`
`
`CORRECTED VERSION I
`
`(19) World Intellectual Property Organization
`International Bureau
`
` (10) International Publication Number
`
`(43) International Publication Date
`WO 2006/110763 Al
`19 October 2006 (19.10.2006)
`International Patent Classification:
`C07D 401/12 (2006.01)
`A61K 31/506 (2006.01)
`
`(51)
`
`[US/US]; 1937 Little Meadow Road, Guilford. Connecti-
`cut 06437 (US). ZHAO, Jin [CN/US]; 50 Village Brook
`Lane, Apt. #5. Natick, Massachusetts 01760 (US).
`
`(74)
`
`Agents: GREENMAN, Jeffrey, M. et a1.; Bayer Phar—
`maceuticals Corporation, 400 Morgan Lane, West Haven,
`Connecticut 06516 (US).
`
`(21)
`
`(22)
`
`International Application Number:
`PCT/US2006/013505
`
`International Filing Date:
`
`7 April 2006 (07.04.2006)
`
`(25)
`
`Filing Language:
`
`(26)
`
`Publication Language:
`
`English
`
`(81)
`
`English
`
`(30)
`
`(71)
`
`t72)
`(75)
`
`Priority Data:
`60/669,462
`
`8 April 2005 (08.04.2005)
`
`US
`
`Applicant (for all designated States except US): BAYER
`PHARMACEUTICALS CORPORATION [US/US];
`400 Morgan Lane, West Haven, Connecticut 06516 (US).
`
`Inventors; and
`Inventors/Applicants (for US only): NAGARATHNAM,
`Dhanapalan [US/US]; 52 Virginia Rail Drive, Bethany,
`Connecticut 06524 (US). CHEN, Yuanwei [US/US]; 15
`Blue Ridge Lane, North Haven, Connecticut 06473 (US).
`FU, Wenlang [CN/US]; 30 Avalon Drive, Unit 5232, Mil-
`ford, Connecticut 06460 (US). WANG, Ming [US/US];
`32 Milford Hunt Lane, Milford, Connecticut 06460 (US).
`BIERER, Donald [US/US]; 46 Hilltop Road, Bethany,
`Connecticut 06524 (US). BRANDS, Michael [DFJDE];
`Kinderbusch 613. 42329 Wuppertal (DE). WANG. Yamin
`[CN/US]; 10 Russett Road, Sandy Hook, Connecticut
`06482 (US). BEAR, Brian, R. [US/US]; 5108 Spencer
`CL, Oceanside, California 92057 (US). MILLER, David
`[US/US]; 410 Stevenston Road, New Haven, Connecticut
`06515 (US). SCHMITT, Aaron [US/US]; 32 Linden
`Avenue, Hamden, Connecticut 06518 (US). MULL, Eric
`
`Designated States (unless otherwise indicated. for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
`GB, GI), GE, (ill, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KNI, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV,
`LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI,
`NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG,
`SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US,
`UZ, VC, VN, YU, ZA, ZM, ZW.
`
`(84)
`
`Designated States (unlers otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM. KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, '11), m).
`
`Published:
`with international search report
`
`(48)
`
`Date of publication of this corrected version:
`6 December 2007
`
`(15)
`
`Information about Correction:
`see PCT Gazette No. 49/2007 of 6 December 2007
`
`[Continued on next page]
`
`
`(54) Title: PYRTMIDINE DERIVATIVES AND THEIR USE FOR THE TREATMENT OF CANCER
`
`.95
`
`"YR “Q .a‘
`
`8
`
`.
`
`N /
`
`N
`N \
`JL' ,
`N‘
`
`HaN
`
`(I)
`
`L-R2
`
`(57) Abstract: This invention relates to novel compounds (I) and processes for their preparation, methods of treating diseases, par-
`ticularly cancer, comprising administering said compounds, and methods of making pharmaceutical compositions for the treatment
`or prevention of disorders, particularly cancer.
`
`
`
`2006/110763A1
`
`W0
`
`
`
`W0 2006/110763 A1
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Nolex on Codes and Abbreviatt'am'" appearing at the begin-
`ning of each regular issue of the PCT Gazette
`
`
`
`W0 2006/1 10763
`
`PCT/U52006/013505
`
`Eyrimidine derivatives
`
`This invention relates to novel compounds and processes for their preparation, methods of
`
`treating diseases, particularly cancer, comprising administering said compounds, and
`
`methods of making pharmaceutical compositions for the treatment or prevention of
`
`disorders, particularly cancer.
`
`Nitrogen-containing heterocycles such as pyrimidine derivatives have been disclosed in
`
`patent and non-patent publications as having a variety of pharmaceutical properties and
`
`utilities. Several such publications are listed below.
`
`W0 03/062225 (Bayer) relates to pyrimidine derivatives as rho—kinase inhibitors, and their
`
`use in treatment of rho—kinase mediated conditions including cancer.
`
`W0 2001/87845 (Fujisawa) relates to N—containing heterocyclic compounds having 5—HT
`
`antagonistic activity. These compounds are stated as being useful for treating or
`
`preventing central nervous system disorders.
`
`W0 95/10506 (Du Pont Merck) relates to lN—alkyl-N—arylpyrimidinamines and
`
`derivatives thereof, which are stated to inhibit the corticopropin releasing factor (CRF)
`
`peptide and to be useful for treatment of psychiatric disorders and neurological diseases.
`
`WO 2004/048365 (Chiron) relates to 2,4,6-trisubstituted pyrimidines as
`
`phosphotidylinositol (PI) 3-kinase inhibitors and their use in treatment of cancer. WO
`
`2004/000820 (Cellular Genomics) relates to N—containing heterocycles and other
`
`compounds as kinase modulators, and their use in treatment of numerous kinase-
`
`associated disorders including cancer.
`
`WO 01/62233 (Hoffmann La Roche) relates to nitrogen-containing heterocycles and their
`
`use in treatment of diseases modulated by the adenosine receptor.
`
`US 2004/0097504 (Vertex) relates to nitrogen-containing heterocycles useful in treatment
`
`of various protein kinase—mediated disorders.
`The pharmaceutical field is always interested in identifying new pharmaceutically active
`
`compounds. Such materials are the subject of the present application.
`
`In one embodiment, the present invention provides a compound of formula (I)
`
`
`
`W0 2006/1 10763
`
`PCT/USZOO6/013505
`
`wherein
`
`A represents an oxygen atom or a group —NRA-, in which RA represents hydrogen or alkyl;
`
`D represents a group —CH— or a nitrogen atom;
`
`L is a 2 carbon atom linker selected from the group consisting of ethandiyl, ethendiyl and
`
`ethyndiyl, which in Case of ethandiyl can optionally be substituted by 0, 1 or 2 alkyl,
`
`hydroxy or alkoxy, in case of ethendiyl can optionally be substituted by O, 1 or 2 alkyl or
`
`alkoxy;
`
`R2 represents alkyl, wherein alkyl can be substituted with 0 to 3 substituents selected from
`
`the group consisting of halo, hydroxy, alkoxy, amino, alkylamino, and
`
`alkylsulfonylamino; or
`
`R2 represents phenyl or heteroaryl, wherein phenyl or heteroaryl can optionally be
`
`substituted by 0, l or 2 substituents selected from the group consisting of halo,
`
`trifluoromethyl, alkyl, hydroxy, alkoxy, amino, alkylcarbonylarnino, alkylamino,
`
`aminocarbonyl, alkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, and,
`
`wherein said alkylaInino, alkylaminocarbonyl, and alkylaminosulfonyl are
`
`optionally substituted by 0, l or 2 substituents selected from the group consisting
`
`of hydroxy, halogen and alkoxy;
`
`R4 is hydrogen or alkyl;
`
`R5 is hydrogen or halo; and
`
`
`
`WO 2006/110763
`
`PCT/U82006/013505
`
`R6 represents alkyl, cyano, aminocarbonyl, alkylaminocarbonyl, trifluoromethyl, amino,
`
`alkylcarbonylamino, alkylcarbonyl, alkenyl, alkynyl or chloro;
`
`or a pharmaceutically acceptable salt thereof.
`
`In another embodiment, the present invention provides a compound of formula (1),
`
`wherein
`
`A represents an oxygen atom;
`
`D represents a group —CH—;
`
`L is a 2 carbon atom linker selected from the group consisting of ethandiyl, cthendiyl and
`
`ethyndyl;
`
`R2 represents alkyl, wherein alkyl can be substituted with O to 2 substituents selected from
`
`the group consisting of halo, hydroxy, alkoxy, amino, alkylamino, and
`
`alkylsulfonylamino; or
`
`R2 represents phenyl or pyridyl, wherein phenyl or pyridyl can optionally be substituted by
`
`O, 1 or 2 substituents selected from the group consisting of halo, alkyl, hydroxy, and
`
`alkoxy;
`
`R4 is hydro gen;
`
`R5 is hydrogen; and
`
`R6 represents alkyl, cyano, aminocarbonyl, chloro or txifluoromethyl;
`
`or a pharmaceutically acceptable salt thereof.
`
`
`
`WO 2006/110763
`
`PCT/USZOO6/013505
`
`In another embodiment, the present invention provides a compound of formula (Ia),
`
`R5
`D
`0
`R5
`\r\“kg/034N
`Nfl
`
`JL/
`HZNNL
`
`wherein
`
`D represents a group ~CH—;
`
`L is a 2 carbon atom linker selected from the group consisting of ethandiyl, ethendiyl and
`
`ethyndyl;
`
`R2 represents phenyl or pyridyl, wherein phenyl or pyridyl can optionally be substituted by
`
`0, 1 or 2 substituents selected from the group consisting of halo, alkyl, hydroxy, and
`
`alkoxy;
`
`R‘L is hydrogen;
`
`R5 is hydrogen; and
`
`R6 represents alkyl, cyano, arninocarbonyl, chloro or trifluoromethyl;
`
`or a pharmaceutically acceptable salt thereof.
`
`Depending on their structure, the compounds according to the invention can exist in
`
`stereoisomeric forms (enantiomers or diastereomers). The invention therefore relates to the
`
`enantiomers or diastereomers and to their respective mixtures. Such mixtures of enantiorners
`
`or diastereomers can be separated into stereoisornerically unitary constituents in a known
`
`manner.
`
`
`
`WO 2006/110763
`
`PCT/U52006/013505
`
`Unless otherwise stated, the following definitions apply for the technical expressions used
`
`throughout this Specification and claims:
`
`Salts for the purposes of the invention are preferably pharmacologically acceptable salts of
`
`the compounds according to the invention.
`
`Pharmaceutically acceptable salts of the compounds (I) include acid addition salts of mineral
`
`acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid,
`
`hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
`
`toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic
`
`acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic
`
`acid.
`
`Pharmaceutically acceptable salts of the compounds (I) also include salts of customary
`
`bases, such as for example and preferably alkali metal salts (for example sodium and
`
`potassium salts, alkaline earth metal salts (for example calcium and magnesium salts) and
`
`ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such
`
`as illustratively and preferably ethylamine, diethylamine, triethylarnine, ethyldiiso-
`
`propylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
`
`dimethylaminoethanol, procaine, dibenzylarnine, N—rnethylmorpholine, dihydroabietylamine,
`
`arginine, lysine, ethylenediamine and methylpipen'dine.
`
`£qu represents a linear or branched alkyl radical having generally 1 to 6, 1 to 4 or 1 to 3
`
`carbon atoms, illustratively representing methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-
`
`pentyl and n—hexyl.
`
`Alkenyl represents a linear or branched alkyl radical having one or more double bonds and 2
`
`to 6, 2 to 4 or 2 to 3 carbon atoms, illustratively representing ethylene or allyl.
`
`ALkmyl represents a linear or branched alkyl radical having one or more triple bonds and
`
`generally 2 to 6, 2 to 4 or 2 to 3 carbon atoms, illustratively representing propargyl.
`
`
`
`WO 2006/110763
`
`PCT/U52006/013505
`
`Alkoxy represents a straight-chain or branched hydrocarbon radical having 1 to 6, 1 to 4 or
`
`1 to 3 carbon atoms and bound via an oxygen atom, illustratively representing methoxy,
`
`ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy.
`
`The terms "alkoxy" and "alkyloxy" are often used synonymously.
`
`fllglamino represents an alkylamino radical having one or two (independently selected)
`
`alkyl substituents, illustratively representing methylamino, ethylamino, n—propylamino,
`
`isopropylamino, tert—butylamino, n-pentylamino, n-hexylamino, MN-dimethylamino, N,N-
`
`, diethylamino, N—ethyl—N-methylamino, N—methyl—N—n-propylamino, N—isopropyl—N-n-
`
`propylamino, N-t—butyl-N-methylamino, N—ethyl—N—n—pentylamino and N—n—hexyl-N-
`
`methylamino.
`
`Allgflaminocarbonyl represents an allcylanfinocarbonyl radical having one or two
`
`(independently selected) alkyl substituents, illustratively representing methylaminocarbonyl,
`
`ethylaminocarbonyl, n—propylarninocarbonyl, isopropylaminocarbonyl, tert—
`
`butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl,
`
`MN—dimethylaminocarbonyl, MN—diethylaminocarbonyl, N—ethyl—N—methylaminocarbonyl,
`
`N—methyl-N—n—propylarninocarbonyl, N—isopropyl—N—n-propylaminocarbonyl, N—t—butyl—
`
`N-rnethylaminocarbonyl, N—ethyl-N-n-pentylamino-carbonyl and N—n—hexyl—N-methyl—
`
`aminocarbonyl.
`
`fllaminosulfonyl represents an aminosulfonyl radical having one or two (independently
`
`selected) alkyl substitutents on the amino moiety, illustratively representing"
`
`methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl,
`
`tert—butylaminosulfonyl, n—pentylaminosulfonyl, n—hexyl—aminosulfonyl, N,N-
`
`dimethylaminosulfonyl, MN—diethylarnjnosulfonyl, N—ethyl—N—methylaminosulfonyl, N—
`
`methyl—N—n—propylaminosulfonyl, N—isopropyl-N—n-propylaminosulfonyl, N-t—butyl-N—
`
`methylaminosulfonyl, N-ethyl—N-n-pentylaminosulfonyl and N—n—hexyl—
`
`N—rnethylaminosulfonyl.
`
`Albdsulfonylamino represents a sulfonylamino radical having an alkyl substitutent on the
`
`sulfonylamino moiety, illustratively representing methylsulfonylamjno, ethylsulfonylamino,
`
`n-propylsulfonylamino, isopropylsulfonylamino, tert—butyl—sulfonylamino, n—
`6
`
`
`
`W0 2006/110763
`
`PCT/USZOO6/013505
`
`pentylsulfonylamino and n—hexylsulfonylamino.
`
`A_r3L1 represents a mono— to tricyclic carbocyclic radical, which is aromatic at least in one
`
`ring and bound via an oxygen atom, having generally 6 to 14 carbon atoms, illustratively
`
`representing phenyl, naphthyl and phenanthrenyl.
`
`Arylcarbonyl represents a carbonyl radical having an aryl substituen, illustratively and
`
`preferably represents phenylcarbonyl and naphthylcarbonyl.
`
`Heteroml represents an mono- or bicyclic radical having 5 to 10 or 5 or 6 ring atoms and
`
`up to 5 or up to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and
`
`sulfur, which is aromatic at least in one ring. It can be attached via a ring carbon atom or a
`
`ring nitrogen atom. If it represents a bicycle, wherein one ring is aromatic and the other
`
`one is not, it can be attached at either ring. Illustrative examples are thienyl, furyl, pyrrolyl,
`
`thiazolyl, oxazolyl, imidazolyl, pyn'dyl, pyrimidyl, pyridazinyl, indolyl, indazolyl,
`
`benzofuranyl, benzothiophenyl, quinolinyl and isoquinolinyl.
`
`Halo or halogen represents fluorine, chlorine, bromine or iodine.
`
`A * symbol next to a bond denotes the point of attachment in the molecule.
`
`Throughout this document, for the sake of simplicity, the use of singular language is given
`
`preference over plural language, but is generally meant to include the plural language if not
`
`otherwise stated. E.g., the expression "A method of treating a disease in a patient,
`
`comprising administering to a patient an effective amount of a compound of claim 1" is
`
`meant to include the simultaneous treatment of more than one disease as well as the
`
`administration of more than one compound of claim 1.
`
`In another embodiment, the present invention provides a process for preparing the
`
`compounds of formula (I), comprising reacting a compound of formula (II)
`
`
`
`WO 2006/110763
`
`PCT/U82006/013505
`
`[A]
`
`with an agent of formula (IHa)
`
`R11—O\B/L\Ra
`I
`(ma)
`R12/0
`in which L and R2 have the meaning indicated above, and R“ and R12 can be H or alkyl, or
`
`[B]
`
`with an agent of formula (IIIb)
`HaI
`O\ /LB
`I
`
`>§<°
`
`(IIIb)
`
`in which L and R2 have the meaning indicated above, or
`
`[C]
`
`with an agent of formula (IlIc)
`
`R“
`
`(DIG)
`
`in which L, R2 and R“ have the meaning indicated above, in the presence of a suitable Pd
`
`catalyst, such as Pd2(dba)3 [tris(dibenzylideneacetone)-dipalladjum(0)], Pd(PPh3)4
`
`[tetrakis(triphenylphosphine)palladium(0)], or PdC12(dppf)-CH2C12 {[1,1’—
`bis(dipheny1phosphino)ferrocene]dichloropalladium(11)comp1ex with dichloromethane } .
`
`The compound of formula (II) can be prepared by condensation of a precursor of formula
`
`(VI)
`
`
`
`WO 2006/110763
`
`PCT/U52006/0l3505
`
`4/NH
`
`R
`
`(IV)
`
`wherein A, D, and R4 to R'5 have the meaning indicated above, with 2—arnino—4,6~
`
`dichloropyrimidine.
`Alternatively, compounds of formula (I) in which L represents ethanediyl are accessible
`
`by hydroboration of an alkene of formula (V)
`
`”Ham
`
`wherein R2 has the meaning indicated above,
`
`with a borane like 9—BBN and subsequent reaction with the intermediate of formula (II) in the
`
`presence of a Palladium catalyst such as Pd2(dba)3 [tris(dibenzylideneacetone)-dipalladium(0)],
`
`Pd(PPh3)4 [tetrakis(triphenylphosphine)palladium(0)], PdClg(dppf) ~CH2C12 {[1, 1 ’—
`
`bis(diphenylphosphino)ferrocene]diclrfloropalladium(]1)complex with dichloromethane} .
`
`In case that L in formula (I) is ethendiyl, it can be converted into the corresponding single
`
`bond by catalytic hydrogenation. Also, residue R2 in formula (I) might contain protecting
`
`groups that can be cleaved off.
`
`In case that L in formula (I) represents ethynediyl, compounds of formula (I) can be prepared by
`
`reaction of a compound of formula (VI)
`
`3.D
`
`HN/JLN:
`
`wherein D, and R4 to R6 have the meaning indicated above, with compounds of formula (VII)
`
`l\
`
`“2 (VII)
`in which R2 stands for an optionally substituted aromatic or heteroaromatic group in the presence
`
`9
`
`
`
`W0 2006/1 10763
`
`PCT/U52006/013505
`
`of a palladium catalyst such as Pd(PPh3)2.C12 and a copper salt such as copperCDiodide.
`
`Compounds of formula (VI) are available by reaction of precursor (IV) with a compound of
`
`formula (VIII)
`Cl
`
`SiMe3 (VIII)
`
`by a condensation reaction and subsequent removal of the trimethylsilyl group using a fluoride
`salt such as TBAF.
`
`Compound (VIII) can be prepared by reacting commercially available 4—aInino-2,6-
`
`dichlorpyrimidine with trirnethylsilyl acetylene in the presence of a palladium catalyst such as
`
`bis(benzonitrile)dichloro palladium(I[) and a copper salt such as copper(I)iodide.
`
`It is also to be understood that starting materials are commercially available or readily
`
`prepared by standard methods well known in the art. Such methods include, but are not
`
`limited to the transformations listed herein.
`
`If not mentioned otherwise, the reactions are usually carried out in inert organic solvents
`
`which do not change under the reaction conditions. These include ethers, such as diethyl
`
`ether, 1 ,4-dioxane or tetrahydrofuran, halogenated hydrocarbons, such as
`
`dichloromethane, trichloromethane, carbon tetrachloride, 1,2—dichloroethane,
`
`trichloroethane or tetrachloroethane, hydrocarbons, such as benzene, toluene, xylene,
`
`hexane, cyclohexane or mineral oil fractions, alcohols, such as methanol, ethanol or iso—
`
`propanol, nitromethane, dimethylformamide or acetonitrile. It is also possible to use
`
`mixtures of the solvents.
`
`The reactions are generally carried out in a temperature range of from 0°C to 150°C,
`
`preferably from 0°C to 70°C. The reactions can be carried out under atmospheric, elevated
`
`or under reduced pressure (for example from 0.5 to 5 bar). In general, they are carried out
`
`under atmospheric pressure of air or inert gas, typically nitrogen.
`
`10
`
`
`
`WO 2006/110763
`
`PCT/U52006/013505
`
`The preparation of a compound of the present invention can be illustrated by means of the
`
`following synthetic methods:
`
`Method A:
`
`.
`n“
`D
`Ft‘
`N \
`NJAQNF +H2N’J‘N’ CI
`
`/
`
`w
`
`.
`
`H
`
`l
`
`IX
`
`__..
`
`R5
`
`R“
`\r0
`base Ugh
`PdCI2(dppf)CH2ch K2005
`brie: 2‘3;m!
`HNA
`
`H“
`N
`
`/ D\
`__
`
`A
`
`R“
`
`n‘
`
`N,
`
`N \
`I
`HzNJ‘N/
`
`XII
`
`Pd,C.H2
`*———-—
`
`F
`
`F‘\l
`D
`I
`\
`N
`_
`
`A
`
`“5
`
`I
`
`,R
`
`N
`
`HzN
`
`*\
`, /
`N
`Xl
`
`F
`
`Thus a compound of formula (IV) can be condensed with the compound of formula (IX) in
`
`an inert solvent such as isopropanol and at elevated temperature in the presence or the
`
`absence of a base. Subsequently, intermediate of formula (II) can be treated with a
`
`boronate such as of formula (X) in the presence of a palladium catalyst such as Pd2(dba)3
`
`[tris(dibenzylideneacetone)—dipalladium(0)] , Pd(PPh3)4
`
`[tetralds(tripheny1phosphine)palladium(0)], 0r PdC12(dppfl-CH2C12 {[1,1 ’-
`
`bis(diphenylphosphino)ferrocene] dichloropalladium(ll)complex with dichloromethane}
`
`and a base such as potassium carbonate. The compound of formula (XI) can be converted
`
`into a compound of formula (XII) by catalytic hydrogenation in the presence of a
`
`palladium catalyst such as 10% palladium on charcoal.
`
`Method B:
`
`1. 9-BBN
`
`2. compound (II), Pd(PPh3)4, NaOH
`
`
`“2“
`
`V
`
`R6)—o
`NJA‘Q
`
`[Eff/L
`
`Xlll
`
`Alkene of formula (V) is hydroborated with an appropriate borane such as 9—BBN
`
`followed by Suzuki coupling employing intermediate of formula (11) in the presence of a
`1 l
`
`
`
`WO 2006/110763
`
`PCT/U52006/013505
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`palladium catalyst such as Pd2(dba)3 [tris(dibenzylideneacetone)—dipalladium(0)],
`Pd(PPh3)4 [tetrakis(triphenylphosphine)palladium(0)], or PdC12(dppf)-CH2C12 {[1,1’-
`bis(diphenylphosphino)ferrocene]dichloropalladium(11)complex with dichloromethane}
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`and a base such as potassium carbonate or sodium hydroxide.
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`Method C:
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`Trimelhylsllylacetylene,
`' bls(benzonltrlle)dlchloro palladiumal).
`
`[(tBu):,PH]BF4 , Cul, dfisopropylamlne
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`Treatment of 4-amino—2,6—dichloropyrimidine (IX) with trimethylsilylacetylene in the
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`presence of a palladium catalyst such as bis(benzonitrile)dichloro palladium(11), a suitable
`ligand for example derived from [(tBu)3PH]BF4, a copperr(l)sa1t such as copper(I)iodide
`and a base such as diisopropylamine furnishes compound (V111), which is subsequently
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`condensed with aniline (IV) to yield intermediate (XIV). From this, the trimethylsilyl
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`group is cleaved off by treatment with a fluoride source such as TBAF and the resulting
`alkyne is reacted with a iodophenyl derivative such as 4—fluoroiodobenzene in the
`presence of a Palladium catalyst such as [bis(dipheny1phosphino)]dichloropalladiumGI)
`complex, a copper(I) salt such as copper(I)iodide and a base such as ethyl
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`didopropylamine to yield compound (XV).
`
`Many compounds of the present invention exhibit useful pharmacological and
`pharrnacokinetic properties. They can therefore be useful for the treatment or prevention
`of disorders in humans and animals, especially hyperproliferative disorders such as
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`cancer.
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`In another embodiment, the present invention provides a pharmaceutical composition
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`comprising at least one compound according to the invention. In another embodiment, the
`
`present invention provides a pharmaceutical composition comprising at least one
`
`compound according to the invention together with one or more pharmacologically safe
`
`excipient or carrier substances. In a further embodiment, the present invention provides
`
`the use of said compound and composition for the treatment of a disease, as well as a
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`method of treating a disease by administering to a patient a therapeutically effective
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`amount of said compound or composition.
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`If used as active compounds, the compounds according to the invention are preferably
`
`isolated in more or less pure form, that is more or less free from residues from the
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`synthetic procedure. The degree of purity can be determined by methods known to the
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`chemist or pharmacist (see Remington's Pharmaceutical Sciences, 18th ed. 1990, Mack
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`Publishing Group, Enolo). Preferably the compounds are greater than 99% pure (w/w),
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`While purities of greater than 95%, 90% or 85% can be employed if necessary.
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`The present invention also relates to a method of using the compounds or compositions
`
`described herein for the treatment or prevention of, or in the manufacture of a medicament
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`for treating or preventing, mammalian hyper—proliferative disorders.
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`This method
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`comprises administering to a patient (or a mammal) in need thereof, including a human, an
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`amount of a compound, a pharmaceutically acceptable salt or ester thereof, or a
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`composition of this invention, which is effective to treat or prevent the disorder.
`
`Hyper—proliferative disorders include but are not limited to solid tumors, such as cancers
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`of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract,
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`eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those
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`disorders also include lymphomas, sarcomas, and leukemias.
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`The present invention also relates to a method for using the compounds of this invention
`
`as prophylactic or chemopreventive agents for prevention of the mammalian hyper-
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`proliferative disorders described herein. This method comprises administering to a
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`~ mammal in need thereof, including a human, an amount of a compound of this invention,
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`or a pharmaceutically acceptable salt or ester thereof, which is effective to delay or
`diminish the onset of the disorder.
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`Examples of breast cancer include, but are not limited to invasive ductal carcinoma,
`invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
`
`Examples of cancers of the respiratory tract include, but are not limited to small—cell and
`non—small-cell
`lung carcinoma, as well as bronchial adenoma and pleuropulmonary
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`blastoma.
`
`Examples of brain cancers include, but are not limited to brain stem and hypophtalmic
`glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as
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`neuroectodermal and pineal tumor.
`
`Tumors of the male reproductive organs include, but are not limited to prostate and
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`testicular cancer. Tumors of the female reproductive organs include, but are not limited to
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`endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the
`uterus.
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`Tumors of the digestive tract include, but are not limited to anal, colon, colorectal,
`esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland
`cancers.
`
`Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal
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`pelvis, ureter, and urethral cancers.
`
`Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
`Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver
`cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic
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`bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
`
`Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi’s sarcoma,
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`malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
`Head-and-neck cancers include, but are not limited to laryngeal / hypopharyngeal /
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`nasopharyngeal / oropharyngeal cancer, and lip and oral cavity cancer.
`Lymphomas include, but are not
`limited to AIDS—related lymphoma, non—Hodgkin’s
`lymphoma, cutaneous T-cell lymphoma, Hodgkin’s disease, and lymphoma of the central
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`nervous system.
`
`Sarcomas include, but are not limited to sarcoma of the soft
`
`tissue, osteosarcoma,
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`malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
`Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic
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`leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell
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`leukemia.
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`These disorders have been well characterized in humans, and also exist with a similar
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`etiology in other mammals which can also be treated by the administration of the
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`compounds and/or pharmaceutical compositions of the present invention.
`
`In another embodiment, the present invention provides a medicament containing at least
`
`one compound according to the invention. In another embodiment, the present invention
`
`provides a medicament containing at least one compound according to the invention
`
`together with one or more pharmacologically safe excipient or carrier substances, for
`
`example hydroxypropylcellulose, and also their use for the above mentioned purposes.
`
`The active component can act systemically and/or locally. For this purpose, it can be
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`applied in a suitable manner, for example orally, parenterally, pulmonally, nasally,
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`sublingually, lingually, buccally, rectally, n‘ansdermally, conjunctivally, otically or as an
`
`implant.
`
`For these application routes, the active component can be administered in suitable
`
`application forms. An overview of application forms is given in Remington's
`
`Pharmaceutical Sciences, 18th ed. 1990, Mack Publishing Group, Enolo.
`
`Useful oral application forms include application forms which release the active
`
`component rapidly and/or in modified form, such as for example tablets (non-coated and
`
`coated tablets, for example with an enteric coating), capsules, sugar-coated tablets,
`
`granules, pellets, powders, emulsions, suspensions, solutions and aerosols. Such sustained-
`
`release pharmaceutical compositions are described in Part 8, Chapter 91 of Remington's
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`Pharmaceutical Sciences, 18th ed. 1990, Mack Publishing Group, Enolo.
`
`Parenteral application can be carried out with avoidance of an absorption step
`
`(intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or with
`
`inclusion of an absorption (intramuscularly, subcutaneously, intracutaneously,
`
`percutaneously or intraperitoneally). Useful parenteral application forms include injection
`
`and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates
`
`and sterile powders. Such parenteral pharmaceutical compositions are described in Part 8,
`
`Chapter 84 of Remington's Pharmaceutical Sciences, 18‘h ed. 1990, Mack Publishing
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`Group, Enolo.
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`In one embodiment, the invention relates to intravenous (i.v.) application of the active
`
`compound, e.g. as bolus injection (that is as single dose, e.g. per syringe), infusion over a
`short period of time (e. g. for up to one hour) or infusion over a long period of time (e. g.
`for more than one hour). The application can also be done by intermittent dosing. The
`
`applied volume can vary dependent on the conditions and usually is 0.5 to 30, or 1 to 20
`ml for bolus injection, 25 to 500, or 50 to 250 ml for infusion over a short period of time
`
`and 50 to 1000, or 100 to 500 ml for infusion over a long period of time.
`
`Such application forms have to be sterile and free of pyrogens. They can be based on
`aqueous solvents or mixtures of aqueous and organic solvents. Examples are ethanol,
`polyethyleneglycol (PEG) 300 or 400, aqueous solutions containing cyclodextrins or
`emulsifiers, such as lecithin, Pluronic F68®, Solutol HS 15® or Cremophor®. Aqueous
`
`solutions are preferred.
`
`For intravenous application the solutions are generally isotonic and euhydric, for example
`
`with a pH of 3 to 11, 6 to 8 or about 7.4.
`Glass or plastic containers can be employed as packaging for i.v.—solutions, e.g. rubber
`
`seal vials. They can contain liquid volumes of 1 to 1000, or 5 to 50 ml. The solution can
`
`directly be withdrawn from the vial to be applied to the patient. For this purpose, it can be
`
`advantageous to provide the active compound in solid form (e.g. as lyophilisate) and
`
`dissolve by adding the solvent to the vial directly before administration.
`
`Solutions for infusion can advantageously be packaged in containers made from glass or
`
`plastic, for example bottles or collapsible containers such as bags. They can contain liquid
`
`volumes of 1 to 1000, or 50 to 500 m1.
`
`Forms suitable for other application routes include for example inhalatory pharmaceutical
`
`forms (including powder inhalers, nebulizers), nasal drops/solutions, sprays; tablets 01'
`
`capsules to be administered lingually, sublingually or buccally, suppositories, ear and eye
`preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic
`
`suspensions, ointments, creams, milk, pastes, dusting powders or implants.
`
`The active components can be converted into said application forms in a manner known
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`PCT/U52006/013505
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`per se. This is carried out using inert non—toxic, pharmaceutically suitable excipients.
`These include inter alia carriers (for example microcrystalline cellulose), solvents (for
`
`example liquid polyethylene glycols), emulsifiers (for example sodium dodecyl sulphate),
`
`dispersing agents (for example polyvinylpyrrolidone), synthetic and natural biopolymers
`(for example albumin), stabilizers (for example antioxidants such as ascorbic acid),
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`colorants (for example inorganic pigments such as iron oxides) or taste and/or odor
`
`corrigents. Exemplary application forms are given in part C of this application.
`
`For human use, in the case of oral administration, it is recommended to administer doses of
`
`from 0.001 to 50 mg/kg, or from 0.01 to 20 mg/kg. In the case of parenteral administration
`
`such as, for example, intravenously or via mucous membranes nasally, buccally or
`
`inhalationall