MX2008008156A

MX2008008156A - Quinazoline derivatives, process for their preparation and their use as anti-cancer agents

Info

Publication number: MX2008008156A
Application number: MXMX/A/2008/008156A
Authority: MX
Inventors: Aquila Brian; Ezhuthachan Jayachandran; Pontz Timothy; Lyne Paul; Zheng Xiaolan
Original assignee: Aquila Brian; Astrazeneca Ab; Astrazeneca Uk Limited; Ezhuthachan Jayachandran; Lyne Paul; Pontz Timothy; Zheng Xiaolan
Priority date: 2005-12-22
Filing date: 2008-06-20
Publication date: 2008-09-26

Abstract

The invention relates to chemical compounds of the formula (I) 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.

Description

QUINAZOLINE DERIVATIVES, PREPARATION PROCESSES AND USE AS ANTI-CANCER AGENTS Description of the invention The invention relates to chemical compounds, or pharmaceutically acceptable salts thereof, which possess B-Raf inhibitory activity and therefore are useful for their anti-cancer activity and therefore in methods of treating the human body or animal The invention also relates to processes for the manufacture of chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an anti-cancer effect in a warm-blooded animal such as a human. . The classic path of Ras, Raf, protein kinase MAP / extracellular signal regulated kinase (MEK), an extracellular signal regulated kinase (ERK), has an important function in the regulation of a variety of cellular functions dependent on the cellular context, including cell proliferation, differentiation, survival, immortalization and angiogenesis (reviewed in Peyssonnaux and Eychene, Biology of the Cell, 2001, 93, 3-62). In this trajectory, members of the Raf family are recruited by the plasma membrane during the binding of charged Ras, with guanosine triphosphate (GTP, for its acronym in English) which results in the phosphorylation and activation of Raf proteins. The activated Rafs then phosphorylate and activate MEKs, which in turn phosphorylate and activate the ERKs. During activation, the ERKs move from the cytoplasm to the nucleus resulting in phosphorylation and regulation of the activity of transcription factors such as Elk-1 and Myc. The trajectory of Ras / Raf / MEK / ERK has been reported to contribute to the tumorigenic phenotype by inducing immortalization, growth factor-independent growth, insensitivity to inhibitory growth signals, invasiveness and metastasis, stimulation of angiogenesis and inhibition of apoptosis (reviewed in Kolch et al., Exp. Rev. Mol. Med., 2002, April 25, http://www.expertreviews.org/02004386h.htm). In fact, ERK phosphorylation is improved in approximately 30% of all human tumors (Hoshino et al., Oncogene, 1999, 18, 813-822). This may be a result of overexpression and / or mutation of the important members of the trajectory. Three isoforms of Raf / threonine serine protein kinase have reported Raf-1 / c-Raf, B-Raf and A-Raf (reviewed in Mercer and Pritchard, Biochim, Biophys. Acta, 2003, 1653, 25-40) , it is thought that such genes have been presented from genetic duplication. The three Raf genes are expressed in most tissues with a high level of B-Raf expression in the neuronal tissue and A-Raf in the urogenital tissue. The members of the highly homologous Raf family overlap but also have distinct biochemical activities and biological functions (Hagemann and Rapp, Expt. Cell Res. 1999, 253, 34-46). The expression of the three Raf genes is required for normal murine development however c-Raf and B-Raf are required to complete the gestation. B-Raf - / - mice die at E12.5 due to vascular hemorrhage caused by increased endothelial cell apoptosis (Wojnowski et al., Nature Genet., 1997, 16, 293-297). B-Raf is reported as the main isoform involved in cell proliferation and in the primary detection of oncogenic Ras. By activating somatic nonsense mutations, it has been exclusively identified that B-Raf occurs with a frequency of 66% in malignant cutaneous melanomas (Davies et al., Nature, 2002, 417, 949-954) and is also presented in a wide range of cases. range of human cancers, including but not limited to papillary tumors of the thyroid (Cohen et al., J. Nati. Cancer Inst., 2003, 95, 625-627), cholangiocarcinomas (Tannapfel et al., Gut, 2003, 52 , 706-712), colon and ovarian cancers (Davies et al., Nature, 2002, 417, 949-954). The most frequent mutation of B-Raf (80%) is a glutamic acid for the substitution of valine at position 600. These mutations increase the basic activity of the B-Raf kinase and are thought to uncouple Raf / MEK signaling / ERK from the upward proliferation drive that includes Ras and the activation of the growth factor receptor by The constitutive activation of ERK results. The mutated B-Raf proteins are transformed into NI H3T3 cells (Davies et al., Nature, 2002, 41 7, 949-954) and melanocytes (Wellbrock et al., Cancer Res., 2004, 64, 2338-2342) they have also been shown to be important for the viability and transformation of the melanoma cell (Hingorani et al., Cancer Res., 2003, 63, 5198-5202). As an important driver of the Raf / M EK / ERK signaling cascade, B-Raf represents a likely point of tumor intervention dependent on this trajectory. WO 00/20402 from AstraZeneca discloses certain amide derivatives which are inhibitors of the production of cytosines such as TN F, particularly TN Fa, and several interleukins, particularly I L-1. The present inventors have surprisingly found that some other novel amide derivatives are potent inhibitors of B-Raf and therefore are expected to be useful in the treatment of neoplastic disease. Accordingly, the present invention provides a compound of formula (I): (i) wherein: ring A is phenyl or a 5- or 6-membered heteroaryl; in wherein if the heteroaryl contains a -NH- moiety the nitrogen can optionally be substituted by a group selected from R5; R is a substituent on carbon and is selected from halo, nitro, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) amino, alkanoylamino of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) carbamoyl,? /,? / - (alkyl of 1 to 6 carbon atoms) 2carbamoyl, alkyl of 1 to 6 carbon atoms-S (O) a wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) sulfamoyl,? /,? / - (alkyl of 1 to 6 carbon atoms) carbon) 2-sulfamoyl, alkylsulfonylamino of 1 to 6 carbon atoms, carbocyclyl or heterocyclyl bonded to carbon; wherein R1 may optionally be substituted on the carbon with one or more R8; and wherein if the heterocyclyl contains an -NH- moiety, the nitrogen may optionally be substituted by a group selected from R9; n is selected from 1-4; wherein the values of R1 may be equal or different; R2 is selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms. carbon, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) ) amino,? /,? / - (alkyl of 1 to 6 carbon atoms) 2-amino, alkanoylamino of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) carbamoyl,? / ,? / - (alkyl of 1 to 6 carbon atoms) 2carbamoyl, alkyl of 1 to 6 carbon atoms-S (O) a wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms,? / - (alkyl from 1 to 6 carbon atoms) sulfamoyl,? /,? / - (alkyl of 1 to 6 carbon atoms) 2-sulfamoyl, alkylsulfonylamino of 1 to 6 carbon atoms, carbocyclyl-R10- or heterocyclyl-R11-; wherein R2 can optionally be substituted on the carbon with one or more R 2; and wherein if the heterocyclyl contains an -NH- moiety, the nitrogen may optionally be substituted by a group selected from R13; R3 and R4 are substituents on the carbon and are independently selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 atoms carbon, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) carbon) amino, N, N- (alkyl of 1 to 6 carbon atoms) 2-amino, alkanoylamino of 1 to 6 carbon atoms, ? - (C 1-6 -alkyl) carbamoyl,? /,? / - (C 1-6 -alkyl) 2-carbamoyl, C 1-6 -alkyl-S (O) a wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) sulfamoyl,? /,? / - (alkyl of 1 to 6 carbon atoms) 2sulfamoyl, alkylsulfonylamino of 1 to 6 carbon atoms, carbocyclyl-R14- or heterocyclyl-R15-; wherein R4 can optionally be substituted on the carbon with one or more R16; and wherein if the heterocyclyl contains an -NH- moiety, the nitrogen may optionally be substituted by a group selected from R17; m is selected from 0-4; wherein the values of R4 may be equal or different; R8 and R12 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms,? /,? / - (alkyl of 1 to 6 carbon atoms) 2-amino, alkanoylamino of 1 to 6 carbon atoms,? - (alkyl of 1 to 6 carbon atoms) carbon) carbamoyl,?,? / - (alkyl of 1 to 6 carbon atoms) 2-carbamoyl, alkyl of 1 to 6 carbon atoms-S (O) a wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms carbon,? / - (alkyl of 1 to 6 carbon atoms) sulfamoyl,? /,? / - (alkyl of 1 to 6 carbon atoms) 2-sulfamoyl, alkylsulfonylamino of 1 to 6 carbon atoms, carbocyclyl-R18- or heterocyclyl -R19-; where R8 and R12 independently each can optionally be substituted on the carbon by one or more R20; and wherein if the heterocyclyl contains an -NH- moiety, the nitrogen may optionally be substituted by a group selected from R21; R16 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms. carbon, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) amino,? /,? / - (alkyl of 1 to 6 carbon atoms) 2-amino, alkanoylamino of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) carbamoyl,? /,? / - (alkyl of 1 to 6 carbon atoms) carbon) 2-carbamoyl, alkyl of 1 to 6 carbon atoms-S (O) a wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms,? /,? - (alkyl of 1 to 6 carbon atoms) 2-sulphamoyl, alkylsulfonylamino of 1 to 6 carbon atoms, carbocyclyl-R22- or heterocyclyl-R23-; wherein R16 can optionally be substituted on the carbon by one or more R24; and wherein if the heterocyclyl contains an -NH- moiety, the nitrogen may be optionally substituted by a group selected from R25; R10, R11, R14, R15, R18, R19, R22 and R23 are independently selected from a direct bond, -O-, -N (R26) -, -C (O) -, -N (R27) C (O ) -, -C (O) N (R28) -, -S (O) s, - SO2N (R29) - or -SO2N (R30); in wherein R26, R27, R28, R29 and R30 are independently selected from hydrogen or alkyl of 1 to 6 carbon atoms and s is 0-2; R5, R9, R13, R17, R21 and R25 are independently selected from alkyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms , carbamoyl,? / - (alkyl of 1 to 6 carbon atoms) carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl; R20 and R24 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, hydroxymethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino ,? -methyl -? / - ethylamino, acetylamino,? / - methylcarbamoyl,? / - ethylcarbamoyl,? /,? / - dimethylcarbamoyl,?,? - diethylcarbamoyl,? / - methyl -? / - ethylcarbamoyl, methylthio, ethylthio, Methylsulfinyl, Ethiisulfinyl, Mesyl, Ethylsulfonyl, Methoxycarbonyl, Ethoxycarbonyl,? / - Methylsulfamoyl, N-Ethylsulfamoyl, ? /,? / - dimethylsulphamoyl,? /,? / - diethylsulphamoyl or? / - methyl -? / - ethylsulfamoyl; or a pharmaceutically accepted salt thereof; with the proviso that the compound is not? / -. { 3 - [(6,7-dimethoxyquinazolin-4-yl) amino] -4-methylphenyl} -3- (trifluoromethyl) benzamide. In this specification the term "alkyl" includes straight and branched chain alkyl groups. References to individual alkyl groups such as "propyl" are specific for the line chain version only and the references to the individual branched chain alkyl groups such as "isopropyl" are specific for the branched chain version only. For example, "C 1-6 alkyl" includes alkyl of 1 to 4 carbon atoms, alkyl of 1 to 3 carbon atoms, propyl, isopropyl and f-butyl. A similar mode is applied to other radicals, for example "phenylalkyl of 1 to 6 carbon atoms" includes phenylalkyl of 1 to 4 carbon atoms, benzyl, 1-phenylethyl and 2-phenylethyl. The term "halo" refers to fluoro, chloro, bromo and iodo. Where the optional substituents are chosen from "one or more" groups, it should be understood that this definition includes all substituents that are chosen from one of the specified groups or the substituents are chosen from two or more of the specified groups. Ring A is a "5- or 6-membered heteroaryl". A "5- or 6-membered heteroaryl" is a fully unsaturated aromatic ring containing 5 or 6 atoms of which at least one atom is selected from nitrogen, sulfur or oxygen. Conveniently the values for the "heteroaryl of 5 or 6"members include pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, furyl, pyrrolyl and imidazolyl 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, sulfur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH2- group may be optionally substituted by -C (O) - and a ring sulfur atom may optionally be oxidized to forming the oxides of S. A heterocyclyl bonded to carbon is a heterocyclyl linked to the next group via a carbon atom in the heterocyclyl ring. Examples and convenient values of the term "heterocyclyl" are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, pyrazolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pi rrolid inyl, thiomorpholino, pyrrolinyl. , homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl,? / - methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine -? / - oxide and quinoline -? / -oxide. 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 selected from nitrogen, sulfur or oxygen, may, unless indicate otherwise, be carbon or nitrogen bound, a -CH2- group may be optionally substituted by -C (O) - and a ring sulfur atom may optionally be oxidized to form oxides of S. A "carbocyclyl" is a ring of saturated, partially saturated or unsaturated, mono or bicyclic carbon containing 3-12 atoms; wherein a -CH2- group can be optionally substituted by -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 the "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 "C 1 -C 6 alkanoyloxy" is acetoxy. Examples of "C 1 -C 6 alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n- and f-butoxycarbonyl. Examples of "C 1 -C 6 alkoxy" include methoxy, ethoxy and propoxy. Examples of "C 1 -C 6 -alkanoylamino" include formamido, acetamido and propionylamino. Examples of "alkyl of 1 to 6 carbon atoms-S (O) a wherein a is 0 to 2", include methylthio, ethylthio, methylisulfinyl, ethylisulfinyl, mesyl and ethylsulphonyl. Examples of "C 1 -C 6 alkanoyl" include propionyl and acetyl. Examples of "N- (alkyl of 1 to 6 carbon atoms) amino" include methylamino and ethylamino. Examples of "? /,? / - (alkyl of 1 to 6 carbon atoms) 2amino" include di -? / - methylamino, di - (? / - ethyl) amino and? / - ethyl -? / - methylamino. Examples of "C 2 -C 6 alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C 2 -C 6 alkynyl" are ethynyl, 1-propynyl and 2-propynyl. The examples of "? / - (alkyl of 1 to 6 carbon atoms) sulfamoyl" are N- (methyl) sulfamoyl and? / - (ethyl) sulfamoyl. Examples of "? / - (alkyl of 1 to 6 carbon atoms) 2-sulfamoyl" are N, N- (dimethyl) sulfamoyl and? / - (methyl) -? / - (ethyl) sulfamoyl. Examples of "? / - (alkyl of 1 to 6 carbon atoms) carbamoyl" are N- (alkyl of 1 to 4 carbon atoms) carbamoyl, methylaminocarbonyl and ethylaminocarbonyl. Examples of "? /,? / - (alkyl of 1 to 6 carbon atoms) 2carbamoyl" are? /,? / - (alkyl of 1 to 4 carbon atoms) 2-carbamoyl, dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of "alkylsulfonyl of 1 to 6 carbon atoms" are mesyl, ethylsulfonyl and isopropylsulfonyl. The examples of "alkylsulfonylamino of 1 to 6 carbon atoms" are methylamino, ethylsulphonylamino and isopropylsulphonylamino. A pharmaceutically acceptable salt acceptable for 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, for example an inorganic acid, or organic, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a convenient 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 salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base that produces a cation physiologically acceptable, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine. Some compounds of formula (I) can have chiral centers and / or geometric isomeric centers (E and Z isomers), and it should be understood that the invention comprises all diastereomers and geometric optical isomers possessing the inhibitory activity of B-Raf. The invention further relates to any and all tautomeric forms of the compounds of formula (I) which possess the B-Raf inhibitory activity. It should also be understood that certain compounds of formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It should be understood that the invention comprises all solvated forms having the inhibitory activity of B-Raf. The particular values of the variable groups are as follows. Such values may be used where appropriate with the definitions, claims or modalities defined herein before or after. Ring A is phenyl or a 5- or 6-membered heteropole. Ring A is phenyl or a 5- or 6-membered heteroaryl; wherein if the heteroaryl contains a -NH- moiety, the nitrogen can be optionally substituted by a group selected from R5; wherein R5 is alkyl of 1 to 6 carbon atoms.

Ring A is phenyl, thienyl or pyridyl. Ring A is phenyl, pyrazolyl, thienyl or pyridyl; wherein the pyridyl can be optionally substituted on the nitrogen by a group selected from R5; wherein R5 is alkyl of 1 to 6 carbon atoms. Ring A is phenyl, thien-2-yl or pyrid-4-yl. Ring A is phenyl, thien-2-yl, 1-f-butyl I -1 H-pyrazol-4-yl, 1-f-butyl-1 H-pyrazol-5-yl or pyrid-4-yl. R1 is a substituent on the carbon and is selected from halo, methyl, alkyl of 1 to 6 carbon atoms-S (O) a wherein a is 2, ? /,? / - (alkyl of 1 to 6 carbon atoms) 2-sulfamoyl, carbocyclyl or heterocyclyl linked to carbon; wherein R1 can be optionally substituted on the carbon by one or more R8; wherein R8 is selected from halo, cyano,? /,? / - (alkyl of 1 to 6 carbon atoms) 2amino. R1 is a substituent on the carbon and is selected from halo, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-S (O) a wherein a is 2,?,? / - (alkyl of 1 to 6 carbon atoms) 2-sulfamoyl, carbocyclyl or heterocyclyl linked to carbon; wherein R1 can be optionally substituted on the carbon by one or more R8; wherein R8 is selected from halo, cyano or? /,? / - (alkyl of 1 to 6 carbon atoms) 2amino. R1 is a substituent on carbon and is selected from fluoro, chloro, isopropyl, mesyl,? /,? / - dimethylsulphamoyl, cyclopropyl, cyclobutyl or 2,3,5,6-tetrahydropyran bonded to carbon; wherein R1 can be optionally substituted on the carbon by one or more R8; wherein R8 is selected from fluoro, cyano,? /,? / - dimethylamine. R is a substituent on carbon and is selected from fluoro, chloro, methyl, isopropyl, mesyl,? /,? / - dimethylsulphamoyl, cyclopropyl, cyclobutyl or 2,3,5,6-tetrahydropyran bonded to carbon; wherein R1 can be optionally substituted on the carbon by one or more R8; wherein R8 is selected from fluoro, cyano or? /,? / - dimethylamine. R1 is a substituent on carbon and is selected from fluoro, chloro, trifluoromethyl, 1-methyl-1-cyanoethyl, 1-cyanocyclobutyl, 4-cyano-2,3,5,6-tetrahydropyran-4-yl, 1-cyanocyclopropyl, isopropyl, mesyl,? /,? / - dimethylsulphamoyl, dimethylaminomethyl and cyclopropyl. R1 is a substituent on carbon and is selected from fluoro, chloro, methyl, trifluoromethyl, 1-methyl-1-cyanoethyl, 1-cyanocyclobutyl, 4-cyano-2,3,5,6-tetrahydropyran-4-yl, 1 - . 1-cyclocyclopropyl, isopropyl, mesyl,? /,? / - dimethylsulphamoyl, dimethylaminomethyl and cyclopropyl. R1 is a substituent on carbon and is selected from 1-methyl-1-cyanoethyl. R1 is not trifluoromethyl. n is selected from 1 or 2; wherein the values of R1 may be the same or different. n is 1. n is 2; wherein the values of R1 may be the same or different. R2 is hydrogen. R3 and R4 are substituents on the carbon and are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms , alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) amino,? /,? / - (alkyl of 1 to 6 carbon atoms) 2amino, alkanolamm of 1 to 6 carbon atoms,? / - (C 1-6 -alkyl) carbamoyl,? /,? / - (C 1-6 -alkyl) 2-carbamoyl, C 1-6 -alkyl-S (O) a wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms,? - (alkyl of 1 to 6 carbon atoms) sulfamoyl,? /,? / - (alkyl of 1 to 6 carbon atoms) 2-sulphamoyl, alkylsulfonylamino of 1 to 6 carbon atoms carbon, carbocyclyl-R14- or heterocyclyl-R15-; wherein R 4 can be optionally substituted on the carbon by one or more R 16; and wherein if the heterocyclyl contains an -NH- moiety, the nitrogen may optionally be substituted by a group selected from R17. R3 and R4 are substituents on carbon and are independently selected from halo, nitro, hydroxy, amino, carboxy, alkyl from 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms; wherein R 4 can be optionally substituted on the carbon by one or more R 16; R16 is selected from halo, amino,? /,? / - (alkyl of 1 to 6 carbon atoms) 2-amino, alkoxycarbonylamino of 1 to 6 carbon atoms, carbocyclyl-R22- or heterocyclyl-R23-; wherein R16 can be optionally substituted on the carbon by one or more R24; and wherein if the heterocyclyl contains an -NH- moiety, the nitrogen may be optionally substituted by a group selected from R25; R22 and R23 are independently selected from a direct bond and -O-; R25 is selected from alkyl of 1 to 6 carbon atoms and alkoxycarbonyl of 1 to 6 carbon atoms; R24 is hydroxymethyl. R3 and R4 are substituents on the carbon and are independently selected from hydrogen, halo, nitro, hydroxy, amino, carboxy, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms; wherein R 4 can be optionally substituted on the carbon by one or more R 6; R16 is selected from halo, amino, alkoxy of 1 to 6 carbon atoms, alkoxycarbonylamino of 1 to 6 carbon atoms, carbocyclyl-R22- or heterocyclyl-R23-; wherein R16 can be optionally substituted on the carbon by one or more R24; and where if the heterocyclyl contains a -NH- portion, the nitrogen it can optionally be replaced by a selected group of R25; R22 and R23 are independently selected from a direct bond and -O-; R25 is selected from alkyl of 1 to 6 carbon atoms and alkoxycarbonyl of 1 to 6 carbon atoms; R24 is hydroxymethyl. R3 and R4 are substituents on the carbon and are independently selected from fluoro, nitro, hydroxy, amino, carboxy, methyl, methoxy, ethoxy, propoxy and isopropoxy; wherein R 4 can be optionally substituted on the carbon by one or more R 6; R16 is selected from fluoro, bromo, amino,? /,? / - dimethylamino, f-butoxyoxycarbonylamino, phenyl-R22-, piperidinyl-R23-, azetidinyl-R23-, pyrrolidinyl-R23- or morpholino-R23-; wherein R16 can be optionally substituted on the carbon by one or more R24; and wherein the piylidyl or piperidinyl group can optionally be substituted on the nitrogen by a group selected from R25; R22 and R23 are independently selected from a direct bond and -O-; R25 is selected from methyl and f-butoxycarbonyl; R24 is hydroxymethyl. R3 and R4 are substituents on the carbon and are independently selected from hydrogen, fluoro, chloro, bromo, nitro, hydroxy, amino, carboxy, methyl, methoxy, ethoxy, propoxy and isopropoxy; wherein R 4 can be optionally substituted on the carbon by one or more R 16; R16 is selected from fluoro, bromo, amino, methoxy, N, N-dimethylamino, f-butoxyoxycarbonylamino, phenyl-R22-, piperidinyl-R23-, azetidinyl-R23-, pyrrolidinyl-R23- or morpholino-R23-; wherein R16 can be optionally substituted on the carbon by one or more R24; and wherein pyrrolidinyl, azetidinyl or piperidinyl may be optionally substituted on the nitrogen by a group selected from R25; R22 and R23 are independently selected from a direct bond and -O-; R25 is selected from methyl and f-butoxycarbonyl; R24 is hydroxymethyl. R3 and R4 are the substituents on the carbon and are independently selected from fluoro, nitro, hydroxy, amino, carboxy, methoxy, benzyloxy, 3-aminopropoxy, 3-morpholinopropoxy, 1-methyl I pyrrolidin-2-yl methoxy, piperid i n-4-i I methoxy, piperidin-3-ylmethoxy, azetidin-2-ylmethoxy, azetidin-3-ylmethoxy, pyrrolidin-2-ylmethoxy, pyrrolidin-3-yloxy , 2- (2-hydroxymethylpyrrolidin-1-yl) ethoxy, 3- (2-hydroxymethylpyrrolidin-1-yl) propoxy, 3-dimethylaminopropoxy, trifluoromethyl, propoxy, isopropoxy, 3- (2-butoxycarbonylamino) propoxy, 3-bromopropoxy, 1- (f-butoxycarbonyl) piperidin-4-ylmethoxy and 1- (7-butoxycarbonyl I) piperidin-3-yl methoxy. R3 and R4 are substituents on the carbon and are independently selected from hydrogen, fluoro, chloro, bromo, nitro, hydroxy, amino, carboxy, methyl, methoxy, benzyloxy, 3-aminopropoxy, 3-morpholinopropoxy, 2-methoxy ethoxy, 1-methylpyrrolidin-2-ylmethoxy, piperidin-4-ylmethoxy, piperid i n-3-i I methoxy, azetidin -2-ylmethoxy, 1-f-butoxycarbonylazetidin-2-ylmethoxy, azetidin-3-ylmethoxy, 1-f-butoxycarbonylazetidin-3-ylmethoxy, pyrrolidin-2-ylmethoxy, 1-f-Butoxycarbonylpyrrolidin-2-ylmethoxy, pyrrolidin-3-yloxy, 1-f-Butoxycarbonylpyrrolidin-3-yloxy, 2- (2-hydroxymethylpyrrolidin-1-yl) ethoxy, 3- (2-hydroxymethylpyrrolidin-1-yl) propoxy, 3-dimethylaminopropoxy, trifluoromethyl, propoxy, isopropoxy, 3- (f-butoxycarbonylamino) propoxy, 3-bromopropoxy, 1- (f-butoxycarbonyl) piperidin-4-ylmethoxy and 1 - (f- bu toxic rbonyl) piperi din-3- Lmetox! R3 is hydrogen. m is selected from 0-2; wherein the values of R4 may be the same or different. m is 0. m is 1. m is 2; wherein the values of R4 may be the same or different. Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein: Ring A is phenyl or a 5- or 6-membered heteroaryl; R1 is a substituent on the carbon and is selected from halo, methyl, alkyl of 1 to 6 carbon atoms alkyl-S (O) a wherein a is 2,? /,? / - (alkyl of 1 to 6 carbon atoms) 2-sulfamoyl, carbocyclyl or heterocyclyl linked to carbon; wherein R1 can be optionally substituted on the carbon by one or more R8; n is selected from 1 or 2; wherein the values of R1 may be the same or different; R2 is hydrogen; R3 and R4 are substituents on the carbon and are independently selected from halo, nitro, hydroxy, amino, carboxy, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms; wherein R 4 can be optionally substituted on the carbon by one or more R 16; m is selected from 0-2; wherein the values of R4 may be the same or different; R8 is selected from halo, cyano,?,? / - (alkyl of 1 to 6 carbon atoms) 2-amino; R16 is selected from halo, amino,? /,? - (alkyl of 1 to 6 carbon atoms) 2-amino, alkoxycarbonylamino of 1 to 6 carbon atoms, carbocyclyl-R22- or heterocyclyl-R23-; wherein R16 can be optionally substituted on the carbon by one or more R24; and wherein if the heterocyclyl contains an -NH- moiety, the nitrogen may be optionally substituted by a group selected from R25; R22 and R23 are independently selected from a direct bond and -O-; R24 is hydroxymethyl; Y R25 is selected from alkyl of 1 to 6 carbon atoms and alkoxycarbonyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof; with the condition that it is composed, it is not? / -. { 3 - [(6,7-Dimethoxyquinazolin-4-yl) amino] -4-met Ufe nil} -3-benzamide (trifluoromethyl) benza mide. Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein: Ring A is phenyl or a 5- or 6-membered heteroaryl; wherein if the heteroaryl contains a -NH- moiety, the nitrogen can be optionally substituted by a group selected from R5; R1 is a substituent on the carbon and is selected from halo, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-S (O) a wherein a is 2,? /,? / - (alkyl 1 to 6 carbon atoms) 2-sulfamoyl, carbocyclyl or heterocyclyl bonded to carbon; wherein R1 can be optionally substituted on the carbon by one or more R8; n is selected from 1 or 2; wherein the values of R1 may be the same or different; R2 is hydrogen; R3 and R4 are substituents on the carbon and are independently selected from hydrogen, halo, nitro, hydroxy, amino, carboxy, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms; wherein R 4 can be optionally substituted on the carbon by one or more R 6; m is selected from 0-2; wherein the values of R4 may be the same or different; R5 is alkyl of 1 to 6 carbon atoms; R8 is selected from halo, cyano or? /,? / - (alkyl of 1 to 6 carbon atoms) 2-amino; R16 is selected from halo, amino, alkoxy of 1 to 6 carbon atoms of 1 to 6 carbon atoms,? /,? - (alkyl of 1 to 6 carbon atoms) 2-amino, alkoxycarbonylamino of 1 to 6 carbon atoms, carbocyclyl-R22- or heterocyclyl-R23-; wherein R16 can be optionally substituted on the carbon by one or more R24; and wherein if the heterocyclyl contains an -NH- moiety, the nitrogen may be optionally substituted by a group selected from R25; R22 and R23 are independently selected from a direct bond and -O-; R25 is selected from alkyl of 1 to 6 carbon atoms and alkoxycarbonyl of 1 to 6 carbon atoms; R24 is hydroxymethyl; or a pharmaceutically acceptable salt thereof; with the condition that it is composed, it is not? / -. { 3 - [(6,7-dimethoxyquinazolin-4-yl) amino] -4-methylphenyl} -3- (trifluoromethyl) benzamide. Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein: Ring A is phenyl, thien-2-yl or pyrid-4-yl; R1 is a substituent on carbon and is selected from fluoro, chloro, trifluoromethyl, 1-methyl-1-cyanoethyl, 1-cyanocyclobutyl, 4-cyano-2,3,5,6-tetrahydropyran-4-yl, 1-cyanocyclopropyl, isopropyl, mesyl,? /,? / - dimethylsulphamoyl, dimethylaminomethyl and cyclopropyl; n is selected from 1 or 2; wherein the values of R1 may be the same or different; R2 is hydrogen; R3 and R4 are substituents on carbon and are independently selected from fluoro, nitro, hydroxy, amino, carboxy, methoxy, benzyloxy, 3-aminopropoxy, 3-morpholinopropoxy, 1 - . 1-methyl pyrrolidin-2-ylmethoxy, piperidin-4-ylmethoxy, piperidin-3-ylmethoxy, azetidin-2-ylmethoxy, azetidin-3-ylmethoxy, pyrrolidin-2-ylmethoxy, pyrrolidin-3-yloxy, 2- (2- hydroxymethylpyrrolidin-1-yl) ethoxy, 3- (2-hydroxymethylpyrrolidin-1-yl) propoxy, 3-di methyl aminopropoxy, trifluoromethyl, propoxy, isopropoxy, 3- (butoxycarbonylamino) propoxy, 3-bromopropoxy, 1- (f-butoxycarbonyl) piperidin-4-ylmethoxy and 1- (f-bu toxic rbonyl) piperi din-3-ylmethoxy; m is selected from 0-2; wherein the values of R4 may be the same or different; or a pharmaceutically acceptable salt thereof; with the condition that it is composed, it is not? / -. { 3 - [(6,7-dimethoxyquinazolin-4-yl) amino] -4-methylphenyl} -3- (trifluoromethyl) benzamide. Therefore in a further aspect of the invention there is provided a compound of formula (I) (as represented above) wherein: Ring A is phenyl, thien-2-yl, 1-y-butyl I- 1 H- pyrazol-4-yl, 1-f-butyl-1 H-pyrazol-5-yl or pyrid-4-yl; R1 is a substituent on carbon and is selected from fluoro, chloro, methyl, trifluoromethyl, 1-methyl-1-cyanoethyl, 1-cyanocyclobutyl, 4-cyano-2,3,5,6-tetrahydropyran-4-yl, -cyanocyclopropyl, isopropyl, mesyl,? /,? / - dimethylsulphamoyl, dimethylaminomethyl and cyclopropyl; n is selected from 1 or 2; wherein the values of R1 may be the same or different; R2 is hydrogen; R3 and R4 are substituents on the carbon and are independently selected from hydrogen, fluoro, chloro, bromo, nitro, hydroxy, amino, carboxy, methyl, methoxy, benzyloxy, 3-aminopropoxy, 3-morpholinopropoxy, 2-methoxy ethoxy, 1 - methyl pyrrole id i n-2-i I methoxy, piperidin-4-ylmethoxy, piperidin-3-ylmethoxy, azetidin-2-ylmethoxy, 1-f-butoxycarbonylazetidin-2-ylmethoxy, azetidin-3-ylmethoxy, 1-f- bu toxica rbonilazetidin-3-ylmethoxy, pyrro lidin-2-ylmethoxy, 1 - . 1 - . 1-f-butoxycarbonylpyrrolidin-2-ylmethoxy, pyrro lidin-3-yloxy, 1 -fb utoxi carbon ¡I pyrrol id i n-3-ilox¡, 2- (2-h id roxi methyl pyrrol id n-1 -il) ethoxy, 3- (2-hidroxymethylpyrrole din-1-il ) propoxy, 3-dimethylaminoproproxy, trifluoromethyl, propoxy, isopropoxy, 3- (f-) butoxycarbonylamino) propoxy, 3-bromopropoxy, 1 - (f-butoxycarbonyl) piperidin-4-ylmethoxy and 1 - (f-butoxycarbonyl) pi pe ri di n-3-ylmethoxy; m is selected from 0-2; wherein the values of R4 may be the same or different; or a pharmaceutically acceptable salt thereof; with the condition that it is composed is not A / -. { 3 - [(6,7-dimethoxyquinazolin-4-yl) amino] -4-methylphenyl} -3- (trifluoromethyl) benzamide. In another aspect of the invention, the preferred compounds of the invention are any 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, the process (wherein the variable is, unless otherwise indicated, as defined in the formula ( I)) comprises the steps of: Process a) reacting an amine of formula (II) (H) with an acid of formula (III): (DO) or an activated acid derivative thereof; Process b) reacting an amine of formula (IV): (TV) with a compound of formula (V): (V) wherein L is a displaceable group Process c) reacting an amine of formula (VI): (VI) with a compound of formula (VII): (VII) and after the above if necessary: i) converting a compound of formula (I) into another compound of formula (I); ii) eliminate any protection group; iii) forming a pharmaceutically acceptable salt. L is a displaceable group, the values suitable for L are, for example, a halo, for example a chlorine, bromine or iodine. G is a displaceable group, the values suitable for G are, for example, halo, for example chlorine, bromine or iodine; tosyl or mesyl. The specific reaction conditions for the above reactions are as follows. Process a) The amines of formula (II) and the acids of formula (III) can be coupled together in the presence of a convenient coupling reagent. Standard peptide coupling reagents known in the art can be used as a convenient coupling reagent, or for example carbonyldiimidazole and dicyclohexylcarbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base per example triethylamine, pyridine, or 2,6-di-a / qft / 7-pyridines such as 2,6-lutidine or 2,6-di-fer-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide. The coupling reaction can be conveniently carried out at a temperature in the -40 to 50 ° C range. Suitable activated acid derivatives include acid halides, for example acid chlorides, and active esters, for example pentafluorophenyl esters. The reaction of these types of compounds with the amines is well known in the art, for example they can be reacted in the presence of a base, such as those described above, and in a convenient solvent, such as those described above. The reaction can be conveniently carried out at a temperature in the range of -40 to 50 ° C. The amines of formula (II) can be prepared according to reaction scheme 1. Reaction scheme 1 The compounds of formula (lia) and (III) are commercially available compounds, or are known in the literature or can be prepared by standard processes known in the art. Process b) and Process c) The compounds of formula (IV) and (V) and the compounds of formula (VI) and (VII) can be reacted together by coupling technology using an appropriate catalyst and ligand such as Pd2 (DBA) 3 and BI NAP respectively and a convenient base such as ferc-butoxide of sodium. The reaction generally requires thermal conditions frequently in the range of 80 ° C to 100 ° C. The compounds of formula (VI) can be prepared according to the reaction scheme 2. Reaction scheme 2 The compounds of formula (VI) can be prepared by a modification of Reaction Scheme 2. The compounds of formula (V), (Vil) and (IVa) are commercially available compounds, or are known in the literature or can be prepared by known processes standard in the art. It will be appreciated that various ring substituents in the compounds of the present invention can be introduced by standard aromatic substitution reactions or generated by conventional modifications of the functional group before or immediately after the processes mentioned above, and as such are included in the aspect of process of the invention. Such reactions and modifications include, for example, the introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The Reagent and conditions for such reaction procedures are well known in the chemical art. Particular examples of the 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 a Lewis acid (such as aluminum trichloride) under by Friedel Crafts; the introduction of an alkyl group using an alkyl halide and a Lewis acid (such as aluminum trichloride) under the Friedel Craft conditions; and the introduction of a halogen group. Particular examples of modifications include the reduction of a nitro group with 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 alkylsulfinyl or alkylsulfonyl. It will also be appreciated that in some of the reactions mentioned herein it may be necessary / desirable to protect any sensitive group in the compounds. Cases where protection is necessary or desirable and methods suitable for protection are known to those skilled in the art. Conventional protection groups can be used according to standard practice (for illustration see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if the reagents include such groups as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

A suitable protection 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 group, ethoxycarbonyl or f-butoxycarbonyl, an arylmethoxycarbonyl group, example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The conditions of deprotection for the previous protection groups necessarily vary with the selection of the protection group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be removed for example, by hydrolysis with a convenient base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a f-butoxycarbonyl group can be removed, for example, by treatment with a convenient acid such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group can be removed, for example, by hydrogenation in a catalyst such as palladium-in-carbon, or by treatment with a Lewis acid for example boron tris (trifluoroacetate). A suitable alternative protection group for a primary amino group is, for example, a phthaloyl group which can 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 conditions of deprotection for the previous protection groups will necessarily vary with the selection of the protection group. Thus, for example, an acyl group such as an alkanoyl or aroyl group can be removed, for example, by hydrolysis with a convenient base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group can be removed, for example, by hydrogenation in a catalyst such as palladium-in-carbon. A suitable protection group for a carboxy group is, for example, an esterification group, for example a methyl or ethyl group which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a group f-butyl which can 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 can be removed, for example, by hydrogenation in a catalyst such as palladium- in-carbon.

Protection groups can be eliminated at any convenient stage in the synthesis using the techniques Conventional well known in the chemical art. As indicated above, the compounds defined in the present invention possess the anti-cancer activity that is believed to arise from the inhibitory activity of B-Raf of the compounds. These characteristics can be determined, for example, using the procedure described below.

In vitro ELISA analysis of B-Raf The activity of the recombinant human recombinant purified His-B-Raf protein kinase was determined in vitro using an enzyme-linked immunosorbent assay (ELISA) format, which measures phosphorylation of MEK1 (unlabeled) derived from His purified human recombinant B-Raf substrate. The reaction uses 2.5 nM B-Raf, 0.15 μM MEK1 and 10 μM adenosine triphosphate (ATP) in 40 mM of N- (2-hydroxyethyl) piperazine-N '- (2-salt of the hexane of ethanesulfonic acid) (HEPES) , 5 mM 1, 4-dithio-DL-threitol, 10 mM MgCl2, 1 mM ethylenediaminetetraacetic acid and 0.2 M NaCl (1X HEPES buffer), with or without the compound at various concentrations, in a total reaction volume of 25 μl in 384-well plates. B-Raf and the compound were pre-incubated in 1X HEPES buffer for 1 hour at 25 ° C. Reactions were initiated with the addition of MEK1 and ATP in 1X HEPES buffer and incubated at 25 ° C for 50 minutes and reactions were stopped by the addition of 10 μL 175 mM EDTA (final concentration of 50 mM) in 1 X buffer of H EPES. 5 μl of the analysis mixture was then diluted 1: 20 to 50 mM EDTA in 1 X H EPES buffer, transferred to black binding plates of many 384-well proteins and incubated overnight at 4 ° C . The plates were washed in buffered saline with tris containing 0.1% Tween20 (TBST), blocked with 50 μl Superblock (Pierce) for 1 hour at 25 ° C, washed in TBST, incubated with 50 μl anti-phospho-M antibody. Polyclonal rabbit EK (Cell Signaling) diluted 1: 1000 in TBS for 2 hours at 25 ° C, washed with TBST, incubated with 50 μl antibody bound to goat anti-rabbit horseradish peroxidase (Cell Signaling) diluted at 1: 2000 in TBS for 1 hour at 25 ° C and washed with TBST. 50 μl of peroxidase fluorogenic substrate (Quantablu-Pierce) was added and after incubation for 45-60 minutes, 50 μl QuantabluSTOP (Pierce) was added. The blue fluorescent product was detected at an excitation of 325 and emission 420 using a TECAN Ultra plate reader. The data were graphically represented and the Cl50s were calculated using Excel Fit (Microsoft).

When tested in the above in vitro analysis, the compounds of the present invention exhibited an activity of less than 30 μM. For example, the following results were obtained: According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in association with a pharmaceutically acceptable diluent or carrier. The composition may be in a form suitable for oral administration as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular 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 can 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 of 1-1000 mg / kg, and this normally provides a therapeutically effective dose. A daily dose in the range of 10-100 mg / kg is preferably used. However, the daily dose will necessarily vary depending on the host treated, particular route of administration, and severity of the disease that is treated. Therefore the optimal dosage can be determined by the doctor who is treating any particular patient. According to a further aspect of the present invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above for use in a method of treating 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 whose property is believed to be presented from their B-Raf inhibitory properties. Accordingly, it is expected that the compounds of the present invention will be useful in the treatment of diseases or conditions mediated only or in part by B-Raf, ie the compounds can be used to produce an inhibitory effect of B-Raf in an animal of hot blood that needs such treatment. Thus the compounds of the present invention provide a method for treating cancer, characterized by the inhibition of B-Raf, ie the compounds can be used to produce an anti-cancer effect mediated only or in part by the inhibition of B-Raf . It is expected that such a compound of the invention possesses a wide range of anti-cancer characteristics since activation mutations in B-Raf have been observed in many human cancers, including but not limited to, melanoma, papillary tumors of the thyroid, cholangiocarcinomas, colon, ovarian and lung cancers . Thus, it is expected that a compound of the invention possesses the anti-cancer activity against these cancers. It is an expected addition that a compound of the present invention possesses activity against a range of leukemias, lymphoid malignancies and solid tumors such as carcinomas and sarcomas in tissues such as liver, kidney, bladder, prostate, breast and pancreas. It is particularly expected that such compounds of the invention advantageously retard the growth of primary and recurrent solid tumors of, for example, the skin, colon, thyroid, lungs and ovaries. More particularly it is expected that such compounds of the invention, or a pharmaceutically acceptable salt thereof, inhibit the growth of primary and recurrent solid tumors associated with B-Raf, especially tumors that are significantly dependent on B-Raf for its growth and spread, including for example, certain skin, colon, thyroid, lung and ovarian tumors. 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 formula (I), or a salt pharmaceutically acceptable thereof, as defined above for use as a medicament. According to a further aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above in the manufacture of a medicament for use in the production of an inhibitory effect. of B-Raf in a warm-blooded animal such as a human. According to this aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above in the manufacture of a medicament for use in the production of an anti-aging effect. cancer in a warm-blooded animal such as a human. According to a further feature of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein above in the manufacture of a medicament for use in the treatment of melanoma, papillary tumors of the thyroid, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors of the skin, colon, thyroid, lungs and ovaries. According to a further aspect of the invention, provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above in the production of an inhibitory effect of B-Raf in a warm-blooded animal such as a human. According to this aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above in the production of an anti-cancer effect in a warm-blooded animal such as a human. According to a further feature of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein above in the treatment of melanoma, papillary tumors of the thyroid, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors 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 an inhibitory effect of B-Raf in a warm-blooded animal, such as a human, which needs such treatment comprising administering to the animal an amount effective 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 a human, that needs such treatment comprising administering to the 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, a method is provided for treating melanoma, papillary tumors of the thyroid, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors of the skin, colon, thyroid, lungs and ovaries, in a warm-blooded animal, such as a human, that needs such treatment comprising administration the animal of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined hereinbefore. In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically acceptable diluent or carrier for use in the production of an inhibitory effect of B-Raf in an animal of warm blood such as a human. In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore 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 a human. In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of melanoma, papillary tumors of the thyroid, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary solid tumors and recurrent skin, colon, thyroid, lungs and ovaries in a warm-blooded animal such as a human. The inhibitory treatment of B-Raf defined above may be applied as the 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-tumor agents: (i) antiproliferative / anti-neoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (eg cis-platinum, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan and nitrosoureas); anti-metabolites (for example antifolates such as fluorouracil 5 similar to fluoropyrimidine and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; anti-tumor antibiotics (for example adriamycin similar to anthracycline, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin -C, dactinomycin and mithramycin), antimitotic agents (for example vincristine similar to vinca alkaloids, vinblastine, vindesine and vinorelbine and taxoids such as taxol and taxotere), and topoisomerase inhibitors (for example etoposide similar to epipodophyllotoxins and teniposide, amsacrine, topotecan and camptothecin), (ii) cytostatic agents such as anti-estrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and idoxifen), infra-regulators of the estrogen receptor (for example fulvestrant), anti-androgens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (eg serelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example such as anastrozole, letrozole, vorazole and exemestane) and 5a-reductase inhibitors such as finasteride; (iii) Agents that inhibit the invasion of cancer cells (for example metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activating receptor function); (iv) Inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (eg, anti-erbb2 trastuzumab antibody [Herceptin ™] and anti-erbbl cetuximab antibody [C225 ]), farnesyl transferase inhibitors, MEK inhibitors, tyrosine kinase inhibitors and serine / threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family of tyrosine kinase inhibitors) such as? / - (3-chloro-4-fluorophenyl) -7-methoxy-6- (fluorophenyl3-morofolinopropoxy) quinazolin-4-amine (gefitinib, AZDI 839),? / - (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -? / - quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido -? / - (3- chloro-4) -7- (3-morpholinopropoxy) quinazolin-4-amine (Cl 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family; (v) Anti-angiogenic agents such as those that inhibit the effects of vascular endothelial growth factor, (e.g. anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin ™], compounds such as those described in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds working by other mechanisms (for example, linomide, inhibitors of the integrin function avß3 and angiostatin); (vi) Vascular damaging agents such as Combretastatin A4 and the compounds described in International Patent Applications WO 99/02166, WO00 / 40529, WO 00/41 669, WO01 / 92224, WO02 / 04434 and WO02 / 0821 3; (vii) Antisense therapeutics, for example those that address the objectives listed above, such as ISIS 2503, an anti-ras antisense; (viii) Genetic therapy methods, including for example methods for replacing abnormal genes such as abnormal p53 or abnormal BRCA1 or B RCA2, GDEPT (gene-directed enzyme prodrug therapy) methods such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and methods for increasing the patient's tolerance to chemotherapy or radiotherapy such as multi-drug resistance genetics therapy; (ix) Immunotherapy methods, including for example ex vivo and in vivo methods for increasing the immunogenicity of the patient's tumor cells, such as transfection with cytosines such as interieukin 2, interieukin 4 or granulocyte-macrophage colony stimulation factor , methods for decreasing T-cell anergy, methods using transfected immune cells such as dendritic cells transfected with cytosine, methods using tumor cell lines transfected with cytosine and methods using anti-idiotypic antibodies; (x) Cell cycle inhibitors including for example CDK inhibitors (for example flavopiridol) and other inhibitors of cell cycle checkpoints (for example checkpoint kinase); inhibitors of aurora kinase and other kinases involved in the regulation of mitosis and cytokinesis (for example 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 ZD1 61 1 (WO 96 40681), atrasentan and YM598.

Such common treatment can be achieved by the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products use the compounds of this invention within the dosage range described above and the other pharmaceutically active agent within their 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 standardization of in vitro and in vivo test systems for evaluation of the effects of B-Raf inhibitors in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

In the above-described pharmaceutical composition, process, method, use and manufacturing characteristics of the drug, the alternative and preferred embodiments of the compounds of the invention described herein are also applied.

EXAMPLES The invention will now be illustrated by the following non-limiting examples wherein, unless otherwise indicated: (i) temperatures are given in degrees centigrade (° C); the operations were performed at room temperature, that is, at a temperature in the range of 8-25 ° C; (ii) the organic solutions were dried over anhydrous sodium sulfate; the evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascal, 4.5-30 mmHg) with a bath temperature of up to 60 ° C; (iii) in general the course of the reactions was followed by TLC and the reaction times are given only for illustration; (iv) the final products had satisfactory proton nuclear magnetic resonance spectra and / or mass spectrum data; (v) productions are given for illustration only and not it is necessary that they can be obtained by the development of the applied process; the preparations were repeated if more material was required; (vi) when given, the RM N data is in the form of delta values for the main diagnostic protons, given in parts per million (ppm) in relation to tetramethylsilane as an internal standard, determined at 400 M Hz using sulfoxide of dimethyl perdeuterio (DMSO-d6) as solvent unless otherwise indicated; (vii) chemical symbols have their common meanings; SI units and symbols are used; (vii) solvent ratios are given in terms of volume: volume (v / v); and (ix) the total spectra were executed with an electron energy of 70 electron volts in the chemical ionization mode (Cl) using a direct exposure probe; where it was stated that the ionization was effected by electron impact, fast atom bombardment (FAB) or rapid electrospray; the values for m / z are given; generally, only ions that indicate the original mass; and unless otherwise indicated, calculate the total ions (M H) +; (x) where a synthesis is described as analogous to that described in a previous example, the quantities used are millimolar equivalent to those used in the previous example; (xi) the following abbreviations have been used: HATU hexafluorophosphate efe O- (7- Azabenzotriazol-1-yl) -? /,? /,? / ',? /' - tetamethyluronium; THF tetrahydrofuran; DMF? /,? / - dimethylformamide; EtOAc ethyl acetate; DIEA? /,? / - diisopropylethylamine; DCM dichloromethane; DMSO dimethylsulfoxide; MeCN acetonitrile; TFA trifluoroacetic acid; DIAD diisopropyl azodicarboxylate; MeOH methanol; (xii) "ISCO" refers to normal phase flash column chromatography using 12 g and 40 g cartridges of pre-packaged silica gel used according to the manufacturer's instruction obtained from ISCO, Inc., 4700 Superior Street Lincoln, NE, USA; and (xiii) "Gilson CLAR" refers to a reversed phase reversed phase CLAR column YMC-AQC 18 with a dimension of 20 mm / 100 and 50 mm / 250 in water / MeCN with 0.1% TFA as mobile phase, obtained (xiv) Parr Hydrogenator or Parr Shaker hydrogenators are systems for treating chemicals with hydrogen in the presence of a catalyst at pressures up to 5 atmospheres (60 psig) and temperatures at 80 ° C.

Example 1 4 - [(2-Methyl-5. {[[3- (trifluoromethyl) benzoyl] ami no.} Phenyl) amino] quinazoline-7-carboxylic acid 4 - [(5-amin-2) acid methylmethyl) amin or] quinazoline-7-carboxylic acid (method 7, 0.100 g, 0.340 mmol), 3- (trifluoromethyl) benzoyl chloride (0.062 ml, 0.408 mmol, 1.2 equiv.) and disopropylethylamine (0.071 ml, 0.510 mmol) , 1.5 equiv.) Were combined in DCM (2 ml) and stirred for 4 h at 25 ° C. The reaction mixture was concentrated under reduced pressure and purified by reverse phase preparative HPLC (0.1% TFA in MeCN and water). NMR: 10.58 (s, 1H), 8.75 (s, 1H), 8.68 (d, 1H), 8.39 (s, 1H), 8.26 (m, 3H), 8.19 (d, 1H), 7.97 (d, 1H) , 7.90 (d, 1H), 7.79 (m, 2H), 7.64 (d, 1H), 7.38 (d, 1H), 2.18 (s, 3H); m / z 467.

Examples 2-3 The following compound was prepared by the procedure of Example 1 using the appropriate MSs.

Example 4 3- (1-cyano-1-methylethyl) -N-. { 3 - [(6,7-dimethoxyquinazolin-4-yl) amino] -4-methylphenyl} benzamide A solution of 4-chloro-6,7-dimethoxyquinazoline (50 mg, 0.170 mmol) and? / - (3-amino-4-methylphenyl) -3- (1-cyano-1-methyl-ethyl) benzamide (method 24, 38 mg, 0.170 mmol) in EtOH (2 mL) was heated at 90 ° C for 12 h. The organics were removed under reduced pressure. The resulting solid was purified by reverse phase preparative HPLC (0.1% TFA in MeCN and water) to provide 82 mg of solid (95%). NMR: 11.07 (s, 1H), 10.43 (s, 1H), 8.73 (s, 1H), 8.05 (m, 2H), 7.91 (m, 2H), 7.75 (d, 1H), 7.61 (m, 2H) , 7.39 (d, 1H), 7.27 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 2.17 (s, 3H), 1.74 (s, 6H); m / z 482.

Example 5 The following compound was prepared by the procedure of Example 4 using the appropriate MSs.

Example 6 3- (1 -cyan o-1-methyl ethyl) -N-. { 3 - [(7-hydroxy-6-m-ethoxy qu i n azo I i n-4-yl) amino] -4-methylphenyl} benzamide A solution of? / - (3- { [7- (benzylloxy) -6-methoxy-4-ylamino-4-yl] amino.} -4-methylphenyl) -3- (1-cyano-1-methylethyl) benzamide ( Example 5: 50 mg, 0.084 mmol) in MeOH (2 ml) and 30% Pd / C (20 mg) was treated with hydrogen. The mixture was allowed to stir at 25 ° C for 12 h before it was filtered through diatomaceous earth and concentrated under reduced pressure. The resulting solid was purified by reverse phase preparative HPLC (0.1% TFA in MeCN and water) to provide 30 mg of solid (71%). NMR: 11.58 (s, 1H), 11.03 (s, 1H), 10.42 (s, 1H), 8.68 (s, 1H), 8.03 (m, 2H), 7.92 (d, 1H), 7.88 (s, 1H) , 7.74 (d, 1H), 7.60 (m, 2H), 7.38 (d, 1H), 7.18 (s, 1H), 3.98 (s, 3H), 2.16 (s, 3H), 1.73 (s, 6H); m / z 468.

Example 7 3- (1-cyanocyclobutyl) -N-. { 3 - [(6,7-dimethoxyquinazolin-4-yl) amino] -4-methylphenyl} benzamide A solution of? / - 3- (6,7-dimethoxyquinazolin-4-yl) -4-methylbenzene-1,3-diamine (method 8, 99 mg, 0.318 mmol), 3- (l-cyanocyclobutyl) benzoic acid (method 17, 64 mg, 0.318 mmol) and DIEA (166 μl, 0.954 mmol, 3.0 equiv.) in DMF (2 ml) was treated with HATU (145 mg, 0.382 mmol, 1.2 equiv.). The reaction was stirred at 50 ° C for 12 h. The reaction was quenched with H2O and extracted with EtOAc. The organics were dried with NaCl (sat) and Na2SO4 (S) and removed under reduced pressure. The resulting solid was purified by reverse phase preparative HPLC (0.1% TFA in MeCN and water) to provide 57 mg (39%). NMR: 11.04 (s, 1H), 10.44 (s, 1H), 8.72 (s5 1H), 8.07 (s, 1H), 7.94 (m, 3H), 7.71 (m, 1H), 7.61 (m, 2H), 7.39 (d, 1H), 7.24 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 2.77 (m, 2H), 2.67 (m, 2H), 2.30 (m, 1H), 2.17 (s, 3H), 2.03 (m, 1H); m / z 494. Examples 8-19 The following compounds were prepared by the procedure of Example 7 using the appropriate MSs.

Example 20 N-3-. { [6-methoxy-7- (3-morpholin-4-ylpropoxl) quinazolin-4-yl] a m i no} -4-m eti I f in i l) -3- (trif luoromethyl) benzamide A solution of? / -. { 3 - [(7-hydroxy-6-methoxyquinazolin-4-yl) amino] -4-methylphenyl} -3- (trifluoromethyl) benzamide (Example 70, 80 mg, 0.171 mmol), 3-morpholin-4-ylpropan-1-ol (28 μl, 0.205 mmol, 1.2 equiv.) And Ph3P (86 mg, 0.328 mmol, 1.9 equiv.) in THF (2 ml) at 0 ° C under Ar was treated with DIAD (65 μl, 0.328 mmol, 1.9 equiv.). The reaction was stirred for 12 h while heating to 25 ° C. The reaction was quenched with 10% HCl, and extracted with EtOAc. The water layer was treated with 10% NaOH and extracted with EtOAc. The organics were dried with NaCl (sat) and Na2SO4 (S) and removed under reduced pressure. The resulting solid was purified by reverse phase preparative HPLC (0.1% TFA in MeCN and water) and by a supercritical fluid purification system. NMR: 10.59 (s, 1H), 8.69 (s, 1H), 8.26 (m, 2H), 8.18 (m, 2H), 7.97 (d, 1H), 7.92 (s, 1H), 7.79 (t, 1H) , 7.62 (d, 1H), 7.38 (d, 1H), 7.31 (s, 1H), 4.30 (m, 2H), 4.00 (m, 5H), 3.76 (m, 2H), 3.51 (m, 2H), 3.35 (m, 2H), 3.12 (m, 2H), 2.31 (m, 2H), 2.17 (s, 3H); m / z 596.

Example 21 N- [3- (7-Benzyloxy-quinazolin-4-ylamino) -4-methyl-phenyl] -3- (cyano-dimethyl-methyl) -benzamide A mixture of 7-benzyloxy-4-chloro-quinazoline ( 1.85 g, 6.8 mmol) and? / - (3-amino-4-methyl-phenyl) -3- (cyano-dimethyl-methyl) -benzamide (method 24; 2 g, 6.8 mmol) in 15 ml of isopropanol (15 g. ml) was refluxed for 4 h. The reaction mixture was cooled to 25 ° C, and the resulting solid was collected by filtration. The product was crystallized again from MeOH to provide 2.6 g of a yellow solid. NMR: 11.45 (s, 1H), 10.45 (s, 1H), 8.80 (m, 2H), 8.10 (s, 1H), 7.96-7.35 (m, 13H), 5.40 (s, 2H), 2.20 (s, 3H), 1.75 (s, 6H); m / z 527.

Example 22. 3- (. {6-Methoxy-4 - [(2-methyl-5. {[[3- (trifluoromethyl) benzoyl] amino] phenyl) amino] quinazolin-7-yl) oxychloride propan-1-aminium A solution of [3- (. {6-methoxy-4 - [(2-methyl-5. {[3- (trifluoromethyl) benzoyl] amino} phenyl) amino] qu nazol i n- Fer-butyl 7-yl.) Oxy) propyl] carbamate (Example 38, 0.065 g, 0.104 mmol) in 4 M HCl in dioxane (2 mL) was stirred at 25 ° C for 45 min. The reaction mixture was concentrated under reduced pressure to provide the desired product. NMR: 11.62 (s, 1H), 10.66 (s, 1H), 8.72 (s, 1H), 8.41 (s, 1H), 8.28 (m, 2H), 8.11 (m, 2H), 7. 96 (d, 1H), 7.90 (s, 1H), 7.78 (t, 1H), 7.68 (d, 1H), 7.42 (s, 1H), 7.37 (d, 1H), 4.30 (m, 2H), 4.02 (s, 3H), 3.00 (m, 2H), 2.17 (m, 5H); m / z 526. EXAMPLE 23 3- (cyano-di methyl-methyl) -N- [3- (7-methoxy-quinazolin-4'i-amino) -4-methyl-phenyl-benzamide A mixture of 4 -chloro-7-methoxy-quinazoline (method 32; 2 g, 10.28 mmol) and? / - (3-amino-4-methylphenyl) -3- (1-cyano-1-methylethyl) benzamide (method 24; 2 g , 6.83 mmol) in isopropanol (15 ml) was refluxed for 12 h. The organics were removed under reduced pressure and the residue was purified by column chromatography using an ISCO (EtOAc) system and then by reverse phase preparative HPLC (0.1% TFA in MeCN and water) to give a light yellow solid (2.1 g, 68%). NMR: 11.50 (s, 1H), 10.45 (s, 1H), 8.75 (m, 2H), 8. 00-7.80 (m, 3H), 7.70-7.40 (m, 4H), 7.30 (m, 2H), 3.91 (s, 3H), 2.10 (s, 3H), 1.70 (s, 6H); m / z 451. Examples 24-36 The following compounds were prepared by the procedure of Example 23, using appropriate substituted 2-amino-benzoic acid as the starting material.

Example 38 [3- [. { 6-methoxy-4 - [(2-methyl-5 { [3- (trifluoromethyl) benzoyl] amyl}. F in i) amino] q uinazolin-7-yl} oxi) propyl] tert-butyl carbamate A solution of? / -. { 3 - [(7-hydroxy-6-methoxyquinazolin-4- il) amino] -4-methylphenyl} -3- (trifluoromethyl) benzamide (Example 70, 100 mg, 0.213 mmol), ferric butyl (3-iodopropyl) carbamate (method 26, 61 mg, 0.213 mmol, 1.2 equiv.) And K2CO3 (44 mg, 0.320 mmol) , 1.5 equiv.) In MeCN (2 ml) were heated at 70 ° C for 12 h. The reaction was stopped with water and extracted with EtOAc. The organics were dried with NaCl (sat) and Na2SO4 (S) and then removed under reduced pressure. The resulting solid was purified by reverse phase preparative HPLC (0.1% TFA in MeCN and water); m / z 626. EXAMPLE 39 3- (1-cyano-1-methylethyl) -N- (4-methyl-3 { [7- (piperidin-4-ylmethoxy) quinazolin-4-yl] amino.} fen i I) benzamide A mixture of 4- (4-. {5- [3- (cyano-dimethyl-methyl) -benzoylamino] -2-methyl-phenylamino} -quinazolin-7-fer- butyl ester. -yloxymethyl) -piperidine-1-carboxylic acid (Example 61, 96 mg, 0.152 mmol) in 4M HCl in dioxane (2 ml) was stirred at 25 ° C for 1 h. The solvents were removed under reduced pressure and the residue was purified by reverse phase preparative HPLC (0.1% TFA in MeCN and water) to provide 75 mg (93%) of a white solid. NMR: 11.40 (s, 1H), 10.55 (s, 1H), 8.85-8.45 (m, 4H), 8.10-7.39 (m, 9H), 4.20 (d, 2H), 3.40 (m, 2H), 3.00 (m, 2H), 2.20 (m, 4H), 2.00 (m, 2H), 1.80 (s) , 6H), 1.62 (m, 2H); m / z 534. Examples 40-44 The following compounds were prepared by the procedure of Example 39, using the appropriate hydroxyl as start material EXAMPLE 45 3- [Cyano-dimethyl-methyl] -N - ('3- {7- [2- (2-hydroxymethyl-pyrroHdin-1-yl) ethoxy] -qumazolin-4-ylamino} -hydrochloride. -4-methyl-phenyl) -benzamide A mixture of? / -. { 3- [7- (2-bromo-ethoxy) -quinazolin-4-ylamino] -4-methyl-phenyl} -3- (cyano-dimethyl-methyl) -benzamide (Example 58; 97 mg, 0.178 mmol), pyrrolidin-2-yl-methanol (20 mg, 0.196 mmol, 1.1 eq.) And K2CO3 (123 mg, 0.89 mmol, 5 eq.) In MeCN (10 mg). ml) was refluxed for 12 h. The heterogeneous mixture was filtered and the solids were heated with MeOH. The organics were concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC (0.1% TFA in MeCN and water) to give 50 mg of (50%) a white solid.

NMR: 11.70 (s, 1H), 10.55 (s, 1H), 10.42 (s, broad, 1H), 8.90 (d, 1H), 8.80 (s, 1H), 8.10 (s, 1H), 7.97 (d, 1H), 7.80 (s, 1H), 7.60 (m, 2H), 7.45 (s5 1H), 7.35 (d, 1H), 4.70 (m, 1H), 4.60 (m, 1H), 3.95 (m, 1H) , 3.75 (m, 2H), 3.60 (m, 2H), 3.25 (m, 2H), 2.20 (s, 3H), 2.15-1.90 (m, 3H), 1.75 (m, 7H); m / z 564. Example 46 N-. { 3- [7- (3-bromo-propoxy) -quinazolin-4-ylamino-1-4-methyl-phenyl} -3- (cyano-dimethyl-methyl) -benzamide A mixture of 3- (cyano-dimethyl-methyl) -? / - [3- (7-hydroxy-quinazolin-4-ylamino) -4-methyl-phenyl] - benzamide (Example 68, 300 mg, 0.686 mmol), 1,3-dibromopropane (277 mg, 1372 mmol) and K2CO3 (189 mg, 1372 mmol) in acetone-1,4-dioxane-DMF (5: 1; 1; 10 ml) was refluxed for 12 h. The heterogeneous mixture was filtered and the solids were heated with MeOH. The organics were concentrated under reduced pressure and the residue was purified by column chromatography using an ISCO system (hexane-EtOAc) to provide 112 mg (29%) of a light yellow solid, m / z 558. Examples 47-52 The following compounds were prepared by the procedure of Example 46, using Example 68 (Examples 47-51) and Example 37 (Example 52) and the appropriate alkyl halide as a starting material Example 53 [3- ( { 4 - [(5-. {[3- (1-cyano-1-methylethyl) benzoyl] amino} -2-methylphenyl) amino] quinazolin-7-yloxy) propyl ] tere-butyl carbamate A mixture of 3- (cyano-dimethyl-methyl) -? / - [3- (7-hydroxy-quinazolin-4-ylamino) -4-methyl-phenyl] -benzamide (Example 68; mg, 0.229mmol), (3-bromo-propyl) -carbamic acid fer-c-butylester (109 mg, 0.458 mmol) and K2CO3 (126 mg, 0.916 mmol) in acetone-1,4-dioxane-DMF (5: 1: 1, 10 ml) was refluxed for 12 h. The heterogeneous mixture was filtered and the solids were heated with MeOH. The organics were concentrated under reduced pressure and the residue was purified by column chromatography using an ISCO system (hexane-EtOAc) to give 90 mg (66%) of the title compound; miz 594. Example 54 4-Di-methyl-amino-methyl- N- [3- (7-m-toxy-a-nolol-4-i-amino) -4-methyl-phenyl] -3-trifluoromethyl-benzamide mixture of? / 3- (7-methoxy-quinazolin-4-yl) -4-methyl-benzene-1,3-diamine (method 62, 80 mg, 0.286 mmol), 4-dimethylaminomethyl-3-trifluoromethyl-benzoic acid (Method 48, 71 mg, 0.286 mmol), HATU (130 mg, 0.343 mmol) and DIEA (147 mg, 1.1 mmol) DMF (2 mL) was stirred at 25 ° C for 2 h. The reaction mixture was purified by reverse phase preparative HPLC (0.1% TFA in MeCN and water) to provide 85 mg (58%) of a white solid. NMR: 11.55 (s, 1H), 11.00 (s, broad, 1H), 10.70 (s, 1H), 8.71 (m, 2H), 8.33 (m, 3H), 7.85 (s, 1H), 7.65 (d, 1H), 7.45-7.28 (m, 3H), 4.50 (s, 2H), 3.92 (s, 6H), 2.72 (s, 3H), 2.10 (s, 3H); m / z 509. EXAMPLE 55 2- (cyano-di-methyl-methylene) -N- [3- (7-toxy-k-nazolin-4-y-amino) -4-methyl-phenyl-isonicotinamide A mixture of 3- (7-methoxy-quinazolin-4-yl) -4-methyl-benzene-1,3-diamine (method 62, 81 mg, 0.289 mmol), 2- (1-cyano-1-) acid methylethyl) isonicotinic (method 60, 55 mg, 0.289 mmol), HATU (132 mg, 0.347 mmol) and DIEA (147 mg, 1.1 mmol) in DMF (2 mL) was stirred at 25 ° C for 2 h. The organics were removed under reduced pressure and the crude reaction mixture was purified by reverse phase preparative HPLC (0.1% TFA in MeCN and water) to provide 45 mg (34%) of a yellow solid. NMR: 11.46 (s, 1H), 10.70 (s, 1H), 8.80 (m, 2H), 8.70 (d, 1H), 7.90 (s, 1H), 7.85 (m, 2H), 7.50 (d, 1H) , 7.40 (d, 1H), 7.22 (s, 1H), 4.00 (s, 3H), 2.15 (s, 3H), 1.80 (s, 6H); m / z 452. Example 56 The following compound was prepared by the procedure of Example 55, using the appropriate starting material.

Example 57 3- (Cyano-dimethyl-methyl) -5-fluoro-N- [3- (7-methyloxy-quinazolin-4-ylamino) -4-methyl-phenyl] -benzamide A mixture of 4-chloro-7- methoxy-quinazoline (method 32, 700 mg, 3.6 mmol) and? / - (3-amino-4-methyl-phenyl) -3- (cyano-dimethyl-methyl) - -Furo-benzamide (method 5, 900 mg, 2.89 mmol) in isopropanol (30 ml) was refluxed for 4 h. The organics were removed under reduced pressure and the residue was purified by column chromatography using an ISCO system (EtOAc) and then purified by reverse phase preparative HPLC (0.1% TFA in MeCN and water) to provide 1.1 g (81%). of a light yellow solid. NMR: 11.48 (s, 1H), 10.55 (s, 1H), 8.80 (s, 1H), 8.70 (d, 1H), 7.95 (s, 1H), 7.90 (s, 1H), 7.80 (d, 1H) , 7.66 (m, 2H), 7.50 (d, 1H), 7.48 (d, 1H), 7.30 (m, 1H), 4.00 (s, 3H), 2.20 (s, 3H), 1.78 (s, 6H); m / z 469. Example 58 N-. { 3- [7- (2-bromo-ethoxy) -quinazolln-4-ylamino] -4-methyl-phenyl} -3- (cyano-dimethyl-methyl) -benzamide A mixture of 3- (cyano-dimethyl-methyl) -? / - [3- (7-hydroxy-quinazolin-4-ylamino) -4-methyl-phenyl] - benzamide (Example 68, 100 mg, 0.229 mmol), 1,2-dibromoethane (86 mg, 0.458 mmol) and K2CO3 (63 mg, 0.458 mmol) in acetone-1,4-dioxane-DMF (5: 1: 1; 10 ml) was refluxed for 12 h. The heterogeneous mixture was filtered and the solids were heated with MeOH. The organics were concentrated under reduced pressure and the residue was purified by column chromatography using an ISCO system (hexane-EtOAc) to provide 97 mg (78%) of a light yellow solid. NMR: 10.36 (s, 1H), 9.65 (s, 1H), 8.46 (d, 1H), 8.40 (s, 1H), 8.10-7.60 (m, 6H), 7.35-7.25 (m, 3H), 4.56 ( t, 2H), 3.92 (t, 2H), 2.20 (s, 3H), 1.80 (s, 6H); m / z 544.

Example 59 3- (Cyano-dimethyl-methyl) -N- (3- {7- [3- (2-hydroxymethyl-pyrrolidin-1-yl) -propoxy] -quinazolin-4-ylamino} -3-hydrochloride. -4-methyl-phenyl) -benzamide A mixture of? / -. { 3- [7- (3-bromo-propoxy) -quinazolin-4-ylamino] -4-methyl-phenyl} -3- (cyano-dimethyl-methyl) -benzamide (Example 46; 112 mg, 0.2 mmol), pyrrolidin-2-yl-methanol (40 mg, 0.4 mmol) and K2CO3 (138 mg, 1 mmol) in MeCN (10 mg). ml) was refluxed for 12 h. The heterogeneous mixture was filtered and the solids were heated with MeOH. The organics were concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC (0.1% TFA in MeCN and water) to provide 75 mg (65%) of a white solid. NMR: 11.50 (s, broad, 1H), 10.50 (s, 1H), 9.85 (s, broad, 1H), 8.80-8.75 (m, 2H), 8.05-7.90 (m, 3H), 7.75-7.50 (m , 4h), 7.38-7.31 (m, 2H), 4.35 (m, 2H), 3. 80-3.15 (m, 8H), 2.20 (m, 2H), 2.18 (s, 3H), 2.10-1.90 (m, 3H), 1.70 (m, 7H); m / z 578. Example 60 N- Hydrochloride. { 3- [7- (3-amino-propoxy) -quinazolin-4-ylamino] -4-methyl-phenyl} -3- (cyano-di-methyl-methyl) -benzamide A mixture of [3- (. {4 - [(5-. {[[3- (1-cyano-1-methylethyl) benzoyl] amino]} -2- methylphenyl) amino] quinazolin-7-yl.}. Oxi) propyl] carbamic acid (Example 53; 90 mg, 0.152 mmol) in 4M HCl in dioxane (2 ml) was stirred at 25 ° C. C for 1 h. The organics were removed under reduced pressure and the residue was purified by reverse phase preparative HPLC (0.1% TFA in MeCN and water) to provide 68 mg (91%) of a white solid. NMR: 11.12 (s, broad, 1H), 10.35 (s, 1H), 8.70 (s, 1H), 8.50 (d, 1H), 7.95-7.16 (m, 12H), 4.20 (m, 2H), 2.95 ( m, 2H), 2.10 (s, 3H), 2.05 (m, 2H), 1.66 (s, 6H); m / z 494.

Example 61 4- (4- {5- [3- (Cyano-dimethyl-methyl) -benzoylamino] -2-methyl-phenylamino} -quinazol-7-yloxymethyl) -piperidine-1-tert-butylester carboxylic acid A mixture of 3- (cyano-dimethyl-methyl) -? / - [3- (7-hydroxy-quinazolin-4-ylamino) -4-methyl-phenyl] -benzamide (Example 68, 150 mg, 0.343 mmol ), 4-hydroxymethyl-piperidine-1-carboxylic acid fer-t-butylester (147 mg, 0.686 mmol), azodicarboxylic acid diethyl ester (40% in toluene, 1.72 mmol, 5 equiv.) and triphenylphosphine (451 mg, 1.72 mmol, 5 equiv.) In THF (10 mL) was stirred at 25 ° C for 12 h. The solvents were removed under reduced pressure. The residue was first purified by column chromatography using an ISCO system (hexane-EtOAc) and then by reverse phase preparative HPLC (0.1% TFA in MeCN and water) to provide 96 mg (44%) of a light yellow solid. NMR: 8.35 (m, 2H), 8.02 (s, 1H), 7.95 (s, 1H), 7.80 (d, 1H), 7.69 (m, 2H), 7.56-7.20 (m, 6H), 4.20 (m, 2H), 4.00 (d, 2H), 2.80 (m, 2H), 2.20 (s, 3H), 2.05 (m, 1H), 1.85 (m, 2H), 1.75 (s, 3H), 1.49 (s, 9H) ), 1.30 (m, 2H); m / z 634.

Examples 62-67 The following compounds were prepared by the procedure of Example 61 using the appropriate intermediates. 1NMR: 11.67 (s, 1H), 11.00 (s, broad, 1H) 5 10.55 (s, 1H), 8.86 (m, 2H), 8.10-7.95 (m, 3H), 7.80-7.62 (m, 4H), 7.42 (m, 2H), 4.67 (m, 2H), 4.00 (m, 1H), 3.45 (m, 1H), 3.05 (s, 3H), 2.40 (m, 2H), 2.25 (s, 3H), 2.13 (m, 1H), 2.07 (m, 1H), 1.96 (m, 1H), 1.80 (s, 6H).

EXAMPLE 68 3- (cyano-di-methyl-methyl) -N- [3- (7-hydroxy-quinazolin-4-ylamide) -4-methyl-phenyl-benzamide A suspension of? / - [3- (7-benzyloxy-quinazolin-4-ylamino) -4-methyl-phenyl] -3- (cyano-dimethyl-methyl) -benzamide (Example 21; 3.13 g, 5.94 mmol) and 10% Pd / C (400 mg) in MeOH (150 ml) was stirred at 25 ° C under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth and the organics were concentrated under reduced pressure to provide 2.6 g (99%) of a light yellow solid. NMR: 10.41 (s, 1H), 10.30 (s, 1H), 9.46 (s, 1H), 8.33 (d, 1H), 8.27 (s, 1H), 8.05 (s, 1H). 7.90 (d, 1H), 7.75 (m, 2H), 7.60 (m, 2H), 7.30 (d, 1H), 7.10 (d, 1H), 7.01 (s, 1H), 2.15 (s, 3H), 1.75 (s, 6H); m / z 437.

Example 69 N- [3- (7-amino-quinazolin-4-ylamino) -4-methyl-phenyl] -3- (cyano-dimethyl-ethyl) -benzamide A mixture of 3- (cyano-dimethyl-methyl) -? / - [3- (7-Nitro-quinazolin-4-ylamino) -4-methyl-phenyl] -benzamide (Example 30; 1.18 g, 2.05 mmol) and 10% Pd / C (100 mg) in MeOH ( 50 ml) was stirred at 25 ° C under a hydrogen atmosphere for 3 h. The reaction mixture was filtered through a bed of diatomaceous earth and the organics were concentrated under reduced pressure. The residue was purified by column chromatography using an ISCO system (EtOAc-DCM-MeOH) to provide 800 mg (90%) of the desired product. NMR: 10.60 (s, 1H), 10.45 (s, 1H), 8.48 (s, 1H), 8.35 (d, 1H), 8.10 (s, 1H), 7.95-7.60 (m, 5H), 7.31 (d, 1H), 7.00-6.65 (m, 4H), 2.16 (s, 3H), 1.75 (s, 6H). Example 70 N-. { 3 - [(7-hydroxy-6-methoxyquinazolin-4-yl) amino] -4-methylphenyl} -3- (trifluoromethyl) benzamide A solution of 4 - [(5-amino-2-methylphenyl) amino] -6-methoxyquinazolin-7-ol (method 6, 900 mg, 3.04 mmol) and triethylamine (1.27 ml, 9.12 mmol, 3.0 equiv.) in DCM (10 ml) was treated with 3- (trifluoromethyl) benzyl chloride (0.55 ml, 3.64 mmol, 1.2 equiv.) at 25 ° C for 12 h. The reaction was quenched with water and extracted with EtOAc. The organics were dried with NaCl (sat) and Na 2 SO 4 (S) and then removed under reduced pressure. The resulting residue was purified by column chromatography using an ISCO system (DCM-MeOH) to provide 0.43 g (30%); m / z 469. Preparation of starting materials Method 1 4-Oxo-3,4-dihydroquinazoline-7'-carboxylic acid A mixture of 2-aminoterephthalic acid (6.90 g, 0.038 mol) and formamide (14 ml) was heated at 180 ° C for 12 h. The reaction was allowed to cool and acetone was added. The resulting precipitate was collected by vacuum filtration (4.38 g, 60%); m / z 191.

Method 2 4-Chloroquinazoline-7'-carboxylic acid A mixture of 4-oxo-3,4-dihydroquinazoline-7-carboxylic acid (method 1, 1.00 g, 5.26 mmol), oxalyl chloride (1.37 ml, 15.8 mmol, 3.0 equiv.) in DCM (15 ml) was treated with DMF (0.1 ml). The reaction mixture was stirred under Ar for 3 h at 25 ° C.

The solvents were removed under reduced pressure; m / z 209.

Method 3 4 - [(2-Methyl-5-nitrophenyl) amino] quinazoline-7-carboxylic acid A mixture of 4-chloroquinazoline-7-carboxylic acid (Method 2, 1.10 g, 5.26 mmol) and 2-methyl-5-nitroaniline (960 mg, 6. 31 mmol, 1.2 equiv.) In DCM (15 ml) was treated with Z-Pr2NEt (1.4 ml, 7.89 mmol, 1.5 equiv.). The reaction mixture was stirred under Ar for 12 h at 25 ° C. The resulting precipitate was collected by vacuum filtration; m / z 325. Method 4 The following compound was prepared by the method of method 3 using the appropriate MSs.

Method 5 N- (3-am i non-4-methyl-f-enyl) -3- (cyano-di-methyl-methyl) -5-fluoro-o-benzamide A mixture of 3- (cyano-dimethyl-methyl) - 5-fluoro-? / - (4-methyl-3-nitro-phenyl) -benzamide (method 21; 2.5 g, 7.33 mmol) and 10% Pd / C (200 mg) in MeOH (150 ml) was treated with a Hydrogen atmosphere for 48 h at 25 ° C. The reaction mixture was filtered through diatomaceous earth and the organics were concentrated under reduced pressure. The residue was purified by column chromatography using an ISCO system (hexane-EtOAc), to provide 900 mg (39.4%) of a white solid. NMR: 7.90 (s, 1H), 7.70 (s, 1H), 7.40 (d, 1H), 7.30 (d, 1H), 7.20 (s, 1H), 6.92 (d, 1H), 6.65 (d, 1H) , 3.30 (s, 2H), 2.10 (s, 3H), 1.70 (s, 6H); m / z 311.

Method 6 The following compound was prepared by the method of method 5, using the appropriate MSs.

Method 7 4 - [(5-Amino-2-methylphenyl) amino] quin azol i-7-carboxylic acid 4 - [(2-Methyl-5-nitrophenyl) amino] quinazoline-7-carboxylic acid (method 3; 1.71 g, 5.26 mmol) and 30% Pd / C (200 mg) in MeOH (30 ml) were stirred in a Parr hydrogenator under 45 psi hydrogen for 3 h. The reaction mixture was filtered through diatomaceous earth, and the resulting filtrate was concentrated under reduced pressure to give the desired compound; m / z 295. Method 8 The following compound was prepared by the method of method 7 using the appropriate MS.

Method 9 3-Cyanomethyl-benzoic acid methyl ester A suspension of methyl-3- (bromomethyl) benzoate (13.5 g, 58. 9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 mL) and water (1 mL) was stirred at 75 ° C for 5 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organics were dried and concentrated under reduced pressure. The resulting residue was purified by column chromatography using an ISCO system (hexane-EtOAc) to provide 7.2 g (70%) of a colorless oil. NMR: 7.90 (s, 1H), 7.86 (d, 1H), 7.60 (d, 1H), 7.50 (m, 1H), 4.10 (s, 2H), 3.80 (s, 3H); m / z 175. Method 10 The following compound was prepared by the procedure of method 9 using the appropriate MS.

Method 11 3- (1-Cyano-1-methylethyl) benzoic acid methyl ester A solution of 3-cyanomethyl-benzoic acid methyl ester (method 9; 7.2 g, 41.1 mmol) in DMSO (80 mL) was treated with sodium hydride (60%, 4.9 g, 123.3 mmol, 3 equiv.). Methyl iodide was added dropwise at 0 ° C. The reaction mixture was stirred at 25 ° C for 12 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organics were dried and concentrated under reduced pressure. The raw product is purified by column chromatography using an ISCO system (hexane-EtOAc) to provide 5.5 g (66%) of a colorless oil. NMR: 8.05 (s, 1H), 7.90 (d, 1H), 7.75 (d, 1H), 7.55 (m, 1H), 3.80 (s, 3H), 1.62 (s, 6H); m / z 203. Methods 12-15 The following compounds were prepared by the procedure of method 11, using the appropriate MSs.

Method 16 3- (1-Cyano-1-ethyl ethyl) benzoic acid A solution of 3- (1-cyano-1-methylethyl) benzoic acid methyl ester (Method 11, 5.5 g, 5 27.1 mmol) in 100 mL of THF-MeOH-H2O (3: 1: 1) was treated with lithium hydroxide (1.95 g) in water (20 ml). The mixture was stirred at 25 ° C for 12 h. The organics were removed under reduced pressure and the residue was diluted with water, and then acidified with 10% HCl to pH = 1-3.

The resulting white solid (4.83 g, 94%) was collected by vacuum filtration. NMR: 13.00 (s, 1H), 7.95 (s, 1H), 7.80 (d, 1H), 7.65 (d, 1H), 7.45 (m, 1H), 1.60 (s, 6H); m / z 189. Methods 17-19 The following compounds were prepared by the procedure of method 16 using the appropriate MSs.

Method 20 6-methoxy-4 - [(2-methyl-5-nitrophenyl) amino] quinazolin-7-ol A solution of 7-benzyloxy-4-chloro-6-methoxy-quinazoline (2.00 g, 6.65 mmol) and 2-methyl -5-nitroaniline (1.01 g, 6.65 mmol) in EtOH (20 ml) was heated at 95 ° C for 12 h. The organics were removed under reduced pressure. The resulting solid was used without further purification; m / z 417. Method 21 3- (cyano-dimethyl-methyl) -5-fluoro-N- (4-methyl-3-nitro-phenyl) -benzamide A mixture of 4-methyl-3-nitro-phenylamine (1.6 g, 10.6 mmol), 3- (cyano-dimethyl-methyl) -5-fluoro-benzoic acid (method 55, 2.2 g, 10.6 mmol), HATU (4.8 g, 12.7 mmol) and DIEA (4.1 g, 31.8 mmol) DMF (15 ml) was stirred at 25 ° C for 3 h. Water was added and the reaction mixture was extracted with EtOAc. The organics were concentrated under reduced pressure, and the residue was purified by column chromatography using an ISCO system (hexane-EtOAc) to give 2.5 g (69%) of a yellow solid. NMR: 8.30 (s, 1H), 8.00 (s, 1H), 7.90 (d, 1H), 7.85 (s, 1H), 7.60 (d, 1H), 7.40 (m, 2H), 2.65 (s, 3H) 1.80 (s, 6H); m / z 341. Method 22 3-lsopropylbenzoic acid 1-bromo3-isopropylbenzene (; 500 mg, 2.51 mmol) in pentane-ether (1: 1) (8 ml) at -78 ° C under Ar was treated with f-BuLi (1.7 M in pentane, 5.02 mmol, 2.0 equiv.). The reaction was stirred for 15 min and then CO2 (g) was bubbled through the reaction mixture. After 10 min, the reaction was stopped with 10% NaOH and extracted with EtOAc. The aqueous layer was acidified with 10% HCl and extracted with EtOAc. The organics were dried with NaCl (sat) and Na 2 SO 4 (s) and then removed under reduced pressure; m / z 165. Method 23 3- (1-ci ano-1-methyl I ethyl) -N- (4-methyl 1-3-nitrophenyl) benzamide A mixture of 4-methyl-3-nitroaniline (2.74 g) 18 mmol), 3- (1-cyano-1-methylethyl) benzoic acid (method 16, 3.4 g, 18 mmol), EDCI (6.9 g, 36 mmol), HOBt (2.43 g, 18 mmol) and diisopropylethylamine (3.48 g, 27 mmol) in DMF (30 ml) was stirred at 25 ° C for 12 h. The reaction mixture was diluted with DCM and washed with water. The organic phase was dried with NaCl (sat) and Na2SO4 (s). The solvent was removed under reduced pressure and the resulting product was purified by column chromatography using an ISCO system (hexane-EtOAc) to provide 4.4 g (53%). NMR: 10.50 (s, 1H), 8.40 (s, 1H), 7.40-7.95 (m, 6H), 3. 20 (s, 3H), 1.65 (s, 6H); m / z 323. Method 24 N- (3-amino-4-m ethyl phenyl) -3- (1-cyano-1-methyl ethyl) benzamide A suspension of 3- (1-cyano-1-methylethyl) -? / - (4-methyl-3-nitro-phenyl) benzamide (method 23.4 g, 13.9 mmol) and 5% Pd / C (400 mg) in hydrazine hydrate (100 ml) and ethanol (100 ml) was heated reflux for 3 h and then stirred at 80 ° C for 12 h. The reaction mixture was filtered through diatomaceous earth and the organics were removed under reduced pressure. The residue was purified by column chromatography using an ISCO system (hexane-EtOAc) to provide 3.7 g (91%) of an orange gum. NMR: 9.95 (s, 1H), 8.00 (s, 1H), 7.90 (d, 1H), 7.70 (d, 1H), 7.55 (m, 1H), 7.05 (s, 1H), 6.80-6.87 (m, 2H), 4.85 (s, 2H), 2.05 (s, 3H), 1.85 (s, 6H); m / z 293. Method 25 3 - [(Dimethylamino) sulfonyl] benzoic acid A solution of 3- (chlorosulfonyl) benzoic acid (2.60 g, 12 mmol) in DCM (20 ml) was treated with dimethylamine (2.0 M in THF, 20 ml, 40 mmol, 3.3 equiv.). After 30 min, the reaction was quenched with 10% HCl and extracted with EtOAc. The organics are They were heated with NaCl (sat) and dried with Na2SO4 (S). The organics were then removed under reduced pressure to provide 1.80 g, 65%; m / z 229. Tert-butyl 26 (3-iodopropyl) carbamate method Triphenylphosphine (11.21 g, 43 mmol) and imidazole (2.91 g, 43 mmol, 1.5 equiv.) in DCM at 0 ° C under Ar were treated with 12 (5.43 g, 21 mmol, 0.74 equiv.). After 5 min, fer-butyl (3-hydroxypropyl) carbamate (4.88 ml, 29 mmol) in DCM was added. The reaction was stirred for 1 h and quenched with 10% HCl. The reaction mixture was extracted with EtOAc and the layer was washed with NaHCO3 (sat). The organics were dried with NaCl (sat) and Na2SO4 (S) and removed under reduced pressure. The residue was purified by column chromatography using an ISCO system (EtOAc-Hexane) to provide 4.54 g (76%); m / z 286. Method 27 2-methyl-2- (2-thienyl) proponon itr ilo A solution of NaH (0.974 g, 24.36 mmol) in DMSO (30 ml) was treated with 2-thienylacetonitrile (1.00 g, 8.12 mmol) by dropwise addition. After stirring for 5 min at ° C, methyl iodide (6.91 g, 48.72 mmol) was added to the reaction mixture via syringe. The resulting solution was stirred at 25 ° C for 3 h before being diluted with H 2 O (100 ml). The resulting solution was extracted with EtOAc. The organics were warmed with NaCl (sat) and dried with MgSO4 (s). The organics were removed under reduced pressure, and the residue was purified by column chromatography using an ISCO system (EtOAc-Hexane) to provide 1.0 g of (81%) a pale yellow oil; m / z 152. Method 28 2- (5-formyl-2-thienyl) -2-methyl propane nitrile A solution of 2-methyl-2- (2-thienyl) propanenitrile (method 27, 0.260 g, 1.71 mmol) in THF (5.8 ml) was cooled to -78 ° C and treated with fer-butyl lithium (1.7 M solution in pentanes, 1.26 ml, 2.14 mmol) by dropwise addition. The resulting bright yellow mixture was stirred for 1 h and treated with DMF (0.330 mL, 4.27 mmol) via syringe. The reaction mixture was stirred for 6 h at -78 ° C and then quenched by the addition of NH CI (sat) (25 ml). The resulting mixture was extracted with EtOAc and the organics were warmed with NaCl (sat) and dried with MgSO (s). The organics were removed under reduced pressure to provide 0.271 g of (88%) a colorless oil; m / z 180. Method 29 5- (1-Cyano-1-methylethylthiophene-2-carboxylic acid A solution of 2- (5-formyl-2-thienyl) -2-methylpropanonitrile (method 28, 0.271 g, 1.51 mmol) in fer-butyl alcohol (7.5 ml) and 2-methyl-2-butene (4.5 ml) was treated with a solution of NaCIO2 (1.22 g, 13.60 mmol) and NaH2PO4 (1.45 mmol). g, 10.57 mmol) (7 ml). The reaction mixture was stirred for 30 min at 25 ° C and then the organics were removed under reduced pressure. The residue was washed with NaHCO3 (SaO and extracted with EtOAc) The organics were warmed with NaCl (sat) and dried with MgSO4 (s) The organics were removed under reduced pressure to provide 0.265 g (90%) of a white solid; z 196. Method 30 2-amino-4-methoxy-benzoic acid A mixture of 4-methoxy-2-nitrobenzoic acid (20 g, 101.5 mmol), 10% Pd / C (1.5 g) in MeOH (200 ml) was added. The mixture was diluted with MeOH and filtered through diatomaceous earth, the organics were removed under reduced pressure to give a light brown solid (14.85 g, 87.6%). NMR: 7.65 (d, 1H), 6.30 (s, 1H), 6.15 (d, 1H), 3.80 (s, 3H), m / z 167. Method 31 7-methoxy-3H-quinazolin-4-one One The mixture of 2-amino-4-methoxy-benzoic acid (method 30, 4.85 g, 88.9 mmol) and formamidine acetate (18.49 g, 177.8 mmol) in 2-methoxyethanol (100 ml) was stirred under reflux for 12 h. reaction mixture was cooled to 25 ° C and diluted with 0.01 M ammonia (100 ml) The mixture was then stirred at 25 ° C for min and the resulting solid was collected by filtration. The solid was washed with 0.01M ammonia and water. The product was dried by high vacuum to obtain a light brown solid 11.5 g (73%). NMR: 12.10 (s, broad, 1H), 8.05 (m, 2H), 7.10 (m, 2H), 3.90 (s, 3H); m / z 167.

Method 32 4-Chloro-7-methoxy-quinol-7-methoxy-3H-quinazolin-4-one (method 31, 11.5 g, 65.3 mmol) was suspended in thionyl chloride (100 ml) and DMF (0.1 ml ). The reaction mixture was heated to reflux for 3.5 h. The organics were removed under reduced pressure to provide a light yellow solid (13.8 g); m / z 195. Methods 33-46 The following compounds were prepared by the procedure of method 32 using the appropriate starting materials.

Method 47 4-Dimethylaminomethyl-5-trifluoromethyl-benzoic acid methyl ester A mixture of 4-bromomethyl-3-trifluoromethyl-benzoic acid methyl ester (method 58, 252 mg, 0.85 mmol), dimethylamine (2.0 M in THF, 2 ml, 4 mmol) and K2CO3 (235 mg, 1.70 mmol) in MeCN (10 ml) was stirred at 80 ° C for 4 h. The heterogeneous mixture was filtered and the solids were heated with MeOH. The organics were concentrated under reduced pressure and the residue was purified by column chromatography using an ISCO system (hexane-EtOAc) to provide 72 mg (41%) of a colorless oil. NMR: 8.25 (d, 1H), 8.20 (s, 1H), 0.79 (d, 1H), 3.90 (s, 3H), 3.60 (s, 2H), 2.18 (s, 6H); miz 261. Method 48 4-Di methylamino-1-ethyl-3-trifluoromethyl-1-benzoic acid A solution of 4-dimethylaminomethyl-5-trifluoromethyl-benzoic acid methyl ester (method 47, 72 mg, 0.3 mmol) in THF-MeOH-H2O (3: 1: 1, 5 ml) was treated with lithium hydroxide (22 mg, 0.919 mmol) in H2O (2 ml). The reaction mixture was stirred at 25 ° C for 12 h. The organics were removed under reduced pressure. NMR: 13.00 (s, broad, 1H), 8.45 (d, 1H), 8.21 (m, 2H), 4. 50 (s, 2H), 2.73 (s, 6H); m / z 247 '. Method 49 5-Fluoro-Isophthalic acid 3-Fluoro-5-methyl-benzoic acid (2 g, 13 mmol) and KMnO 4 (8.22 g, 52 mmol) was dissolved in water (200 ml), and the reaction mixture was heated at reflux for 12 h. The hot reaction mixture was then filtered through diatomaceous earth. The resulting solution was cooled to 25 ° C and then acidified with HCl (conc.). The resulting solid was collected by vacuum filtration to provide 2.4 g (100%). NMR: 8.25 (s, 1H), 7.88 (d, 2H).

Method 50 5-Fluoroisophthalic acid dimethyl ester A solution of 5-fluoroisophthalic acid (method 49, 1.3 g, 7.1 mmol) in MeOH (30 ml) was treated with sulfuric acid (conc.) (0.25 ml). The reaction mixture was then refluxed for 12 h. The organics were removed under reduced pressure and the residue was then neutralized with NaHCO3 (sat) and extracted with DCM. The organics were warmed with NaCl (sat) and dried with Na2SO (s) and then concentrated under reduced pressure to provide 1.25 g (83%) as a white solid. NMR: 8. 42 (s, 1H), 7.88 (d, 2H), 3.90 (s, 6H).

Method 51 3-Fluoro-5-hydroxymethyl-benzoic acid methyl ester A solution of 5-fluoroisophthalic acid dimethyl ester (method 50; 301 mg, 1.42 mmol) in THF (15 ml) at 0 ° C was treated with lithium aluminum hydride (30 mg, 0.7 mmol). The reaction mixture was stirred at 25 ° C for 2 h. The reaction mixture was quenched with H2O and extracted with EtOAc. The organics were warmed with NaCl (sat) and dried with Na2SO4 (s) and then concentrated under reduced pressure. The residue was purified by column chromatography using an ISCO system (hexane-EtOAc) to provide (120 mg, 50%) of a colorless oil. NMR: 780 (s, 1H), 7.62 (d, 1H), 7.31 (d, 1H), 4.76 (s, 2H), 3.95 (s, 3H), 1.85 (s, broad, 1H).

Method 52 3-Fluoro-5-methanesulfonyloxymethyl-benzoic acid methyl ester A solution of 3-fluoro-5-hydroxymethyl-benzoic acid methyl ester (method 51, 120 mg, 0.65 mmol) in DCM (5 ml) at 0 ° C, was treated with methanesulfonyl chloride (148 mg, 1.3 mmol) and triethylamine (198 mg, 1.96 mmol). The reaction mixture was stirred at 25 ° C for 0.5 h. The organics were removed under reduced pressure and the residue was purified by column chromatography using an ISCO (hexane-EtOAc) system to provide (166 mg, 97%) of a colorless oil. NMR: 7.79 (s, 1H), 7.17 (d, 1H), 7.26 (d, 1H), 5.19 (s, 2H), 3.87 (s, 3H), 2.95 (s, 3H).

Method 53 3-Cyanomethyl-5-fluoro-benzoic acid methyl ester A solution of 3-fluoro-5-methanesulfonyloxymethyl-benzoic acid methyl ester (method 52, 50 mg, 0.19 mmol) in MeCN (2 ml) was treated with cyanide of sodium (19 mg, 0.38 mmol) and 18-Crown-6 (10 mg). The reaction mixture was stirred at 65 ° C for 2 h. The heterogeneous mixture was filtered and the solids were heated with DCM. The organics were concentrated under reduced pressure and the residue was purified by column chromatography using an ISCO system (hexane-EtOAc) to provide (30 mg, 81.7%) of a colorless oil. NMR: 7.78 (s, 1H), 7.65 (d, 1H), 7.20 (d, 1H), 3.90 (s, 3H), 3.78 (s, 2H).

Method 54 3- (Cyano-dimethyl-methyl) -5-fluoro-benzoic acid methyl ester A solution of 3-cyanomethyl-5-fluoro-benzoic acid methyl ester (method 53, 1.7 g, 8.79 mmol) in DMSO (50 ml ) under nitrogen was treated with sodium hydride (60% dispersed in mineral oil, 1.05 g, 26.4 mmol). The reaction mixture was cooled to 0 ° C and methyl iodide (12.49 g, 5.49 mL, 87.9 mmol) was added dropwise. The reaction mixture was stirred at 25 ° C for 5 h and then quenched with H2O. The reaction mixture was then extracted with EtOAc and the organics were warmed with NaCl (sat), dried with Na2SO (S) and then concentrated under reduced pressure. The residue was purified by column chromatography using an ISCO system (hexane-EtOAc) to provide 1.94 g (100%) of a colorless oil. NMR: 7.82 (s, 1H), 7.58 (d, 1H), 7.31 (d, 1H), 3.89 (s, 3H), 1.70 (s, 6H). Method 55 3- (Cyano-dimethyl-methyl) -5-fluoro-benzoic acid A solution of 3- (cyano-dimethyl-methyl) -5-fluoro-benzoic acid methyl ester (method 54, 1.94 g, 8.79 mmol) in THF-MeOH-H2O (3: 1: 1, 50 mL) was treated with lithium hydroxide (633 mg, 26.4 mmol) in H2O (5 mL). The reaction mixture was stirred at 25 ° C for 12 h. The organics were removed under reduced pressure and then H2O was added. The reaction was then acidified with 10% HCl and the resulting solid was collected by vacuum filtration to provide 1.8 g (100%) as a white solid.

NMR: 7.95 (s, 1H), 7.68 (d, 1H), 7.41 (d, 1H), 1.70 (s, 6H). Method 56 Acid 3-c icloprop i-5-flu benzoic acid 3-bromo-5-fluorobenzoic acid (1.00 g, 4.57 mmol), cyclopropylboronic acid (1.18 g, 13.71 mmol, 3.0 equiv.) And K3PO4 (7.76 g, 36.56 mmol, 8.0 equiv.) In toluene-H2O (25: 1, 31 ml) were treated with Pd (Ph3P) 4 (1.05 g, 0.912 mmol, 20 mol%). The reaction mixture was heated at 100 ° C for 12 h. The reaction was quenched with 10% NaOH and extracted with EtOAc. The aqueous layer was acidified with 10% HCl and extracted with EtOAc. The organics were dried with NaCl (sat) and Na 2 SO 4 (S) and removed under reduced pressure; m / z 181. Method 57 4-Methyl-3-trifluoromethyl-benzoic acid methyl ester A suspension of potassium hydroxide (84 mg, 1.5 mmol) in DMSO was treated with a solution of 4-methyl-3-trifluoromethyl-benzoic acid. (306 mg, 1.5 mmol) in DMSO, (5 mL). The resulting mixture was stirred for 15 min and cooled with an ice bath. After the addition of methyl iodide (426 mg, 3 mmol), the mixture was stirred for 2 h at 25 ° C. The reaction mixture was quenched with water and extracted with EtOAc. The organics were warmed with NaCl (sat), dried with Na 2 SO 4 (s) and concentrated under reduced pressure to provide 327 mg (100%). NMR: 8.10 (m, 2H), 7.60 (s, 1H), 3.86 (s, 3H), 2.45 (s, 3H); m / z 218.

Method 58 4-Bromomethyl-3-trifluoromethyl-benzoic acid methyl ester A suspension of 4-methyl-3-trifluoromethyl-benzoic acid methyl ester (method 57; 327 mg, 1.5 mmol),? / - bromosuccinimide (267 mg, 1.5 mmol ) and benzoyl peroxide (catalytic) in CCI4 (10 ml) was heated to reflux for 3 h. The reaction mixture was cooled to 25 ° C and filtered through a pad of silica gel. The organics were removed under reduced pressure and the residue was purified by column chromatography using an ISCO system (hexane-EtOAc) to provide 252 mg (56.5%) of a colorless oil. NMR: 7.70-8.25 (m, 3H), 4.85 (s, 2H), 3.91 (s, 3H); m / z 297. Method 59 2-methyl-2- (4-methylpyridin-2-yl) propanenitrile A solution of 2-fluoro-4-methylpyridine (1.00 g, 9.00 mmol), 2-methylpropanonitrile (2.48 g, 36 mmol) in toluene (30 ml) was treated with potassium hexamethyldisilazide (13.5 mmol) and the reaction was refluxed for 1 h. The reaction was quenched with NH 4 Cl (sat) and extracted with EtOAc. The organics were dried with MgSO (s) and concentrated under reduced pressure. The residue was purified by column chromatography using an ISCO system (hexane-EtOAc) to provide 0.870 g (60%) of a colorless oil; m / z 161. Method 60 2- (1-Cyano-1-methylethyl) isonicotinic acid A solution of 2-methyl-2- (4-methylpyridin-2-yl) propanenitrile (method 59; 0.870 g, 5.43 mmol) in H 2 O (15 ml) at 60 ° C was treated with KMnO (4.3 g, 27 mmol ). The reaction was refluxed for 2 h and then filtered through diatomaceous earth. The pH was adjusted to 4 by the addition of 1N HCl and the aqueous phase was extracted with EtOAc. The organics were dried with MgSO 4 (s) and concentrated under reduced pressure. The residue was purified by column chromatography using an ISCO system (EtOAc-MeOH) to provide 0.700 g (68%) of a white solid: m / z 191. Method 61 The following compounds were prepared by the procedure of method 60 , using the starting material.

Method 62 N3- (7-methoxy-quinazolin-4-yl) -4-methyl-benzene-1,3-diamine A suspension of (7-methoxy-quinazolin-4-yl) - (2-methyl-5-nitro) phenyl) -amine (method 63; 4.6 g, 14.8 mmol) and 10% Pd / C (500 mg) in MeOH (200 ml) was stirred at 25 ° C under hydrogen for 12 h. The reaction mixture filtered through diatomaceous earth and concentrated under reduced pressure to 5 ml. EtOAc (5 mL) was added to the solution and the resulting solid was collected by vacuum filtration to provide 2.5 g (60.2%) of a solid color yellow; m / z 280. Method 63 (7-methoxy-quinazolin-4-yl) - (2-methyl-5-nitro-phenyl) -amine A mixture of 4-chloro-7-methoxy-quinazoline (method 32; 3.5 g , 18 mmol) and 2-methyl-5-nitro-phenylamine (2.3 g, 15 mmol) in isopropanol (150 ml) was refluxed for 12 h. The reaction mixture was cooled to 25 ° C and the resulting precipitate was collected by vacuum filtration. The solid was washed with ether and dried under reduced pressure to provide 4.6 g (98.9%) of a light yellow solid. NMR: 11.55 (s, broad, 1H), 8.85 (s, 1H), 8.75 (d, 1H), 8.30 (s, 1H), 8.20 (d, 1H), 7.75 (d, 1H), 7.52 (d, 1H), 7.30 (s, 1H), 4.02 ( s, 3H), 2.40 (s, 3H); m / z 310. Method 64 Ethyl 3-formyl-4-oxobutanoate A solution of ethyl formate (10.0 g, 367.9 mmol) in anhydrous diethyl ether was treated with sodium hydride (60% in mineral oil) (1.8 g, 44.2 mmol). The reaction mixture was cooled to 0 ° C and ethyl 3-ethoxy-3-methoxypropanoate (7.0 g, 36.8 mmol) was added. The reaction mixture was stirred at 0 ° C for 5 h and then at 25 ° C for 12 h. The reaction mixture was quenched with cold H2O and extracted with diethyl ether. The aqueous layer was then acidified with 10% HCl and then extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product (3.3 g, 57%) was used directly. H NMR (300 MHz): 1.29 (t, 3H), 4.24 (q, 2H), 9.08 (s, 2H).

Method 65 1-tert-bute I-1 H -prazole I-3-caboxymate A solution of ethyl 3-formyl-4-oxobutanoate (method 64, 350 mg, 2.2 mmol) in EtOH (5 ml ) was treated with triethylamine (465 μl, 3.3 mmol) and f-butyl-hydrazine hydrochloride. The reaction was stirred for 12 h at 25CC. EtOH was removed under reduced pressure and the residue was redissolved in EtOAc and washed with H2O. The organics were dried with Na2SO4 (S) and concentrated under reduced pressure. The residue was purified by column chromatography using an ISCO system (5% MeOH in CH 2 Cl 2) to provide 327 mg (76%) of an oil. 1 H NMR (300 MHz): 1.29-1.35 (m, 3H), 1.57 (s, 9H), 4.25 (q, 2H), 7.86 (s, 1H), 8.20 (s, 1H). Method 66 1-tert-Butyl-1H-pyrazole-4-carboxylic acid A solution of ethyl 1-fer-butyl-1 H-pyrazole-3-carboxylate (method 65, 327 mg, 1.66 mmol) in THF-MeOH H2O (3: 1: 1, 8 mL) was treated with LiOH (120 mg, 5.0 mmol). The reaction mixture was stirred at 25 ° C for 12 h. H2O and EtOAc were added to the reaction mixture and the resulting solution was acidified with 10% HCl. The organics were dried with Na2SO (s) and concentrated under reduced pressure to provide 217 mg (78%). m / z 168. Method 61 5,7-dimethoxy-3H-quinazolin-4-one A suspension of 5,7-difluoro-3H-quinazolin-4-one (1 g, . 49 mmol) in anhydrous DMF (15 ml) was treated with sodium methoxide (890 mg, 16.47 mmol, 3 equiv.). The reaction mixture was stirred at 25 ° C for 30 min and then at 90 ° C for 5 h. The reaction mixture was poured into 10% ammonium chloride (100 ml) and the resulting precipitate was collected by vacuum filtration to give a white solid (1.13 g, 100%). NMR (400MHz, DMSO-d6): 11.70 (s, broad, 1H), 7.90 (s, 1H), 6.62 (s, 1H), 6.50 (s, 1H), 3.88 (s, 3H), 3.80 (s, 3H); m / z: 206. Method 68 3-Fluoro-5-isopropylbenzoic acid 3-Cyclopropyl-5-fluorobenzoic acid (450 mg, 2.50 mmol) and PtO2 (20 mg) in AcOH (10 ml) were stirred under 45 psi hydrogen in a Parr hydrogenator for 3 h. The reaction mixture was filtered through diatomaceous earth, and the resulting filtrate was concentrated under reduced pressure to give the desired compound (400 mg, 88%); m / z 181. Method 69 N- (3-amino-4-methylphenyl) -3- (trifluoromethyl) benzamide? / - (4-methyl-3-nitrophenyl) -3- (trifluoromethyl) benzamide hydrochloride (method 70) (3.7 g, 11.41 mmol) and 10% palladium on carbon (370 mg) in methanol (20 ml) was stirred under 40 psi H2 for 3 hours. The reaction mixture was then filtered on diatomaceous earth and the solvent was removed under reduced pressure. The residue was placed in 30 ml 4N HCl in dioxane and the solvent was removed under pressure reduced to provide the title compound (3.66 g, 97%). m / z 295. Method 70 N- (4-m eti 1-3-n-tro f en il) -3- (trifluoromethyl) benzamide Chloride of 3- (trifluoromethyl) benzoyl (2.70 g, 12.95 mmol) in 10 ml anhydrous DCM was added to 4-methyl-3-nitroaniline (1.9 g, 12.95 mmol), and TEA (5.4 mL, 38.85 mmol) in DCM (65 mL) and the reaction mixture was allowed to stir at 25 ° C for 1 h. h. The resulting mixture was washed with 1N HCl, water and brine. The organic extracts were dried and the solvent was removed under reduced pressure to give the title compound as a yellow solid (3.70 g, 88%). m / z 325

Claims

CLAIMS A compound of formula (I): (i) wherein: ring A is phenyl or a 5- or 6-membered heteroaryl; wherein if the heteroaryl contains a -NH- moiety the nitrogen may optionally be substituted by a group selected from R5; R1 is a substituent on carbon and is selected from halo, nitro, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) amino, alkanoylamino of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) carbamoyl,? /,? / - (alkyl of 1 to 6 carbon atoms) 2carbamoyl, alkyl of 1 to 6 carbon atoms-S (O) a wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) sulfamoyl,? /,? / - (alkyl of 1 to 6 carbon atoms) carbon) 2-sulfamoyl, alkylsulfonylamino of 1 to 6 carbon atoms, carbocyclyl or heterocyclyl bonded to carbon; wherein R1 may optionally be substituted on the carbon with one or more R8; and wherein if the heterocyclyl contains an -NH- moiety, the nitrogen may optionally be substituted by a group selected from R9; n is selected from 1-4; wherein the values of R1 may be equal or different; R 2 is selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) amino,? /,? / - (alkyl of 1 to 6 carbon atoms) 2amino, alkanoylamino of 1 to 6 carbon atoms, N, N- (alkyl of 1 to 6 carbon atoms) carbamoyl,? /,? / - (alkyl of 1 to 6 carbon atoms) 2carbamoyl, alkyl of 1 to 6 carbon atoms-S (O) a wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 atoms carbon) sulfamoyl,? /,? / - (alkyl of 1 to 6 carbon atoms) 2-sulphamoyl, alkylsulfonylamino of 1 to 6 carbon atoms, carbocyclyl-R10- or heterocyclyl-R11-; wherein R2 may optionally be substituted on the carbon with one or more R12; and wherein if the heterocyclyl contains an -NH- moiety, the nitrogen may optionally be substituted by a group selected from R13; R3 and R4 are substituents on carbon and are independently selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 atoms carbon, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) carbon) amino, N, N- (alkyl of 1 to 6 carbon atoms) 2-amino, alkanoylamino of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) carbamoyl,? V,? / - (alkyl of 1 to 6 carbon atoms) 2-carbamoyl, alkyl of 1 to 6 carbon atoms-S (O) a wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms,? / - (alkyl 1 to 6 carbon atoms) sulfamoyl,? /,? / - (alkyl of 1 to 6 carbon atoms) 2-sulphamoyl, alkylsulfonylamino of 1 to 6 carbon atoms, carbocyclyl-R14- or heterocyclyl-R15-; wherein R4 can optionally be substituted on the carbon with one or more R16; and wherein if the heterocyclyl contains an -NH- moiety, the nitrogen may optionally be substituted by a group selected from R17; m is selected from 0-4; wherein the values of R4 may be the same or different; R8 and R12 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy from 1 to 6 carbon atoms,? /,? / - (alkyl of 1 to 6 carbon atoms) 2-amino, alkanoylamino of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) carbamoyl, ? /,? / - (alkyl of 1 to 6 carbon atoms) 2-carbamoyl, alkyl of 1 to 6 carbon atoms-S (O) a wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) sulfamoyl,? /,? / - (alkyl of 1 to 6 carbon atoms) 2sulfamoyl, alkylsulfonylamino of 1 to 6 carbon atoms, carbocyclyl-R18- or heterocyclyl-R19-; wherein R 8 and R 12 independently each may optionally be substituted on the carbon with one or more R 20; and wherein if the heterocyclyl contains an -NH- moiety, the nitrogen may optionally be substituted by a group selected from R21; R 6 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon, alkoxy of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) amino,? /,? / - (alkyl of 1 to 6 carbon atoms) 2-amino, alkanoylamino of 1 to 6 carbon atoms,? / - (alkyl of 1 to 6 carbon atoms) carbamoyl,? /,? / - (alkyl of 1 to 6 atoms carbon) 2carbamoyl, alkyl of 1 to 6 carbon atoms-S (O) a wherein a is 0 to 2, alkoxycarbonyl of 1 to 6 carbon atoms,? /,? / - (alkyl of 1 to 6 carbon atoms) carbon) 2-sulfamoyl, alkylsulfonylamino of 1 to 6 carbon atoms, carbocyclyl-R22- or heterocyclyl-R23-; wherein R16 can optionally be substituted on the carbon by one or more R24; and wherein if the heterocyclyl contains a -NH- moiety, the nitrogen may optionally be substituted by a selected group of R25; R10, R11, R14, R15, R18, R19, R22 and R23 are independently selected from a direct bond, -O-, -N (R26) -, -C (O) -, -N (R27) C (O) -, -C (O) N (R28) -, -S (O) s, - SO2N (R29) - or -SO2N (R30); wherein R26, R27, R28, R29 and R30 are independently selected from hydrogen or alkyl of 1 to 6 carbon atoms and s is 0-2; R5, R9, R13, R17, R21 and R25 are independently selected from alkyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms , carbamoyl,? / - (alkyl of 1 to 6 carbon atoms) carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl; R20 and R24 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, hydroxymethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino ,? / - methyl -? / - ethylamino, acetylamino,? / - methylcarbamoyl,? / - ethylcarbamoyl,? /,? / - dimethylcarbamoyl,? f,? - diethylcarbamoyl,? / - methyl -? / - ethylcarbamoyl, methylthio, ethylthio, methylisulfinyl, etiisulfinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl,? / - methylsulfamoyl, N-ethylsulphamoyl, ? /,? / - dimethylsulphamoyl,? /,? / - diethylsulphamoyl or? -methyl- / V-ethylsulphamoyl; or a pharmaceutically accepted salt thereof; with the proviso that the compound is not? / -. { 3 - [(6,7-dimethoxyquinazolin-4-yl) amino] -4-methylphenyl} -3- (trifluoromethyl) benzamide. 2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is phenyl or a heteroaryl of 5 or 6 members; wherein if the heteroaryl contains a -NH- moiety, the nitrogen can be optionally substituted by a group selected from R5; wherein R5 is alkyl of 1 to 6 carbon atoms. 3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2, wherein R1 is a substituent on carbon and is selected from halo, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-S (O) a wherein a is 2,? /,? / - (alkyl of 1 to 6 carbon atoms) 2-sulfamoyl, carbocyclyl or heterocyclyl linked to carbon; wherein R1 can be optionally substituted on the carbon by one or more R8; wherein R8 is selected from halo, cyano or? /,? / - (alkyl of 1 to 6 carbon atoms) 2amino. 4. A compound of formula (I) or a salt pharmaceutically acceptable thereof, according to any of claims 1-3, wherein n is selected from 1 or 2; wherein the values of R1 may be the same or different. 5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any of claims 1-4, wherein R3 and R4 are substituents on the carbon and are independently selected from hydrogen, halo, nitro, hydroxy , amino, carboxy, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms; where R4 can optionally be substituted on the carbon by one or more R16; wherein R16 is selected from halo, amino, alkoxy of 1 to 6 carbon atoms,? /,? / - (alkyl of 1 to 6 carbon atoms) 2-amino, alkoxycarbonylamino of 1 to 6 carbon atoms, carbocyclyl-R22- or heterocyclyl-R23-; wherein R 6 can be optionally substituted on the carbon by one or more R 24; and wherein if the heterocyclyl contains an -NH- moiety, the nitrogen may be optionally substituted by a group selected from R25; R22 and R23 are independently selected from a direct bond and -O-; R25 is selected from alkyl of 1 to 6 carbon atoms and alkoxycarbonyl of 1 to 6 carbon atoms; R24 is hydroxymethyl. 6. A compound of formula (I) or a salt pharmaceutically acceptable thereof, according to any of claims 1-5, wherein m is selected from 0-2; wherein the values of R4 may be the same or different. 7. A compound of formula (I): > Ring A is phenyl, thien-2-yl, 1-y-butyl-1 H -pyrazol-4-yl, 1-f-butyl-1 H -pyrazol-5-yl or pyrid-4-yl; R is a substituent on carbon and is selected from fluoro, chloro, methyl, trifluoromethyl, 1-methyl-1-cyanoethyl, 1-cyanocyclobutyl, 4-cyano-2,3,5,6-tetrahydropyran-4-yl, 1-cyanocyclopropyl, isopropyl, mesyl,? /,? / - dimethylsulphamoyl, dimethylaminomethyl and cyclopropyl; n is selected from 1 or 2; wherein the values of R1 may be the same or different; R2 is hydrogen; R3 and R4 are substituents on the carbon and are independently selected from hydrogen, fluoro, chloro, bromo, nitro, hydroxy, amino, carboxy, methyl, methoxy, benzyloxy, 3-aminopropoxy, 3-morphol i nonpropoxy, 2-methoxy ethoxy, 1-methyl pyrrole id i n-2-i I methoxy, piperidin-4-ylmethoxy, piperidin-3-ylmethoxy, azetidin-2-ylmethoxy, 1-f-butoxycarbonylazetidin-2-ylmethoxy, azetidin-3-ylmethoxy, 1-y-butoxycarbonylazetidin-3-ylmethoxy, pyrrolidin-2-ylmethoxy, 1-f-butoxycarbon I pyrrole id i n-2-i I methoxy, pyrrolidin-3-yloxy, 1 - . 1-f-Butoxycarbonylpyrrolidin-3-yloxy, 2- (2-hydroxymethylpyrrolidin-1-yl) ethoxy, 3- (2-hydroxymethylpyrrolidin-1-yl) propoxy, 3-dimethylaminoproproxy, trifluoromethyl, propoxy, isopropoxy, 3- (f-butoxycarbonylamino) propoxy, 3-bromopropoxy, 1- (f-butoxycarbonyl) piperidin-4-ylmethoxy and 1- (f-bu toxic rbonyl) piperi din-3- ilmethoxy; m is selected from 0-2; wherein the values of R4 may be the same or different; or a pharmaceutically acceptable salt thereof; with the condition that it is composed, it is not? / -. { 3 - [(6,7-dimethoxyquinazolin-4-yl) amino] -4-methylphenyl} -3- (trifluoromethyl) benzamide. 8. A compound of formula (I): OR) selected from: 3- (cyano-dimethyl-methyl) -? / - [3- (7-methoxy-quinazolin-4-ylamino) -4-methyl-phenyl] -benzamide; 3- (cyano-dimethyl-methyl) -5-fluoro -? / - [3- (7-methoxy-quinazolin-4- ilamino) -4-methyl-phenyl-benzamide; 3- (1-cyano-1-methylethyl) -2-fluoro -? / -. { 3 - [(7-methoxy-quinazolin-4-yl) amino] -4-methylphenyl} benzamide; 3- (Cyano-dimethyl-methyl) -? / - [3- (5,7-dimethoxy-quinazolin-4-ylamino) -4-methyl-phenyl] -benzamide; 3- (1-cyano-1-methylethyl) -? / -. { 3 - [(7-isopropoxyquinazolin-4-yl) amino] -4-methylphenyl} benzamide; ? / -. { 3- [6,7-dimethoxyquinazolin-4-ylamino] -4-methylphenyl} 3-fluoro-5-isopropylbenzamide; 2- (cyano-dimethyl-methyl) -N- [3- (7-methoxy-quinazolin-4-ylamino) -4-methyl-phenyl] -isonicotinamide; 3- (cyano-dimethyl-meth) -N-. { 3- [7- (3-dimethylamino-propoxy) -quinazolin-4-ylamine] -4-methyl-phenyl} -benzamide; 4-dimethylaminomethyl-N- [3- (7-methoxy-quinazolin-4-ylamino) -4-methyl-phenyl] -3-trifluoromethyl-benzamide; and 3- (cyano-dimethyl-methyl) -? / - [3- (7-methyl-quinazolin-4-ylamino) -4-methyl-phenyl] -benzamide; or a pharmaceutically acceptable salt thereof. 9. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the variables are, unless otherwise indicated, as defined in claim 1, comprising: Process a) reacting an amine of formula (II) with an acid of formula (III): or an activated acid derivative thereof; Process b) reacting an amine of formula (IV): wherein L is a displaceable group Process c) reacting an amine of formula (VI): with a compound of formula (VII): (p) and after the above if necessary: i) converting a compound of formula (I) into another compound of formula (I); ii) eliminate any protection group; iii) forming a pharmaceutically acceptable salt. 10. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1-8, in association with a pharmaceutically acceptable diluent or carrier. 11. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1-8, for use as a medicament. 12. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1-8, in the manufacture of a medicament for use in the production of an inhibitory effect of B -Raf in a warm-blooded animal such as a human. 13. The use of a compound of formula (I), or a salt A pharmaceutically acceptable salt thereof according to any one of claims 1-8, in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as a human. or 14. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1-8, in the manufacture of a medicament for use in the treatment of melanoma, papillary tumors. of the thyroid, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and pri marium and recurrent solid tumors of the skin, colon, thyroid, lungs and ovaries. 5. A method for producing an inhibitory effect of B-Raf in a warm-blooded animal, such as a human in need of such treatment, comprising administering to the animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1 -8. 16. A method for producing an anti-cancer effect in a warm-blooded animal, such as a human in need of such treatment, which comprises administering to the animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt of the animal. same, according to any of claims 1 -8. 17. A method to treat melanoma, papillary tumors of the thyroid, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, leukemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and tumors primary and recurrent solids of the skin, colon, thyroid, lungs and ovaries, in a warm-blooded animal, such as a human in need of such treatment, comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in accordance with any of the claims 1-8. 18. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1-8, in association with a pharmaceutically acceptable diluent or carrier for use in the production of an inhibitory effect of B-Raf in a warm-blooded animal such as a human. 19. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of the claims

1-8, 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 a human. 20. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1-8, in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of melanoma, papillary tumors of the thyroid, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer , leukemias, lymphoid malignancies, carcinomas and sarcomas in the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors of the skin, colon, thyroid, lungs and ovaries in a warm-blooded animal such as a human. SUMMARY The invention relates to chemical compounds of formula (I) or pharmaceutically acceptable salts thereof, which possess B-Raf inhibitory activity and therefore are useful for their anti-cancer activity and therefore in body treatment methods. human or animal The invention also relates to processes for the manufacture of chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an anti-cancer effect in a warm-blooded animal such as a human. .