 1H), 7.33 (t, 1H), 7.92 (s, 1H), 8.04 (d, 1H). Rf: 0.20 (AcOEt)
    37-42
    Figure US20110098280A1-20110428-C00450
    1H-NMR (400 MHz, CDCl3): 2.34 (s, 3H), 2.55-2.37 (m, 4H), 3.86-3.38 (m, 4H), 4.00 (s, 3H), 7.13 (d, 1H). 7.66 (dd, 1H). 7.93 (d, 1H). Rf: 0.30 (AcOEt:MeOH = 4:1)
    37-43
    Figure US20110098280A1-20110428-C00451
    1H-NMR (400 MHz, CDCl3): 2.43 (s, 3H), 2.74 (s, 6H), 7.91 (dd, 1H), 7.23 (d, 1H), 7.24 (d, 1H), 7.46 (dd, 1H). Rf: 0.70 (Hexane:AcOEt = 5:1)
    37-44
    Figure US20110098280A1-20110428-C00452
    1H-NMR (400 MHz, CDCl3): 2.15 (s, 3H), 3.80-3.48 (m, 2H), 6.87 (dd, 1H), 6.92 (dd, 1H), 7.09 (d, 1H), 7.40 (dd, 2H), 8.54 (dd, 2H).
    37-45
    Figure US20110098280A1-20110428-C00453
    1H-NMR (400 MHz, CDCl3): 3.86 (s, 3H), 4.00 (s, 3H), 6.78 (d, 1H), 6.99 (dd, 2H), 7.14 (d, 1H), 7.48 (dd, 2H), 7.71 (dd, 1H), 8.03 (d, 1H). Rf: 0.30 (Hexane:AcOEt = 3:1)
    37-46
    Figure US20110098280A1-20110428-C00454
    1H-NMR (400 MHz, CDCl3): 1.44 (t, 3H), 3.10 (t, 4H), 3.86 (t, 4H), 4.13 (q, 2H), 7.01 (dd, 1H), 7.08 (dd, 1H), 7.35 (d, 1H). Rf: 0.25 (Hexane:AcOEt = 3:1)
    37-47
    Figure US20110098280A1-20110428-C00455
    1H-NMR (400 MHz, CDCl3): 1.26 (t, 3H), 3.32 (t, 4H), 3.85 (t, 4H), 4.15 (q, 2H), 6.34 (d, 1H), 6.42 (dd, 1H), 7.98 (d, 1H). Rf: 0.45 (Hexane:AcOEt = 5:1)
    37-48
    Figure US20110098280A1-20110428-C00456
    1H-NMR (400 MHz, CDCl3): 3.45 (s, 3H), 3.77 (dd, 2H), 3.81 (s, 3H), 4.06 (t, 2H), 7.08-7.08 (m, 2H), 7.37 (t, 1H). Rf: 0.45 (Hexane:AcOEt = 3:1)
    37-49
    Figure US20110098280A1-20110428-C00457
    1H-NMR (400 MHz, CDCl3): 2.44 (t, 1H), 3.83 (s, 3H), 3.96 (ddd, 2H), 4.20 (t, 2H), 7.06 (d, 1H), 7.12 (dd, 1H), 7.40 (d, 1H). Rf: 0.10 (Hexane:AcOEt = 3:1)
    37-50
    Figure US20110098280A1-20110428-C00458
    1H-NMR (400 MHz, CDCl3): 1.45 (t, 3H), 3.81 (s, 3H), 4.13 (q, 2H), 7.01 (d, 1H) 7.08 (dd, 1H), 7.36 (d, 1H). Rf: 0.20 (Hexane:AcOEt = 3:1)
    37-51
    Figure US20110098280A1-20110428-C00459
    1H-NMR (400 MHz, CDCl3): 1.35 (s, 3H), 1.36 (s, 3H), 3.81 (s, 3H), 4.52 (sept, 1H), 7.08-7.01 (m, 2H), 7.31 (d, 1H). Rf: 0.30 (Hexane:AcOEt = 3:1)
    37-52
    Figure US20110098280A1-20110428-C00460
    1H-NMR (400 MHz, CDCl3): 1.05 (t, 3H), 1.83 (ddd, 2H), 3.81 (s, 3H), 4.01 (t, 2H), 7.01 (d, 1H), 7.08 (dd, 1H), 7.36 (d, 1H). Rf: 0.35 (Hexane:AcOEt = 3:1)
    37-53
    Figure US20110098280A1-20110428-C00461
    1H-NMR (400 MHz, CDCl3): 3.86 (s, 6H), 3.79 (s, 3H), 6.91 (dd, 1H), 7.00 (d, 1H), 7.18 (d, 1H). Rf: 0.5 (Hexane:AcOEt = 9:1)
    37-54
    Figure US20110098280A1-20110428-C00462
    1H-NMR (400 MHz, CDCl3): 4.04 (s, 3H), 7.22 (d, 1H), 7.48 (dd, 2H), 7.83 (dd, 1H), 8.16 (d, 1H), 8.69 (dd, 2H). Rf: 0.12 (Hexane:AcOEt = 1:1)
    37-55
    Figure US20110098280A1-20110428-C00463
    1H-NMR (400 MHz, CDCl3): 4.02 (s, 3H), 7.22 (d, 1H), 7.39 (ddd, 1H), 7.77 (dd, 1H), 7.85 (ddd, 1H), 8.08 (d, 1H), 8.63 (dd, 1H), 8.83 (d, 1H). Rf: 0.55 (Hexane:AcOEt = 2:1)
    37-56
    Figure US20110098280A1-20110428-C00464
    1H-NMR (400 MHz, CDCl3): 4.03 (s, 3H), 7.19 (d, 1H), 7.28-7.24 (m, 1H), 7.72 (dd, 1H), 7.80-7.76 (m, 1H), 8.25 (dd, 1H), 8.52 (d, 1H), 8.69 (ddd, 1H). Rf: 0.55 (Hexane:AcOEt = 2:1)
    37-57
    Figure US20110098280A1-20110428-C00465
    mp 90.7° C.; 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.68 (m; 2H), 2.00 (m; 2H), 2.36 (s; 1H), 2.62 (bs; 4H), 2.72 (m; 2H), 3.62 (m; 2H), 3.78 (bs; 4H), 3.90 (s; 3H), 6.99 (d; 1H); 7.13 (dd; 1H), 7.26 (s; 1H); 7.40 (s; 1H).
  • 38 Preparation of 1-[4-(4-Methoxy-3-nitro-phenyl)-piperazin-1-yl]-ethanone
  • Figure US20110098280A1-20110428-C00466
  • To a solution of 5-bromo-1-methoxy-2-nitrobenzene (300 mg, 1.29 mmol) in dioxane, 1-acetyl piperazine (400 mg, 3.12 mmol), cesium carbonate (1.0 g, 3.07 mmol), palladium diacetate (29.0 mg, 0.129 mmol) and 2-(di-t-butylphosphino)biphenyl (77 mg, 0.258 mmol) are added and stirred at 100° C. for 8 hours. After cooling, the mixture is filtered to remove insoluble material. The filtrate is poured into water and extracted with ethyl acetate twice. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:ethyl acetate gradient) to afford 1-[4-(4-Methoxy-3-nitro-phenyl)-piperazin-1-yl]ethanone (319 mg, 44%) as yellow solids.
  • 1H-NMR (400 MHz, CDCl3, δ, ppm): 2.14 (s, 3H), 3.63 (ddd, 4H), 3.63 (t, 2H), 3.78 (t, 2H), 3.92 (s, 3H), 7.03 (d, 1H), 7.12 (d, 1H), 7.41 (d, 1H). Rf (ethyl acetate): 0.18
  • 39 Preparation of 1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-one
  • Figure US20110098280A1-20110428-C00467
  • To a solution of 4-piperidone hydrochloride monohydrate (10.0 g, 0.065 mol) in DMF (80 mL) are added 4-Fluoro-2-methoxy-1-nitro-benzene (10.0 g, 0.058 mol) and potassium carbonate (20.2 g), and the mixture is stirred at 70° C. for 20 h. After a filtration, the filtrate is poured into H2O (ca. 300 mL), and the resulting precipitates are collected by a filtration followed by washing with H2O for several times to give title compound (8.98 g) in 61% yield. Orange solid. 1H-NMR (400 MHz, CDCl3, δ): 2.65-2.62 (4H, m), 3.81-3.78 (4H, m), 3.98 (3H, s), 6.34 (1H, d), 6.45 (1H, dd), 8.05 (1H, d).
  • 40 Preparation of 1-[1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-yl]-4-methyl-piperazine
  • Figure US20110098280A1-20110428-C00468
  • To a solution of 1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-one (4.96 g, 0.020 mol) in dichloroethane (50 ml) is added N-methylpiperazine (2.7 ml, 0.024 mol) at 0° C. and the mixture is stirred at room temperature. After 4 h, sodium triacetoxy-borohydride (5.04 g, 0.024 mol) is added and the mixture is further stirred at room temperature for 24 h. After addition of 1N sodium hydroxide at 0° C., the mixture is poured into water and extracted three times with dichloromethane. The organic layer is combined and extracted three times with 1N hydrochloride. The water layer is basified with 2N sodium hydroxide and extracted three times with dichloromethane. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo to give the title compound as yellow solids (6.04 g) in 91% yield.
  • 1H-NMR (400 MHz, CDCl3, δ): 1.70-1.57 (2H, m), 2.03-1.93 (2H, m), 2.29 (3H, s), 2.55-2.38 (5H, m), 2.70-2.56 (4H, m), 2.97 (2H, ddd), 3.97-3.92 (2H, m), 3.95 (3H, s), 6.31 (1H, d,), 6.42 (1H, dd), 8.00 (1H, d).
  • 41 Preparation of 4′-Methoxy-4-methyl-3-nitro-biphenyl
  • Figure US20110098280A1-20110428-C00469
  • To a solution of 4-methoxyphenyl-boronic acid (500 mg, 3.29 mmol) in toluene (5.2 mL) and ethanol (1.3 mL), potassium carbonate (910 mg, 6.58 mmol), tetrakis(triphenylphosphine)-palladium (228.1 mg, 0.099 mmol) and 4-bromo-1-methyl-2-nitrobenzene (711 mg, 3.29 mmol) are added and stirred at 100° C. for 7 hours. The mixture is poured into water and extracted with ethyl acetate two times. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1) to afford the 4′-methoxy-4-methyl-3-nitro-biphenyl (630 mg, 79%) as a yellow solid.
  • 1H-NMR (400 MHz, CDCl3, δ, ppm): 2.62 (s, 3H), 3.86 (s, 3H), 7.02-6.98 (m, 2H), 7.37 (d, 1H), 7.54 (dd, 2H), 7.68 (dd, 1H), 8.18 (d, 1H). Rf (hexane:ethyl acetate=3:1): 0.40.
  • 42 Preparation of 4-(2-Ethoxy-ethoxy)-1-(3-methoxy-4-nitro-phenyl)-piperidine
  • Figure US20110098280A1-20110428-C00470
  • To a solution of 1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-ol (300 mg, 1.2 mmol) in N,N-dimethylformamide (3.0 mL), sodium hydride (1.52 g, 3.8 mmol) is added. After stirring, 2-bromoethyl methyl ether (150 μl, 1.6 mmol) is added and the mixture is further stirred at 70° C. for 15 hours. After addition of saturated aqueous ammonium chloride, the mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane-ethyl acetate gradient) to afford 4-(2-Methoxy-ethoxy)-1-(3-methoxy-4-nitro-phenyl)-piperidine (111 mg, 29%) as a yellow oil.
  • 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.52 (t, 3H), 1.95-2.00 (m, 2H), 1.70-1.79 (m, 2H), 3.23 (ddd, 2H), 3.58-3.64 (m, 2H), 3.65-3.68 (m, 2H), 3.64-3.72 (m, 2H), 3.95 (s, 3H), 6.31 (d, 1H), 6.42 (dd, 1H), 8.00 (d, 1H). Rf 0.53 (n-hexane:AcOEt=1:1).
  • According the procedure described above using appropriate alkyl halides, the following compounds are prepared.
  • Ex-
    No. Rx Identification
    42-1
    Figure US20110098280A1-20110428-C00471
    1H-NMR (400 MHz, CDCl3, δ, ppm): 2.04-2.21 (m, 1H), 2.63 (t, 2H), 2.68 (t, 2H), 3.42 (t, 4H), 3.87 (t, 4H), 3.96 (s, 3H), 6.33 (d, 1H), 6.44 (dd, 1H), 8.02 (d, 1H). Rf 0.09 (AcOEt).
    42-2
    Figure US20110098280A1-20110428-C00472
    1H-NMR (400 MHz, CDCl3, δ, ppm): 1.71-1.79 (m, 2H), 1.95- 2.02 (m, 2H), 3.22 (ddd, 2H), 3.40 (s, 3H), 3.55-3.57 (m, 2H), 3.59-3.73 (m, 3H), 3.65-3.67 (m, 2H), 3.95 (s, 3H), 6.31 (d, 1H), 6.42 (dd, 1H), 8.00 (d, 1H). Rf 0.35 (n-hexane: AcOEt = 1:1)
  • Example: 43 2-Methoxy-4-(1-methyl-piperidin-4-yloxy)-phenylamine 4-(3-Methoxy-4-nitro-phenoxy)-1-methyl-piperidine
  • Figure US20110098280A1-20110428-C00473
  • To a solution of 4-Fluoro-2-methoxy-1-nitro-benzene (10.3 g, 60 mmol) in toluene (50 mL) and 25% KOH aq. (50 mL), 4-hydroxy-1-methylpiperidine (13.8 g, 120 mmol) and tetra-n-butyl ammonium bromide (3.87 g, 12 mmol) are added at room temperature. The mixture is heated at 60° C. for 1 day. The reaction mixture is cooled to room temperature, poured into ice water and extracted twice with ethyl acetate. The organic layer is successively washed with dil.HCl and brine, dried over sodium sulfate, and evaporated in vacuo to afford the crude compound in quantitative yield (13.4 g).
  • Rf=0.22 (methanol:dichloromethane=1:4). 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.84-1.92 (m, 2H), 2.0-2.1 (m, 2H), 2.3-2.4 (m, 2H), 2.33 (s, 3H), 2.65-2.75 (m, 2H), 3.94 (s, 3H), 4.39-4.46 (m, 1H), 6.49 (dd, 1H), 6.99 (d, 1H), 6.54 (d, 1H), 7.99 (d, 1H).
  • Example: 44 2-Methoxy-4-(2-morpholin-4-yl-ethoxy)-phenylamine 3-Methoxy-4-nitro-phenol
  • Figure US20110098280A1-20110428-C00474
  • To a solution of 3-Fluoro-4-nitro-phenol (15.7 g, 100 mmol) in THF (300 mL), 30% KOMe in Methanol (49 mL, 210 mmol) is added at 0° C. The mixture is heated to gentle reflux for 18 hours.
  • 4-[2-(3-Methoxy-4-nitro-phenoxy)-ethyl]-morpholine
  • Figure US20110098280A1-20110428-C00475
  • To a solution of 3-Methoxy-4-nitro-phenol (1.69 g, 10 mmol) in DMF (25 mL), 4-(2-Chloroethyl)morpholine hydrochloride (2.05 g, 11 mmol), K2CO3 (1.52 g, 11 mmol), KI (332 mg, 2 mmol) are added at room temperature. The mixture is heated to gentle reflux for 4 hours. The reaction mixture is cooled to room temperature and quenched with water. The resulting mixture is extracted twice with ethyl acetate and then the organic layer is successively washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude compound in 90% yield (2.55 g).
  • Rf=0.11 (AcOEt only). 1H-NMR (400 MHz, CDCl3), δ (ppm): 2.56-2.61 (m, 4H), 2.83 (t, The reaction mixture is cooled to room temperature and quenched slowly with 1 NHCl aq at 0° C. The resulting mixture is extracted twice with ethyl acetate and then the organic layer is successively washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude compound in 94% yield (15.9 g).
  • Rf=0.22 (methanol:dichloromethane=1:4). 1H-NMR (400 MHz, CDCl3), δ (ppm): 3.95 (s, 3H), 5.49 (s, 1H), 6.44 (dd, 1H, J=8.8, 2.52 Hz), 6.54 (d, 1H, J=2.52 Hz), 7.96 (d, 1H J=8.6 Hz). 3.72-3.76 (m, 4H), 3.94 (s, 3H), 4.18 (t, 2H), 6.51 (dd, 1H, J=9.08, 2.52 Hz), 6.56 (d, 1H, J=2.48 Hz), 8.00 (d, 1H J=9.08 Hz). 2H),
  • Example: 45 2-Methoxy-4-(2-morpholin-4-yl-ethoxy)-phenylamine Acetic acid 4-methoxy-3-nitro-phenyl ester
  • Figure US20110098280A1-20110428-C00476
  • To a solution of 4-Methoxyphenol (12.4 g, 100 mmol) in AcOH (50 mL), Ac2O (50 mL) is added at room temperature. The mixture is heated to gentle reflux for 1.5 hour. The reaction mixture is cooled to room temperature and c.HNO3 (d=1.38, 10 mL) is added slowly at 0° C. The mixture is heated to 55° C. for 1.5 h. The reaction mixture is cooled to room temperature and quenched with water at 0° C. The resulting solid is filtered on Buchner funnel to afford the crude compound in 76% yield (16.0 g).
  • Rf=0.59 (AcOEt:n-Hexane=3:7). 1H-NMR (400 MHz, CDCl3), δ (ppm): 2.31 (s, 3H), 3.96 (s, 3H), 7.08 (d, 1H, J=9.04 Hz), 7.31 (dd, 1H, J=9.04, 3.04 Hz), 7.96 (d, 1H J=3.04 Hz).
  • 4-Methoxy-3-nitro-phenol
  • Figure US20110098280A1-20110428-C00477
  • To a solution of Acetic acid 4-methoxy-3-nitro-phenyl ester (1.06 g, 5 mmol) in EtOH (20 mL), 1N NaOH aq (5.5 mL) is added at 0° C. The mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with AcOH and extracted twice with ethyl acetate. The organic layer is successively washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude compound in quantitative yield (840 mg).
  • Rf=0.59 (AcOEt:n-Hexane=3:7). 1H-NMR (400 MHz, CDCl3), δ (ppm): 3.91 (s, 3H), 6.99 (d, 1H, J=9.04 Hz), 7.17 (dd, 1H, J=9.04, 3.00 Hz), 7.38 (d, 1H J=3.04 Hz).
  • 4-[2-(4-Methoxy-3-nitro-phenoxy)-ethyl]-morpholine
  • Figure US20110098280A1-20110428-C00478
  • To a solution of 4-Methoxy-3-nitro-phenol (1.01 g, 6 mmol) in DMF (15 mL), 4-(2-Chloroethyl)morpholine hydrochloride (1.34 g, 7.2 mmol), K2CO3 (2.49 g, 18 mmol), KI (2.99 g, 18 mmol) are added at room temperature. The mixture is heated to 80° C. for 4 hours. The reaction mixture is cooled to room temperature and quenched with saturated NH4Cl solution in water. The resulting mixture is extracted twice with ethyl acetate and then the organic layer is successively washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude compound in quantitative yield (1.70 g). Rf=0.14 (AcOEt only). 1H-NMR (400 MHz, DMSO, δ, ppm): 2.36-2.51 (m, 4H), 2.67 (t, J=5.5, 2H), 3.52-3.60 (m, 4H), 3.86 (s, 3H), 4.11 (t, J=6.0, 2H), 7.25-7.29 (m, 2H), 7.46-7.49 (m, 1H).
  • Preparation of 2-Methoxy-4-(1-methyl-piperidin-4-yloxy)-phenylamine
  • Figure US20110098280A1-20110428-C00479
  • To a solution of 4-(3-Methoxy-4-nitro-phenoxy)-1-methyl-piperidine (3.0 g, 11.3 mmol) in ethanol (50 mL), 5% palladium on carbon (300 mg) is added under a nitrogen atmosphere. The reaction vessel is fitted with a balloon adapter and charged with hydrogen and evacuated three times until the reaction is under a hydrogen atmosphere. The reaction is allowed to stir overnight. The reaction mixture is filtered through a pad of Celite and washed with methanol. The filtrate is concentrated in vacuo to afford 2-Methoxy-4-(1-methyl-piperidin-4-yloxy)-phenylamine in quantitative yield (2.7 g).
  • Rf=0.41 (methanol:dichloromethane=1:1). 1H-NMR (400 MHz, CDCl3), δ (ppm): 1.75-1.86 (m, 2H), 1.92-2.05 (m, 2H), 2.2-2.32 (m, 2H), 2.30 (s, 3H), 3.4-3.7 (brs, 2H), 3.82 (s, 3H), 4.1-4.2 (m, 1H), 6.37 (dd, 1H), 6.46 (d, 1H), 6.61 (d, 1H).
  • By repeating the procedures described above using appropriate starting materials and conditions the following compounds are obtained.
  • Ex-
    No. Rx Identification
    46-1
    Figure US20110098280A1-20110428-C00480
    1H-NMR (400 MHz, CDCl3, δ, ppm): 3.92 (s, 3H), 3.97 (br, 2H), 6.75 (d, 1H), 7.00 (dd, 1H), 7.12 (d, 1H), 8.06 (s, 1H), 8.41 (s, 1H). Rf 0.32 (AcOEt)
    46-2
    Figure US20110098280A1-20110428-C00481
    1H-NMR (400 MHz, CDCl3, δ, ppm): 1.13 (t, 3H), 1.77-1.86 (m, 1H), 2.19-2.27 (m, 1H), 2.67-2.75 (m, 2H), 3.01-3.06 (m, 1H), 3.20-3.26 (m, 1H), 3.33-3.38 (m, 1H), 3.42-3.49 (m, 2H), 3.84 (s, 3H), 6.04-6.07 (m, 1H), 6.14-6.15 (m, 1H), 6.64-6.66 (m, 1H). Rf 0.2 (AcOEt only)
    46-3
    Figure US20110098280A1-20110428-C00482
    1H-NMR (400 MHz, CDCl3, δ, ppm): 2.44 (s, 3H), 2.70-2.73 (m, 4H), 3.13-3.17 (m, 4H), 3.48 (brs, 2H), 3.84 (s, 3H), 6.41 (dd, 1H, J = 8.5, 2.52 Hz), 6.51 (d, 1H, J = 2.52 Hz), 6.64 (d, 1H, J = 8.5 Hz). Rf 0.2 (AcOEt only).
    46-4
    Figure US20110098280A1-20110428-C00483
    1H-NMR (400 MHz, CDCl3, δ, ppm): 1.01-1.12 (m, 1H), 1.57- 2.13 (m, 6H), 2.26 (s,3H), 2.74-2.77 (m, 1H), 2.93-2.96 (m, 1H), 3.47 (bs, 2H), 3.70-3.80 (m, 2H), 3.82 (s, 3H), 6.31-6.34 (m, 1H), 6.44-6.45 (m, 1H), 6.60-6.62 (m, 1H). Rf 0.2 (AcOEt only)
    46-5
    Figure US20110098280A1-20110428-C00484
    1H-NMR (400 MHz, CDCl3) 1.80-1.67 (2H, m), 1.99-1.90 (2H, m), 2.42-2.27 (1H, m), 2.56-2.43 (4H, m), 2.68-2.58 (2H, m), 2.76-2.58 (4H, m), 3.57-3.48 (2H, m), 3.83 (3H. s), 6.41 (1H, dd), 6.52 (1H, d), 6.63 (1H, d). Rf (hexane/acetone 1:1) 0.44.
    46-6
    Figure US20110098280A1-20110428-C00485
    1H-NMR (400 MHz, CDCl3, δ, ppm): 1.83-1.95 (m, 2H), 1.97- 2.08 (m, 2H), 2.20-2.31 (m, 1H), 2.60-2.72 (m, 2H), 3.46-3.53 (m, 2H), 3.84 (s, 3H), 5.42-5.60 (m, 1H), 6.43 (dd, 1H), 6.53 (d, 1H), 6.64 (d, 1H).
    46-7
    Figure US20110098280A1-20110428-C00486
    1H-NMR (400 MHz, CDCl3, δ, ppm) : 2.13 (s, 3H), 3.01-3.05 (m, 4H), 3.59 (t, 2H), 3.75 (t, 2H), 3.81 (s, 3H), 6.30 (dd, 1H), 6.39 (bs, 1H), 6.71 (d, 1H).
    46-8
    Figure US20110098280A1-20110428-C00487
    1H-NMR (400 MHz, CDCl3, δ, ppm): 1.84-1.97 (m, 2H), 1.98- 2.07 (m, 2H), 2.20-2.32 (m, 1H), 2.61-2.72 (m, 2H), 3.47-3.55 (m, 2H), 3.95 (s, 3H), 5.20-5.38 (m, 1H), 5.40-5.56 (m, 2H), 6.43 (d, 1H), 6.53 (bs, 1H), 6.64 (d, 1H).
    46-9
    Figure US20110098280A1-20110428-C00488
    1H-NMR (400 MHz, CDCl3, δ, ppm) : 2.59-2.67 (m, 2H), 2.77- 2.68 (m, 4H), 3.08-3.15 (m, 4H), 3.49-3.56 (m, 1H), 3.67-3.77 (m, 2H), 3.98 (s, 3H), 6.41-6.43 (m, 1H), 6.52 (bs, 1H), 6.65 (d, 1H).
    46-10
    Figure US20110098280A1-20110428-C00489
    1H-NMR (400 MHz, CDCl3, δ, ppm): 1.72-1.96 (m, 2H), 1.98- 2.10 (m, 2H), 2.63 (s, 3H), 2.73-2.84 (m, 2H), 3.40 (s, 3H), 3.34-3.42 (m, 2H), 3.44-3.49 (m, 1H), 3.55-3.57 (m, 2H), 3.64- 3.66 (m, 2H), 3.83 (s, 3H), 6.41-6.43 (m, 1H), 6.53 (bs, 1H), 6.63 (d, 1H).
    46-11
    Figure US20110098280A1-20110428-C00490
    1H-NMR (400 MHz, CDCl3, δ, ppm) : 1.22 (t, 3H), 1.72-1.84 (m, 2H), 2.00-2.10 (m, 2H), 2.72-2.82 (m, 2H), 3.33-3.38 (m, 2H), 3.43-3.49 (m, 1H), 3.55 (q, 2H), 3.58-3.61 (m, 2H), 3.64-3.66 (m, 2H), 3.83 (s, 3H), 6.41-6.43 (m, 1H), 6.53 (bs, 1H), 6.63 (d, 1H).
    46-12
    Figure US20110098280A1-20110428-C00491
    1H-NMR (400 MHz, CDCl3, δ, ppm) : 2.20 (s, 3H), 3.84 (s, 3H), 6.87 (d, 1H), 6.89 (dd, 1H), 6.95 (d, 2H), 7.09 (d, 1H), 7.48 (d, 2H). Rf (n-hexane:ethyl acetate = 1:1): 0.50.
    46-13
    Figure US20110098280A1-20110428-C00492
    1H- NMR (400 MHz, CDCl3, δ, ppm): 1.49 - 1.59 (m, 3H), 1.70-1.95 (m, 6H), 2.00-2.20 (m, 2H), 2.60-2.90 (m, 7H), 3.50-3.60 (m, 3H), 3.83 (s, 3H), 3.85-3.91 (m, 1H), 6.41 (dd, 1H, J = 8.0, 2.5 Hz), 6.50 (d, 1H, J = 2.5 Hz), 6.63 (d, 1H, J = 8.0 Hz )
    46-14
    Figure US20110098280A1-20110428-C00493
    1H-NMR (400 MHz, DMSO-d6, δ, ppm): 1.87-1.79(m, 1H), 2.22 (ddd, 1H), 2.48 (s, 3H), 3.05 (dd, 1H), 3.28-3.21 (m, 1H), 3.40-3.32 (m, 2H), 3.45 (dd, 1H), 3.84 (s, 3H), 6.06 (dd, 1H), 6.15 (d, 1H)), 6.66 (d, 1H)
    46-15
    Figure US20110098280A1-20110428-C00494
    1H-NMR (400 MHz, CDCl3, δ, ppm): 2.35-2.73 (m, 4H), 2.68- 2.75 (m, 1H), 2.82-2.93 (m, 2H), 3.14-3.19 (m, 1H), 3.29- 3.40 (m, 2H), 3.50-3.60 (bs, 2H), 3.69-3.78 (m, 2H), 3.84 (s, 3H), 3.85-3.91 (m, 1H), 6.40 (dd, 1H, J = 8.0, 2.5 Hz), 6.50 (d, 1H, J = 2.5 Hz), 6.64 (d, 1H, J = 8.0 Hz)
    46-16
    Figure US20110098280A1-20110428-C00495
    1H-NMR (400 MHz, DMSO-d6, δ, ppm): 1.95-1.85 (m, 1H), 2.22-2.14 (m, 1H), 2.31 (s, 3H), 2.89-2.79 (m, 1H), 3.10 (t, 1H), 3.39-3.25 (m, 3H), 3.42 (t, 1H), 3.85 (s, 3H), 6.05 (dd, 1H), 6.14 (d, 1H), 6.67 (d, 1H)
    46-17
    Figure US20110098280A1-20110428-C00496
    1H-NMR (400 MHz, CDCl3, δ, ppm): 1.68-1.81 (m, 2H), 1.97- 2.09 (m, 2H), 2.74-2.87 (m, 2H), 3.31-3.41 (m, 2H), 3.77-3.88 (m, 1H), 3.84 (s, 3H), 6.40-6.48 (m, 1H), 6.65 (bs, 1H), 6.64 (d, 1H).
    46-18
    Figure US20110098280A1-20110428-C00497
    1H-NMR (400 MHz, CDCl3), δ (ppm): 2.55-2.61 (m, 4H), 2.80 (t, 2H), 3.72-3.77 (m, 4H), 3.81 (s, 3H), 4.05 (t, 2H), 6.24 (dd, 1H, J = 8.56, 2.52 Hz), 6.34 (d, 1H, J = 2.52 Hz), 6.68 (d, 1H J = 8.56 Hz). Rf = 0.31 (methanol:dichloromethane = 1:9).
    46-19
    Figure US20110098280A1-20110428-C00498
    1H-NMR (400 MHz, CDCl3), δ (ppm): 2.55-2.61 (m, 4H), 2.78 (t, 2H), 3.72-3.77 (m, 4H), 3.82 (s, 3H), 4.05 (t, 2H), 6.35 (dd, 1H, J = 8.56, 2.52 Hz), 6.47 (d, 1H, J = 2.52 Hz), 6.63 (d, 1H J = 8.56 Hz). Rf = 0.61 (methanol:dichloromethane = 1:4).
    46-20
    Figure US20110098280A1-20110428-C00499
    1H-NMR (DMSO), δ (ppm): 3.84 (s, 3H), 6.95-7.00 (m, 1H), 7.08-7.12 (m, 2H).
    46-21
    Figure US20110098280A1-20110428-C00500
    1H-NMR (400 MHz, CDCl3): 1.47-1.34 (m, 2H), 1.75-1.63 (m, 1H), 1.86-1.79 (m, 2H), 2.64-2.58 (m, 2H), 3.28 (d, 2H), 3.61 (d, 3H), 3.87 (s, 3H), 3.36 (s, 1H), 3.49-3.45 (m, 2H), 3.84 (s,3H), 6.43 (dd, 1H), 6.53 (d, 1H) 6.64 (d, 1H)
    46-22
    Figure US20110098280A1-20110428-C00501
    1H-NMR (400 MHz, CDCl3): 1.13 (t, 3H), 2.49 (dd, 2H), 2.68-2.59 (m, 4H), 3.10 (t, 4H), 3.84 (s,3H), 6.43 (dd, 1H), 6.53 (d, 1H) 6.65 (d, 1H)
    46-23
    Figure US20110098280A1-20110428-C00502
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