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WO2007113005A2 - 2-substituted 3-aminosulfonyl-thiophene derivatives as aurora kinase inhibitors - Google Patents

2-substituted 3-aminosulfonyl-thiophene derivatives as aurora kinase inhibitors Download PDF

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Publication number
WO2007113005A2
WO2007113005A2 PCT/EP2007/003011 EP2007003011W WO2007113005A2 WO 2007113005 A2 WO2007113005 A2 WO 2007113005A2 EP 2007003011 W EP2007003011 W EP 2007003011W WO 2007113005 A2 WO2007113005 A2 WO 2007113005A2
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atom
leu
arg
glu
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PCT/EP2007/003011
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French (fr)
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WO2007113005A3 (en
Inventor
Joe Lewis
Elena Conti
Arulanandam Arockia Jeyaprakash
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European Molecular Biology Laboratory (Embl)
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Publication of WO2007113005A2 publication Critical patent/WO2007113005A2/en
Publication of WO2007113005A3 publication Critical patent/WO2007113005A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention provides novel compounds that inhibit cell proliferation, in particular by inhibiting Aurora A kinase activity and uses of these compounds for treating, ameliorating or preventing diseases, conditions or disorders benefiting from the inhibition of aurora activity, in particular hyperproliferative diseases.
  • Mitosis is a fundamental mode of nuclear division of eukaryotic cells and a highly coordinated process by which eukaryotic cells assure the fidelity of chromosome segregation.
  • the number of chromosomes is often a multiple of the basic number unique to the species, but errors during mitosis result in an individual having one to several chromosomes added to or deleted from the multiple (aneuploid), which may cause cell death or oncogenesis.
  • Aurora identified in Drosophila melanogaster and its most closely related homolog IPL-I (Francisco , et al. (1994.) MoI. Cell. Biol. 14:4731-40) in budding yeast (Saccharomyces cerevisiae) are members of serine/threonine kinase family involved in controlling cell growth, differentiation and regulation of the cell cycle. These kinases are thought to participate in M phase of mitosis and are thought to be required for high-fidelity chromosome segregation.
  • Aurora kinases A also known as Aurora, Aurora-2, AIK, AIR-I, AIRKl, AYKl, BTAK, Eg2, MmIAKl and STK15
  • Aurora B also known as Aurora-1, AIM-I, AIK2, AIR-2, AIRK-2, ARK2, IAL-I and STK12
  • Aurora C also known as AIK3
  • the present invention provides a compound class capable of competitively inhibiting binding of ATP to the ATP-binding pocket of Aurora kinases and through the provision of a 3D structure of the ATP-binding pocket of Aurora A kinase a tool to identify further competitive inhibitors of Aurora A kinase.
  • the present invention provides compounds capable of inhibiting Aurora kinase activity, in particular Aurora A kinase activity by competitively binding to the ATP-binding site of Aurora kinases. Data presented herein establishes that compounds of formula (I) can inhibit Aurora kinase, in particular Aurora A kinase activity.
  • the present invention relates to the use of a compound of formula (I)
  • R 1 is alkyl, cycloalkyl, heterocylcoalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted;
  • R 2 and R 3 are independent of each other selected from H; halogen; CN; NO 2 ; NR 7 R 8 ; alkyl, alkyloxy, aryl or heteroaryl, optionally substituted; wherein R 7 and R 8 are independent of each other hydrogen, alkyl, alkenyl, or alkynyl,
  • R 4 is alkyl, optionally interrupted one or more times by O, N or S; -OOC-R 6 ; -COO-R 6' ; alkoxy; aryl; heteroaryl; aralkyl; heteroaralkyl; optionally substituted wherein R 6 is alkyl, alkenyl, alkynyl, aryl or heteroaryl; optionally substituted and R 6 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl; optionally substituted R 5 is H, alkyl, alkenyl, alkynyl, optionally substituted or R 1 and R 5 are taken together to form a heteroaryl or heterocylcoalkyl; optionally substituted and pharmaceutically acceptable salts thereof, for the production of a medicament for treating, ameliorating or preventing diseases, conditions and/or disorders which benefit from a reduced aurora kinase activity.
  • the compound has a structure according to formula (VII)
  • the present invention is directed at a method of identifying a compound structure that can bind to the ATP binding pocket of Aurora A kinase, comprising the steps of:
  • the present invention is directed at a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of at least one compound of the present invention and a pharmaceutically acceptable carrier or excipient.
  • the present invention is directed at the use of a compound of the invention for the production of a medicament for treating, ameliorating or preventing diseases, conditions and/or disorders which benefit from a reduced aurora kinase activity.
  • alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alicyclic system, alkenyl, cycloalkenyl, and alkynyl are provided.
  • alkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 e.g. methyl, ethyl methyl, ethyl, propyl, /s ⁇ -propyl, butyl, /so-butyl, te/t-butyl, pentyl, hexyl, heptyl, octyl.
  • Alkyl groups are optionally substituted.
  • heteroalkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 e.g. methyl, ethyl, propyl, /s ⁇ -propyl, butyl, wo-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms.
  • the heteroatoms are selected from O, S, and N, e.g. CH 2 -O-CH 3 , CH 2 -O-C 2 H 5 , C 2 H 4 - 0-CH 3 , C 2 H 4 -O-C 2 H 5 etc.
  • Heteroalkyl groups are optionally substituted.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.
  • cycloalkyl and “heterocycloalkyl” are also meant to include bicyclic, tricyclic and polycyclic versions thereof.
  • bicyclic, tricyclic or polycyclic rings are formed it is preferred that the respective rings are connected to each other at two adjacent carbon atoms, however, alternatively the two rings are connected via the same carbon atom, i.e. they form a spiro ring system or they form "bridged" ring systems.
  • heterocycloalkyl preferably refers to a saturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms.
  • Cycloalkyl and “heterocycloalkyl” groups are optionally substituted.
  • a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • Preferred examples of cycloalkyl include C 3 -Cio-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo
  • heterocycloalkyl examples include C 3 -C 10 - heterocycloalkyl, in particular l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro- [5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 di
  • alicyclic system refers to mono, bicyclic, tricyclic or polycyclic version of a cycloalkyl or heterocycloalkyl comprising at least one double and/or triple bond.
  • an alicyclic system is not aromatic or heteroaromatic, i.e. does not have a system of conjugated double bonds/free electron pairs.
  • the number of double and/or triple bonds maximally allowed in an alicyclic system is determined by the number of ring atoms, e.g. in a ring system with up to 5 ring atoms an alicyclic system comprises up to one double bond, in a ring system with 6 ring atoms the alicyclic system comprises up to two double bonds.
  • the "cycloalkenyl" as defined below is a preferred embodiment of an alicyclic ring system.
  • Alicyclic systems are optionally substituted.
  • aryl preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing 10 carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphthalenyl or anthracenyl. The aryl group is optionally substituted.
  • alkyl refers to an alkyl moiety, which is substituted by aryl, wherein alkyl and aryl have the meaning as outlined above.
  • An example is the benzyl radical.
  • the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl, propyl, is ⁇ -propyl, butyl, iso-butyl, sec-butenyl, ter/-butyl, pentyl, hexyl, heptyl, octyl.
  • the aralkyl group is optionally substituted at the alkyl and/or aryl part of the group.
  • the aryl attached to the alkyl has the meaning phenyl, naphthalenyl or anthracenyl.
  • heteroaryl preferably refers to a five or six-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1, 2, or 3 (for the five membered ring) or 1, 2, 3, or 4 (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S; an aromatic bicyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 8, 9, 10, 11 or 12 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S; or an aromatic tricyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 13, 14, 15, or 16 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S.
  • heteroarylkyl refers to an alkyl moiety, which is substituted by heteroaryl, wherein alkyl and heteroaryl have the meaning as outlined above.
  • An example is the (2- pyridinyl) ethyl, (3-pyridinyl) ethyl, or (2-pyridinyl) methyl.
  • the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g.
  • heteroaralkyl group is optionally substituted at the alkyl and/or heteroaryl part of the group.
  • the heteroaryl attached to the alkyl has the meaning oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3- triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzo
  • alkenyl and cycloalkenyl refer to olefinic unsaturated carbon atoms containing chains or rings with one or more double bonds. Examples are propenyl and cyclohexenyl.
  • the alkenyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g.
  • the cycloalkenyl ring comprises from 3 to 14 carbon atoms, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, e.g.
  • alkynyl refers to unsaturated carbon atoms containing chains or rings with one or more triple bonds.
  • An example is the propargyl radical.
  • the alkynyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, heptynyl, octynyl.
  • carbon atoms or hydrogen atoms in alkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more elements selected from the group consisting of O, S, and N or with groups containing one ore more elements selected from the group consisting of O, S, and N.
  • Embodiments include alkoxy, cycloalkoxy, aryloxy, aralkoxy, alkenyloxy, cycloalkenyloxy, alkynyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, alkenylthio, cycloalkenylthio, alkynylthio, alkylamino, cycloalkylamino, arylamino, aralkylamino, alkenylamino, cycloalkenylamino, alkynylamino radicals.
  • hydrogen atoms in alkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one ore more halogen atoms.
  • One radical is the trifluoromethyl radical.
  • radicals can be selected independently from each other, then the term “independently” means that the radicals may be the same or may be different.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention. Suitable pharmaceutically acceptable salts of the compound of the present invention include acid addition salts which may, for example, be formed by mixing a solution of compounds of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate).
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sul
  • Illustrative examples of pharmaceutically acceptable salts include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of formula (I).
  • a prodrug is a pharmacologically active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme.
  • prodrugs are well known by those skilled in the art.
  • Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups have been masked as esters and ethers.
  • EP 0 039 051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • the starting materials can also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the present invention.
  • the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry at a sterogenic center is (S) or (R).
  • the compounds having one stereochemistry e.g., (R)
  • Certain compounds of the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.
  • the compounds of this invention include mixtures of stereoisomers, especially mixtures of enantiomers, as well as purified stereoisomers, especially purified enantiomers, or stereoisomerically enriched mixtures, especially enantiomerically enriched mixtures.
  • the individual isomers of the compounds represented by formulas (I) and (VII) below as well as any wholly or partially equilibrated mixtures thereof.
  • the present invention also covers the individual isomers of the compounds represented by the formulas below as mixtures with isomers thereof in which one or more chiral centers are inverted.
  • Racemates obtained can be resolved into the isomers mechanically or chemically by methods known per se.
  • Diastereomers are preferably formed from the racemic mixture by reaction with an optically active resolving agent.
  • suitable resolving agents are optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids, such as -camphorsulfonic acid.
  • optically active resolving agent for example dinitrobenzoylphenylglycine
  • an example of a suitable eluent is a hexane/isopropanol/acetonitrile mixture.
  • the diastereomer resolution can also be carried out by standard purification processes, such as, for example, chromatography or fractional crystallization.
  • optically active compounds of formulas (I) and (VII) by the methods described above by using starting materials which are already optically active.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • the present invention provides compositions, compounds and uses of compounds for inhibiting Aurora kinase, in particular Aurora A kinase in a cell.
  • the compositions which are useful as inhibitors will typically be those which contain an effective amount of an Aurora kinase inhibitory compound.
  • an effective amount of an aurora kinase inhibitory compound is a concentration of the compound that will produce a 50 percent decrease in an Aurora kinase activity assay as described in the examples below.
  • the present invention provides the use of compounds of formula (I)
  • R 1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aralkyl; or heteroaralkyl; optionally substituted, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO 2 ; NR 7 R 8 ; alkyl, in particular Cj- C 6 alkyl, e.g.
  • Ci C 2 , C 3 , C 4 , Cs, or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 ,
  • alkanoyl preferably Cj-C 6 alkanoyl, e.g. Cj, C 2 , C 3 , C 4 , C 5 , or C 6 alkanoyl
  • alkenoyl in particular C 3 -C 6 alkenoyl, e.g. C 3 , C 4 , C 5 , or C 6 alkenoyl, preferably propenoyl
  • alkynoyl in particular C 3 -C 6 alkynoyl, e.g.
  • alkoxy in particular Cj-C 6 alkoxy, e.g. Cj, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, preferably methoxy, ethoxy, propoxy, z ' so-propoxy, butoxy, wo-butoxy, tert-butoxy, pentoxy, or hexoxy
  • alkoxyalkyl in particular Ci-C 6 alkoxy-Ci-C 6 alkyl, e.g.
  • aryl in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazin
  • R 7 and R 8 are independent of each other hydrogen, alkyl, in particular Ci-C 6 alkyl, e.g.
  • Ci C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, alkenyl, in particular C 2 -C 6 alkenyl, e.g. C 2 , C 3 , C 4 , Cs, or C 6 alkenyl, or alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; optionally substituted; or R 7 and R 8 together form a heterocycle; optionally substituted; R 9 is alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 ,
  • R 10 is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; or two or more of substituents of R 1 are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, optionally substituted; optionally the alkyl moiety of R 1 , including the alkyl moiety of the aralkyl and the heteroaralkyl moiety, respectively is interrupted 1, 2, 3, 4 or more times by O, N, and/or
  • R 1 are substituents of the aryl and heteroaryl moiety, respectively;
  • R 2 and R 3 are independent of each other selected from H; halogen; CN; NO 2 ; NR 7 R 8 ; alkyl, alkyloxy, aryl or heteroaryl, optionally substituted, preferably both R 2 and R 3 are H; wherein R 7 and R 8 are independent of each other hydrogen, alkyl, alkenyl, or alkynyl, R 4 is alkyl, optionally interrupted one or more times by O, N or S; -OOC-R 6 ; -COO-R 6 ; alkoxy; aryl; heteroaryl; aralkyl; heteroaralkyl; optionally substituted, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO 2 ; NR 7 R 8 ; alkyl, in particular Ci-
  • halogen e.g. F
  • C 6 alkyl e.g. Cj, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or Ce alkynyl; alkanoyl, preferably CpC 6 alkanoyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or
  • alkenoyl in particular C 3 -C 6 alkenoyl, e.g. C 3 , C 4 , C 5 , or C 6 alkenoyl, preferably propenoyl
  • alkynoyl in particular C 3 -C 6 alkynoyl, e.g. C 3 , C 4 , C 5 , or C 6 alkynoyl, preferably propynoyl
  • alkoxy in particular Ci-C 6 alkoxy, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, preferably methoxy, ethoxy, propoxy, w ⁇ -propoxy, butoxy, wobutoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C 6 alkoxy-Ci-C 6 alkyl, e.g.
  • R 7 and R 8 are independent of each other hydrogen, alkyl, in particular Ci-C 6 alkyl, e.g.
  • R 9 is alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 ,
  • R 10 is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; or two or more of substituents of R 4 are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, optionally substituted; R 6 is alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular Ci-C 6 alkyl, e.g.
  • C 6 alkenyl, or alkynyl in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; optionally substituted;
  • R 6 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular Ci-C 6 alkyl, e.g. Ci,
  • alkenyl in particular C 2 -C 6 alkenyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl, or alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; optionally substituted;
  • R 5 is H, alkyl, alkenyl, alkynyl; optionally substituted, preferably H; or R 1 and R 5 are taken together to form a heteroaryl or heterocycloalkyl; optionally substituted and pharmaceutically acceptable salts thereof, for the production of a medicament for the for treating, ameliorating or preventing diseases, conditions and/or disorders which benefit from a reduced aurora kinase activity.
  • Preferred salts comprise Na + , K + , and Ca 2+ salts.
  • Lie is a conventional leaving group such as halogen, sulfonyl or the like or is an activating group for the sulfonyl group, i.e. an activated ester.
  • the above process comprises reacting a compound of the genera formula (1) with a thienylsulfonyl group providing agent of the general formula (2) in an organic solvent to obtain a compound of the general formula (3).
  • the compound of the general formual (3) may be reacted with an alkylating agent in the presence of a base to give a compound of the general formula (5), wherein the nitrogen residue is substituted with R and wherein R does not mean hydrogen.
  • the reaction may be carried out in a conventional organic solvent such as, for example, tetrahydrofuran, dichloromethane, acetonitrile, chloroform and dimethylformamide.
  • reaction is preferably carried out in the presence of a coupling agent such as a conventional inorganic or an organic base.
  • Such conventional inorganic or organic bases used in the reaction may include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and DBU.
  • the reaction may be carried out at a temperature between 3°C and boiling point of the solvent used, preferably at 50 0 C-IOO 0 C and for 5-48 hours, preferably for 10-24 hours. Then, the compound of the formula (3) may be reacted with an alkylating agent
  • the alkylating agent used in the above step may include alkylhalide, preferably (C 1-8 )- alkylhalide; alkylsulfonate, preferably (Ci -8 )-alkylsulfonate; alkenyl halide, preferably (Ci -8 )- alkenyl halide; alkynyl halide, preferably (Ci -8 )-alkynyl halide; alkenyl sulfonate, preferably (Ci-
  • alkynyl sulfonate preferably (Ci ⁇ -alkynyl sulfonate;which all may or may not be substituted as indicated in more detail below.
  • Substituted or unsubstituted (C] -8 )-alkylhalide preferably means methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl chloride, propyl bromide, propyl iodide, butyl chloride, butyl bromide, butyl iodide, pentyl chloride, pentyl bromide, pentyl iodide, bromo ehtylacetate or the like.
  • Substituted or unsubstituted (Ci.g)-alkylsulfonate preferably means methyl sulfonate, ethyl sulfonate, propyl sulfonate, butyl sulfonate, pentyl sulfonate or the like.
  • the reaction may be carried out in a conventional organic solvent as such as, for example, tetrahydrofuran, dichloromethane, chloroform, dimethyl sulfoxide,acetonitrile and dimethylformamide.
  • a conventional organic solvent as such as, for example, tetrahydrofuran, dichloromethane, chloroform, dimethyl sulfoxide,acetonitrile and dimethylformamide.
  • the conventional inorganic or organic base used in above step may include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and DBU.
  • a basic material may be added as a scavenger in order to eliminate the acid material from the reaction phase.
  • Such basic material may be alkali metal hydroxide, alkali earth metal hydroxide, alkali metal oxide, alkali earth metal oxide, alkali metal carbonate, alkali earth metal carbonate, alkali metal hydrogen carbonate, alkali earth metal hydrogen carbonate such as for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, potassium carbonate, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium bicarbonate, calcium bicarbonate or the like, and organic amines.
  • R 2 , R 3 , or R 4 or any substituent of R 1 , R 2 , R 3 , R 4 , and/or R 5 which would undergo unwanted reactions when carrying out a synthesis according to scheme I may be protected by a conventional protecting group, which is cleavable under known conditions.
  • a conventional protecting group which is cleavable under known conditions.
  • the skilled person is aware of a large variety of protection groups, which can be employed in organic synthesis.
  • Protecting groups are reviewed in, for example, Wuts, P.G.M. and Greene, T. W., Protective Groups in Organic Chemistry, 3 rd Ed., 1999; Wily & Sons Inc. and in Kocienski, P. J., Protecting groups. 2 nd Ed., 2000, Thieme Medical Publishing.
  • Protecting groups are organized in these reference books according to the functionalities that are protected as well as according to the conditions which remove the respective protecting groups selectively.
  • Particularly preferred protective groups, which can be used are:
  • protective group removed at acidic conditions preferably at a pH between 4 and 6, which is selected from the group consisting of Boc or Trityl protecting groups;
  • a protecting group removed by a nucleophile which is selected from the group consisting of Fmoc or Dde protecting groups
  • a protecting group removed by radiation which is selected from the group consisting of nitroveratryloxy carbonyl, nitrobenzyloxy carbonyl, dimethyl dimethoxybenzyloxy carbonyl, 5-bromo-7-nitroindolinyl, o-hydroxy- ⁇ -methyl cinnamoyl, and 2-oxymethylene anthraquinone.
  • R 1 is selected from the group consisting of phenyl, napthyl, anthracenyl, furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3- triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzo furanyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl,
  • R 1 is IH- indazolyl, which is preferably attached to the amine at position 6 of the indazolyl ring system.
  • R 1 is selected form the group consisting of (2-furanyl) methyl, (3-furanyl) methyl, (2-furanyl) ethyl, (3-furanyl) ethyl, (2-oxazolyl) methyl, (4-oxazolyl) methyl, (5-oxazolyl) methyl, (2-oxazolyl) ethyl, (4-oxazolyl) ethyl, (5-oxazolyl) ethyl, (2- isoxazolyl) methyl, (3 -isoxazolyl) methyl, (4-isoxazolyl) methyl, (2-isoxazolyl) ethyl, ethyl (3- isoxazolyl), ethyl (4-isoxazolyl), (3
  • alkyl in particular C,-C 6 alkyl, e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyi, tert-butyl, pentyl, hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1- /so-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; alkanoyl, preferably Ci-C 6 alkanoyl, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkanoyl; alkenoyl, in particular C 3 -C 6 alkenoyl, e.g. C 3 , C 4 , C 5 , or C 6 alkenoyl, preferably propenoyl; alkynoyl, in particular C 3 -C 6 alkynoyl, e.g. C 3 , C 4 , C 5 , or C 6 alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C 6 alkoxy, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C5, or C 6 alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, zso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C 6 alkoxy-Ci-C 6 alkyl, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, alkenyl, in particular C 2 -C 6 alkenyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl, or alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; optionally substituted; or R 7 and R 8 together form a heterocycle; optionally substituted; R 9 is alkyl, alkenyl, alkynyl, in particular Ci-C 6 alkyl, e.g.
  • R 10 is hydrogen, alkyl, alkenyl, alkynyl, in particular C]-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , Cs, or C 6 alkyl.
  • R 1 has a structure according to formulas (II) to (V)
  • A, B, and C are each independently of each other selected from carbon, oxygen, sulphur and nitrogen atoms, with the proviso that at least one of A, B, and D is a carbon atom. More preferably A is a nitrogen atom and B and D are carbon atoms; A is a nitrogen atom B is a sulphur atom or an oxygen atom and D is a carbon atom; A is a nitrogen atom, D is a sulphur atom or an oxygen atom and B is a carbon atom; or A and B are nitrogen atoms and D is a carbon atom;
  • R 11 is halogen, e.g. F, Cl, Br or I; CN; NO 2 ; NR 7 R 8' ; alkyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-w ⁇ -propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; alkanoyl, preferably C]-C 6 alkanoyl, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkanoyl; alkenoyl, in particular C 3 -C 6 alkenoyl, e.g. C 3 , C 4 , C 5 , or C 6 alkenoyl, preferably propenoyl; alkynoyl, in particular C 3 -C 6 alkynoyl, e.g. C 3 , C 4 , C 5 , or C 6 alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C 6 alkoxy, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, preferably methoxy, ethoxy, propoxy, iso-p ⁇ opoxy, butoxy, iso-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C 6 alkoxy-Ci-C 6 alkyl, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, alkenyl, in particular C 2 -C 6 alkenyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl, or alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl, optionally substituted; or R 7 and R 8 together form a heterocycle; optionally substituted; R 9 is alkyl, alkenyl, alkynyl, in particular Ci-C 6 alkyl, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; optionally substituted; and R 10 is hydrogen, alkyl, alkenyl, alkynyl, in particular Cj-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 ,
  • C 5 , or C 6 alkyl optionally substituted; m is 0, 1 , 2, or, 3 preferably 0 or 1 ; R 12 is halogen, e.g. F, Cl, Br or I; CN; NO 2 ; NR r R 8" ; alkyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-buty ⁇ , pentyl, hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-w ⁇ -propenyl, 2-/so-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; alkanoyl, preferably Ci-C 6 alkanoyl, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkanoyl; alkenoyl, in particular C 3 -C 6 alkenoyl, e.g. C 3 , C 4 , C 5 , or C 6 alkenoyl, preferably propenoyl; alkynoyl, in particular C 3 -C 6 alkynoyl, e.g. C 3 , C 4 , C 5 , or C 6 alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C 6 alkoxy, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, preferably methoxy, ethoxy, propoxy, is ⁇ -propoxy, butoxy, wo-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Cj-C 6 alkoxy-Ci-C 6 alkyl, e.g.
  • R 7 and R 8 are independent of each other hydrogen, alkyl, in particular Ci-C 6 alkyl, e.g.
  • R 9 is alkyl, alkenyl, alkynyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; optionally substituted; and R 10 is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 ,
  • n 0, 1 , 2, or 3, preferably 0 or 1.
  • the substituents according to formulas (II) to (V) comprise one or two nitrogen atoms.
  • one nitrogen atom may be substituted, preferably with alkyl, in particular Ci-C 6 alkyl, e.g. Cj, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, alkenyl, in particular C 2 -C 6 alkenyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl, or alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or
  • R has a structure according to formula (VI)
  • R 11 is halogen, e.g. F, Cl, Br or I; CN; NO 2 ; NR 7 R 8' ; alkyl, in particular C 1 -C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, wo-butyl, tert-buty ⁇ , pentyl, hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; alkanoyl, preferably Ci-C 6 alkanoyl, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkanoyl; alkenoyl, in particular C 3 -C 6 alkenoyl, e.g. C 3 , C 4 , C 5 , or C 6 alkenoyl, preferably propenoyl; alkynoyl, in particular C 3 -C 6 alkynoyl, e.g. C 3 , C 4 , C 5 , or C 6 alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C 6 alkoxy, e.g.
  • Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy preferably methoxy, ethoxy, propoxy, /s ⁇ -propoxy, butoxy, wo-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C 6 alkoxy-Ci-C ⁇ alkyl, e.g.
  • R 7 and R 8 are independent of each other hydrogen, alkyl, in particular Ci-C 6 alkyl, e.g.
  • R 9 is alkyl, alkenyl, alkynyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; optionally substituted; and R 10 is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 ,
  • R 12 is halogen, e.g. F, Cl, Br or I; CN; NO 2 ; NR 7" R 8" ; alkyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, /s ⁇ -butyl, ter/-butyl, pentyl, hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1-propenyl, 2-propenyl, 1-w ⁇ -propenyl, 2-/s ⁇ -propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; alkanoyl, preferably Ci-C 6 alkanoyl, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkanoyl; alkenoyl, in particular C 3 -C 6 alkenoyl, e.g. C 3 , C 4 , C 5 , or C 6 alkenoyl, preferably propenoyl; alkynoyl, in particular C 3 -C 6 alkynoyl, e.g. C 3 , C 4 , C5, or C 6 alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C 6 alkoxy, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, wo-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C 6 alkoxy-Ci-C 6 alkyl, e.g.
  • R 7 and R 8 are independent of each other hydrogen, alkyl, in particular Ci-C 6 alkyl, e.g.
  • R 9 is alkyl, alkenyl, alkynyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; optionally substituted; and R 10 is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 ,
  • n 0, 1, 2, or 3, preferably 0 or 1, depending on the number of heteroatoms.
  • R 6 or R 6 is Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; optionally substituted. It is particularly preferred that R 6 has this meaning, if R 1 has the meaning heteroaryl, heterocycloalkyl or forms together with R 5 a heteroaryl or heterocycloalkyl.
  • R 1 has the meaning furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3- triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzo furanyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazo
  • This structure may be substituted one or more times, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO 2 ; NR 7 R 8 ; alkyl, in particular C 1 -C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, /so-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C 2 -C 6 alkenyl, e.g.
  • alkenyl preferably ethenyl, 1 -propenyl, 2-propenyl, l-/s ⁇ -propenyl, 2- /so-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; alkanoyl, preferably Ci-C 6 alkanoyl, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkanoyl; alkenoyl, in particular C 3 -C 6 alkenoyl, e.g. C 3 , C 4 , C 5 , or C 6 alkenoyl, preferably propenoyl; alkynoyl, in particular C 3 -C 6 alkynoyl, e.g. C 3 , C 4 , C 5 , or C 6 alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C 6 alkoxy, e.g.
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, iso-butoxy, ter /-butoxy, pentoxy, or hexoxy; alkoxy alkyl, in particular CpC 6 alkoxy-Ci-C 6 alkyl, e.g.
  • alkenyl in particular C 2 -C 6 alkenyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkenyl, or alkynyl, in particular C 2 -C 6 alkynyl, e.g. C 2 , C 3 , C 4 , C 5 , or C 6 alkynyl; optionally substituted; or R 7 and R 8 together form a heterocycle; optionally substituted; R 9 is alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular C]-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 ,
  • R 10 is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular Ci-C 6 alkyl, e.g. Cj,
  • the compounds used in the present invention show an Aurora kinase, preferably an Aurora A kinase inhibiting activity, preferably they have an IC 50 of 500 ⁇ M or less, preferably of 50 ⁇ M, more preferably of 10 ⁇ M or less, and more preferably of 1 ⁇ M or less.
  • This activity is preferably measured in a biological assay, for example, an in vitro Aurora kinase assay, for example, as set out below.
  • the Aurora kinase inhibitors used in the present invention preferably have an IC 50 in the range from about 0.001 ⁇ M to about 50 ⁇ M, more preferably about in the range from about 0.001 ⁇ M to about 10 ⁇ M or less, or more preferably in the range from about 0.001 ⁇ M to about 1 ⁇ M or less.
  • the inhibitors of the present invention preferentially inhibit Aurora A kinase.
  • An compound usable in the present invention is considered an Aurora A kinase specific inhibitor, if th IC 50 for the compound is at least 20%, preferably 30%, more preferably 40%, more preferably 50%, more preferably 60% or more lower for Aurora kinase A than for other Aurora kinases, in particular Aurora kinase B and/or Aurora kinase C.
  • the present invention relates to the compounds of formula (I) and any preferred or particularly preferred embodiment thereof the use of which is outlined above, e.g. a compound according to formula (VII).
  • the present invention relates to a method of identifying a compound structure that can bind to the ATP binding pocket of Aurora A kinase, comprising the steps of:
  • a kinase Preferably, such candidate compound makes contacts in the ATP binding pocket of
  • Aurora A kinase which are similar or identical to the contacts of methyl 3-(lH-indazol-6- ylsulfamoyl)thiophene-2-carboxylate.
  • a compound is considered to make similar contacts, if it contacts at least with 2, preferably 3, 4, 5, 6, 7, 8, 9 or more amino acids of Aurora A kinase, preferably in the ATP-binding pocket, which are also contacted by methyl 3-(lH-indazol-6- ylsulfamoyl)thiophene-2-carboxylate.
  • a three dimensional structure of Aurora A kinase which substantially conforms to a specified set of atomic coordinates can be modeled by a suitable modeling computer program such as MODELER (A. SaIi and T. L. Blundell, J. MoI. Biol., vol. 234:779-815, 1993 as implemented in the Insight II Homology software package (Insight II (97.0), MSI, San Diego)), using information, for example, derived from the following data: (1) the amino acid sequence of the Aurora A kinase protein; and, (2) the atomic coordinates of the specified three dimensional configuration as set out in Fig. 4.
  • MODELER A. SaIi and T. L. Blundell, J. MoI. Biol., vol. 234:779-815, 1993 as implemented in the Insight II Homology software package (Insight II (97.0), MSI, San Diego)
  • a three dimensional structure of an Aurora A kinase protein which substantially conforms to a specified set of atomic coordinates can also be calculated by a method such as molecular replacement.
  • a suitable three dimensional structure of an Aurora A kinase protein for use in modeling or calculating the three dimensional structure of Aurora kinase protein comprises the set of atomic coordinates represented in Fig. 4.
  • the set of three dimensional coordinates set forth in Fig. 4 is represented in standard Protein Data Bank format and also comprise a preferred competitive inhibitor.
  • the coordinates of the inhibitor may be disregarded for the purpose of modeling a three dimensional structure of Aurora kinase protein.
  • a preferred structure of an Aurora kinase protein substantially conforms to the atomic coordinates, and the B-values and/or the thermal parameters represented in Fig. 4. Such values as listed in Fig. 4 can be interpreted by one of skill in the art.
  • a more preferred three dimensional structure of an Aurora kinase protein substantially conforms to the three dimensional coordinates represented in Fig. 4.
  • An even more preferred three dimensional structure of an Aurora kinase is a most probable fit with the three dimensional coordinates represented in Fig. 4. Methods to determine a substantially conforming and probable fit are within the expertise of skill in the art.
  • a preferred Aurora kinase protein that has a three dimensional structure which substantially conforms to the atomic coordinates represented by Fig. 4 includes an Aurora kinase proteins having an amino acid sequence that is at least about 25%, preferably at least about 30%, more preferably at least about 40%, more preferably at least about 50%, more preferably at least about 60%, more preferably at least about 70%, more preferably at least about 80%, more preferably at least about 90% and most preferably 100% identical to an amino acid sequence of Aurora A kinase protein, preferably as set out in GeneBank Ace. No. NM l 98434.
  • a three dimensional structure of an Aurora kinase protein preferably of Aurora A kinase can be used to derive a model of the three dimensional structure of another Aurora kinase (i.e., a structure to be modeled).
  • a "structure” of a protein refers to the components and the manner of arrangement of the components to constitute the protein.
  • model refers to a representation in a tangible medium of the three dimensional structure of a protein, polypeptide or peptide.
  • a model can be a representation of the three dimensional structure in an electronic file, on a computer screen, on a piece of paper (i.e., on a two dimensional medium), and/or as a ball-and- stick figure.
  • Physical three-dimensional models are tangible and include, but are not limited to, stick models and space-filling models.
  • imaging the model on a computer screen refers to the ability to express (or represent) and manipulate the model on a computer screen using appropriate computer hardware and software technology known to those skilled in the art. Such technology is available from a variety of sources including, for example, Evans and Sutherland, Salt Lake City, Utah, and Biosym Technologies, San Diego, Calif.
  • the phrase "providing a picture of the model” refers to the ability to generate a "hard copy" of the model. Hard copies include both motion and still pictures.
  • Computer screen images and pictures of the model can be visualized in a number of formats including space-filling representations, ⁇ -carbon traces, ribbon diagrams (see, for example, Fig. 3 which is a three-dimensional structure of the ATP-binding pocket of human Aurora A kinase with the bound inhibitor.
  • the compound structure contacts one or more of the amino acids residues of the ATP binding pocket, preferably the amino acid residues as defined by compound (VII), i.e.
  • the compound structure contacts 1, 2, 3, 4, 5, 6, 7, 8, 9 or more amino acids in the ATP binding pocket, in particular 1 or more amino acids selected from the group consisting of Leul39, Vall47, Alal ⁇ O, Lysl62, Glu260, Asn261, Leu263, Ala273, Asp274.
  • the compound structure additional contacts one or more residues in the 'hinge region', in particular Leu210, Glu211 and/or Tyr212.
  • candidate compound structures that inhibit Aurora kinase activity can be designed entirely de novo or may be based upon one of the pre-existing competitive Aurora kinase inhibitors like, e.g. methyl 3-(lH-indazol-6- ylsulfamoyl)thiophene-2-carboxylate .
  • Aurora kinase inhibitors like, e.g. methyl 3-(lH-indazol-6- ylsulfamoyl)thiophene-2-carboxylate .
  • Either of these approaches can be facilitated by computationally screening databases and libraries of small molecules for chemical entities, agents, ligands, or compounds that can bind in whole, or in part, to the ATP-binding pocket of Aurora kinases, in particular of Aurora A kinase.
  • the quality of fit of such entities or compounds to the binding site or sites may be judged either by shape complementarity or by estimated interaction energy (Meng et al (1992) J. Comp. Chem. 13: 505-524).
  • the design of molecules that bind to or inhibit the functional activity of Aurora kinases according to this invention generally involves consideration of two factors. First, the molecule must be capable of physically and structurally associating with the ATP-binding pocket of Aurora kinases, in particular of Aurora A kinase.
  • Non-covalent molecular interactions important in the association of the ATP-binding pocket of Aurora kinases, in particular of Aurora A kinase with the compound structure include hydrogen bonding, van der Waals and hydrophobic interactions.
  • the molecule must be able to assume a conformation that allows it to associate with the ATP-binding pocket. Although certain portions of the molecule may not directly participate in this association with the ATP-binding pocket those portions may still influence the overall conformation of the molecule. This, in turn, may have a significant impact on binding affinities, therapeutic efficacy, drug-like qualities, and potency.
  • conformational requirements include the overall three-dimensional structure and orientation of the chemical entity or molecule in relation to all or a portion of the ATP-binding pocket of Aurora kinases or the spacing between functional groups of a molecule comprising several chemical entities that directly interact with the ATP-binding pocket.
  • the potential, predicted, inhibitory or binding effect of a molecule on Aurora kinase, in particular on Aurora A kinase may be analyzed prior to its actual synthesis and testing by the use of computer modeling techniques. If the theoretical structure of the given molecule suggests insufficient interaction and association between it and the ATP-binding pocket, synthesis and testing of the molecule is obviated. However, if computer modeling indicates a strong interaction, the molecule may then be synthesized and tested for its ability to interact with the ATP-binding pocket and inhibit kinase activity. In this manner, synthesis of inoperative molecules may be avoided.
  • inactive molecules are synthesized predicted on modeling and then tested to develop a SAR (structure-activity relationship) for molecules interacting with a specific region of the ATP-binding pocket of Aurora kinases, in particular of Aurora A kinase.
  • SAR structure-activity relationship
  • the term "SAR" shall collectively refer to the structure- activity/structure property relationships pertaining to the relationship(s) between a compound's activity/properties and its chemical structure.
  • One skilled in the art may use one of several methods to identify compound structures or entities, compounds, or other agents for their ability to associate with the ATP-binding pocket of Aurora kinases. This process may begin by visual inspection or computer assisted modeling of, for example, the target site on the computer screen based on the atomic co-ordinates of the ATP- binding pocket of Aurora A kinases and/or its complexes with the compounds of the present invention (see Fig. 4).
  • compound design uses computer modeling programs which calculate how different molecules interact with the ATP-binding site.
  • Selected chemical moieties or entities, compounds, or agents may then be positioned in a variety of orientations, or docked, within at least a portion of the ATP-binding pocket of Aurora kinases, in particular of Aurora A kinase.
  • Databases of chemical structures are available from, for example, Cambridge Crystallographic Data Center (Cambridge, U.K.) and Chemical Abstracts Service (Columbus, Ohio). Docking may be accomplished using software such as Cerius, Quanta or Sybyl, followed by energy minimization and molecular dynamics with standard molecular mechanics forcefields, such as OPLS-AA, CHARMM or AMBER.
  • Specialized computer programs may also assist in the process of selecting chemical entities. These include, but are not limited to: (1) GRID (Goodford, P. J., "A Computational Procedure for Determining Energetically Favorable Binding Sites on Biologically Important Macromolecules” (1985) J. Med. Chem. 28, 849-857).
  • Software such as GRID, a program that determines probable interaction sites between probes with various functional group characteristics and the macromolecular surface, can be used to analyze the surface sites to determine structures of similar inhibiting proteins or molecules.
  • the GRID calculations, with suitable inhibiting groups on molecules (e.g., protonated primary amines) as the probe, are used to identify potential hotspots around accessible positions at suitable energy contour levels.
  • GRID is available from Oxford University, Oxford, UK.
  • MCSS is available from Molecular Simulations, Burlington, Mass.
  • AUTODOCK Goodsell, D. S. and A. J. Olsen (1990) "Automated Docking of Substrates to Proteins by Simulated Annealing" Proteins: Structure, Function, and Genetics 8: 195- 202).
  • AUTODOCK is available from Scripps Research Institute, La Jolla, Calif.
  • DOCK Zantz, I. D. et al. (1982) "A Geometric Approach to Macromolecule-Ligand Interactions" J. MoI. Biol. 161 : 269-288).
  • DOCK may be used to analyze an active site or ligand binding site and suggest ligands with complementary steric properties. DOCK is available from University of California, San Francisco, Calif.
  • ALADDIN An Integrated Tool of Computer Assisted Molecular Design and Pharmacophore Recognition From Geometric, Steric and Substructure Searching of Three-Dimensional Structures" J. Comp- Aided MoI. Des. 3: 225).
  • suitable chemical moieties or entities, compounds, or agents can be assembled into a single molecule. Assembly may proceed by visual inspection and/or computer modeling and computational analysis of the spatial relationship of the chemical moieties or entities, compounds or agents with respect to one another in three-dimensional space. This could then be followed by model building using software such as Quanta or Sybyl.
  • CAVEAT Bartlett, P. A. et al. (1989) "CAVEAT: A Program to Facilitate the Structure- Derived Design of Biologically Active Molecules". In molecular Recognition in Chemical and Biological Problems", Special Pub., Royal Chem. Soc. 78: 82-196) and
  • CAVEAT uses databases of cyclic compounds which can act as "spacers" to connect any number of chemical fragments already positioned in the active site. This allows one skilled in the art to quickly generate hundreds of possible ways to connect the fragments already known or suspected to be necessary for tight binding. CAVEAT is available from the University of California,
  • 3D Database systems such as MACCS-3D (MDL Information Systems, San Leandro, (CA). This area is reviewed in Martin, Y. C, (1992) "3D Database Searching in Drug Design", J Med Chem. 35: 2145-2154. (3) HOOK (available from Molecular Simulations, Burlington, Mass.).
  • the molecule of interest may be designed as a whole using either an empty active site or optionally including some portion or portions of an inhibitor of the present invention.
  • Software that implements these methods include:
  • LUDI Bohm, H.-J. (1992) "The Computer Program LUDI: A New Method for the De Novo Design of Enzyme Inhibitors” J. Comp. Aid. Molec. Design 6: 61-78).
  • the program LUDI can determine a list of interaction sites into which to place both hydrogen bonding and hydrophobic fragments. LUDI then uses a library of approximately 600 linkers to connect up to four different interaction sites into fragments. Then smaller "bridging" groups such as — CH 2 — and — COO — are used to connect these fragments. For example, for the enzyme DHFR, the placements of key functional groups in the well-known inhibitor methotrexate were reproduced by LUDI. See also, Rotstein and Murcko, (1992) J. Med. Chem. 36:1700-1710. LUDI is available from Biosym Technologies, San Diego, Calif.
  • LEGEND (Nishibata, Y. and A. Itai (1991) Tetrahedron 47, 8985). LEGEND is available from Molecular Simulations, Burlington, Mass.
  • Programs suitable for pharmacophore selection and design include:
  • DISCO Abbot Laboratories, Abbot Park, 111.
  • knowledge of the spatial relationship between an Aurora kinase inhibitor and the ATP -binding site permits the design of modified inhibitors that may have better binding properties, for example, higher binding affinity and/or specificity, relative to the molecule from which it was derived.
  • knowledge of inhibitor contact sites within the ATP-binding site permits the synthesis of a new molecule that contains, for example, a portion of a first molecule (for example, an antibiotic or an analogue or derivative thereof) that binds to the contact site and another portion that contributes additional functionality.
  • the resulting Aurora kinase inhibitors preferably have a molecular weight no greater than about 1,500, more preferably no greater than about 1,000, more preferably no greater than 750 and, most preferably no greater than about 500.
  • the Aurora kinase inhibitors preferably have a molecular weight in the range from about 150 to about 1500, and more preferably in the range from about 200 to about 1200.
  • the Aurora kinase inhibitors have a minimal inhibitor concentration preferably less than 50 ⁇ M, more preferably less than 10 ⁇ M, more preferably less than 1 ⁇ M and most preferably less than 0.1 to ⁇ M inhibit 50% activity (IC 50 ) in a biological assay, for example, an in vitro kinase assay, for example, as set out below.
  • the Aurora kinase inhibitors preferably have an IC 50 in the range from about 0.001 ⁇ M to about 50 ⁇ M, or in the range from about 0.01 ⁇ M to about 10 ⁇ M, or in the range from about 0.1 ⁇ M to about 1 ⁇ M.
  • the inhibitors of the present invention preferentially inhibit Aurora A kinase.
  • the affinity with which that molecule may bind to the ATP -binding pocket of Aurora kinase may be tested and optimized by computational evaluation and/or by testing biological activity after synthesizing the compound.
  • Candidate molecules may interact with the ATP-binding pocket of Aurora kinase in more than one conformation each of which has a similar overall binding energy.
  • the deformation energy of binding may be considered to be the difference between the energy of the free molecule and the average energy of the conformations observed when the molecule binds to the ATP-binding pocket of the Aurora kinase.
  • a molecule designed or selected as binding to an Aurora kinase ATP-binding pocket may be further computationally optimized so that in its bound state it preferably lacks repulsive electrostatic interaction with the target region.
  • Such non-complementary (e.g., electrostatic) interactions include repulsive charge-charge, dipole-dipole and charge-dipole interactions.
  • the sum of all electrostatic interactions between the inhibitor and the enzyme when the inhibitor is bound to the ATP-binding pocket of Aurora kinase preferably make a neutral or favorable contribution to the enthalpy of binding.
  • Weak binding compounds can also be designed by these methods so as to determine SAR.
  • substitutions may then be made in some of its atoms or side groups in order to improve or modify its binding properties.
  • initial substitutions are conservative, i.e., the replacement group will approximate the same size, shape, hydrophobicity and charge as the original group. It should, of course, be understood that components known in the art to alter conformation should be avoided.
  • substituted chemical compounds may then be analyzed for efficiency of fit to the ATP-binding pocket of Aurora kinase by the same computer methods described in detail, above.
  • the actual ATB-binding site ligands, complexes or mimetics may be crystallized and analyzed using X-ray diffraction.
  • the diffraction pattern co-ordinates are similarly used to calculate the three-dimensional interaction of a ligand and the Aurora kinase to confirm that the ligand binds to the ATP-binding pocket.
  • a compound structure identified by the method of the present invention, which may serve as a lead structure is in a further preferred embodiment produced to test it for its ability to inhibit Aurora kinase activity, in particular Aurora A kinase activity.
  • a compound structure can be, but is not limited to, at least one selected from a lipid, nucleic acid, peptide, small organic or inorganic molecule, chemical compound, element, saccharide, isotope, carbohydrate, imaging agent, lipoprotein, glycoprotein, enzyme, analytical probe, and an antibody or fragment thereof, any combination of any of the foregoing, and any chemical modification or variant of any of the foregoing.
  • a lead molecule may optionally comprise a detectable label.
  • Such labels include, but are not limited to, enzymatic labels, radioisotope or radioactive compounds or elements, fluorescent compounds or metals, chemiluminescent compounds and bioluminescent compounds. Well known methods may be used for attaching such a detectable label to a lead molecule.
  • Methods useful for synthesizing lead molecules such as lipids, nucleic acids, peptides, small organic or inorganic molecules, chemical compounds, elements, saccharides, isotopes, carbohydrates, imaging agents, lipoproteins, glycoproteins, enzymes, analytical probes, antibodies, and antibody fragments are well known in the art.
  • Such methods include the traditional approach of synthesizing one such lead molecule, such as a single defined peptide, at a time, as well as combined synthesis of multiple lead molecules in a one or more containers.
  • Such multiple lead molecules may include one or more variants of a previously identified lead molecule.
  • Methods for combined synthesis of multiple lead molecules are particularly useful in preparing combinatorial libraries, which may be used in screening techniques known in the art.
  • the peptides are synthesized by linking an amino group of an N- ⁇ -deprotected amino acid to a ⁇ -carboxy group of an N- ⁇ -protected amino acid that has been activated by reacting it with a reagent such as dicyclohexylcarbodiimide.
  • a reagent such as dicyclohexylcarbodiimide.
  • the attachment of a free amino group to the activated carboxyl leads to peptide bond formation.
  • the most commonly used N- ⁇ -protecting groups include Boc which is acid labile and Fmoc which is base labile.
  • the C-terminal N- ⁇ -protected amino acid is first attached to the polystyrene beads. Then, the N- ⁇ -protecting group is removed. The deprotected ⁇ -amino group is coupled to the activated a-carboxylate group of the next N- ⁇ -protected amino acid. The process is repeated until the desired peptide is synthesized. The resulting peptides are cleaved from the insoluble polymer support and the amino acid side chains deprotected. Longer peptides, for example greater than about 50 amino acids in length, typically are derived by condensation of protected peptide fragments.
  • a synthetic peptide in accordance with the invention may comprise naturally occurring amino acids, unnatural amino acids, and/or amino acids having specific characteristics, such as, for example, amino acids that are positively charged, negatively charged, hydrophobic, hydrophilic, or aromatic.
  • naturally occurring amino acids refers to the L-isomers of amino acids normally found in proteins.
  • the predominant naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, and lysine. Unless specifically indicated, all amino acids are referred to in this application are in the L-form. Furthermore, as used herein, the term "unnatural amino acids" refers to amino acids that are not naturally found in proteins. For example, selenomethionine.
  • Amino acids that are "positively charged” include any amino acid having a positively charged side chain under normal physiological conditions.
  • positively charged naturally occurring amino acids include, for example, arginine, lysine, and histidine.
  • amino acids that are "negatively charged” include any amino acid having a negatively charged side chains under normal physiological conditions.
  • negatively charged naturally occurring amino acids include, for example, aspartic acid and glutamic acid.
  • hydrophobic amino acid includes any amino acids having an uncharged, nonpolar side chain that is relatively insoluble in water.
  • naturally occurring hydrophobic amino acids include, for example, alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine.
  • hydrophilic amino acid refers to any amino acids having an uncharged, polar side chain that is relatively soluble in water. Examples of naturally occurring hydrophilic amino acids include, for example, serine, threonine, tyrosine, asparagine, glutamine and cysteine.
  • aromatic refers to amino acid residues which side chains have delocalized conjugated system.
  • aromatic residues include, for example, phenylalanine, tryptophan, and tyrosine.
  • non-peptide small organic molecules which act as a ligand in the present invention
  • these molecules can be synthesized using standard organic chemistries well known and thoroughly documented in the patent and other literatures.
  • Many of the known methods useful in synthesizing lead of the present invention may be automated, or may otherwise be practiced on a commercial scale. As such, once a lead molecule has been identified as having commercial potential, mass quantities of that molecule may easily be produced.
  • Molecules designed, selected and/or optimized by methods described above, once produced, may be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity.
  • the molecules may be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
  • the Aurora A kinase inhibitory activity of the compound structures identified by the method of the present invention can be assessed.
  • the method further comprises the step of determining whether the compound structure inhibits aurora kinase activity.
  • a compound is considered to inhibit Aurora kinase activity, if the Aurora kinase activity is reduced by more than 50%, preferably by more than 60%, preferably by more than 70%, preferably by more than 80%, preferably by more than 90% at a concentration of 1 mM, if assayed, e.g. in an in vitro kinase assay as set out below.
  • the inhibitory activity is selective for Aurora A kinase.
  • An inhibitor is considered an Aurora A kinase specific inhibitor, if th IC 50 for the compound is at least 20%, preferably 30%, more preferably 40%, more preferably 50%, more preferably 60% or more lower for Aurora kinase A than for other Aurora kinases, in particular Aurora kinase B and/or Aurora kinase C.
  • the method further comprises the step of formulating the Aurora A kinase inhibitor produced with above described method with one or more pharmaceutically acceptable excipient and/or carrier.
  • a further aspect of the present invention is a pharmaceutical composition comprising an effective amount of at least one compound according to formula (I) or any of its preferred embodiments or a compound produced according to the method of the present invention and a pharmaceutically acceptable carrier or excipient.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% to 80%, more preferably from 20% to 70% of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. Liquid forms are particularly preferred for topical applications to the eye. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the present invention concerns the use of compounds produced in above described method in the production of a medicament for treating, ameliorating or preventing diseases, conditions and/or disorders which benefit from reduced aurora kinase activity, in particular Aurora A kinase activity.
  • aurora kinases are known to have a central role in the cell cycle and in particular aurora A kinase shows an elevated expression in more than 50% of colorectal, ovarian and gastric cancers and in more than 95% of invasive adenocarcinomas in a preferred embodiment of the present invention
  • the diseases, conditions and/or disorders, which can be prevented, ameliorated or treated with the compounds of the present invention are hyperproliferative diseases.
  • a disease is considered to benefit from reduced aurora kinase, in particular Aurora A kinase activity, if a reduction of Aurora kinase activity of at least 10%, preferably of at least 20%, preferably of at least 30%, leads to an improvement of at least one clinical indicator of that disease.
  • Examples of such indicators are proliferation rate, which is preferably reduced, cellular differentiation, which is preferably induced etc.
  • the activity of Aurora kinases, in particular Aurora A kinase can be assayed by art know methods, including but not limited to those described below.
  • the hyperproliferative diseases are selected from the group consisting of precancerosis; dysplasia; metaplasia; carcinomas of the gastrointestinal or colorectal tract, liver, pancreas, kidney, bladder, prostate, endometrium, ovary, testes, melanoma, dysplastic oral mucosa, invasive oral cancers, small cell and non-small cell lung carcinomas, hormone-dependent breast cancers, hormone-independent breast cancers, transitional and squamous cell cancers, neurological malignancies including neuroblastoma, gliomas, astrocytomas, osteosarcomas, soft tissue sarcomas, hemangioamas, endocrinological tumors, hematologic neoplasias including leukemias, lymphomas, and other myeloproliferative and lymphoproliferative diseases, carcinomas in situ, hyperplastic lesions, adenomas, f ⁇ bromas, histiocytosis
  • the precancerosis treatable with the compounds of the present invention are preferably selected from the group consisting of precancerosis of the skin, in particular actinic keratosis, cutaneaous horn, actinic cheilitis, tar keratosis, arsenic keratosis, x-ray keratosis, Bowen's disease, bowenoid papulosis, lentigo maligna, lichen sclerosus, and lichen rubber mucosae; precancerosis of the digestive tract, in particular erythroplakia, leukoplakia, Barrett's esophagus, Plummer-Vinson syndrome, crural ulcer, gastropathia hypertrophica gigantea, borderline carcinoma, neoplastic intestinal polyp, rectal polyp, porcelain gallbladder; gynaecological precancerosis, in particular carcinoma ductale in situ (CDIS), cervical intraepithelial ne
  • Dysplasia is frequently a forerunner of cancer, and is found mainly in the epithelia; it is the most disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells.
  • Dysplastic cells often have abnormally large, deeply stained nuclei, and exhibit pleomorphism.
  • Dysplasia characteristically occurs where there exist chronic irritation or inflammation.
  • Dysplastic disorders which can be treated with the compounds of the present invention include, but are not limited to, anhidrotic ectodermal dysplasia, anterofacial dysplasia, asphyxiating thoracic dysplasia, atriodigital dysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia, chondroectodermal dysplasia, cleidocranial dysplasia, congenital ectodermal dysplasia, craniodiaphysial dysplasia, craniocarpotarsal dysplasia, craniometaphysial dysplasia, dentin dysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia, encephalo-ophthalmic dysplasia, dysplasia epiphysialis heminelia, dysplasia epiphysialis multiplex, dysplasia epiphysali
  • Metaplasia is a form of controlled cell growth in which one type of adult or fully differentiated cell substitutes for another type of adult cell.
  • Metaplastic disorders which are treatable are preferably selected from the group consisting of agnogenic myeloid metaplasia, apocrine metaplasia, atypical metaplasia, autoparenchymatous metaplasia, connective tissue metaplasia, epithelial metaplasia, intestinal metaplasia, metaplastic anemia, metaplastic ossification, metaplastic polyps, myeloid metaplasia, primary myeloid metaplasia, secondary myeloid metaplasia, squamous metaplasia, squamous metaplasia of amnion, symptomatic myeloid metaplasia and regenerative metaplasia.
  • keratinocytes and/or T cells are characterized by hyperproliferation of keratinocytes and/or T cells.
  • diseases which are treatable with the compounds of the present invention comprise without limitations psoriasis in particular psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa; neurodermatitis; ichtyosises; alopecia areata; alopecia totalis; alopecia subtotalis; alopecia universalis; alopecia diffusa; atopic dermatitis; lupus erythematodes of the skin; dermatomyositis of the skin; atopic eczema; morphea; scleroderma; alopecia areata Ophiasis type; androgenic alopecia; allergic contact dermatitis; irritative contact dermatitis; contact dermatitis;
  • the hyperproliferative disorders which are treatable by the Aurora kinase inhibitors of the present invention are those which benefit from a reduced estrogen receptor signalling. It is known that an increased activity of genes controlled by estrogen receptor is responsible or contributes to various hyperproliferative diseases.
  • preferred diseases, conditions and/or disorders which can be treated with the compounds of the present invention are selected from the group consisting of mammary tumors, endometrial tumors and tumors of the uterus. The ability of the compounds of the present invention to inhibit estrogen receptor signalling can be confirmed with any of a number of art known methods involving, e.g.
  • ER recognition sequences upstream of reporter genes e.g. CAT, luciferase etc.
  • reporter genes e.g. CAT, luciferase etc.
  • someone of skill in the art is capable of assessing whether a given hyperproliferative disease involves increased estrogen receptor signalling by determining the expression level of an ER controlled gene, e.g. cathepsin D, lactoferrin, or IGF-I etc.
  • the quantity of active component in a unit dose preparation administered in the use of the present invention may be varied or adjusted from about 1 mg to about 1000 mg per m 2 , preferably about 5 mg to about 150 mg/m 2 according to the particular application and the potency of the active component.
  • the pharmaceutical composition can, if desired, also contain other compatible therapeutic agents (e.g., cytotoxic or cytostatic compounds, including, but not limited to, pure or mixed anti -estrogens such as faslodex, tamoxifen or raloxifen; any inhibitors of topoisomerase I or II, such as camptothecin (topo I) or etoposide (topo II); any compound that acts through inhibiting aromatase activity, such as anastrozole or letrozole; any preparation that interferes with HER2 signalling such as herceptin; any compound that interchelates DNA, such as doxorubicin.
  • cytotoxic or cytostatic compounds including, but not limited to, pure or mixed anti -estrogens such as faslodex, tamoxifen or raloxifen; any inhibitors of topoisomerase I or II, such as camptothecin (topo I) or etoposide (topo II);
  • cytostatic or cytotoxic drugs which can be combined with the compounds of the present invention are alkylating substances, anti-metabolites, antibiotics, epothilones, nuclear receptor agonists and antagonists, anti-androgenes, anti-estrogens, platinum compounds, hormones and antihormones, interferons and inhibitors of cell cycle-dependent protein kinases (CDKs), inhibitors of cyclooxygenases and/or lipoxygenases, biogeneic fatty acids and fatty acid derivatives, including prostanoids and leukotrienes, inhibitors of protein kinases, inhibitors of protein phosphatases, inhibitors of lipid kinases, platinum coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analogs, alkylsulfonates, folic acid analogs, anthracendiones, substituted urea, methylhydrazin derivatives, in
  • the compounds employed in this use of the invention are administered at an initial dosage of about 0.05 mg/kg to about 20 mg/kg daily.
  • a daily dose range of about 0.05 mg/kg to about 2 mg/kg is preferred, with a daily dose range of about 0.05 mg/kg to about 1 mg/kg being most preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • Fig. 1 Summarizes the results of various assays performed with a particular preferred compound of the present invention. Depicted are from left to right the IC 50 against Aurora A kinase, kinase activity of Aurora kinase A, B, C and FLT3, the cytotoxicity on
  • Fig 2 Depicts the evidence that methyl 3-(lH-indazol-6-ylsulfamoyl)thiophene-2-carboxylate is an ATP competitive compound. Increasing the ATP concentration results in a shift of the IC 50 to less potency
  • Fig. 3 Depicts the co-crystal structure of a preferred compound of the present invention in the ATP-binding pocket of Aurora A kinase. The fo-fc map shown in the figure is contoured at 2.8 sigma.
  • Fig. 4 The spatial coordinates of co-crystals of Aurora A kinase fragment spanning 127 GIn to 390 PrO with methyl 3-(lH-indazol-6-ylsulfamoyl)thiophene-2-carboxylate are depicted.
  • Methyl 3-(lH-indazol-6-ylsulfamoyl)thiophene-2-carboxylate was identified from a screen for inhibitors of Aurora A kinase using 20 ⁇ M ATP and kemptide peptide (amino acid sequence LRRASLG; SEQ ID NO:1) as substrate.
  • the level of ATP consumption was monitored using couple luciferase (easylite-Kinase Luminescence Assay System PerkinElmer). Inhibitors of the kinase cause reduction of ATP turnover and increase in luminescence.
  • Dose response curves from active compounds were generated in a two fold 11 point serial dilution from a top concentration of 200 ⁇ M.
  • the dose response curves were plotted in XLfit (IDBS, UK) and the IC 50 values reported in micromolar ( ⁇ M).
  • IC 50 IC 50 for the compound was determined at 3 different final ATP concentrations (20, 200, and 1000 ⁇ M) using Z'Lyte Kinase Assay Kit Ser/Thr Peptide 1 (PV3174) kit as described by the manufacturer.
  • kinases were expressed in Sf9 insect cells as human recombinant GST-fusion proteins or His-tagged proteins by means of a baculovirus expression system.
  • Kinases were purified by affinity chromatography using either GSH-agarose (Sigma) or Ni-NTH-agarose (Qiagen). The purity of each kinase was checked by SDS-P AGE/silver staining and the identity of each kinase was verified by western blot analysis with kinase specific antibodies or by mass spectroscopy.
  • a protein kinase assay ( PanQinase Activity Assay) was used for measuring the kinase
  • TM activity of the 4 protein kinases All kinase assays were performed in 96- well FlashPlates from Perkin Elmer/NEN (Boston, MA,- USA) in a 50 ⁇ l reaction volume. The reaction cocktail was pipetted in 4 steps in the following order: • 20 ⁇ l of assay buffer
  • the assay for all enzymes contained 60 mM HEPES-NaOH, pH 7.5, 3 mM MgCl , 3 mM MnCl 2 , 3 ⁇ M Na-orthovanadate, 1.2 mM DTT, 50 ⁇ g/ml PEG 2 ⁇ 0 ( 0 ⁇ 0 n 0, 1 ⁇ M [ ⁇ - P]-ATP (approx. 5
  • reaction cocktails were incubated at 3O 0 C for 80 minutes.
  • the reaction was stopped with 50 ⁇ l of 2% (v/v) H PO , plates were aspirated and washed two times with 200 ⁇ l of 0.9 %
  • Res. Activity (%) 100 X [(cpm of compound - low control) / (high control - low control)] i.e. a low value is indicative of strong inhibition.
  • tumour cells e.g. HeLa cells
  • normal human cells e.g. foreskin fibroblasts
  • Growth inhibition was tested from 50 ⁇ M to 97.7 nM in a 10 point two-fold serial dilution and cells incubated under standard mammalian tissue culture conditions for 72 hours in triplicate.
  • Cell viability was measured by measuring ATP levels in viable cells using the ATPLite kit (PerkinElmer) as described in the user manual.
  • Raw data was transformed to percentage inhibition of growth compared to a DMSO only control and values are expressed as IC 50 .

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Abstract

The present invention provides novel compounds that inhibit cell proliferation, in particular by inhibiting Aurora kinase activity and uses of these compounds for treating, ameliorating or preventing diseases, conditions or disorders benefiting from the inhibition of Aurora kinase activity, in particular hyperproliferative diseases.

Description

AURORA KINASE INHIBITORS
The present invention provides novel compounds that inhibit cell proliferation, in particular by inhibiting Aurora A kinase activity and uses of these compounds for treating, ameliorating or preventing diseases, conditions or disorders benefiting from the inhibition of aurora activity, in particular hyperproliferative diseases.
BACKGROUND OF THE INVENTION
Mitosis is a fundamental mode of nuclear division of eukaryotic cells and a highly coordinated process by which eukaryotic cells assure the fidelity of chromosome segregation. The number of chromosomes is often a multiple of the basic number unique to the species, but errors during mitosis result in an individual having one to several chromosomes added to or deleted from the multiple (aneuploid), which may cause cell death or oncogenesis.
Aurora (Glover et al. (1995) Cell 81 :95-105) identified in Drosophila melanogaster and its most closely related homolog IPL-I (Francisco, et al. (1994.) MoI. Cell. Biol. 14:4731-40) in budding yeast (Saccharomyces cerevisiae) are members of serine/threonine kinase family involved in controlling cell growth, differentiation and regulation of the cell cycle. These kinases are thought to participate in M phase of mitosis and are thought to be required for high-fidelity chromosome segregation. Homologous proteins have been identified in vertebrates termed Aurora kinases A (also known as Aurora, Aurora-2, AIK, AIR-I, AIRKl, AYKl, BTAK, Eg2, MmIAKl and STK15), Aurora B (also known as Aurora-1, AIM-I, AIK2, AIR-2, AIRK-2, ARK2, IAL-I and STK12) and Aurora C (also known as AIK3). These protein kinases participate in several biological processes, including cytokinesis and dysregulated chromosome segregation. These important regulators of mitosis are over-expressed in diverse solid tumors including prostate, colorectal, ovarian and gastric cancers. Overexpression of Aurora A kinase is found in >95% of all invasive adenocarcinomas. Consistently, amplification of this locus correlates strongly with poor clinical prognosis suggesting that inhibition of Aurora A kinase activity could inhibit tumour cell growth (Keen, N. & Taylor, S. (2004) Aurora-kinase inhibitors as anticancer agents. Nature Reviews Cancer 4, 927-936). The effectiveness of Aurora A kinase inhibitors in the suppression of tumor growth in vivo has been described for a compound named VX-680 (see, e.g. Harrington E.A. et. al. (2004) 10: 262-7 and Doggrell S.A. (2004) 13: 1199- 1201).
Accordingly, there is a need in the art to identify inhibitors of Aurora kinases, in particular of Aurora A kinase. The present invention provides a compound class capable of competitively inhibiting binding of ATP to the ATP-binding pocket of Aurora kinases and through the provision of a 3D structure of the ATP-binding pocket of Aurora A kinase a tool to identify further competitive inhibitors of Aurora A kinase.
SUMMARY OF THE INVENTION
The present invention provides compounds capable of inhibiting Aurora kinase activity, in particular Aurora A kinase activity by competitively binding to the ATP-binding site of Aurora kinases. Data presented herein establishes that compounds of formula (I) can inhibit Aurora kinase, in particular Aurora A kinase activity.
In a first aspect the present invention relates to the use of a compound of formula (I)
Figure imgf000003_0001
(I) wherein
R1 is alkyl, cycloalkyl, heterocylcoalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted; R2 and R3 are independent of each other selected from H; halogen; CN; NO2; NR7R8; alkyl, alkyloxy, aryl or heteroaryl, optionally substituted; wherein R7 and R8 are independent of each other hydrogen, alkyl, alkenyl, or alkynyl,
R4 is alkyl, optionally interrupted one or more times by O, N or S; -OOC-R6; -COO-R6'; alkoxy; aryl; heteroaryl; aralkyl; heteroaralkyl; optionally substituted wherein R6 is alkyl, alkenyl, alkynyl, aryl or heteroaryl; optionally substituted and R6 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl; optionally substituted R5 is H, alkyl, alkenyl, alkynyl, optionally substituted or R1 and R5 are taken together to form a heteroaryl or heterocylcoalkyl; optionally substituted and pharmaceutically acceptable salts thereof, for the production of a medicament for treating, ameliorating or preventing diseases, conditions and/or disorders which benefit from a reduced aurora kinase activity.
In a preferred embodiment of the use of the present invention the compound has a structure according to formula (VII)
Figure imgf000004_0001
(VII).
In a further aspect the present invention is directed at a method of identifying a compound structure that can bind to the ATP binding pocket of Aurora A kinase, comprising the steps of:
(a) constructing a three dimensional structure of the ATP binding pocket of Aurora A kinase using as a template a three dimensional structure of the ATP binding pocket of Aurora A kinase comprising the inhibitor according to formula (VII), i.e. methyl 3-(lH-indazol-6- ylsulfamoyl)thiophene-2-carboxylate, defined by atomic coordinates represented in Fig. 4;
(b) performing computer-assisted, structure based drug design with said structure of (a); and
(c) identifying at least one candidate compound structure that is predicted to have a compatible conformation with a target site on the constructed structure of the ATP binding pocket of Aurora A kinase as defined by the inhibitor according to formula (VII), i.e. methyl 3-(lH-indazol-6-ylsulfamoyl)thiophene-2-carboxylate such that the compound having the compound structure is predicted to bind to the ATP binding pocket of Aurora A kinase.
In a further aspect the present invention is directed at a pharmaceutical composition comprising an effective amount of at least one compound of the present invention and a pharmaceutically acceptable carrier or excipient.
In a further aspect the present invention is directed at the use of a compound of the invention for the production of a medicament for treating, ameliorating or preventing diseases, conditions and/or disorders which benefit from a reduced aurora kinase activity. DETAILED DESCRIPTION Definitions
Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
In the following definitions of the terms: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alicyclic system, alkenyl, cycloalkenyl, and alkynyl are provided. These terms will in each instance of its use in the remainder of the specification have the respectively defined meaning and preferred meanings. Nevertheless in some instances of their use throughout the specification preferred meanings of these terms are indicated.
The term "alkyl" refers to a saturated straight or branched carbon chain. Preferably, the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 e.g. methyl, ethyl methyl, ethyl, propyl, /sø-propyl, butyl, /so-butyl, te/t-butyl, pentyl, hexyl, heptyl, octyl. Alkyl groups are optionally substituted.
The term "heteroalkyl" refers to a saturated straight or branched carbon chain. Preferably, the chain comprises from 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 e.g. methyl, ethyl, propyl, /sø-propyl, butyl, wo-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms. Preferably the heteroatoms are selected from O, S, and N, e.g. CH2-O-CH3, CH2-O-C2H5, C2H4- 0-CH3, C2H4-O-C2H5 etc. Heteroalkyl groups are optionally substituted.
The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc. The terms "cycloalkyl" and "heterocycloalkyl" are also meant to include bicyclic, tricyclic and polycyclic versions thereof. If bicyclic, tricyclic or polycyclic rings are formed it is preferred that the respective rings are connected to each other at two adjacent carbon atoms, however, alternatively the two rings are connected via the same carbon atom, i.e. they form a spiro ring system or they form "bridged" ring systems. The term "heterocycloalkyl" preferably refers to a saturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms. "Cycloalkyl" and "heterocycloalkyl" groups are optionally substituted. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Preferred examples of cycloalkyl include C3-Cio-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, bicyclo[4.2.0]octyl, octahydro-pentalenyl, octahydro-indenyl, decahydro-azulenyl, adamantly, or decahydro-naphthalenyl. Preferred examples of heterocycloalkyl include C3-C10- heterocycloalkyl, in particular l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro- [5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-spiro[5,4] decyl, 1- aza-7,l l-dioxo-spiro[5,5] undecyl, l,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, or 2-piperazinyl.
The term "alicyclic system" refers to mono, bicyclic, tricyclic or polycyclic version of a cycloalkyl or heterocycloalkyl comprising at least one double and/or triple bond. However, an alicyclic system is not aromatic or heteroaromatic, i.e. does not have a system of conjugated double bonds/free electron pairs. Thus, the number of double and/or triple bonds maximally allowed in an alicyclic system is determined by the number of ring atoms, e.g. in a ring system with up to 5 ring atoms an alicyclic system comprises up to one double bond, in a ring system with 6 ring atoms the alicyclic system comprises up to two double bonds. Thus, the "cycloalkenyl" as defined below is a preferred embodiment of an alicyclic ring system. Alicyclic systems are optionally substituted.
The term "aryl" preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing 10 carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphthalenyl or anthracenyl. The aryl group is optionally substituted.
The term "aralkyl" refers to an alkyl moiety, which is substituted by aryl, wherein alkyl and aryl have the meaning as outlined above. An example is the benzyl radical. Preferably, in this context the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl, propyl, isø-propyl, butyl, iso-butyl, sec-butenyl, ter/-butyl, pentyl, hexyl, heptyl, octyl. The aralkyl group is optionally substituted at the alkyl and/or aryl part of the group. Preferably the aryl attached to the alkyl has the meaning phenyl, naphthalenyl or anthracenyl.
The term "heteroaryl" preferably refers to a five or six-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1, 2, or 3 (for the five membered ring) or 1, 2, 3, or 4 (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S; an aromatic bicyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 8, 9, 10, 11 or 12 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S; or an aromatic tricyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 13, 14, 15, or 16 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S. Examples are furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2- benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1- benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl.
The term "heteroaralkyl" refers to an alkyl moiety, which is substituted by heteroaryl, wherein alkyl and heteroaryl have the meaning as outlined above. An example is the (2- pyridinyl) ethyl, (3-pyridinyl) ethyl, or (2-pyridinyl) methyl. Preferably, in this context the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, sec-butenyl, tert-butyl, pentyl, hexyl, heptyl, octyl. The heteroaralkyl group is optionally substituted at the alkyl and/or heteroaryl part of the group. Preferably the heteroaryl attached to the alkyl has the meaning oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3- triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, 2,3- benzodiazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl.
The terms "alkenyl" and "cycloalkenyl" refer to olefinic unsaturated carbon atoms containing chains or rings with one or more double bonds. Examples are propenyl and cyclohexenyl. Preferably, the alkenyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethenyl, 1-propenyl, 2-propenyl, /sø-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso- butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, heptenyl, octenyl. Preferably the cycloalkenyl ring comprises from 3 to 14 carbon atoms, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, e.g. cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctyl, cyclononenyl, cyclodecenyl, spiro[3,3]heptenyl, spiro[3,4]octenyl, spiro[4,3]octenyl, spiro[3,5]nonenyl, spiro[5,3]nonenyl, spiro[3,6]decenyl, spiro[6,3]decenyl, spiro[4,5]decenyl, spiro[5,4]decenyl, bicyclo[4.1.0]heptenyl, bicyclo[3.2.0]heptenyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octenyl, bicyclo[5.1.0]octenyl, bicyclo[4.2.0]octenyl, hexahydro-pentalenyl, hexahydro-indenyl, octahydro-azulenyl, or octahydro-naphthalenyl. The term "alkynyl" refers to unsaturated carbon atoms containing chains or rings with one or more triple bonds. An example is the propargyl radical. Preferably, the alkynyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, heptynyl, octynyl. In one embodiment, carbon atoms or hydrogen atoms in alkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more elements selected from the group consisting of O, S, and N or with groups containing one ore more elements selected from the group consisting of O, S, and N. Embodiments include alkoxy, cycloalkoxy, aryloxy, aralkoxy, alkenyloxy, cycloalkenyloxy, alkynyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, alkenylthio, cycloalkenylthio, alkynylthio, alkylamino, cycloalkylamino, arylamino, aralkylamino, alkenylamino, cycloalkenylamino, alkynylamino radicals. Other embodiments include hydroxyalkyl, hydroxycycloalkyl, hydroxyaryl, hydroxyaralkyl, hydroxyalkenyl, hydroxycycloalkenyl, hydroxyalinyl, mercaptoalkyl, mercaptocycloalkyl, mercaptoaryl, mercaptoaralkyl, mercaptoalkenyl, mercaptocycloalkenyl, mercaptoalkynyl, aminoalkyl, aminocycloalkyl, aminoaryl, aminoaralkyl, aminoalkenyl, aminocycloalkenyl, aminoalkynyl radicals. In another embodiment, hydrogen atoms in alkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one ore more halogen atoms. One radical is the trifluoromethyl radical.
If two or more radicals can be selected independently from each other, then the term "independently" means that the radicals may be the same or may be different. The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention. Suitable pharmaceutically acceptable salts of the compound of the present invention include acid addition salts which may, for example, be formed by mixing a solution of compounds of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compound of the invention carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, for example, Berge, S. M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of formula (I). A prodrug is a pharmacologically active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 16.5 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups have been masked as esters and ethers. EP 0 039 051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use. Compounds and also the starting materials for their preparation according to the invention can be synthesized by methods and standard procedures known to those skilled in the art, i.e. as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known to those skilled in the art and suitable for the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.
If desired, the starting materials can also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the present invention. On the other hand, it is possible to carry out the reaction stepwise. It should be noted that the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry at a sterogenic center is (S) or (R). In addition, the compounds having one stereochemistry (e.g., (R)) can often be utilized to produce those having opposite stereochemistry (i.e., (S)) using well-known methods, for example, by inversion.
Certain compounds of the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.
Accordingly, the compounds of this invention include mixtures of stereoisomers, especially mixtures of enantiomers, as well as purified stereoisomers, especially purified enantiomers, or stereoisomerically enriched mixtures, especially enantiomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formulas (I) and (VII) below as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas below as mixtures with isomers thereof in which one or more chiral centers are inverted. Also, it is understood that all tautomers and mixtures of tautomers of the compounds of formulae formulas (I) and (VII) are included within the scope of the compounds of formulae formulas (I) and (VII) and preferably the formulae and subformulae corresponding thereto.
Racemates obtained can be resolved into the isomers mechanically or chemically by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active resolving agent.
Examples of suitable resolving agents are optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids, such as -camphorsulfonic acid. Also advantageous is enantiomer resolution with the aid of a column filled with an optically active resolving agent (for example dinitrobenzoylphenylglycine); an example of a suitable eluent is a hexane/isopropanol/acetonitrile mixture.
The diastereomer resolution can also be carried out by standard purification processes, such as, for example, chromatography or fractional crystallization.
It is also possible to obtain optically active compounds of formulas (I) and (VII) by the methods described above by using starting materials which are already optically active.
The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
General
The present invention provides compositions, compounds and uses of compounds for inhibiting Aurora kinase, in particular Aurora A kinase in a cell. The compositions which are useful as inhibitors will typically be those which contain an effective amount of an Aurora kinase inhibitory compound. In general, an effective amount of an aurora kinase inhibitory compound is a concentration of the compound that will produce a 50 percent decrease in an Aurora kinase activity assay as described in the examples below.
Embodiments of the Invention
The present invention provides the use of compounds of formula (I)
Figure imgf000013_0001
(I) wherein
R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aralkyl; or heteroaralkyl; optionally substituted, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO2; NR7R8; alkyl, in particular Cj- C6 alkyl, e.g. Ci, C2, C3, C4, Cs, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2,
C3, C4, C5, or C6 alkynyl; alkanoyl, preferably Cj-C6 alkanoyl, e.g. Cj, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably propynoyl; alkoxy, in particular Cj-C6 alkoxy, e.g. Cj, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy, propoxy, z'so-propoxy, butoxy, wo-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C6 alkoxy-Ci-C6 alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R9; -COO- R10; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or
1 ,2,4-benzotriazinyl; aralkyl; or heteroaralkyl; optionally substituted, wherein
R7 and R8 are independent of each other hydrogen, alkyl, in particular Ci-C6 alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl, alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, Cs, or C6 alkenyl, or alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; optionally substituted; or R7 and R8 together form a heterocycle; optionally substituted; R9 is alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular Ci-C6 alkyl, e.g. Ci, C2,
C3, C4, C5, or C6 alkyl; R10 is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl; or two or more of substituents of R1 are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, optionally substituted; optionally the alkyl moiety of R1, including the alkyl moiety of the aralkyl and the heteroaralkyl moiety, respectively is interrupted 1, 2, 3, 4 or more times by O, N, and/or
S; it is further preferred that the substituents of R1 are substituents of the aryl and heteroaryl moiety, respectively; R2 and R3 are independent of each other selected from H; halogen; CN; NO2; NR7R8; alkyl, alkyloxy, aryl or heteroaryl, optionally substituted, preferably both R2 and R3 are H; wherein R7 and R8 are independent of each other hydrogen, alkyl, alkenyl, or alkynyl, R4 is alkyl, optionally interrupted one or more times by O, N or S; -OOC-R6; -COO-R6 ; alkoxy; aryl; heteroaryl; aralkyl; heteroaralkyl; optionally substituted, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO2; NR7R8; alkyl, in particular Ci-
C6 alkyl, e.g. Cj, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wo-propenyl, 2-iso- propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or Ce alkynyl; alkanoyl, preferably CpC6 alkanoyl, e.g. Ci, C2, C3, C4, C5, or
C6 alkanoyl; alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C6 alkoxy, e.g. Ci, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy, propoxy, wø-propoxy, butoxy, wobutoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C6 alkoxy-Ci-C6 alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R9; -COO-R10; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofiiranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or
1,2,4-benzotriazinyl; aralkyl; or heteroaralkyl; optionally substituted, wherein
R7 and R8 are independent of each other hydrogen, alkyl, in particular Ci-C6 alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl, alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, or alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; optionally substituted; or R7 and R8 together form a heterocycle; optionally substituted;
R9 is alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular Ci-C6 alkyl, e.g. Ci, C2,
C3, C4, C5, or C6 alkyl; R10 is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl; or two or more of substituents of R4 are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, optionally substituted; R6 is alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or
C6 alkenyl, or alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; optionally substituted;
R6 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular Ci-C6 alkyl, e.g. Ci,
C2, C3, C4, C5, or C6 alkyl, alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, or alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; optionally substituted;
R5 is H, alkyl, alkenyl, alkynyl; optionally substituted, preferably H; or R1 and R5 are taken together to form a heteroaryl or heterocycloalkyl; optionally substituted and pharmaceutically acceptable salts thereof, for the production of a medicament for the for treating, ameliorating or preventing diseases, conditions and/or disorders which benefit from a reduced aurora kinase activity. Preferred salts comprise Na+, K+, and Ca2+ salts.
The compounds of the general formula (I) usable according to the present invention may be prepared according to the following scheme I:
Figure imgf000016_0001
(5) wherein R1, R2, R3, R4 and R5 are as defined above, or have the particularly preferred meanings as defined below, Lie is a conventional leaving group such as halogen, sulfonyl or the like or is an activating group for the sulfonyl group, i.e. an activated ester. The above process comprises reacting a compound of the genera formula (1) with a thienylsulfonyl group providing agent of the general formula (2) in an organic solvent to obtain a compound of the general formula (3). Then the compound of the general formual (3) may be reacted with an alkylating agent in the presence of a base to give a compound of the general formula (5), wherein the nitrogen residue is substituted with R and wherein R does not mean hydrogen. The reaction may be carried out in a conventional organic solvent such as, for example, tetrahydrofuran, dichloromethane, acetonitrile, chloroform and dimethylformamide.
And also the reaction is preferably carried out in the presence of a coupling agent such as a conventional inorganic or an organic base.
Such conventional inorganic or organic bases used in the reaction may include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and DBU.
The reaction may be carried out at a temperature between 3°C and boiling point of the solvent used, preferably at 500C-IOO0C and for 5-48 hours, preferably for 10-24 hours. Then, the compound of the formula (3) may be reacted with an alkylating agent
(including agents that are capable of transferring a alkyl, alkenyl or alkynyl) in the presence of a conventional organic or inorganic base to give a compound of the general formula (5). The alkylating agent used in the above step may include alkylhalide, preferably (C1-8)- alkylhalide; alkylsulfonate, preferably (Ci-8)-alkylsulfonate; alkenyl halide, preferably (Ci-8)- alkenyl halide; alkynyl halide, preferably (Ci-8)-alkynyl halide; alkenyl sulfonate, preferably (Ci-
8)-alkenyl sulfonate; alkynyl sulfonate, preferably (Ci ^-alkynyl sulfonate;which all may or may not be substituted as indicated in more detail below.
Substituted or unsubstituted (C]-8)-alkylhalide preferably means methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl chloride, propyl bromide, propyl iodide, butyl chloride, butyl bromide, butyl iodide, pentyl chloride, pentyl bromide, pentyl iodide, bromo ehtylacetate or the like. Substituted or unsubstituted (Ci.g)-alkylsulfonate preferably means methyl sulfonate, ethyl sulfonate, propyl sulfonate, butyl sulfonate, pentyl sulfonate or the like.
The reaction may be carried out in a conventional organic solvent as such as, for example, tetrahydrofuran, dichloromethane, chloroform, dimethyl sulfoxide,acetonitrile and dimethylformamide. The conventional inorganic or organic base used in above step may include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and DBU.
In the above reaction process, if any acid material is formed, a basic material may be added as a scavenger in order to eliminate the acid material from the reaction phase. Such basic material may be alkali metal hydroxide, alkali earth metal hydroxide, alkali metal oxide, alkali earth metal oxide, alkali metal carbonate, alkali earth metal carbonate, alkali metal hydrogen carbonate, alkali earth metal hydrogen carbonate such as for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, potassium carbonate, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium bicarbonate, calcium bicarbonate or the like, and organic amines.
R2, R3, or R4 or any substituent of R1, R2, R3, R4, and/or R5 which would undergo unwanted reactions when carrying out a synthesis according to scheme I may be protected by a conventional protecting group, which is cleavable under known conditions. The skilled person is aware of a large variety of protection groups, which can be employed in organic synthesis. Protecting groups are reviewed in, for example, Wuts, P.G.M. and Greene, T. W., Protective Groups in Organic Chemistry, 3rd Ed., 1999; Wily & Sons Inc. and in Kocienski, P. J., Protecting groups. 2nd Ed., 2000, Thieme Medical Publishing. Protecting groups are organized in these reference books according to the functionalities that are protected as well as according to the conditions which remove the respective protecting groups selectively. Particularly preferred protective groups, which can be used are:
(i) protective group removed at acidic conditions, preferably at a pH between 4 and 6, which is selected from the group consisting of Boc or Trityl protecting groups;
(ii) a protecting group removed by a nucleophile, which is selected from the group consisting of Fmoc or Dde protecting groups;
(iii) a protecting group removed by hydrogenolysis consisting of the allyl type, the tert-butyl type, the benzyl type or Dmab (4,4-dimethyl-2,6-dicyclohexylidene)-3-methylbutylj- amino } benzyl ester ;
(iv) a protecting group removed by radiation, which is selected from the group consisting of nitroveratryloxy carbonyl, nitrobenzyloxy carbonyl, dimethyl dimethoxybenzyloxy carbonyl, 5-bromo-7-nitroindolinyl, o-hydroxy-α-methyl cinnamoyl, and 2-oxymethylene anthraquinone. In a preferred embodiment use of the compounds of the present invention R1 is selected from the group consisting of phenyl, napthyl, anthracenyl, furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3- triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1 -benzo furanyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, and 1,2,4-benzotriazinyl; optionally substituted. In a particular preferred embodiment R1 is IH- indazolyl, which is preferably attached to the amine at position 6 of the indazolyl ring system. In a further preferred embodiment R1 is selected form the group consisting of (2-furanyl) methyl, (3-furanyl) methyl, (2-furanyl) ethyl, (3-furanyl) ethyl, (2-oxazolyl) methyl, (4-oxazolyl) methyl, (5-oxazolyl) methyl, (2-oxazolyl) ethyl, (4-oxazolyl) ethyl, (5-oxazolyl) ethyl, (2- isoxazolyl) methyl, (3 -isoxazolyl) methyl, (4-isoxazolyl) methyl, (2-isoxazolyl) ethyl, ethyl (3- isoxazolyl), ethyl (4-isoxazolyl), (3-(l,2,5-oxadiazolyl)) methyl, (4-(l,2,5-oxadiazolyl)) methyl, (3-(l,2,5-oxadiazolyl)) ethyl, (4-( 1,2,5-oxadiazolyl)) ethyl, (4-(l,2,3-oxadiazolyl)) methyl, (5- (1,2,3-oxadiazolyl)) methyl, (4-( 1,2,3-oxadiazolyl)) ethyl, (5 -(1,2,3-oxadiazolyl)) ethyl, (2- pyrrolyl) methyl, (3-pyrrolyl) methyl, (2-pyrrolyl) ethyl, (3-pyrrolyl) ethyl, (2-imidazolyl) methyl, (4-imidazolyl) methyl, (2-imidazolyl) ethyl, (4-imidazolyl) ethyl, (3-pyrazolyl) methyl, (4-pyrazolyl) methyl, (3-pyrazolyl) ethyl, (4-pyrazolyl) ethyl, (4-( 1,2,3-triazolyl) methyl, (4- (1,2,3-triazolyl) ethyl, (3-(l,2,4-triazolyl) methyl, (3-(l,2,4-triazolyl) ethyl, (2-thienyl) methyl, (3-thienyl) methyl, (2-thienyl) ethyl, (3-thienyl) ethyl, (2-thiazolyl) methyl, (4-thiazolyl) methyl, (5-thiazolyl) methyl, (2-thiazolyl) ethyl, (4-thiazolyl) ethyl, (5-thiazolyl) ethyl, (3-isothiazolyl) methyl, (4-isothiazolyl) methyl, (5-isothiazolyl) methyl, (3-isothiazolyl) ethyl, (4-isothiazolyl) ethyl, (5-isothiazolyl) ethyl, (4-(l,2,3,-thiadiazolyl)) methyl, (5-(l,2,3,-thiadiazolyl)) methyl, (4- (1,2,3,-thiadiazolyl)) ethyl, (5-(l,2,3,-thiadiazolyl)) ethyl, (3-(l,2,5-thiadiazolyl)), (3-(l,2,5- thiadiazolyl)) ethyl, (2-pyridinyl) methyl, (3-pyridinyl) methyl, (4-pyridinyl) methyl, (2- pyridinyl) ethyl, (3-pyridinyl) ethyl, (4-pyridinyl) ethyl, (2-pyrimidinyl) methyl, (4-pyrimidinyl) methyl, (5-pyrimidinyl) methyl, (2-pyrimidinyl) ethyl, (4-pyrimidinyl) ethyl, (5-pyrimidinyl) ethyl, (2-pyrazinyl) methyl, (3-pyrazinyl) methyl, (2-pyrazinyl) ethyl, (3-pyrazinyl) ethyl, (4- (1,2,3-triazinyl) methyl, (5-(l,2,3-triazinyl)) methyl, (4-(l,2,3-triazinyl)) ethyl, (5-(l,2,3- triazinyl)) ethyl, (3-(l,2,4-triazinyl)) methyl, (5-(l,2,4-triazinyl)) methyl, (6-(l,2,4-triazinyl)) methyl, (3-(l,2,4-triazinyl)) ethyl, (5-(l,2,4-triazinyl)) ethyl, (6-(l,2,4-triazinyl)) ethyl, (2-(l,3,5- triazinyl) methyl, (2-(l,3,5-triazinyl) ethyl, (2-(l-benzofuranyl)) methyl, (3-(l-benzofuranyl)) methyl, (4-(l-benzofurany I)) methyl, (ό-(l-benzofuranyl)) methyl, (7-(l-benzoflιranyl)) methyl, (2-(l-benzofuranyl)) ethyl, (3-(l-benzofuranyl)) ethyl, (4-(l-benzoflιranyl)) ethyl, (6-(l- benzofuranyl)) ethyl, (7-(l-benzofuranyl)) methyl, (4-(l-benzofuranyl)) ethyl, (l-(2- benzofuranyl)) methyl, (4-(2-benzoflιranyl)) methyl, (5-(2-benzofuranyl)) methyl, (l-(2- benzofuranyl)) ethyl, (4-(2-benzofuranyl)) ethyl, (5-(2-benzofuranyl)) ethyl, (2-indolyl) methyl, (3-indolyl) methyl, (4-indolyl) methyl, (5-indolyl) methyl, (6-indolyl) methyl, (7-indolyl) methyl, (2-indolyl) ethyl, (3-indolyl) ethyl, ethyl (4-indolyl), ethyl (5-indolyl), ethyl (6-indolyl), ethyl (7-indolyl), methyl (1-isoindolyl), (4-isoindolyl) methyl, (5-isoindolyl) methyl, (1- isoindolyl) ethyl, (4-isoindolyl) ethyl, (5-isoindolyl) ethyl, (2-(l-benzothienyl)) methyl, (3-(l- benzothienyl)) methyl, (4-(l-benzothienyl)) methyl, (6-(l-benzothienyl)) methyl, (7-(l- benzothienyl)) methyl, (2-(l-benzothienyl)) ethyl, (3-(l-benzothienyl)) ethyl, (4-(l- benzothienyl)) ethyl, (6-(l -benzothienyl)) ethyl, (7-(l -benzothienyl)) methyl, (l-(2- benzothienyl)) methyl, (4-(2 -benzothienyl)) methyl, (5-(2-benzothienyl)) methyl, (l-(2- benzothienyl)) ethyl, (4-(2-benzothienyl)) ethyl, (5-(2-benzothienyl)) ethyl, (1-indazolyl) methyl, (4-(lH-indazolyl)) methyl, (5-(lH-indazolyl)) methyl, (ό-(lH-indazolyl)) methyl, (7-(1H- indazolyl)) methyl, (1-indazolyl) ethyl, (4-(lH-indazolyl)) ethyl, (5-(lH-indazolyl)) ethyl, (6- (lH-indazolyl)) ethyl, (7-(lH-indazolyl)) ethyl, (2-benzimidazolyl) methyl, (4-benzimidazolyl) methyl, (5-benzimidazolyl) methyl, (2-benzimidazolyl) ethyl, (4-benzimidazolyl) ethyl, (5- benzimidazolyl) ethyl, (2-benzoxazolyl) methyl, (4-benzoxazolyl) methyl, (5-benzoxazolyl) methyl, (6-benzoxazolyl) methyl, (7-benzoxazolyl) methyl, (2-benzoxazolyl) ethyl, (4- benzoxazolyl) ethyl, (5-benzoxazolyl) ethyl, (6-benzoxazolyl) ethyl, (7-benzoxazolyl) ethyl, (3- indoxazinyl) methyl, (4-indoxazinyl) methyl, (5-indoxazinyl) methyl, (6-indoxazinyl) methyl, (7-indoxazinyl) methyl, (3-indoxazinyl) ethyl, (4-indoxazinyl) ethyl, (5-indoxazinyl) ethyl, (6- indoxazinyl) ethyl, (7-indoxazinyl) ethyl, (3-(2,l-benzoxazolyl)) methyl, (4-(2,l-benzoxazolyl)) methyl, (5-(2,l-benzoxazolyl)) methyl, (6-(2,l-benzoxazolyl)) methyl, (7-(2,l-benzoxazolyl)) methyl, (3-(2,l-benzoxazolyl)) ethyl, (4-(2,l-benzoxazolyl)) ethyl, (5-(2,l-benzoxazolyl)) ethyl, (6-(2,l-benzoxazolyl)) ethyl, (7-(2,l-benzoxazolyl)) ethyl, (2-benzothiazolyl) methyl, (4- benzothiazolyl) methyl, (5-benzothiazolyl) methyl, (6-benzothiazolyl) methyl, (7-benzothiazolyl) methyl, (2-benzothiazolyl) ethyl, (4-benzothiazolyl) ethyl, (5-benzothiazolyl) ethyl, (6- benzothiazolyl) ethyl, (7-benzothiazolyl) ethyl, (3-(l,2-benzisothiazolyl)) methyl, (4-(l,2- benzisothiazolyl)) methyl, (5-(l,2-benzisothiazolyl)) methyl, (6-(l,2-benzisothiazolyl)) methyl, (7-(l,2-benzisothiazolyl)) methyl, (3-(l,2-benzisothiazolyl)) ethyl, (4-(l,2-benzisothiazolyl)) ethyl, (5-(l,2-benzisothiazolyl)) ethyl, (6-(l,2-benzisothiazolyl)) ethyl, (7-(l,2-benzisothiazolyl)) ethyl, (3-(2,l-benzisothiazolyl)) methyl, (4-(2,l-benzisothiazolyl)) methyl, (5-(2,l- benzisothiazolyl)) methyl, (6-(2,l-benzisothiazolyl)) methyl, (7-(2,l-benzisothiazolyl)) methyl, (3-(2,l-benzisothiazolyl)) ethyl, (4-(2,l -benzisothiazolyl)) ethyl, (5-(2,l -benzisothiazolyl)) ethyl, (6-(2,l -benzisothiazolyl)) ethyl, (7-(2,l -benzisothiazolyl)) ethyl, (4-benzotriazolyl) methyl, (5- benzotriazolyl) methyl, (4-benzotriazolyl) ethyl, (5-benzotriazolyl) ethyl, (2-quinolinyl) methyl, (3-quinolinyl) methyl, (4-quinolinyl) methyl, (5-quinolinyl) methyl, (7-quinolinyl) methyl, (8- quinolinyl) methyl, (2-quinolinyl) ethyl, (3-quinolinyl) ethyl, (4-quinolinyl) ethyl, (5-quinolinyl) ethyl, (7-quinolinyl) ethyl, (8-quinolinyl) ethyl, (1-isoquinolinyl) methyl, (3-isoquinolinyl) methyl, (4-isoquinolinyl) methyl, (5-isoquinolinyl) methyl, (6-isoquinolinyl) methyl, (J- isoquinolinyl) methyl, (8-isoquinolinyl) methyl, (1-isoquinolinyl) ethyl, (3-isoquinolinyl) ethyl, (4-isoquinolinyl) ethyl, (5-isoquinolinyl) ethyl, (6-isoquinolinyl) ethyl, (7-isoquinolinyl) ethyl, (8-isoquinolinyl) ethyl, (l-(2,3-benzodiazinyl)) methyl, (4-(2,3-benzodiazinyl)) methyl, (5-(2,3- benzodiazinyl)) methyl, (6-(2,3-benzodiazinyl)) methyl, (7-(2,3-benzodiazinyl)) methyl, (8-(2,3- benzodiazinyl)) methyl, (l-(2,3-benzodiazinyl)) ethyl, (4-(2,3-benzodiazinyl)) ethyl, (5-(2,3- benzodiazinyl)) ethyl, (6-(2,3-benzodiazinyl)) ethyl, (7-(2,3-benzodiazinyl)) ethyl, (8-(2,3- benzodiazinyl)) ethyl, (2-quinoxalinyl) methyl, (3-quinoxalinyl) methyl, (5-quinoxalinyl) methyl, (6-quinoxalinyl) methyl, (2-quinoxalinyl) ethyl, (3-quinoxalinyl) ethyl, (5-quinoxalinyl) ethyl, (6-quinoxalinyl) ethyl, (2-quinazolinyl) methyl, (4-quinazolinyl) methyl, (5-quinazolinyl) methyl, (6-quinazolinyl) methyl, (7-quinazolinyl) methyl, (8-quinazolinyl) methyl, (2- quinazolinyl) ethyl, (4-quinazolinyl) ethyl, (5-quinazolinyl) ethyl, (6-quinazolinyl) ethyl, (J- quinazolinyl) ethyl, (8-quinazolinyl) ethyl, (4-(l,2,3-benzotriazinyl)) methyl, (5-(l,2,3- benzotriazinyl)) methyl, (6-(l ,2,3-benzotriazinyl)) methyl, (7-(l,2,3-benzotriazinyl)) methyl, (8- (1,2,3-benzotriazinyl)) methyl, (4-(l,2,3-benzotriazinyl)) ethyl, (5-(l ,2,3-benzotriazinyl)) ethyl, (6-(l,2,3-benzotriazinyl)) ethyl, (7-(l,2,3-benzotriazinyl)) ethyl, (8-(l,2,3-benzotriazinyl)) ethyl, (3-(l,2,4-benzotriazinyl)) methyl, (5-(l,2,4-benzotriazinyl)) methyl, (6-(l,2,4-benzotriazinyl)) methyl, (7-(l ,2,4-benzotriazinyl)) methyl, (8-(l,2,4-benzotriazinyl)) methyl, (3-(l,2,4- benzotriazinyl)) ethyl, (5-(l,2,4-benzotriazinyl)) ethyl, (6-(l ,2,4-benzotriazinyl)) ethyl, (7-(l,2,4- benzotriazinyl)) ethyl, or (8-(l,2,4-benzotriazinyl)) ethyl, optionally substituted preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO2; NR7R8; alkyl, in particular C,-C6 alkyl, e.g. C1, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyi, tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1- /so-propenyl, 2-wo-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkanoyl, preferably Ci-C6 alkanoyl, e.g. Ci, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C6 alkoxy, e.g. Ci, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy, propoxy, /so-propoxy, butoxy, zso-butoxy, tert-butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C6 alkoxy-Ci-C6 alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R ; -COO-R ; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3- oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1 ,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,- thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4- benzotriazinyl; optionally substituted, wherein R7 and R8 are independent of each other hydrogen, alkyl, in particular CpC6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, or alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; optionally substituted; or R7 and R8 together form a heterocycle; optionally substituted; R9 is alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl; and R10 is hydrogen, alkyl, alkenyl, alkynyl, in particular C]-C6 alkyl, e.g. Ci, C2, C3, C4, Cs, or C6 alkyl. In a preferred embodiment R1 has a structure according to formulas (II) to (V)
Figure imgf000022_0001
wherein * indicates the bond between R1 and the nitrogen atom,
A, B, and C are each independently of each other selected from carbon, oxygen, sulphur and nitrogen atoms, with the proviso that at least one of A, B, and D is a carbon atom. More preferably A is a nitrogen atom and B and D are carbon atoms; A is a nitrogen atom B is a sulphur atom or an oxygen atom and D is a carbon atom; A is a nitrogen atom, D is a sulphur atom or an oxygen atom and B is a carbon atom; or A and B are nitrogen atoms and D is a carbon atom;
R11 is halogen, e.g. F, Cl, Br or I; CN; NO2; NR7 R8'; alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wσ-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkanoyl, preferably C]-C6 alkanoyl, e.g. Ci, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C6 alkoxy, e.g. Ci, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy, propoxy, iso-pτopoxy, butoxy, iso-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C6 alkoxy-Ci-C6 alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R9 ; -COO-R10 aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; wherein R7 and R8 are independent of each other hydrogen, alkyl, in particular Ci-C6 alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl, alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, or alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl, optionally substituted; or R7 and R8 together form a heterocycle; optionally substituted; R9 is alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl; optionally substituted; and R10 is hydrogen, alkyl, alkenyl, alkynyl, in particular Cj-C6 alkyl, e.g. Ci, C2, C3, C4,
C5, or C6 alkyl optionally substituted; m is 0, 1 , 2, or, 3 preferably 0 or 1 ; R12 is halogen, e.g. F, Cl, Br or I; CN; NO2; NRr R8"; alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-buty\, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wø-propenyl, 2-/so-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkanoyl, preferably Ci-C6 alkanoyl, e.g. Ci, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C6 alkoxy, e.g. Ci, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy, propoxy, isø-propoxy, butoxy, wo-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Cj-C6 alkoxy-Ci-C6 alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R9 ; -COO-R10 aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; wherein
R7 and R8 are independent of each other hydrogen, alkyl, in particular Ci-C6 alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl, alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, or alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; optionally substituted; or R7 and R8 together form a heterocycle; optionally substituted;
R9 is alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl; optionally substituted; and R10 is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4,
C5, or C6 alkyl optionally substituted; n is 0, 1 , 2, or 3, preferably 0 or 1.
In a preferred embodiment the substituents according to formulas (II) to (V) comprise one or two nitrogen atoms. In this case one nitrogen atom may be substituted, preferably with alkyl, in particular Ci-C6 alkyl, e.g. Cj, C2, C3, C4, C5, or C6 alkyl, alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, or alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or
C6 alkynyl.
In a preferred embodiment R has a structure according to formula (VI)
Figure imgf000024_0001
(VI), wherein *indicates the bond between R1 and the nitrogen atom,
R11 is halogen, e.g. F, Cl, Br or I; CN; NO2; NR7 R8'; alkyl, in particular C1-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, wo-butyl, tert-buty\, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, l-wo-propenyl, 2-wo-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkanoyl, preferably Ci-C6 alkanoyl, e.g. Ci, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C6 alkoxy, e.g. Ci, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy, propoxy, /sσ-propoxy, butoxy, wo-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C6 alkoxy-Ci-Cδ alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R9 ; -COO-R10 aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1 ,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1 ,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; optionally substituted; wherein
R7 and R8 are independent of each other hydrogen, alkyl, in particular Ci-C6 alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl, alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, or alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; optionally substituted; or R7 and R8 together form a heterocycle; optionally substituted;
R9 is alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl; optionally substituted; and R10 is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4,
C5, or C6 alkyl optionally substituted; m is 0, 1, 2, or, 3 preferably 0 or 1;
R12 is halogen, e.g. F, Cl, Br or I; CN; NO2; NR7"R8"; alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, /sø-butyl, ter/-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1-propenyl, 2-propenyl, 1-wø-propenyl, 2-/sø-propenyl, 1- butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkanoyl, preferably Ci-C6 alkanoyl, e.g. Ci, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C6 alkoxy, e.g. Ci, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, wo-butoxy, tert- butoxy, pentoxy, or hexoxy; alkoxyalkyl, in particular Ci-C6 alkoxy-Ci-C6 alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; -OOC-R9 ; -COO-R10 aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1 ,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1 ,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl; optionally substituted; wherein
R7 and R8 are independent of each other hydrogen, alkyl, in particular Ci-C6 alkyl, e.g.
Ci, C2, C3, C4, C5, or C6 alkyl, alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4,
C5, or C6 alkenyl, or alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; optionally substituted; or R7 and R8 together form a heterocycle; optionally substituted;
R9 is alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl; optionally substituted; and R10 is hydrogen, alkyl, alkenyl, alkynyl, in particular Ci-C6 alkyl, e.g. Ci, C2, C3, C4,
C5, or C6 alkyl optionally substituted; n is 0, 1, 2, or 3, preferably 0 or 1, depending on the number of heteroatoms.
In a preferred embodiment R6 or R6 is Ci-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl; optionally substituted. It is particularly preferred that R6 has this meaning, if R1 has the meaning heteroaryl, heterocycloalkyl or forms together with R5 a heteroaryl or heterocycloalkyl. It is particular preferred in this context that R1 has the meaning furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3- triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzo furanyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, and 1,2,4-benzotriazinyl; optionally substituted; preferably, lH-indazol-4-yl, lH-indazol-5-yl, lH-indazol-6-yl or lH-indazol-7-yl; optionally substituted. In a particular preferred embodiment the compound has a structure according to formula (VII)
Figure imgf000027_0001
(VII).
This structure may be substituted one or more times, preferably with 1, 2, 3, 4 or more substituents selected from the group consisting of halogen, e.g. F, Cl, Br or I; CN; NO2; NR7R8; alkyl, in particular C1-C6 alkyl, e.g. Ci, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, /so-butyl, tert-butyl, pentyl, hexyl; alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, preferably ethenyl, 1 -propenyl, 2-propenyl, l-/sø-propenyl, 2- /so-propenyl, 1-butenyl, 2-butenyl, 3-butenyl; alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; alkanoyl, preferably Ci-C6 alkanoyl, e.g. Ci, C2, C3, C4, C5, or C6 alkanoyl; alkenoyl, in particular C3-C6 alkenoyl, e.g. C3, C4, C5, or C6 alkenoyl, preferably propenoyl; alkynoyl, in particular C3-C6 alkynoyl, e.g. C3, C4, C5, or C6 alkynoyl, preferably propynoyl; alkoxy, in particular Ci-C6 alkoxy, e.g. Ci, C2, C3, C4, C5, or C6 alkoxy, preferably methoxy, ethoxy, propoxy, wo-propoxy, butoxy, iso-butoxy, ter /-butoxy, pentoxy, or hexoxy; alkoxy alkyl, in particular CpC6 alkoxy-Ci-C6 alkyl, e.g. methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, or propoxypropyl; - OOC-R9; -COO-R10; aryl, in particular phenyl, naphthalenyl or anthracenyl; heteroaryl, in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl, 1,2- benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3- benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl; aralkyl; or heteroaralkyl; optionally substituted, wherein R7 and R8 are independent of each other hydrogen, alkyl, in particular Ci-C6 alkyl, e.g. Ci, C2,
C3, C4, C5, or C6 alkyl, alkenyl, in particular C2-C6 alkenyl, e.g. C2, C3, C4, C5, or C6 alkenyl, or alkynyl, in particular C2-C6 alkynyl, e.g. C2, C3, C4, C5, or C6 alkynyl; optionally substituted; or R7 and R8 together form a heterocycle; optionally substituted; R9 is alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular C]-C6 alkyl, e.g. Ci, C2, C3, C4,
C5, or C6 alkyl; optionally substituted; R10 is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl, in particular Ci-C6 alkyl, e.g. Cj,
C2, C3, C4, C5, or C6 alkyl; optionally substituted; or two or more of substituents of R4 are taken together to form a cycloalkyl, heterocycloalkyl, alicyclic ring system, aryl or heteroaryl, optionally substituted.
The compounds used in the present invention show an Aurora kinase, preferably an Aurora A kinase inhibiting activity, preferably they have an IC50 of 500 μM or less, preferably of 50 μM, more preferably of 10 μM or less, and more preferably of 1 μM or less. This activity is preferably measured in a biological assay, for example, an in vitro Aurora kinase assay, for example, as set out below. The Aurora kinase inhibitors used in the present invention preferably have an IC50 in the range from about 0.001 μM to about 50 μM, more preferably about in the range from about 0.001 μM to about 10 μM or less, or more preferably in the range from about 0.001 μM to about 1 μM or less. Preferably, the inhibitors of the present invention preferentially inhibit Aurora A kinase. An compound usable in the present invention is considered an Aurora A kinase specific inhibitor, if th IC50 for the compound is at least 20%, preferably 30%, more preferably 40%, more preferably 50%, more preferably 60% or more lower for Aurora kinase A than for other Aurora kinases, in particular Aurora kinase B and/or Aurora kinase C.
In a further aspect the present invention relates to the compounds of formula (I) and any preferred or particularly preferred embodiment thereof the use of which is outlined above, e.g. a compound according to formula (VII).
In a further aspect the present invention relates to a method of identifying a compound structure that can bind to the ATP binding pocket of Aurora A kinase, comprising the steps of:
(a) constructing a three dimensional structure of the ATP binding pocket of Aurora A kinase using as a template a three dimensional structure of the ATP binding pocket of Aurora A kinase comprising the inhibitor of formula (VII), i.e. methyl 3-(lH-indazol-6- ylsulfamoyl)thiophene-2-carboxylate defined by atomic coordinates represented in Fig. 4;
(b) performing computer-assisted, structure based drug design with said structure of (a); and
(c) identifying at least one candidate compound structure that is predicted to have a compatible conformation with a target site on the constructed structure of the ATP binding pocket of Aurora A kinase as defined by the inhibitor of formula (VII), i.e. methyl 3-(lH-indazol-6-ylsulfamoyl)thiophene-2-carboxylate such that the compound having the compound structure is predicted to bind to the ATP binding pocket of Aurora
A kinase. Preferably, such candidate compound makes contacts in the ATP binding pocket of
Aurora A kinase, which are similar or identical to the contacts of methyl 3-(lH-indazol-6- ylsulfamoyl)thiophene-2-carboxylate. A compound is considered to make similar contacts, if it contacts at least with 2, preferably 3, 4, 5, 6, 7, 8, 9 or more amino acids of Aurora A kinase, preferably in the ATP-binding pocket, which are also contacted by methyl 3-(lH-indazol-6- ylsulfamoyl)thiophene-2-carboxylate.
A three dimensional structure of Aurora A kinase which substantially conforms to a specified set of atomic coordinates can be modeled by a suitable modeling computer program such as MODELER (A. SaIi and T. L. Blundell, J. MoI. Biol., vol. 234:779-815, 1993 as implemented in the Insight II Homology software package (Insight II (97.0), MSI, San Diego)), using information, for example, derived from the following data: (1) the amino acid sequence of the Aurora A kinase protein; and, (2) the atomic coordinates of the specified three dimensional configuration as set out in Fig. 4. A three dimensional structure of an Aurora A kinase protein which substantially conforms to a specified set of atomic coordinates can also be calculated by a method such as molecular replacement. A suitable three dimensional structure of an Aurora A kinase protein for use in modeling or calculating the three dimensional structure of Aurora kinase protein comprises the set of atomic coordinates represented in Fig. 4. The set of three dimensional coordinates set forth in Fig. 4 is represented in standard Protein Data Bank format and also comprise a preferred competitive inhibitor. The coordinates of the inhibitor may be disregarded for the purpose of modeling a three dimensional structure of Aurora kinase protein.
A preferred structure of an Aurora kinase protein substantially conforms to the atomic coordinates, and the B-values and/or the thermal parameters represented in Fig. 4. Such values as listed in Fig. 4 can be interpreted by one of skill in the art. A more preferred three dimensional structure of an Aurora kinase protein substantially conforms to the three dimensional coordinates represented in Fig. 4. An even more preferred three dimensional structure of an Aurora kinase is a most probable fit with the three dimensional coordinates represented in Fig. 4. Methods to determine a substantially conforming and probable fit are within the expertise of skill in the art.
A preferred Aurora kinase protein that has a three dimensional structure which substantially conforms to the atomic coordinates represented by Fig. 4 includes an Aurora kinase proteins having an amino acid sequence that is at least about 25%, preferably at least about 30%, more preferably at least about 40%, more preferably at least about 50%, more preferably at least about 60%, more preferably at least about 70%, more preferably at least about 80%, more preferably at least about 90% and most preferably 100% identical to an amino acid sequence of Aurora A kinase protein, preferably as set out in GeneBank Ace. No. NM l 98434.
According to the present invention, a three dimensional structure of an Aurora kinase protein, preferably of Aurora A kinase can be used to derive a model of the three dimensional structure of another Aurora kinase (i.e., a structure to be modeled). As used herein, a "structure" of a protein refers to the components and the manner of arrangement of the components to constitute the protein. As used herein, the term "model" refers to a representation in a tangible medium of the three dimensional structure of a protein, polypeptide or peptide. For example, a model can be a representation of the three dimensional structure in an electronic file, on a computer screen, on a piece of paper (i.e., on a two dimensional medium), and/or as a ball-and- stick figure. Physical three-dimensional models are tangible and include, but are not limited to, stick models and space-filling models. The phrase "imaging the model on a computer screen" refers to the ability to express (or represent) and manipulate the model on a computer screen using appropriate computer hardware and software technology known to those skilled in the art. Such technology is available from a variety of sources including, for example, Evans and Sutherland, Salt Lake City, Utah, and Biosym Technologies, San Diego, Calif. The phrase "providing a picture of the model" refers to the ability to generate a "hard copy" of the model. Hard copies include both motion and still pictures. Computer screen images and pictures of the model can be visualized in a number of formats including space-filling representations, α-carbon traces, ribbon diagrams (see, for example, Fig. 3 which is a three-dimensional structure of the ATP-binding pocket of human Aurora A kinase with the bound inhibitor. In a preferred embodiment of the method of the present invention the compound structure contacts one or more of the amino acids residues of the ATP binding pocket, preferably the amino acid residues as defined by compound (VII), i.e. methyl 3-(lH-indazol-6- ylsulfamoyl)thiophene-2-carboxylate in Fig. 4. It is particularly preferred that the compound structure contacts 1, 2, 3, 4, 5, 6, 7, 8, 9 or more amino acids in the ATP binding pocket, in particular 1 or more amino acids selected from the group consisting of Leul39, Vall47, AlalόO, Lysl62, Glu260, Asn261, Leu263, Ala273, Asp274. In a particular preferred embodiment the compound structure additional contacts one or more residues in the 'hinge region', in particular Leu210, Glu211 and/or Tyr212. It is contemplated that candidate compound structures that inhibit Aurora kinase activity, in particular Aurora A kinase activity, can be designed entirely de novo or may be based upon one of the pre-existing competitive Aurora kinase inhibitors like, e.g. methyl 3-(lH-indazol-6- ylsulfamoyl)thiophene-2-carboxylate . Either of these approaches can be facilitated by computationally screening databases and libraries of small molecules for chemical entities, agents, ligands, or compounds that can bind in whole, or in part, to the ATP-binding pocket of Aurora kinases, in particular of Aurora A kinase. In this screening, the quality of fit of such entities or compounds to the binding site or sites may be judged either by shape complementarity or by estimated interaction energy (Meng et al (1992) J. Comp. Chem. 13: 505-524). The design of molecules that bind to or inhibit the functional activity of Aurora kinases according to this invention generally involves consideration of two factors. First, the molecule must be capable of physically and structurally associating with the ATP-binding pocket of Aurora kinases, in particular of Aurora A kinase. Non-covalent molecular interactions important in the association of the ATP-binding pocket of Aurora kinases, in particular of Aurora A kinase with the compound structure, include hydrogen bonding, van der Waals and hydrophobic interactions. Second, the molecule must be able to assume a conformation that allows it to associate with the ATP-binding pocket. Although certain portions of the molecule may not directly participate in this association with the ATP-binding pocket those portions may still influence the overall conformation of the molecule. This, in turn, may have a significant impact on binding affinities, therapeutic efficacy, drug-like qualities, and potency. Such conformational requirements include the overall three-dimensional structure and orientation of the chemical entity or molecule in relation to all or a portion of the ATP-binding pocket of Aurora kinases or the spacing between functional groups of a molecule comprising several chemical entities that directly interact with the ATP-binding pocket. The potential, predicted, inhibitory or binding effect of a molecule on Aurora kinase, in particular on Aurora A kinase may be analyzed prior to its actual synthesis and testing by the use of computer modeling techniques. If the theoretical structure of the given molecule suggests insufficient interaction and association between it and the ATP-binding pocket, synthesis and testing of the molecule is obviated. However, if computer modeling indicates a strong interaction, the molecule may then be synthesized and tested for its ability to interact with the ATP-binding pocket and inhibit kinase activity. In this manner, synthesis of inoperative molecules may be avoided. In some cases, inactive molecules are synthesized predicted on modeling and then tested to develop a SAR (structure-activity relationship) for molecules interacting with a specific region of the ATP-binding pocket of Aurora kinases, in particular of Aurora A kinase. As used herein, the term "SAR", shall collectively refer to the structure- activity/structure property relationships pertaining to the relationship(s) between a compound's activity/properties and its chemical structure.
One skilled in the art may use one of several methods to identify compound structures or entities, compounds, or other agents for their ability to associate with the ATP-binding pocket of Aurora kinases. This process may begin by visual inspection or computer assisted modeling of, for example, the target site on the computer screen based on the atomic co-ordinates of the ATP- binding pocket of Aurora A kinases and/or its complexes with the compounds of the present invention (see Fig. 4). In one embodiment, compound design uses computer modeling programs which calculate how different molecules interact with the ATP-binding site. Selected chemical moieties or entities, compounds, or agents may then be positioned in a variety of orientations, or docked, within at least a portion of the ATP-binding pocket of Aurora kinases, in particular of Aurora A kinase. Databases of chemical structures are available from, for example, Cambridge Crystallographic Data Center (Cambridge, U.K.) and Chemical Abstracts Service (Columbus, Ohio). Docking may be accomplished using software such as Cerius, Quanta or Sybyl, followed by energy minimization and molecular dynamics with standard molecular mechanics forcefields, such as OPLS-AA, CHARMM or AMBER.
Specialized computer programs may also assist in the process of selecting chemical entities. These include, but are not limited to: (1) GRID (Goodford, P. J., "A Computational Procedure for Determining Energetically Favorable Binding Sites on Biologically Important Macromolecules" (1985) J. Med. Chem. 28, 849-857). Software such as GRID, a program that determines probable interaction sites between probes with various functional group characteristics and the macromolecular surface, can be used to analyze the surface sites to determine structures of similar inhibiting proteins or molecules. The GRID calculations, with suitable inhibiting groups on molecules (e.g., protonated primary amines) as the probe, are used to identify potential hotspots around accessible positions at suitable energy contour levels. GRID is available from Oxford University, Oxford, UK.
(2) MCSS (Miranker, A. and M. Karplus (1991) "Functionality Maps of Binding Sites: A Multiple Copy Simultaneous Search Method." Proteins: Structure, Function and
Genetics 11 : 29-34). MCSS is available from Molecular Simulations, Burlington, Mass.
(3) AUTODOCK (Goodsell, D. S. and A. J. Olsen (1990) "Automated Docking of Substrates to Proteins by Simulated Annealing" Proteins: Structure, Function, and Genetics 8: 195- 202). AUTODOCK is available from Scripps Research Institute, La Jolla, Calif. (4) DOCK (Kuntz, I. D. et al. (1982) "A Geometric Approach to Macromolecule-Ligand Interactions" J. MoI. Biol. 161 : 269-288). The program DOCK may be used to analyze an active site or ligand binding site and suggest ligands with complementary steric properties. DOCK is available from University of California, San Francisco, Calif. (5) ALADDIN (Van Drie et al. (1989) "ALADDIN: An Integrated Tool of Computer Assisted Molecular Design and Pharmacophore Recognition From Geometric, Steric and Substructure Searching of Three-Dimensional Structures" J. Comp- Aided MoI. Des. 3: 225).
(6) CLIX (Davie and Lawrence (1992) "CLIX: A Search Algorithm for Funding Novel Ligands Capable of Binding Proteins of Known Three-Dimensional Structure" Proteins
12: 3141).
(7) GROUPBUILD (Rotstein and Murcko (1993) "GroupBuild: A Fragment-Based Method for De Novo Drug Design" J. Med. Chem 36: 1700).
(8) GROW (Moon and Howe (1991) "Computer Design of Bioactive Molecules: A Method for Receptor-Based De Novo Ligand Design" Proteins 11: 314).
Once suitable chemical moieties or entities, compounds, or agents have been selected, they can be assembled into a single molecule. Assembly may proceed by visual inspection and/or computer modeling and computational analysis of the spatial relationship of the chemical moieties or entities, compounds or agents with respect to one another in three-dimensional space. This could then be followed by model building using software such as Quanta or Sybyl.
Useful programs to aid one of skill in the art in connecting the individual chemical entities, compounds, or agents include but are not limited to:
(1) CAVEAT (Bartlett, P. A. et al. (1989) "CAVEAT: A Program to Facilitate the Structure- Derived Design of Biologically Active Molecules". In molecular Recognition in Chemical and Biological Problems", Special Pub., Royal Chem. Soc. 78: 82-196) and
(Bacon et al. (1992) J MoI. Biol. 225: 849-858). CAVEAT uses databases of cyclic compounds which can act as "spacers" to connect any number of chemical fragments already positioned in the active site. This allows one skilled in the art to quickly generate hundreds of possible ways to connect the fragments already known or suspected to be necessary for tight binding. CAVEAT is available from the University of California,
Berkeley, Calif.
(2) 3D Database systems such as MACCS-3D (MDL Information Systems, San Leandro, (CA). This area is reviewed in Martin, Y. C, (1992) "3D Database Searching in Drug Design", J Med Chem. 35: 2145-2154. (3) HOOK (available from Molecular Simulations, Burlington, Mass.).
Instead of proceeding to build a molecule of interest in a step-wise fashion one chemical entity at a time as described above, the molecule of interest may be designed as a whole using either an empty active site or optionally including some portion or portions of an inhibitor of the present invention. Software that implements these methods include:
(1) LUDI (Bohm, H.-J. (1992) "The Computer Program LUDI: A New Method for the De Novo Design of Enzyme Inhibitors" J. Comp. Aid. Molec. Design 6: 61-78). The program LUDI can determine a list of interaction sites into which to place both hydrogen bonding and hydrophobic fragments. LUDI then uses a library of approximately 600 linkers to connect up to four different interaction sites into fragments. Then smaller "bridging" groups such as — CH2 — and — COO — are used to connect these fragments. For example, for the enzyme DHFR, the placements of key functional groups in the well-known inhibitor methotrexate were reproduced by LUDI. See also, Rotstein and Murcko, (1992) J. Med. Chem. 36:1700-1710. LUDI is available from Biosym Technologies, San Diego, Calif.
(2) LEGEND (Nishibata, Y. and A. Itai (1991) Tetrahedron 47, 8985). LEGEND is available from Molecular Simulations, Burlington, Mass.
(3) LeapFrog (available from Tripos Associates, St. Louis, Mo.).
(4) Aladdin (available from Daylight Chemical Information Systems, Irvine, Calif.). Other molecular modeling techniques may also be employed in accordance with the method of the invention. See, e.g., Cohen, N. C. et al. (1990) "Molecular Modeling Software and Methods for Medicinal Chemistry, J. Med. Chem. 33: 883-894. See also, Navia, M. A. and M. A. Murcko (1992) "The Use of Structural Information in Drug Design", Current Opinions in Structural Biology 2: 202-210; and Jorgensen (1998) "BOSS — Biochemical and Organic Simulation System" in the Encyclopedia of Computational Chemistry (P. V. R. Schleyer, ed.) Wiley & Sonstra., Athens, U.S.A. 5: 3281-3285).
It is contemplated that during modeling, it may be possible to introduce into the molecule of interest, chemical moieties that may be beneficial for a molecule that is to be administered as a pharmaceutical. For example, it may be possible to introduce into or omit from the molecule of interest, chemical moieties that may not directly affect binding of the molecule to the target area but which contribute, for example, to the overall solubility of the molecule in a pharmaceutically acceptable carrier, the bioavailability of the molecule and/or the toxicity of the molecule. Considerations and methods for optimizing the pharmacology of the molecules of interest can be found, for example, in "Goodman and Gilman's The Pharmacological Basis of Therapeutics" Eighth Edition (Goodman, Gilman, Rail, Nies, & Taylor (eds.))- Pergamon Press (1985); Jorgensen & Duffy (2000) Bioorg. Med. Chem. Lett. 10: 1155-1158. Furthermore, the computer program "Qik Prop" can be used to provide rapid predictions for physically significant descriptions and pharmaceutically-relevant properties of an organic molecule of interest. A 'Rule of Five1 probability scheme can be used to estimate oral absorption of the newly synthesized compounds (Lipinski et al. (1997) Adv. Drug Deliv. Rev. 23: 3).
Programs suitable for pharmacophore selection and design include:
(1) DISCO (Abbot Laboratories, Abbot Park, 111.).
(2) Catalyst (Bio-CAD Corp., Mountain View, Calif). (3) Chem DBS-3D (Chemical Design Ltd., Oxford, U.K.).
Furthermore, the skilled artisan may use the information available on how to design suitable therapeutically active and pharmaceutically useful compounds, and use this information in the design of new Aurora kinase inhibitors of the invention. See, for example, Lipinski et al. (1997) Ad Drug Deliv. Reviews 23: 3-25; Van de Waterbeemd et al. (1996) Quantitative Structure-Activity Relationships 15: 480-490; and Cruciani et al. (2000), Theochem-J. MoI. Struct. 503: 17-30.
Instead of designing molecules of interest entirely de novo it is contemplated that the compounds of the present invention, in particular methyl 3-(lH-indazol-6- ylsulfamoyl)thiophene-2-carboxylate , may be used as a starting point for the design of a new candidate. It is contemplated that many of the approaches useful for designing molecules de novo may also be useful for modifying existing molecules.
It is contemplated that knowledge of the spatial relationship between an Aurora kinase inhibitor and the ATP -binding site permits the design of modified inhibitors that may have better binding properties, for example, higher binding affinity and/or specificity, relative to the molecule from which it was derived. Alternatively, knowledge of inhibitor contact sites within the ATP-binding site permits the synthesis of a new molecule that contains, for example, a portion of a first molecule (for example, an antibiotic or an analogue or derivative thereof) that binds to the contact site and another portion that contributes additional functionality.
Based on the information provided herein, the skilled artisan may readily identify and produce hybrid Aurora kinase inhibitors that comprise an ATP-binding pocket binding domain and a binding domain interacting with another part of the Aurora kinase.
The resulting Aurora kinase inhibitors preferably have a molecular weight no greater than about 1,500, more preferably no greater than about 1,000, more preferably no greater than 750 and, most preferably no greater than about 500. The Aurora kinase inhibitors preferably have a molecular weight in the range from about 150 to about 1500, and more preferably in the range from about 200 to about 1200. In addition, the Aurora kinase inhibitors have a minimal inhibitor concentration preferably less than 50 μM, more preferably less than 10 μM, more preferably less than 1 μM and most preferably less than 0.1 to μM inhibit 50% activity (IC 50) in a biological assay, for example, an in vitro kinase assay, for example, as set out below. The Aurora kinase inhibitors preferably have an IC50 in the range from about 0.001 μM to about 50 μM, or in the range from about 0.01 μM to about 10 μM, or in the range from about 0.1 μM to about 1 μM. Preferably, the inhibitors of the present invention preferentially inhibit Aurora A kinase.
It is contemplated that the tools and methodologies of the present invention can be used to obtain inhibitors of Aurora kinases, in particular of Aurora A kinase.
Once a compound structure has been designed or selected by the above methods, the affinity with which that molecule may bind to the ATP -binding pocket of Aurora kinase may be tested and optimized by computational evaluation and/or by testing biological activity after synthesizing the compound. Candidate molecules may interact with the ATP-binding pocket of Aurora kinase in more than one conformation each of which has a similar overall binding energy. In those cases, the deformation energy of binding may be considered to be the difference between the energy of the free molecule and the average energy of the conformations observed when the molecule binds to the ATP-binding pocket of the Aurora kinase.
A molecule designed or selected as binding to an Aurora kinase ATP-binding pocket may be further computationally optimized so that in its bound state it preferably lacks repulsive electrostatic interaction with the target region. Such non-complementary (e.g., electrostatic) interactions include repulsive charge-charge, dipole-dipole and charge-dipole interactions. Specifically, the sum of all electrostatic interactions between the inhibitor and the enzyme when the inhibitor is bound to the ATP-binding pocket of Aurora kinase, preferably make a neutral or favorable contribution to the enthalpy of binding. Weak binding compounds can also be designed by these methods so as to determine SAR.
Specific computer programs that can evaluate a compound deformation energy and electrostatic interaction are available in the art. Examples of suitable programs include: Gaussian 92, revision C (M. J. Frisch, Gaussian, Inc., Pittsburgh, Pa.); AMBER, version 4.0 (P. A. Kollman, University of California at San Francisco, Calif.); QUANTA/CHARMM (Molecular Simulations, Inc., Burlington, Mass.); OPLS-AA ("OPLS Force Fields." W. L. Jorgensen. Encyclopedia of Computational Chemistry, Schleyer, Ed.; Wiley: New York, 1998; Vol. 3, pp 1986-1989.) and Insight II/Discover (Biosysm Technologies Inc., San Diego, Calif.). These programs may be implemented, for instance, using a Silicon Graphics workstation, IRIS 4D/35 or IBM RISC/6000 workstation model 550. Other hardware systems and software packages are known to those skilled in the art.
Once a molecule of interest has been selected or designed, as described above, substitutions may then be made in some of its atoms or side groups in order to improve or modify its binding properties. Generally, initial substitutions are conservative, i.e., the replacement group will approximate the same size, shape, hydrophobicity and charge as the original group. It should, of course, be understood that components known in the art to alter conformation should be avoided. Such substituted chemical compounds may then be analyzed for efficiency of fit to the ATP-binding pocket of Aurora kinase by the same computer methods described in detail, above.
In addition, the actual ATB-binding site ligands, complexes or mimetics may be crystallized and analyzed using X-ray diffraction. The diffraction pattern co-ordinates are similarly used to calculate the three-dimensional interaction of a ligand and the Aurora kinase to confirm that the ligand binds to the ATP-binding pocket. A compound structure identified by the method of the present invention, which may serve as a lead structure is in a further preferred embodiment produced to test it for its ability to inhibit Aurora kinase activity, in particular Aurora A kinase activity.
A compound structure can be, but is not limited to, at least one selected from a lipid, nucleic acid, peptide, small organic or inorganic molecule, chemical compound, element, saccharide, isotope, carbohydrate, imaging agent, lipoprotein, glycoprotein, enzyme, analytical probe, and an antibody or fragment thereof, any combination of any of the foregoing, and any chemical modification or variant of any of the foregoing. In addition, a lead molecule may optionally comprise a detectable label. Such labels include, but are not limited to, enzymatic labels, radioisotope or radioactive compounds or elements, fluorescent compounds or metals, chemiluminescent compounds and bioluminescent compounds. Well known methods may be used for attaching such a detectable label to a lead molecule.
Methods useful for synthesizing lead molecules such as lipids, nucleic acids, peptides, small organic or inorganic molecules, chemical compounds, elements, saccharides, isotopes, carbohydrates, imaging agents, lipoproteins, glycoproteins, enzymes, analytical probes, antibodies, and antibody fragments are well known in the art. Such methods include the traditional approach of synthesizing one such lead molecule, such as a single defined peptide, at a time, as well as combined synthesis of multiple lead molecules in a one or more containers. Such multiple lead molecules may include one or more variants of a previously identified lead molecule. Methods for combined synthesis of multiple lead molecules are particularly useful in preparing combinatorial libraries, which may be used in screening techniques known in the art.
By way of example, it is well known in the art that multiple peptides and oligonucleotides may be simultaneously synthesized. Lead molecules that are small peptides up to 50 amino acids in length may be synthesized using standard solid-phase peptide synthesis procedures, for example, procedures similar to those described in Merrifield (1963) J. Am. Chem. Soc, 85: 2149. For example, during synthesis, N-α-protected amino acids having protected side chains are added stepwise to a growing polypeptide chain linked by its C-terminal end to an insoluble polymeric support, e.g., polystyrene beads. The peptides are synthesized by linking an amino group of an N-α-deprotected amino acid to a α-carboxy group of an N-α-protected amino acid that has been activated by reacting it with a reagent such as dicyclohexylcarbodiimide. The attachment of a free amino group to the activated carboxyl leads to peptide bond formation. The most commonly used N-α-protecting groups include Boc which is acid labile and Fmoc which is base labile.
Briefly, the C-terminal N-α-protected amino acid is first attached to the polystyrene beads. Then, the N-α-protecting group is removed. The deprotected α-amino group is coupled to the activated a-carboxylate group of the next N-α-protected amino acid. The process is repeated until the desired peptide is synthesized. The resulting peptides are cleaved from the insoluble polymer support and the amino acid side chains deprotected. Longer peptides, for example greater than about 50 amino acids in length, typically are derived by condensation of protected peptide fragments. Details of appropriate chemistries, resins, protecting groups, protected amino acids and reagents are well known in the art and so are not discussed in detail herein. See for example, Atherton et al. (1963) Solid Phase Peptide Synthesis: A Practical Approach (IRL Press), and Bodanszky (1993) Peptide Chemistry, A Practical Textbook, 2nd Ed. Springer- Verlag, and Fields et al. (1990) Int. J. Peptide Protein Res. 35: 161-214. Purification of the resulting peptide is accomplished using conventional procedures, such as preparative HPLC, e.g., gel permeation, partition and/or ion exchange chromatography. The choice of appropriate matrices and buffers are well known in the art and so are not described in detail herein.
It is contemplated that a synthetic peptide in accordance with the invention may comprise naturally occurring amino acids, unnatural amino acids, and/or amino acids having specific characteristics, such as, for example, amino acids that are positively charged, negatively charged, hydrophobic, hydrophilic, or aromatic. As used herein, the term "naturally occurring amino acids" refers to the L-isomers of amino acids normally found in proteins. The predominant naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, and lysine. Unless specifically indicated, all amino acids are referred to in this application are in the L-form. Furthermore, as used herein, the term "unnatural amino acids" refers to amino acids that are not naturally found in proteins. For example, selenomethionine.
Amino acids that are "positively charged" include any amino acid having a positively charged side chain under normal physiological conditions. Examples of positively charged naturally occurring amino acids include, for example, arginine, lysine, and histidine. Conversely, amino acids that are "negatively charged" include any amino acid having a negatively charged side chains under normal physiological conditions. Examples of negatively charged naturally occurring amino acids include, for example, aspartic acid and glutamic acid.
As used herein, the term "hydrophobic amino acid" includes any amino acids having an uncharged, nonpolar side chain that is relatively insoluble in water. Examples of naturally occurring hydrophobic amino acids include, for example, alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine. In addition, as used herein, the term "hydrophilic amino acid" refers to any amino acids having an uncharged, polar side chain that is relatively soluble in water. Examples of naturally occurring hydrophilic amino acids include, for example, serine, threonine, tyrosine, asparagine, glutamine and cysteine.
Finally, as used herein, the term "aromatic" refers to amino acid residues which side chains have delocalized conjugated system. Examples of aromatic residues include, for example, phenylalanine, tryptophan, and tyrosine.
With regard to the production of non-peptide small organic molecules which act as a ligand in the present invention, these molecules can be synthesized using standard organic chemistries well known and thoroughly documented in the patent and other literatures. Many of the known methods useful in synthesizing lead of the present invention may be automated, or may otherwise be practiced on a commercial scale. As such, once a lead molecule has been identified as having commercial potential, mass quantities of that molecule may easily be produced.
Molecules designed, selected and/or optimized by methods described above, once produced, may be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules may be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity. In addition, the Aurora A kinase inhibitory activity of the compound structures identified by the method of the present invention can be assessed. Accordingly, in a further embodiment the method further comprises the step of determining whether the compound structure inhibits aurora kinase activity. A compound is considered to inhibit Aurora kinase activity, if the Aurora kinase activity is reduced by more than 50%, preferably by more than 60%, preferably by more than 70%, preferably by more than 80%, preferably by more than 90% at a concentration of 1 mM, if assayed, e.g. in an in vitro kinase assay as set out below. Preferably, the inhibitory activity is selective for Aurora A kinase. An inhibitor is considered an Aurora A kinase specific inhibitor, if th IC50 for the compound is at least 20%, preferably 30%, more preferably 40%, more preferably 50%, more preferably 60% or more lower for Aurora kinase A than for other Aurora kinases, in particular Aurora kinase B and/or Aurora kinase C.
In a preferred embodiment the method further comprises the step of formulating the Aurora A kinase inhibitor produced with above described method with one or more pharmaceutically acceptable excipient and/or carrier. A further aspect of the present invention is a pharmaceutical composition comprising an effective amount of at least one compound according to formula (I) or any of its preferred embodiments or a compound produced according to the method of the present invention and a pharmaceutically acceptable carrier or excipient.
For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from 5% to 80%, more preferably from 20% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. Liquid forms are particularly preferred for topical applications to the eye. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
In a further aspect the present invention concerns the use of compounds produced in above described method in the production of a medicament for treating, ameliorating or preventing diseases, conditions and/or disorders which benefit from reduced aurora kinase activity, in particular Aurora A kinase activity.
Since aurora kinases are known to have a central role in the cell cycle and in particular aurora A kinase shows an elevated expression in more than 50% of colorectal, ovarian and gastric cancers and in more than 95% of invasive adenocarcinomas in a preferred embodiment of the present invention the diseases, conditions and/or disorders, which can be prevented, ameliorated or treated with the compounds of the present invention are hyperproliferative diseases. A disease is considered to benefit from reduced aurora kinase, in particular Aurora A kinase activity, if a reduction of Aurora kinase activity of at least 10%, preferably of at least 20%, preferably of at least 30%, leads to an improvement of at least one clinical indicator of that disease. Examples of such indicators are proliferation rate, which is preferably reduced, cellular differentiation, which is preferably induced etc. The activity of Aurora kinases, in particular Aurora A kinase can be assayed by art know methods, including but not limited to those described below.
It is further preferred that the hyperproliferative diseases are selected from the group consisting of precancerosis; dysplasia; metaplasia; carcinomas of the gastrointestinal or colorectal tract, liver, pancreas, kidney, bladder, prostate, endometrium, ovary, testes, melanoma, dysplastic oral mucosa, invasive oral cancers, small cell and non-small cell lung carcinomas, hormone-dependent breast cancers, hormone-independent breast cancers, transitional and squamous cell cancers, neurological malignancies including neuroblastoma, gliomas, astrocytomas, osteosarcomas, soft tissue sarcomas, hemangioamas, endocrinological tumors, hematologic neoplasias including leukemias, lymphomas, and other myeloproliferative and lymphoproliferative diseases, carcinomas in situ, hyperplastic lesions, adenomas, fϊbromas, histiocytosis, chronic inflammatory proliferative diseases, vascular proliferative diseases and virus-induced proliferative diseases, skin diseases characterized by hyperproliferation of keratinocytes and/or T cells. Particular preferred diseases treatable with the compounds of the present invention are colorectal, ovarian, prostatic and gastric cancers and adenocarcinomas, more preferably invasive adenocarcinomas.
The precancerosis treatable with the compounds of the present invention are preferably selected from the group consisting of precancerosis of the skin, in particular actinic keratosis, cutaneaous horn, actinic cheilitis, tar keratosis, arsenic keratosis, x-ray keratosis, Bowen's disease, bowenoid papulosis, lentigo maligna, lichen sclerosus, and lichen rubber mucosae; precancerosis of the digestive tract, in particular erythroplakia, leukoplakia, Barrett's esophagus, Plummer-Vinson syndrome, crural ulcer, gastropathia hypertrophica gigantea, borderline carcinoma, neoplastic intestinal polyp, rectal polyp, porcelain gallbladder; gynaecological precancerosis, in particular carcinoma ductale in situ (CDIS), cervical intraepithelial neoplasia (CIN), leukoplakia, endometrial hyperplasia (grade III), vulvar dystrophy, vulvar intraepithelial neoplasia (VIN), hydatidiform mole; urologic precancerosis, in particular bladder papillomatosis, Queyrat's erythroplasia, testicular intraepithelial neoplasia (TIN), leukoplakia; carcinoma in situ (CIS); precancerosis caused by chronic inflammation, in particular pyoderma, osteomyelitis, acne conglobata, lupus vulgaris, and fistula.
Dysplasia is frequently a forerunner of cancer, and is found mainly in the epithelia; it is the most disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells. Dysplastic cells often have abnormally large, deeply stained nuclei, and exhibit pleomorphism. Dysplasia characteristically occurs where there exist chronic irritation or inflammation. Dysplastic disorders which can be treated with the compounds of the present invention include, but are not limited to, anhidrotic ectodermal dysplasia, anterofacial dysplasia, asphyxiating thoracic dysplasia, atriodigital dysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia, chondroectodermal dysplasia, cleidocranial dysplasia, congenital ectodermal dysplasia, craniodiaphysial dysplasia, craniocarpotarsal dysplasia, craniometaphysial dysplasia, dentin dysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia, encephalo-ophthalmic dysplasia, dysplasia epiphysialis heminelia, dysplasia epiphysialis multiplex, dysplasia epiphysalis punctata, epithelial dysplasia, faciodigitogenital dysplasia, familial fibrous dysplasia of jaws, familial white folded dysplasia, fϊbromuscular dysplasia, fibrous dysplasia of bone, florid osseous dysplasia, hereditary renal-retinal dysplasia hidrotic ectodermal dysplasia, hypohidrotic ectodermal dysplasia, lymphopenic thymic dysplasia, mammary dysplasia, mandibulofacial dysplasia, metaphysical dysplasia, Mondini dysplasia, monostotic fibrous dysplasia, mucoepithelial dysplasia, multiple epiphysial dysplasia, oculoauriculovertebral dysplasia, oculodentodigital dysplasia, oculovertebral dysplasia, odontogenic dysplasia, ophthalmomandibulomelic dysplasia, periapical cemental dysplasia, polyostotic fibrous dysplasia, pseudoachondroplastic spondyloepiphysial dysplasia, retinal dysplasia, septo-optic dysplasia, spondyloepiphysial dysplasia, and ventriculoradial dysplasia. Metaplasia is a form of controlled cell growth in which one type of adult or fully differentiated cell substitutes for another type of adult cell. Metaplastic disorders, which are treatable are preferably selected from the group consisting of agnogenic myeloid metaplasia, apocrine metaplasia, atypical metaplasia, autoparenchymatous metaplasia, connective tissue metaplasia, epithelial metaplasia, intestinal metaplasia, metaplastic anemia, metaplastic ossification, metaplastic polyps, myeloid metaplasia, primary myeloid metaplasia, secondary myeloid metaplasia, squamous metaplasia, squamous metaplasia of amnion, symptomatic myeloid metaplasia and regenerative metaplasia.
Many skin diseases are characterized by hyperproliferation of keratinocytes and/or T cells. Examples of such diseases which are treatable with the compounds of the present invention comprise without limitations psoriasis in particular psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa; neurodermatitis; ichtyosises; alopecia areata; alopecia totalis; alopecia subtotalis; alopecia universalis; alopecia diffusa; atopic dermatitis; lupus erythematodes of the skin; dermatomyositis of the skin; atopic eczema; morphea; scleroderma; alopecia areata Ophiasis type; androgenic alopecia; allergic contact dermatitis; irritative contact dermatitis; contact dermatitis; pemphigus vulgaris; pemphigus foliaceus; pemphigus vegetans; scarring mucous membrane pemphigoid; bullous pemphigoid; mucous membrane pemphigoid; dermatitis; dermatitis herpetiformis Duhring; urticaria; necrobiosis lipoidica; erythema nodosum; prurigo simplex; prurigo nodularis; prurigo acuta; linear IgA dermatosis; polymorphic light dermatosis; erythema Solaris; exanthema of the skin; drug exanthema; purpura chronica progressiva; dihydrotic eczema; eczema; fixed drug exanthema; photoallergy skin reaction; and periorale dermatitis.
It is suspected that Aurora kinases are also involved in mediating activation of estrogen receptor (ER) controlled genes. Thus, in a further preferred embodiment the hyperproliferative disorders which are treatable by the Aurora kinase inhibitors of the present invention are those which benefit from a reduced estrogen receptor signalling. It is known that an increased activity of genes controlled by estrogen receptor is responsible or contributes to various hyperproliferative diseases. Thus preferred diseases, conditions and/or disorders which can be treated with the compounds of the present invention are selected from the group consisting of mammary tumors, endometrial tumors and tumors of the uterus. The ability of the compounds of the present invention to inhibit estrogen receptor signalling can be confirmed with any of a number of art known methods involving, e.g. the transfection of cells with plasmids comprising ER recognition sequences upstream of reporter genes, e.g. CAT, luciferase etc. Similarly, someone of skill in the art is capable of assessing whether a given hyperproliferative disease involves increased estrogen receptor signalling by determining the expression level of an ER controlled gene, e.g. cathepsin D, lactoferrin, or IGF-I etc.
The quantity of active component in a unit dose preparation administered in the use of the present invention may be varied or adjusted from about 1 mg to about 1000 mg per m2, preferably about 5 mg to about 150 mg/m2 according to the particular application and the potency of the active component. The pharmaceutical composition can, if desired, also contain other compatible therapeutic agents (e.g., cytotoxic or cytostatic compounds, including, but not limited to, pure or mixed anti -estrogens such as faslodex, tamoxifen or raloxifen; any inhibitors of topoisomerase I or II, such as camptothecin (topo I) or etoposide (topo II); any compound that acts through inhibiting aromatase activity, such as anastrozole or letrozole; any preparation that interferes with HER2 signalling such as herceptin; any compound that interchelates DNA, such as doxorubicin. Particularly preferred cytostatic or cytotoxic drugs, which can be combined with the compounds of the present invention are alkylating substances, anti-metabolites, antibiotics, epothilones, nuclear receptor agonists and antagonists, anti-androgenes, anti-estrogens, platinum compounds, hormones and antihormones, interferons and inhibitors of cell cycle-dependent protein kinases (CDKs), inhibitors of cyclooxygenases and/or lipoxygenases, biogeneic fatty acids and fatty acid derivatives, including prostanoids and leukotrienes, inhibitors of protein kinases, inhibitors of protein phosphatases, inhibitors of lipid kinases, platinum coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analogs, alkylsulfonates, folic acid analogs, anthracendiones, substituted urea, methylhydrazin derivatives, in particular acediasulfone, aclarubicine, ambazone, aminoglutethimide, L-asparaginase, azathioprine, bleomycin, busulfan, calcium folinate, carboplatin, carpecitabine, carmustine, celecoxib, chlorambucil, cis-platin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel, doxorubicin, enediynes, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide fosfestrol, furazolidone, gemcitabine, gonadotropin releasing hormone analog, hexamethylmelamine, hydroxycarbamide, hydroxymethylnitrofurantoin, hydroxyprogesteronecaproat, hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon α, irinotecan, leuprolide, lomustine, lurtotecan, mafenide sulfate olamide, mechlorethamine, medroxyprogesterone acetate, megastrolacetate, melphalan, mepacrine, mercaptopurine, methotrexate, metronidazole, mitomycin C, mitopodozide, mitotane, mitoxantrone, mithramycin, nalidixic acid, nifuratel, nifuroxazide, nifuralazine, nifurtimox, nimustine, ninorazole, nitrofurantoin, nitrogen mustards, oleomucin, oxolinic acid, pentamidine, pentostatin, phenazopyridine, phthalylsulfathiazole, pipobroman, prednimustine, prednisone, preussin, procarbazine, pyrimethamine, raltitrexed, rapamycin, rofecoxib, rosiglitazone, salazosulfapyridine, scriflavinium chloride, semustine streptozocine, sulfacarbamide, sulfacetamide, sulfachlopyridazine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfaethidole, sulfafurazole, sulfaguanidine, sulfaguanole, sulfamethizole, sulfamethoxazole, co-trimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sulfathiazole, sulfisomidine, staurosporin, tamoxifen, taxol, teniposide, tertiposide, testolactone, testosteronpropionate, thioguanine, thiotepa, tinidazole, topotecan, triaziquone, treosulfan, trimethoprim, trofosfamide, UCN-01, vinblastine, vincristine, vindesine, vinblastine, vinorelbine, and zorubicin, or their respective derivatives or analogs thereof. Several of the above indicated drugs are now administered simultaneously for cancer therapy and, consequently, it is also envisioned that more than one cytostatic and/or cytotoxic drug is comprised in compositions of the present invention.
In therapeutic use as an inhibitor of aurora kinase activity, preferably aurora A kinase activity, the compounds employed in this use of the invention are administered at an initial dosage of about 0.05 mg/kg to about 20 mg/kg daily. A daily dose range of about 0.05 mg/kg to about 2 mg/kg is preferred, with a daily dose range of about 0.05 mg/kg to about 1 mg/kg being most preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
BRIEF DESCRIPTION OF THE FIGURES
Fig. 1: Summarizes the results of various assays performed with a particular preferred compound of the present invention. Depicted are from left to right the IC50 against Aurora A kinase, kinase activity of Aurora kinase A, B, C and FLT3, the cytotoxicity on
HeLa, and the cytotoxicity on fibroblasts.
Fig 2: Depicts the evidence that methyl 3-(lH-indazol-6-ylsulfamoyl)thiophene-2-carboxylate is an ATP competitive compound. Increasing the ATP concentration results in a shift of the IC50 to less potency Fig. 3: Depicts the co-crystal structure of a preferred compound of the present invention in the ATP-binding pocket of Aurora A kinase. The fo-fc map shown in the figure is contoured at 2.8 sigma.
Fig. 4: The spatial coordinates of co-crystals of Aurora A kinase fragment spanning 127GIn to 390PrO with methyl 3-(lH-indazol-6-ylsulfamoyl)thiophene-2-carboxylate are depicted. EXPERIMENTAL SECTION
Assay for the identification of compounds
Methyl 3-(lH-indazol-6-ylsulfamoyl)thiophene-2-carboxylate (Compound according to formula VII) was identified from a screen for inhibitors of Aurora A kinase using 20 μM ATP and kemptide peptide (amino acid sequence LRRASLG; SEQ ID NO:1) as substrate. The level of ATP consumption was monitored using couple luciferase (easylite-Kinase Luminescence Assay System PerkinElmer). Inhibitors of the kinase cause reduction of ATP turnover and increase in luminescence. Serial dilutions of the compounds were assayed using Z-lite (Invitrogen at 2, 20, 200, and 1000 μM to determine whether they were ATP competive. This assay was screened against 53,000 compounds from a commercial library obtained under CDA.
Dose response curves from active compounds were generated in a two fold 11 point serial dilution from a top concentration of 200 μM. The dose response curves were plotted in XLfit (IDBS, UK) and the IC50 values reported in micromolar (μM). To determine whether compounds were ATP competitive the IC50 for the compound was determined at 3 different final ATP concentrations (20, 200, and 1000 μM) using Z'Lyte Kinase Assay Kit Ser/Thr Peptide 1 (PV3174) kit as described by the manufacturer. After resolution of the phosphorylation reaction the plates were read in an Envision HTS (PerkinElmer) and the dose response curves fitted as percent inhibitions in XLfit (IDBS, UK) and the IC50 values reported in micromolar (μM). When the calculated IC50 value increased by greater than 5-fold per log 10 increase in ATP concentration the respective compound was deemed to be ATP competitive. Compounds that did not fulfill these criteria were deemed to be ATP noncompetitive. The dose response for compound methyl 3-(lH-indazol-6-ylsulfamoyl)thiophene-2- carboxylate is depicted in Fig. 2. For the purpose of this invention only those compounds were further evaluated, which were ATP competitive inhibitors according to these criteria.
Single point determination of aurora kinase activity (radioactive assay)
On the day, on which the assays were performed, 90 μl H O were added to each well of the master plate. To minimize precipitation, the H O was added to each well only a few minutes before the transfer of the compound solutions into the assay plates. The plate was shaken
-4 thoroughly, resulting in a "compound dilution plate" with a concentration of 5 x 10 M/10% DMSO. This plate was used for the transfer of 5 μl compound solution into the assay plates. The final volume of the assay was 50 μl. All compounds were tested at a final assay concentration of 5 x 10 M/1% DMSO in singlicate. The compound dilution plate was disposed at the end of the working day.
The following 4 protein kinases were used for determination of inhibitory profiles: i) Aurora-A ii) Aurora-B iii) Aurora-C iv) FLT3
All protein kinases were expressed in Sf9 insect cells as human recombinant GST-fusion proteins or His-tagged proteins by means of a baculovirus expression system. Kinases were purified by affinity chromatography using either GSH-agarose (Sigma) or Ni-NTH-agarose (Qiagen). The purity of each kinase was checked by SDS-P AGE/silver staining and the identity of each kinase was verified by western blot analysis with kinase specific antibodies or by mass spectroscopy.
Protein Kinase Assay
33 ®
A protein kinase assay ( PanQinase Activity Assay) was used for measuring the kinase
TM activity of the 4 protein kinases. All kinase assays were performed in 96- well FlashPlates from Perkin Elmer/NEN (Boston, MA,- USA) in a 50 μl reaction volume. The reaction cocktail was pipetted in 4 steps in the following order: • 20 μl of assay buffer
• 5 μl of ATP solution (in H2O)
• 5 μl of test compound (in 10 % DMSO)
• 10 μl of substrate / 10 μl of enzyme solution (premixed)
The assay for all enzymes contained 60 mM HEPES-NaOH, pH 7.5, 3 mM MgCl , 3 mM MnCl 2 , 3 μM Na-orthovanadate, 1.2 mM DTT, 50 μg/ml PEG 2 Λ0(0ΛΛ0n0, 1 μM [γ- P]-ATP (approx. 5
5 x 10 cpm per well).
For the 4 kinases the following amounts of enzyme and substrate were used per well:
# Kinase Kinase Kinase Substrate Substrate
Lot # ng/50 μl ng/SOμl
1 Aurora-A SP004 50 tetra(LRRWSLG) 500
2 Aurora-B SP006 200 tetra(LRRWSLG) 250 3 Aurora-C SP007 200 tetra(LRRWSLG) 500
4 FLT3 SP006 100 PoIy(AIa3GIu3LyS3TyI)6 2 5., 125
The reaction cocktails were incubated at 3O0C for 80 minutes. The reaction was stopped with 50 μl of 2% (v/v) H PO , plates were aspirated and washed two times with 200 μl of 0.9 %
33
(w/v) NaCl. Incorporation of P. was determined with a microplate scintillation counter (Microbeta Trilux, Wallac). All assays were performed with a BeckmanCoulter/Sagian robotic system.
The median value of the counts in column 1 (n=8) of each assay plate was defined as
"low control". This value reflects unspecific binding of radioactivity to the plate in the absence of a protein kinase but in the presence of the substrate. The median value of the counts in column 2 of each assay plate (n=8) was taken as the "high control", i.e. full activity in the absence of any inhibitor. The difference between high and low control was taken as 100 % activity.
As part of the data evaluation the low control value from a particular plate was subtracted from the high control value as well as from all 80 "compound values" of the corresponding plate. The residual activity (in %) for each well of a particular plate was calculated by using the following formula:
Res. Activity (%) = 100 X [(cpm of compound - low control) / (high control - low control)] i.e. a low value is indicative of strong inhibition.
Determination of cytotoxicity of preferred compounds of the invention Compounds were analysed for their ability to inhibit growth of tumour cells (e.g. HeLa cells) and normal human cells (e.g. foreskin fibroblasts). Growth inhibition was tested from 50 μM to 97.7 nM in a 10 point two-fold serial dilution and cells incubated under standard mammalian tissue culture conditions for 72 hours in triplicate. Cell viability was measured by measuring ATP levels in viable cells using the ATPLite kit (PerkinElmer) as described in the user manual. Raw data was transformed to percentage inhibition of growth compared to a DMSO only control and values are expressed as IC50.
Determination of the co-structure of aurora A kinase with methyl 3 -( 1 H-indazol-6- ylsulfamoylithiophene-Σ-carboxylate (Compound according to formula CVlY)) Hexagonal prism crystals of the wild-type AuroraΔN kinase (127GIn to 390Pro) alone, approximately 50 μm in all dimensions, were grown by vapor diffusion using 10% PEG8000, 8% ethylene glycol, 100 mM Hepes pH 7.5 as well as buffer and sitting drops comprising a 1 :1 mix of well buffer and 10 mg/ml protein. Crystals were soaked in the same precipitating solution containing 1 mM inhibitor for 24 hours. Diffraction data were collected at 100 K and pro-cessed using the CCP4 suite of programs (CCP4, 1994). Structures were solved by molecular replacement using CNS (Brunger et al., 1998) and the coordinates of the wild-type AuroraΔN kinase was used as an initial model (Bayliss et al., 2003). CNS was used for refinement and Coot (Emsley and Kowton, 2004) for model building. Figure 3 showing the electron density was prepared using PyMOL (DeLano, 2002). The residues interacting with the inhibitor were identified using the CCP4 suite of programs (CCP4, 1994) with the distance criteria. Protein atoms, which are within 3.5 A to any of the inhibitor atoms are considered to be interacting. The spatial coordinates of the co-crystals are depicted in Fig. 4.

Claims

Claims
1. Use of a compound of formula (I)
Figure imgf000051_0001
(I) wherein R1 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted; R2 and R3 are independent of each other selected from H; halogen; CN; NO2; NR7R8; alkyl, alkyloxy, aryl or heteroaryl, optionally substituted; wherein R7 and R8 are independent of each other hydrogen, alkyl, alkenyl, or alkynyl;
R4 is alkyl, optionally interrupted one or more times by O, N or S; -OOC-R6; -COO-R6 ; ,alkoxy; aryl; heteroaryl; aralkyl; heteroaralkyl; optionally substituted; wherein R6 is alkyl, alkenyl, alkynyl, aryl or heteroaryl; optionally substituted and R6 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl; optionally substituted; R5 is H, alkyl, alkenyl, alkynyl, optionally substituted; or R1 and R5 are taken together to form a heteroaryl or heterocycloalkyl; optionally substituted; and pharmaceutically acceptable salts thereof, for the production of a medicament for treating, ameliorating or preventing diseases, conditions and/or disorders which benefit from a reduced Aurora kinase activity.
2. Use according to claim 1 , wherein R1 is selected from the group consisting of furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1 ,2,3-triazolyl, thiazolyl, isothiazolyl, 1 ,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1- benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, IH- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazolyl, benzothiazolyl,
1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3- benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, and 1,2,4-benzotriazinyl; optionally substituted.
3. Use according to claims 1 or 2, wherein R6 is Ci-C6 alkyl.
4. Use according to claims 1 to 3, wherein the compound has a structure according to formula (VII)
Figure imgf000052_0001
A method of identifying a compound structure that can bind to the ATP binding pocket of Aurora A kinase, comprising the steps of:
(a) constructing a three dimensional structure of the ATP binding pocket of Aurora A kinase using as a template a three dimensional structure of the ATP binding pocket of Aurora A kinase comprising the inhibitor according to formula (VII) defined by atomic coordinates represented in Fig. 4;
(b) performing computer-assisted, structure based drug design with said structure of (a); and
(c) identifying at least one candidate compound structure that is predicted to have a compatible conformation with a target site on the constructed structure of the ATP binding pocket of Aurora A kinase as defined by the inhibitor according to formula (VII) such that the compound having the compound structure is predicted to bind to the ATP binding pocket of Aurora A kinase.
The method of claim 5, wherein the compound structure contacts one or more of the amino acids selected from the group consisting of Leu 139, Vall47, AlalβO, Lysl62, Glu260, Asn261, Leu263, Ala273, and Asp274 in the ATP binding pocket of Aurora A kinase.
7. The method of claims 5 or 6, wherein the compound structure is produced.
8. The method of claim 7, wherein the method further comprises the step of determining whether the compound structure inhibits aurora kinase activity.
9. The method of any of claims 7 or 8, wherein the method further comprises the step of formulating the compound with one or more pharmaceutically acceptable excipient and/or carrier.
10. Use of a compound produced according to any of claims 7 to 9 for the production of a medicament for treating, ameliorating or preventing diseases, conditions and/or disorders which benefit from a reduced Aurora kinase activity.
11. Use of claims 1 to 5 or 10, wherein the diseases, conditions and/or disorders are hyperproliferative diseases.
12. Use of claim 11, wherein the hyperproliferative diseases are selected from the group consisting of precancerosis; dysplasia; metaplasia; carcinomas of the gastrointestinal or colorectal tract, liver, pancreas, kidney, bladder, prostate, endometrium, ovary, testes, melanoma, dysplastic oral mucosa, invasive oral cancers, small cell and non-small cell lung carcinomas, hormone-dependent breast cancers, hormone-independent breast cancers, transitional and squamous cell cancers, neurological malignancies including neuroblastoma, gliomas, astrocytomas, osteosarcomas, soft tissue sarcomas, hemangioamas, endocrinological tumors, hematologic neoplasias including leukemias, lymphomas, and other myeloproliferative and lymphoproliferative diseases, carcinomas in situ, hyperplastic lesions, adenomas, fibromas, histiocytosis, chronic inflammatory proliferative diseases, vascular proliferative diseases and virus-induced proliferative diseases, skin diseases characterized by hyperproliferation of keratinocytes and/or T cells.
13. Use of claim 11, wherein the hyperproliferative diseases are characterized by the hyperproliferation of T-cells and/or keratinocytes.
14. Use of claim 13, wherein the diseases are selected from the group consisting of psoriasis in particular psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa; neurodermatitis; ichtyosises; alopecia areata; alopecia totalis; alopecia subtotalis; alopecia universalis; alopecia diffusa; atopic dermatitis; lupus erythematodes of the skin; dermatomyositis of the skin; atopic eczema; morphea; scleroderma; alopecia areata Ophiasis type; androgenic alopecia; allergic contact dermatitis; irritative contact dermatitis; contact dermatitis; pemphigus vulgaris; pemphigus foliaceus; pemphigus vegetans; scarring mucous membrane pemphigoid; bullous pemphigoid; mucous membrane pemphigoid; dermatitis; dermatitis herpetiformis Duhring; urticaria; necrobiosis lipoidica; erythema nodosum; prurigo simplex; prurigo nodularis; prurigo acuta; linear IgA dermatosis; polymorphic light dermatosis; erythema Solaris; exanthema of the skin; drug exanthema; purpura chronica progressiva; dihydrotic eczema; eczema; fixed drug exanthema; photoallergic skin reaction; and periorale dermatitis.
15. Use of claim 11, wherein the hyperproliferative disorders are those which benefit from a reduced estrogen receptor signalling.
16. Use of claim 15, wherein the diseases, conditions and/or disorders are selected from the group consisting of mammary tumors, endometrial tumors and tumors of the uterus.
2/39 H Juni 200? Fig. 2
Inψtøijion [%]
Figure imgf000055_0001
ATP [μM] IC50 [μM] r* Hill-Slope
20 6.68 0.997 1.163
200 49.8 0.997 1.06
1000 >100 0.975 0.42 3/39
H Juni 200/
Fig. 3
Figure imgf000056_0001
4/39
Fig. 4
REMARK coordinates from restrained individual B-factor refinement
REMARK refinement resolution: 30.0 - 2.8 A
REMARK starting r= 0.3024 free_r= 0.3443
REMARK final r= 0.2653 free_r= 0.3159
REMARK B rmsd for bonded mainchain atoms= 1.342 target= 1.5
REMARK B rmsd for bonded sidechain atoms= 1.499 target= 2.0
REMARK B rmsd for angle mainchain atoms= 2.429 target= 2.0
REMARK B rmsd for angle sidechain atoms= 2. All target= 2.5
REMARK rweight= 0.1000 (with wa= 4.59272)
REMARK target= mlf steps= 50
REMARK sg= P6(l)22 a= 81.60 b= 81.60 C= 169.85 alpha= 90 beta= 90 gamma=
120
REMARK parameter file 1 : CNS_TOPPAR:protein_rep . param
REMARK parameter file 2 : CNS_TOPPAR:water_rep.param
REMARK parameter file 4 : j 2.param
REMARK molecular structure file: genl.mtf
REMARK input coordinates: minl.pdb
REMARK reflection file= j2.cv
REMARK ncs= none
REMARK B-correction resolution: 8.0 - 2.8
REMARK initial B-factor correction applied to fobs :
REMARK BIl= 6.925 B22= 6.925 B33= -13.851
REMARK B12= -8.178 B13= 0.000 B23= 0.000
REMARK B-factor correction applied to coordinate array B: -10.303
REMARK bulk solvent: density level= 0.326162 e/A~3, B-factor= 20.0777
AΛ2
REMARK reflections with I Fobs | /sigma_F < 0.0 rejected
REMARK reflections with I Fobs | > 10000 * rms(Fobs) rejected
REMARK theoretical total number of refl. in resol. range: . 8798 (
100.0 % ) -
REMARK number of unobserved reflections (no entry or |F|=0): 13 (
0.1 % )
REMARK number of reflections rejected: 0 (
0.0 % )
REMARK total number of reflections used: 8785 (
99.9 % )
REMARK number of reflections in working set: 7938 (
90.2 % )
REMARK number of reflections in test set: 847 (
9.6 % )
CRYSTl 81.600 81.600 169.850 90.00 90.00 120.00 P 61 2 2
REMARK FILENAME="bindil.pdb"
REMARK VERSION: 1.1
ATOM 1 CB GLN 127 269.492 -62.236 88.975 1.00 86.73
ATOM 2 CG GLN 127 268.814 -62.580 87.659 1.00 87.74
ATOM 3 CD GLN 127 268.643 -61.371 86.748 1.00 87.89
ATOM 4 OEl GLN 127 268.139 -61.488 85.631 1.00 88.49
ATOM 5 NE2 GLN 127 269.059 -60.206 87.224 1.00 86.83
ATOM 6 C GLN 127 271.294 -60.825 89.958 1.00 85.87
ATOM 7 O GLN 127 272.356 -60.210 89.971 1.00 86.36
ATOM 8 N GLN 127 271.851 -62.978 88.765 1.00 86.49
ATOM 9 CA GLN 127 270.951 -61.791 88.830 1.00 86.41
ATOM 10 N TRP 128 270.380 -60.704 90.908 1.00 84.70
ATOM 11 CA TRP 128 270.548 -59.803 92.030 1.00 83.21
ATOM 12 CB TRP 128 269.267 -59.809 92.851 1.00 83.58
ATOM 13 CG TRP 128 268.092 -59.473 92.017 1.00 83.46
ATOM 14 CD2 TRP 128 267.657 -58.161 91.658 1.00 83.12
ATOM 15 CE2 TRP 128 266.545 -58.311 90.801 1.00 82.95
ATOM 16 CE3 TRP 128 268.102 -56.870 91.974 1.00 83.13 5/39
ATOM 17 CDl TRP 128 267.254 -60.345 91.385 1.00 83.40
ATOM 18 NEl TRP 128 266.319 -59.655 90.653 1.00 83.13
ATOM 19 CZ2 TRP 128 265.869 -57.218 90.255 1.00 83.42
ATOM 20 CZ3 TRP 128 267.431 -55.782 91.432 1.00 83.86
ATOM 21 CH2 TRP 128 266.324 -55.964 90.580 1.00 84.42
ATOM 22 C TRP 128 271.737 -60.086 92.931 1.00 82.21
ATOM 23 O TRP 128 272.267 -61.194 92.949 1.00 81.94
ATOM 24 N ALA 129 272.142 -59.064 93.681 1.00 81.27
ATOM 25 CA ALA 129 273.258 -59.165 94.618 1.00 81.07
ATOM 26 CB ALA 129 274.567 -58.832 93.924 1.00 80.47
ATOM 27 C ALA 129 273.036 -58.218 95.794 1.00 80.82
ATOM 28 O ALA 129 272.420 -57.164 95.643 1.00 80.67
ATOM 29 N LEU 130 273.539 -58.604 96.962 1.00 79.93
ATOM 30 CA LEU 130 273.402 -57.803 98.171 1.00 79.43
ATOM 31 CB LEU 130 274.145 -58.471 99.320 1.00 77.69
ATOM 32 CG LEU 130 274.077 -57.709 100.636 1.00 76.70
ATOM 33 CDl LEU 130 272.630 -57.610 101.100 1.00 75.71
ATOM 34 CD2 LEU 130 274.930 -58.412 101.659 1.00 76.72
ATOM 35 C LEU 130 273.931 -56.383 97.988 1.00 80.51
ATOM 36 O LEU 130 273.684 -55.504 98.808 1.00 80.67
ATOM 37 N GLU 131 274.668 -56.165 96.908 1.00 81.75
ATOM 38 CA GLU 131 275.227 -54.853 96.625 1.00 81.47
ATOM 39 CB GLU 131 276.403 -54.978 95.634 1.00 83.31
ATOM 40 CG GLU 131 277.742 -55.502 96.222 1.00 85.03
ATOM 41 CD GLU 131 277.661 -56.909 96.839 1.00 86.87
ATOM 42 OEl GLU 131 277.199 -57.851 96.160 1.00 87.25
ATOM 43 OE2 GLU 131 278.076 -57.079 98.007 1.00 87.44
ATOM 44 C GLU 131 274.143 -53.944 96.051 1.00 80.17
ATOM 45 O GLU 131 274.315 -52.732 95.994 1.00 79.35
ATOM 46 N ASP 132 273.021 -54.530 95.639 1.00 79.26
ATOM 47 CA ASP 132 271.922 -53.748 95.056 1.00 78.58
ATOM 48 CB ASP 132 271.222 -54.522 93.933 1.00 78.90
ATOM 49 CG, ASP 132 272.183 -55.198 93.002 1.00 79.24
ATOM 50 ODl ASP 132 273.157 -54.543 92.584 1.00 79.97
ATOM 51 OD2 ASP 132 271.952 -56.383 92.680 1.00 79.49
ATOM 52 C ASP 132 270.836 -53.316 96.036 1.00 77.49
ATOM 53 O ASP 132 269.886 -52.646 95.639 1.00 76.27
ATOM 54 N PHE 133 270.953 -53.599 97.302 1.00 76.63
ATOM 55 CA PHE 133 269.932 -53.333 98.267 1.00 75.55
ATOM 56 CB PHE 133 269.152 -54.561 98.710 1.00 75.74
ATOM 57 CG PHE 133 268.555 -55.338 97.591 1.00 75.79
ATOM 58 CDl PHE 133 269.320 -56.247 96.869 1.00 75.65
ATOM 59 CD2 PHE 133 267.216 -55.179 97.265 1.00 75.64
ATOM 60 CEl PHE 133 268.759 -56.992 95.836 1.00 76.35
ATOM 61 CE2 PHE 133 266.639 -55.916 96.234 1.00 76.51
ATOM 62 CZ PHE 133 267.412 -56.827 95.516 1.00 76.66
ATOM 63 C PHE 133 270.438 -52.661 99.519 1.00 75.50
ATOM 64 O PHE 133 271.399 -53.119 100.132 1.00 75.58
ATOM 65 N GLU 134 269.782 -51.570 99.902 1.00 74.83
ATOM 66 CA GLU 134 270.128 -50.888 101.139 1.00 72.78
ATOM 67 CB GLU 134 269.751 -49.414 101.092 1.00 71.74
ATOM 68 CG GLU 134 270.312 -48.632 99.950 1.00 70.17
ATOM 69 CD GLU 134 270.136 -47.152 100.184 1.00 69.77
ATOM 70 OEl GLU 134 269.011 -46.743 100.537 1.00 72.33
ATOM 71 OE2 GLU 134 271.115 -46.394 100.028 1.00 68.58
ATOM 72 C GLU 134 269.199 -51.589 102.117 1.00 72.72
ATOM 73 O GLU 134 267.976 -51.467 101.997 1.00 72.50
ATOM 74 N ILE 135 269.759 -52.336 103.063 1.00 72.84
ATOM 75 CA ILE 135 268.935 -53.056 104.024 1.00 72.15
ATOM 76 CB ILE 135 269.734 -54.184 104.709 1.00 72.39
ATOM 77 CG2 ILE 135 268.805 -55.059 105.533 1.00 71.80
ATOM 78 CGl ILE 135 270.452 -55.035 103.650 1.00 74.37
ATOM 79 CD ILE 135 271.813 -54.472 103.171 1.00 73.96 6/39
ATOM 80 C ILE 135 268.378 -52.106 105.081 1.00 71.81
ATOM 81 O ILE 135 269.087 -51.247 105.597 1.00 72.19
ATOM 82 N GLY 136 267.097 -52.267 105.394 1.00 71.60
ATOM 83 CA GLY 136 266.464 -51.418 106.383 1.00 70.29
ATOM 84 C GLY 136 265.999 -52.124 107.643 1.00 69.59
ATOM 85 O GLY 136 266.546 -53.144 108.054 1.00 69.07
ATOM 86 N ARG 137 264.970 -51.557 108.260 1.00 70.01
ATOM 87 CA ARG 137 264.413 -52.092 109.485 1.00 70.04
ATOM 88 CB ARG 137 263.154 -51.326 109.874 1.00 68.95
ATOM 89 CG ARG 137 262.444 -51.944 111.063 1.00 69.45
ATOM 90 CD ARG 137 261.252 -51.126 111.505 1.00 69.11
ATOM 91 NE ARG 137 260.092 -51.296 110.638 1.00 67.38
ATOM 92 CZ ARG 137 259.297 -52.359 110.658 1.00 67.46
ATOM 93 NHl ARG 137 259.539 -53.350 111.501 1.00 67.98
ATOM 94 NH2 ARG 137 258.247 -52.422 109.848 1.00 65.74
ATOM 95 C ARG 137 264.064 -53.562 109.373 1.00 70.47
ATOM 96 O ARG 137 263.473 -54.001 108.385 1.00 71.31
ATOM 97 N PRO 138 264.419 -54.342 110.398 1.00 70.44
ATOM 98 CD PRO 138 265.171 -53.943 111.598 1.00 70.34
ATOM 99 CA PRO 138 264.131 -55.777 110.412 1.00 70.34
ATOM 100 CB PRO 138 264.868 -56.265 111.656 1.00 68.89
ATOM 101 CG PRO 138 264.858 -55.071 112.548 1.00 69.95
ATOM 102 C PRO 138 262.626 -56.015 110.472 1.00 71.21
ATOM 103 O PRO 138 261.943 -55.511 111.362 1.00 70.80
ATOM 104 N LEU 139 262.125 -56.774 109.501 1.00 72.50
ATOM 105 CA LEU 139 260.712 -57.090 109.400 1.00 73.91
ATOM 106 CB LEU 139 260.351 -57.362 107.958 1.00 70.99
ATOM 107 CG LEU 139 260.415 -56.172 107.024 1.00 69.45
ATOM 108 CDl LEU 139 259.806 -56.596 105.717 1.00 68.55
ATOM 109 CD2 LEU 139 259.645 -54.999 107.588 1.00 69.47
ATOM 110 C LEU 139 260.280 -58.278 110.244 1.00 11.22
ATOM 111 O LEU 139 259.137 -58.355 110.689 1.00 77.74
ATOM 112 N GLY 140 261.184 -59.221 110.455 1.00 80.74
ATOM 113 CA GLY 140 260.818 -60.362 111.262 1.00 84.99
ATOM 114 C GLY 140 261.901 -61.399 111.430 1.00 88.28
ATOM 115 O GLY 140 262.850 -61.475 110.643 1.00 87.79
ATOM 116 N LYS 141 261.750 -62.194 112.483 1.00 91.64
ATOM 117 CA LYS 141 262.680 -63.270 112.786 1.00 95.06
ATOM 118 CB LYS 141 262.868 -63.398 114.308 1.00 95.67
ATOM 119 CG LYS 141 262.966 -64.834 114.838 1.00 96.69
ATOM 120 CD LYS 141 261.594 -65.368 115.279 1.00 97.41
ATOM 121 CE LYS 141 261.562 -66.897 115.386 1.00 97.65
ATOM 122 NZ LYS 141 262.491 -67.434 116.412 1.00 97.51
ATOM 123 C LYS 141 262.116 -64.563 112.198 1.00 96.87
ATOM 124 O LYS 141 261.092 -65.071 112.657 1.00 97.83
ATOM 125 N GLY 142 262.759 -65.068 111.150 1.00 98.17
ATOM 126 CA GLY 142 262.307 -66.309 110.554 1.00 99.17
ATOM 127 C GLY 142 262.886 -67.404 111.425 1.00 99.82
ATOM 128 O GLY 142 263.062 -67.216 112.630 1.00100.73
ATOM 129 N LYS 143 263.197 -68.547 110.840 1.00 99.25
ATOM 130 CA LYS 143 263.771 -69.616 111.633 1.00 98.59
ATOM 131 CB LYS 143 263.108 -70.951 111.259 1.00 98.88
ATOM 132 CG LYS 143 263.134 -72.027 112.350 1.00 98.25
ATOM 133 CD LYS 143 262.102 -73.124 112.065 1.00 98.24
ATOM 134 CE LYS 143 261.899 -74.061 113.261 1.00 97.78
ATOM 135 NZ LYS 143 260.724 -74.972 113.078 1.00 96.36
ATOM 136 C LYS 143 265.265 -69.641 111.324 1.00 98.26
ATOM 137 O LYS 143 266.106 -69.599 112.225 1.00 98.44
ATOM 138 N PHE 144 265.573 -69.650 110.031 1.00 97.34
ATOM 139 CA PHE 144 266.941 -69.723 109.530 1.00 96.11
ATOM 140 CB PHE 144 266.953 -70.554 108.241 1.00 97.23
ATOM 141 CG PHE 144 266.110 -71.812 108.311 1.00 97.56
ATOM 142 CDl PHE 144 264.728 -71.736 108.470 1.00 98.06 7/39
ATOM 143 CD2 PHE 144 266.699 -73.068 108.214 1.00 97.51
ATOM 144 CEl PHE 144 263.949 -72.887 108.530 1.00 98.15
ATOM 145 CE2 PHE 144 265.926 -74.227 108.273 1.00 98.08
ATOM 146 CZ PHE 144 264.550 -74.135 108.432 1.00 97.95
ATOM 147 C PHE 144 267.599 -68.369 109.273 1.00 94.87
ATOM 148 O PHE 144 268.620 -68.279 108.594 1.00 94.74
ATOM 149 N GLY 145 267.012 -67.317 109.821 1.00 93.52
ATOM 150 CA GLY 145 267.562 -65.989 109.633 1.00 90.98
ATOM 151 C GLY 145 266.518 -64.949 109.967 1.00 88.72
ATOM 152 O GLY 145 265.679 -65.170 110.842 1.00 89.00
ATOM 153 N ASN 146 266.570 -63.816 109.276 1.00 85.95
ATOM 154 CA ASN 146 265.613 -62.734 109.492 1.00 83.02
ATOM 155 CB ASN 146 266.247 -61.580 110.289 1.00 86.10
ATOM 156 CG ASN 146 266.439 -61.901 111.762 1.00 88.46
ATOM 157 ODl ASN 146 265.505 -62.321 112.454 1.00 90.82
ATOM 158 ND2 ASN 146 267.653 -61.682 112.255 1.00 88.82
ATOM 159 C ASN 146 265.127 -62.173 108.166 1.00 78.40
ATOM 160 O ASN 146 265.682 -62.466 107.112 1.00 77.35
ATOM 161 N VAL 147 264.076 -61.368 108.232 1.00 73.56
ATOM 162 CA VAL 147 263.544 -60.716 107.050 1.00 68.98
ATOM 163 CB VAL 147 262.040 -60.989 106.865 1.00 68.41
ATOM 164 CGl VAL 147 261.486 -60.123 105.757 1.00 66.76
ATOM 165 CG2 VAL 147 261.828 -62.445 106.514 1.00 67.31
ATOM 166 C VAL 147 263.785 -59.238 107.296 1.00 65.61
ATOM 167 O VAL 147 263.704 -58.774 108.429 1.00 63.06
ATOM 168 N TYR 148 264.115 -58.507 106.241 1.00 63.28
ATOM 169 CA TYR 148 264.381 -57.083 106.365 1.00 61.95
ATOM 170 CB TYR 148 265.869 -56.762 106.192 1.00 64.61
ATOM 171 CG TYR 148 266.787 -57.364 107.211 1.00 66.95
ATOM 172 CDl TYR 148 267.153 -58.706 107.147 1.00 68.45
ATOM 173 CEl TYR 148 268.007 -59.261 108.092 1.00 70.03
ATOM 174 CD2 TYR 148 267.296 -56.590 108.243 1.00 67.98
ATOM 175 CE2 TYR 148 268.147 -57.133 109.192 1.00 70.13
ATOM 176 CZ TYR 148 268.498 -58.465 109.114 1.00 70.67
ATOM 177 OH TYR 148 269.329 -58.989 110.074 1.00 71.84
ATOM 178 C TYR 148 263.658 -56.286 105.318 1.00 60.25
ATOM 179 O TYR 148 263.456 -56.740 104.199 1.00 58.71
ATOM 180 N LEU 149 263.275 -55.081 105.695 1.00 59.14
ATOM 181 CA LEU 149 262.642 -54.174 104.763 1.00 57.59
ATOM 182 CB LEU 149 262.059 -52.988 105.528 1.00 57.50
ATOM 183 CG LEU 149 261.446 -51.832 104.735 1.00 56.60
ATOM 184 CDl LEU 149 260.200 -52.291 103.997 1.00 56.60
ATOM 185 CD2 LEU 149 261.115 -50.716 105.690 1.00 54.59
ATOM 186 C LEU 149 263.854 -53.739 103.927 1.00 56.98
ATOM 187 O LEU 149 264.977 -53.696 104.446 1.00 56.36
ATOM 188 N ALA 150 263.666 -53.439 102.649 1.00 55.97
ATOM 189 CA ALA 150 264.820 -53.026 101.858 1.00 56.04
ATOM 190 CB ALA 150 265.666 -54.228 101.531 1.00 56.69
ATOM 191 C ALA 150 264.469 -52.284 100.585 1.00 56.01
ATOM 192 O ALA 150 263.349 -52.364 100.077 1.00 55.10
ATOM 193 N ARG 151 265.441 -51.557 100.060 1.00 56.71
ATOM 194 CA ARG 151 265.181 -50.816 98.844 1.00 58.64
ATOM 195 CB ARG 151 265.152 -49.311 99.134 1.00 57.83
ATOM 196 CG ARG 151 264.643 -48.491 97.947 1.00 56.10
ATOM 197 CD ARG 151 264.644 -47.008 98.225 1.00 53.17
ATOM 198 NE ARG 151 265.940 -46.565 98.722 1.00 53.07
ATOM 199 CZ ARG 151 266.327 -45.297 98.754 1.00 51.53
ATOM 200 NHl ARG 151 265.505 -44.348 98.308 1.00 50.86
ATOM 201 NH2 ARG 151 267.536 -44.984 99.212 1.00 44.97
ATOM 202 C ARG 151 266.182 -51.120 97.730 1.00 59.76
ATOM 203 O ARG 151 267.393 -51.069 97.937 1.00 59.40
ATOM 204 N GLU 152 265.643 -51.459 96.559 1.00 62.11
ATOM 205 CA GLU 152 266.429 -51.763 95.368 1.00 64.50 8/39
ATOM 206 CB GLU 152 265.501 -52.194 94.224 1.00 65.60
ATOM 207 CG GLU 152 266.167 -52.834 93.020 1.00 66.69
ATOM 208 CD GLU 152 267.010 -51.872 92.230 1.00 69.58
ATOM 209 OEl GLU 152 268.125 -51.549 92.681 1.00 72.35
ATOM 210 OE2 GLU 152 266.558 -51.436 91.155 1.00 70.03
ATOM 211 C GLU 152 267.101 -50.444 95.048 1.00 65.34
ATOM 212 O GLU 152 266.471 -49.504 94.572 1.00 65.06
ATOM 213 N LYS 153 268.393 -50.398 95.331 1.00 66.83
ATOM 214 CA LYS 153 269.219 -49.219 95.160 1.00 67.06
ATOM 215 CB LYS 153 270.680 -49.630 95.339 1.00 66.65
ATOM 216 CG LYS 153 271.563 -48.564 95.955 1.00 67.12
ATOM 217 CD LYS 153 272.925 -49.130 96.336 1.00 66.85
ATOM 218 CE LYS 153 272.799 -50.205 97.395 1.00 68.32
ATOM 219 NZ LYS 153 274.128 -50.761 97.764 1.00 68.77
ATOM 220 C LYS 153 269.052 -48.411 93.878 1.00 68.33
ATOM 221 o LYS 153 269.129 -47.182 93.922 1.00 68.06
ATOM 222 N GLN 154 268.801 -49.075 92.750 1.00 70.10
ATOM 223 CA GLN 154 268.681 -48.361 91.474 1.00 72.72
ATOM 224 CB GLN 154 269.366 -49.163 90.354 1.00 76.44
ATOM 225 CG GLN 154 270.894 -48.952 90.322 1.00 80.44
ATOM 226 CD GLN 154 271.589 -49.689 89.185 1.00 83.45
ATOM 227 OEl GLN 154 271.238 -49.530 88.013 1.00 83.60
ATOM 228 NE2 GLN 154 272.590 -50.496 89.531 1.00 84.93
ATOM 229 C GLN 154 267.315 -47.882 90.998 1.00 71.45
ATOM 230 o GLN 154 267.236 -46.932 90.220 1.00 72.45
ATOM 231 N SER 155 266.243 -48.519 91.445 1.00 69.97
ATOM 232 CA SER 155 264.908 -48.081 91.038 1.00 68.34
ATOM 233 CB SER 155 264.138 -49.243 90.411 1.00 66.19
ATOM 234 OG SER 155 263.970 -50.285 91.344 1.00 62.89
ATOM 235 C SER 155 264.133 -47.520 92.244 1.00 67.89
ATOM 236 o SER 155 263.003 -47.040 92.112 1.00 66.90
ATOM 237 N LYS 156 264.759 -47.579 93.416 1.00 67.25
ATOM 238 CA LYS 156 264.148 -47.088 - 94.-647 1.00 67.41
ATOM" "239 CB LYS 156 263.775 -45.599 94.492 1.00 67.01
ATOM 240 CG LYS 156 264.986 -44.668 94.517 1.00 65.50
ATOM 241 CD LYS 156 264.627 -43.190 94.679 1.00 64.22
ATOM 242 CE LYS 156 264.056 -42.570 93.420 1.00 62.93
ATOM 243 NZ LYS 156 263.693 -41.147 93.658 1.00 61.77
ATOM 244 C LYS 156 262.925 -47.911 95.099 1.00 66.86
ATOM 245 o LYS 156 262.101 -47.440 95.886 1.00 67.09
ATOM 246 N PHE 157 262.841 -49.150 94.621 1.00 65.14
ATOM 247 CA PHE 157 261.743 -50.061 94.944 1.00 63.58
ATOM 248 CB PHE 157 261.781 -51.223 93.956 1.00 62.27
ATOM 249 CG PHE 157 260.544 -52.067 93.937 1.00 62.82
ATOM 250 CDl PHE 157 259.769 -52.148 92.783 1.00 63.59
ATOM 251 CD2 PHE 157 260.190 -52.850 95.025 1.00 63.53
ATOM 252 CEl PHE 157 258.661 -53.004 92.715 1.00 62.63
ATOM 253 CE2 PHE 157 259.084 -53.706 94.962 1.00 64.27
ATOM 254 CZ PHE 157 258.323 -53.781 93.805 1.00 61.64
ATOM 255 C PHE 157 261.856 -50.583 96.376 1.00 62.96
ATOM 256 o PHE 157 262.945 -50.919 96.836 1.00 62.25
ATOM 257 N ILE 158 260.732 -50.636 97.086 1.00 62.33
ATOM 258 CA ILE 158 260.745 -51.142 98.451 1.00 61.56
ATOM 259 CB ILE 158 259.963 -50.233 99.416 1.00 60.92
ATOM 260 CG2 ILE 158 259.320 -51.055 100.518 1.00 60.83
ATOM 261 CGl ILE 158 260.921 -49.233 100.053 1.00 59.19
ATOM 262 CD ILE 158 260.304 -48.436 101.177 1.00 61.85
ATOM 263 C ILE 158 260.177 -52.545 98.495 1.00 61.24
ATOM 264 o ILE 158 259.139 -52.821 97.905 1.00 59.72
ATOM 265 N LEU 159 260.871 -53.425 99.212 1.00 61.38
ATOM 266 CA LEU 159 260.481 -54.824 99.320 1.00 62.25
ATOM 267 CB LEU 159 261.063 -55.594 98.134 1.00 61.89
ATOM 268 CG LEU 159 262.528 -55.290 97.773 1.00 61.64 9/39
ATOM 269 CDl LEU 159 263.459 -55.788 98.859 1.00 61.18
ATOM 270 CD2 LEU 159 262.873 -55.943 96.454 1.00 61.29
ATOM 271 C LEU 159 260.964 -55.463 100.611 1.00 62.84
ATOM 272 O LEU 159 261.639 -54.822 101.415 1.00 63.29
ATOM 273 N ALA 160 260.610 -56.733 100.794 1.00 63.85
ATOM 274 CA ALA 160 261.014 -57.512 101.963 1.00 64.51
ATOM 275 CB ALA 160 259.827 -58.280 102.530 1.00 63.80
ATOM 276 C ALA 160 262.087 -58.482 101.503 1.00 65.72
ATOM 277 O ALA 160 261.913 -59.186 100.512 1.00 66.45
ATOM 278 N LEU 161 263.202 -58.518 102.219 1.00 67.54
ATOM 279 CA LEU 161 264.315 -59.396 101.861 1.00 68.48
ATOM 280 CB LEU 161 265.581 -58.554 101.701 1.00 66.87
ATOM 281 CG LEU 161 266.829 -59.117 101.027 1.00 67.18
ATOM 282 CDl LEU 161 266.534 -59.515 99.585 1.00 67.96
ATOM 283 CD2 LEU 161 267.916 -58.052 101.067 1.00 65.77
ATOM 284 C LEU 161 264.529 -60.473 102.925 1.00 69.79
ATOM 285 O LEU 161 265.032 -60.191 104.009 1.00 69.73
ATOM 286 N LYS 162 264.137 -61.704 102.601 1.00 71.75
ATOM 287 CA LYS 162 264.271 -62.856 103.501 1.00 73.65
ATOM 288 CB LYS 162 263.326 -63.963 103.023 1.00 72.65
ATOM 289 CG LYS 162 263.035 -65.060 104.019 1.00 11.11
ATOM 290 CD LYS 162 261.856 -65.892 103.541 1.00 69.96
ATOM 291 CE LYS 162 261.547 -67.046 104.481 1.00 69.76
ATOM 292 NZ LYS 162 260.334 -67.804 104.035 1.00 69.40
ATOM 293 C LYS 162 265.721 -63.366 103.528 1.00 75.92
ATOM 294 O LYS 162 266.219 -63.913 102.539 1.00 75.85
ATOM 295 N VAL 163 266.388 -63.179 104.666 1.00 79.34
ATOM 296 CA VAL 163 267.786 -63.589 104.848 1.00 83.11
ATOM 297 CB VAL 163 268.586 -62.473 105.575 1.00 83.83
ATOM 298 CGl VAL 163 269.810 -63.053 106.298 1.00 83.47
ATOM 299 CG2 VAL 163 269.015 -61.421 104.565 1.00 83.66
ATOM 300 C VAL 163 267.962 -64.899 105.616 1.00 85.35
ATOM 301 O VAL 163 267.793 -64.945 106.842 1.00 85.82
ATOM 302 N LEU 164 268.319 -65.959 104.897 1.00 87.87
ATOM 303 CA LEU 164 268.519 -67.259 105.528 1.00 90.62
ATOM 304 CB LEU 164 267.382 -68.213 105.132 1.00 90.54
ATOM 305 CG LEU 164 266.675 -67.956 103.795 1.00 91.34
ATOM 306 CDl LEU 164 267.627 -68.285 102.667 1.00 91.68
ATOM 307 CD2 LEU 164 265.410 -68.797 103.680 1.00 89.89
ATOM 308 C LEU 164 269.883 -67.882 105.230 1.00 92.16
ATOM 309 O LEU 164 270.265 -68.060 104.071 1.00 91.73
ATOM 310 N PHE 165 270.611 -68.203 106.297 1.00 94.37
ATOM 311 CA PHE 165 271.934 -68.802 106.194 1.00 96.77
ATOM 312 CB PHE 165 272.618 -68.828 107.561 1.00 98.12
ATOM 313 CG PHE 165 272.719 -67.491 108.226 1.00 99.42
ATOM 314 CDl PHE 165 271.846 -67.148 109.256 1.00100.09
ATOM 315 CD2 PHE 165 273.709 -66.585 107.851 1.00 99.57
ATOM 316 CEl PHE 165 271.959 -65.921 109.912 1.00100.49
ATOM 317 CE2 PHE 165 273.833 -65.353 108.498 1.00100.03
ATOM 318 CZ PHE 165 272.956 -65.020 109.532 1.00100.52
ATOM 319 C PHE 165 271.891 -70.232 105.657 1.00 97.62
ATOM 320 O PHE 165 271.031 -71.023 106.047 1.00 97.18
ATOM 321 N LYS 166 272.836 -70.557 104.774 1.00 98.95
ATOM 322 CA LYS 166 272.944 -71.896 104.190 1.00 99.80
ATOM 323 CB LYS 166 274.023 -71.924 103.105 1.00 99.45
ATOM 324 CG LYS 166 273.858 -70.885 102.008 1.00100.16
ATOM 325 CD LYS 166 275.126 -70.773 101.162 1.00100.77
ATOM 326 CE LYS 166 275.057 -69.612 100.168 1.00101.16
ATOM 327 NZ LYS 166 276.377 -69.329 99.516 1.00100.16
ATOM 328 C LYS 166 273.346 -72.852 105.308 1.00100.18
ATOM 329 O LYS 166 272.694 -73.868 105.547 1.00 99.75
ATOM 330 N ALA 167 274.435 -72.511 105.987 1.00100.67
ATOM 331 CA ALA 167 274.930 -73.319 107.085 1.00101.78 10/39
ATOM 332 CB ALA 167 275.887 -72.501 107.935 1.00101.29
ATOM 333 C ALA 167 273.744 -73.780 107.919 1.00102.75
ATOM 334 O ALA 167 273.533 -74.976 108.105 1.00102.79
ATOM 335 N GLN 168 272.958 -72.816 108.393 1.00104.25
ATOM 336 CA GLN 168 271.782 -73.087 109.217 1.00105.52
ATOM 337 CB GLN 168 271.071 -71.775 109.554 1.00107.60
ATOM 338 CG GLN 168 271.202 -71.333 111.001 1.00110.83
ATOM 339 CD GLN 168 270.459 -70.029 111.283 1.00113.24
ATOM 340 OEl GLN 168 269.226 -69.965 111.197 1.00113.57
ATOM 341 NE2 GLN 168 271.212 -68.980 111.617 1.00114.04
ATOM 342 C GLN 168 270.757 -74.056 108.620 1.00105.03
ATOM 343 O GLN 168 270.315 -74.987 109.295 1.00104.91
ATOM 344 N LEU 169 270.372 -73.839 107.366 1.00104.44
ATOM 345 CA LEU 169 269.373 -74.697 106.738 1.00104.68
ATOM 346 CB LEU 169 268.780 -74.004 105.507 1.00104.18
ATOM 347 CG LEU 169 269.685 -73.283 104.510 1.00103.49
ATOM 348 CDl LEU 169 270.540 -74.274 103.724 1.00103.80
ATOM 349 CD2 LEU 169 268.799 -72.488 103.570 1.00102.66
ATOM 350 C LEU 169 269.858 -76.100 106.386 1.00105.31
ATOM 351 O LEU 169 269.068 -77.052 106.373 1.00105.33
ATOM 352 N GLU 170 271.148 -76.234 106.095 1.00105.62
ATOM 353 CA GLU 170 271.705 -77.543 105.780 1.00105.10
ATOM 354 CB GLU 170 273.201 -77.432 105.456 1.00105.27
ATOM 355 CG GLU 170 273.510 -76.808 104.094 1.00105.96
ATOM 356 CD GLU 170 275.002 -76.589 103.872 1.00106.37
ATOM 357 OEl GLU 170 275.775 -77.561 104.017 1.00107.05
ATOM 358 OE2 GLU 170 275.405 -75.447 103.551 1.00106.28
ATOM 359 C GLU 170 271.493 -78.427 107.007 1.00104.65
ATOM 360 O GLU 170 270.945 -79.522 106.901 1.00105.26
ATOM 361 N LYS 171 271.906 -77.929 108.172 1.00103.35
ATOM 362 CA LYS 171 271.770 -78.653 109.434 1.00102.26
ATOM 363 CB LYS 171 272.253 -77.772 110.590 1.00102.13
ATOM 364 CG LYS 171 273.707 -77.341 110.480 1.00101.45
ATOM 365 CD LYS 171 274.600 -78.043 111.507 1.00101.48
ATOM 366 CE LYS 171 274.634 -77.319 112.864 1.00101.21
ATOM 367 NZ LYS 171 273.342 -77.358 113.624 1.00101.03
ATOM 368 C LYS 171 270.332 -79.103 109.706 1.00102.21
ATOM 369 O LYS 171 270.066 -79.796 110.692 1.00102.90
ATOM 370 N ALA 172 269.407 -78.704 108.839 1.00101.54
ATOM 371 CA ALA 172 268.007 -79.076 108.992 1.00100.82
ATOM 372 CB ALA 172 267.165 -77.837 109.254 1.00100.47
ATOM 373 C ALA 172 267.522 -79.786 107.736 1.00100.61
ATOM 374 O ALA 172 266.390 -80.272 107.679 1.00100.46
ATOM 375 N GLY 173 268.388 -79.840 106.728 1.00100.37
ATOM 376 CA GLY 173 268.043 -80.496 105.480 1.00 99.96
ATOM 377 C GLY 173 266.714 -80.034 104.913 1.00 99.53
ATOM 378 O GLY 173 265.775 -80.820 104.771 1.00 99.25
ATOM 379 N VAL 174 266.637 -78.749 104.583 1.00 98.94
ATOM 380 CA VAL 174 265.417 -78.175 104.034 1.00 97.71
ATOM 381 CB VAL 174 264.827 -77.098 104.982 1.00 97.17
ATOM 382 CGl VAL 174 263.403 -77.456 105.355 1.00 96.53
ATOM 383 CG2 VAL 174 265.676 -76.981 106.239 1.00 97.54
ATOM 384 C VAL 174 265.692 -77.549 102.674 1.00 97.24
ATOM 385 O VAL 174 264.833 -76.899 102.101 1.00 96.99
ATOM 386 N GLU 175 266.898 -77.753 102.161 1.00 97.44
ATOM 387 CA GLU 175 267.289 -77.214 100.864 1.00 97.81
ATOM 388 CB GLU 175 268.639 -77.805 100.433 1.00 98.33
ATOM 389 CG GLU 175 269.765 -77.603 101.445 1.00 99.00
ATOM 390 CD GLU 175 269.393 -78.094 102.838 1.00 99.73
ATOM 391 OEl GLU 175 268.900 -79.237 102.949 1.00 99.83
ATOM 392 OE2 GLU 175 269.591 -77.342 103.817 1.00 99.16
ATOM 393 C GLU 175 266.220 -77.561 99.832 1.00 97.58
ATOM 394 O GLU 175 265.949 -76.785 98.914 1.00 97.19 11/39
ATOM 395 N HIS 176 265.617 -78.735 99.995 1.00 97.81
ATOM 396 CA HIS 176 264.571 -79.202 99.090 1.00 97.81
ATOM 397 CB HIS 176 264.341 -80.704 99.286 1.00 99.18
ATOM 398 CG HIS 176 263.891 -81.076 100.666 1.00101.04
ATOM 399 CD2 HIS 176 264.595 -81.439 101.765 1.00101.92
ATOM 400 NDl HIS 176 262.565 -81.080 101.043 1.00101.68
ATOM 401 CEl HIS 176 262.470 -81.431 102.313 1.00102.66
ATOM 402 NE2 HIS 176 263.688 -81.654 102.776 1.00102.69
ATOM 403 C HIS 176 263.276 -78.443 99.353 1.00 96.80
ATOM 404 O HIS 176 262.529 -78.124 98.431 1.00 96.68
ATOM 405 N GLN 177 263.026 -78.159 100.627 1.00 95.71
ATOM 406 CA GLN 177 261.832 -77.441 101.060 1.00 94.24
ATOM 407 CB GLN 177 261.703 -77.577 102.588 1.00 94.26
ATOM 408 CG GLN 177 260.446 -76.983 103.221 1.00 94.80
ATOM 409 CD GLN 177 260.261 -77.390 104.689 1.00 95.11
ATOM 410 OEl GLN 177 259.971 -78.552 104.993 1.00 95.40
ATOM 411 NE2 GLN 177 260.429 -76.432 105.601 1.00 93.76
ATOM 412 C GLN 177 261.928 -75.969 100.640 1.00 93.46
ATOM 413 O GLN 177 260.943 -75.367 100.213 1.00 92.77
ATOM 414 N LEU 178 263.134 -75.415 100.746 1.00 92.21
ATOM 415 CA LEU 178 263.420 -74.023 100.405 1.00 90.49
ATOM 416 CB LEU 178 264.821 -73.653 100.899 1.00 89.73
ATOM 417 CG LEU 178 265.339 -72.217 100.776 1.00 89.08
ATOM 418 CDl LEU 178 265.419 -71.803 99.324 1.00 88.63
ATOM 419 CD2 LEU 178 264.432 -71.286 101.557 1.00 89.33
ATOM 420 C LEU 178 263.334 -73.775 98.908 1.00 90.06
ATOM 421 O LEU 178 262.801 -72.759 98.466 1.00 89.75
ATOM 422 N ARG 179 263.876 -74.701 98.127 1.00 90.21
ATOM 423 CA ARG 179 263.857 -74.559 96.680 1.00 90.25
ATOM 424 CB ARG 179 264.894 -75.486 96.045 1.00 91.85
ATOM 425 CG ARG 179 265.768 -74.772 95.021 1.00 93.59
ATOM 426 CD ARG 179 267.220 -75.253 95.050 1.00 95.20
ATOM 427 NE ARG 179 267.354 -76.702 94.899 1.00 96.85
ATOM 428 CZ ARG 179 266.658 -77.442 94.039 1.00 97.82
ATOM 429 NHl ARG 179 265.759 -76.884 93.240 1.00 98.71
ATOM 430 NH2 ARG 179 266.869 -78.747 93.968 1.00 97.38
ATOM 431 C ARG 179 262.467 -74.848 96.139 1.00 88.75
ATOM 432 O ARG 179 262.127 -74.443 95.029 1.00 88.10
ATOM 433 N ARG 180 261.664 -75.542 96.939 1.00 87.63
ATOM 434 CA ARG 180 260.293 -75.866 96.555 1.00 86.37
ATOM 435 CB ARG 180 259.766 -77.039 97.386 1.00 86.68
ATOM 436 CG ARG 180 258.570 -77.738 96.768 1.00 86.37
ATOM 437 CD ARG 180 257.776 -78.498 97.817 1.00 88.04
ATOM 438 NE ARG 180 258.577 -79.468 98.563 1.00 88.49
ATOM 439 CZ ARG 180 258.729 -79.458 99.886 1.00 88.66
ATOM 440 NHl ARG 180 258.140 -78.525 100.625 1.00 88.13
ATOM 441 NH2 ARG 180 259.462 -80.393 100.475 1.00 89.50
ATOM 442 C ARG 180 259.430 -74.620 96.797 1.00 85.21
ATOM 443 O ARG 180 258.448 -74.384 96.093 1.00 84.12
ATOM 444 N GLU 181 259.807 -73.833 97.804 1.00 83.65
ATOM 445 CA GLU 181 259.112 -72.596 98.129 1.00 81.89
ATOM 446 CB GLU 181 259.717 -71.965 99.390 1.00 82.22
ATOM 447 CG GLU 181 259.030 -70.684 99.855 1.00 80.37
ATOM 448 CD GLU 181 259.742 -70.017 101.020 1.00 80.88
ATOM 449 OEl GLU 181 260.281 -70.736 101.892 1.00 79.68
ATOM 450 OE2 GLU 181 259.744 -68.768 101.070 1.00 80.53
ATOM 451 C GLU 181 259.315 -71.650 96.948 1.00 81.27
ATOM 452 O GLU 181 258.358 -71.150 96.355 1.00 80.98
ATOM 453 N VAL 182 260.583 -71.425 96.615 1.00 80.00
ATOM 454 CA VAL 182 260.987 -70.544 95.523 1.00 78.64
ATOM 455 CB VAL 182 262.505 -70.479 95.442 1.00 77.39
ATOM 456 CGl VAL 182 262.924 -69.662 94.249 1.00 76.64
ATOM 457 CG2 VAL 182 263.056 -69.901 96.725 1.00 76.89 12/39
ATOM 458 C VAL 182 260.470 -70.990 94.168 00 79.38
ATOM 459 O VAL 182 260.377 -70.198 93.234 00 77.72
ATOM 460 N GLU 183 260.135 -72.271 94.084 00 80.75
ATOM 461 CA GLU 183 259.654 -72.885 92.860 00 82.82
ATOM 462 CB GLU 183 259.994 -74.370 92.903 00 87.18
ATOM 463 CG GLU 183 260.177 -75.044 91.560 00 92.17
ATOM 464 CD GLU 183 261.182 -76.183 91.652 1.00 96.00
ATOM 465 OEl GLU 183 260.888 -77.192 92.344 .00 96.53
ATOM 466 OE2 GLU 183 262.275 -76.052 91.045 .00 97.71
ATOM 467 C GLU 183 258.159 -72.703 92.662 .00 81.69
ATOM 468 O GLU 183 257.712 -72.370 91.572 .00 81.12
ATOM 469 N ILE 184 257.393 -72.933 93.724 .00 81.35
ATOM 470 CA ILE 184 255.940 -72.800 93.683 .00 80.85
ATOM 471 CB ILE 184 255.275 -73.414 94.948 ,00 80.95
ATOM 472 CG2 ILE 184 253.763 -73.376 94.814 1.00 79.97
ATOM 473 CGl ILE 184 255.749 -74.854 95.167 1 .00 80.85
ATOM 474 CD ILE 184 255.219 -75.853 94.179 1.00 80.59
ATOM 475 C ILE 184 255.542 -71.327 93.621 1.00 80.83
ATOM 476 O ILE 184 254.922 -70.878 92.658 1.00 79.81
ATOM 477 N GLN 185 255.921 -70.582 94.659 1.00 80.75
ATOM 478 CA GLN 185 255.594 -69.162 94.781 1.00 80.29
ATOM 479 CB GLN 185 256.102 -68.635 96.131 1.00 79.87
ATOM 480 CG GLN 185 255.767 -67.184 96.414 1.00 80.25
ATOM 481 CD GLN 185 256.041 -66.794 97.854 1 .00 81.12
ATOM 482 OEl GLN 185 256.963 -67.308 98.481 1.00 82.28
ATOM 483 NE2 GLN 185 255.249 -65.868 98.379 1.00 80.92
ATOM 484 C GLN 185 256.126 -68.300 93.639 1.00 79.96
ATOM 485 O GLN 185 255.513 -67.297 93.268 1.00 78.45
ATOM 486 N SER 186 257.262 -68.697 93.080 1.00 79.88
ATOM 487 CA SER 186 257.852 -67.945 91.987 1.00 79.91
ATOM 488 CB SER 186 259.103 -68.658 91.477 1.00 79.34
ATOM 489 OG SER 186 259.889 -67.799 90.675 1.00 78.99
ATOM 490 C SER 1.86 256.842 -67.789- 90.855 1.00 80.26
ATOM ' 491 O SER 186 256.648 -66.696 90.331 1.00 79.83
ATOM 492 N HIS 187 256.181 -68.885 90.500 1.00 81.54
ATOM 493 CA HIS 187 255.211 -68.870 89.409 1.00 82.75
ATOM 494 CB HIS 187 255.253 -70.202 88.647 00 85.18
ATOM 495 CG HIS 187 256.552 -70.462 87.950 00 87. .08
ATOM 496 CD2 HIS 187 256.849 -70.569 86.634 1.00 87.53
ATOM 497 NDl HIS 187 257.742 -70.629 88.626 1.00 87.38
ATOM 498 CEl HIS 187 258.717 -70.826 87.756 .00 87.90
ATOM 499 NE2 HIS 187 258.201 -70.795 86.540 .00 88.57
ATOM 500 C HIS 187 253.773 -68.579 89.816 .00 82.29
ATOM 501 O HIS 187 252.857 -68.757 89.015 .00 81.77
ATOM 502 N LEU 188 253.561 -68.145 91.054 1.00 81.67
ATOM 503 CA LEU 188 252.204 -67.831 91.506 1.00 80.41
ATOM 504 CB LEU 188 251.992 -68.236 92.969 1.00 79.58
ATOM 505 CG LEU 188 251.209 -69.515 93.257 1.00 78.41
ATOM 506 CDl LEU 188 252.089 -70.707 93.022 1.00 78.78
ATOM 507 CD2 LEU 188 250.745 -69.513 94.697 1.00 78.79
ATOM 508 C LEU 188 251.916 -66.344 91.360 00 79.61
ATOM 509 O LEU 188 252.692 -65.500 91.810 00 79. ,90
ATOM 510 N ARG 189 250.792 -66.023 90.736 1.00 78.39
ATOM 511 CA ARG 189 250.434 -64.635 90.544 1.00 77.51
ATOM 512 CB ARG 189 250.837 -64.186 89.138 1.00 79.59
ATOM 513 CG ARG 189 252.343 -64.232 88.851 1.00 83.91
ATOM 514 CD ARG 189 253.139 -63.321 89.795 1.00 87.01
ATOM 515 NE ARG 189 254.498 -63.048 89.322 1.00 88.52
ATOM 516 CZ ARG 189 254.788 -62.368 88.213 1.00 89.48
ATOM 517 NHl ARG 189 253.814 -61.888 87.449 1.00 89.42
ATOM 518 NH2 ARG 189 256.054 -62.157 87.869 1.00 89.22
ATOM 519 C ARG 189 248.947 -64.393 90.767 1.00 75.62
ATOM 520 O ARG 189 248.133 -64.546 89.861 1.00 75.21 13/39
ATOM 521 N HIS 190 248.609 -64.012 91.992 .00 73.80
ATOM 522 CA HIS 190 247.234 -63.728 92.389 .00 71.66
ATOM 523 CB HIS 190 246.627 -64.981 93.042 .00 71.47
ATOM 524 CG HIS 190 245.202 -64.830 93.470 .00 71.41
ATOM 525 CD2 HIS 190 244.108 -65.585 93.207 .00 70.99
ATOM 526 NDl HIS 190 244.775 -63.821 94.304 .00 72.15
ATOM 527 CEl HIS 190 243.480 -63.958 94.536 .00 72.55
ATOM 528 NE2 HIS 190 243.051 -65.022 93.882 .00 71.42
ATOM 529 C HIS 190 247.369 -62.571 93.389 .00 70.15
ATOM 530 O HIS 190 248.410 -62.418 94.032 .00 69.79
ATOM 531 N PRO 191 246.337 -61.722 93.508 .00 68.55
ATOM 532 CD PRO 191 245.133 -61.619 92.664 .00 68.44
ATOM 533 CA PRO 191 246.411 -60.591 94.442 .00 66.94
ATOM 534 CB PRO 191 245.236 -59.713 94.009 .00 66.65
ATOM 535 CG PRO 191 244.257 -60.695 93.474 1.00 67.46
ATOM 536 C PRO 191 246.385 -60.929 95.939 1. 00 65.50
ATOM 537 O PRO 191 246.751 -60.100 96.774 1.00 64.72
ATOM 538 N ASN 192 245.965 -62.140 96.284 1.00 62.98
ATOM 539 CA ASN 192 245.945 -62.505 97.685 1.00 60.84
ATOM 540 CB ASN 192 244.605 -63.093 98.059 1.00 61.89
ATOM 541 CG ASN 192 243.495 -62.126 97.842 1.00 63.06
ATOM 542 ODl ASN 192 242.902 -62.081 96.772 00 64.09
ATOM 543 ND2 ASN 192 243.217 -61.316 98.851 00 62.74
ATOM 544 C ASN 192 247.048 -63.461 98.070 00 59.24
ATOM 545 O ASN 192 246.968 -64.119 99.109 00 60.13
ATOM 546 N ILE 193 248.069 -63.535 97.222 00 56.39
ATOM 547 CA ILE 193 249.231 -64.382 97.457 00 55.43
ATOM 548 CB ILE 193 249.440 -65.399 96.326 00 54.27
ATOM 549 CG2 ILE 193 250.797 -66.061 96.470 00 52.66
ATOM 550 CGl ILE 193 248.333 -66.454 96.345 00 55.12
ATOM 551 CD ILE 193 246.988 -65.943 95.971 00 56.12
ATOM 552 C ILE 193 250.431 -63.456 97.460 00 56.76
ATOM 553 O ILE 193 250.631 -62.705 96.504 00 58.27
ATOM 554 N LEU 194 251.227 -63.487 98.525 00 57.48
ATOM 555 CA LEU 194 252.398 -62.618 98.581 00 57.62
ATOM 556 CB LEU 194 253.181 -62.804 99.873 00 54.23
ATOM 557 CG LEU 194 254.219 -61.697 100.013 00 51.51
ATOM 558 CDl LEU 194 253.465 -60.386 100.195 00 52.59
ATOM 559 CD2 LEU 194 255.143 -61.944 101.176 00 49.21
ATOM 560 C LEU 194 253.277 -62.987 97.414 00 58.90
ATOM 561 O LEU 194 253.456 -64.162 97.118 00 59.46
ATOM 562 N ARG 195 253.829 -61.992 96.740 00 61.11
ATOM 563 CA ARG 195 254.671 -62.283 95.594 00 63.45
ATOM 564 CB ARG 195 254.642 -61.128 94.585 00 66.27
ATOM 565 CG ARG 195 253.501 -61.176 93.564 00 71.46
ATOM 566 CD ARG 195 253.968 -60.617 92.212 00 75.60
ATOM 567 NE ARG 195 255.165 -61.320 91.744 00 81.32
ATOM 568 CZ ARG 195 255.932 -60.930 90.729 00 83.45
ATOM 569 NHl ARG 195 255.639 -59.828 90.051 00 84.01
ATOM 570 NH2 ARG 195 257.000 -61.647 90.391 00 84.38
ATOM 571 C ARG 195 256.113 -62.566 95.956 00 63.24
ATOM 572 O ARG 195 256.611 -62.119 96.992 1.00 63.95
ATOM 573 N LEU 196 256.761 -63.353 95.104 1.00 62.98
ATOM 574 CA LEU 196 258.175 -63.656 95.239 1.00 62.88
ATOM 575 CB LEU 196 258.446 -65.135 95.455 1.00 60.21
ATOM 576 CG LEU 196 259.958 -65.380 95.515 1.00 59.03
ATOM 577 CDl LEU 196 260.559 -64.622 96.676 1.00 58.22
ATOM 578 CD2 LEU 196 260.235 -66.850 95.663 1 .00 60.69
ATOM 579 C LEU 196 258.717 -63.246 93.887 1.00 64.55
ATOM 580 O LEU 196 258.329 -63.812 92.861 1.00 64.60
ATOM 581 N TYR 197 259.595 -62.249 93.886 1.00 65.91
ATOM 582 CA TYR 197 260.168 -61.725 92.651 1.00 67.48
ATOM 583 CB TYR 197 260.622 -60.287 92.857 1.00 67.03 14/39
ATOM 584 CG TYR 197 259.539 -59.370 93.346 1.00 66.21
ATOM 585 CDl TYR 197 259.753 -58.555 94.457 1.00 66.06
ATOM 586 CEl TYR 197 258.770 -57.696 94.915 1.00 66.42
ATOM 587 CD2 TYR 197 258.305 -59.304 92.699 1.00 64.38
ATOM 588 CE2 TYR 197 257.313 -58.448 93.145 1.00 65.64
ATOM 589 CZ TYR 197 257.551 -57.640 94.256 1.00 66.42
ATOM 590 OH TYR 197 256.595 -56.754 94.703 1.00 66.60
ATOM 591 C TYR 197 261.338 -62.517 92.108 1.00 68.85
ATOM 592 O TYR 197 261.359 -62.868 90.929 1.00 68.20
ATOM 593 N GLY 198 262.319 -62.777 92.966 1.00 70.63
ATOM 594 CA GLY 198 263.490 -63.514 92.538 1.00 73.23
ATOM 595 C GLY 198 264.337 -63.906 93.717 1.00 75.03
ATOM 596 O GLY 198 263.844 -63.925 94.842 1.00 73.83
ATOM 597 N TYR 199 265.608 -64.210 93.467 1.00 78.09
ATOM 598 CA TYR 199 266.499 -64.612 94.546 1.00 81.11
ATOM 599 CB TYR 199 266.041 -65.980 95.086 1.00 84.18
ATOM 600 CG TYR 199 266.805 -67.171 94.545 1.00 87.52
ATOM 601 CDl TYR 199 267.985 -67.602 95.164 1.00 89.36
ATOM 602 CEl TYR 199 268.726 -68.663 94.654 1.00 90.25
ATOM 603 CD2 TYR 199 266.379 -67.842 93.396 1.00 88.05
ATOM 604 CE2 TYR 199 267.115 -68.908 92.876 1.00 89.33
ATOM 605 CZ TYR 199 268.291 -69.311 93.512 1.00 90.58
ATOM 606 OH TYR 199 269.048 -70.346 93.004 1.00 92.42
ATOM 607 C TYR 199 267.983 -64.654 94.150 1.00 81.30
ATOM 608 O TYR 199 268.345 -64.409 93.000 1.00 81.12
ATOM 609 N PHE 200 268.831 -64.955 95.130 1.00 82.35
ATOM 610 CA PHE 200 270.272 -65.057 94.936 1.00 83.97
ATOM 611 CB PHE 200 270.834 -63.702 94.471 1.00 83.70
ATOM 612 CG PHE 200 270.689 -62.592 95.483 1.00 82.79
ATOM 613 CDl PHE 200 271.718 -62.300 96.371 1.00 83.23
ATOM 614 CD2 PHE 200 269.519 -61.852 95.559 1.00 82.38
ATOM 615 CEl PHE 200 271.584 -61.287 97.317 1.00 82.52
ATOM 616 CE2 PHE 200 269.378 -60.839 96.506 1.00 82.47
ATOM 617 CZ PHE 200 270.414 -60.559 97.385 1.00 81.99
ATOM 618 C PHE 200 270.893 -65.482 96.266 1.00 85.46
ATOM 619 O PHE 200 270.189 -65.575 97.272 1.00 85.76
ATOM 620 N HIS 201 272.194 -65.766 96.271 1.00 87.56
ATOM 621 CA HIS 201 272.880 -66.148 97.506 1.00 90.07
ATOM 622 CB HIS 201 272.745 -67.650 97.766 1.00 91.54
ATOM 623 CG HIS 201 273.546 -68.504 96.836 1.00 93.88
ATOM 624 CD2 HIS 201 273.168 -69.302 95.809 1.00 93.59
ATOM 625 NDl HIS 201 274.918 -68.603 96.915 1.00 94.68
ATOM 626 CEl HIS 201 275.351 -69.428 95.980 1.00 94.78
ATOM 627 NE2 HIS 201 274.310 -69.864 95.294 1.00 94.07
ATOM 628 C HIS 201 274.346 -65.756 97.413 1.00 90.78
ATOM 629 O HIS 201 274.879 -65.597 96.319 1.00 90.78
ATOM 630 N ASP 202 274.995 -65.580 98.557 1.00 92.09
ATOM 631 CA ASP 202 276.396 -65.188 98.567 1.00 93.62
ATOM 632 CB ASP 202 276.591 -63.967 99.483 1.00 94.03
ATOM 633 CG ASP 202 276.382 -64.290 100.958 1.00 95.18
ATOM 634 ODl ASP 202 275.529 -65.146 101.269 1.00 95.08
ATOM 635 OD2 ASP 202 277.066 -63.681 101.809 1.00 96.25
ATOM 636 C ASP 202 277.266 -66.353 99.023 1.00 94.70
ATOM 637 O ASP 202 277.259 -67.423 98.414 1.00 94.40
ATOM 638 N ALA 203 278.020 -66.133 100.092 1.00 95.78
ATOM 639 CA ALA 203 278.891 -67.158 100.644 1.00 96.14
ATOM 640 CB ALA 203 280.171 -66.516 101.173 1.00 96.04
ATOM 641 C ALA 203 278.182 -67.908 101.770 1.00 96.23
ATOM 642 O ALA 203 278.014 -69.128 101.717 1.00 95.89
ATOM 643 N THR 204 277.754 -67.154 102.778 1.00 95.92
ATOM 644 CA THR 204 277.090 -67.707 103.954 1.00 95.22
ATOM 645 CB THR 204 277.289 -66.764 105.185 1.00 96.06
ATOM 646 OGl THR 204 278.602 -66.189 105.145 1.00 96.00 15/39
ATOM 647 CG2 THR 204 277.113 -67.534 106.507 1.00 96.36
ATOM 648 C THR 204 275.585 -67.949 103.803 1.00 94.14
ATOM 649 O THR 204 275.054 -68.928 104.336 1.00 93.92
ATOM 650 N ARG 205 274.900 -67.074 103.069 1.00 92.93
ATOM 651 CA ARG 205 273.445 -67.182 102.953 1.00 90.71
ATOM 652 CB ARG 205 272.804 -66.132 103.870 1.00 91.50
ATOM 653 CG ARG 205 273.405 -64.741 103.701 1.00 91.95
ATOM 654 CD ARG 205 273.784 -64.137 105.041 1.00 94.17
ATOM 655 NE ARG 205 274.549 -62.899 104.895 1.00 96.63
ATOM 656 CZ ARG 205 274.955 -62.143 105.914 1.00 97.76
ATOM 657 NHl ARG 205 274.672 -62.489 107.168 1.00 98.12
ATOM 658 NH2 ARG 205 275.652 -61.038 105.682 1.00 98.02
ATOM 659 C ARG 205 272.772 -67.094 101.591 1.00 88.36
ATOM 660 O ARG 205 273.406 -66.894 100.555 1.00 88.09
ATOM 661 N VAL 206 271.453 -67.262 101.638 1.00 85.72
ATOM 662 CA VAL 206 270.580 -67.188 100.477 1.00 82.74
ATOM 663 CB VAL 206 269.776 -68.483 100.273 1.00 81.96
ATOM 664 CGl VAL 206 268.887 -68.357 99.055 1.00 80.17
ATOM 665 CG2 VAL 206 270.705 -69.647 100.120 1.00 81.51
ATOM 666 C VAL 206 269.597 -66.064 100.774 1.00 81.39
ATOM 667 O VAL 206 269.138 -65.903 101.910 1.00 80.28
ATOM 668 N TYR 207 269.279 -65.282 99.754 1.00 79.92
ATOM 669 CA TYR 207 268.363 -64.178 99.931 1.00 78.19
ATOM 670 CB TYR 207 269.074 -62.854 99.661 1.00 78.73
ATOM 671 CG TYR 207 270.402 -62.671 100.361 1.00 80.27
ATOM 672 CDl TYR 207 271.592 -63.039 99.741 1.00 80.21
ATOM 673 CEl TYR 207 272.825 -62.802 100.343 1.00 80.77
ATOM 674 CD2 TYR 207 270.476 -62.070 101.618 1.00 81.50
ATOM 675 CE2 TYR 207 271.710 -61.833 102.235 1.00 81.77
ATOM 676 CZ TYR 207 272.879 -62.198 101.588 1.00 81.84
ATOM 677 OH TYR 207 274.101 -61.948 102.178 1.00 83.38
ATOM 678 C TYR 207 267.185 -64.305 98.982 1.00 76.75
ATOM 679 O TYR 207 . . 267.361 -64.668 97.822 1.00 75.73
ATOM 680 N LEU 208 265.988 -64.008 99.487 1.00 74.97
ATOM 681 CA LEU 208 264.776 -64.052 98.674 1.00 73.10
ATOM 682 CB LEU 208 263.726 -64.968 99.290 1.00 73.80
ATOM 683 CG LEU 208 264.095 -66.381 99.723 1.00 75.25
ATOM 684 CDl LEU 208 262.809 -67.119 100.074 1.00 74.96
ATOM 685 CD2 LEU 208 264.837 -67.105 98.615 1.00 76.27
ATOM 686 C LEU 208 264.173 -62.660 98.573 1.00 71.54
ATOM 687 O LEU 208 263.943 -62.010 99.593 1.00 71.69'
ATOM 688 N ILE 209 263.924 -62.211 97.345 1.00 68.96
ATOM 689 CA ILE 209 263.318 -60.900 97.092 1.00 66.07
ATOM 690 CB ILE 209 263.687 -60.342 95.690 1.00 67.49
ATOM 691 CG2 ILE 209 262.798 -59.165 95.362 1.00 67.55
ATOM 692 CGl ILE 209 265.138 -59.845 95.653 1.00 68.44
ATOM 693 CD ILE 209 266.187 -60.913 95.824 1.00 70.49
ATOM 694 C ILE 209 261.793 -61.043 97.158 1.00 64.19
ATOM 695 O ILE 209 261.149 -61.476 96.192 1.00 62.31
ATOM 696 N LEU 210 261.225 -60.658 98.299 1.00 61.41
ATOM 697 CA LEU 210 259.795 -60.757 98.530 1.00 58.42
ATOM 698 CB LEU 210 259.553 -61.344 99.910 1.00 57.85
ATOM 699 CG LEU 210 259.804 -62.834 100.076 1.00 58.79
ATOM 700 CDl LEU 210 259.778 -63.168 101.531 1.00 58.89
ATOM 701 CD2 LEU 210 258.746 -63.625 99.323 1.00 57.81
ATOM 702 C LEU 210 259.014 -59.466 98.436 1.00 57.48
ATOM 703 O LEU 210 259.558 -58.381 98.549 1.00 57.30
ATOM 704 N GLU 211 257.716 -59.599 98.234 1.00 56.90
ATOM 705 CA GLU 211 256.860 -58.437 98.203 1.00 57.26
ATOM 706 CB GLU 211 255.470 -58.777 97.675 1.00 57.55
ATOM 707 CG GLU 211 254.463 -57.682 97.956 1.00 57.43
ATOM 708 CD GLU 211 253.096 -57.972 97.389 1.00 58.83
ATOM 709 OEl GLU 211 252.203 -57.119 97.561 1.00 59.51 16/39
ATOM 710 OE2 GLU 211 252.906 -59.042 96.772 1.00 59.21
ATOM 711 C GLU 211 256.754 -57.978 99.654 1.00 57.49
ATOM 712 O GLU 211 256.898 -58.778 100.578 1.00 57.36
ATOM 713 N TYR 212 256.498 -56.686 99.840 1.00 57.31
ATOM 714 CA TYR 212 256.395 -56.080 101.165 1.00 56.01
ATOM 715 CB TYR 212 257.250 -54.810 101.199 1.00 56.60
ATOM 716 CG TYR 212 256.908 -53.852 102.308 1.00 58.38
ATOM 717 CDl TYR 212 257.014 -54.237 103.647 1.00 58.60
ATOM 718 CEl TYR 212 256.715 -53.347 104.678 1.00 60.24
ATOM 719 CD2 TYR 212 256.493 -52.548 102.020 1.00 59.09
ATOM 720 CE2 TYR 212 256.194 -51.652 103.034 1.00 62.23
ATOM 721 CZ TYR 212 256.306 -52.055 104.365 1.00 63.21
ATOM 722 OH TYR 212 256.011 -51.161 105.373 1.00 64.16
ATOM 723 C TYR 212 254.955 -55.773 101.558 1.00 54.48
ATOM 724 O TYR 212 254.256 -55.046 100.859 1.00 54.36
ATOM 725 N ALA 213 254.527 -56.345 102.683 1.00 52.94
ATOM 726 CA ALA 213 253.177 -56.178 103.210 1.00 50.87
ATOM 727 CB ALA 213 252.682 -57.487 103.757 1.00 49.44
ATOM 728 C ALA 213 253.165 -55.122 104.306 1.00 50.66
ATOM 729 O ALA 213 253.373 -55.445 105.482 1.00 49.51
ATOM 730 N PRO 214 252.874 -53.856 103.935 1.00 51.33
ATOM 731 CD PRO 214 252.297 -53.573 102.610 1.00 50.57
ATOM 732 CA PRO 214 252.808 -52.645 104.765 1.00 51.93
ATOM 733 CB PRO 214 252.132 -51.634 103.847 1.00 51.68
ATOM 734 CG PRO 214 252.489 -52.098 102.500 1.00 51.09
ATOM 735 C PRO 214 252.099 -52.718 106.112 1.00 53.29
ATOM 736 O PRO 214 252.590 -52.167 107.097 1.00 52.30
ATOM 737 N LEU 215 250.957 -53.397 106.155 1.00 54.91
ATOM 738 CA LEU 215 250.167 -53.485 107.379 1.00 56.09
ATOM 739 CB LEU 215 248.682 -53.371 107.033 1.00 57.70
ATOM 740 CG LEU 215 248.353 -52.166 106.153 1.00 60.05
ATOM 741 CDl LEU 215 246.854 -52.098 105.889 1.00 60.87
ATOM 742 CD2 LEU 215 248.841 -50.907 106.842 1.00 60.02
ATOM 743 C LEU 215 250.395 -54.707 108.261 1.00 56.25
ATOM 744 O LEU 215 249.502 -55.110 109.017 1.00 57.41
ATOM 745 N GLY 216 251.581 -55.300 108.163 1.00 55.07
ATOM 746 CA GLY 216 251.911 -56.440 109.002 1.00 52.15
ATOM 747 C GLY 216 251.079 -57.684 108.817 1.00 50.86
ATOM 748 O GLY 216 250.436 -57.881 107.787 1.00 50.48
ATOM 749 N THR 217 251.084 -58.522 109.843 1.00 49.54
ATOM 750 CA THR 217 250.353 -59.775 109.801 1.00 47.39
ATOM 751 CB THR 217 251.165 -60.916 110.485 1.00 47.43
ATOM 752 OGl THR 217 251.138 -60.763 111.910 1.00 46.72
ATOM 753 CG2 THR 217 252.606 -60.901 110.000 1.00 43.88
ATOM 754 C THR 217 248.958 -59.715 110.414 1.00 46.61
ATOM 755 O THR 217 248.575 -58.737 111.046 1.00 45.04
ATOM 756 N VAL 218 248.199 -60.780 110.181 1.00 46.73
ATOM 757 CA VAL 218 246.850 -60.916 110.700 1.00 45.71
ATOM 758 CB VAL 218 246.042 -61.937 109.860 1.00 44.06
ATOM 759 CGl VAL 218 244.696 -62.215 110.498 1.00 42.55
ATOM 760 CG2 VAL 218 245.840 -61.403 108.477 1.00 40.74
ATOM 761 C VAL 218 247.014 -61.402 112.138 1.00 47.20
ATOM 762 O VAL 218 246.114 -61.284 112.953 1.00 45.47
ATOM 763 N TYR 219 248.187 -61.952 112.427 1.00 49.50
ATOM 764 CA TYR 219 248.512 -62.428 113.754 1.00 52.96
ATOM 765 CB TYR 219 249.880 -63.106 113.758 1.00 54.41
ATOM 766 CG TYR 219 250.385 -63.457 115.144 1.00 55.54
ATOM 767 CDl TYR 219 250.116 -64.695 115.708 1.00 56.31
ATOM 768 CEl TYR 219 250.530 -65.001 116.991 1.00 57.12
ATOM 769 CD2 TYR 219 251.092 -62.527 115.907 1.00 55.39
ATOM 770 CE2 TYR 219 251.509 -62.821 117.193 1.00 56.45
ATOM 771 CZ TYR 219 251.226 -64.063 117.732 1.00 57.83
ATOM 772 OH TYR 219 251.649 -64.379 119.004 1.00 57.39 17/39
ATOM 773 C TYR 219 248.586 -61.188 114.618 1.00 55.40
ATOM 774 O TYR 219 248.044 -61.139 115.714 1.00 55.52
ATOM 775 N ARG 220 249.284 -60.183 114.114 1.00 58.99
ATOM 776 CA ARG 220 249.442 -58.928 114.834 1.00 62.95
ATOM 111 CB ARG 220 250.523 -58.071 114.159 1.00 66.57
ATOM 778 CG ARG 220 250.421 -56.573 114.419 1.00 71.49
ATOM 779 CD ARG 220 251.797 -55.935 114.563 1.00 76.17
ATOM 780 NE ARG 220 252.305 -56.043 115.935 1.00 81.07
ATOM 781 CZ ARG 220 252.844 -57.138 116.481 1.00 83.22
ATOM 782 NHl ARG 220 253.261 -57.098 117.747 1.00 84.17
ATOM 783 NH2 ARG 220 252.990 -58.260 115.774 1.00 82.38
ATOM 784 C ARG 220 248.126 -58.161 114.929 1.00 63.45
ATOM 785 O ARG 220 247.887 -57.470 115.915 1.00 63.18
ATOM 786 N GLU 221 247.273 -58.296 113.915 1.00 64.19
ATOM 787 CA GLU 221 245.975 -57.618 113.909 1.00 65.16
ATOM 788 CB GLU 221 245.370 -57.629 112.504 1.00 66.98
ATOM 789 CG GLU 221 244.591 -56.369 112.143 1.00 68.92
ATOM 790 CD GLU 221 245.470 -55.123 112.130 1.00 71.62
ATOM 791 OEl GLU 221 244.966 -54.043 111.766 1.00 73.24
ATOM 792 OE2 GLU 221 246.667 -55.217 112.481 1.00 72.15
ATOM 793 C GLU 221 245.020 -58.319 114.868 1.00 64.94
ATOM 794 O GLU 221 244.051 -57.738 115.348 1.00 64.09
ATOM 795 N LEU 222 245.320 -59.581 115.143 1.00 65.19
ATOM 796 CA LEU 222 244.515 -60.410 116.024 1.00 64.90
ATOM 797 CB LEU 222 244.629 -61.861 115.589 1.00 62.54
ATOM 798 CG LEU 222 243.617 -62.854 116.129 1.00 60.78
ATOM 799 CDl LEU 222 242.199 -62.338 115.984 1.00 59.76
ATOM 800 CD2 LEU 222 243.789 -64.122 115.329 1.00 61.41
ATOM 801 C LEU 222 245.028 -60.249 117.440 1.00 65.61
ATOM 802 O LEU 222 244.302 -60.416 118.412 1.00 65.59
ATOM 803 N GLN 223 246.302 -59.921 117.545 1.00 67.00
ATOM 804 CA GLN 223 246.928 -59.708 118.837 1.00 67.57
ATOM 805 CB GLN 223 . 248.441 -59.673 118.633 1.00 68.29
ATOM 806 CG GLN 223 249.274 -59.676 119.874 1.00 70.42
ATOM 807 CD GLN 223 250.696 -60.067 119.559 1.00 72.40
ATOM 808 OEl GLN 223 251.338 -59.476 118.687 1.00 72.81
ATOM 809 NE2 GLN 223 251.197 -61.074 120.261 1.00 72.13
ATOM 810 C GLN 223 246.402 -58.350 119.306 1.00 67.22
ATOM 811 O GLN 223 246.091 -58.141 120.480 1.00 66.91
ATOM 812 N LYS 224 246.273 -57.449 118.339 1.00 66.15
ATOM 813 CA LYS 224 245.814 -56.087 118.549 1.00 65.46
ATOM 814 CB LYS 224 246.097 -55.320 117.257 1.00 66.30
ATOM 815 CG LYS 224 245.707 -53.872 117.173 1.00 67.01
ATOM 816 CD LYS 224 246.021 -53.405 115.750 1.00 68.25
ATOM 817 CE LYS 224 245.173 -52.221 115.321 1.00 67.99
ATOM 818 NZ LYS 224 244.911 -52.279 113.849 1.00 66.62
ATOM 819 C LYS 224 244.332 -56.016 118.948 1.00 64.85
ATOM 820 O LYS 224 244.003 -55.532 120.028 1.00 64.49
ATOM 821 N LEU 225 243.450 -56.532 118.091 1.00 63.79
ATOM 822 CA LEU 225 242.001 -56.516 118.337 1.00 60.74
ATOM 823 CB LEU 225 241.260 -56.482 117.002 1.00 60.33
ATOM 824 CG LEU 225 241.923 -55.620 115.924 1.00 61.43
ATOM 825 CDl LEU 225 241.222 -55.784 114.598 1.00 60.09
ATOM 826 CD2 LEU 225 241.902 -54.175 116.356 1.00 61.74
ATOM 827 C LEU 225 241.500 -57.707 119.160 1.00 59.91
ATOM 828 O LEU 225 240.346 -57.740 119.544 1.00 58.99
ATOM 829 N SER 226 242.381 -58.671 119.427 1.00 60.57
ATOM 830 CA SER 226 242.082 -59.900 120.184 1.00 59.56
ATOM 831 CB SER 226 241.815 -59.593 121.670 1.00 59.66
ATOM 832 OG SER 226 240.474 -59.231 121.918 1.00 60.75
ATOM 833 C SER 226 240.955 -60.772 119.604 1.00 58.34
ATOM 834 O SER 226 240.956 -61.985 119.803 1.00 58.06
ATOM 835 N LYS 227 240.011 -60.158 118.892 1.00 57.82 18/39
ATOM 836 CA LYS 227 238.901 -60.861 118.242 1.00 58.40
ATOM 837 CB LYS 227 237.707 -61.063 119.198 1.00 58.58
ATOM 838 CG LYS 227 237.850 -62.190 120.215 1.00 62.20
ATOM 839 CD LYS 227 236.545 -62.503 120.989 1.00 64.61
ATOM 840 CE LYS 227 235.908 -61.267 121.674 1.00 67.68
ATOM 841 NZ LYS 227 236.781 -60.472 122.628 1.00 67.94
ATOM 842 C LYS 227 238.441 -60.032 117.031 1.00 57.80
ATOM 843 O LYS 227 238.721 -58.840 116.958 1.00 57.18
ATOM 844 N PHE 228 237.740 -60.661 116.087 1.00 58.31
ATOM 845 CA PHE 228 237.237 -59.974 114.889 1.00 58.47
ATOM 846 CB PHE 228 237.864 -60.562 113.616 1.00 56.47
ATOM 847 CG PHE 228 239.342 -60.381 113.519 1.00 55.58
ATOM 848 CDl PHE 228 240.074 -61.130 112.610 1.00 55.86
ATOM 849 CD2 PHE 228 240.013 -59.482 114.343 1.00 55.42
ATOM 850 CEl PHE 228 241.462 -60.993 112.522 1.00 55.57
ATOM 851 CE2 PHE 228 241.395 -59.333 114.270 1.00 55.75
ATOM 852 CZ PHE 228 242.122 -60.091 113.358 1.00 56.24
ATOM 853 C PHE 228 235.717 -60.102 114.763 1.00 60.06
ATOM 854 O PHE 228 235.136 -61.109 115.163 1.00 59.03
ATOM 855 N ASP 229 235.068 -59.086 114.201 1.00 62.50
ATOM 856 CA ASP 229 233.621 -59.160 114.008 1.00 63.84
ATOM 857 CB ASP 229 233.003 -57.762 113.802 1.00 63.91
ATOM 858 CG ASP 229 233.581 -57.020 112.601 1.00 65.37
ATOM 859 ODl ASP 229 233.576 -57.572 111.479 1.00 67.28
ATOM 860 OD2 ASP 229 234.028 -55.869 112.778 1.00 64.45
ATOM 861 C ASP 229 233.354 -60.040 112.782 1.00 65.09
ATOM 862 O ASP 229 234.245 -60.257 111.948 1.00 64.48
ATOM 863 N GLU 230 232.130 -60.543 112.672 1.00 66.22
ATOM 864 CA GLU 230 231.772 -61.402 111.559 1.00 67.32
ATOM 865 CB GLU 230 230.347 -61.911 111.730 1.00 66.38
ATOM 866 CG GLU 230 230.126 -62.651 113.014 1.00 65.94
ATOM 867 CD GLU 230 228.758 -63.284 113.083 1.00 66.84
ATOM 868 OEl GLU 230 227.757 --62.549 112.994 1.00 66.42
ATOM 869 OE2 GLU 230 228.683 -64.520 113.227 1.00 67.37
ATOM 870 C GLU 230 231.911 -60.732 110.200 1.00 68.77
ATOM 871 O GLU 230 231.789 -61.393 109.172 1.00 69.85
ATOM 872 N GLN 231 232.162 -59.431 110.175 1.00 70.28
ATOM 873 CA GLN 231 232.304 -58.759 108.889 1.00 72.12
ATOM 874 CB GLN 231 231.921 -57.283 109.010 1.00 74.88
ATOM 875 CG GLN 231 231.524 -56.675 107.670 1.00 80.10
ATOM 876 CD GLN 231 231.897 -55.215 107.546 1.00 82.47
ATOM 877 OEl GLN 231 231.449 -54.373 108.329 1.00 84.02
ATOM 878 NE2 GLN 231 232.728 -54.905 106.553 1.00 83.88
ATOM 879 C GLN 231 233.750 -58.886 108.402 1.00 71.13
ATOM 880 O GLN 231 234.022 -59.198 107.244 1.00 70.81
ATOM 881 N ARG 232 234.670 -58.643 109.318 1.00 70.23
ATOM 882 CA ARG 232 236.092 -58.717 109.050 1.00 69.14
ATOM 883 CB ARG 232 236.821 -58.186 110.272 1.00 71.31
ATOM 884 CG ARG 232 238.267 -57.846 110.103 1.00 72.86
ATOM 885 CD ARG 232 238.767 -57.457 111.470 1.00 76.95
ATOM 886 NE ARG 232 240.154 -57.028 111.472 1.00 80.74
ATOM 887 CZ ARG 232 240.554 -55.814 111.120 1.00 82.69
ATOM 888 NHl ARG 232 239.660 -54.906 110.737 1.00 83.05
ATOM 889 NH2 ARG 232 241.845 -55.509 111.166 1.00 83.33
ATOM 890 C ARG 232 236.481 -60.169 108.804 1.00 67.63
ATOM 891 O ARG 232 237.125 -60.501 107.809 1.00 67.49
ATOM 892 N THR 233 236.082 -61.029 109.731 1.00 65.04
ATOM 893 CA THR 233 236.376 -62.443 109.637 1.00 62.99
ATOM 894 CB THR 233 235.665 -63.217 110.739 1.00 62.11
ATOM 895 OGl THR 233 236.024 -62.672 112.011 1.00 61.57
ATOM 896 CG2 THR 233 236.062 -64.680 110.690 1.00 61.56
ATOM 897 C THR 233 235.928 -63.000 108.301 1.00 63.22
ATOM 898 O THR 233 236.703 -63.658 107.597 1.00 63.13 19/39
ATOM 899 N ALA 234 234.669 -62.733 107.956 1.00 62.61
ATOM 900 CA ALA 234 234.082 -63.220 106.705 1.00 61.50
ATOM 901 CB ALA 234 232.606 -62.847 106.640 1.00 60.71
ATOM 902 C ALA 234 234.823 -62.659 105.502 1.00 60.77
ATOM 903 O ALA 234 234.961 -63.310 104.469 1.00 60.46
ATOM 904 N THR 235 235.317 -61.442 105.654 1.00 60.34
ATOM 905 CA THR 235 236.051 -60.789 104.586 1.00 60.11
ATOM 906 CB THR 235 236.239 -59.313 104.923 1.00 60.03
ATOM 907 OGl THR 235 234.954 -58.743 105.223 1.00 57.09
ATOM 908 CG2 THR 235 236.903 -58.575 103.752 1.00 58.63
ATOM 909 C THR 235 237.406 -61.462 104.363 1.00 59.95
ATOM 910 O THR 235 237.798 -61.723 103.223 1.00 59.26
ATOM 911 N TYR 236 238.118 -61.737 105.456 1.00 59.59
ATOM 912 CA TYR 236 239.417 -62.409 105.385 1.00 57.78
ATOM 913 CB TYR 236 240.072 -62.496 106.766 1.00 56.92
ATOM 914 CG TYR 236 240.698 -61.219 107.254 1.00 56.77
ATOM 915 CDl TYR 236 241.478 -60.428 106.412 1.00 56.58
ATOM 916 CEl TYR 236 242.112 -59.290 106.894 1.00 55.87
ATOM 917 CD2 TYR 236 240.569 -60.834 108.584 1.00 56.41
ATOM 918 CE2 TYR 236 241.198 -59.701 109.070 1.00 56.11
ATOM 919 CZ TYR 236 241.961 -58.941 108.225 1.00 55.36
ATOM 920 OH TYR 236 242.552 -57.821 108.726 1.00 57.06
ATOM 921 C TYR 236 239.243 -63.825 104.839 1.00 56.91
ATOM 922 O TYR 236 240.033 -64.265 103.983 1.00 55.07
ATOM 923 N ILE 237 238.227 -64.541 105.341 1.00 55.15
ATOM 924 CA ILE 237 237.976 -65.898 104.858 1.00 54.05
ATOM 925 CB ILE 237 236.780 -66.568 105.555 1.00 52.14
ATOM 926 CG2 ILE 237 236.257 -67.687 104.683 1.00 50.42
ATOM 927 CGl ILE 237 237.176 -67.093 106.952 1.00 50.62
ATOM 928 CD ILE 237 238.356 -68.047 106.989 1.00 49.98
ATOM 929 C ILE 237 237.711 -65.874 103.355 1.00 55.00
ATOM 930 O ILE 237 238.159 -66.762 102.637 1.00 55.46
ATOM 931 N THR 238 236.998 -64.853 102.882 1.00 56.24
ATOM 932 CA THR 238 236.698 -64.720 101.449 1.00 58.79
ATOM 933 CB THR 238 235.739 -63.520 101.163 1.00 59.31
ATOM 934 OGl THR 238 234.421 -63.828 101.633 1.00 60.10
ATOM 935 CG2 THR 238 235.674 -63.219 99.664 1.00 58.24
ATOM 936 C THR 238 237.964 -64.528 100.615 1.00 60.00
ATOM 937 O THR 238 238.205 -65.270 99.666 1.00 60.40
ATOM 938 N GLU 239 238.762 -63.521 100.962 1.00 60.63
ATOM 939 CA GLU 239 239.999 -63.244 100.241 1.00 61.50
ATOM 940 CB GLU 239 240.715 -62.050 100.869 1.00 61.99
ATOM 941 CG GLU 239 239.782 -61.092 101.575 1.00 64.68
ATOM 942 CD GLU 239 240.459 -59.806 102.007 1.00 66.78
ATOM 943 OEl GLU 239 239.997 -59.191 102.994 1.00 67.49
ATOM 944 OE2 GLU 239 241.441 -59.399 101.353 1.00 68.45
ATOM 945 C GLU 239 240.874 -64.486 100.342 1.00 61.65
ATOM 946 O GLU 239 241.638 -64.808 99.436 1.00 60.59
ATOM 947 N LEU 240 240.734 -65.192 101.460 1.00 62.21
ATOM 948 CA LEU 240 241.505 -66.394 101.700 1.00 62.16
ATOM 949 CB LEU 240 241.347 -66.844 103.150 1.00 64.06
ATOM 950 CG LEU 240 242.535 -67.650 103.677 1.00 63.97
ATOM 951 CDl LEU 240 243.834 -66.887 103.433 1.00 64.75
ATOM 952 CD2 LEU 240 242.362 -67.892 105.148 1.00 64.82
ATOM 953 C LEU 240 241.078 -67.502 100.762 1.00 61.66
ATOM 954 O LEU 240 241.913 -68.079 100.073 1.00 61.91
ATOM 955 N ALA 241 239.786 -67.804 100.726 1.00 61.01
ATOM 956 CA ALA 241 239.302 -68.855 99.843 1.00 61.05
ATOM 957 CB ALA 241 237.802 -68.976 99.951 1.00 60.05
ATOM 958 C ALA 241 239.710 -68.579 98.394 1.00 61.74
ATOM 959 O ALA 241 240.137 -69.485 97.680 1.00 61.14
ATOM 960 N ASN 242 239.573 -67.325 97.967 1.00 62.24
ATOM 961 CA ASN 242 239.943 -66.926 96.613 1.00 62.37 20/39
ATOM 962 CB ASN 242 239.811 -65.414 96.454 1.00 63.23
ATOM 963 CG ASN 242 238.378 -64.962 96.281 1.00 64.01
ATOM 964 ODl ASN 242 238.082 -63.765 96.365 1.00 63.13
ATOM 965 ND2 ASN 242 237.479 -65.911 96.025 1.00 63.55
ATOM 966 C ASN 242 241.383 -67.322 96.334 1.00 62.84
ATOM 967 O ASN 242 241.663 -68.079 95.409 1.00 63.28
ATOM 968 N ALA 243 242.291 -66.786 97.141 1.00 63.36
ATOM 969 CA ALA 243 243.720 -67.056 97.017 1.00 63.01
ATOM 970 CB ALA 243 244.465 -66.379 98.152 1.00 61.66
ATOM 971 C ALA 243 244.005 -68.552 97.030 1.00 63.30
ATOM 972 O ALA 243 244.910 -69.031 96.348 1.00 63.05
ATOM 973 N LEU 244 243.230 -69.290 97.812 1.00 64.31
ATOM 974 CA LEU 244 243.414 -70.733 97.912 1.00 67.00
ATOM 975 CB LEU 244 242.711 -71.263 99.171 1.00 66.71
ATOM 976 CG LEU 244 243.396 -71.098 100.536 1.00 65.44
ATOM 977 CDl LEU 244 242.381 -71.410 101.638 1.00 65.76
ATOM 978 CD2 LEU 244 244.618 -72.024 100.639 1.00 63.40
ATOM 979 C LEU 244 242.940 -71.519 96.676 1.00 68.68
ATOM 980 O LEU 244 243.626 -72.432 96.212 1.00 68.26
ATOM 981 N SER 245 241.774 -71.173 96.144 1.00 70.27
ATOM 982 CA SER 245 241.270 -71.872 94.975 1.00 71.80
ATOM 983 CB SER 245 239.927 -71.302 94.533 1.00 72.25
ATOM 984 OG SER 245 240.112 -70.123 93.782 1.00 75.33
ATOM 985 C SER 245 242.283 -71.714 93.858 1.00 72.02
ATOM 986 O SER 245 242.528 -72.646 93.099 1.00 73.68
ATOM 987 N TYR 246 242.870 -70.530 93.756 1.00 71.68
ATOM 988 CA TYR 246 243.873 -70.293 92.735 1.00 72.14
ATOM 989 CB TYR 246 244.417 -68.884 92.854 1.00 71.05
ATOM 990 CG TYR 246 245.649 -68.654 92.022 1.00 70.85
ATOM 991 CDl TYR 246 245.553 -68.311 90.677 1.00 70.55
ATOM 992 CEl TYR 246 246.692 -68.084 89.910 1.00 70.47
ATOM 993 CD2 TYR 246 246.917 -68.773 92.584 1.00 70.75
ATOM 994 CE2 TYR 246 248.059 -68.552 91.828 1.00 71.04
ATOM 995 CZ TYR 246 247.938 -68.207 90.493 1.00 71.03
ATOM 996 OH TYR 246 249.066 -67.989 89.742 1.00 71.71
ATOM 997 C TYR 246 245.016 -71.288 92.913 1.00 73.46
ATOM 998 O TYR 246 245.563 -71.802 91.941 1.00 73.15
ATOM 999 N CYS 247 245.372 -71.559 94.163 1.00 74.57
ATOM 1000 CA CYS 247 246.450 -72.488 94.453 1.00 76.16
ATOM 1001 CB CYS 247 246.804 -72.457 95.941 1.00 75.58
ATOM 1002 SG CYS 247 247.756 -71.024 96.447 1.00 73.70
ATOM 1003 C CYS 247 246.086 -73.904 94.059 1.00 11.13
ATOM 1004 O CYS 247 246.877 -74.597 93.418 1.00 78.16
ATOM 1005 N HIS 248 244.890 -74.331 94.453 1.00 79.52
ATOM 1006 CA HIS 248 244.425 -75.682 94.156 1.00 81.40
ATOM 1007 CB HIS 248 243.133 -75.979 94.929 1.00 81.28
ATOM 1008 CG HIS 248 243.281 -75.872 96.418 1.00 82.07
ATOM 1009 CD2 HIS 248 244.329 -75.490 97.187 1.00 81.88
ATOM 1010 NDl HIS 248 242.254 -76.161 97.292 1.00 81.69
ATOM 1011 CEl HIS 248 242.663 -75.960 98.532 1.00 81.05
ATOM 1012 NE2 HIS 248 243.918 -75.552 98.496 1.00 79.95
ATOM 1013 C HIS 248 244.206 -75.863 92.655 1.00 82.45
ATOM 1014 O HIS 248 244.391 -76.961 92.119 1.00 82.30
ATOM 1015 N SER 249 243.826 -74.775 91.986 1.00 82.83
ATOM 1016 CA SER 249 243.588 -74.796 90.546 1.00 82.89
ATOM 1017 CB SER 249 242.864 -73.532 90.086 1.00 81.93
ATOM 1018 OG SER 249 243.773 -72.626 89.484 1.00 79.68
ATOM 1019 C SER 249 244.925 -74.876 89.836 1.00 83.73
ATOM 1020 O SER 249 244.987 -74.905 88.609 1.00 84.15
ATOM 1021 N LYS 250 245.999 -74.871 90.613 1.00 83.97
ATOM 1022 CA LYS 250 247.329 -74.990 90.050 1.00 84.30
ATOM 1023 CB LYS 250 248.144 -73.711 90.275 1.00 84.62
ATOM 1024 CG LYS 250 248.942 -73.312 89.035 1.00 86.43 21/39
ATOM 1025 CD LYS 250 249.121 -71.793 88.875 1.00 87.83
ATOM 1026 CE LYS 250 250.456 -71.315 89.441 1.00 90.15
ATOM 1027 NZ LYS 250 250.584 -71.580 90.917 1.00 90.86
ATOM 1028 C LYS 250 247.952 -76.185 90.752 1.00 84.32
ATOM 1029 O LYS 250 249.163 -76.400 90.694 1.00 85.42
ATOM 1030 N ARG 251 247.088 -76.955 91.417 1.00 83.44
ATOM 1031 CA ARG 251 247.472 -78.171 92.129 1.00 83.06
ATOM 1032 CB ARG 251 248.093 -79.167 91.142 1.00 85.74
ATOM 1033 CG ARG 251 247.264 -80.422 90.903 1.00 88.58
ATOM 1034 CD ARG 251 247.258 -81.267 92.159 1.00 92.19
ATOM 1035 NE ARG 251 246.430 -82.468 92.078 1.00 93.73
ATOM 1036 CZ ARG 251 246.218 -83.271 93.117 1.00 94.88
ATOM 1037 NHl ARG 251 246.773 -82.985 94.287 1.00 95.57
ATOM 1038 NH2 ARG 251 245.449 -84.346 92.998 1.00 94.88
ATOM 1039 C ARG 251 248.427 -77.945 93.290 1.00 81.30
ATOM 1040 O ARG 251 249.213 -78.827 93.631 1.00 81.01
ATOM 1041 N VAL 252 248.350 -76.767 93.900 1.00 79.37
ATOM 1042 CA VAL 252 249.220 -76.419 95.021 1.00 76.50
ATOM 1043 CB VAL 252 249.863 -75.025 94.803 1.00 76.37
ATOM 1044 CGl VAL 252 250.798 -74.690 95.948 1.00 75.69
ATOM 1045 CG2 VAL 252 250.610 -74.995 93.488 1.00 75.66
ATOM 1046 C VAL 252 248.466 -76.389 96.349 1.00 74.61
ATOM 1047 O VAL 252 247.342 -75.901 96.419 1.00 74.52
ATOM 1048 N ILE 253 249.081 -76.926 97.398 1.00 72.10
ATOM 1049 CA ILE 253 248.472 -76.906 98.726 1.00 70.29
ATOM 1050 CB ILE 253 248.099 -78.351 99.212 1.00 70.52
ATOM 1051 CG2 ILE 253 246.930 -78.874 98.411 1.00 70.73
ATOM 1052 CGl ILE 253 249.259 -79.320 99.009 1.00 70.99
ATOM 1053 CD ILE 253 248.925 -80.753 99.381 1.00 70.17
ATOM 1054 C ILE 253 249.465 -76.226 99.681 1.00 68.70
ATOM 1055 O ILE 253 250.585 -76.703 99.866 1.00 69.26
ATOM 1056 N HIS 254 249.063 -75.096 100.262 1.00 66.32
ATOM 1057 CA HIS 254 249.934 -74.333 101.164 l.oo- 64.38
ATOM 1058 CB HIS 254 249.257 -73.012 101.556 1.00 63.65
ATOM 1059 CG HIS 254 250.164 -72.036 102.252 1.00 63.06
ATOM 1060 CD2 HIS 254 250.905 -71.009 101.769 1.00 60.17
ATOM 1061 NDl HIS 254 250.368 -72.043 103.618 1.00 61.34
ATOM 1062 CEl HIS 254 251.191 -71.063 103.945 1.00 60.23
ATOM 1063 NE2 HIS 254 251.531 -70.421 102.841 1.00 59.92
ATOM 1064 C HIS 254 250.348 -75.100 102.415 1.00 63.54
ATOM 1065 O HIS 254 251.509 -75.065 102.810 1.00 62.61
ATOM 1066 N ARG 255 249.385 -75.768 103.043 1.00 63.38
ATOM 1067 CA ARG 255 249.621 -76.583 104.235 1.00 63.18
ATOM 1068 CB ARG 255 250.654 -77.669 103.917 1.00 64.37
ATOM 1069 CG ARG 255 250.290 -78.505 102.713 1.00 65.54
ATOM 1070 CD ARG 255 251.083 -79.784 102.679 1.00 67.48
ATOM 1071 NE ARG 255 252.521 -79.552 102.596 1.00 68.80
ATOM 1072 CZ ARG 255 253.429 -80.522 102.604 1.00 67.81
ATOM 1073 NHl ARG 255 253.040 -81.784 102.691 1.00 66.86
ATOM 1074 NH2 ARG 255 254.719 -80.233 102.521 1.00 66.71
ATOM 1075 C ARG 255 250.007 -75.880 105.543 1.00 61.93
ATOM 1076 O ARG 255 249.877 -76.460 106.616 1.00 62.81
ATOM 1077 N ASP 256 250.505 -74.656 105.474 1.00 60.44
ATOM 1078 CA ASP 256 250.851 -73.963 106.701 1.00 59.05
ATOM 1079 CB ASP 256 252.363 -73.804 106.836 1.00 58.49
ATOM 1080 CG ASP 256 252.769 -73.343 108.226 1.00 59.62
ATOM 1081 ODl ASP 256 252.053 -73.675 109.196 1.00 60.74
ATOM 1082 OD2 ASP 256 253.803 -72.658 108.364 1.00 60.50
ATOM 1083 C ASP 256 250.153 -72.614 106.779 1.00 58.67
ATOM 1084 O ASP 256 250.780 -71.576 106.986 1.00 58.93
ATOM 1085 N ILE 257 248.834 -72.657 106.613 1.00 58.04
ATOM 1086 CA ILE 257 247.984 -71.477 106.662 1.00 55.52
ATOM 1087 CB ILE 257 246.655 -71.724 105.955 1.00 53.83 22/39
ATOM 1088 CG2 ILE 257 245.752 -70.540 106.150 1.00 51.22
ATOM 1089 CGl ILE 257 246.888 -71.977 104.474 1.00 54.68
ATOM 1090 CD ILE 257 247.457 -70.793 103.758 1.00 55.86
ATOM 1091 C ILE 257 247.656 -71.138 108.102 1.00 56.84
ATOM 1092 O ILE 257 246.980 -71.906 108.784 1.00 58.25
ATOM 1093 N LYS 258 248.137 -69.996 108.576 1.00 57.19
ATOM 1094 CA LYS 258 247.829 -69.577 109.932 1.00 56.75
ATOM 1095 CB LYS 258 248.745 -70.261 110.943 1.00 55.88
ATOM 1096 CG LYS 258 250.217 -70.109 110.703 1.00 57.21
ATOM 1097 CD LYS 258 250.957 -71.094 111.587 1.00 58.91
ATOM 1098 CE LYS 258 252.467 -71.015 111.451 1.00 61.29
ATOM 1099 NZ LYS 258 253.078 -72.268 112.018 1.00 61.84
ATOM 1100 C LYS 258 247.922 -68.075 110.077 1.00 57.17
ATOM 1101 O LYS 258 248.443 -67.381 109.195 1.00 57.58
ATOM 1102 N PRO 259 247.402 -67.542 111.190 1.00 56.64
ATOM 1103 CD PRO 259 246.709 -68.207 112.306 1.00 55.34
ATOM 1104 CA PRO 259 247.452 -66.100 111.386 1.00 56.43
ATOM 1105 CB PRO 259 246.995 -65.938 112.827 1.00 56.61
ATOM 1106 CG PRO 259 246.008 -67.061 112.966 1.00 54.52
ATOM 1107 C PRO 259 248.846 -65.566 111.129 1.00 56.81
ATOM 1108 O PRO 259 248.984 -64.556 110.451 1.00 58.02
ATOM 1109 N GLU 260 249.874 -66.243 111.637 1.00 57.17
ATOM 1110 CA GLU 260 251.248 -65.780 111.412 1.00 57.38
ATOM 1111 CB GLU 260 252.271 -66.704 112.047 1.00 60.60
ATOM 1112 CG GLU 260 252.430 -66.571 113.532 1.00 65.73
ATOM 1113 CD GLU 260 251.826 -67.752 114.237 1.00 69.98
ATOM 1114 OEl GLU 260 250.573 -67.903 114.175 1.00 70.15
ATOM 1115 OE2 GLU 260 252.608 -68.537 114.824 1.00 70.38
ATOM 1116 C GLU 260 251.635 -65.630 109.945 1.00 56.09
ATOM 1117 O GLU 260 252.410 -64.745 109.636 1.00 55.96
ATOM 1118 N ASN 261 251.112 -66.486 109.057 1.00 53.85
ATOM 1119 CA ASN 261 251.437 -66.424 107.622 1.00 51.89
ATOM 1120 CB ASN 261 251.591 -67.820 107.031 1.00 52.08
ATOM 1121 CG ASN 261 252.709 -68.573 107.657 1.00 52.27
ATOM 1122 ODl ASN 261 253.578 -67.980 108.294 1.00 52.50
ATOM 1123 ND2 ASN 261 252.712 -69.886 107.483 1.00 49.74
ATOM 1124 C ASN 261 250.485 -65.642 106.725 1.00 51.02
ATOM 1125 O ASN 261 250.570 -65.721 105.495 1.00 49.99
ATOM 1126 N LEU 262 249.572 -64.895 107.328 1.00 49.99
ATOM 1127 CA LEU 262 248.676 -64.067 106.538 1.00 49.40
ATOM 1128 CB LEU 262 247.232 -64.205 107.030 1.00 47.31
ATOM 1129 CG LEU 262 246.664 -65.634 106.921 1.00 46.91
ATOM 1130 CDl LEU 262 245.255 -65.728 107.548 1.00 45.61
ATOM 1131 CD2 LEU 262 246.642 -66.072 105.460 1.00 45.16
ATOM 1132 C LEU 262 249.174 -62.619 106.656 1.00 50.18
ATOM 1133 O LEU 262 249.228 -62.062 107.745 1.00 51.02
ATOM 1134 N LEU 263 249.581 -62.032 105.536 1.00 50.62
ATOM 1135 CA LEU 263 250.071 -60.653 105.529 1.00 51.16
ATOM 1136 CB LEU 263 251.348 -60.523 104.681 1.00 50.15
ATOM 1137 CG LEU 263 252.565 -61.158 105.340 1.00 49.79
ATOM 1138 CDl LEU 263 253.849 -60.944 104.498 1.00 46.22
ATOM 1139 CD2 LEU 263 252.703 -60.531 106.707 1.00 51.32
ATOM 1140 C LEU 263 249.010 -59.711 104.995 1.00 50.86
ATOM 1141 O LEU 263 248.146 -60.119 104.234 1.00 51.40
ATOM 1142 N LEU 264 249.080 -58.452 105.401 1.00 50.70
ATOM 1143 CA LEU 264 248.115 -57.466 104.941 1.00 51.87
ATOM 1144 CB LEU 264 247.434 -56.799 106.153 1.00 49.73
ATOM 1145 CG LEU 264 246.769 -57.834 107.074 1.00 48.18
ATOM 1146 CDl LEU 264 246.500 -57.265 108.438 1.00 47.84
ATOM 1147 CD2 LEU 264 245.493 -58.328 106.439 1.00 46.78
ATOM 1148 C LEU 264 248.781 -56.427 104.023 1.00 52.85
ATOM 1149 o LEU 264 249.843 -55.880 104.325 1.00 52.34
ATOM 1150 N GLY 265 248.148 -56.189 102.880 1.00 54.81 23/39
ATOM 1151 CA GLY 265 248.663 -55.223 101.929 1.00 57.34
ATOM 1152 C GLY 265 248.286 -53.783 102.278 1.00 58.63
ATOM 1153 O GLY 265 247.770 -53.507 103.364 1.00 57.35
ATOM 1154 N SER 266 248.535 -52.865 101.349 1.00 59.43
ATOM 1155 CA SER 266 248.236 -51.458 101.576 1.00 61.27
ATOM 1156 CB SER 266 248.681 -50.616 100.375 1.00 61.38
ATOM 1157 OG SER 266 247.819 -50.808 99.262 1.00 62.82
ATOM 1158 C SER 266 246.746 -51.240 101.834 1.00 62.28
ATOM 1159 O SER 266 246.363 -50.614 102.836 1.00 62.44
ATOM 1160 N ALA 267 245.906 -51.756 100.938 1.00 61.33
ATOM 1161 CA ALA 267 244.469 -51.595 101.090 1.00 61.13
ATOM 1162 CB ALA 267 243.780 -51.801 99.759 1.00 60.66
ATOM 1163 C ALA 267 243.924 -52.577 102.109 1.00 62.24
ATOM 1164 O ALA 267 242.757 -52.968 102.036 1.00 62.25
ATOM 1165 N GLY 268 244.777 -52.981 103.048 1.00 63.14
ATOM 1166 CA GLY 268 244.383 -53.931 104.077 1.00 62.91
ATOM 1167 C GLY 268 244.036 -55.336 103.586 1.00 62.69
ATOM 1168 O GLY ' 268 243.576 -56.176 104.384 1.00 62.39
ATOM 1169 N GLU 269 244.261 -55.604 102.295 1.00 61.02
ATOM 1170 CA GLU 269 243.939 -56.912 101.721 1.00 61.15
ATOM 1171 CB GLU 269 244.042 -56.883 100.190 1.00 60.85
ATOM 1172 CG GLU 269 245.454 -56.822 99.619 1.00 60.63
ATOM 1173 CD GLU 269 245.956 -55.401 99.450 1.00 62.42
ATOM 1174 OEl GLU 269 245.797 -54.596 100.397 1.00 61.83
ATOM 1175 OE2 GLU 269 246.516 -55.088 98.375 1.00 61.59
ATOM 1176 C GLU 269 244.798 -58.052 102.254 1.00 61.54
ATOM 1177 O GLU 269 246.005 -57.912 102.435 1.00 61.92
ATOM 1178 N LEU 270 244.159 -59.186 102.499 1.00 60.93
ATOM 1179 CA LEU 270 244.836 -60.371 103.005 1.00 60.95
ATOM 1180 CB LEU 270 243.771 -61.356 103.499 1.00 61.71
ATOM 1181 CG LEU 270 244.132 -62.698 104.123 1.00 62.25
ATOM 1182 CDl LEU 270 242.876 -63.305 104.712 1.00 61.50
ATOM 1183 CD2 LEU 270 - 244.720 -63.618- 103.069- 1.00" 62.98
ATOM 1184 C LEU 270 245.719 -60.983 101.902 1.00 60.39
ATOM 1185 O LEU 270 245.314 -61.068 100.744 1.00 60.67
ATOM 1186 N LYS 271 246.930 -61.386 102.278 1.00 59.48
ATOM 1187 CA LYS 271 247.911 -61.967 101.359 1.00 58.27
ATOM 1188 CB LYS 271 248.960 -60.920 100.986 1.00 57.74
ATOM 1189 CG LYS 271 248.537 -59.973 99.890 1.00 57.70
ATOM 1190 CD LYS 271 249.540 -58.853 99.715 1.00 57.46
ATOM 1191 CE LYS 271 249.272 -58.025 98.463 1.00 57.65
ATOM 1192 NZ LYS 271 249.952 -58.572 97.256 1.00 59.77
ATOM 1193 C LYS 271 248.608 -63.153 102.018 1.00 58.20
ATOM 1194 O LYS 271 249.346 -62.991 102.986 1.00 58.38
ATOM 1195 N ILE 272 248.387 -64.345 101.492 1.00 57.71
ATOM 1196 CA ILE 272 248.999 -65.522 102.075 1.00 58.85
ATOM 1197 CB ILE 272 248.309 -66.775 101.555 1.00 59.70
ATOM 1198 CG2 ILE 272 248.743 -67.974 102.364 1.00 60.16
ATOM 1199 CGl ILE 272 246.791 -66.596 101.669 1.00 60.92
ATOM 1200 CD ILE 272 245.993 -67.767 101.171 1.00 60.90
ATOM 1201 C ILE 272 250.483 -65.575 101.742 1.00 59.77
ATOM 1202 O ILE 272 250.895 -65.117 100.680 1.00 59.96
ATOM 1203 N ALA 273 251.289 -66.113 102.651 1.00 60.70
ATOM 1204 CA ALA 273 252.728 -66.207 102.410 1.00 63.04
ATOM 1205 CB ALA 273 253.410 -64.942 102.888 1.00 60.79
ATOM 1206 C ALA 273 253.363 -67.430 103.082 1.00 65.03
ATOM 1207 O ALA 273 252.668 -68.258 103.675 1.00 64.15
ATOM 1208 N ASP 274 254.687 -67.533 102.982 1.00 67.58
ATOM 1209 CA ASP 274 255.441 -68.638 103.579 1.00 70.45
ATOM 1210 CB ASP 274 255.139 -68.768 105.062 1.00 71.04
ATOM 1211 CG ASP 274 256.378 -68.679 105.905 1.00 72.12
ATOM 1212 ODl ASP 274 257.428 -69.200 105.475 1.00 73.86
ATOM 1213 OD2 ASP 274 256.304 -68.094 107.004 1.00 73.83 24/39
ATOM 1214 C ASP 274 255.139 -69.960 102.929 1.00 72.00
ATOM 1215 O ASP 274 254.409 -70.785 103.474 1.00 72.33
ATOM 1216 N PHE 275 255.713 -70.182 101.764 1.00 73.95
ATOM 1217 CA PHE 275 255.450 -71.424 101.086 1.00 76.21
ATOM 1218 CB PHE 275 255.372 -71.169 99.583 1.00 75.86
ATOM 1219 CG PHE 275 254.077 -70.535 99.161 1.00 75.24
ATOM 1220 CDl PHE 275 253.720 -69.273 99.633 1.00 75.82
ATOM 1221 CD2 PHE 275 253.188 -71.223 98.338 1.00 73.62
ATOM 1222 CEl PHE 275 252.486 -68.703 99.291 1.00 76.18
ATOM 1223 CE2 PHE 275 251.961 -70.670 97.990 1.00 73.25
ATOM 1224 CZ PHE 275 251.603 -69.408 98.465 1.00 74.86
ATOM 1225 C PHE 275 256.441 -72.522 101.427 1.00 78.10
ATOM 1226 O PHE 275 256.588 -73.498 100.690 1.00 78.69
ATOM 1227 N GLY 276 257.099 -72.362 102.572 1.00 79.51
ATOM 1228 CA GLY 276 258.060 -73.348 103.014 1.00 81.13
ATOM 1229 C GLY 276 257.428 -74.717 103.107 1.00 82.95
ATOM 1230 O GLY 276 258.044 -75.710 102.749 1.00 83.91
ATOM 1231 N TRP 277 256.185 -74.783 103.566 1.00 84.37
ATOM 1232 CA TRP 277 255.522 -76.070 103.703 1.00 85.85
ATOM 1233 CB TRP 277 254.847 -76.176 105.071 1.00 88.13
ATOM 1234 CG TRP 277 255.758 -76.712 106.112 1.00 89.85
ATOM 1235 CD2 TRP 277 255.741 -78.036 106.667 1.00 92.20
ATOM 1236 CE2 TRP 277 256.833 -78.126 107.560 1.00 93.30
ATOM 1237 CE3 TRP 277 254.909 -79.155 106.496 1.00 92.54
ATOM 1238 CDl TRP 277 256.821 -76.073 106.674 1.00 89.50
ATOM 1239 NEl TRP 277 257.473 -76.913 107.543 1.00 92.59
ATOM 1240 CZ2 TRP 277 257.120 -79.296 108.288 1.00 94.16
ATOM 1241 CZ3 TRP 277 255.193 -80.322 107.219 1.00 94.12
ATOM 1242 CH2 TRP 277 256.291 -80.379 108.105 1.00 95.01
ATOM 1243 C TRP 277 254.519 -76.415 102.620 1.00 85.91
ATOM 1244 O TRP 277 253.702 -77.321 102.794 1.00 84.56
ATOM 1245 N SER 278 254.579 -75.707 101.500 1.00 86.88
ATOM 1246 CA SER 278 . 253.653 -75.984- 100.411 1.00 88.61
ATOM 1247 CB SER 278 253.353 -74.712 99.625 1.00 87.01
ATOM 1248 OG SER 278 254.515 -74.241 98.975 1.00 85.98
ATOM 1249 C SER 278 254.232 -77.033 99.472 1.00 90.44
ATOM 1250 O SER 278 255.368 -76.916 99.013 1.00 90.49
ATOM 1251 N VAL 279 253.448 -78.064 99.192 1.00 92.35
ATOM 1252 CA VAL 279 253.894 -79.116 98.302 1.00 94.49
ATOM 1253 CB VAL 279 253.757 -80.494 98.968 1.00 95.11
ATOM 1254 CGl VAL 279 252.284 -80.858 99.107 1.00 94.96
ATOM 1255 CG2 VAL 279 254.536 -81.535 98.170 1.00 95.39
ATOM 1256 C VAL 279 253.040 -79.037 97.046 1.00 95.71
ATOM 1257 O VAL 279 251.943 -78.481 97.073 1.00 95.01
ATOM 1258 N HIS 280 253.540 -79.596 95.950 1.00 97.80
ATOM 1259 CA HIS 280 252.818 -79.525 94.696 1.00100.00
ATOM 1260 CB HIS 280 253.806 -79.343 93.543 1.00101.09
ATOM 1261 CG HIS 280 253.255 -78.531 92.417 1.00103.47
ATOM 1262 CD2 HIS 280 252.613 -78.899 91.282 1.00104.68
ATOM 1263 NDl HIS 280 253.257 -77.153 92.425 1.00104.69
ATOM 1264 CEl HIS 280 252.638 -76.707 91.347 1.00105.50
ATOM 1265 NE2 HIS 280 252.237 -77.746 90.637 1.00105.68
ATOM 1266 C HIS 280 251.878 -80.683 94.367 1.00100.77
ATOM 1267 O HIS 280 251.418 -80.784 93.232 1.00101.44
ATOM 1268 N ALA 281 251.563 -81.542 95.331 1.00101.07
ATOM 1269 CA ALA 281 250.676 -82.664 95.031 1.00102.15
ATOM 1270 CB ALA 281 251.342 -83.564 93.989 1.00102.20
ATOM 1271 C ALA 281 250.290 -83.484 96.263 1.00102.85
ATOM 1272 O ALA 281 250.746 -83.200 97.367 1.00103.73
ATOM 1273 N PRO 282 249.441 -84.518 96.087 1.00103.26
ATOM 1274 CD PRO 282 248.723 -84.869 94.850 1.00102.72
ATOM 1275 CA PRO 282 248.996 -85.382 97.191 1.00103.42
ATOM 1276 CB PRO 282 247.908 -86.240 96.544 1.00102.65 25/39
ATOM 1277 CG PRO 282 247.445 -85.433 95.386 1.00102.39
ATOM 1278 C PRO 282 250.119 -86.260 97.739 1.00104.21
ATOM 1279 O PRO 282 250.605 -87.140 97.031 1.00104.96
ATOM 1280 N SER 283 250.518 -86.051 98.993 1.00104.57
ATOM 1281 CA SER 283 251.593 -86.858 99.570 1.00105.62
ATOM 1282 CB SER 283 252.948 -86.281 99.152 1.00106.03
ATOM 1283 OG SER 283 253.078 -84.934 99.570 1.00105.61
ATOM 1284 C SER 283 251.546 -86.983 101.091 1.00106.03
ATOM 1285 o SER 283 250.472 -87.047 101.683 1.00106.06
ATOM 1286 N SER 284 252.726 -87.045 101.707 1.00106.89
ATOM 1287 CA SER 284 252.871 -87.138 103.161 1.00107.77
ATOM 1288 CB SER 284 253.050 -88.593 103.601 1.00107.68
ATOM 1289 OG SER 284 254.275 -89.121 103.133 1.00107.98
ATOM 1290 C SER 284 254.108 -86.329 103.540 1.00108.12
ATOM 1291 O SER 284 255.155 -86.470 102.914 1.00108.63
ATOM 1292 N ARG 285 253.989 -85.483 104.559 1.00108.84
ATOM 1293 CA ARG 285 255.104 -84.637 104.979 1.00109.70
ATOM 1294 CB ARG 285 254.824 -83.996 106.340 1.00109.52
ATOM 1295 CG ARG 285 255.194 -84.884 107.500 1.00109.47
ATOM 1296 CD ARG 285 255.047 -84.173 108.817 1.00110.24
ATOM 1297 NE ARG 285 255.288 -85.097 109.927 1.00111.90
ATOM 1298 CZ ARG 285 254.537 -86.169 110.192 1.00112.06
ATOM 1299 NHl ARG 285 253.483 -86.450 109.423 1.00112.04
ATOM 1300 NH2 ARG 285 254.844 -86.969 111.218 1.00111.52
ATOM 1301 C ARG 285 256.426 -85.392 105.058 1.00110.33
ATOM 1302 o ARG 285 256.473 -86.614 104.911 1.00110.12
ATOM 1303 N ARG 286 257.495 -84.642 105.310 1.00110.80
ATOM 1304 CA ARG 286 258.840 -85.196 105.403 1.00110.25
ATOM 1305 CB ARG 286 259.760 -84.488 104.398 1.00109.35
ATOM 1306 CG ARG 286 260.084 -83.036 104.743 1.00107.08
ATOM 1307 CD ARG 286 258.858 -82.132 104.784 1.00104.58
ATOM 1308 NE ARG 286 258.414 -81.701 103.460 1.00103.10
ATOM 1309 CZ ARG 286 257.635 -82.410 102.651 1.00101.63
ATOM 1310 NHl ARG 286 257.195 -83.602 103.012 1.00100.75
ATOM 1311 NH2 ARG 286 257.286 -81.918 101.474 1.00101.68
ATOM 1312 C ARG 286 259.408 -85.057 106.818 1.00110.30
ATOM 1313 O ARG 286 259.541 -83.949 107.347 1.00109.85
ATOM 1314 N LEU 289 257.973 -83.698 112.133 1.00111.52
ATOM 1315 CA LEU 289 257.094 -82.951 113.032 1.00111.28
ATOM 1316 CB LEU 289 256.551 -83.883 114.132 1.00110.71
ATOM 1317 CG LEU 289 257.442 -84.802 114.986 1.00110.08
ATOM 1318 CDl LEU 289 258.174 -84.039 116.094 1.00108.90
ATOM 1319 CD2 LEU 289 256.542 -85.850 115.623 1.00109.89
ATOM 1320 C LEU 289 257.800 -81.740 113.652 1.00111.22
ATOM 1321 O LEU 289 258.313 -81.806 114.772 1.00111.70
ATOM 1322 N CYS 290 257.795 -80.622 112.930 1.00110.11
ATOM 1323 CA CYS 290 258.475 -79.413 113.395 1.00108.46
ATOM 1324 CB CYS 290 259.689 -79.175 112.502 1.00109.88
ATOM 1325 SG CYS 290 259.333 -79.541 110.756 1.00112.06
ATOM 1326 C CYS 290 257.639 -78.131 113.467 1.00106.04
ATOM 1327 O CYS 290 257.771 -77.249 112.617 1.00106.03
ATOM 1328 N GLY 291 256.802 -78.020 114.495 1.00102.81
ATOM 1329 CA GLY 291 255.977 -76.832 114.650 1.00 97.69
ATOM 1330 C GLY 291 254.702 -77.083 115.432 1.00 93.30
ATOM 1331 O GLY 291 254.542 -78.138 116.056 1.00 93.30
ATOM 1332 N THR 292 253.792 -76.113 115.405 1.00 88.19
ATOM 1333 CA THR 292 252.529 -76.263 116.116 1.00 82.80
ATOM 1334 CB THR 292 251.959 -74.908 116.610 1.00 83.12
ATOM 1335 OGl THR 292 250.815 -75.149 117.441 1.00 79.35
ATOM 1336 CG2 THR 292 251.554 -74.021 115.428 1.00 81.92
ATOM 1337 C THR 292 251.489 -76.938 115.230 1.00 79.07
ATOM 1338 O THR 292 251.333 -76.626 114.035 1.00 78.06
ATOM 1339 N LEU 293 250.771 -77.864 115.846 1.00 73.82 26/39
ATOM 1340 CA LEU 293 249.755 -78.632 115.160 1.00 68.88
ATOM 1341 CB LEU 293 249.445 -79.873 115.979 1.00 69.60
ATOM 1342 CG LEU 293 250.653 -80.734 116.318 1.00 69.55
ATOM 1343 CDl LEU 293 250.205 -81.924 117.141 1.00 70.47
ATOM 1344 CD2 LEU 293 251.325 -81.189 115.044 1.00 68.26
ATOM 1345 C LEU 293 248.473 -77.860 114.928 1.00 64.84
ATOM 1346 O LEU 293 247.718 -78.152 114.005 1.00 63.66
ATOM 1347 N ASP 294 248.253 -76.864 115.773 1.00 60.43
ATOM 1348 CA ASP 294 247.056 -76.053 115.741 1.00 57.24
ATOM 1349 CB ASP 294 247.343 -74.689 116.374 1.00 56.02
ATOM 1350 CG ASP 294 247.179 -74.712 117.878 1.00 55.95
ATOM 1351 ODl ASP 294 246.090 -75.099 118.348 1.00 55.74
ATOM 1352 OD2 ASP 294 248.131 -74.351 118.588 1.00 55.82
ATOM 1353 C ASP 294 246.286 -75.879 114.442 1.00 55.75
ATOM 1354 O ASP 294 245.080 -75.717 114.487 1.00 54.02
ATOM 1355 N TYR 295 246.936 -75.930 113.288 1.00 55.46
ATOM 1356 CA TYR 295 246.182 -75.743 112.059 1.00 55.28
ATOM 1357 CB TYR 295 246.687 -74.522 111.316 1.00 54.21
ATOM 1358 CG TYR 295 246.739 -73.310 112.189 1.00 53.32
ATOM 1359 CDl TYR 295 247.788 -73.125 113.077 1.00 53.51
ATOM 1360 CEl TYR 295 247.819 -72.025 113.927 1.00 54.74
ATOM 1361 CD2 TYR 295 245.715 -72.367 112.165 1.00 52.17
ATOM 1362 CE2 TYR 295 245.735 -71.271 113.006 1.00 53.49
ATOM 1363 CZ TYR 295 246.792 -71.107 113.886 1.00 54.52
ATOM 1364 OH TYR 295 246.833 -70.035 114.732 1.00 56.19
ATOM 1365 C TYR 295 246.180 -76.911 111.110 1.00 56.89
ATOM 1366 O TYR 295 245.511 -76.869 110.080 1.00 58.20
ATOM 1367 N LEU 296 246.910 -77.958 111.453 1.00 57.77
ATOM 1368 CA LEU 296 246.997 -79.111 110.581 1.00 59.71
ATOM 1369 CB LEU 296 248.357 -79.764 110.766 1.00 59.17
ATOM 1370 CG LEU 296 249.405 -78.653 110.770 1.00 58.53
ATOM 1371 CDl LEU 296 250.762 -79.236 111.136 1.00 58.66
ATOM 1372 CD2 LEU 296 _ 249.414 -77.940 109.408 1.00 56.83
ATOM 1373 C LEU 296 245.882 -80.097 110.840 1.00 61.42
ATOM 1374 O LEU 296 245.522 -80.351 111.986 1.00 62.52
ATOM 1375 N PRO 297 245.312 -80.668 109.766 1.00 62.66
ATOM 1376 CD PRO 297 245.626 -80.369 108.356 1.00 62.05
ATOM 1377 CA PRO 297 244.217 -81.636 109.865 1.00 64.13
ATOM 1378 CB PRO 297 243.661 -81.670 108.441 1.00 62.14
ATOM 1379 CG PRO 297 244.877 -81.447 107.615 1.00 62.17
ATOM 1380 C PRO 297 244.634 -83.010 110.382 1.00 65.72
ATOM 1381 O PRO 297 245.824 -83.306 110.498 1.00 64.69
ATOM 1382 N PRO 298 243.650 -83.868 110.709 1.00 67.44
ATOM 1383 CD PRO 298 242.200 -83.608 110.619 1.00 67.71
ATOM 1384 CA PRO 298 243.909 -85.217 111.221 1.00 68.43
ATOM 1385 CB PRO 298 242.504 -85.825 111.316 1.00 68.19
ATOM 1386 CG PRO 298 241.634 -84.632 111.569 1.00 67.69
ATOM 1387 C PRO 298 244.836 -86.048 110.319 1.00 69.15
ATOM 1388 O PRO 298 245.723 -86.752 110.815 1.00 67.93
ATOM 1389 N GLU 299 244.628 -85.959 109.005 1.00 70.19
ATOM 1390 CA GLU 299 245.435 -86.716 108.055 1.00 72.15
ATOM 1391 CB GLU 299 244.933 -86.515 106.622 1.00 72.22
ATOM 1392 CG GLU 299 244.791 -85.073 106.190 1.00 71.78
ATOM 1393 CD GLU 299 243.383 -84.563 106.369 1.00 71.98
ATOM 1394 OEl GLU 299 242.862 -84.641 107.501 1.00 71.42
ATOM 1395 OE2 GLU 299 242.799 -84.086 105.376 1.00 72.71
ATOM 1396 C GLU 299 246.918 -86.385 108.123 1.00 73.75
ATOM 1397 O GLU 299 247.751 -87.285 108.192 1.00 73.59
ATOM 1398 N MET 300 247.266 -85.104 108.086 1.00 75.58
ATOM 1399 CA MET 300 248.672 -84.754 108.173 1.00 77.81
ATOM 1400 CB MET 300 248.868 -83.262 107.906 1.00 77.45
ATOM 1401 CG MET 300 249.680 -82.989 106.654 1.00 77.40
ATOM 1402 SD MET 300 249.836 -81.254 106.275 1.00 79.23 27/39
ATOM 1403 CE MET 300 251.284 -80.813 107.233 1.00 77.99
ATOM 1404 C MET 300 249.167 -85.143 109.571 1.00 79.65
ATOM 1405 O MET 300 250.229 -85.747 109.725 1.00 80.09
ATOM 1406 N ILE 301 248.371 -84.807 110.580 1.00 81.87
ATOM 1407 CA ILE 301 248.669 -85.122 111.976 1.00 84.08
ATOM 1408 CB ILE 301 247.382 -84.913 112.859 1.00 86.05
ATOM 1409 CG2 ILE 301 247.217 -86.047 113.878 1.00 85.70
ATOM 1410 CGl ILE 301 247.429 -83.542 113.550 1.00 87.50
ATOM 1411 CD ILE 301 248.077 -83.540 114.942 1.00 87.47
ATOM 1412 C ILE 301 249.170 -86.560 112.133 1.00 84.92
ATOM 1413 O ILE 301 250.076 -86.824 112.930 1.00 84.08
ATOM 1414 N GLU 302 248.585 -87.473 111.355 1.00 85.75
ATOM 1415 CA GLU 302 248.925 -88.895 111.411 1.00 86.58
ATOM 1416 CB GLU 302 247.636 -89.697 111.625 1.00 86.17
ATOM 1417 CG GLU 302 246.849 -89.266 112.857 1.00 86.27
ATOM 1418 CD GLU 302 245.371 -89.637 112.785 1.00 87.16
ATOM 1419 OEl GLU 302 244.714 -89.269 111.788 1.00 88.10
ATOM 1420 OE2 GLU 302 244.859 -90.285 113.725 1.00 86.88
ATOM 1421 C GLU 302 249.686 -89.448 110.187 1.00 87.58
ATOM 1422 O GLU 302 249.527 -90.617 109.826 1.00 87.63
ATOM 1423 N GLY 303 250.503 -88.618 109.545 1.00 88.25
ATOM 1424 CA GLY 303 251.264 -89.076 108.391 1.00 88.89
ATOM 1425 C GLY 303 250.494 -89.702 107.232 1.00 89.51
ATOM 1426 O GLY 303 251.104 -90.210 106.291 1.00 90.28
ATOM 1427 N ARG 304 249.167 -89.686 107.284 1.00 89.47
ATOM 1428 CA ARG 304 248.378 -90.243 106.195 1.00 88.97
ATOM 1429 CB ARG 304 246.902 -90.290 106.576 1.00 88.78
ATOM 1430 CG ARG 304 246.595 -91.265 107.699 1.00 90.13
ATOM 1431 CD ARG 304 245.144 -91.709 107.639 1.00 92.56
ATOM 1432 NE ARG 304 244.237 -90.756 108.270 1.00 95.35
ATOM 1433 CZ ARG 304 243.869 -90.817 109.547 1.00 97.19
ATOM 1434 NHl ARG 304 244.335 -91.792 110.321 1.00 97.68
ATOM 1435 NH2 ARG 304 243.034 -89-.909 110.051 1.00 97.02
ATOM 1436 C ARG 304 248.576 -89.351 104.985 1.00 89.34
ATOM 1437 O ARG 304 249.094 -88.246 105.116 1.00 89.85
ATOM 1438 N MET 305 248.187 -89.824 103.806 1.00 90.09
ATOM 1439 CA MET 305 248.343 -89.020 102.596 1.00 89.98
ATOM 1440 CB MET 305 248.081 -89.854 101.332 1.00 92.12
ATOM 1441 CG MET 305 249.238 -90.779 100.908 1.00 95.52
ATOM 1442 SD MET 305 249.330 -92.406 101.775 1.00 99.71
ATOM 1443 CE MET 305 250.487 -92.011 103.219 1.00 99.55
ATOM 1444 C MET 305 247.354 -87.867 102.673 1.00 88.58
ATOM 1445 O MET 305 246.270 -88.021 103.237 1.00 88.72
ATOM 1446 N HIS 306 247.728 -86.714 102.119 1.00 86.78
ATOM 1447 CA HIS 306 246.861 -85.538 102.150 1.00 84.30
ATOM 1448 CB HIS 306 247.338 -84.570 103.235 1.00 82.63
ATOM 1449 CG HIS 306 248.782 -84.170 103.117 1.00 80.17
ATOM 1450 CD2 HIS 306 249.364 -83.078 102.564 1.00 79.40
ATOM 1451 NDl HIS 306 249.809 -84.916 103.656 1.00 79.22
ATOM 1452 CEl HIS 306 250.958 -84.299 103.446 1.00 78.33
ATOM 1453 NE2 HIS 306 250.715 -83.182 102.786 1.00 78.32
ATOM 1454 C HIS 306 246.753 -84.791 100.821 1.00 83.63
ATOM 1455 O HIS 306 247.663 -84.854 99.994 1.00 84.31
ATOM 1456 N ASP 307 245.639 -84.085 100.622 1.00 82.20
ATOM 1457 CA ASP 307 245.429 -83.311 99.399 1.00 80.75
ATOM 1458 CB ASP 307 244.422 -84.024 98.485 1.00 81.37
ATOM 1459 CG ASP 307 243.017 -84.062 99.057 1.00 81.90
ATOM 1460 ODl ASP 307 242.827 -84.624 100.154 1.00 81.75
ATOM 1461 OD2 ASP 307 242.094 -83.533 98.399 1.00 82.67
ATOM 1462 C ASP 307 244.962 -81.882 99.717 1.00 79.86
ATOM 1463 O ASP 307 245.052 -81.441 100.861 1.00 79.87
ATOM 1464 N GLU 308 244.471 -81.161 98.708 1.00 78.34
ATOM 1465 CA GLU 308 244.005 -79.780 98.887 1.00 76.83 28/39
ATOM 1466 CB GLU 308 243.340 -79.253 97.612 1.00 77.53
ATOM 1467 CG GLU 308 244.245 -79.123 96.408 1.00 78.69
ATOM 1468 CD GLU 308 244.273 -80.368 95.544 1.00 79.79
ATOM 1469 OEl GLU 308 244.913 -80.319 94.471 1.00 78.73
ATOM 1470 OE2 GLU 308 243.657 -81.387 95.931 1.00 79.04
ATOM 1471 C GLU 308 243.023 -79.587 100.034 1.00 75.24
ATOM 1472 O GLU 308 242.739 -78.456 100.429 1.00 74.26
ATOM 1473 N LYS 309 242.490 -80.683 100.555 1.00 73.26
ATOM 1474 CA LYS 309 241.534 -80.588 101.645 1.00 71.90
ATOM 1475 CB LYS 309 240.781 -81.918 101.811 1.00 72.64
ATOM 1476 CG LYS 309 239.648 -82.144 100.791 1.00 73.16
ATOM 1477 CD LYS 309 238.423 -81.273 101.090 1.00 74.08
ATOM 1478 CE LYS 309 237.280 -81.487 100.086 1.00 73.45
ATOM 1479 NZ LYS 309 237.574 -80.977 98.712 1.00 73.58
ATOM 1480 C LYS 309 242.161 -80.154 102.972 1.00 70.22
ATOM 1481 O LYS 309 241.442 -79.752 103.882 1.00 70.01
ATOM 1482 N VAL 310 243.489 -80.222 103.088 1.00 68.01
ATOM 1483 CA VAL 310 244.153 -79.805 104.328 1.00 65.68
ATOM 1484 CB VAL 310 245.701 -79.971 104.276 1.00 65.57
ATOM 1485 CGl VAL 310 246.071 -81.394 103.945 1.00 66.23
ATOM 1486 CG2 VAL 310 246.293 -79.028 103.270 1.00 66.11
ATOM 1487 C VAL 310 243.859 -78.327 104.575 1.00 64.15
ATOM 1488 O VAL 310 243.553 -77.922 105.704 1.00 63.22
ATOM 1489 N ASP 311 243.947 -77.539 103.503 1.00 61.45
ATOM 1490 CA ASP 311 243.705 -76.111 103.556 1.00 59.45
ATOM 1491 CB ASP 311 244.073 -75.475 102.214 1.00 59.71
ATOM 1492 CG ASP 311 245.557 -75.593 101.900 1.00 60.33
ATOM 1493 ODl ASP 311 246.391 -75.208 102.746 1.00 60.22
ATOM 1494 OD2 ASP 311 245.900 -76.066 100.801 1.00 63.00
ATOM 1495 C ASP 311 242.273 -75.741 103.941 1.00 59.22
ATOM 1496 O ASP 311 242.040 -74.684 104.525 1.00 59.75
ATOM ' 1497 N LEU 312 241.301 -76.591 103.632 1.00 57.50
ATOM 1498 CA LEU 312 . 239.930 -76.255 104.008 I.ΌO 55.55
ATOM 1499 CB LEU 312 238.919 -76.979 103.113 1.00 55.94
ATOM 1500 CG LEU 312 238.902 -76.152 101.816 1.00 57.13
ATOM 1501 CDl LEU 312 239.775 -76.812 100.750 1.00 55.47
ATOM 1502 CD2 LEU 312 237.478 -75.966 101.346 1.00 57.88
ATOM 1503 C LEU 312 239.705 -76.530 105.476 1.00 53.18
ATOM 1504 O LEU 312 238.809 -75.983 106.094 1.00 52.93
ATOM 1505 N TRP 313 240.559 -77.369 106.035 1.00 51.94
ATOM 1506 CA TRP 313 240.512 -77.665 107.453 1.00 51.52
ATOM 1507 CB TRP 313 241.296 -78.946 107.752 1.00 50.67
ATOM 1508 CG TRP 313 241.538 -79.179 109.208 1.00 48.97
ATOM 1509 CD2 TRP 313 240.733 -79.966 110.097 1.00 49.18
ATOM 1510 CE2 TRP 313 241.317 -79.877 111.376 1.00 48.19
ATOM 1511 CE3 TRP 313 239.571 -80.736 109.936 1.00 48.33
ATOM 1512 CDl TRP 313 242.543 -78.661 109.959 1.00 48.21
ATOM 1513 NEl TRP 313 242.420 -79.073 111.264 1.00 49.95
ATOM 1514 CZ2 TRP 313 240.781 -80.527 112.491 1.00 47.49
ATOM 1515 CZ3 TRP 313 239.041 -81.383 111.046 1.00 46.72
ATOM 1516 CH2 TRP 313 239.645 -81.273 112.305 1.00 47.70
ATOM 1517 C TRP 313 241.153 -76.458 108.154 1.00 51.48
ATOM 1518 O TRP 313 240.625 -75.957 109.148 1.00 51.02
ATOM 1519 N SER 314 242.286 -75.993 107.618 1.00 50.52
ATOM 1520 CA SER 314 242.989 -74.835 108.159 1.00 50.20
ATOM 1521 CB SER 314 244.231 -74.539 107.320 1.00 49.42
ATOM 1522 OG SER 314 245.261 -75.474 107.570 1.00 50.84
ATOM 1523 C SER 314 242.076 -73.601 108.172 1.00 50.76
ATOM 1524 O SER 314 242.053 -72.825 109.135 1.00 50.59
ATOM 1525 N LEU 315 241.338 -73.442 107.079 1.00 50.56
ATOM 1526 CA LEU 315 240.387 -72.352 106.872 1.00 49.70
ATOM 1527 CB LEU 315 239.750 -72.529 105.502 1.00 50.77
ATOM 1528 CG LEU 315 239.153 -71.338 104.770 1.00 51.51 29/39
ATOM 1529 CDl LEU 315 240.116 -70.178 104.789 1.00 53.34
ATOM 1530 CD2 LEU 315 238.864 -71.761 103.337 1.00 50.45
ATOM 1531 C LEU 315 239.316 -72.395 107.958 1.00 49.81
ATOM 1532 O LEU 315 238.821 -71.361 108.416 1.00 49.27
ATOM 1533 N GLY 316 238.961 -73.613 108.357 1.00 49.52
ATOM 1534 CA GLY 316 237.974 -73.808 109.399 1.00 49.40
ATOM 1535 C GLY 316 238.569 -73.432 110.741 1.00 48.75
ATOM 1536 O GLY 316 237.887 -72.875 111.591 1.00 49.19
ATOM 1537 N VAL 317 239.849 -73.743 110.932 1.00 48.24
ATOM 1538 CA VAL 317 240.540 -73.416 112.176 1.00 46.73
ATOM 1539 CB VAL 317 241.912 -74.139 112.257 1.00 45.75
ATOM 1540 CGl VAL 317 242.597 -73.856 113.599 1.00 45.08
ATOM 1541 CG2 VAL 317 241.706 -75.605 112.081 1.00 42.71
ATOM 1542 C VAL 317 240.736 -71.901 112.215 1.00 45.19
ATOM 1543 O VAL 317 240.627 -71.284 113.263 1.00 43.38
ATOM 1544 N LEU 318 241.011 -71.319 111.054 1.00 44.72
ATOM 1545 CA LEU 318 241.198 -69.888 110.938 1.00 45.98
ATOM 1546 CB LEU 318 241.605 -69.505 109.534 1.00 44.98
ATOM 1547 CG LEU 318 242.960 -68.832 109.406 1.00 48.89
ATOM 1548 CDl LEU 318 243.765 -68.897 110.703 1.00 47.66
ATOM 1549 CD2 LEU 318 243.695 -69.544 108.290 1.00 51.21
ATOM 1550 C LEU 318 239.911 -69.186 111.247 1.00 48.45
ATOM 1551 O LEU 318 239.861 -68.337 112.140 1.00 49.05
ATOM 1552 N CYS 319 238.858 -69.538 110.511 1.00 49.37
ATOM 1553 CA CYS 319 237.574 -68.889 110.724 1.00 49.19
ATOM 1554 CB CYS 319 236.479 -69.557 109.891 1.00 49.31
ATOM 1555 SG CYS 319 234.891 -68.671 109.914 1.00 50.58
ATOM 1556 C CYS 319 237.212 -68.905 112.204 1.00 48.98
ATOM 1557 O CYS 319 236.698 -67.922 112.735 1.00 50.43
ATOM 1558 N TYR 320 237.507 -70.010 112.875 1.00 47.53
ATOM 1559 CA TYR 320 237.205 -70.118 114.287 1.00 47.80
ATOM 1560 CB TYR 320 237.444 -71.556 114.765 1.00 45.75
ATOM 1561 CG TYR 320 237.108 -71.814 116.229 1.00 44.39
ATOM 1562 CDl TYR 320 237.800 -71.165 117.269 1.00 42.86
ATOM 1563 CEl TYR 320 237.525 -71.444 118.604 1.00 42.57
ATOM 1564 CD2 TYR 320 236.130 -72.742 116.576 1.00 44.59
ATOM 1565 CE2 TYR 320 235.850 -73.033 117.912 1.00 44.82
ATOM 1566 CZ TYR 320 236.551 -72.384 118.919 1.00 45.21
ATOM 1567 OH TYR 320 236.277 -72.711 120.226 1.00 42.98
ATOM 1568 C TYR 320 238.044 -69.137 115.109 1.00 49.72
ATOM 1569 O TYR 320 237.511 -68.381 115.936 1.00 50.01
ATOM 1570 N GLU 321 239.354 -69.150 114.873 1.00 50.26
ATOM 1571 CA GLU 321 240.285 -68.282 115.595 1.00 50.64
ATOM 1572 CB GLU 321 241.710 -68.503 115.107 1.00 51.33
ATOM 1573 CG GLU 321 242.700 -68.258 116.197 1.00 53.60
ATOM 1574 CD GLU 321 244.127 -68.331 115.730 1.00 56.19
ATOM 1575 OEl GLU 321 244.465 -69.241 114.938 1.00 55.39
ATOM 1576 OE2 GLU 321 244.917 -67.474 116.178 1.00 59.23
ATOM 1577 C GLU 321 239.954 -66.798 115.478 1.00 49.07
ATOM 1578 O GLU 321 240.032 -66.050 116.454 1.00 47.45
ATOM 1579 N PHE 322 239.596 -66.389 114.267 1.00 48.18
ATOM 1580 CA PHE 322 239.236 -65.011 113.988 1.00 48.10
ATOM 1581 CB PHE 322 238.814 -64.856 112.527 1.00 46.32
ATOM 1582 CG PHE 322 239.956 -64.886 111.549 1.00 44.50
ATOM 1583 CDl PHE 322 241.275 -64.804 111.992 1.00 42.28
ATOM 1584 CD2 PHE 322 239.708 -64.979 110.173 1.00 43.09
ATOM 1585 CEl PHE 322 242.330 -64.814 111.092 1.00 41.49
ATOM 1586 CE2 PHE 322 240.771 -64.991 109.241 1.00 41.28
ATOM 1587 CZ PHE 322 242.080 -64.907 109.702 1.00 42.51
ATOM 1588 C PHE 322 238.113 -64.488 114.878 1.00 49.59
ATOM 1589 O PHE 322 238.156 -63.349 115.314 1.00 50.69
ATOM 1590 N LEU 323 237.114 -65.319 115.147 1.00 49.49
ATOM 1591 CA LEU 323 235.981 -64.906 115.960 1.00 49.40 30/39
ATOM 1592 CB LEU 323 234.700 -65.569 115.447 1.00 49.24
ATOM 1593 CG LEU 323 234.248 -65.356 113.998 1.00 50.16
ATOM 1594 CDl LEU 323 233.303 -66.465 113.617 1.00 48.79
ATOM 1595 CD2 LEU 323 233.599 -63.999 113.815 1.00 49.28
ATOM 1596 C LEU 323 236.121 -65.206 117.445 1.00 50.75
ATOM 1597 O LEU 323 235.620 -64.455 118.280 1.00 51.81
ATOM 1598 N VAL 324 236.803 -66.294 117.788 1.00 52.07
ATOM 1599 CA VAL 324 236.942 -66.672 119.191 1.00 50.75
ATOM 1600 CB VAL 324 236.926 -68.195 119.328 1.00 50.25
ATOM 1601 CGl VAL 324 236.905 -68.586 120.779 1.00 50.68
ATOM 1602 CG2 VAL 324 235.717 -68.751 118.611 1.00 48.64
ATOM 1603 C VAL 324 238.172 -66.101 119.887 1.00 50.73
ATOM 1604 O VAL 324 238.167 -65.897 121.097 1.00 50.44
ATOM 1605 N GLY 325 239.221 -65.829 119.126 1.00 50.71
ATOM 1606 CA GLY 325 240.420 -65.272 119.727 1.00 51.08
ATOM 1607 C GLY 325 241.603 -66.220 119.827 1.00 51.39
ATOM 1608 O GLY 325 242.708 -65.803 120.120 1.00 51.17
ATOM 1609 N LYS 326 241.364 -67.505 119.612 1.00 52.08
ATOM 1610 CA LYS 326 242.422 -68.503 119.644 1.00 52.91
ATOM 1611 CB LYS 326 242.848 -68.798 121.096 1.00 54.64
ATOM 1612 CG LYS 326 241.761 -69.276 122.021 1.00 55.79
ATOM 1613 CD LYS 326 242.312 -69.391 123.424 1.00 58.03
ATOM 1614 CE LYS 326 241.459 -70.314 124.277 1.00 61.96
ATOM 1615 NZ LYS 326 240.007 -69.943 124.268 1.00 62.82
ATOM 1616 C LYS 326 241.879 -69.738 118.927 1.00 50.93
ATOM 1617 O LYS 326 240.664 -69.872 118.789 1.00 49.16
ATOM 1618 N PRO 327 242.773 -70.642 118.460 1.00 50.12
ATOM 1619 CD PRO 327 244.194 -70.633 118.845 1.00 50.28
ATOM 1620 CA PRO 327 242.454 -71.882 117.733 1.00 48.95
ATOM 1621 CB PRO 327 243.815 -72.533 117.494 1.00 48.82
ATOM 1622 CG PRO 327 244.808 -71.430 117.730 1.00 50.41
ATOM 1623 C PRO 327 241.564 -72.796 118.525 1.00 48.71
ATOM 1624 O PRO 327 241.705 -72.890 119.746 1.00 49.30
ATOM 1625 N PRO 328 240.653 -73.502 117.834 1.00 47.95
ATOM 1626 CD PRO 328 240.451 -73.424 116.377 1.00 46.93
ATOM 1627 CA PRO 328 239.698 -74.440 118.432 1.00 48.89
ATOM 1628 CB PRO 328 238.811 -74.813 117.257 1.00 46.81
ATOM 1629 CG PRO 328 239.709 -74.684 116.099 1.00 46.90
ATOM 1630 C PRO 328 240.284 -75.672 119.101 1.00 50.55
ATOM 1631 O PRO 328 239.610 -76.322 119.886 1.00 53.18
ATOM 1632 N PHE 329 241.532 -75.997 118.799 1.00 52.23
ATOM 1633 CA PHE 329 242.149 -77.195 119.361 1.00 53.48
ATOM 1634 CB PHE 329 242.607 -78.106 118.225 1.00 52.65
ATOM 1635 CG PHE 329 241.512 -78.488 117.279 1.00 51.41
ATOM 1636 CDl PHE 329 240.470 -79.316 117.699 1.00 51.02
ATOM 1637 CD2 PHE 329 241.516 -78.023 115.967 1.00 50.85
ATOM 1638 CEl PHE 329 239.434 -79.683 116.817 1.00 53.08
ATOM 1639 CE2 PHE 329 240.492 -78.379 115.072 1.00 52.23
ATOM 1640 CZ PHE 329 239.447 -79.212 115.494 1.00 52.70
ATOM 1641 C PHE 329 243.315 -76.896 120.281 1.00 54.28
ATOM 1642 o PHE 329 243.993 -77.803 120.761 1.00 52.69
ATOM 1643 N GLU 330 243.526 -75.611 120.531 1.00 56.33
ATOM 1644 CA GLU 330 244.612 -75.158 121.386 1.00 58.27
ATOM 1645 CB GLU 330 244.503 -73.656 121.621 1.00 58.10
ATOM 1646 CG GLU 330 245.744 -73.095 122.275 1.00 60.76
ATOM 1647 CD GLU 330 245.495 -71.791 122.989 1.00 63.48
ATOM 1648 OEl GLU 330 246.033 -70.746 122.535 1.00 64.95
ATOM 1649 OE2 GLU 330 244.754 -71.822 124.004 1.00 63.77
ATOM 1650 C GLU 330 244.660 -75.861 122.741 1.00 59.33
ATOM 1651 O GLU 330 243.746 -75.742 123.546 1.00 59.64
ATOM 1652 N ALA 331 245.732 -76.598 122.989 1.00 60.28
ATOM 1653 CA ALA 331 245.901 -77.290 124.258 1.00 60.14
ATOM 1654 CB ALA 331 245.848 -78.800 124.050 1.00 59.57 31/39
ATOM 1655 C ALA 331 247.258 -76.852 124.794 1.00 60.06
ATOM 1656 O ALA 331 247.950 -76.068 124.150 1.00 59.56
ATOM 1657 N ASN 332 247.651 -77.333 125.965 1.00 60.80
ATOM 1658 CA ASN 332 248.937 -76.904 126.507 1.00 62.00
ATOM 1659 CB ASN 332 248.872 -76.813 128.037 1.00 62.66
ATOM 1660 CG ASN 332 248.428 -75.442 128.507 1.00 64.84
ATOM 1661 ODl ASN 332 249.072 -74.430 128.208 1.00 65.00
ATOM 1662 ND2 ASN 332 247.320 -75.396 129.232 1.00 65.65
ATOM 1663 C ASN 332 250.115 -77.757 126.084 1.00 61.58
ATOM 1664 O ASN 332 251.259 -77.306 126.129 1.00 61.54
ATOM 1665 N THR 333 249.833 -78.981 125.656 1.00 61.25
ATOM 1666 CA THR 333 250.888 -79.879 125.242 1.00 61.33
ATOM 1667 CB THR 333 251.013 -81.093 126.210 1.00 60.98
ATOM 1668 OGl THR 333 249.983 -82.048 125.936 1.00 57.75
ATOM 1669 CG2 THR 333 250.886 -80.629 127.665 1.00 61.45
ATOM 1670 C THR 333 250.645 -80.375 123.827 1.00 62.11
ATOM 1671 O THR 333 249.512 -80.471 123.370 1.00 61.46
ATOM 1672 N TYR 334 251.737 -80.663 123.133 1.00 63.77
ATOM 1673 CA TYR 334 251.691 -81.158 121.772 1.00 64.95
ATOM 1674 CB TYR 334 253.117 -81.459 121.292 1.00 65.04
ATOM 1675 CG TYR 334 253.224 -82.134 119.942 1.00 63.89
ATOM 1676 CDl TYR 334 253.622 -81.418 118.817 1.00 64.00
ATOM 1677 CEl TYR 334 253.728 -82.030 117.577 1.00 64.44
ATOM 1678 CD2 TYR 334 252.931 -83.490 119.792 1.00 62.69
ATOM 1679 CE2 TYR 334 253.031 -84.110 118.555 1.00 63.30
ATOM 1680 CZ TYR 334 253.433 -83.373 117.453 1.00 64.22
ATOM 1681 OH TYR 334 253.559 -83.977 116.226 1.00 66.25
ATOM 1682 C TYR 334 250.876 -82.423 121.855 1.00 66.13
ATOM 1683 O TYR 334 250.151 -82.779 120.927 1.00 67.29
ATOM 1684 N GLN 335 251.004 -83.088 122.997 1.00 67.01
ATOM 1685 CA GLN 335 250.290 -84.327 123.268 1.00 67.85
ATOM 1686 CB GLN 335 250.767 -84.916 124.608 1.00 68.78
ATOM 1687 CG GLN 335 252.093 -85.690 124.524 1.00 69.78
ATOM 1688 CD GLN 335 253.335 -84.808 124.517 1.00 70.20
ATOM 1689 OEl GLN 335 254.288 -85.081 123.792 1.00 70.06
ATOM 1690 NE2 GLN 335 253.338 -83.762 125.344 1.00 69.82
ATOM 1691 C GLN 335 248.749 -84.171 123.250 1.00 67.46
ATOM 1692 O GLN 335 248.078 -84.832 122.451 1.00 67.42
ATOM 1693 N GLU 336 248.187 -83.309 124.106 1.00 67.15
ATOM 1694 CA GLU 336 246.736 -83.118 124.124 1.00 66.64
ATOM 1695 CB GLU 336 246.277 -82.386 125.401 1.00 68.32
ATOM 1696 CG GLU 336 247.115 -81.171 125.841 1.00 74.34
ATOM 1697 CD GLU 336 246.588 -80.487 127.138 1.00 77.45
ATOM 1698 OEl GLU 336 245.480 -79.884 127.102 1.00 74.55
ATOM 1699 OE2 GLU 336 247.291 -80.556 128.189 1.00 79.13
ATOM 1700 C GLU 336 246.198 -82.414 122.867 1.00 65.28
ATOM 1701 O GLU 336 245.081 -82.699 122.422 1.00 64.48
ATOM 1702 N THR 337 246.986 -81.515 122.278 1.00 63.10
ATOM 1703 CA THR 337 246.543 -80.831 121.070 1.00 59.88
ATOM 1704 CB THR 337 247.599 -79.848 120.552 1.00 59.01
ATOM 1705 OGl THR 337 247.772 -78.793 121.504 1.00 59.30
ATOM 1706 CG2 THR 337 247.166 -79.254 119.213 1.00 56.00
ATOM 1707 C THR 337 246.298 -81.876 119.998 1.00 59.68
ATOM 1708 O THR 337 245.350 -81.770 119.212 1.00 58.75
ATOM 1709 N TYR 338 247.164 -82.888 119.987 1.00 59.33
ATOM 1710 CA TYR 338 247.092 -83.982 119.026 1.00 59.09
ATOM 1711 CB TYR 338 248.218 -84.983 119.276 1.00 60.52
ATOM 1712 CG TYR 338 248.208 -86.163 118.333 1.00 62.74
ATOM 1713 CDl TYR 338 249.074 -86.214 117.246 1.00 63.94
ATOM 1714 CEl TYR 338 249.048 -87.286 116.356 1.00 66.92
ATOM 1715 CD2 TYR 338 247.311 -87.221 118.511 1.00 63.68
ATOM 1716 CE2 TYR 338 247.274 -88.300 117.624 1.00 64.98
ATOM 1717 CZ TYR 338 248.144 -88.325 116.548 1.00 67.58 32/39
ATOM 1718 OH TYR 338 248.109 -89.374 115.654 1.00 70.62
ATOM 1719 C TYR 338 245.761 -84.703 119.110 1.00 58.47
ATOM 1720 O TYR 338 245.096 -84.897 118.089 1.00 57.16
ATOM 1721 N LYS 339 245.368 -85.106 120.318 1.00 58.48
ATOM 1722 CA LYS 339 244.099 -85.817 120.474 1.00 59.07
ATOM 1723 CB LYS 339 244.020 -86.502 121.846 1.00 62.48
ATOM 1724 CG LYS 339 244.161 -85.570 123.010 1.00 68.09
ATOM 1725 CD LYS 339 244.181 -86.324 124.322 1.00 71.72
ATOM 1726 CE LYS 339 244.317 -85.342 125.481 1.00 75.93
ATOM 1727 NZ LYS 339 244.364 -86.044 126.796 1.00 77.98
ATOM 1728 C LYS 339 242.880 -84.918 120.217 1.00 56.00
ATOM 1729 O LYS 339 241.925 -85.349 119.589 1.00 54.96
ATOM 1730 N ARG 340 242.928 -83.667 120.660 1.00 54.70
ATOM 1731 CA ARG 340 241.832 -82.724 120.407 1.00 54.33
ATOM 1732 CB ARG 340 242.180 -81.335 120.962 1.00 54.76
ATOM 1733 CG ARG 340 242.423 -81.258 122.478 1.00 57.48
ATOM 1734 CD ARG 340 241.139 -81.064 123.268 1.00 59.18
ATOM 1735 NE ARG 340 240.366 -79.934 122.746 1.00 64.42
ATOM 1736 CZ ARG 340 240.660 -78.648 122.941 1.00 65.98
ATOM 1737 NHl ARG 340 241.717 -78.300 123.660 1.00 68.79
ATOM 1738 NH2 ARG 340 239.898 -77.705 122.405 1.00 65.53
ATOM 1739 C ARG 340 241.587 -82.620 118.885 1.00 53.50
ATOM 1740 O ARG 340 240.457 -82.439 118.434 1.00 52.13
ATOM 1741 N ILE 341 242.659 -82.730 118.103 1.00 53.62
ATOM 1742 CA ILE 341 242.571 -82.654 116.640 1.00 53.86
ATOM 1743 CB ILE 341 243.947 -82.259 116.020 1.00 52.87
ATOM 1744 CG2 ILE 341 243.953 -82.542 114.535 1.00 53.27
ATOM 1745 CGl ILE 341 244.227 -80.771 116.242 1.00 52.97
ATOM 1746 CD ILE 341 245.700 -80.402 116.212 1.00 52.72
ATOM 1747 C ILE 341 242.139 -84.002 116.060 1.00 54.45
ATOM 1748 O ILE 341 241.304 -84.084 115.157 1.00 53.33
ATOM 1749 N SER 342 242.730 -85.063 116.584 1.00 55.84
ATOM 1750 CA SER 342 242.409 -86.395 116.121 1.00 57.16
ATOM 1751 CB SER 342 243.295 -87.419 116.837 1.00 57.60
ATOM 1752 OG SER 342 243.164 -88.689 116.225 1.00 59.71
ATOM 1753 C SER 342 240.924 -86.706 116.350 1.00 56.84
ATOM 1754 O SER 342 240.307 -87.428 115.570 1.00 58.26
ATOM 1755 N ARG 343 240.345 -86.144 117.405 1.00 56.29
ATOM 1756 CA ARG 343 238.937 -86.382 117.710 1.00 56.52
ATOM 1757 CB ARG 343 238.808 -86.765 119.170 1.00 55.51
ATOM 1758 CG ARG 343 239.626 -87.979 119.498 1.00 54.92
ATOM 1759 CD ARG 343 239.893 -88.091 120.955 1.00 52.30
ATOM 1760 NE ARG 343 240.849 -89.155 121.178 1.00 53.24
ATOM 1761 CZ ARG 343 241.260 -89.540 122.374 1.00 55.40
ATOM 1762 NHl ARG 343 240.787 -88.933 123.458 1.00 54.59
ATOM 1763 NH2 ARG 343 242.129 -90.538 122.482 1.00 53.78
ATOM 1764 C ARG 343 238.008 -85.213 117.407 1.00 56.86
ATOM 1765 O ARG 343 236.815 -85.281 117.680 1.00 57.59
ATOM 1766 N VAL 344 238.564 -84.149 116.836 1.00 56.99
ATOM 1767 CA VAL 344 237.810 -82.952 116.474 1.00 56.23
ATOM 1768 CB VAL 344 236.860 -83.265 115.264 1.00 56.01
ATOM 1769 CGl VAL 344 236.402 -81.977 114.584 1.00 52.84
ATOM 1770 CG2 VAL 344 237.587 -84.161 114.250 1.00 54.96
ATOM 1771 C VAL 344 237.038 -82.435 117.701 1.00 56.43
ATOM 1772 O VAL 344 235.849 -82.180 117.654 1.00 56.54
ATOM 1773 N GLU 345 237.757 -82.272 118.800 1.00 56.88
ATOM 1774 CA GLU 345 237.190 -81.809 120.057 1.00 56.99
ATOM 1775 CB GLU 345 237.983 -82.403 121.220 1.00 58.38
ATOM 1776 CG GLU 345 237.184 -83.255 122.177 1.00 61.03
ATOM 1777 CD GLU 345 238.071 -84.208 122.949 1.00 62.64
ATOM 1778 OEl GLU 345 238.760 -85.026 122.304 1.00 60.22
ATOM 1779 OE2 GLU 345 238.083 -84.135 124.195 1.00 63.65
ATOM 1780 C GLU 345 237.171 -80.300 120.210 1.00 56.42 33/39
ATOM 1781 O GLU 345 238.058 -79.731 120.844 1.00 55.91
ATOM 1782 N PHE 346 236.157 -79.649 119.652 1.00 56.51
ATOM 1783 CA PHE 346 236.044 -78.196 119.779 1.00 56.89
ATOM 1784 CB PHE 346 236.476 -77.531 118.471 1.00 55.86
ATOM 1785 CG PHE 346 235.447 -77.602 117.383 1.00 55.10
ATOM 1786 CDl PHE 346 234.483 -76.604 117.260 1.00 55.18
ATOM 1787 CD2 PHE 346 235.430 -78.676 116.483 1.00 55.97
ATOM 1788 CEl PHE 346 233.512 -76.666 116.258 1.00 55.76
ATOM 1789 CE2 PHE 346 234.461 -78.754 115.469 1.00 54.98
ATOM 1790 CZ PHE 346 233.496 -77.743 115.356 1.00 55.96
ATOM 1791 C PHE 346 234.627 -77.739 120.180 1.00 56.29
ATOM 1792 O PHE 346 233.639 -78.411 119.889 1.00 54.94
ATOM 1793 N THR 347 234.547 -76.604 120.872 1.00 57.28
ATOM 1794 CA THR 347 233.267 -76.031 121.309 1.00 56.79
ATOM 1795 CB THR 347 232.986 -76.340 122.807 1.00 56.51
ATOM 1796 OGl THR 347 234.164 -76.104 123.587 1.00 54.34
ATOM 1797 CG2 THR 347 232.556 -77.790 122.973 1.00 55.18
ATOM 1798 C THR 347 233.201 -74.514 121.076 1.00 56.79
ATOM 1799 O THR 347 234.182 -73.796 121.245 1.00 56.51
ATOM 1800 N PHE 348 232.033 -74.032 120.674 1.00 57.28
ATOM 1801 CA PHE 348 231.856 -72.611 120.395 1.00 56.40
ATOM 1802 CB PHE 348 230.779 -72.385 119.337 1.00 54.70
ATOM 1803 CG PHE 348 231.060 -73.056 118.025 1.00 55.06
ATOM 1804 CDl PHE 348 230.428 -74.246 117.690 1.00 53.90
ATOM 1805 CD2 PHE 348 231.918 -72.467 117.095 1.00 55.24
ATOM 1806 CEl PHE 348 230.635 -74.829 116.454 1.00 54.45
ATOM 1807 CE2 PHE 348 232.133 -73.046 115.850 1.00 54.33
ATOM 1808 CZ PHE 348 231.486 -74.229 115.529 1.00 54.96
ATOM 1809 C PHE 348 231.462 -71.831 121.614 1.00 56.36
ATOM 1810 O PHE 348 230.677 -72.296 122.441 1.00 56.33
ATOM 1811 N PRO 349 232.043 -70.640 121.774 1.00 57.10
ATOM 1812 CD PRO 349 233.151 -70.010 121.036 1.00 57.01
ATOM 1813 CA PRO 349 231.658 -69.860 122.945 1.00 56.69
ATOM 1814 CB PRO 349 232.750 -68.792 123.019 1.00 56.58
ATOM 1815 CG PRO 349 233.134 -68.600 121.585 1.00 57.72
ATOM 1816 C PRO 349 230.281 -69.331 122.538 1.00 56.96
ATOM 1817 O PRO 349 229.981 -69.256 121.340 1.00 55.54
ATOM 1818 N ASP 350 229.445 -69.002 123.518 1.00 58.05
ATOM 1819 CA ASP 350 228.085 -68.528 123.257 1.00 58.94
ATOM 1820 CB ASP 350 227.435 -68.100 124.569 1.00 60.53
ATOM 1821 CG ASP 350 227.050 -69.284 125.432 1.00 63.18
ATOM 1822 ODl ASP 350 226.746 -69.079 126.626 1.00 62.87
ATOM 1823 OD2 ASP 350 227.041 -70.422 124.908 1.00 64.61
ATOM 1824 C ASP 350 227.894 -67.432 122.217 1.00 58.28
ATOM 1825 O ASP 350 226.928 -67.472 121.463 1.00 59.14
ATOM 1826 N PHE 351 228.801 -66.464 122.162 1.00 56.76
ATOM 1827 CA PHE 351 228.683 -65.371 121.196 1.00 56.60
ATOM 1828 CB PHE 351 229.571 -64.192 121.604 1.00 56.54
ATOM 1829 CG PHE 351 231.044 -64.493 121.545 1.00 55.06
ATOM 1830 CDl PHE 351 231.721 -64.929 122.679 1.00 53.16
ATOM 1831 CD2 PHE 351 231.749 -64.351 120.353 1.00 53.43
ATOM 1832 CEl PHE 351 233.061 -65.214 122.630 1.00 51.51
ATOM 1833 CE2 PHE 351 233.100 -64.636 120.291 1.00 53.98
ATOM 1834 CZ PHE 351 233.762 -65.067 121.427 1.00 53.45
ATOM 1835 C PHE 351 229.012 -65.718 119.746 1.00 57.29
ATOM 1836 O PHE 351 229.252 -64.820 118.940 1.00 58.40
ATOM 1837 N VAL 352 229.066 -67.000 119.408 1.00 58.04
ATOM 1838 CA VAL 352 229.359 -67.367 118.033 1.00 58.60
ATOM 1839 CB VAL 352 230.265 -68.609 117.940 1.00 57.96
ATOM 1840 CGl VAL 352 230.423 -69.029 116.494 1.00 56.10
ATOM 1841 CG2 VAL 352 231.619 -68.306 118.549 1.00 56.71
ATOM 1842 C VAL 352 228.014 -67.663 117.405 1.00 60.86
ATOM 1843 O VAL 352 227.278 -68.552 117.855 1.00 60.55 34/39
ATOM 1844 N THR 353 227.685 -66.895 116.374 1.00 62.64
ATOM 1845 CA THR 353 226.410 -67.067 115.705 1.00 64.36
ATOM 1846 CB THR 353 226.220 -66.019 114.614 1.00 63.19
ATOM 1847 OGl THR 353 227.086 -66.305 113.509 1.00 61.18
ATOM 1848 CG2 THR 353 226.540 -64.644 115.173 1.00 61.77
ATOM 1849 C THR 353 226.317 -68.455 115.091 1.00 66.50
ATOM 1850 O THR 353 227.337 -69.104 114.847 1.00 67.17
ATOM 1851 N GLU 354 225.087 -68.903 114.853 1.00 67.82
ATOM 1852 CA GLU 354 224.849 -70.210 114.267 1.00 68.53
ATOM 1853 CB GLU 354 223.364 -70.579 114.380 1.00 71.21
ATOM 1854 CG GLU 354 222.714 -70.313 115.764 1.00 76.84
ATOM 1855 CD GLU 354 223.235 -71.203 116.906 1.00 79.20
ATOM 1856 OEl GLU 354 223.395 -72.434 116.694 1.00 80.44
ATOM 1857 OE2 GLU 354 223.460 -70.664 118.022 1.00 78.64
ATOM 1858 C GLU 354 225.277 -70.150 112.801 1.00 67.04
ATOM 1859 O GLU 354 225.468 -71.174 112.147 1.00 66.56
ATOM 1860 N GLY 355 225.429 -68.936 112.287 1.00 66.14
ATOM 1861 CA GLY 355 225.864 -68.789 110.910 1.00 65.75
ATOM 1862 C GLY 355 227.346 -69.119 110.781 1.00 64.76
ATOM 1863 o GLY 355 227.782 -69.751 109.816 1.00 63.92
ATOM 1864 N ALA 356 228.130 -68.679 111.755 1.00 63.67
ATOM 1865 CA ALA 356 229.553 -68.962 111.736 1.00 63.41
ATOM 1866 CB ALA 356 230.283 -68.070 112.719 1.00 63.43
ATOM 1867 C ALA 356 229.696 -70.422 112.139 1.00 63.05
ATOM 1868 o ALA 356 230.411 -71.197 111.494 1.00 63.10
ATOM 1869 N ARG 357 228.992 -70.793 113.205 1.00 61.99
ATOM 1870 CA ARG 357 229.023 -72.160 113.703 1.00 61.27
ATOM 1871 CB ARG 357 227.925 -72.363 114.749 1.00 59.13
ATOM 1872 CG ARG 357 228.095 -71.494 115.984 1.00 58.29
ATOM 1873 CD ARG 357 227.271 -71.997 117.156 1.00 56.05
ATOM 1874 NE ARG 357 227.616 -71.279 118.374 1.00 55.70
ATOM 1875 CZ ARG 357 227.369 -71.728 119.594 1.00 55.64
ATOM 1876 NHl ARG 357 . 226.772 -72.895 119.752 1.00 54.57
ATOM 1877 NH2 ARG 357 227.747 -71.024 120.653 1.00 56.82
ATOM 1878 C ARG 357 228.855 -73.175 112.578 1.00 61.80
ATOM 1879 O ARG 357 229.511 -74.212 112.566 1.00 61.89
ATOM 1880 N ASP 358 227.979 -72.862 111.629 1.00 62.33
ATOM 1881 CA ASP 358 227.711 -73.749 110.507 1.00 61.11
ATOM 1882 CB ASP 358 226.503 -73.262 109.708 1.00 62.90
ATOM 1883 CG ASP 358 226.173 -74.187 108.543 1.00 65.39
ATOM 1884 ODl ASP 358 225.488 -75.207 108.775 1.00 64.89
ATOM 1885 OD2 ASP 358 226.619 -73.906 107.402 1.00 64.98
ATOM 1886 C ASP 358 228.886 -73.867 109.562 1.00 59.93
ATOM 1887 o ASP 358 229.223 -74.958 109.117 1.00 60.00
ATOM 1888 N LEU 359 229.495 -72.735 109.241 L.00 58.41
ATOM 1889 CA LEU 359 230.624 -72.718 108.322 1.00 57.34
ATOM 1890 CB LEU 359 230.978 -71.275 107.950 1.00 53.95
ATOM 1891 CG LEU 359 232.253 -71.087 107.125 1.00 51.17
ATOM 1892 CDl LEU 359 232.256 -72.054 105.924 1.00 48.32
ATOM 1893 CD2 LEU 359 232.373 -69.630 106.684 1.00 47.29
ATOM 1894 C LEU 359 231.843 -73.428 108.909 1.00 58.34
ATOM 1895 O LEU 359 232.595 -74.090 108.178 1.00 58.55
ATOM 1896 N ILE 360 232.023 -73.294 110.223 1.00 58.66
ATOM 1897 CA ILE 360 233.143 -73.914 110.935 1.00 60.34
ATOM 1898 CB ILE 360 233.275 -73.376 112.401 1.00 60.64
ATOM 1899 CG2 ILE 360 234.540 -73.898 113.024 1.00 60.96
ATOM 1900 CGl ILE 360 233.282 -71.840 112.445 1.00 60.17
ATOM 1901 CD ILE 360 234.555 -71.199 112.035 1.00 58.23
ATOM 1902 C ILE 360 232.966 -75.435 111.014 1.00 61.38
ATOM 1903 O ILE 360 233.886 -76.181 110.696 1.00 61.89
ATOM 1904 N SER 361 231.785 -75.884 111.440 1.00 62.65
ATOM 1905 CA SER 361 231.479 -77.313 111.589 1.00 63.42
ATOM 1906 CB SER 361 230.108 -77.495 112.248 1.00 63.07 35/39
ATOM 1907 OG SER 361 230.163 -77.188 113.631 1.00 64.57
ATOM 1908 C SER 361 231.523 -78.136 110.301 1.00 64.31
ATOM 1909 O SER 361 231.656 -79.371 110.339 1.00 63.85
ATOM 1910 N ARG 362 231.422 -77.448 109.167 1.00 64.79
ATOM 1911 CA ARG 362 231.443 -78.096 107.864 1.00 65.16
ATOM 1912 CB ARG 362 230.580 -77.293 106.899 1.00 68.52
ATOM 1913 CG ARG 362 229.107 -77.324 107.284 1.00 72.59
ATOM 1914 CD ARG 362 228.316 -76.210 106.631 1.00 77.18
ATOM 1915 NE ARG 362 226.900 -76.545 106.535 1.00 80.85
ATOM 1916 CZ ARG 362 226.401 -77.388 105.634 1.00 82.65
ATOM 1917 NHl ARG 362 227.211 -77.971 104.758 1.00 83.08
ATOM 1918 NH2 ARG 362 225.097 -77.645 105.603 1.00 82.26
ATOM 1919 C ARG 362 232.850 -78.261 107.311 1.00 63.84
ATOM 1920 O ARG 362 233.109 -79.170 106.524 1.00 64.05
ATOM 1921 N LEU 363 233.760 -77.387 107.732 1.00 62.12
ATOM 1922 CA LEU 363 235.147 -77.444 107.278 1.00 60.06
ATOM 1923 CB LEU 363 235.747 -76.045 107.224 1.00 57.85
ATOM 1924 CG LEU 363 235.125 -75.037 106.274 1.00 55.35
ATOM 1925 CDl LEU 363 235.433 -73.653 106.777 1.00 55.57
ATOM 1926 CD2 LEU 363 235.654 -75.238 104.886 1.00 54.45
ATOM 1927 C LEU 363 235.968 -78.294 108.229 1.00 59.89
ATOM 1928 O LEU 363 237.013 -78.813 107.865 1.00 60.47
ATOM 1929 N LEU 364 235.489 -78.432 109.455 1.00 59.94
ATOM 1930 CA LEU 364 236.194 -79.223 110.445 1.00 60.85
ATOM 1931 CB LEU 364 236.123 -78.534 111.810 1.00 59.74
ATOM 1932 CG LEU 364 236.836 -77.170 111.802 1.00 58.89
ATOM 1933 CDl LEU 364 236.599 -76.438 113.109 1.00 56.34
ATOM 1934 CD2 LEU 364 238.331 -77.378 111.546 1.00 56.22
ATOM 1935 C LEU 364 235.664 -80.640 110.528 1.00 62.76
ATOM 1936 O LEU 364 235.207 -81.081 111.581 1.00 63.33
ATOM 1937 N LYS 365 235.726 -81.336 109.396 1.00 65.32
ATOM 1938 CA LYS 365 235.290 -82.724 109.291 1.00 66.93
ATOM 1939 CB LYS 365 234.524 -82.963 107.983 1.00 67.06
ATOM 1940 CG LYS 365 233.146 -82.334 107.928 1.00 67.86
ATOM 1941 CD LYS 365 232.227 -82.907 108.992 1.00 66.70
ATOM 1942 CE LYS 365 230.840 -82.335 108.864 1.00 66.65
ATOM 1943 NZ LYS 365 229.976 -82.826 109.967 1.00 67.71
ATOM 1944 C LYS 365 236.535 -83.595 109.298 1.00 68.08
ATOM 1945 O LYS 365 237.480 -83.347 108.537 1.00 67.15
ATOM 1946 N HIS 366 236.543 -84.608 110.160 1.00 70.55
ATOM 1947 CA HIS 366 237.689 -85.506 110.235 1.00 72.24
ATOM 1948 CB HIS 366 237.436 -86.653 111.223 1.00 72.62
ATOM 1949 CG HIS 366 238.638 -87.520 111.456 1.00 75.86
ATOM 1950 CD2 HIS 366 239.330 -87.802 112.585 1.00 76.71
ATOM 1951 NDl HIS 366 239.286 -88.185 110.436 1.00 77.34
ATOM 1952 CEl HIS 366 240.328 -88.833 110.926 1.00 78.23
ATOM 1953 NE2 HIS 366 240.377 -88.618 112.228 1.00 78.36
ATOM 1954 C HIS 366 237.922 -86.080 108.847 1.00 72.44
ATOM 1955 O HIS 366 239.060 -86.208 108.389 1.00 72.68
ATOM 1956 N ASN 367 236.826 -86.407 108.173 1.00 72.95
ATOM 1957 CA ASN 367 236.907 -86.980 106.849 1.00 73.95
ATOM 1958 CB ASN 367 235.649 -87.801 106.569 1.00 73.45
ATOM 1959 CG ASN 367 235.870 -88.847 105.510 1.00 73.82
ATOM 1960 ODl ASN 367 236.150 -88.530 104.355 1.00 73.04
ATOM 1961 ND2 ASN 367 235.762 -90.111 105.900 1.00 74.34
ATOM 1962 C ASN 367 237.067 -85.878 105.815 1.00 74.72
ATOM 1963 O ASN 367 236.153 -85.077 105.617 1.00 76.16
ATOM 1964 N PRO 368 238.231 -85.824 105.137 1.00 75.01
ATOM 1965 CD PRO 368 239.362 -86.766 105.245 1.00 74.04
ATOM 1966 CA PRO 368 238.510 -84.803 104.120 1.00 75.50
ATOM 1967 CB PRO 368 239.780 -85.325 103.458 1.00 74.73
ATOM 1968 CG PRO 368 240.478 -86.005 104.587 1.00 73.50
ATOM 1969 C PRO 368 237.368 -84.597 103.113 1.00 76.57 36/39
ATOM 1970 O PRO 368 237.021 -83.457 102.771 1.00 76.02
ATOM 1971 N SER 369 236.790 -85.707 102.659 1.00 76.87
ATOM 1972 CA SER 369 235.703 -85.684 101.689 1.00 77.17
ATOM 1973 CB SER 369 235.183 -87.099 101.453 1.00 76.72
ATOM 1974 OG SER 369 236.184 -87.929 100.893 1.00 78.05
ATOM 1975 C SER 369 234.538 -84.787 102.083 1.00 77.94
ATOM 1976 O SER 369 233.993 -84.066 101.239 1.00 78.38
ATOM 1977 N GLN 370 234.146 -84.834 103.356 1.00 78.42
ATOM 1978 CA GLN 370 233.031 -84.013 103.823 1.00 78.68
ATOM 1979 CB GLN 370 232.540 -84.477 105.194 1.00 80.10
ATOM 1980 CG GLN 370 231.790 -85.770 105.163 1.00 82.61
ATOM 1981 CD GLN 370 232.607 -86.879 105.744 1.00 85.59
ATOM 1982 OEl GLN 370 232.704 -87.024 106.966 1.00 86.65
ATOM 1983 NE2 GLN 370 233.230 -87.663 104.875 1.00 87.76
ATOM 1984 C GLN 370 233.332 -82.523 103.897 1.00 77.76
ATOM 1985 O GLN 370 232.438 -81.727 104.208 1.00 78.09
ATOM 1986 N ARG 371 234.579 -82.139 103.636 1.00 76.71
ATOM 1987 CA ARG 371 234.927 -80.726 103.678 1.00 76.01
ATOM 1988 CB ARG 371 236.437 -80.529 103.872 1.00 76.05
ATOM 1989 CG ARG 371 236.939 -80.924 105.256 1.00 74.95
ATOM 1990 CD ARG 371 238.456 -80.955 105.311 1.00 73.57
ATOM 1991 NE ARG 371 238.910 -81.916 106.311 1.00 73.68
ATOM 1992 CZ ARG 371 240.137 -82.428 106.371 1.00 72.95
ATOM 1993 NHl ARG 371 241.066 -82.072 105.484 1.00 71.77
ATOM 1994 NH2 ARG 371 240.426 -83.316 107.313 1.00 71.08
ATOM 1995 C ARG 371 234.477 -80.095 102.377 1.00 75.21
ATOM 1996 O ARG 371 234.732 -80.623 101.297 1.00 75.57
ATOM 1997 N PRO 372 233.784 -78.957 102.465 1.00 74.61
ATOM 1998 CD PRO 372 233.489 -78.187 103.688 1.00 74.47
ATOM 1999 CA PRO 372 233.299 -78.259 101.274 1.00 74.00
ATOM 2000 CB PRO 372 232.739 -76.952 101.836 1.00 73.86
ATOM 2001 CG PRO 372 232.351 -77.313 103.240 1.00 73.87
ATOM 2002 C PRO 372 234.446 -77.990 100.327 1.00 73.87
ATOM 2003 O PRO 372 235.598 -78.250 100.644 1.00 73.48
ATOM 2004 N MET 373 234.115 -77.486 99.151 1.00 74.84
ATOM 2005 CA MET 373 235.122 -77.117 98.177 1.00 75.31
ATOM 2006 CB MET 373 234.656 -77.346 96.748 1.00 77.60
ATOM 2007 CG MET 373 234.249 -78.740 96.391 1.00 80.93
ATOM 2008 SD MET 373 233.483 -78.636 94.762 1.00 85.51
ATOM 2009 CE MET 373 231.733 -78.593 95.229 1.00 84.74
ATOM 2010 C MET 373 235.146 -75.630 98.407 1.00 74.49
ATOM 2011 O MET 373 234.360 -75.107 99.194 1.00 73.43
ATOM 2012 N LEU 374 236.012 -74.933 97.698 1.00 73.79
ATOM 2013 CA LEU 374 236.074 -73.506 97.891 1.00 73.76
ATOM 2014 CB LEU 374 237.389 -72.970 97.320 1.00 71.72
ATOM 2015 CG LEU 374 238.559 -73.540 98.136 1.00 69.46
ATOM 2016 CDl LEU 374 239.855 -72.953 97.666 1.00 69.15
ATOM 2017 CD2 LEU 374 238.371 -73.228 99.609 1.00 68.33
ATOM 2018 C LEU 374 234.850 -72.783 97.338 1.00 74.09
ATOM 2019 O LEU 374 234.358 -71.852 97.965 1.00 74.08
ATOM 2020 N ARG 375 234.341 -73.220 96.189 1.00 75.58
ATOM 2021 CA ARG 375 233.153 -72.594 95.601 1.00 76.34
ATOM 2022 CB ARG 375 232.667 -73.401 94.389 1.00 78.58
ATOM 2023 CG ARG 375 231.453 -72.808 93.645 1.00 81.73
ATOM 2024 CD ARG 375 231.837 -71.644 92.711 1.00 84.15
ATOM 2025 NE ARG 375 232.913 -72.017 91.787 1.00 86.56
ATOM 2026 CZ ARG 375 233.166 -71.412 90.624 1.00 88.14
ATOM 2027 NHl ARG 375 232.418 -70.390 90.213 1.00 88.98
ATOM 2028 NH2 ARG 375 234.175 -71.834 89.864 1.00 88.85
ATOM 2029 C ARG 375 232.037 -72.534 96.654 1.00 75.15
ATOM 2030 O ARG 375 231.364 -71.522 96.799 1.00 72.98
ATOM 2031 N GLU 376 231.854 -73.632 97.380 1.00 74.83
ATOM 2032 CA GLU 376 230.843 -73.704 98.426 1.00 75.33 37/39
ATOM 2033 CB GLU 376 230.823 -75.109 99.039 1.00 76.64
ATOM 2034 CG GLU 376 229.868 -76.085 98.358 1.00 78.73
ATOM 2035 CD GLU 376 230.173 -77.536 98.695 1.00 80.52
ATOM 2036 OEl GLU 376 230.988 -78.146 97.975 1.00 81.61
ATOM 2037 OE2 GLU 376 229.612 -78.067 99.678 1.00 80.55
ATOM 2038 C GLU 376 231.113 -72.666 99.515 1.00 75.08
ATOM 2039 O GLU 376 230.227 -71.889 99.879 1.00 76.37
ATOM 2040 N VAL 377 232.337 -72.651 100.037 1.00 73.31
ATOM 2041 CA VAL 377 232.697 -71.698 101.075 1.00 70.84
ATOM 2042 CB VAL 377 234.228 -71.753 101.407 1.00 70.79
ATOM 2043 CGl VAL 377 234.625 -70.599 102.335 1.00 69.84
ATOM 2044 CG2 VAL 377 234.567 -73.076 102.084 1.00 68.72
ATOM 2045 C VAL 377 232.315 -70.288 100.644 1.00 70.57
ATOM 2046 O VAL 377 231.586 -69.610 101.362 1.00 70.81
ATOM 2047 N LEU 378 232.798 -69.857 99.474 1.00 69.89
ATOM 2048 CA LEU 378 232.514 -68.513 98.944 1.00 69.82
ATOM 2049 CB LEU 378 233.068 -68.358 97.520 1.00 68.42
ATOM 2050 CG LEU 378 234.538 -68.031 97.234 1.00 67.53
ATOM 2051 CDl LEU 378 235.134 -67.332 98.451 1.00 68.32
ATOM 2052 CD2 LEU 378 235.321 -69.280 96.889 1.00 66.31
ATOM 2053 C LEU 378 231.022 -68.185 98.912 1.00 70.76
ATOM 2054 O LEU 378 230.603 -67.051 99.173 1.00 69.71
ATOM 2055 N GLU 379 230.231 -69.192 98.568 1.00 72.11
ATOM 2056 CA GLU 379 228.794 -69.037 98.486 1.00 74.25
ATOM 2057 CB GLU 379 228.270 -69.622 97.157 1.00 76.16
ATOM 2058 CG GLU 379 228.491 -71.127 96.957 1.00 79.33
ATOM 2059 CD GLU 379 228.583 -71.526 95.484 1.00 81.28
ATOM 2060 OEl GLU 379 228.656 -72.748 95.201 1.00 82.81
ATOM 2061 OE2 GLU 379 228.598 -70.622 94.614 1.00 80.82
ATOM 2062 C GLU 379 228.104 -69.696 99.675 1.00 73.88
ATOM 2063 O GLU 379 227.369 -70.670 99.517 1.00 75.17
ATOM 2064 N HIS 380 228.359 -69.173 100.870 1.00 72.36
ATOM 2065 CA HIS 380 227.720 -69.700 102.065 1.00 70.42
ATOM 2066 CB HIS 380 228.754 -70.248 103.057 1.00 68.56
ATOM 2067 CG HIS 380 228.172 -70.670 104.371 1.00 66.07
ATOM 2068 CD2 HIS 380 228.001 -71.897 104.918 1.00 64.68
ATOM 2069 NDl HIS 380 227.677 -69.771 105.292 1.00 65.62
ATOM 2070 CEl HIS 380 227.231 -70.423 106.352 1.00 63.42
ATOM 2071 NE2 HIS 380 227.415 -71.716 106.150 1.00 62.75
ATOM 2072 C HIS 380 226.929 -68.557 102.688 1.00 70.05
ATOM 2073 O HIS 380 227.434 -67.441 102.813 1.00 69.17
ATOM 2074 N PRO 381 225.672 -68.825 103.076 1.00 70.19
ATOM 2075 CD PRO 381 225.098 -70.182 103.161 1.00 70.96
ATOM 2076 CA PRO 381 224.769 -67.846 103.684 1.00 70.16
ATOM 2077 CB PRO 381 223.819 -68.720 104.491 1.00 70.31
ATOM 2078 CG PRO 381 223.674 -69.908 103.613 1.00 71.74
ATOM 2079 C PRO 381 225.484 -66.833 104.560 1.00 70.34
ATOM 2080 O PRO 381 225.407 -65.629 104.327 1.00 70.80
ATOM 2081 N TRP 382 226.190 -67.343 105.559 1.00 70.57
ATOM 2082 CA TRP 382 226.906 -66.517 106.516 1.00 70.49
ATOM 2083 CB TRP 382 227.385 -67.378 107.682 1.00 69.45
ATOM 2084 CG TRP 382 227.976 -66.578 108.777 1.00 69.00
ATOM 2085 CD2 TRP 382 229.356 -66.277 108.953 1.00 68.28
ATOM 2086 CE2 TRP 382 229.467 -65.471 110.104 1.00 68.45
ATOM 2087 CE3 TRP 382 230.515 -66.607 108.243 1.00 68.39
ATOM 2088 CDl TRP 382 227.314 -65.960 109.795 1.00 69.71
ATOM 2089 NEl TRP 382 228.204 -65.292 110.600 1.00 69.52
ATOM 2090 CZ2 TRP 382 230.689 -64.992 110.565 1.00 68.89
ATOM 2091 CZ3 TRP 382 231.735 -66.130 108.697 1.00 68.48
ATOM 2092 CH2 TRP 382 231.813 -65.328 109.851 1.00 69.55
ATOM 2093 C TRP 382 228.084 -65.767 105.919 1.00 70.72
ATOM 2094 O TRP 382 228.421 -64.682 106.382 1.00 72.13
ATOM 2095 N ILE 383 228.717 -66.338 104.900 1.00 70.81 38/39
ATOM 2096 CA ILE 383 229.855 -65.679 104.267 1.00 70.59
ATOM 2097 CB ILE 383 230.626 -66.633 103.332 1.00 70.23
ATOM 2098 CG2 ILE 383 231.382 -65.836 102.261 1.00 69.76
ATOM 2099 CGl ILE 383 231.600 -67.469 104.164 1.00 71.13
ATOM 2100 CD ILE 383 232.616 -66.624 104.955 1.00 70.30
ATOM 2101 C ILE 383 229.433 -64.465 103.471 1.00 70.60
ATOM 2102 O ILE 383 229.846 -63.349 103.763 1.00 71.17
ATOM 2103 N THR 384 228.615 -64.692 102.454 1.00 70.53
ATOM 2104 CA THR 384 228.133 -63.611 101.606 1.00 70.17
ATOM 2105 CB THR 384 227.185 -64.151 100.533 1.00 70.41
ATOM 2106 OGl THR 384 226.250 -65.048 101.144 1.00 69.12
ATOM 2107 CG2 THR 384 227.971 -64.883 99.439 1.00 70.43
ATOM 2108 C THR 384 227.396 -62.587 102.453 1.00 69.04
ATOM 2109 O THR 384 227.614 -61.387 102.329 1.00 68.76
ATOM 2110 N ALA 385 226.533 -63.074 103.330 1.00 67.94
ATOM 2111 CA ALA 385 225.767 -62.202 104.203 1.00 68.39
ATOM 2112 CB ALA 385 224.867 -63.038 105.088 1.00 67.16
ATOM 2113 C ALA 385 226.627 -61.286 105.076 1.00 69.29
ATOM 2114 O ALA 385 226.105 -60.369 105.699 1.00 68.77
ATOM 2115 N ASN 386 227.934 -61.530 105.127 1.00 70.48
ATOM 2116 CA ASN 386 228.818 -60.723 105.962 1.00 71.45
ATOM 2117 CB ASN 386 229.203 -61.502 107.221 1.00 71.76
ATOM 2118 CG ASN 386 228.200 -61.338 108.348 1.00 72.98
ATOM 2119 ODl ASN 386 228.096 -60.263 108.957 1.00 73.96
ATOM 2120 ND2 ASN 386 227.456 -62.404 108.638 1.00 72.18
ATOM 2121 C ASN 386 230.087 -60.250 105.279 1.00 72.53
ATOM 2122 O ASN 386 230.689 -59.273 105.705 1.00 71.72
ATOM 2123 N SER 387 230.499 -60.945 104.229 1.00 74.87
ATOM 2124 CA SER 387 231.723 -60.594 103.513 1.00 78.29
ATOM 2125 CB SER 387 232.149 -61.754 102.609 1.00 77.02
ATOM 2126 OG SER 387 233.294 -61.404 101.851 1.00 76.43
ATOM 2127 C SER 387 231.581 -59.327 102.675 1.00 81.66
ATOM 2128 O SER 387 230.640 -59.195 101.898 1.00 83.18
ATOM 2129 N SER 388 232.523 -58.400 102.818 1.00 84.96
ATOM 2130 CA SER 388 232.471 -57.162 102.053 1.00 88.61
ATOM 2131 CB SER 388 232.853 -55.967 102.937 1.00 88.76
ATOM 2132 OG SER 388 234.239 -55.963 103.229 1.00 88.00
ATOM 2133 C SER 388 233.384 -57.198 100.829 1.00 91.15
ATOM 2134 O SER 388 233.682 -56.152 100.245 1.00 91.95
ATOM 2135 N LYS 389 233.822 -58.393 100.433 1.00 94.10
ATOM 2136 CA LYS 389 234.703 -58.529 99.275 1.00 97.03
ATOM 2137 CB LYS 389 235.800 -59.539 99.589 1.00 97.44
ATOM 2138 CG LYS 389 237.160 -58.864 99.748 1.00 98.93
ATOM 2139 CD LYS 389 237.430 -57.893 98.585 1.00 99.55
ATOM 2140 CE LYS 389 238.809 -57.261 98.673 1.00101.12
ATOM 2141 NZ LYS 389 239.917 -58.272 98.551 1.00101.69
ATOM 2142 C LYS 389 233.959 -58.869 97.970 1.00 99.33
ATOM 2143 O LYS 389 232.733 -58.723 97.920 1.00 99.64
ATOM 2144 N PRO 390 234.670 -59.324 96.900 1.00101.49
ATOM 2145 CD PRO 390 236.018 -59.928 96.816 1.00102.43
ATOM 2146 CA PRO 390 233.924 -59.623 95.660 1.00102.14
ATOM 2147 CB PRO 390 234.931 -60.445 94.827 1.00102.24
ATOM 2148 CG PRO 390 235.786 -61.103 95.867 1.00102.11
ATOM 2149 C PRO 390 232.585 -60.343 95.849 1.00102.47
ATOM 2150 O PRO 390 231.530 -59.701 95.915 1.00102.40
ATOM 2151 CAA DRG 1 253.790 -64.232 107.949 1.00 72.13
ATOM 2152 OAN DRG 1 255.049 -64.871 108.207 1.00 70.55
ATOM 2153 CAP DRG 1 255.856 -64.681 107.122 1.00 69.92
ATOM 2154 OAB DRG 1 255.451 -64.090 106.126 1.00 71.29
ATOM 2155 CAS DRG 1 257.269 -65.244 107.133 1.00 69.93
ATOM 2156 SAO DRG 1 258.097 -65.743 108.543 1.00 72.48
ATOM 2157 CAE DRG 1 259.499 -66.177 107.661 1.00 71.07
ATOM 2158 CAF DRG 1 259.299 -65.932 106.359 1.00 71.18 ATOM 2159 CAR DRG 1 258.112 -65.412 106.040 1.00 69.70
ATOM 2160 SAV DRG 1 257.859 -64.329 104.686 1.00 67.38
ATOM 2161 OAC DRG 1 258.960 -64.490 103.678 1.00 69.78
ATOM 2162 OAD DRG 1 256.547 -64.478 103.968 1.00 66.81
ATOM 2163 NAL DRG 1 257.989 -62.966 105.577 1.00 65.34
ATOM 2164 CAQ DRG 1 257.857 -61.678 105.288 1.00 62.82
ATOM 2165 CAJ DRG 1 257.331 -61.201 104.090 1.00 62.38
ATOM 2166 CAU DRG 1 256.944 -59.864 104.034 1.00 60.65
ATOM 2167 NAM DRG 1 256.407 -59.109 103.082 1.00 59.69
ATOM 2168 NAK DRG 1 256.231 -57.961 103.508 1.00 59.23
ATOM 2169 CAI DRG 1 256.626 -57.838 104.773 1.00 58.27
ATOM 2170 CAT DRG 1 257.093 -59.027 105.136 1.00 60.02
ATOM 2171 CAH DRG 1 257.659 -59.499 106.313 1.00 60.89
ATOM 2172 CAG DRG 1 258.041 -60.833 106.378 1.00 61.71
END
PCT/EP2007/003011 2006-04-03 2007-04-03 2-substituted 3-aminosulfonyl-thiophene derivatives as aurora kinase inhibitors WO2007113005A2 (en)

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