CHEMICAL COMPOUNDS-576

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. The classical 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). In this pathway, Raf 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. Activated Rafs then phosphorylate and activate MEKs, which in turn phosphorylate and activate 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. Med., 2002, 25 April, http://www.expertreviews.org/02004386h.htm). In fact, 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.

Three 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). Expression of all three Raf genes is required for normal murine

development however both c-Raf and B-Raf are required to complete gestation. B-Raf -/- mice die at E 12.5 due to vascular haemorrhaging caused by increased apoptosis of endothelial cells (Wojnowski et al., Nature Genet., 1997, 16, 293-297). B-Raf is reportedly the major isoform involved in cell proliferation and the primary target of oncogenic Ras. Activating 5 somatic missense mutations have been identified exclusively for B-Raf, occurring with a frequency of 66% in malignant cutaneous melanomas (Davies et al., Nature, 2002, 417, 949- 954) and also present in a wide range of human cancers, including but not limited to papillary thyroid tumours (Cohen et al., J. Natl. Cancer Inst., 2003, 95, 625-627), cholangiocarcinomas (Tannapfel et al., Gut, 2003, 52, 706-712), colon and ovarian cancers (Davies et al., Nature,

10 2002, 417, 949-954). 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,

15 417, 949-954) and melanocytes (Wellbrock et al., Cancer Res., 2004, 64, 2338-2342) and have also been shown to be essential for melanoma cell viability and transformation (Hingorani et al., Cancer Res., 2003, 63, 5198-5202). As a key driver of the Raf/MEK/ERK signalling cascade, B-Raf represents a likely point of intervention in tumours dependent on this pathway.

20 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.

Amgen's PCT publication WO 2006/039718, published 13 April 2006, describes aryl nitrogen-containing bicyclic compounds for use in treating protein kinase mediated disease

25 states, including inflammation, cancer and related conditions.

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.

30 Accordingly, the present invention provides a compound of formula (I):

(I) wherein:

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- _ό 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'-(Cι-6aϊkyϊ)2- N-CQ-oalky^ureido, Ci.6alkanoylamino, N-(C _1-(5 alkyl)carbamoyl, C _1-6 alkylS(O) _a wherein a is 0 to 2, Cμgalkoxycarbonyl, N^C _ϊ -ealkytysulphamoyl, N,N-(Ci.6alkyl) ₂ sulphamoyl, C _1- 6alkylsulphonylamino, carbocyclyl-R ³ - and heterocyclyl-R ⁴ -; wherein R ¹ may be optionally substituted on carbon by one or more R ⁵ ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ⁶ ; n is selected from 0-4; wherein the values of R ¹ may be the same or different; R ² is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C^alkyl, C _2- 6alkenyl, C ₂ - ₆ alkynyl, C^alkoxy, Ci-ealkanoyl, C _ϊ -βalkanoyloxy, N-(C _1-6 alkyl)amino, Ci-ealkanoylamino, N,N-(C _1- 6alkyl) ₂ carbamoyl, Ci _-6 alkylS(O) _a wherein a is 0 to 2, Ci- _δ alkoxycarbonyl, d-βalkylsulphonylamino, carbocyclyl-R ⁷ - and heterocyclyl-R ⁸ -; wherein 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, Ci-βalkyl, C _2-6 alkenyl, C _2-6 alkynyl, Ci-βalkoxy, Ci-βalkanoyl, C^eallcanoyloxy, N-(Ci. ₆ alkyl)amino, N,N-(C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, N-(Ci.6alkyl)carbamoyl, N,N-(Ci-6alkyl) ₂ carbamoyl, C^alkylS^ _a wherein a is 0 to 2, C _1-6 alkoxycarbonyl, N-(Ci- ₆ alkyl)sulphamoyl,

N,N-(Ci- ₆ alkyl) ₂ sulphamoyl, C _1-6 alkylsulphonylamino, carbocyclyl-R ¹¹ - and heterocyclyl-R ¹² -; wherein R ⁵ and R ⁹ independently of each other may be optionally substituted on carbon by one or more R ¹³ ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ¹⁴ ; 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) ₃ -, -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 _h alky!, Q-βalkanoyl, Cμ _δ alkylsulphonyl, Q-βalkoxycarbonyl, 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, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl and N-methyl-N-ethylsulphamoyl; or a pharmaceutically acceptable salt thereof. Accordingly, the present invention provides a compound of formula (I):

(I) wherein:

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-βalkoxy, 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-βalkanoylamino, N-(C _1-6 alkyl)carbamoyl, N,N-(C _1-6 aUcyl) ₂ carbamoyl, C _1-6 alkylS(O) _a wherein a is 0 to 2,

Ci-βalkoxycarbonyl, C _1-6 alkylsulphonylamino, (R ²⁰ )(R ²¹ )P(O)-, (R ²⁷ )(R ²⁸ )P(O)νH-, (R ²⁹ )(R ³⁰ )P(O)(C _1-6 alkyl)N-, (R ²⁴ )(R ²⁵ )(R ²⁶ )Si-, carbocyclyl-R ³ - and heterocyclyl-R ⁴ -; wherein R ¹ may be optionally substituted on carbon by one or more R ⁵ ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ; n is selected from 0-4; wherein the values of R ¹ may be the same or different;

R ² is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-βalkyl, C _2-6 alkenyl, C _2-6 alkynyl, d-βalkoxy, C _1-6 alkanoyl, d-βalkanoyloxy, N-(Ci- ₆ alkyl)amino, N,N-(Ci- ₆ alkyl) ₂ amino, d-βalkanoylamino, N-(C ₁ -ealky^carbamoyl, N,N-(Ci- ₆ alkyl) ₂ carbamoyl, Ci _-6 alkylS(O) _a wherein a is 0 to 2, d-βalkoxycarbonyl, N-(Ci- ₆ ah<yl)sulphamoyl,

N,N-(C _1-6 alkyl) ₂ sulphamoyl, C _1-6 alkylsulphonylamino, carbocyclyl-R ⁷ - and heterocyclyl-R ⁸ -; wherein 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-βalkanoyl, d^allcanoyloxy, N-(d- ₆ alkyi)amino, N,N-(C _1-6 alkyl) ₂ amino, d-βalkanoylamino, N-(d _-6 alkyl)d. ₆ alkanoylamino,

N,N-(d-6alkyl) ₂ carbamoyl, C _1- 6alkylS(O) _a wherein a is 0 to 2, d-βalkoxycarbonyl, Ci-βalkoxycarbonylamino, N,N-(d- ₆ alkyl) ₂ sulphamoyl, C _1-6 alkylsulphonylamino, (N-d-ealky^d-ealkylsulphonylamino, (R ²² )(R ²³ )P(O)-, (R ³² )(R ³² )P(O)νH-, (R ³³ )(R ³⁴ )P(O)(C _1-6 alkyl)N-, carbocyclyl-R ¹¹ - and heterocyclyl-R ¹² -; wherein R ⁵ and R ⁹ independently of each other may be optionally substituted on carbon by one or more R ¹³ ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ¹⁴ ;

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-βalkoxy 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, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl and N-methyl-N-ethylsulphamoyl; or a pharmaceutically acceptable salt thereof.

In this specification the term "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. For example, "C _h alky!" includes C _1-4 alkyl, C^alkyl, propyl, isopropyl and f-butyl. A similar convention applies to other radicals, for example "phenylQ-βalkyl" includes phenylC _1-4 alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term "halo" refers to fluoro, chloro, bromo and iodo.

Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.A "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. 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,. A particular example of the term "heterocyclyl" is pyrazolyl. In one aspect of the invention 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-βalkanoyloxy" is acetoxy. Examples of "C _1-6 alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n- and ^-butoxycarbonyl. Examples of "Cμβalkoxy" 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. Examples of "N,N-(C _1-6 alkyl) ₂ amino" include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of "C _2- 6alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C _2-6 alkynyl" 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 "Cμδalkylsulphonyl" are mesyl, ethylsulphonyl and isopropylsulphonyl. Examples of "Cμealkylsulphonylamino" 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. In addition 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.

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.

It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess B-Raf inhibitory activity.

Particular values of variable groups are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.

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-βalkoxy, 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-βalkoxy, heterocyclyl-R ⁴ -, Ci-βalkanoyl, N-(C _1-6 alkyl)sulphamoyl, Ci-ealkanoylamino, N-CQ-galkyOCi-ealkanoylamino, Cμβalkylsulphonylamino, N,N-(Ci- ₆ alkyl) ₂ carbamoyl, and

N^C _ϊ -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-βalkytycarbamoyl, N-(Ci- ₆ alkyl)amino, N,N-(C _1-6 alkyl) ₂ amino, Q-ealkanoylamino, Q-βalkoxycarbonylamino, N- (N-Ci-βalkytyCi-ealkylsulphonylamino, (R ³³ )(R ³⁴ )P(O)(C _1-6 alkyl)ν-, 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.

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-moφholinopropyl)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-methoxypropanoyl-N-methyl-amino)ethyl, 1-(N- acetyl-N-methyl-amino)ethyl, 1 -(N-acetyl-N-methyl-amino)propyl, 1 -(N-dimethylphosphoryl- N-methyl-amino)ethyl, l-(N-methyl-N-methylsulfonyl-amino)ethyl, 1-N-acetamidoethyl, 2- (l-N-methylpyrrolidin-2-yl)ethylcarbamoyl, 2-cyanoethyl, N-(2- dimethylaminoethyl)carbamoyl, N-(2-dimethylaminoethyl)-N-methyl-carbamoyl, 2- dimethylaminoethylsulfamoyl, N-2-hydroxyethylsulfamoyl, N-(2-methoxyethyl)carbamoyl, N-2-methoxyethylcarbamoylmethyl, N-2-methoxyethyl-N-methyl-carbamoyl, N-2- methoxyethyl-N-methyl-sulfamoyl, N-2-methoxyethylsulfamoyl, 2-oxopyrrolidin-l-yl, 2- pyrrolidin-1-ylethoxy, N-(2-pyrrolidin-l-ylethyl)carbamoyl, N-(3- dimethylaminopropyl)carbamoyl, N-(3 -methoxypropanoyl)amino, N-3 -methoxypropanoyl- N- methyl-amino, N-3-moφholinopropyl)carbamoyl, acetyl, N-acetyl-N-methyl-amino, cyano, dimethylamino, formyl, hydrogen, N-methyl-Nmethylsulfonyl-amino, and propylsulfamoyl.n is selected from 1 or 2; wherein the values of R ¹ may be the same or different. n is 1. n is 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-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 ² ) _m includes a methyl group in the 4-position of the pyridyl ring of formula (I).

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 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-βalkyl; or a pharmaceutically acceptable salt thereof.

R ¹ is selected from cyano, Ci-βalkyl, C^alkoxy heterocyclyl-R ⁴ -, Ci-ealkanoyl, Ci-galkanoylamino, Ci-βalkylsulphonylamino, 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-βalkoxy, , N-(Ci- ₆ ahVyl)carbamoyl, N-(Ci- ₆ alkyl)amino, Ci- ₆ alkanoylamino, Q-ealkoxycarbonylamino, N- (Ci-ealkytyQ-ealkanoylamino, (N-Ci-ealkytyQ-βalkylsulphonylamino,

(R ³³ )(R ³⁴ )P(O)(C _1-6 alkyl)ν-, 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;

In a further aspect of the invention there is provided a compound of formula (I) which is a compound of formula (Ia):

Ca) wherein 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.

In some embodiments, the invention relates to a compound of the formula (I) which is a compound of the formula I(b);

(Ib) wherein: R ³⁷ is selected from hydrogen, halo, and Q-βalkoxy;

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-βalkoxy; R ⁴² is selected from hydrogen, cyano, Ci^alkyl, and Cμealkoxy;

R ⁴³ is selected from hydrogen, cyano, Ci-βalkanoyl, N ₃ N-(C i- ₆ alkyl) ₂ amino, -NR ⁵⁰ SO ₂ R ⁵¹ , -SO ₂ NR ⁵² , -NR ⁵³ (C=O)R ⁵⁴ , -CR ⁵⁵ R ⁵⁶ NR ⁵⁷ R ⁵⁸ , -CR ⁵⁵ R ⁵⁶ NR ⁵⁷ (C=O)R ⁵⁹ , - CR ⁵⁵ R ⁵⁶ NR ⁵⁷ CSO ₂ )R ⁶⁰ , -CR ⁵⁵ R ⁵⁶ NR ⁵⁷ (P=O)R ⁶¹ R ⁶² , heterocyclyl, and -X(CH ₂ ) _n R ⁴⁵ ;

X is selected from bond, -(C=O)NR ⁴⁴ -, -SO ₂ NR ⁴⁶ -, -CHR ⁴⁷ (C=O)NR ⁴⁸ -, - CHR ⁴⁷ N(C=O)-, -CHR ⁴⁷ NR ⁴⁸ -, and-NR ⁴⁹ (C=O)-; n is 2 or 3;

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 - _δ 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.

In further embodiments, R ³⁷ , R ³⁸ , and R ⁴⁰ are hydrogen; and R ³⁹ is methyl. In another aspect of the invention, 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):

(H) with a compound of formula (III):

(III) wherein L is a displaceable atom or group; or Process b) reacting a compound of formula (IV):

(IV) wherein L is a displaceable atom or group; with an amine of formula (V):

(V) or

Process c) reacting a compound of formula (VI):

(VI) wherein M is an organometallic or organoboron reagent; with a compound of formula (VII):

(VII) wherein D is a displaceable atom or group; or Process d) reacting a compound of formula (VIII):

(VIII) wherein D is a displaceable atom or group; with a compound of formula (IX):

(IX) wherein M is an organometallic or organoboron reagent; and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt.

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 .

Specific reaction conditions for the above reactions are as follows. Processes a) and b) Compounds of formula (II) and (III) and compounds of formula (IV) and

(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. The reaction usually requires thermal conditions often in the range of

80 ⁰ C to 100 °C. Amines of formula (II) may be prepared according to Scheme 1 :

(Ha) (lib)

Scheme 1 wherein the NH ₂ group may optionally need protecting.

Compounds of formula (IV) may be prepared according to Scheme 1) wherein the NH ₂ group is an L group.

Compounds of formula (Ha), (lib), (III) and (V) are commercially available compounds, or they are known in the literature or they may be prepared by standard processes known in the art.

Processes c) and d) Compounds of formula (VI) and (VII), and (VIII) and (IX) may be reacted together by coupling chemistry utilizing an appropriate catalyst. Such reactions are well known in the art. For example, where M is an organoboron group, Pd(PPh ₃ ) ₄ and a suitable base such as sodium carbonate or caesium carbonate can be utilized. In the case where M is an organotin reagent, Pd(PPh ₃ ) ₄ can be utilized as the catalyst. The reactions take place in suitable solvents and may require thermal conditions. Compounds of formula (VI) may be prepared according to Scheme 2:

(Via) (VIb)

Scheme 2 wherein L is a displaceable atom or group as defined herein above.

Compounds of formula (VIII) may be prepared according to Scheme 2) wherein the M group is a D group.

Compounds of formula (Via), (VIb), (VII) and (IX) are commercially available compounds, or they are known in the literature or they may be prepared by standard processes known in the art.

In other embodiments, 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):

(III) wherein L is a displaceable atom or group; Process b) reacting a compound of formula (TV):

(IV) wherein L is a displaceable atom or group; with an amine of formula (V):

(V) or

Process c) reacting a compound of formula (VI):

(VI) wherein M is an organometallic or organoboron reagent; with a compound of formula (VII):

(VII) wherein D is a displaceable atom or group; or Process d) reacting a compound of formula (VIII):

(VHI) wherein D is a displaceable atom or group; with a compound of formula (IX):

(IX) wherein M is an organometallic or organoboron reagent; and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I) ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt.

It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of 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. Particular examples of 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.

It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

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. Thus, for example, 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. Alternatively 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. Thus, for example, 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.

Alternatively 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.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.

As stated hereinbefore 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. Biological Activity B-Raf Alpha screen assay

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. MT B-Raf may be expressed in insect cells and affinity purified by Ni ⁺² agarose followed by Q-Sepharose chromatography. 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, 5μl of enzyme/substrate/adenosine triphosphate (ATP) mix consisting of 0.12nM MT B-Raf, 84nM biotinylated HIS-MEK-AVI, and 24μM ATP in 1.2x buffer may be preincubated with 2μl of compound for 20 minutes at 25 ⁰ C. (In some instances, the procedure utilized 5ul of Enzyme/Substrate/adenosine triphosphate (ATP) mix consisting of 0.06nM MT B-RAF, 84nM biotinylated HIS-MEK- AVI, and 12mM ATP in 1.2x buffer solution.) Reactions can be initiated with 5μl 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 5μl 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), 40μg/ml

Streptavidin donor beads (Perkin Elmer, MA, Catalog #6760002), and 40μg/ml Protein A acceptor beads (Perkin Elmer, MA, Catalog #6760137). 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).

When tested in the above in vitro B-Raf Alpha screen assay, the compounds of the present invention exhibited activity less than 30 μM. For example the following results were obtained: in a B-Raf Alpha screen comparable to the above wherein results quoted may be an average of two or more results

According to a further aspect of the invention there is provided 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. In general 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. Preferably a daily dose in the range of 10-100 mg/kg is employed. However 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.

According to a further aspect of the present invention there is provided 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.

We have found that the compounds defined in the present invention, or a pharmaceutically acceptable salt thereof, 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.

Thus 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.

Such 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. Thus it is expected that a compound of the invention will possess anti-cancer activity against these cancers. It is in addition expected that 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. In particular 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. More particularly such compounds of the invention, or a pharmaceutically acceptable salt thereof, 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.

Thus according to this aspect of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use as a medicament.

According to a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of a B-Raf inhibitory effect in a warm-blooded animal such as man.

According to this aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as man.

According to a further feature of the invention, there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in the manufacture of a medicament 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.

According to a further aspect of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the production of a B-Raf inhibitory effect in a warm-blooded animal such as man.

According to this aspect of the invention there is provided 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.

According to a further feature of the invention, there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before 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.

According to a further feature of this aspect of the invention there is provided 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.

According to a further feature of this aspect of the invention there is provided 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.

According to an additional feature of this aspect of the invention there is provided 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.

In a further aspect of the invention there is provided 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.

In a further aspect of the invention there is provided 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. In a further aspect of the invention there is provided 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);

(ii) 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 5α-reductase such as finasteride;

(iii) 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-y l]-2-methylpyrimidin-4- ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem.. 2004, 47, 6658- 6661), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase); (iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], 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. 54, ppl 1-29); such 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-ami ne (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-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib

(BAY 43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases, inhibitors of the hepatocyte growth factor family, c-kit inhibitors, abl kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZDl 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) 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 (Avastin™) 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 ™; WO 01/60814), compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin)];

(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in

International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669,

WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) 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;

(ix) 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;

(x) 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

(xi) 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.

Therefore, in a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent selected from:

(i) antiproliferative/antineoplastic drugs; and/or (ii) cytostatic agents; and/or

(iii) anti-invasion agents; and/or

(iv) inhibitors of growth factor function; and/or

(v) antiangiogenic agents; and/or

(vi) vascular damaging agents; and/or (vii) antisense therapies; and/or

(viii) gene therapy approaches; and/or

(ix) immunotherapy approaches; and/or

(x) cell cycle inhibitors; and/or

(xi) endothelin antagonists. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

In addition to their use in therapeutic medicine, 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.

In further embodiments, 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

B-Raf substrate phosphorylation is inhibited.

In the above other pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and preferred embodiments of the compounds of the invention described herein also apply.

Examples The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:

(i) 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;

(ii) organic solutions were dried over anhydrous sodium sulphate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals;

4.5-30mmHg) with a bath temperature of up to 60 ⁰ C;

(iii) in general, the course of reactions was followed by TLC and reaction times are given for illustration only;

(iv) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectral data;

(v) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;

(vii) 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-dβ) as solvent unless otherwise indicated;

(vii) chemical symbols have their usual meanings; SI units and symbols are used;

(viii) solvent ratios are given in volume:volume (v/v) terms; and

(ix) mass spectra were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported; and unless otherwise stated, the mass ion quoted is (MH) ⁺ ;

(x) where a synthesis is described as being analogous to that described in a previous example the amounts used are the millimolar ratio equivalents to those used in the previous example;

(xi) the following abbreviations have been used:

DMF N,N-dimethylformamide;

EtOAc ethyl acetate;

Pd ₂ (dba) ₃ tris(dibenzylideneacetone)dipalladium (0);

BINAP (+/-)-2,2'-bis(diphenylphosphino)-l,l '-binaphthyl;

Pd(Ph ₃ P) ₄ tetrakis(1riphenylphosphme)palladium(0);

DMSO dimethylsulphoxide; DIPEA N,N,-diisopropylethylamine;

HATU N ₃ N ₅ N ¹ ,N ^l -tetramethyl-O-(7-azabenzotriazol- 1 -yl)uronium hexafluorophosphate;

DMA N, N,-dimethylacetamide;

MeOH methanol; PdCl ₂ (dppf)-CH ₂ Cl ₂ dichloro[l,l'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct;

XAνTPHOS 9,9-dimethyl-4,5-bis(diphenyl-phosphino)xanthene;

TFA trifluoroacetic acid;

DCM dichloromethane; DME 1,2-dimethoxyethane;

THF tetrahydrofuran;

Et ₃ N triethylamine;

(xii) "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.

(xiii) "Gilson 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.

(xiv) "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 1

N-f2-MethoxyethylV4-(r6-f4-methylpyridin-3-yDquinazolin-2 -vnamino)benzamide

6-(4-Methylpyridin-3-yl)quinazolin-2-amine (Method 11; 64 mg, 0.271 mmol), 4- bromo-N-(2-methoxyethyl)benzamide (Method 1; 77 mg, 0.298 mmol, 1.1 equiv), Cs ₂ CO ₃

(265 mg, 0.813 mmol, 3.0 equiv), and BINAP (34 mg, 0.055 mmol, 0.2 equiv) in dioxane (3 ml) were treated with Pd ₂ (dba) ₃ (25 mg, 0.027 mmol, 0.1 equiv). The reaction mixture was heated to 100 ⁰ C for 3 h. The reaction was cooled and filtered. The crude mixture was purified directly by a Gilson HPLC (0.1% 1OmM ammonium acetate in CH ₃ CN and water) to give 62 mg (55%) of the desired product. NMR: 10.26 (s, IH), 9.40 (s, IH), 8.47 (m, 2H), 8.38 (m, IH), 8.07 (m, 2H), 8.00 (s, IH), 7.84 (m, 4H), 7.37 (d, IH), 3.44 (m, 4H), 3.27 (s, 3H), 2.32 (s, 3H); m/z 414.

Examples 2-26 The following compounds were prepared by the procedures indicated below.

Formic acid used in the Gilson HPLC, therefore compounds were isolated as the formic acid salts.

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.

Example 27 S-rMethyl^-lfό-^-methylpyridin-S-vDquinazolin-σ-yllaminolb enzvDaminolpropan-l-ol

{[6-(4-methylpyridin-3-yl)quinazolin-2-yl]amino}benzaldeh yde (Example 56, 80 mg, 0.23 mmol) and 3-(methylamino)propan-l-ol (0.13 ml, 126 mg, 1.41mmol, 6 equiv) in 5 ml

MeOH (with 3 A molecular sieves) and 3 ml DCM were stirred at room temperature whereupon a few drops of acetic acid was added. NaBH ₃ CN (24 mg, 1.6 equiv) was then added and the reaction mixture was stirred at 30 ⁰ C for 48 hours followed by quenching with NaOH (IN, aq., ~5 ml). The reaction mixture was extracted with EtOAc, and the water layers were then extracted with EtOAc three times. The combined organic layers were washed with water and brine, evaporated and purified by Gilson HPLC (0.1% formic acid in CH ₃ CN and water) to give 46 mg (41%) of the desired product. NMR: 9.96 (s, IH), 9.34 (s, IH), 8.46 (m, 2H), 8.18 (s, IH), 7.93 (m, 3H), 7.86 (m, IH), 7.72 (d, IH), 7.38 (d, IH), 7.24 (d, 2H), 3.46 (m, 4H), 2.43 (m, 2H), 2.32 (s, 3H), 2.14 (s, 3H), 1.62 (m, 2H); m/z 414.

Example 28

The following compound was prepared by the procedure of Example 27, using the indicated starting materials.

Example 29

3-Methoxy-N-r4-(6-r4-methylpyridin-3-yDquinazolin-2-ylamino ^' )phenyl ^' )propanamide

To a 100 ml round bottom flask was added 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 μmol) 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. The crude material was purified by an ISCO system (0 to 10 % MeOH in DCM) to yield the title yellow solid (19.0 mg, 0.05 mmol, 36.9 % yield). νMR (400 MHz): 9.90 - 9.83 (m, 2H), 9.32 (s, 1 H), 8.51 -

8.46 (m, 2H), 7.94 (s, IH), 7.91 - 7.83 (m, 3H), 7.73 (d, IH), 7.55 (d, 2H), 7.41 (s, IH), 3.61 (t, 2H), 3.24 (s, 3H), 2.55 - 2.52 (m, 2H), 2.33 (s, 3H); m/z 414.

Examples 30-41 The following compounds were prepared by the procedure of Example 29, using the indicated starting materials.

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

3 -Methoxy-N- [ 1 -(4- { [6-( ^" 4-methylpyridin-3 -vDquinazolin-2 yllaminolphenyliethylipropanamide

6-(4-Methylpyridin-3-yl)quinazolin-2-amine (Method 11; 0.100 mg, 0.42 mmol), N- [l-(4-Bromophenyl)ethyl]-3-methoxypropanamide (Method 33; 0.121 g, 0.42 mmol, 1.0 equiv), Cs ₂ CO ₃ (0.414 g, 1.27 mmol, 3.0 equiv), and XAνTPHOS (0.024 mg, 0.04 mmol, 0.2 equiv) in dioxane (5 ml) were treated with palladium (II) acetate (0.019 mg, 0.08 mmol, 0.1 equiv). The reaction mixture was heated in a microwave at 150-160 °C for 30 minutes to 1 hour. The reaction was then purified by a Gilson HPLC (0.1% ammonium acetate in CH ₃ CN and water) to give the desired product. NMR: 9.92 (s, IH), 9.33 (s, IH), 8.47 (m, 2H), 8.25 (d, IH), 7.95 (s, IH), 7.90 (m, 2H), 7.83 (m, IH), 7.72 (m, IH), 7.39( m, IH), 7.26 (m, 2H), 4.92 (m, IH), 3.52 (m, 2H), 3.21 (s, 3H), 2.32 (m, 5H), 1.34 (d, 3H); m/z 442.

Examples 43-54 The following compounds were prepared by the procedure of Example 42, using the indicated starting materials.

The compound was isolated as a by-product under the reaction conditions of Example 42.

Example 55 N-{4-rrii?Vl-Aminoethyllphenyl>-6-( ^' 4-methylpyridiii-3-vDquinazolm-2-amme

A solution of tert-Butyl [(li?)-l-(4-{[6-(4-methylpyridin-3-yl)quinazolin-2- yl]amino}phenyl)ethyl]carbamate (Example 53, 2.08 g, 4.57 mmol) in DCM (10 ml) was treated with HCl IM in ether (10 ml). After 12 h, the solvents were removed under reduced pressure to yield the desired product. νMR: 10.17 (s, IH), 9.39 (s, IH), 8.89 (s, IH), 8.83 (d, IH), 8.48 (bs, 3H), 8.11 (s, IH), 8.08 (d, IH), 8.02 (d, 2H), 7.96 (d, IH), 7.82 (d, IH), 7.49 (d, 2H), 4.35 (m, IH), 2.57 (s, 3H), 1.52 (d, 3H); m/z 356.

Example 56

4-(r6-r4-Methvbvridin-3-vl ⁾ quinazolin-2-vllamino}benzaldehvde

6-(4-methylpyridm-3-yl)quinazolin-2-amine (Method 11, 1.0O g, 4.23 mmol), 4- bromobenzaldehyde (0.862 g, 4.66 mmol), Cs ₂ CO ₃ (4.14 g, 12.7 mmol, 3.0 equiv), and BINAP (0.528 g, 0.848 mmol, 0.2 equiv) in dioxane (30 ml) were treated with Pd ₂ (dba) ₃ (0.388 g, 0.423 mmol). 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.

Preparation of Starting Materials

Method 1

4-Bromo-N-(2-methoxyethyl)benzamide

2-Methoxyethylamine (10 ml) at 0 ⁰ C was treated with 4-bromobenzoyl chloride (2.0 g, 9.1 mmol). After 15 min, 10% HCl was added to the reaction mixture. The resulting white solid (2.00 g, 85%) was collected by vacuum filtration. νMR: 8.59 (t, IH), 7.78 (d, 2H), 7.66 (d, 2H), 3.42 (m, 4H), 3.25 (s, 3H).

Methods 2-9

The following compounds were prepared by the procedure of Method 1 using the appropriate starting materials. If solid did not precipitate upon addition of the 10% HCl, the mixture was extracted with EtOAc, organic layers collected, and concentrated under reduced pressure to afford the crude product which was used directly in the subsequent reaction or purified on an ISCO system (100% hexanes to 100% ethyl acetate gradient).

Compounds were prepared by the procedure of Method 1 but using 1 equivalent of DIPEA and purification on an ISCO system (100% hexanes to 100% ethyl acetate gradient).

Method 10 6-Bromoquinazolin-2-amine

2-Fluoro-5-bromobenzaldehyde (1.0 g, 4.9 mmol) and guanidine carbonate (1.3 g, 7.4 mmol, 1.5 equiv) were dissolved in DMA and heated to 140 ⁰ C for 5 h. The reaction was treated with H ₂ O and the resulting precipitate was collected by vacuum filtration; m/z 225.

Method 11

6-C4-Methylpyridm-3-vDquinazolin-2-amme

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.

Method 17

4-Bromo-N-r2-(dimethylamino ^> )ethvn-2-methylbenzamide N,N-Dimethylethane- 1 ,2-diamine (0.407 ml, 3.73 mmol), 4-bromo-2-methylbenzoic acid (802 mg, 3.73 mmol), and DIPEA (0.714 ml, 3.73 mmol) were dissolved in DMF (5 ml) followed by the addition of HATU (1.56 g, 4.10 mmol). The reaction mixture was stirred for 12 h at 25 ⁰ C whereupon the mixture was extracted with saturated NH ₄ Cl solution and washed with EtOAc three times. The organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude mixture which was purified using an ISCO system (EtOAc-MeOH) to afford the title compound; m/z 286.

Methods 18-36

The following compounds were prepared by the procedure of Method 17 using the appropriate starting materials.

Method 37

N-(4-AminophenylV3-methoxy-N-methylpropanamide

A 200 ml round bottom flask containing tert-buty\ {4-[(3- methoxypropanoyl)(methyl)amino]phenyl}carbamate (Method 23, 280 mg, 0.91 mmol) in DCM (4 ml) and TFA (1.6 ml) was stirred overnight at room temperature. To the reaction mixture was then added a few drops of concentrated HCl followed by extraction with water. To the combined aqueous layers was added a 4M NaOH solution until a pH of greater than 8 was obtained. The organic layer was concentrated under reduced pressure to yield a clear oil of N-(4-aminophenyl)-3-methoxy-N-methylpropanamide (83 mg, 0.40 mmol, 43.9 %) which was used directly without further purification. νMR (300 MHz): 6.95 (d, 2H), 6.72 (d, 2H), 3.55 (t, 2H), 3.23 (s, 3H), 3.16 (s, 3H), 2.33 (t, 2H).

Methods 38-40 The following compounds were prepared by the procedure of Method 37 using the appropriate starting material.

Method 41

N-r4-r6-bromoquinazolin-2-ylamino)phenylV3-methoxypropana mide 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 %) .

Methods 42-52

The following compounds were prepared by the procedure of Method 41 using the appropriate starting material.

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.

Method 53 N-f2-Methoxyethyl)-4-nitroberizenesulfonamide

To a solution of 4-nitrobenzenesulfonyl chloride (5.0 g, 22.6 mmol) and Et ₃ N (9.4 ml, 67.7 mmol) in THF was added 2-methoxyethylamine (2.1 ml, 24.8 mmol). The reaction mixture was allowed to stir overnight at room temperature. The white solid was filtered and

the remaining filtrate was evaporated under reduced pressure to yield 6.0 g of crude material. The material was used for the next step without further purification; m/z 261.

Methods 54-59 The following compounds were prepared by the procedure of Method 53 using the appropriate starting material.

Method 60

4-Amino-N-(2-methoxyethvDbenzenesulfonamide

A solution of N-(2-methoxyethyl)-4-nitrobenzenesulfonamide (Method 53, 1.0 g, 3.8 mmol) and Pd/C (100 mg, 10% by weight) in MeOH was purged 3X with H ₂ . The reaction mixture was then stirred for 3 hr and filtered through Celite. The solution was concentrated under reduced pressure to yield 752 mg (85 %) of dark green oil; m/z 231.

Methods 61-66

The following compounds were prepared by the procedure of Method 60 using the appropriate starting material.

Method 67 ri-(4-Bromophenyl)ethyll(2-methoxyethvDamine l-(4-Bromophenyl)ethanone (1.2 g, 6.03 mmol), titanium (IV) isopropoxide (0.883 ml, 3.01 mmol), and 2-(methoxyethyl)amine (0.433 ml, 5.02 mmol) were added to dry THF (15 ml) and stirred at room temperature under nitrogen overnight. Sodium borohydride (0.570 g, 15.1 mmol) and dry ethanol (5 ml) were then added and the mixture was stirred at room temperature for another eight hours. The mixture was then poured into aqueous ammonia (2M, 20 ml), filtered, and washed with diethyl ether. The organic phase was separated, and the aqueous layer was extracted with diethyl ether twice. The combined organic layers were extracted with IM HCl (20 ml). The aqueous layer was washed with diethyl ether and treated with IM NaOH until reaching pH 12. The basic solution was extracted with diethyl ether, dried over MgSO ₄ , and concentrated under reduced pressure to afford 796 mg of a colourless oil. The residue was taken on to the next step without further purification; m/z 259.

Methods 68-69

The following compounds were prepared by the procedure of Method 67, using the appropriate starting materials.

Method 70 tert-Butyl r(li?)-l-(4-bromophenyDethyl]carbamate

A solution of (i?)-l-(4-bromophenyl)ethanamine (5.00 g, 24.99 mmol) in THF (40 ml) was treated with di-tert-butyl dicarbonate (6.38 ml, 27.4 mmol). The reaction was stirred for 10 12 hours at 60 ⁰ C under argon. The reaction mixture was then concentrated under reduced pressure to afford the title compound; m/z 301.