Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • 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 invention relates to chemical compounds, or pharmaceutically acceptable salts thereof, which possess B-Raf inhibitory activity and are accordingly useful for their anti-cancer activity and thus in methods of treatment of the human or animal body.
• the invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm-blooded animal such as man.
• Ras, Raf, MAP protein kinase/extracellular signal -regulated kinase kinase (MEK), extracellular signal -regulated kinase (ERK) pathway plays a central role in the regulation of a variety of cellular functions dependent upon cellular context, including cellular proliferation, differentiation, survival, immortalization and angiogenesis (reviewed in Peyssonnaux and Eychene, Biology of the Cell, 2001, 93,3-62).
• Rasf family members are recruited to the plasma membrane upon binding to guanosine triphosphate (GTP) loaded Ras resulting in the phosphorylation and activation of Raf proteins.
• GTP guanosine triphosphate
• Rafs Activated Rafs then phosphorylate and activate MEKs, which in turn phosphorylate and activate ERKs.
• ERKs Upon activation, ERKs translocate from the cytoplasm to the nucleus resulting in the phosphorylation and regulation of activity of transcription factors such as EIk-I andMyc.
• the Ras/Raf/MEK/ERK pathway has been reported to contribute to the tumorigenic phenotype by inducing immortalisation, growth factor-independent growth, insensitivity to growth-inhibitory signals, ability to invade and metastasis, stimulating angiogenesis and inhibition of apoptosis (reviewed in Kolch et al, Exp.Rev. MoI.
• ERK phosphorylation is enhanced in approximately 30% of all human tumours (Hoshino et al., Oncogene, 1999, 18, 813-822). This may be a result of overexpression and/or mutation of key members of the pathway.
• Raf serine/threonine protein kinase isoforms have been reported Raf-1 /c-Raf, B-Raf and A-Raf (reviewed in Mercer and Pritchard, Biochim. Biophys. Acta, 2003, 1653, 25-40), the genes for which are thought to have arisen from gene duplication. All three Raf genes are expressed in most tissues with high-level expression of B-Raf in neuronal tissue and A-Raf in urogenital tissue. The highly homologous Raf family members have overlapping but distinct biochemical activities and biological functions (Hagemann and Rapp, Expt. Cell Res. 1999, 253, 34-46).
• B-Raf The most frequent mutation in B-Raf (80%) is a glutamic acid for valine substitution at position 600. These mutations increase the basal kinase activity of B-Raf and are thought to uncouple Raf/MEKL/ERK signalling from upstream proliferation drives including Ras and growth factor receptor activation resulting in constitutive activation of ERK. Mutated B-Raf proteins are transforming in NIH3T3 cells (Davies et al., Nature, 2002,
• B-Raf represents a likely point of intervention in tumours dependent on this pathway.
• AstraZeneca has filed certain international applications directed towards B-Raf inhibitors: PCT publication Nos. WO 2005/123696, WO 2006/003378, WO 2006/024834, WO 2006/024836, WO 2006/040568, WO 2006/067446 and WO 2006/079791.
• the present application is based on a class of compound which are novel B-Raf inhibitors and it is expected that these compound possess beneficial efficacious, metabolic and / or toxicological profiles that make them particularly suitable for in vivo administration to a warm blooded animal, such as man.
• R 1 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci- 6 alkoxy, Ci- ⁇ alkanoyl, N,N-(C 1-6 alkyl) 2 amino, N'-(C 1-6 alkyl)ureido, N',N'-(Ci -6 alkyl) 2 ureido, N'-(Ci -6 alkyl)- N-(C 1-6 alkyl)ureido, N',N'-(C ⁇ -6a ⁇ ky ⁇ )2- N-CQ-oalky ⁇ ureido, Ci.6alkanoylamino, N-(C 1-(5 alkyl)carbamoyl, C 1-6 alkylS(O) a wherein a is
• R 15 , R 16 , R 17 , R 18 and R 19 is hydrogen, C 1-6 alkoxycarbonyl or C 1-6 alkyl and s is 0-2;
• R 6 , R 10 and R 14 are independently selected from C h alky!, Q- ⁇ alkanoyl, C ⁇ ⁇ alkylsulphonyl, Q- ⁇ alkoxycarbonyl, carbamoyl, ⁇ (Ci-ealky ⁇ carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
• R 13 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbon
• R 1 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, ureido, C ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Q- ⁇ alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N-(C 1-6 alkyl)amino, N,N-(C 1-6 alkyl) 2 amino, N'-(Ci -6 alkyl)ureido, N',N'-(Ci -6 alkyl) 2 ureido, N'-(C 1-6 alkyl)- N-(C 1-6 alkyl)ureido, N-(Ci -6 aUcyl)ureido, Ci- ⁇ alkanoylamino, N-(C 1-6 alkyl)carbamoyl, N,N-(C
• R 2 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci- ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, d- ⁇ alkoxy, C 1-6 alkanoyl, d- ⁇ alkanoyloxy, N-(Ci- 6 alkyl)amino, N,N-(Ci- 6 alkyl) 2 amino, d- ⁇ alkanoylamino, N-(C 1 -ealky ⁇ carbamoyl, N,N-(Ci- 6 alkyl) 2 carbamoyl, Ci -6 alkylS(O) a wherein a is 0 to 2, d- ⁇ alkoxycarbonyl, N-(Ci- 6 ah ⁇ yl)sulphamoyl,
• R 2 may be optionally substituted on carbon by one or more R 9 ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 10 ; m is selected from 0-4; wherein the values of R 2 may be the same or different;
• R 5 and R 9 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, d ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, d. 6 alkoxy, d- ⁇ alkanoyl, d ⁇ allcanoyloxy, N-(d- 6 alkyi)amino, N,N-(C 1-6 alkyl) 2 amino, d- ⁇ alkanoylamino, N-(d -6 alkyl)d. 6 alkanoylamino,
• R 3 , R 4 , R 7 , R 8 , R 11 and R 12 are independently selected from a direct bond, -O-, -N(R 15 )-, -C(O)-, -N(R 16 )C(O)-, -C(O)N(R 17 )-, -S(O) 5 -, -SO 2 N(R 18 )- and -N(R 19 )SO 2 -; wherein R 15 , R 16 , R 17 , R 18 and R 19 is hydrogen, C 1-6 alkoxycarbonyl or C 1-6 alkyl and s is 0-2;
• R 6 , R 10 and R 14 are independently selected from C ⁇ aUcyl, C 1-6 alkanoyl, C 1-6 alkylsulphonyl, d- 6 alkoxycarbonyl, carbamoyl, N-(C 1-6 alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
• R 20 , R 21 , R 22 , R 23 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34 are independently selected from amino, Q- ⁇ alkoxy and carbocyclyl;
• R 24 , R 25 and R 26 are independently selected from hydroxy, C 1-6 alkyl, C ⁇ alkoxy and carbocyclyl; or R 24 and R 25 together with the silicon to which they are attached form a ring; wherein R 24 , R 25 and R 26 may be independently optionally substituted on carbon by one or more R 35 ;
• R 13 and R 35 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl,
• alkyl includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only.
• C h alky! includes C 1-4 alkyl, C ⁇ alkyl, propyl, isopropyl and f-butyl.
• phenylQ- ⁇ alkyl includes phenylC 1-4 alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.
• halo refers to fluoro, chloro, bromo and iodo.
• heterocyclyl is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)-, and a ring sulphur atom may be optionally oxidised to form the S-oxides.
• heterocyclyl examples and suitable values of the term "heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, pyrazolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, , 4-pyridone, 1-isoquinolone, 2-pyrrolidone, and 4-thiazolidone,.
• heterocyclyl is pyrazolyl.
• a “heterocyclyl” is a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a -CH 2 - group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxides.
• a “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH 2 - group can optionally be replaced by a -C(O)-. Particularly “carbocyclyl” is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms.
• Suitable values for "carbocyclyl” include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.
• a particular example of “carbocyclyl” is phenyl.
• An example of "Q- ⁇ alkanoyloxy” is acetoxy.
• Examples of "C 1-6 alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n- and ⁇ -butoxycarbonyl.
• Examples of “C ⁇ alkoxy” include methoxy, ethoxy andpropoxy.
• Examples of “Q-ealkanoylamino” include formamido, acetamido and propionylamino.
• Examples of "C 1-6 alkylS(O) a wherein a is 0 to 2” include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl.
• Examples of “C ⁇ alkanoyl” include propionyl and acetyl.
• Examples of "N-(C 1-6 alkyl)amino” include metbylamino and ethylamino.
• N,N-(C 1-6 alkyl) 2 amino examples include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino.
• C 2- 6alkenyl examples are vinyl, allyl and 1-propenyl.
• C 2-6 alkynyl examples are ethynyl, 1-propynyl and 2-propynyl. Examples of re N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of are N,N-(dimethyl)sulphamoyl and
• N-(methyl)-N-(ethyl)sulphamoyl examples of “N-CC ⁇ ealky ⁇ carbamoyl” are N-(C 1-4 alkyl)carbamoyl, methylaminocarbonyl and ethylaminocarbonyl. Examples of are N,N-(C 1-4 alkyl) 2 carbamoyl, dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of “C ⁇ alkylsulphonyl” are mesyl, ethylsulphonyl and isopropylsulphonyl.
• Examples of “C ⁇ ealkylsulphonylamino” are mesylamino, ethylsulphonylamino and isopropylsulphonylamino.
• Examples of “N-(C 1-6 aUcoxy)sulphamoyl” include N-(methoxy)sulphamoyl and N-(ethoxy)sulphamoyl.
• Examples of “N-(C 1-6 alkyl)-N-(Ci -6 alkoxy)sulphamoyl” include N-(methyl)-N-(methoxy)sulphamoyl andN-(propyl)-N-(ethoxy)sulphamoyl.
• a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, formic, citric or maleic acid.
• a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morphorine or tris-(2-hydroxyethyl)arnine.
• an alkali metal salt for example a sodium or potassium salt
• an alkaline earth metal salt for example a calcium or magnesium salt
• an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation
• a salt with methylamine, dimethylamine, trimethylamine, piperidine, morphorine or tris-(2-hydroxyethyl)arnine for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morphorine or tris
• Some compounds of the formula (I) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess B-Raf inhibitory activity.
• the invention further relates to any and all tautomeric forms of the compounds of the formula (I) that possess B-Raf inhibitory activity.
• R 1 is selected from cyano, wherein R 1 may be optionally substituted on carbon by one or more R 5 ; wherein
• R 5 is selected from Q- ⁇ alkoxy, N,N-(C 1- 6alkyl) 2 amino and heterocyclyl-R 12 -; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 14 ;
• R 12 is a direct bond; and R 14 is C 1-6 alkyl.
• R 1 is selected from cyano, C ⁇ alkyl, Ci- ⁇ alkoxy, heterocyclyl-R 4 -, Ci- ⁇ alkanoyl, N-(C 1-6 alkyl)sulphamoyl, Ci-ealkanoylamino, N-CQ-galkyOCi-ealkanoylamino, C ⁇ alkylsulphonylamino, N,N-(Ci- 6 alkyl) 2 carbamoyl, and N ⁇ C ⁇ -ealkytycarbamoyl; wherein R 1 may be optionally substituted on carbon by one or more R 5 ; wherein
• R 4 is a direct bond
• R 5 is selected from cyano, amino, hydroxy, C 1-6 alkoxy, N-td- ⁇ alkytycarbamoyl, N-(Ci- 6 alkyl)amino, N,N-(C 1-6 alkyl) 2 amino, Q-ealkanoylamino, Q- ⁇ alkoxycarbonylamino, N- (N-Ci- ⁇ alkytyCi-ealkylsulphonylamino, (R 33 )(R 34 )P(O)(C 1-6 alkyl) ⁇ -, and heterocyclyl-R 12 -; wherein R 5 may be optionally substituted on carbon by R 13 ; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 14 ; R 12 is a direct bond;
• R 13 is selected from hydroxy and alkoxyl
• R 14 is C 1-6 alkyl
• R 33 and R 34 are Ci -6 alkyl.
• R 1 is selected from cyano, methyl, C 1-6 alkoxy, N-ethylcarbamoyl and N-propylcarbamoyl; wherein R 1 may be optionally substituted on carbon by one or more R 5 ; wherein
• R 5 is selected from methoxy, dimethylamino and pyrrolidinyl-R 12 -; wherein said pyrrolidinyl may be optionally substituted on nitrogen by a group selected from R 14 ;
• R 12 is a direct bond; and R 14 is methyl.
• R 1 is selected from cyano, methyl, ethyl, propyl, C 1-6 alkoxy, N-ethylcarbamoyl and N-propylcarbamoyl, N-methyl-N-ethylcarbamoyl, 2-pyrrolidinonyl, acetyl, N-ethylsulphamoyl, methanoylamino, ethanoylamino, (N-methyl)ethanoylamino, N-methylsulphamoylamino; wherein R 1 may be optionally substituted on carbon by one or more R 5 ; wherein
• R 5 is selected from cyano, amino, methoxy, hydroxy, N-ethylcarbamoyl, ethylamino, dimethylamino, N-methyl-N-propylamino, methanoylamino, ethanoylamino, (N- methyl)methanoylamino, (N-methyl)ethanoylamino, (N-methyl)methylsulphonylamino, t- butoxycarbonylamino, Me 2 P(O)(Me)N-, morpholin-1-yl, pyrrolidin-1-yl-R 12 - and pyrrolidin- 2-yl-R 12 -; wherein R 5 may be optionally substituted on carbon by R 13 wherein said pyrrolidine-2-yl may be optionally substituted on nitrogen by a group selected from R 14 ;
• R 12 is a direct bond
• R 13 is selected from hydroxy and methoxy; and R 14 is methyl.
• R 1 is selected from N-(2-methoxyethyl)carbamoyl, cyano, methyl, N-(2-dimethylaminoethyl)carbamoyl, N-(3-dimethylaminopropyl)carbamoyl, N-[2-(l-methylpyrrolidin-2-yl)ethyl]carbamoyl, N- [2-(pyrrolidin-l-yl)ethyl] carbamoyl, N-(3-mo ⁇ holinopropyl)carbamoyl, and 2-(pyrrolidin-l-yl)ethoxy.
• R 1 is selected from (lR)-l-(N-3-methoxypropanoylamino)ethyl, (IR)-I-(N- acetamido)ethyl, ( 1 S)- 1 -(N-3 -methoxypropanoylamino)ethyl, (IS)-I -(N-tert- butoxycarbonylamino)ethyl, (lS)-l-N-acetamidoethyl, (lS)-l-aminoethyl, (N-2- hydroxyethyl-N-methyl-amino)methyl, (N-3 -hydroxypropyl-N-methyl-amino)methyl, (N- acetyl-N-methyl-amino)methyl, l-(N-2-methoxyethylamino)ethyl, l-(N-3- methoxypropanoylamino)ethyl, l-(N-3-
• R 2 is selected from halo, C 1-6 alkyl and Q-ealkoxy.
• R 2 is selected from fluoro, methyl and methoxy. m is selected from 0-2; wherein the values of R 2 may be the same or different. m is 0. m is l. m is 2; wherein the values of R 2 may be the same or different.
• (R 2 ) m is a methyl group in the 4-position of the pyridyl ring of formula (I).
• R 1 is selected from cyano, C 1-6 alkyl, C 1-6 alkoxy andN-(C 1-6 alkyl)carbamoyl; wherein R 1 may be optionally substituted on carbon by one or more R ; n is selected from 1 or 2; wherein the values of R 1 may be the same or different;
• R 2 is selected from halo, C 1-6 alkyl and Q ⁇ alkoxy; m is selected from 0-2; wherein the values of R 2 may be the same or different; R 5 is selected from C 1-6 alkoxy, N,N-(C 1-6 aUcyl) 2 amino and heterocyclyl-R 12 -; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 14 ;
• R 12 is a direct bond; and R 14 is Ci- ⁇ alkyl; or a pharmaceutically acceptable salt thereof.
• R 1 is selected from cyano, Ci- ⁇ alkyl, C ⁇ alkoxy heterocyclyl-R 4 -, Ci-ealkanoyl, Ci-galkanoylamino, Ci- ⁇ alkylsulphonylamino, N,N-(C 1-6 aU ⁇ yl) 2 amino, and wherein R 1 may be optionally substituted on carbon by one or more R 5 ; n is selected from 1 or 2; wherein the values of R 1 may be the same or different; R 2 is selected from halo, C 1-6 alkyl and C ⁇ alkoxy; m is selected from 0-2; wherein the values of R 2 may be the same or different; R 4 is a direct bond;
• R 5 is selected from cyano, amino, hydroxy, Q- ⁇ alkoxy, , N-(Ci- 6 ahVyl)carbamoyl, N-(Ci- 6 alkyl)amino, Ci- 6 alkanoylamino, Q-ealkoxycarbonylamino, N- (Ci-ealkytyQ-ealkanoylamino, (N-Ci-ealkytyQ- ⁇ alkylsulphonylamino,
• R 33 (R 34 )P(O)(C 1-6 alkyl) ⁇ -, and heterocyclyl-R 12 -; wherein R 5 may be optionally substituted on carbon by R 13 ; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 14 ;
• R 12 is a direct bond
• R 13 is selected from hydroxy and alkoxyl
• R 14 is C 1-6 alkyl; and R 33 and R 34 are Ci -6 alkyl. or a pharmaceutically acceptable salt thereof. Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein:
• R 1 is selected from N-(2-methoxyethyl)carbamoyl, cyano, methyl, N-(2-dimethylaminoethyl)carbamoyl, N-(3-dimethylaminopropyl)carbamoyl, N-[2-(l-methylpyrrolidin-2-yl)ethyl]carbamoyl, N-[2-(pyrrolidin-l-yl)ethyl]carbamoyl, N-(3-morpholinopropyl)carbamoyl and 2-(pyrrolidin-l-yl)ethoxy; n is selected from 1 or 2; wherein the values of R 1 may be the same or different;
• R 2 is selected from fluoro, methyl and methoxy; m is selected from 0-2; wherein the values of R 2 may be the same or different; or a pharmaceutically acceptable salt thereof;
• variable groups are as defined for formula (I) and x is selected from 0-3; wherein the values of R 2 may be the same or different; or a pharmaceutically acceptable salt thereof. Particularly x is 0.
• the invention relates to a compound of the formula (I) which is a compound of the formula I(b);
• R 37 is selected from hydrogen, halo, and Q- ⁇ alkoxy
• R 38 is selected from hydrogen and halo
• R 39 is selected from hydrogen and C 1-6 alkyl
• R 40 is selected from hydrogen and halo
• R 41 is selected from hydrogen and Ci- ⁇ alkoxy
• R 42 is selected from hydrogen, cyano, Ci ⁇ alkyl, and C ⁇ ealkoxy;
• R 45 is selected from hydrogen, cyano, C 1-6 alkoxy, N,N-(C 1-6 alkyl) 2 amino, and heterocyclyl;
• R 44 , R 46 , R 47 , R 48 , R 49 , R 55 , R 56 , R 57 , and R 58 are each independently selected from hydrogen and C i - ⁇ alkyl;
• R 50 , R 51 , R 52 , R 53 , R 54 , R 60 , R 61 , R 62 , are C 1-6 alkyl; R 59 is selected from C 1 ⁇ aIkVl and C 1 ⁇ aIkOXy; or pharmaceutically acceptable salts thereof.
• R 37 , R 38 , and R 40 are hydrogen; and R 39 is methyl.
• preferred compounds of the invention are any one of the Examples or a pharmaceutically acceptable salt thereof.
• Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof which process (wherein variable are, unless otherwise specified, as defined in formula (I), comprises of: Process a) reacting an amine of formula (II):
• L is a displaceable atom or group, suitable values for L are for example, a halo or sulphonyloxy group, for example a chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy group.
• D is a displaceable atom or group
• suitable values for L include chloro, bromo, tosyl and trifluoromethylsulphonyloxy.
• M is an organometallic or organoboron reagent, suitable values for M include organoboron and organotin reagents, in particular B(OR Z ) 2 where R z is hydrogen or C 1-6 alkyl for example B(OH) 2 ; and Sn(R y ) 3 where R y is for example Sn(Bu) 3 .
• V can be reacted together by coupling chemistry utilizing an appropriate catalyst and ligand such as Pd 2 (dba) 3 and BINAP respectively and a suitable base such as sodium terf-butoxide or caesium carbonate.
• an appropriate catalyst and ligand such as Pd 2 (dba) 3 and BINAP respectively and a suitable base such as sodium terf-butoxide or caesium carbonate.
• a suitable base such as sodium terf-butoxide or caesium carbonate.
• the reaction usually requires thermal conditions often in the range of
• Amines of formula (II) may be prepared according to Scheme 1 :
• the invention relates to a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, as disclosed herein, which process comprises of: Process a) reacting an amine of formula (II): with a compound of formula (III):
• aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
• modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
• a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
• the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
• an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• an acyl group such as a 7-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
• a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
• a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
• the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
• an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
• a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
• a base such as sodium hydroxide
• a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
• the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
• the compounds defined in the present invention possesses anti-cancer activity which is believed to arise from the B-Raf inhibitory activity of the compound. These properties may be assessed, for example, using the procedure set out below.
• MT B- Raf Activity of purified full length His-tagged Mutant B-Raf (V600E) enzyme (MT B- Raf) may be determined in vitro using an Amplified Luminescent Proximity Homogeneous Assay (ALPHA) (Perkin Elmer, MA), which measures phosphorylation of the MT B-Raf substrate, biotinylated HIS-MEK-AVI (PLAZA internal database, construct #pAZB0141), as described below.
• APHA Amplified Luminescent Proximity Homogeneous Assay
• MA Amplified Luminescent Proximity Homogeneous Assay
• MA Biotinylated HIS-MEK-AVI
• Typical yields can be 1.08 mg/ml at >90% purity.
• the phosphorylation of the MT B-Raf substrate in the presence and absence of the compound of interest may be determined. Briefly, 5 ⁇ l of enzyme/substrate/adenosine triphosphate (ATP) mix consisting of 0.12nM MT B-Raf, 84nM biotinylated HIS-MEK-AVI, and 24 ⁇ M ATP in 1.2x buffer may be preincubated with 2 ⁇ l of compound for 20 minutes at 25 0 C.
• enzyme/substrate/adenosine triphosphate (ATP) mix consisting of 0.12nM MT B-Raf, 84nM biotinylated HIS-MEK-AVI, and 24 ⁇ M ATP in 1.2x buffer may be preincubated with 2 ⁇ l of compound for 20 minutes at 25 0 C.
• ATP Enzyme/Substrate/adenosine triphosphate
• Reactions can be initiated with 5 ⁇ l of Metal mix consisting of 24mM MgCl 2 in 1.2x buffer and incubated at 25 0 C for 60 minutes and reactions can be stopped by addition of 5 ⁇ l of Detection mix consisting of 2OmM HEPES, 102mM ethylenediamine tetraacetic acid, 1.65mg/ml BSA, 136mM NaCl, 3.4nM Phospho- MEK1/2 (Ser217/221) antibody (Catalog #9121, Cell Signaling Technology, MA), 40 ⁇ g/ml Streptavidin donor beads (Perkin Elmer, MA, Catalog #6760002), and 40 ⁇ g/ml Protein A acceptor beads
• Plates may be incubated at 25 0 C for 18 hours in the dark.
• Phosphorylated substrate can be detected by an En Vision plate reader (Perkin Elmer, MA) 680nm excitation, 520-620nm emission. Data can be graphed and IC 50 S calculated using Excel Fit (Microsoft).
• a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in association with a pharmaceutically-acceptable diluent or carrier.
• the composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
• parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
• a sterile solution, suspension or emulsion for topical administration as an ointment or cream or for rectal administration as a suppository.
• the above compositions may be prepared in a conventional manner using conventional excipients.
• the compound of formula (I) will normally be administered to a warm-blooded animal at a unit dose within the range 1-1000 mg/kg, and this normally provides a therapeutically-effective dose.
• a daily dose in the range of 10-100 mg/kg is employed.
• the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
• a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
• the compounds defined in the present invention are effective anti-cancer agents which property is believed to arise from their B-Raf inhibitory properties. Accordingly the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by B-Raf, i.e. the compounds may be used to produce a B-Raf inhibitory effect in a warm-blooded animal in need of such treatment.
• the compounds of the present invention provide a method for treating cancer characterised by inhibition of B-Raf, i.e. the compounds may be used to produce an anti- cancer effect mediated alone or in part by the inhibition of B-Raf.
• a compound of the invention is expected to possess a wide range of anti-cancer properties as activating mutations in B-Raf have been observed in many human cancers, including but not limited to, melanoma, papillary thyroid tumours, cholangiocarcinomas, colon, ovarian and lung cancers.
• a compound of the invention will possess anti-cancer activity against these cancers.
• a compound of the present invention will possess activity against a range of leukaemias, lymphoid malignancies and solid tumours such as carcinomas and sarcomas in tissues such as the liver, kidney, bladder, prostate, breast and pancreas.
• solid tumours such as carcinomas and sarcomas in tissues such as the liver, kidney, bladder, prostate, breast and pancreas.
• such compounds of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the skin, colon, thyroid, lungs and ovaries.
• Such compounds of the invention are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with B-Raf, especially those tumours which are significantly dependent on B-Raf for their growth and spread, including for example, certain tumours of the skin, colon, thyroid, lungs and ovaries.
• Particularly the compounds of the present invention are useful in the treatment of melanomas.
• a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
• a method for producing a B-Raf inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
• a method for producing an anti-cancer effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
• a method of treating melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein before.
• a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of a B-Raf inhibitory effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a compound of the formula (T), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries in a warm-blooded animal such as man.
• the invention relates to a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for the production of a B-Raf inhibitory effect in a warm-blooded animal such as man.
• the invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for producing an anti-cancer effect in a warm-blooded animal, such as man.
• the invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for treatment of melanoma, papillary thyroid tumours, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukaemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumours of the skin, colon, thyroid, lungs and ovaries in a warm-blooded animal such as man.
• the B-Raf inhibitory treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
• Such chemotherapy may include one or more of the following categories of anti-tumour agents: (i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);
• cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride;
• antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
• antiandrogens for example
• anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2- chloro-6-methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-l-yl]-2-methylpyrimidin-4- ylamino ⁇ thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem..
• inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
• inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZDl 839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet
• antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti- vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo- 2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3- pyrrolidin-l-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SUl 1248 (Sutent TM; WO 01/60814), compounds such as those disclosed in International Patent Applications WO 97/22596,
• antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
• gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drag therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drag resistance gene therapy;
• GDEPT gene-directed enzyme pro-drag therapy
• immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies;
• cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
• cell cycle inhibitors including for example CDK inhibitiors (eg flavopiridol) and other inhibitors of cell cycle checkpoints (eg checkpoint kinase); inhibitors of aurora kinase and other kinases involved in mitosis and cytokinesis regulation (eg mitotic kinesins); and histone deacetylase inhibitors; and
• endothelin antagonists including endothelin A antagonists, endothelin B antagonists and endothelin A and B antagonists; for example ZD4054 and ZD1611 (WO 96 40681), atrasentan and YM598.
• the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of B-Raf in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
• the invention relates to a method of inhibiting B-Raf phosphorylation comprising providing a compound of the formula (I), or pharmaceuticaly acceptable salts thereof and mixing with B-Raf and B-Raf substrate under conditions such that
• temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C;
• NMR data when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulphoxide (DMSO-d ⁇ ) as solvent unless otherwise indicated;
• ISCO refers to normal phase flash column chromatography using 12g and 4Og pre- packed silica gel cartridges used according to the manufacturers instruction obtained from ISCO, Inc, 4700 superior street Lincoln, NE, USA.
• Glass HPLC refers to a YMC-AQC 18 reverse phase HPLC Column with dimension 20mm/100 and 50mm/250 in water-CH 3 CN with 0.1% TFA, 0.1% formic acid, or 0.1% 1OmM ammonium acetate as mobile phase, obtained from Waters Corporation 34, Maple street, Milford, MA 3 USA.
• Microwave refers to a CEM Explorer® series microwave purchased from CEM Corporation, P.O. Box 200, 3100 Smith Farm Rd., Matthews, NC, 28106, (704)-821-7015.
• Example 2 The compound was prepared by the procedure of Example 1 but using sodium /-butoxide as the base and a 20-24 hr reaction time. The compound was prepared by the procedure of Example 1 but using potassium ⁇ -butoxide as the base and toluene as solvent. Compound was purified using an ISCO system eluting with 0-10% MeOH/DCM gradient.
• N-(4-(6-bromoqumazolin-2- ylammo)phenyl)-3-methoxypropanamide (Method 41, 50 mg, 0.12 mmol), potassium carbonate (43.1 mg, 0.31 mmol), 4-methylpyridine-3-boronic acid (20.48 mg, 0.15 mmol), PdCl 2 (dppf)-CH 2 Cl 2 (5.09 mg, 6.23 ⁇ mol) and DME:water (3 ml:l ml).
• the reaction mixture was degassed with argon and heated overnight at 100 °C. The reaction mixture was then filtered and the filtrate was evaporated under reduced pressure.
• Example 29 The compound was isolated as a by-product under the reaction conditions of Example 29. 2
• the compound was prepared by the procedure of Example 29 but using Pd(Ph 3 P) 4 and cesium carbonate in 1,4-dioxane/water (3 ml/1 ml).
• Example 42 The compound was isolated as a by-product under the reaction conditions of Example 42.
• the reaction mixture was heated to 100 0 C for 3 h.
• the reaction was cooled and filtered.
• the crude mixture was purified on an ISCO system (EtOAc/Et 3 N) to give 1.05 g (73% yield) of the desired product; m/z 341.
• 6-Bromoquinazolin-2-amme (Method 10, 100 mg, 0.446 mmol), (4-methylpyridin-3- yl)boronic acid (92 mg, 0.671 mmol, 1.5 equiv) and Cs 2 CO 3 (436 mg, 1.33 mmol, 3.0 equiv) in dioxane/H 2 O (4:1, 5 ml) were treated with Pd(Ph 3 P) 4 (52 mg, 0.045 mmol, 0.1 equiv). The reaction was stirred at 80 0 C for 2 h. The crude reaction mixture was filtered, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography utilizing an ISCO system (EtOAc/Hexane) to give 68 mg (65%) of the desired product; m/z 237.
• Methods 12-16 The following compounds were prepared by the procedure of Method 11 using the appropriate starting materials.
• N-r4-r6-bromoquinazolin-2-ylamino)phenylV3-methoxypropanamide To a 200 ml round-bottom flask was added 6-bromo-2-chloroquinazoline (prepared in analogy to WO92/15569) (85 mg, 0.35 mmol), N-(4-aminophenyl)-3-methoxypropanamide (Method 38, 68 mg, 0.35 mmol), and 3 ml of 2-propanol. The reaction mixture was stirred for two hours at 100 °C whereupon the yellow solids were filtered to yield the title compound (105 mg, 0.26 mmol, 74.7 %) .
• Compound was prepared by the procedure of Method 41 but using acetonitrile as solvent and heating in a microwave at 125 0 C for 30 minutes.

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