MX2008007353A - Quinazolinone derivatives as vanilloid antagonists - Google Patents

Abstract

The invention relates to quinazolinone compounds of the formula (I) wherein the R groups are defined in the specification, processes for their preparation and their use as pharmaceuticals, particularly in the treatment of disorders ameliorated by administration of TRPV1 antagonists.

Description

QUINAZOLINONE DERIVATIVES AS VANILOID ANTAGONISTS The present invention relates to quinazolinone derivatives as vanilloid antagonists, to processes for preparing them, to their use as pharmaceutical agents and to pharmaceutical compositions containing them. In a first aspect, the present invention provides a quinazolinone compound of the Formula where .LUÍ is a simple link or a double link; R2 is selected from the group consisting of (a) alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) -amino or di- (alkyl of 1 to 6) carbon atoms) -amino; or (b) NH2l hydroxy-alkylamino of 1 to 6 carbon atoms-, amino-alkylamino of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, di (trifluoromethyl) -alkyl of 1 to 6 carbon atoms , R9-O- (alkyl of 1 to 6 carbon atoms) -, wherein the alkyl chain is optionally substituted by trifluoromethyl, (NC) - alkyl of 1 to 6 carbon atoms-, (R10-RnN-) - alkyl of 1 to 6 carbon atoms-, (alkyl of 1 to 6 carbon atoms) -SO2- (alkyl of 1 to 6 carbon atoms) -, wherein R9, R10 and n each, independently, is an H atom or an alkyl radical of 1 to 6 carbon atoms; phenyl optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted with halogen, hydroxyalkyl of 1 to 6 carbon atoms carbon, cyano or a group - (C = O) -R2a, wherein R2a is an alkyl radical of 1 to 6 carbon atoms; or a 5-6 or 7-membered saturated or unsaturated heterocyclic ring, directly attached to the quinazolinone ring or linked through an alkyl radical of 1 to 6 carbon atoms-, containing one, two or three heteroatoms which are selected from the group consists of N, O and S, and optionally substituted with one, two or three substituents which are selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo , R 10 RnN-, R 9 -O- (C = O) -, - (C = O) -N-R 10 Rp, = O and phenyl; R3 is selected from the group consisting of (a ') a phenyl radical substituted with one, two or three substituents, wherein each is independently selected from the group consisting of halogen radicals, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted with halogen, hydroxyalkyl of 1 to 6 carbon atoms, cyano or a group -C (= O) -R3a, wherein R3a is an alkyl radical of 1 to 6 atoms of carbon; or (b1): an alkyl radical of 1 to 6 carbon atoms, (NC) -alkyl of 1 to 6 carbon atoms-, R9-O- (alkyl of 1 to 6 carbon atoms) -, R9-O- (alkyl of 1 to 6 carbon atoms) -O- (alkyl of 1 to 6 carbon atoms) -, R? 0RnN- (alkyl of 1 to 6 carbon atoms) -, R? 0RnN- (C = O) - (alkyl of 1 to 6 carbon atoms) - or (alkyl of 1 to 6 carbon atoms) -SO2- (alkyl of 1 to 6 carbon atoms) -, wherein R9, R10 and Rn are each independently selected of the group consisting of an H atom or an alkyl radical of 1 to 6 carbon atoms; or an unsubstituted phenyl radical, phenyl substituted with one or two substituents selected from the group consisting of - (C 1-6 alkoxy) -, R 10 RnN-, R 10 RnN- (C 1-6 alkyl) radicals ) -, -SO2- (alkyl of 1 to 6 carbon atoms, R9-O- (C = O) -, wherein R9, R10 and Rn are as previously defined, or with a phenyl radical substituted with halo or a saturated or unsaturated, 5 or 6 membered heterocyclic ring, having one, two or three heteroatoms which are selected from the group consisting of N, O and S, and optionally including another substituent selected from the group consisting of halo radicals, or phenyl substituted with three or four substituents which are selected from the group consisting of halo, hydroxyl and alkyl radicals of 1 to 6 carbon atoms, or a cycloalkyl ring having 3, 4, 5 or 6 carbon atoms, directly attached to the quinazolinone ring or bound through of a radical - alkyl of 1 to 6 carbon atoms - and optionally substituted with one or two substituents selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, R10RnN-, R9-O- (C = O) -, - (C = O) -N-R10Rn, and phenyl; or benzyl, or phenyl- (alkyl of 1 to 6 carbon atoms) -, phenoxy- (alkyl of 1 to 6 carbon atoms) - or phenyl- (C = O) - (alkyl of 1 to 6 carbon atoms) -, optionally substituted with one, two or three substituents selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, R10RnN-, R9-O - (C = O) -, - (C = O) -N-R10R11 and phenyl; or a saturated, unsaturated, 5-, 6- or 7-membered heterocyclic ring, directly attached to the quinazolinone ring, or linked through a radical -alkyl of 1 to 6 carbon atoms-, containing one, two or three heteroatoms that are selected from the group consisting of N, O and S, and optionally substituted with one, two or three substituents which are selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy , cyano, halo, R 10 RnN-, R 9 -O- (C = O) -, - (C = O) -N-R 10 R 11, = O and phenyl; or a 9 or 10 membered aromatic or heterocyclic fused ring, directly attached to the quinazolinone ring or linked through a radical - alkyl of 1 to 6 carbon atoms - containing zero, one, two or three heteroatoms which are selected of the a group consisting of N, O and S, and optionally substituted with one, two, three or four substituents which are selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy , cyano, halo, R 10 RnN-, R 9 -O- (C = O) -, - (C = O) -N-R 10 R n and phenyl; and R5 and R6 each, independently, is a hydrogen atom, a halogen radical, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, hydroxy, alkyl of 1 to 6 carbon atoms substituted with hydroxy, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cyano, -C (= O) H-phenyl, (cycloalkyl of 3 to 6 carbon atoms) -alkyl of 1 to 6 carbon atoms, (cycloalkyl of 3 to 6 carbon atoms) -alkoxy of 1 to 6 carbon atoms), (alkoxycarbonylamino of 1 to 6 carbon atoms) -alkoxy of 1 to 6 carbon atoms ) or (alkylcarbonylamino of 1 to 6 carbon atoms) -alkoxy of 1 to 6 carbon atoms, (amino acid) -alkoxy of 1 to 6 carbon atoms, (dimethylamino) -alkoxy of 1 to 6 carbon atoms or (alkoxycarbonyl) from 1 to 6 carbon atoms) -alkoxy of 1 to 6 carbon atoms; R 12 is a hydrogen atom, a formyl radical, alkylcarbonyl of 1 to 6 carbon atoms or benzyl, which phenyl group is optionally substituted with 1, 2 or 3 substituents which are selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, hydroxy, hydroxy-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms-alkoyl having 1 to 6 carbon atoms, halo-alkoxy having 1 to 6 carbon atoms, alkylthio having 1 to 6 carbon atoms, halo-alkylthio having 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, haloalkyl sulfyl nyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, haloalkyl sulfonyl of 1 to 6 carbon atoms, cycloalkyl d3 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- (alko I of 1 to 6 carbon atoms) -amino, alkoxycarbonylamino of 1 to 6 carbon atoms, cyano, formyl and alkylcarbonyl from 1 to 6 carbon atoms, or is substituted on two adjacent carbon atoms, with radicals -O-CH2-O- or -OC F2-O-; and -I 3 and Re considered j untes, represent, together with the three-member portion -NCC- to which they are linked, a heterocyclic partial or completely unsaturated, optionally substituted, of five, six, seven or eight members, which contains 1 nitrogen atom in the ring and optionally 1 nitrogen atom in the additional ring, an oxygen or sulfur atom, or 2 additional nitrogen atoms in the ring, wherein, in the heterocyclic ring each atom of Oxygen or sulfur in the ring is bonded to 2 ring carbon atoms, the optional substituents of said heterocyclic ring being selected from the group consists of halogen radicals, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, hydroxy alkyl of 1 to 6 carbon atoms, C (O) -alkyl of 1 to 6 atoms of carbon and oxo, in free form or in the form of a salt. If at least one asymmetric carbon atom is present in a compound of Formula I, such a compound may exist in optically active form or in the form of mixtures of optical isomers, for example in the form of racemic mixtures. All optical isomers and their mixtures, including racemic mixtures, are parts of the present invention. The compounds of Formula I are useful as vanilloid antagonists; that is, they exhibit an antagonistic activity of human vanilloid substances and, more particularly, demonstrate antagonism in the TRPVI receptor. As such, they are indicated in the treatment of diseases and disorders in which the activity of the vanilloid receptor plays a role or is indicated. In the compounds of Formula I, certain substituents may be preferred, independently, collectively or in any combination or sub-combination. For example, the ^ m symbol of preference is a double bond. In certain embodiments, in the compound of Formula I, R2 may preferably be an alkyl radical of 1 to 8 carbon atoms or cycloalkyl, more preferably alkyl of 1 to 6 atoms of carbon, for example alkyl of 1 to 4 carbon atoms. In a particularly preferred value, R 2 is isopropyl. In other embodiments, R 2 may preferably be N-H 2 or alkenyl of 2 to 6 carbon atoms, for example alkenyl of 2 to 4 carbon atoms, such as isopropenyl. When R2 is a heterocyclic ring as described above, it is preferably a 5 or 6 membered ring, with one or two heteroatoms which are selected from the group consisting of N, O and S; A preferred substituent for the heterocyclic ring is alkyl of 1 to 6 carbon atoms, for example alkylene of 1 to 4 carbon atoms, such as methyl; wherein it is preferred that the heterocyclic ring be one to the quinazolinone ring through an alkyl radical of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms, such as propyl, ethyl and, most preferably, methyl. Examples of suitable heterocyclic rings include pyridine, furanyl, isoxazole, pyrrolidone, imidazole, thiophene, morpholine, pyrazine, pyrrole, piperidine and thiazole; when R3 is an alkyl radical of 1 to 6 carbon atoms, (NC) -alkyl of 1 to 6 carbon atoms-, R9-O- (alkyl of 1 to 6 carbon atoms) -, R9-O- (alkyl) of 1 to 6 carbon atoms) -O- (alkyl of 1 to 6 carbon atoms) -, R 10Rn N- (alkyl of 1 to 6 carbon atoms) -, R10Rn N- (C = O) - (alkyl from 1 to 6 carbon atoms) - or (alkyl of 1 to 6 carbon atoms) -SO2- (alkoxy of 1 to 6 carbon atoms) -, wherein R9, R1 0 and Rn each is independently an atom of an alkalyl radical of 1 to 6 carbon atoms, preferably it can be one of the following: alkyl of 1 to 6 carbon atoms, for example alkyl of 1 to 4 carbon atoms, such as isopropyl, propyl, methylbutyl; (NC) -alkyl of 1 to 6 carbon atoms-, for example (NC) -alkyl of 1 to 4 carbon atoms, such as acetonitrile; R9-O- (alkyl of 1 to 6 carbon atoms), for example R9-O- (alkyl of 1 to 4 carbon atoms), such as hydroxyethyl, methoxyethyl; R? 0R? N- (alkyl of 1 to 6 carbon atoms) -, for example R10RnN- (alkyl of 1 to 4 carbon atoms) -, such as dimethylaminoethyl, methylaminoethyl; R10R ??N- (C = O) - (alkyl of 1 to 6 carbon atoms) -, such as R10R ??N- (C = O) - (alkyl of 1 to 4 carbon atoms), such as dimethylacetamide; R9-O- (alkyl of 1 to 6 carbon atoms) -O- (alkyl of 1 to 6 carbon atoms) -, such as R9-O- (alkyl of 1 to 4 carbon atoms) -O- (alkyl) from 1 to 4 carbon atoms) -, such as hydroxyethoxyethyl; (alkyl of 1 to 6 carbon atoms) -SO2- (alkyl of 1 to 6 carbon atoms) -, such as (alkyl of 1 to 4 carbon atoms) -SO2- (alkyl of 1 to 4 carbon atoms) -, such as methylisulfonylethyl; when R3 is an unsubstituted phenyl radical or substituted phenyl according to the foregoing, it could preferably be one of the following: unsubstituted phenyl; alkoxyphenyl of 1 to 6 carbon atoms, for example alkoxyphenyl of 1 to 4 carbon atoms, such as methoxyphenyl; or phenyl substituted with halogen according to the above, such as phenyl substituted with halogen, for example chlorine, and with R 0Rn N- (alkyl of 1 to 6 carbon atoms) -, for example R? 0R? ? N- (alkyl of 1 to 4 carbon atoms) -, such as dimethylaminomethyl, or substituted phenyl, three or four times, wherein the substituents are selected from the group consisting of halo, for example chlorine and fluoro; hydroxyl, methoxy, trifluoromethyl and methyl; phenyl substituted with a saturated or unsaturated 5 or 6 membered heterocyclic ring, having or not, two or three heteroatoms which are selected from the group consisting of N, O and S, for example oxazole, or phenyl substituted with phenyl substituted with halo, for example, fluoro-biphenyl; when R3 is cycloalkyl as defined above, it may preferably be one of the following: cycloalkyl of 3 to 6 carbon atoms directly attached to the ring q uinazolinone, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; cycloalkyl of 3 to 6 carbon atoms attached to the ring of quinazolinone, through an alkyl radical of 1 to 6 carbon atoms, for example alkylene of 1 to 4 carbon atoms, such as propyl, isopropyl, ethyl or, particularly, methyl; substituted cycloalkyl of 3 to 6 carbon atoms having for example a single substituent selected from the group which consists of - (C = O) OR9, for example - (C = O) O-alkyl of 1 to 6 carbon atoms, such as - (C = O) O -alkyl of 1 to 4 carbon atoms , for example - (C = O) OMe or, particularly, - (C = O) -OEt; when R3 is benzyl or phenyl (C1-C6alkyl) -, phenoxy- (C1-C6 alkyl) - or phenyl (C = O) - (C1-C6 alkoxy) ) -, each or not as previously defined, could preferably be one of the following: benzyl; benzyl substituted with one or two substituents which are selected from the group consisting of alkyl of 1 to 6 carbon atoms, for example alkylene of 1 to 4 carbon atoms, such as methyl, alkoxy of 1 to 6 carbon atoms carbon, for example alkoxy of 1 to 4 carbon atoms, such as methoxy, phenylethyl; ilpropyl fen; phenyl (C = O) - (alkyl of 1 to 6 carbon atoms) -, for example phenyl (C = O) - (alkyl of 1 to 4 carbon atoms) -, such as -C H2- (C = O ) -Ph; when R3 is a saturated or unsaturated 5, 6 or 7 membered heterocyclic ring as defined above, it may preferably be one of the following: i) a saturated or unsaturated, 5- or 6-membered heterocyclic ring, directly attached to the quinazolinone ring; ii) a saturated or unsaturated heterocyclic ring, of 5 or 6 members, one to the ring q uinazolinone through a methyl or ethyl ligand; iii) a saturated or unsaturated heterocyclic ring, of 5 or 6 members, directly attached to the quinazolinone ring or a ring to the quinazolinone ring through a methyl or ethyl ligand, containing one or two heteroatoms which are selected from the group consisting of N, O and S; iv) any of the preceding i) -iii), substituted with a substituent selected from the group consisting of cyano, alkoxy of 1 to 6 carbon atoms, for example, alkyl of 1 to 4 carbon atoms, such as ethyl or, particularly, methyl, halo, for example fluoro or, particularly, chloro, halofen ilo, for example fluoro- or, particularly, chlorophenyl; R9-O- (C = O) -, for example C (O) OMe or, particu larly, C (O) OEt, or = O; v) any of items i) -iv) above, wherein the saturated or unsaturated heterocyclic ring, of 5 or 6 members, is selected from the group consisting of pyridine, furan ilo, isoxazole, pyrrolidone, imidazole, thiophene, morpholine, pyrazine, pyrrole, piperidine and thiazole; when R3 is a 9 or 10 membered fused aromatic or heterocyclic ring, as described above, it can preferably be one of the following: i) a 9 or 10 membered fused aromatic or heterocyclic ring, having zero , one or two heteroatoms that are selected from the group consisting of N, O and S; ii) a 9 or 10 membered fused aromatic or heterocyclic ring, in accordance with item i), directly attached to the quinazolinone ring; iii) a 9 or 10 membered fused aromatic or heterocyclic ring, in accordance with item i), attached to the quinazolinone ring through a methyl or ethyl ligand; iv) a fused aromatic or heterocyclic ring of 9 or members, in accordance with subparagraph ii) or Mi) optionally substituted with a substituent selected from the group consisting of halo, for example fluoro or, preferably chloro, or hydroxyl; v) a fused aromatic or heterocyclic ring of 9 or members, according to items ii), iii) or iv), which is selected from the group consisting of naphthalene, benzothiazole, benzodioxole and quinoline; and when R3 is selected from the group (a1), it is preferably phenyl substituted with chlorine, bromine, alkyl of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms or (cycloalkyl of 3 to 6 carbon atoms) ) -alkoxy of 1 to 4 carbon atoms; R5 more preferably is a hydrogen atom or a hydroxyl radical; R6 more preferably is a hydrogen atom or a hydroxyl radical; R12 is preferably a hydrogen atom, a formyl radical, alkylcarbonyl of 1 to 6 carbon atoms or benzyl, The phenyl group is optionally substituted with 1, 2 or 3 substituents which are selected from the group consisting of halogen radicals, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, hydroxy, hydroxy -alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, halo-alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, haloalkylsulfinyl of 1 to 6 carbon atoms, alkylsulphonyl of 1 to 6 carbon atoms, haloalkyl-ilsulfonyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- (a) 1 to 6 carbon atoms) -amino, alkoxycarbonylamino of 1 to 6 carbon atoms, cyano, formyl and alkylcarbonyl of 1 to 6 carbon atoms, or is substituted on two adjacent carbon atoms, with -O-CH2 radicals -O- or -OC F2-O- preferably a hydrogen atom, a radical formyl, an alkylenecarbonyl of 1 to 6 carbon atoms or benzyl, more preferably a hydrogen atom or a radical formyl, preferably hydrogen; R? 3 and R8 considered together represent, together with the three-member portion -NCC- to which they are linked, a partially or completely unsaturated heterocyclic ring, optionally substituted, of five, six, seven or eight members, which contains 1 nitrogen atom in the ring and optionally 1 carbon atom. Nitrogen in the additional ring, an oxygen or sulfur atom, or 2 additional nitrogen atoms in the ring, where, in the heterocyclic ring, each oxygen or sulfur atom in the ring is bonded to 2 carbon atoms of the ring, the optional substituents of said heterocyclic ring being selected from the group consisting of halogen radicals, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, hydroxy alkyl of 1 to 6. carbon atoms, C (O) -alkyl of 1 to 6 carbon atoms and oxo, or R13 and Re taken together represent, together with the three-member portion -NCC- to which they are linked, a partially or completely unsaturated heterocyclic ring, optionally substituted, of five, six or seven members, which contains 1 atom of nitrogen in the ring and optionally 1 nitrogen atom in the additional ring, an oxygen or sulfur atom, or 2 additional nitrogen atoms in the ring, wherein, in the heterocyclic ring, each oxygen or sulfur atom in the ring is linked to 2 ring carbon atoms, the optional substituents of said heterocyclic ring being selected from the group consisting of halogen radicals, alkyl of 1 to 6 carbon atoms, C (O) -alkyl of 1 to 6 carbon atoms and oxo, haloalkyl of 1 to 6 carbon atoms, hydroxy alkyl of 1 to 6 carbon atoms and oxo, or N-R13 and R8-, considered together, represent a portion NXO- (Ibb), where -X- is a radical -C (= O) - or - (CH2) a-, where a has a value of 2 or 3 and wherein any methylene group, independently of any other methylene group in the Ibb portion, is optionally monosubstituted with oxo or substituted with 1 or 2 substituents which are selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms , C (O-alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms and hydroxy-alkyl of 1 to 6 carbon atoms, or N-R13 and R8-, considered together, represent a portion NC (Ra) = C (Rb) - (Idd), in which Ra is a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms or hydroxy-alkyl of 1 to 6 carbon atoms and Rb is a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms or hydroxy-alkyl of 1 to 6 carbon atoms, or N-R13 and R8-, considered together, represent a portion NC (RC) = N- (read), wherein Rc is a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms or haloalkyl of 1 to 6 carbon atoms, or N-R13 and R8-, taken together, represent a portion NN = C (Rd) - (Iff), where R is a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms or halo-alkyl of 1 to 6 carbon atoms, or N-R13 and R8-, taken together, represent a portion NN = C (Rf) - (Ig), wherein Rf is a hydrogen atom, or N-R13 and R8-, considered together, represent a portion NN = N- (Ih), or N-R13 and R8- considered together, represent a portion N- (CH2) 2-N (H) -C (Rg) H- (lii), wherein Rg is a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms or haloalkyl of 1 to 6 carbon atoms , preferably, N-R13 and R8-, considered together, represent a portion NXO- (Ibb), where -X- is a radical -C (= O) - or - (CH2) a-, wherein a has a value of 2 or 3 and wherein any methylene group, independently of any other methylene group in the Ibb portion, is optionally substituted with 1 or 2 substituents which are selected from the group consisting of alkyl of 1 to 6 carbon atoms and hydroxy -alkyl of 1 to 6 carbon atoms, or N-R13 and R8-, taken together, represent a portion NC (Ra) = C (R) - (Idd), where Ra is a hydrogen atom and Rb is a alkyl radical of 1 to 6 carbon atoms, or N-R13 and R8-, taken together, represent a portion NC (RC) = N- (read), wherein Rc is a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms or haloalkyl from 1 to 6 át carbon atoms, or N-R13 and R8-, taken together, represent a portion NN = C (Rd) - (Iff), where Rd is a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms, or N-R13 and R8-, taken together, represent a portion NN = C (R) - (Ig), where Rf is a halogen atom, or N-R13 and R8-, considered together, represent a portion NN = N - (Ih), or N-R13 and R8 - taken together, represent a portion N- (CH2) 2-N (H) -C (Rg) H- (lii), wherein Rg is a hydrogen atom. The term "alkyl of 1 to 8 carbon atoms" denotes a alkyl radical of 1 to 6 carbon atoms straight or branched chain; the term "alkyl of 1 to 6 carbon atoms" denotes an alkyl radical of 1 to 6 carbon atoms straight or branched chain; and the term "alkyl of 1 to 4 carbon atoms" denotes an alkyl radical of 1 to 6 carbon atoms of straight or branched chain; for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or fe-butyl. The term "alkenyl of 2 to 6 carbon atoms" denotes a straight-chain or branched alkenyl radical of 2 to 6 carbon atoms, for example ethenyl, n-propenyl or isopropenyl. The term "C 1 -C 6 alkoxy" denotes an alkyloxy radical of 1 to 6 carbon atoms straight or branched chain, for example methoxy, ethoxy, n-propoxy or isopropoxy. The term "halo" denotes a halogen atom, which can be I, Br, Cl or F. The term "esterified hydroxy" denotes an acyloxy radical, preferably alkanoyloxy of 1 to 6 carbon atoms, more preferably alkanoyloxy of 1 to 4 carbon atoms. The term "hydrotroxy etherified" denotes an alkoxy radical of 1 to 6 carbon atoms, preferably alkoxy of 1 to 4 carbon atoms. The quinazolinone compounds of the present invention exist in free form or in salt form. The invention should be understood to include the compounds of Formula (I) in free form or in salt form. The present invention also relates to a process for the preparation of a compound of Formula I, in free form or in salt form, in accordance with the following representative reaction schemes, in which the term "Ar" denotes R 3 as defined above.

Cat In the above reaction schemes, R may be an alkenyl group or other suitable group. The detailed reaction conditions are described in the Examples. The processing of the reaction mixtures and the purification of the compounds thus obtained can be carried out according to known procedures. Acid addition salts can be produced from the free bases, in a known manner, and vice versa. The compounds of the formula (I) in optically pure form can be obtained from the corresponding racemates, in accordance with known procedures, for example C LAR with q ull matrix. Alternatively, optically pure raw materials can be used. Stereoisomeric mixtures, for example mixtures of diastereoisomers, can be separated into their corresponding isomers in a manner known per se by means of suitable separation methods. Diastereomeric mixtures, for example, can be separated into their individual diastereoisomers, by fractional crystallization, chromatography, distribution in solvents and similar procedures. This separation can be carried out at the level of a raw material compound, or in a compound of Formula (I) itself. The enantiomers can be separated by the formation of diastereoisomeric salts, for example by the formation of salts with an enantiomerically pure chiral acid, or by chromatography, for example by HPLC, using chromatographic substrates with aqueous ligands. At any additional process step, carried out in the desired manner, there may be present functional groups of the raw material compounds, which should not take part in the reaction, and which may be in unprotected form or may be protected. , for example by means of one or more of the protective groups mentioned below. The protective groups are subsequently removed partially or completely, in accordance with one of the methods described herein. The protective groups may already be present in the precursors and should protect the desired functional groups against undesirable secondary reactions. It is a characteristic of the protective groups, which are eliminated quickly; that is, without unwanted side reactions, to be removed, typically by solvolysis, reduction, photolysis or also by enzymatic activity, for example under conditions analogous to physiological conditions, and are not present in the finished products. Technicians in the field know or can easily establish, that Protective groups are suitable for the aforementioned reactions and those that will be mentioned later. The protection of such functional groups with protecting groups, the protecting groups themselves and their removal reactions, are described, for example, in standard reference documents, such as J.F.W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, London and NY (1973); T.W. Greene, Protective Groups in Organic Synthesis, Wiley, NY (1981); The Peptides; Volume 3, E. Gross and J. Meienhofer, Eds., Academic Press, London and NY (1981); Methoden der organischen Chemie (Methods of organic chemistry), Houben Weyl, 4th Edition, Volume 15/1, Georg Thieme Verlag, Stutgart (1974); H.D. Jakubke and H. Jescheit, Aminosauren, Peptide, Proteine (Amino acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel (1982); and Jochen Lehmann, Chemie der Kohlenhydrate: Monosaccharide und Derivat (Chemistry of carbohydrates: monosaccharides and derivatives), Georg Thieme Verlag .; Stuttgart (1974). All the process steps described herein can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence or, normally, in the presence of solvents or diluents, preferably they are inert to the reagents used and are capable of dissolving them, in the absence or presence of catalysts, condensation agents or neutralizing agents, for example ion exchangers, typically cation exchangers, for example in H + form, depending on the type of reaction and / or reagents at reduced, normal or elevated temperature, for example in the range of -100 to about 190 ° C, preferably from about -80 to about 150 ° C, for example at a temperature of -80 to 60 ° C, at room temperature, at a temperature of -20 to 40 ° C, or at the boiling point of the solvent used, at atmospheric pressure or in a closed container, when appropriate under pressure, and / or in an inert atmosphere, for example under an argon or nitrogen atmosphere. Another aspect of the present invention relates to the fact that the compounds of Formula (I) and their pharmaceutically acceptable salts, have beneficial pharmacological activity and, therefore, are useful as pharmaceuticals. In particular, the compounds of Formula (I) exhibit vanilloid antagonist activity in humans. More particularly, the compounds of the Formula (I) are active in the TRPVI receptor as demonstrated by their ability to inhibit capsaicin and / or decrease the pH activation of the TRPVI ion channel, as follows: Ovarian cells were cultured of Hamster Chinese-K1 (CHO-K1), transfected to express the TRPV1 receptor either from humans, rat or guinea pig, in Minimum Essential Medium (MEM) medium alpha, without supplement with nucleosides, with fetal bovine serum (at 10%), L -glutamine 2 mM, 100 IU / mL of penicillin, 100 μg / mL of streptomycin and 350-700 μg / mL of geneticin. All the reagents were provided by Invitrogen. The cells were cultivated in T-175 flasks or transparent plates of 96 or 384 wells and kept at 37 ° C in an incubator with 90% humidity, with an atmosphere of 5% CO2 and 95% air. The cells were passed twice a week and, for experimentation, the cells were harvested at approximately 80% confluence and inoculated into the plates at the rate of 35,000-40,000 cells per well, in 100 μL of medium, and cultured during one night. Calcium mobilization assay On the day of the assay, the medium is aspirated and the cells are washed with 10 mM N-2- (hydroxyethylpiperazine-N '- [2-ethanesulfonic acid] (HEPES), buffered with Hank's Balanced Saline solution. SSBH), pH 7.4.The cells are then incubated with a fluorescence-sensitive calcium-binding dye, typically fluo-4 / AM (from Molecular Probes), prepared in HEPES buffered with SSBH, containing pluronic F-127 with or without probenecid For the pH test, the HEPES is omitted and the pH of the SSBH is adjusted to 7.4 After washing, the cells are incubated with the test compounds (prepared in SSBH, pH 7.4), in duplicate. TRPV1 is stimulated by the addition of capsaicin at an approximate concentration of CE80, or a solution with low buffered pH [60 mM 2- [N-morpholino] -ethanesulfonic acid (MES), in SSBH], to obtain a final pH of 5.5. The cellular responses are monitored in a fluorescent plate reader, typically an eq Molecular Devices Flexstation. The response in the presence of the antagonist is calculated as percentage of the control response to capsaicin or at low pH, and plotted against the concentration of the antagonist. The Cl50 values (concentrations of antagonist that inhibit the responses of pH 5.5 or of capsaicin by 50%), are estimated through a non-linear regression analysis, to sigmoid-logistic curves. These values are averaged (mean and standard error of the mean) for at least three independent experiments. A specific example of a calcium mobilization assay is the following: On the day of the capsaicin test, the medium is aspirated and the cells are washed with 100 μL of N-2- (hydroxyethylpiperazine-N '- [2-ethanesulfonic acid] ] (HEPES) 10 mM, buffered with Hank's Balanced Saline Solution (SSBH), pH 7.4.The cells are then incubated for 40-60 minutes with the calcium binding dye fluo-4 / AM 2.3 μM (from Molecular Probes) ), prepared in HEPES buffered with SSBH, containing 0.01% pluronic F-127 and 2 mM probenecid. For the pH test, the HEPES is omitted and the pH of the SSBH is adjusted to 7.4. After washing twice with 100 μL of assay buffer, the cells were incubated for 10 minutes with 100 μL of the test compounds (prepared in SSBH, pH 7.4), in duplicate. The plate was subsequently placed in a Molecular Devices Flexstation device. The TRPV1 receptor was stimulated by the application of either capsaicin or a low pH. To test the effect of the compounds with respect to a possible antagonism, capsaicin was used at a concentration approximate C E80 of 0.05 μM. For the pH experiments, a buffered solution of low pH [2- [N-morpholino] -ethanesulfonic acid (M ES) 60 mM in SSBH] was added to the test wells, to produce a final pH of 5.5. To determine antagonist Cl50 values (concentrations of the antagonist that inhibits the response either at pH 5.5 or to capsaicin, by 50%), at least 10 antagonist concentrations were measured, in duplicate. The response in the presence of the antagonist was calculated as a percentage of the control response to capsaicin or at low pH, and was plotted against the concentration of antagonist. The Cl50 was estimated by means of a non-linear regression analysis, sigmoid-logistic curves, with the Activity-Base software (v 5.0.1 0) or the Microcal Origina software (v 7.03). These values were averaged (mean and standard error of the median) for at least three independent experiments. The agents of the invention are useful in the prevention and treatment of diseases and disorders in which the activation of human VR 1 plays a role or is involved, and is therefore susceptible to treatment by modulation (preferably antagonism) of the receptors. VR1. Some disorders include, in particular, acute or chronic pain of somatic or visceral origin, inflammatory or obstructive respiratory disease, urinary incontinence or bladder hyperactivity, inflammatory skin diseases, inflammatory disorders of the gastrointestinal tract, diabetes, obesity and disease related to obesity, psychiatric disorders and treatment of the consequences of exposure to VR1 antagonists. The agents of the invention are particularly useful in the treatment or prevention of chronic pain with an inflammatory component, such as rheumatoid arthritis; bone and joint pain (osteoarthritis); postoperative or traumatic pain, including dental pain, for example after a third molar extraction, post-mastectomy pain and pain associated with sprains or fractures; musculoskeletal pain such as fibromyalgia; myofascial pain syndromes; headache, including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain; earache; pain due to episiotomy; pain from burns and especially primary hyperalgesia associated with them; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, abdominal pain, gynecological pain, such as dysmenorrhea, and labor pain; hemorrhoids; pain associated with the urogenital tract, such as cystitis and vulvadynia; chronic pain associated with nerve injuries and / or diseases affecting the nervous system, such as neuropathic pain associated with postherpetic neuralgia, diabetic neuropathy, chemotherapy-induced neuropathy, amputations ("phantom limb pain"), pinching of nerves and avulsions of the brachial plexus, lower back pain, sciatica and ankylosing spondylitis, reflex sympathetic dystrophy and other chronic nerve injuries; complex regional pain syndromes; glossodynia or burnt mouth syndrome; central nervous system pain, such as pain caused by damage to the spine or brainstem, multiple sclerosis or stroke, gout, scarring pain, pain associated with carcinomas, often referred to as cancer pain; pain associated with virus-induced neuropathy (eg HIV), alcohol and narcotic abuse, pain and other symptoms associated with sunburn or UV, exposure to VR1 agonists (eg, capsaicin, acid, tear gas, harmful heat or pepper spray), bites or bites from snakes, spiders or insects, and jellyfish stings. Gastrointestinal disorders to be treated according to the invention, include those associated with gastrointestinal hypersensitivity, visceral pain and / or altered motor responses (including electrolyte / water secretion), such as intestinal function disorders and gastrointestinal functional disorders, including irritable bowel syndrome (SIL), functional dyspepsia, heartburn, non-erosive reflux disease, intestinal pseudo-obstruction, functional abdominal bloating and functional abdominal pain; other disorders associated with visceral hypersensitivity, including gastroesophageal reflux disease and emesis, esophagitis, postoperative visceral pain, postoperative ileus, visceral smooth muscle spasms, ulcerative colitis, Crohn's disease, ulcers, chronic constipation, diarrhea, early satiety, epigastric pain, nausea, vomiting, regurgitation, anal incontinence, fecal urgency and rectal hypersensitivity, gastroparesis, for example diabetic gastroparesis, pancreatitis and Hirschsprung's disease. Urinary incontinence ("UI") or overactive bladder to be treated according to the invention are broad terms encompassing a range of disorders and symptoms, including urgent UI, stress UI, urgent UI / mixed stress, UI neurogenic, bladder detrusor hyperreflexia (detrusor neurogenic hyperactivity), detrusor instability (idiopathic detrusor overactivity), decreased bladder performance, urethral sphincter weakness, obstruction of urinary output, interstitial cystitis, nephritis, uveitis, sensory urgency, motor urgency, nocturia and visceral pain related to the bladder. The agents of the invention are also useful as agents for the treatment of hyperreactive, inflammatory or obstructive diseases of the respiratory tract, including asthma, inflammatory airway disease, for example chronic obstructive pulmonary disease or obstructive airways disease ( COPD or EOVR), adult respiratory distress syndrome (ARDS), chronic bronchitis, pneumoconiosis, eg aluminosis, anthracosis, asbestosis, calicosis, ptilosis, siderosis, silicosis, tabacosis, byssinosis; rhinitis, including allergic rhinitis, such as seasonal and perennial rhinitis, and non-allergic rhinitis; cough, either idiopathic or associated with respiratory diseases such as COPD, asthma, cystic fibrosis, cancer or alterations gastrointestinal, such as gastroesophageal reflux. The agents of the invention may also have a therapeutic benefit in inflammatory disorders of the skin, for example psoriasis and eczema, or pruritus of non-specific origin; contact dermatitis and hypersensitivity; autoimmune and inflammatory diseases, including Crohn's disease, ulcerative colitis and Guillain-Barré syndrome; sensitivity to multiple chemical substances, neurological diseases such as anxiety, panic disorders, depression, schizophrenia, cognitive diseases, Parkinson's disease and Alzheimer's disease; Hair loss; diabetes; obesity and diseases related to obesity; as antispasmodics, for example for the treatment of spasms of the gastrointestinal tract or the uterus; for the treatment of septic shock, for example as anti-hypovolemic and / or hypotensive agents; cerebral edema. For the aforementioned indications, the appropriate dose, of course, will depend on, for example, the compound employed, the host, the route of administration and the nature and severity of the disorder being treated. However, in general, satisfactory results are obtained in animals at a daily dose of from about 0.05 to about 150, preferably from about 0.1 to about 100 mg / kg of animal body weight. In large mammals, for example humans, an indicated daily dose is in the range of from about 0.5 to about 5,000, preferably from about 1 to about 500 mg of a compound of Formula (I), conveniently administered, for example, in divided doses up to four times a day, or in sustained release form. The agents of the invention can be administered in vivo, either alone or in combination with other pharmaceutical agents, for example agents effective in the treatment of diseases and disorders in which activation of human VR1 plays a role or is involved. A suitable combination consists of a compound of the present invention, with a compound selected from the class or among members of the following list: dopamine D2 antagonists, for example domperidone, metoclopramide and itopride; 5HT receptor agonists, for example cisapride, cinitapride, mosapride, renzapride, prucalopride, tegaserod and compounds described in International Patent Publication WO 2005068461 (ex Aryx), for example AT-7505, US Patent 2005228014 and International Patent Publication WO 2005080389 (from Theravance), for example TDI-2749, US Patents US 2006100426, US 2006100236, US 2006135764, US 20060183901; International Patent Publications WO 200610827, WO 2006094063, WO 2006090224, WO 2006090279, US Patent US 2005277671, International Patent Publications WO 2005092882, WO 2005073222, Japanese Patent JP 2005104896, JP 2005082508, International Patent Publication WO 2005021539, Japanese Patent JP 2004277319, JP 2004277318, International Patent Publication WO 2004026869 and European Patent 1362857; 5HT3 agonists, for example pumosetrag; CCKA receptor antagonists > for example loxiglumide and dexloxiglumide; motilin receptor agonists, for example motilin, atilmotilin, erythromycin, alemcinal, mitemcinal, KOS-2187 and compounds described in International Patent Publication WO 2005060693; μ opioid antagonists, for example alvimopan and methylnaltrexone; opioid agonists, for example asimadoline, loperamide and codeine; CRF-1 receptor antagonists, for example GSK876008 and compounds described in International Patent Publications WO 2004069257, WO 9940089; US Patent 6844351, International Patent Publications WO 2005013997, WO 2005014557, WO 2005023806, WO 2005026126, WO 2005028480, WO 2005044793, WO 2005051954, WO 2005051954, WO 2005115399, WO 2005028480, WO 2005023806, WO 2006044958; US Patent 20060211710 and International Patent Publication WO 2006108698; glutamate receptor antagonists, for example AZD9272 and compounds described in International Patent Publications WO 9902497, WO 2000020001, WO 200304758 and WO 2005030723; antagonists of neurokinin receptor, for example casopitant, nepadutrent, saredutant, DNK-333, SLV-317, SLV321, SLV317 and compounds described in European Patent EP 96-810237; 5HT3 receptor antagonists, for example, alosetron, cilansetron, ramosetron, azasetron, ondansetron, granisetron, tropisetron and DDP225; Histamine H2 antagonists, for example famotidine, cimetidine, ranitidine and nizatidine; histamine H4 antagonists, for example JNJ7777120, JNJ10191584 and compounds described in US Patent No. 2006111416; International Patent Publications WO 2006050965, WO 2005092066, WO 2005054239; US Patents US 2005070550, US 2005070527 and European Patent EP 1505064; proton pump inhibitors, for example omeprazole, lansoprazole, rabeprazole, tentoprazole, pantoprazole, esomeprazole, revaprazan, soraprazan and AGN201904; activators of the chlorine channel, for example lubiprostone; activators of guanylate cyclase, for example linaclotide; muscarinic antagonists, for example darifenacin, solifenacin, atropine, dicycloverine, hicosine butylbromide, propantheline, oxybutynin, cymethropium bromide, pinaverium bromide and otilonium bromide; antispasmodics, for example mebeverine, tiroopramide, alverine and peppermint oil; stimulant laxatives, for example bisacodyl; osmotic laxatives, for example activated carbon with sorbitol, lactulose, magnesium hydroxide, and phosphate buffer saline; fecal softeners, for example, senna concentrate, liquid paraffin and peanut oil; absorbers and fiber supplements, for example whole fiber laxatives, such as bran, methylcellulose, ispaghula shell and sterculia; antacids, for example aluminum, magnesium and calcium antacids, simethicone and preparations containing alginate; gastrointestinal relaxants, for example cholestyramine resin; bismuth compounds, for example bismuth subsalicylate; vanilloid receptor antagonists, for example compounds described in International Patent Publications WO 2002076946, WO 2004033435, WO 2005121116 and WO 2005120510; anticonvulsants, for example carbamazepine, oxycarbamazepine, lamotrigine, gabapentin and pregabalin; non-steroidal anti-inflammatory drugs (NSAIDs), for example aspirin, acetaminophen, ibuprofen, diclofenac, naproxen, flurbiprofen, indomethacin, piroxicam, ketoprofen, sulindac and diflunisal; COX-2 inhibitors, for example celecoxib, rofecoxib, lumiracoxib, valdecoxib, etoricoxib and compounds described in International Patent Publication WO 2004048314; opiates, for example morphine, buprenorphine, diamorphine, dihydrocodeine, fentanyl and pethidine; modulators of GABAb, for example racemic baclofen and (R) -baclofen, AZD3355, XP19986 and compounds described in International Patent Publications WO 2006001750 and WO 2004000856; ligands of the CB receptor, for example compounds described in International Patent Publications WO 2002042248 and WO 2003066603; calcium channel blockers, for example ziconotide, AG10-003, PD-217014 and compounds described in International Patent Publications WO 2006038594, WO 2006030211 and WO 2005068448; sodium channel blockers, for example lamotrigine and compounds described in International Patent Publications WO 2006023757, WO 2005097136; Japanese Patent JP 2005206590 and International Patent Publication WO 2005047270; tricyclic antidepressants, for example clomipramine, amoxapine, nortriptyline, amitriptyline, imipramine, desipramine, doxepin, trimipramine and protiptilin; selective serotonin reuptake inhibitors, for example fluoxetine, paroxetine, citaprolam, sertalin, fluvoxamine, duloxetine; anxiolytic agents, for example milnacipran, thianeptin, MCI-225 and dextofisopam; antagonists of the peptide related to the calcitonin gene (PRGC), for example olcegepant and cizolirtine; 5HT1 antagonists, for example almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmatriptan; and bradykinin receptor antagonists, for example compounds described in International Patent Publications WO 2000075107, WO 2002092556 and WO 20050851298. Pharmaceutical compositions for separate administration of the components of the combination and for administration in a fixed combination, for example , a single galenic composition comprising at least a combination of two components, according to the present invention, can be prepared in a known manner and compositions suitable for enteral administration, for example oral or rectal, and parenteral administration to mammals, including human beings, comprise a therapeutically effective amount of at least one pharmacologically active component alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral administration. The pharmaceutical compositions contain, for example, from about 0.1 to about 99.9%, preferably from about 20 to about 60% of the ingredients assets. Pharmaceutical preparations for combination therapy for enteral or parenteral administration, for example, are those in dosage forms, such as tablets, including sugar-coated tablets, capsules, suppositories and ampoules. These are prepared in a manner known per se, for example by conventional mixing, granulating, sugar coating, dissolving or lyophilizing processes. It will be noted that the unit content of a component contained in a combination, in an individual dose of each dosage form, need not constitute an effective amount by itself, since the effective amount needed can be achieved by administering a drug. plurality of doses u nitarias. Another aspect of the present invention involves novel compositions comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound of Formula (I), in free form or in the form of a salt. In accordance with the foregoing, the present invention also provides: (1) a compound of Formula (I) in free form or in salt form, for use as a vanilloid receptor blocker, for example for use in any of the indications previously established individuals; (2) a compound of Formula (I) in free or salt form, for the treatment of a disease or disorder in which the vanilloid receptor plays a role or is involved; (3) a method for treating any particular indication of those set forth above, in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of a compound of Formula (I) in free form or in the form of Salt; (4) a method for the treatment or prevention of a disease or disorder, in which the vanilloid receptor performs a function or is involved, wherein the method comprises administering to a mammal in need thereof, a therapeutically effective amount of a compound of Formula (I), in free form or in salt form; (5) the use of a compound of the Formula (I) in free form or in the form of a salt, for the manufacture of a medicament for the treatment or prevention of a disease or disorder in which the activity of the vanilloid receptor performs a function or be involved; (6) a method as set forth above, comprising the co-administration, for example concomitantly or in sequence, of a therapeutically effective amount of a vanilloid receptor antagonist, for example a compound of Formula (I), in free form or in form of a salt, and a second drug substance, wherein the second drug substance, for example, is used in any of the particular indications set forth above; (7) a combination comprising a therapeutically effective amount of a compound of Formula (I) in free form or in the form of a "salt, and a second drug substance, wherein the second drug substance is used, for example, in any of the particular indications previously established. EXAMPLES In the Examples presented below, which are not intended to limit in any way the scope of the present invention, the following abbreviations were used: eq. equivalent (s) h hour (s) min. minute (s) The retention time (TR) data of the HPLC correspond to the following conditions: Phenomenex Moon column of reverse phase C18, 3 microns (30 x 4.6 mm); column temperature 25 ° C; elusion gradient % MeCN in water (+ 0.08% formic acid) up to MeCN at 100%, in a period of 10 minutes (speed = 3.0 mL / minute). The purity values were obtained at 254 nm.

Examples Preparations 3- (4-chlorophenyl) -2-isopropyl-7-nitro-3H-quinazolin-4-one A suspension of isobutyramide of 4-nitroanthranilic acid (4 g, 15.8 mmol), 4-chloroaniline (2.2 g, 17.2 mmol), phosphorus trichloride (5.6 mL) in toluene (150 mL), was heated to reflux (bath temperature, 150 ° C) for 2 hours. The reaction mixture was allowed to cool to room temperature and then evaporated to dryness. The residue was partitioned into water and EtOAc, and the aqueous phase was extracted (x2) with EtOAc. The organic phases were combined and the combined was washed with water, dried (Na2SO) and evaporated in vacuo. Trituration with isopropyl ether afforded the title compound as a brown solid (4.2 g, 77%). 7-amino-3- (4-chlorophenyl) -2-isopropyl-3H-quinazolin-4-one A mixture of 3- (4-chlorophenyl) -2-isopropyl-7-nitro-3H-quinazolin-4-one (2.4 g, 6.98 mmol), powdered iron (1.16 g, 20.8 mmol) and glacial acetic acid (70 mL), was stirred at 50 ° C for 2.5 hours. The reaction mixture was allowed to cool to room temperature and then evaporated to dryness in vacuo. The residue was partitioned into water and EtOAc, and the aqueous phase was extracted (x2) with EtOAc. The organic phases were combined and the combined was washed with water, dried (Na2SO) and evaporated in vacuo to obtain a brown solid. Purification by automated flash chromatography (elution gradient: EtOAc / DCM from 0 to 50%), afforded the title compound as a light yellow solid (1.74 g, 79%). 7-amino-8-bromo-3- (4-chlorophenyl) -2-isopropyl-3H-quinazolin-4-one To a solution of 7-amino-3- (4-chlorophenyl) -2-isopropyl-3H-quinazolin-4-one (1.0 g, 3.2 mmol) in chloroform (20 mL) was added N-bromosuccinimide. After stirring for 5 minutes at room temperature, thin layer chromatography (TLC) indicated complete transformation. The reaction mixture was diluted with water and dichloromethane, and the aqueous phase was extracted with dichloromethane. The aqueous extracts were combined and combined dried over anhydrous sodium sulfate and evaporated to obtain a dark brown solid. The crude product was triturated with diethyl ether, to obtain the title compound as a gray solid, which was recovered by filtration and dried (1.02 g, 2.6 mmol, 81%). 7-amino-8-iodo-3- (4-chlorophenyl) -2-isopropyl-3H-quinazolin-4-one The title compound was prepared in a manner analogous to 7-amino-8-bromo-3- (4-chlorophenyl) -2-isopropyl-3H-quinazolin-4-one, using N-iodosuccinimide instead of N-bromosuccinimide and extending the reaction time to 1.5 hours. Purification by flash automatic elution gradient chromatography (eluent, hexane to hexane / ethyl acetate, 7: 3), afforded the title compound as a light brown solid, 94%. N- [3- (4-chlorophenyl) -8-iodo-2-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl] -acetamide To a solution of 7-amino-8-iodo-3- (4-chlorophenyl) -2-isopropyl-3H-quinazolin-4-one (300 mg, 0.682 mmol) in THF / acetic anhydride 20: 1 (21 mL) was added concentrated hydrochloric acid (3 drops). The reaction mixture was stirred at room temperature overnight and the TLC / LCMS analysis indicated complete transformation. The reaction mixture was diluted with water and extracted with ethyl acetate (x2). The organic extracts were combined and the combined was dried over anhydrous sodium sulfate and evaporated to yield the title compound as an off-white solid (320 mg, 0.664 mmol, 97%), which was used without further purification. N- [8-bromo-3- (4-chlorophenyl) -2-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl] -acetamide The title compound was prepared in a manner analogous to N- [3- (4-chlorophenyl) -8-iodo-2-isoprosyl-4-oxo-3,4-dihydroquinazolin-7-yl] -acetamide. Yield: 97%. 2-. { acetyl- [3- (4-chlorophenyl) -8-iodo-2-isopropyl-4-oxo-3s4-dihydroquinazolin-7-yl] -amino} Acetic acid ethyl ester To a solution of N- [3- (4-chlorophenyl) -8-iodo-2-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl] -acetamide (300 mg, 0.622 mmol) in DMF was added. added sodium hydride (37 mg, 60% dispersion in mineral oil, 0.933 mmol), and the mixture was stirred at room temperature for 20 minutes. 2-Bromoethyl acetate (0.066 mL, 0.933 mmol) was added and stirring was continued overnight. The analysis by CCF and CLEM indicated an incomplete transformation. Cesium carbonate (202 mg, 0.622 mmol), plus 2-bromoethyl acetate (0.44 mL, 0.622 mmol) and potassium iodide (catalytic) were added and stirring was continued for 4 hours. The analysis by CCF and CLEM, indicated that traces of the raw material remained. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The organic extracts were combined and the combined was dried over anhydrous sodium sulfate, and evaporated. Purification by flash automatic gradient elution chromatography (eluent: from hexane to ethyl acetate) yielded 326 mg of the title compound, 0.574 mmol., 92%. N- [3- (4-chlorophenyl) -8-iodo-2-ylpropyl-4-oxo-3,4-dihydroquinazolin-7-yl] -N- (2-hydroxyethyl) acetamide To a solution of 2-. { acetyl- [3- (4-chlorophenyl) -8-iodo-2-isopropyl-4-oxo-3,4-dihydroquinoline-7-yl] -amino} Acetic acid ethyl ester (300 mg, 0.528 mmol) in methanol / water 2: 1 (6 mL), potassium carbonate (88 mg, 0.634 mmol) was added and the reaction mixture was stirred at room temperature for 20 minutes . Analysis by CLEM indicated that the reaction had been completed. The reaction mixture was diluted with water and extracted with dichloromethane (x2). The organic extracts were combined and the combined was dried over anhydrous sodium sulfate and evaporated, to obtain the title compound as a foam, 271 mg, 0.51, 6 mmol, 97%. 3- (4-chlorophenyl) -7- (2-hydroxyethylamino) -8-iodo-2-isopropyl-3H-qui nazoli n-4-one To a solution of N- [3- (4-chlorophenyl) -8-iodo-2-isopropyl-4-oxo-3,4-dihydroquinoline-7-yl] -N- (2-hydroxyethyl) acetamide (1 35 mg, 0. 257 mmol) in methanol (2 mL) was added a solution of potassium hydroxide M% (1 mL). The reaction mixture was stirred at room temperature for 10 min. and then heated to 50 ° C in an oil bath for 20 minutes. The CCF and LCMS analyzes indicated the complete transformation. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate (x2). The organic extracts were combined and the combined was dried over anhydrous sodium sulfate and evaporated to obtain a white solid. Purification by flash chromatography with automatic elution gradient (eluent: from hexane to ethyl acetate), afforded the title compound as a white solid, 98 mg, 0.203 mmol, 79%. N - [8-bromo-3- (4-chlorofenyl) -2-isopropyl I -4-0X0-3,4-dihydroquinazolin-7-yl] -acrylamide To a solution of 7-amino-8-bromo-3- (4-chlorophenyl) -2-isopropyl-3H-quinazolin-4-one (60 mg, 0.153 mmol) in dichloromethane, in a microwave vial, was added triethylamine (0.032 mL, 0.229 mmol), followed by acryloyl chloride (0.014 mol, 0.168 mmol). The vial was sealed with a pressure cap, and the mixture was heated at 150 ° C for 3000 sec., Under microwave irradiation.

The analysis by TLC and LCMS indicated the complete transformation. The reaction mixture was evaporated and the residue was partitioned between water and dichloromethane. The organic phase was dried over anhydrous sodium sulfate and evaporated to obtain a yellow oil. Purification by flash chromatography with automatic elution gradient (eluent: from hexane to hexane / ethyl acetate, 7: 3), afforded the title compound as a yellow solid, 57 mg, 0.127 mmol, 84%. N- [3- (4-chlorophenyl) -2-isopropyl-4-oxo-8-vinyl-3,4-dihydro-quinazolin-7-yl] -acetamide To a suspension of N- [8-bromo-3- (4-chlorophenyl) -2-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl] -acetamide (250 mg, 0.573 mmol) in toluene / THF 2: 1 (6 mL) in a microwave vial, was added tributyl (vinyl) tin (0.814 mL, 0.629 mmol) and (tetrakistriphenylphosphine) palladium (O) (66 mg, 0.057 mmol). The vial was sealed with a pressure cap, and the mixture was heated at 120 ° C for 1 hour, under microwave irradiation. The analysis by CCF indicated that there was still raw material. THF (1 mL) was added to the vial, which was sealed again and heated at 150 ° C for 1 hour under microwave irradiation. The CCF showed that the reaction It was complete. The reaction mixture was filtered through Celite and washed with methane. The solution was evaporated and the residue was purified by flash gradient automatic chromatography (12 g of silica, eluent: hexane (+ 2% triethylamine) to hexane (+ 2% triethylamine) / ethyl acetate, 1: 1), to obtain the title compound as a white solid, 159 mg, 0.414 mmol, 72%. N-allyl-N- [3- (4-chlorophenyl) -2-isopropyl-4-oxo-8-vinyl-3,4-dihydroquinazole i n-7-i I] -acetamide To a solution of N- [3- (4-chlorophenyl) -2-isopropyl-4-oxo-8-vinyl-3,4-dihydroquinazolin-7-yl] -acetamide (155 mg, 0.404 mmol) in DMF (3 mL), allyl bromide (0.037 mL, 0.42 mmol) and cesium carbonate (270 mg, 0.82 mmol) were added. The suspension was stirred for 1 h at room temperature, then heated to 60 ° C (external temperature) in an oil bath. The CCF showed that the reaction was complete. The mixture was diluted with water and ethyl acetate, and the aqueous phase was extracted with ethyl acetate (x2). The organic phases were combined and the combined was dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash chromatography with gradient of automatic elution (12 g of silica, eluent: from hexane to hexane / ethyl acetate, 1: 1), to obtain the title compound as a white foam, 156 mg, 0.37 mmol, 91%. N- [3- (4-chlorophenyl) -2-isopropyl-4-oxo-8-vinyl-3,4-dihydroquinazolin-7-yl] -N- (2-methyl-allyl) -acetamide The title compound was prepared in a manner analogous to N-allyl-N- [3- (4-chlorophenyl) -2-isopropyl-4-oxo-8-vinyl-3,4-dihydroquinazolin-7-yl] - acetamide, using 3-bromo-2-methylpropene instead of allyl bromide. Performance, 89%. N- [3- (4-chlorophenyl) -8-iodo-2-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl] -N- (4-methylpent-3-enyl) acetamide To a solution of N- [3- (4-chlorophenyl) -8-iodo-2-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl] -acetamide (150 mg, 0.312 mmol) in DMF (2). mL) in a microwave vial, carbonate was added to the cesium (203 mg, 0.624 mmol) and 5-bromo-2-methyl-2-pentene (0.046 mL, 0.343 mmol). The vial was sealed with a pressure cap and the mixture was heated at 80 ° C for 20 min., Under microwave irradiation. Additional 5-bromo-2-methyl-2-pentene (0.046 mL, 0.343 mmol) was added, and the mixture was heated at 80 ° C for 1 h under microwave irradiation. The CCF and LCMS analyzes indicated a complete transformation. The reaction mixture was diluted with water, extracted with ethyl acetate (x3), the organic extracts were combined and the combined was dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash gradient automatic chromatography (eluent: from hexane to 15% ethyl acetate in hexane), to obtain the title compound as a colorless oil (136 mg, 0.241 mmol, 77%). . N-But-3-en i l-N- [3- (4-chlorofenyl) -8-iodo-2-isopropy I -4-0X0-3,4-dihydroquinazolin-7-yl] -acetamide The title compound was prepared in a manner analogous to N- [3- (4-chlorophenyl) -8-iodo-2-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl] -N- (4 -methyl-pent-3-enyl) acetamJda, using 4-bromobutene, instead of 5-bromo-2-methyl-2-pentene. The purification by flash chromatography with automatic elution gradient (eluent: from hexane to 15% ethyl acetate in hexane), afforded the title compound as a clear oil, 61%. N- [8-allyl-3- (4-chlorophenyl) -2-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl] -acetamide To a solution of N- [3- (4-chlorophenyl) -8-iodo-2-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl] -acetamide (0.2 g, 0.447 mmol) and Pd (PPh3) ) 4 (0.077 g, 0.067 mmol) in toluene (5 mL), was added allyltributyltin (0.17 mL, 0.5 mmol). The resulting mixture was heated in a microwave oven for 1 h, at 140 ° C. The mixture was cooled to room temperature, filtered through celite and the pellet was washed with EtOAc. The filtrate was washed with HCl (2M), the organic phase was dried over MgSO 4 (anhydrous) and concentrated. The crude material was purified by flash chromatography (10% EtOAc / cyclohexane) to obtain 0.1 g (62%) of N- (8-allyl-3- (4-chlorophenyl) -2-isopropyl-4-oxo-3- phenyl-3,4-dihydroquinazolin-7-yl) -acetamide. 7-am no-3- (4-chlorofenyl) -2-isopropyl-8-trimethyl Isi lani leti ni I-3H-quinazolin-4-one A mixture of 7-amino-3- (4-chlorophenyl) -8-iodo-2-isopropyl-3H-quinazolin-4-one (100 mg, 0.229 mmol), (tetrakistriphenylphosphine) palladium (O) (52 mg, 0.044 mmol), trimethylsilylacetylene (0.162 mL, 1.14 mmol), triethylamine (0.158 mL, 1.14 mmol), copper iodide (1) (18.4 mg, 0.088 mmol) and DMF were sealed in a microwave vial with a pressure cap. The reaction mixture was heated at 60 ° C for 1.5 h under microwave irradiation. The mixture was evaporated and the residue was purified by flash chromatography with automatic elution gradient (eluent: from hexane to ethyl acetate), to obtain the title compound (55 mg, 0.134 mmol, 59%). 7-amino-3- (4-chlorophenyl) -8-ethynyl-2-isopropyl-3H-quinazolin-4-one To a solution of 7-amino-3- (4-chlorophenyl) -2-isopropyl-8-trimethylsilanylethynyl-3H-quinazolin-4-one (90 mg, 0.22 mmol) in THF (8 mL) was added fluoride. tetrabutylammonium (1M in THF, 0.247 mL, 0.247 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned with water / ethyl acetate, and the aqueous phase was extracted with ethyl acetate. Evaporation afforded the title compound (74 mg, 0.219 mmol, 100%), which was used without further purification. EXAMPLE 1 7- (4-chlorophenyl) -6-isopropyl-2,3-dihydro-1H, 7H-4-oxa-1,5,7-triazafenantren-8-one To an oven-dried microwave vial, 3- (4-chlorophenyl) -7- (2-hydroxyethylamino) -8-iodo-2-isopropyl-3H-quinazolin-4-one (70 mg, 0.145 mmol) was added. , cesium carbonate (94 mg, 0.290 mmol), copper iodide (I) (27.6 mg, 0.145 mmol) and acetonitrile. The vial was sealed with a pressure cap, and the mixture was heated at 150 ° C for 5000 sec. under microwave irradiation. The analysis by TLC and LCMS indicated the complete transformation. The reaction mixture was subjected to extraction by partition between water and acetate of ethyl. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to obtain a dark oil. Purification by preparative automatic HPLC yielded the title compound as a white solid, 14 mg, 0.039 mmol, 27%). 1 H-NMR dH (400 MHz, CDCl 3) 6.69 (1H, d), 7.50 (2H, d), 7.19 (2H, d), 6.69 (1H, d), 4.45 (2H, t), 4.27 (1H, brs ), 3.57 (2H, t), 2.67 (1H, m), 1.23 (6H, d). EXAMPLE 2 3- (4-chlorophenyl) -2-isopropyl-9-methyl-7,9-dihydro-3H-pyrrolo [2,3-h] quinazoline-4,8-dione To a solution of N- [8-bromo-3- (4-chlorophenyl) -2-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl] -acrylamide (41 mg, 0.092 mmol) in acetonitrile (4.5 mL) in a microwave vial was added (tetrakistriphenylphosphine) palladium (O) (10 mg, 0.0086 mmol), followed by triethylamine (0.064 mL, 0.46 mmol). The vial was sealed with a pressure cap and the mixture was heated at 150 ° C for 5000 sec., Under microwave irradiation. The analysis by CCF indicated the complete transformation. The reaction mixture was filtered through Celite. The filtrate was evaporated, and the yellow residue was purified by flash chromatography with automatic elution gradient (12 g of silica, eluent: from hexane to hexane / ethyl acetate, 7: 3), to obtain the title compound as a yellow solid, 10.5 mg, 0.028 mmol, 31%). H-NMR dH (400 MHz, CDCl 3) 8.18 (1H, d), 7.53 (2H, d), 7.21 (2H, d), 7.01 (1H, d), 3.85 (1H, q), 2.65 (1H, m ), 1.76 (3H, d), 1.23 (6H, m). EXAMPLE 3 3- (4-chlorophenyl) -2-cyclopropyl-9-methyl-7,9-dihydro-3H-pyrrolo [2,3-h] quinazoline-4,8-dione Prepared analogously to Example 2. (MH +) 366.

CLAR retention time 4.6 minutes. 1 H NMR (400 MHz, CDCl 3): 8.18 (d, 1H), 8.16 (s, 1H), 7.5 (d, 2H), 7.3 (d, 2H), 6.9 (d, J = 8.3 Hz, 1H), 1.7 (d, 3H), 1.4 (t, 2H), 1.3 (m, 1H), 1.2 (m, 1H), 0.9 (t, 2H). EXAMPLE 4 7-Acetyl-3- (4-chlorophenyl) -2-isopropyl-7,8-dihydro-3H-pyrido [2,3-h] quinazolin-4-one To a solution of N-allyl-N- [3- (4-chlorophenyl) -2-isopropyl-4-oxo-8-vinyl-3,4-dihydroquinazolin-7-yl] -acetamide (62 mg, 0.147 mmol) in DCM (5 mL) in a microwave vial, the Grubbs second-generation ring-closure catalyst was added by metathesis reaction (10.6 mg, 0.012 mmol). The vial was sealed with a pressure cap and the mixture was heated at 60 ° C for 1 h under microwave irradiation. The CCF showed that the reaction was complete. The mixture was evaporated and the residue was purified by flash chromatography with automatic elution gradient (4 g of silica, eluent: from hexane to hexane / ethyl acetate, 3: 2), to obtain the title compound as a foam. colorless, 55.5 mg, 0.141 mmol, 96%. EXAMPLE 5 7-Acetyl-3- (4-chlorophenyl) -2-isopropyl-9-methyl-7,8-dihydro-3H-pyrido [2,3-h] quinazolin-4-one The title compound was prepared analogously to 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-7,8-dihydro-3H-pyrido [2,3-h] quinazolin-4-one, using N- [3- (4-chlorophenyl) -2-isopropyl-4-oxo-8-vinyl-3,4-dihydro-quinazolin-7-yl] -N- (2-methylalyl) -acetamide, instead of N-allyl-N- [3- (4-chlorophenyl) -2-isopropyl-4-oxo-8-vinyl-3,4-dihydroquinazolin-7-yl] -acetamide, increased the catalyst load to 20 mol% and extended the reaction time at 17 hours. Yield, 42%. EXAMPLE 6 7-Acetyl-3- (4-chlorophenyl) -2-isopropyl-7,8,9,10-tetrahydro-3 H -pyrido [2,3-h] -quinazolin-4-one To a solution of 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-7,8-dihydro-3H-pyrido [2,3-h] -quinazolin-4-one (55 mg, 0.139 mmol) in glacial acetic acid (4 mL), a catalytic amount of palladium on activated charcoal (10% Pd-C) was added and the mixture was stirred under a hydrogen atmosphere (balloon flask) for 2 hours. Analysis by LCMS showed that the reaction was complete. The suspension was filtered through Celite and evaporated to obtain the title compound as a light yellow oil (58.1 mg,> 100%), which was used without purification. EXAMPLE 7 7-Acetyl-3- (4-chlorophenyl) -2-isopropyl-9-methyl-7,8,9,10-tetrahydro-3 H -pyrido [2,3-h] quinazolin-4-one The title compound was prepared analogously to 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-7,8,9,10-tetrahydro-3H-pyrido [2,3, -h] quinazolin- 4-one, replacing 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-7,8-dihydro-3H-pyrido [2,3, -h] quinazolin-4-one by 7-acetyl-3 - (4-chlorophenyl) -2-isopropyl-9-methyl-7,8-dihydro-3H-pyrido [2,3-h] quinazolin-4-one. Performance, 89%. EXAMPLE 8 3- (4-Chlorophenyl) -2-isopropyl-7,8,9,10-tetrahydro-3 H -pyrido [2,3-h] quinazolin-4-one To a solution of 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-7,8,9,10-tetrahydro-3H-pyrido [2,3-h] quinazolin-4-one (29 mg, 0.074) mmol) in methanol (2 mL) in a microwave vial, was added 2M HCl (1 mL). The vial was sealed with a pressure cap, and the mixture was heated at 100 ° C for 0.5 h, under microwave irradiation. The CCF showed that the reaction was complete. The mixture of The reaction was made alkaline to pH 9, by the addition of a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate (x3). The organic phases were combined and the combined was dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash chromatography with automatic elution gradient (4 g of silica, eluent: hexane to hexane / ethyl acetate, 3: 2), to obtain the title compound as a white crystalline solid, 11.9 mg, 0.034 mmol, 46%. 1 H-NMR dH (400 MHz, CDCl 3) 7.86 (1H, d) 7.49 (2H, d), 7.17 (2H, d), 6.55 (1H, d), 4.40 (1H, brs), 3.40 (2H, t) , 3.12 (2H, t), 2.61 (1H, m), 2.00 (2H, m), 1.19 (6H, d). EXAMPLE 9 3- (4-chlorofenyl) -2-isopropyl-9-methyl 1-7,8,9, 10-tetrahydro-3H-pyrido [2,3-h] quinazolin-4-one The title compound was prepared in a manner analogous to 3- (4-chlorophenyl) -2-isopropyl-7,8,9,10-tetrahydro-3H-pyrido [2,3-h] quinazolin-4-one, replacing 7-acetyl-3- (4- chlorophenyl) -2-isopropi 1-7,8, 9,10-tetrahydro-3H-pyrido [2,3-h] quinazole i n-4-one by 7-acetyl-3- (4-chlorophenyl) - 2-isopropyl-9-methyl 1-7,8,9,10-tetrahydro-3 H -pyrido [2,3-h] quinazolin-4-one. 50% yield. 1H-NMR dH (400 MHz, CDCl 3) 7.86 (1H, d), 7.48 (2H, d), 7.17 (2H, d), 6.56 (1H, d), 4.42 (1H, brs), 3.44 (1H, dd), 3.37 (1H, brd), 2.98 (1H, t), 2.61 (1H, m), 2.48 (1H, dd), 2.08 (brm), 1.20 (3H, d), 1.14 (3H, d). EXAMPLE 10 7-Acetyl-3- (4-chlorophenyl) -2-isopropyl-9-methyl-3H, 7H-pyrrolo [2,3-h] quinazolin-4-one, 3- (4-chlorophenyl) -2- isopropyl-9-methyl-3H, 7H-pyrrolo [2,3-h] quinazolin-4-one and 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-9-methylene-8,9-dihydroxy- 3H, 7H-pyrrolo [2,3-h] quinazolin-4-one to a solution of N- [8-bromo-3- (4-chlorophenyl) -2-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl] -acetamide (92 mg, 0.211 mmol) in DMF (3 mL) in a microwave vial, cesium carbonate (140 mg, 0.43 mmol) and allyl bromide (0.02 mL, 0.231 mmol) were added. The reaction mixture was stirred at room temperature overnight. The analysis by CCF and CLEM indicated the complete loss of raw material. Added (tetrakistriphenylphosphine) palladium (O) (40 mg, 0.035 mmol), the vial was resealed with a pressure cap and the mixture was heated to 100 ° C for 20 min., Under microwave irradiation. Analysis by LCMS indicated the complete loss of the N-allyl intermediate. The reaction mixture was evaporated and the residue was subjected to extraction by partition in ethyl acetate / water. The aqueous phase was extracted with ethyl acetate (x2), the organic extracts were combined and the combined was dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash chromatography with automatic elution gradient (12 g of silica, eluent: hexane to hexane / ethyl acetate, 1: 1), to obtain the title compounds. 7-Acetyl-3- (4-chlorophenyl) -2-isopropyl-9-methyl-3H, 7H-pyrrolo [2,3-h] quinazolin-4-one (eluting first, 8.8 mg, 0.022 mmol, 11%) , 3- (4-chlorophenyl) -2-isopropyl-9-methyl-3H, 7H-pyrrolo [2,3-h] quinazolin-4-one (eluting second, 6 mg, 0.015 mmol, 8%) and 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-9-methylene-8,9-dihydro-3H, 7H-pyrrolo [2,3-h] quinazolin-4-one (eluting third, 48 mg, 0.122 mmol, 58%). Total recovery: 77%. EXAMPLE 11 7-Acetyl-3- (4-chlorophenyl) -2-isopropyl-9-methyl-3H, 7H-pyrrolo [2,3-h] quinazolin-4-one To a solution of 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-9-methylene-8,9-dihydro-3H, 7H-pyrrolo [2,3-h] quinazolin-4-one (48 mg , 0. 122 mmol) in DCM (2 mL), camphor sulfonic acid (29 mg, 0.122 mmol) was added. The reaction mixture was stirred for 20 h at room temperature. CLEM demonstrated the complete loss of raw material. The reaction mixture was diluted with water and ethyl acetate. The aqueous phase was extracted with ethyl acetate (x2), the organic extracts were combined and the combined was dried over anhydrous sodium sulfate and evaporated, to obtain the title compound (48 mg, 0.122 mmol, 100%). , it was used without purification. EXAMPLE 12 3- (4-chlorophenyl) -2-isopropyl-9-methyl-3H, 7H-pyrrolo [2,3-h] quinazolin-4-one To a solution of 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-9-methylene-8,9-dihydro-3H, 7H-pyrrolo [2,3-h] quinazolin-4-one (48 mg , 0.122 mmol) in methanol / water, 2: 1 (3 mL) in a microwave vial, potassium carbonate (150 mg, 1087 mmol) was added. The vial was sealed with a pressure cap and the mixture was heated at 120 ° C for 0.5 hours under microwave irradiation. The analysis by CCF showed that the reaction was complete. The reaction mixture was diluted with water and ethyl acetate. The aqueous phase was extracted with ethyl acetate (x2), the organic extracts were combined and the combined was dried over anhydrous sodium sulfate and It vanished. The residue was purified by flash chromatography with automatic elution gradient (4 g of silica, eluent: from hexane to hexane / ethyl acetate, 1: 1), to obtain the title compound as a yellow solid (25.4 mg, 0.072 mmol, 59%). 1 H-NMR dH (400 MHz, CDCl 3) 8.33 (1H, brs), 8.00 (1H, d), 7.53 (2H, d), 7.39 (1H, d), 7.23 (2H, d), 7.06 (1H, m ), 2.76 (3H, s), 2.71 (1H, m), 1.27 (6H, d). EXAMPLE 13 7-Acetyl-3- (4-chlorophenyl) -10-isopropenyl-2-isopropyl-7,8,9,10-tetrahydro-3H-pyrido [2,3-h] quinazolin-4-one To an oven-dried microwave vial, N- [3- (4-chlorophenyl) -8-iodo-2-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl] -N- (4 -methylpent-3-enyl) acetamide (61 mg, 0.108 mmol), (tetrakistriphenylphosphine) palladium (O) (25 mg, 0.022 mmol), cesium carbonate (176 mg, 0.541 mmol) and DMF (2.5 mL). Nitrogen was applied to the vial, sealed with a pressure stopper, and the mixture was heated at 120 ° C for 1 h under microwave irradiation. The analyzes by TLC and LCMS indicated that the reaction was complete. The reaction mixture was poured into water, subjected to extraction with ethyl acetate. ethyl (x2), the organic extracts were combined and the combined was dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash chromatography with automatic elution gradient (eluent: from hexane to 15% ethyl acetate in hexane), to obtain the title compound as a light yellow clear oil (46 mg, 0.105 mmol , 98%). EXAMPLE 14 7-Acetyl-3- (4-chlorophenyl) -2,10-diisopropyl-7,8,9,10-tetrahydro-3 H -pyrido [2,3-h] quinazolin-4-one To a solution of 7-acetyl-3- (4-chlorophenyl) -10-isopropenyl-2-isopropy 1-7,8,9,10-tetrahydro-3H-pyrido [2,3-h] quinazolin-4 -one (44 mg, 0.101 mmol) in absolute ethanol / glacial acetic acid 1: 1 (3 mL), a catalytic amount of palladium on activated charcoal (10% Pd-C, 10 mg) was added and the mixture was stirred under a hydrogen atmosphere (balloon flask) for 5 hours. Analysis by LCMS showed that the reaction was complete. The suspension was filtered through Celite and the filtrate was neutralized with a saturated aqueous solution of sodium hydrogen carbonate. The aqueous solution was extracted with dichloromethane, the organic extracts were combined and the combined was evaporated. The residue was purified by chromatography fast with automatic elution gradient (eluent: from hexane to 20% ethyl acetate in hexane), to obtain the title compound as a clear oil (37 mg, 0.084 mmol, 84%). EXAMPLE 15 3- (4-chloro-enyl) -2,10-d-isopropyl-7,8,9,1-tetrahydro-3H-pyrido [2,3-h] quinazolin-4-one To a solution of 7-acetyl-3- (4-chlorophenyl) -2,10-diisopropyl-7,8,9,10-tetrahydro-3H-pyrido [2,3-h] quinazolin-4-one (30 mg , 0.068 mmol) in methanol (1 mL) in a microwave vial, was added an aqueous solution of sodium hydroxide (1M, 1 mL). The vial was sealed with a pressure cap and the mixture was heated to 100IC for 10 min. under microwave irradiation. The analysis by TLC and LCMS indicated that the reaction was complete. The reaction mixture was diluted with dilute hydrochloric acid and extracted with ethyl acetate (x2). The organic extracts were combined, the combined was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and evaporated, to obtain a clear oil (24 mg, 0.060 mmol, 89%). H-NMR dH (400 MHz, CDCl 3) 7.88 (1H, d), 7.48 (2H, m), 7.22 (1H, m), 7.16 (1H, m), 6.55 (1H, d), 4.45 (1H, brs) ), 3.61 (1H, m), 3.44 (2H, m), 2. 62 (1H, m), 2.14 (1H, dd), 1.93 (1H, m), 1.69 (1H, m), 1.19 (6H, m), 1.04 (3H, d), 0.90 (3H, d). EXAMPLE 16 7-Acetyl-3- (4-chlorophenyl) -2-isopropyl-10-methylene-7,8,9,10-tetrahydro-3H-pyrido [2,3-h] -quinazolin-4-one and -acetyl-3- (4-chlorophenyl) -2-isopropyl-10-methyl-7,8-dihydro-3H-pyrido [2,3-h] quinazolin-4-one To an oven-dried microwave vial, but-3-enyl-N- [3- (4-chlorophenyl) -8-iodo-2-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl was added. ] -acetamide (350 mg, 0.654 mmol), DMF (5 mL), (tetrakistriphenylphosphine) palladium (O) (151 mg, 0.131 mmol) and cesium carbonate (1.1 g, 3.4 mmol). Nitrogen was applied to the vial, sealed with a pressure cap, and the mixture was heated at 100 ° C for 1 h under microwave irradiation. The analysis by TLC and LCMS indicated that the reaction was complete. The reaction mixture was filtered through Celite and evaporated. Ethyl acetate / water was added to the residue and the organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated, to obtain a dark oil. The residue was purified by flash chromatography with automatic elution gradient (eluent: from hexane to 25% ethyl acetate in hexane), to obtain the isomeric compounds of the title: 7-acetyl-3- (4- chlorophenyl) -2-isopropyl-10-methylene-7,8,9,10-tetrahydro-3H-pyrido [2,3-h] -quinazolin-4-one (108 mg, 0.265 mmol, 41%) and 7- acetyl-3- (4-chlorophenyl) -2-isopropyl-10-methyl-7,8-dihydro-3H-pyrido [2,3-h] quinazolin-4-one (138 mg, 0.338 mmol, 52%). Total recovery: 93%. EXAMPLE 17 7-Acetyl-3- (4-chlorophenyl) -2-isopropyl-10-methyl-7,8,9,10-tetrahydro-3 H -pyrido [2,3-h] quinazolin-4-one To a solution of 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-10-methyl-7,8-dihydro-3H-pyrido [2,3-h] quinazolin-4-one (100 mg, 0.246 mmol) in absolute ethanol / glacial acetic acid, 1:10 (5.5 mL), was added a catalytic amount of palladium in activated carbon (Pd-C al %, 10 mg) and the mixture was stirred under a hydrogen atmosphere (flask ball) for 20 hours. Analysis by LCMS showed that the reaction was complete. The suspension was filtered through Celita and evaporated. The residue was purified by flash chromatography with automatic elution gradient (eluent: from hexane to 30% ethyl acetate in hexane), to obtain the title compound as a clear oil (89 mg, 0.218 mmol, 89%). .

EXAMPLE 18 3- (4-Cl orofenyl) -2-isopropi 1-10-meti 1-7,8, 9, 10-tetrahydro-3 H -pyrido [2,3-h] quinazolin-4-one To a solution of 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-10-methyl-7,8,9,10-tetrahydro-3H-pyrido [2,3-h] quinazolin-4-one ( 84.5 mg, 0.207 mmol) in methanol (5 mL) in a microwave vial was added an aqueous solution of potassium hydroxide (5M, 1 mL). The vial was sealed with a pressure cap and the mixture was heated at 100 ° C for 10 min. under microwave irradiation. The analysis by TLC and LCMS indicated that the reaction was complete. The reaction mixture was diluted with water and extracted with ethyl acetate (x2). The organic extracts were combined, the combined was dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash chromatography with automatic elution gradient (eluent: from hexane to 20% ethyl acetate in hexane), to obtain the title compound as a white solid (60 mg, 0.163 mmol, 79 %). 1 H-NMR dH (400 MHz, CDCl 3) 7.86 (1H, d), 7.48 (2H, d), 7.18 (2H, m), 6.54 (1H, d), 4.49 (1H, brs), 3.83 (1H, m ), 3.48 (1H, m), 3.36 (1H, m), 2.61 (1H, m), 1.93 (1H, m), 1.82 (1H, m), 1.33 (3H, d), 1.21 (6H, m) .

EXAMPLE 19 3- (4-chlorofenyl) -2-isopropyl-1-10-methylene-7, 8, 9, 10-tetrahydro-3H-pyrido [2,3-h] quinazolin-4-one To a solution of 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-10-methylene-7,8,9,10-tetrahydro-3H-pyrido [2,3-h] quinazolin-4-one ( 60 mg, 0.147 mmol) in methanol (3 mL) in a microwave vial, was added an aqueous solution of potassium hydroxide (5M, 1 mL). The vial was sealed with a pressure cap and the mixture was heated at 100 ° C for 10 min. under microwave irradiation. The analysis by TLC and LCMS indicated that the reaction was complete. The reaction mixture was acidified to pH 6-7 with hydrochloric acid (2M) and extracted with ethyl acetate (x2). The organic extracts were combined, the combined was dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash chromatography with automatic elution gradient (eluent: from hexane to 20% ethyl acetate in hexane), to obtain the title compound as a white solid (35 mg, 0.096 mmol, 65%). %). 1 H-NMR dH (400 MHz, CDCl 3) 7.90 (1H, d), 7.49 (2H, d), 7.19 (2H, d), 6.63 (1H, d), 6.55 (1H, d), 5.32 (1H, bm ), 4.63 (1H, brs), 3.50 (2H, brt), 2.66 (3H, overlap of m), 1.20 (6H, d).

EXAMPLE 20 7-Acetyl-3- (4-chlorophenyl) -2-isopropyl-8,9-dihydro-3H, 7H-pyrido [2,3-h] quinazoline-4,10-dione A solution of 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-10-methylene-7,8,9,10-tetrahydro-3H-pyrido [2,3-h] quinazolin-4-one (85 mg, 0.208 mmol) in methanol / dichloromethane, 2: 1 (5 mL), cooled to -78 ° C and a constant stream of ozone was bubbled into the reaction mixture, for 0.5 hours. The reaction mixture was allowed to warm to -20 ° C while being purged with a constant stream of argon. After, the solution was cooled to -78 ° C and dimethyl sulfide (3 drops) was added. The stirring solution was allowed to reach room temperature overnight and then evaporated. The residue was purified by flash chromatography with automatic elution gradient (eluent: from hexane to 80% ethyl acetate in hexane), to obtain the title compound as a white solid (38 mg, 0.093 mmol, 44%). %). EXAMPLE 21 3- (4-chlorophenyl) -2-isopropyl-8,9-dihydro-3H, 7H-pyrido [2,3-h] quinazoline-4,10-dione To a solution of 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-8,9-dihydro-3H, 7H-pyrido [2,3-h] quinazolin-4,10-dione (30 mg, 0.073 mmol) in methanol (4 mL), an aqueous solution of potassium hydroxide (5M, 1 mL) was added. After 2 min., The analysis by TLC and LCMS indicated that the reaction was complete. The reaction mixture was diluted with water and extracted with ethyl acetate (x2). The organic extracts were combined, the combined was dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash chromatography with automatic elution gradient (eluent: from hexane to 70% ethyl acetate), to obtain the title compound as a white solid (11.9 mg, 0.032 mmol, 44%) . 1 H-NMR dH (400 MHz, CDCl 3) 8.07 (1H, d), 7.51 (2H, d), 7.17 (2H, d), 6.66 (1H, d), 5.12 (1H, brs), 3.70 (2H, brm ), 2.81 (2H, t), 2.66 (1H, m), 1.26 (6H, d). EXAMPLE 22 7-Acetyl-3- (4-chlorophenyl) -2-isopropyl-8-methyl-3H, 7H, pyrrolo [2,3-h] quinazolin-4-one To a solution of N- (8-allyl-2-isopropyl-4-oxo-3-phenyl-3,4-dihydro-quinazolin-7-yl) -acetamide (2) (0.02 g, 0.05 mmol) in THF ( 3 mL), PdCI2 (MeCN) 2 (0.013 g, 0.05 mmol) was added and stirred at room temperature for 1 hour. To this solution was added Et3N (0.02 mL, 0.15 mmol) and stirred for 2 hours. The reaction mixture was filtered through Celite and the pellet was washed with EtOAc. The filtrate was concentrated and purified by flash chromatography (10% EtOAc / cyclohexane) to obtain 0.01 g (51%) of 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-8-methyl-3H, 7H- pyrrolo [2,3-h] quinazolin-4-one. EXAMPLE 23 3- (4-chlorophenyl) -2-isopropyl-8-methyl-3H, 7H-pyrrolo [2,3-h] quinazolin-4-one To a solution of 7-acetyl-3- (4-chlorophenyl) -2-isopropyl-8-methyl-3H, 7H-pyrrolo [2,3-h] quinazolin-4-one (3) (0.02 g, 0.05 mmol ) in MeOH (0.5 mL), 2 mL of KOH (5M) was added and heated in the microwave oven at 100 ° C for 2 hours. The reaction mixture was diluted with H2O, extracted with EtOAc, the organic phase was dried over MgSO (anhydrous) and concentrated to obtain 0.016 g (90%) of 3- (4-chlorophenyl) -2-isopropyl. -8-methyl-3H, 7H-pyrrolo [2,3-h] quinazolin-4-one. (MH +) = 352. CLAR retention time = 5.7 min. dH (400 MHz, CDCl 3) 8.28 (s, 1H), 7.9 (d, 1H), 7.5 (d, 2H), 7.3 (d, 1H), 7.2 (d, 2H), 6.8 (s, 1H), 2.7 (m, 1H), 2.5 (s, 3H), 1.2 (d, 6H). EXAMPLE 24 3- (4-chlorophenyl) -2-isopropyl-3H-7H-pyrrolo [2,3-h] quinazolin-4-one To a suspension of potassium hydride CAUTION, IS PIROFORIC (30% dispersion in mineral oil, 36 mg, 0.27 mmol) in NMP, in a microwave vial with argon blown and oven dried, a solution of 7- amino-3- (4-chlorophenyl) -8-ethynyl-2-isopropyl-3H-quinazolin-4-one (33.5 mg, 0.099 mmol) in NMP. The microwave vial was sealed with a pressure plug and the reaction mixture was stirred overnight at room temperature. Analysis by LCMS indicated that the reaction had been completed by 50%. The reaction mixture was heated to 70 ° C for 1 h under microwave irradiation. Analysis by LCMS indicated that the reaction was complete. The reaction mixture was diluted with water and extracted with ethyl acetate (x2). The organic extracts were combined, the combined was dried over anhydrous sodium sulfate and evaporated. Alternate procedure: To a suspension of potassium rerf-butoxide (36 mg, 0.32 mmol) in NMP, in a microwave vial with argon blown and oven drying, was added a solution of 7-amino-3- (4- chlorophenyl) -8-ethynyl-2-isopropyl-3H-quinazolin-4-one (43 mg, 0.127 mmol) in NMP. The microwave vial was sealed with a pressure cap and the reaction mixture was heated at 80 ° C for 1 h under microwave irradiation. Analysis by LCMS indicated that the reaction was complete. The reaction mixture was diluted with water and extracted with ethyl acetate (x2). The organic extracts were combined, the combined was dried over anhydrous sodium sulfate and evaporated. The combined residues of the two procedures were purified by flash chromatography with automatic elution gradient (eluent: from 5 to 100% ethyl acetate in hexane), to obtain the title compound (40 mg, 0.119 mmol, 52%). 1 H-NMR dH (400 MHz, CDCl 3) 8.54 (1H, brs), 8.04 (1H, d), 7.52 (2H, m), 7.47 (1H, d), 7.33 (1H, t), 7.23 (3H, m ), 2.71 (1H, m) 1.26 (6H, d).

Claims (6)

1. CLAIMS A compound of q uinazolinone of the Formula where zzn is a simple link or a double link; R2 is selected from the group consisting of (a) alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) -amino or di- (alkyl of 1 to 6 carbon atoms) -amino; or (b) N H2, hydroxy alkylamine of 1 to 6 carbon atoms-, amino-alkylamino of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, di (trifluoromethyl) -alkyl of 1 to 6 carbon atoms, R9-O- (alkyl of 1 to 6 carbon atoms) -, wherein the alkyl chain is optionally substituted by trifluoromethyl, (NC) -alkyl of 1 to 6 carbon atoms-, (R Rn N -) - alkyl having from 1 to 6 carbon atoms-, (alkyl having from 1 to 6 carbon atoms) -SO2- (from 1 to 6 carbon atoms) -, wherein R9, R 10 and R n each, independently, is an H atom or an alkalyl radical of 1 to 6 carbon atoms; phenyl optionally substituted with one, two or three substituents, each independently selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted with halogen, hydroxyalkyl of 1 to 6 carbon atoms, cyano or a group - (C = O) -R2a, wherein R2a is an alkyl radical of 1 to 6 carbon atoms; or a 5-6 or 7-membered saturated or unsaturated heterocyclic ring, directly attached to the quinazolinone ring or linked through an alkyl radical of 1 to 6 carbon atoms-, containing one, two or three heteroatoms which are selected from the group consists of N, O and S, and optionally substituted with one, two or three substituents which are selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo , R 10 RnN-, R 9 -O- (C = O) -, - (C = O) -N-R 10 R n, = O and phenyl; R3 is selected from the group consisting of (a ') a phenyl radical substituted with one, two or three substituents, wherein each is independently selected from the group consisting of halogen radicals, alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted with halogen, hydroxyalkyl of 1 to 6 carbon atoms, cyano or a group -C (= O) -R3a, wherein R3a is an alkyl radical of 1 to 6 carbon atoms; or (b '): an alkyl radical of 1 to 6 carbon atoms, (NC) -alkyl of 1 to 6 carbon atoms-, R9-O- (alkyl of 1 to 6 carbon atoms) -, R9-O - (alkyl of 1 to 6 carbon atoms) -O- (alkyl of 1 to 6 carbon atoms) -, R? 0RnN- (alkyl of 1 to 6 carbon atoms) -, R? 0RnN- (C = O ) - (alkyl of 1 to 6 carbon atoms) - or (alkyl of 1 to 6 carbon atoms) -SO2- (alkyl of 1 to 6 carbon atoms) carbon) -, wherein R9, R1 0 and Rn each is independently selected from the group consisting of an H atom or an alkylic radical of 1 to 6 carbon atoms; or an unsubstituted phenyl radical, phenyl substituted with one or two substituents selected from the group consisting of - (C 1 -C 6 -alkoxy) -, R 1 0R n N-, R 1 0 Rn N- (alkyl) radicals 1 to 6 carbon atoms) -, -SO 2 - (alkyl of 1 to 6 carbon atoms, R 9 -O- (C = O) -, wherein R 9, R y or n are as defined above, or with a phenyl radical substituted with halo or a saturated or unsaturated, 5 or 6 membered heterocyclic ring, having or not, two or three heteroatoms which are selected from the group consisting of N, O and S, and optionally including another substituent selected from the group consisting of A radical consisting of halo radicals, or substituted phenyl with three or four substituents selected from the group consisting of halo, hydroxyl, and alkali radicals of 1 to 6 carbon atoms, or a cycloalkyl ring having 3, 4 , 5 or 6 carbon atoms, directly attached to the quinazolinone ring or gone through a radical - alkyl 1 to 6 carbon atoms - and which is optionally substituted with one or two substituents which are selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo , R1 0Rn N-, R9-O- (C = O) -, - (C = O) -N-R1 0Rn, and phenyl; or benzyl, or phenyl- (alkyl of 1 to 6 carbon atoms) -, phenoxy- (alkyl of 1 to 6 carbon atoms) - or phenyl- (C = O) - (alkyl of 1 to 6 carbon atoms), optionally substituted with one, two or three substituents selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano , halo, R 10 R n N-, R 9 -O- (C = O) -, - (C = O) -N-R 10 R 11 and phenyl; or a saturated, unsaturated, 5-, 6- or 7-membered heterocyclic ring directly attached to the quinazolinone ring, or linked through a radical - alkyl of 1 to 6 carbon atoms - which contains one, two or three heteroatoms which are selected from the group consisting of N, O and S, and optionally substituted with or without, two or three substituents which are selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms of carbon, hydroxy, cyano, halo, R10Rn N-, R9-O- (C = O) -, - (C = O) -N- a 9 or 10 membered aromatic or heterocyclic fused ring, directly attached to the ring of q uinazolinone or a ring through a radical - alkyl of 1 to 6 carbon atoms - containing zero, one, two or three heteroatoms they are selected from the group consisting of N, O and S, and optionally substituted with one, two, three or four substituents which are selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6. carbon, hydroxy, cyano, halo, R10Rn N-, R9-O- (C = O) -, - (C = O) -N-R10Rn atoms and phenyl; and R5 and R6 each, independently, is a hydrogen atom, a halogen radical, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, hydroxy, alkyl of 1 to 6 carbon atoms substituted with hydroxy, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cyano, -C (= O) H- phenyl, (cycloalkyl of 3 to 6 carbon atoms) -alkyl of 1 to 6 carbon atoms, (cycloalkyl of 3 to 6 carbon atoms) -alkoxy from 1 to 6 carbon atoms), (alkoxycarbonylamino of 1 to 6 carbon atoms) -alkoxy of 1 to 6 carbon atoms) or (alkylcarbonylamino of 1 to 6 carbon atoms) -alkoxy of 1 to 6 carbon atoms, (amino acid) -alkoxy of 1 to 6 carbon atoms, (dimethylamino) -alkoxy of 1 to 6 carbon atoms or (alkoxycarbonyl of 1 to 6 carbon atoms) -alkoxy of 1 to 6 carbon atoms; R 2 is a hydrogen atom, a formyl radical, alkylcarbonyl of 1 to 6 carbon atoms or benzyl, which phenyl group is optionally substituted with 1, 2 or 3 substituents which are selected from the group consisting of halogen, alkyl, 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, hydroxy, hydroxy alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms -alkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, haloalkylthio of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms , haloalkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, haloalkylsulfonyl of 1 to 6 carbon atoms, cycloalkyl d3 3 to 6 carbon atoms, cycloalkyl of 3 to 6 atoms carbon-alkyl of 1 to 6 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, di- (C 1-6 alkyl) -amino, alkoxycarbonylamino of 1 to 6 carbon atoms, cyano, formyl and alkylcarbonyl of 1 to 6 carbon atoms, or is substituted on two adjacent carbon atoms, with radicals - O-CH2-O- or -O-CF2-O-; and R 3 and Rs taken together represent, together with the three-member portion -NCC- to which they are linked, a partially or completely unsaturated, optionally substituted, five, six, seven or eight membered heterocyclic ring, which contains 1 nitrogen atom in the ring and optionally 1 nitrogen atom in the additional ring, an oxygen or sulfur atom, or 2 additional nitrogen atoms in the ring, wherein, in the heterocyclic ring each oxygen or sulfur atom in the ring is linked to 2 ring carbon atoms, optional substituents of said heterocyclic ring, selected from the group consisting of halogen radicals, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, hydroxy-alkyl of 1 to 6 carbon atoms, C (O) -alkyl of 1 to 6 carbon atoms and oxo, in free form or in the form of a salt
2. 2. The use of a quinazolinone compound of the Formula (I) as defined in claim 1, for the manufacture of a medicament for the treatment or prevention of a disease or disorder in which the activation of the vanilloid receptor plays a role or is involved.
3. 3. A method for the treatment or prevention of a disease or disorder, wherein the activation of the vanilloid receptor plays a role or is involved, which comprises administering to a mammal in need, a therapeutically effective amount of a compound of quinazolinone of the Formula (I), as defined in claim 1.
4. 4. A pharmaceutical composition comprising a compound as defined in claim 1 of Formula I, in free form or in the form of a pharmaceutically acceptable salt, in association with a pharmaceutical vehicle or diluent.
5. 5. A compound as defined in claim 1 of Formula I, in free form or in the form of a pharmaceutically acceptable salt, for use as a medicament.
6. 6. A combination comprising a therapeutically effective amount of a compound as defined in claim 1 of Formula I, in free form or in the form of a pharmaceutically acceptable salt, and a second medicament substance, for administration simultaneous or sequential.