MX2008007362A

MX2008007362A - Trisubstituted quinazolinone derivatives as vanilloid antagonists

Info

Publication number: MX2008007362A
Application number: MX/A/2008/007362A
Authority: MX
Inventors: Beattie David; Bhalay Gurdip; John Ritchie Timothy; James Culshaw Andrew; Thomas Brain Christopher; Karol Dziadulewicz Edward; Jagdis Bala Kamlesh; Hughes Glyn; Brewer Alice
Original assignee: Novartis Ag
Priority date: 2005-12-08
Filing date: 2008-06-06
Publication date: 2008-10-03

Abstract

The present invention relates to quinazolinone compounds of the formula wherein R2, R3, R5, R6R7and R8are as defined in the specification and in the claims, in free form or in salt form, processes for their preparation and their use as pharmaceuticals, particularly in the treatment of disorders ameliorated by administration of TRPV1 antagonists.

Description

DERIVATIVES OF QUI NAZOLI NON A T RIS USTITUTIOS 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 zm. it 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) NH2, 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 carbon, R9-0- (alkyl of 1 to 6 carbon atoms) -, where the alkyl chain is optionally substituted by trifluoromethyl, (NC) -alkyl of 1 to 6 carbon atoms-, (R 0 -Rn N- ) -alkyl of 1 to 6 carbon atoms-, (alkyl of 1 to 6 carbon atoms) -S02- (alkyl of 1 to 6 carbon atoms) -, where R9, Rio and R each or no, independently, is an H atom or an alkenyl 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, alkyou of 1 to 6 carbon atoms substituted with halogen, hydroxyalkyl of 1 to 6 atoms carbon, cyano oung rupo - (C = 0) -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-, which contains one, two or three heteroatoms which are selected from the group which 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, R1 0Rn N-, R9-0- (C = 0) -, - (C = O) -N-R10Rn, = 0 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 from 1 to 6 carbon atoms substituted by halogen, hydroxyalkyl of 1 to 6 carbon atoms, cyano or a group -C (= 0) -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-, R9-0- (alkyl of 1 to 6 carbon atoms) -, Rg-0 - (alkyl of 1 to 6 carbon atoms) -0- (alkoxy of 1 to 6 carbon atoms) -, Ri0R N- (alkyl of 1 to 6 carbon atoms) -, R10R N- (C = O) - (alkyl of 1 to 6 carbon atoms) - or (alkyl of 1 to 6 carbon atoms) -S02- (alkyl of 1 to 6 carbon atoms) -, wherein R9, R1 0 and R are each selected independently 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 -C 6 -alkoxy) -, R 10 R N-, R 10 R n N- radicals (alkoxy of 1 to 6 carbon atoms) -, -S02- (alkyl of 1 to 6 carbon atoms, R9-0- (C = 0) -, where R9, R1 0 and Rn are as defined above, or with a radical phenyl substituted with halo or a 5 or 6 membered saturated or unsaturated 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 which consists 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 through a radical - alkyl of 1 to 6 carbon atoms - and which is optionally substituted with one or two substituents that are selected from the group consisting of alkylene radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, R1 0Rn N-, R9-0- (C = 0) -, - (C = O) -N-R1 0R i 1, and phenyl; or benzyl, or phenyl- (alkyl of 1 to 6 carbon atoms) -, phenoxy- (alkyl of 1 to 6 carbon atoms) - or phenyl- (C = 0) - (alkyl of 1 to 6 carbon atoms) -, optionally substituted with or without, 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 0Rn N- , R9-0- (C = 0) -, - (C = 0) -N-R10R 1 1 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 one, two or three substituents which are selected from the group consisting of alkylene radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, carbon, hydroxy, cyano, halo, R 1 0R N-, R 9-0- (C = 0) -, - (C = 0) -NR 0R n, = 0 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 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 atoms , hydroxy, cyano, halo, R10RnN-, R9-0- (C = 0) -, - (C = O) -N-R10R and phenyl; R7 is a hydroxy radical, esterified hydroxy, etherified hydroxy, amino, (alkyl of 1 to 6 carbon atoms) -amino, an group wherein R a is an alkyl radical of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms substituted with halogen, or a group wherein R7 is a benzyl or phenylethyl radical; ys 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 (= 0) H-phenyl, (cycloalkyl of 3 to 6 carbon atoms) -alkyl from 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) of 1 to 6 carbon atoms) -alkoxy of 1 to 6 carbon atoms; and R8 is additionally suitably a cycloalkyl radical of 3 to 6 carbon atoms) -alkyl (of 1 to 6 carbon atoms) substituted with hydroxy, phenyl-alkyl of 1 to 6 carbon atoms substituted with hydroxy, heteroaryl- alkyl of 1 to 6 carbon atoms substituted with hydroxy, alkylcarbonyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms or heteroaryl-alkyl of 1 to 6 carbon atoms carbon, in free form or in the form of a salt, provided that, in Formula (I), when R2 is selected from group (a), R3 is selected from group (b ') and when R3 is selected from the group (b), R3 is selected from the group (a ') and excluding the compounds wherein R7 is a hydroxyl radical and R5 > R6 and Re each, independently, are a hydrogen atom and R2 is an isopropyl radical and R3 is a pyridin-5-yl radical substituted at the 2-position with Cl or CN. In a further aspect of the present invention, there is also provided a compound of Formula (I), wherein R 2 is a phenyl-alkyloxycarbonylamino radical of 1 to 6 carbon atoms-alkyl and 1 to 6 carbon atoms. If at least one asymmetric carbon atom is present in a compound of Formula I, such a compound can 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, subject to the above condition. The zzzz symbol. preferably it 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 carbon atoms, for example alkyl of 1 to 4 carbon atoms. carbon. In a particularly preferred value, R2 is sopropyl. In other embodiments, R2 may preferably be NH2 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 alkyl of 1 to 4 carbon atoms, such as methyl; wherein it is preferred that the heterocyclic ring be attached 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, more preferably, methyl. Examples of suitable heterocyclic rings include pyridine, furanyl, isoxazole, pyrrolidone, imidazole, thiophene, morpholine, pyrazine, pyrrole, piperidine and thiazole wherein R 2 is a phenyl-alkoxycarbonylamino radical of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, this is suitably 1-benzyloxycarbonylaminoethyl. Preferably, R 2 is an isopropyl, ethyl, tert-butyl, hydroxyisopropyl, dimethylamino or 2-isopropenyl radical, especially isopropyl. when R 3 is an alkyl radical of 1 to 6 carbon atoms, (NC) -alkyl of 1 to 6 carbon atoms-, R 9-0- (alkyl of 1 to 6 carbon atoms) -, R 9-0- (alkyl of 1 to 6 carbon atoms) -0- (alkyl of 1 to 6 carbon atoms) -, R 1 0 R i 1 N- (alkyl of 1 to 6 carbon atoms) -, R 1 0 R n N- (C = O) - (alkyl of 1 to 6 carbon atoms) - or (alkyl of 1 to 6 carbon atoms) -S02- (alkyl of 1 to 6 carbon atoms) -, wherein R 9. R 1 and 1 1 each independently is an H atom or an alkyl radical of 1 to 6 carbon atoms, preferably it may 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 aceton itrilo; ? R9-0- (alkyl of 1 to 6 carbon atoms), for example R9-0- (alkyl of 1 to 4 carbon atoms), such as hydroxyethyl, methoxyethyl; R 10 R N- (alkyl of 1 to 6 carbon atoms) -, for example Ri 0Ri i N- (alu uMo of 1 to 4 carbon atoms) -, such as dimethylaminoethyl, methylaminoethyl; R10Ri i N- (C = O) - (alkyl of 1 to 6 carbon atoms) -, such as R 0Rn N- (C = O) - (alkyl of 1 to 4 carbon atoms), such as dimethylacetamide; R9-0- (alkyl of 1 to 6 carbon atoms) -0- (alkoxy of 1 to 6 carbon atoms) -, such as R9-0- (alkyl of 1 to 4 carbon atoms) -0 - (alkyl of 1 to 4 carbon atoms) -, such as hydroxyethoxyethyl; (alkyl of 1 to 6 carbon atoms) -S02- (alkyl of 1 to 6 carbon atoms) -, such as (alkyl of 1 to 4 carbon atoms) -S02- (alkyl of 1 to 4 carbon atoms) ) -, such as methylsulfonylethyl; 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 by halogen according to the above, such as phenyl substituted with halogen, for example chloro, and with R 0Ri and N- (alkoxy of 1 to 6 carbon atoms) -, for example Ri 0 ii 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 chloro 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 quinazolinone ring, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; cycloalkyl of 3 to 6 carbon atoms attached to the quinazolinone ring, through an alkyl radical of 1 to 6 carbon atoms, for example alkyl of 1 to 4 carbon atoms, such as propyl, isopropyl, ethyl or, in particular, methyl; substituted cycloalkyl of 3 to 6 carbon atoms having, for example, a single substituent selected from the group consisting of - (C = 0) OR 9, for example - (C = 0) 0-alkyl of 1 to 6 carbon atoms , such as - (C = 0) 0 -alkyl of 1 to 4 carbon atoms, for example - (C = 0) OMe or, particularly, - (C = 0) -OEt; when R3 is benzyl or phenyl (alkyl of 1 to 6 carbon atoms) -, phenoxy- (alkyl of 1 to 6 carbon atoms) - or phenyl (C = 0) - (alkyl of 1 to 6 carbon atoms) -, each as previously defined, preferably could be one of the following: benzyl; benzyl substituted with one or two substituents 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, C 1 -C 4 alkoxy example, such as methoxy, phenylethyl; phenylpropyl; phenyl (C = 0) - (alkyl of 1 to 6 carbon atoms) -, for example phenyl (C = 0) - (alkoxy of 1 to 4 carbon atoms) -, such as -CH2- (C = 0) ) -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 5- or 6-membered saturated or unsaturated heterocyclic ring, directly attached to the quinazolinone ring; ii) a 5 or 6 membered saturated or unsaturated heterocyclic ring attached to the quinazolinone ring through a methyl or ethyl ligand; iii) a 5 or 6 membered saturated or unsaturated heterocyclic ring, directly attached to the quinazolinone ring or linked to the ring q uinazolinone via 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 items i) - iii) above, substituted with a substituent selected from the group consisting of cyano, alkyl 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, halophenyl, for example fluoro- or, particularly, chlorophenyl; R9-0- (C = 0) -, for example C (0) OMe or, particularly, C (0) OEt, or = 0; v) any of items i) -iv) above, wherein the 5- or 6-membered saturated or unsaturated heterocyclic ring is selected from the group consisting of pyridine, furanyl, 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, or no or two heteroatoms that are selected from the group consisting of N, O and S; ii) a fused aromatic or heterocyclic ring of 9 or 10 members, 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 9 or 10 membered fused aromatic or heterocyclic ring, in accordance with subparagraph ii) or iii) optionally substituted with a substituent selected from the group consisting of halo, for example fluoro or, preferably chlorine, or hydroxyl; v) a fused aromatic or heterocyclic ring of 9 or 10 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 (a '), 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). carbon) -alkoxy of 1 to 4 carbon atoms; Wherein R3 is a substituted phenyl radical, wherein the substituents are preferably 4-chloro, 4-chloro-3-fluoro, 4-methyl, 4-methylcarbonyl, 4-iodo, 4-ethyl, 4-chloro-2- fluoro, 4-cyano-3-methoxy, 4-chloro-3-hydroxy, 4-chloro-3-propoxy, 4-chloro-3-methoxymethyl, 4-chloro-3-hydroxymethyl or 4-cyano. Wherein R 3 is a substituted pyridyl radical, wherein the pyridyl is preferably substituted at the 3-position and the substituent (s) are preferably 2-chloro, 2-bromo-, 2-trifluoromethyl, 2-cyano, 2-chloro -3-methyl, 2-chloro-3-hydroxy, 2-cyano-3-methoxy, 2,3-dichloro, 2-trifluoromethyl-3-methyl, 2-trifluoromethyl-3-methoxy, 2-cyano-3- methyl, 2-chloro-3-iodo or 2-methyl. Preferably, R 3 is a phenyl, pyridyl or pyrimidyl radical, wherein each ring is substituted with one or two halo, trifluoromethyl, 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, hydroxyalkyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, cyano or hydroxyl, or R3 is an indazolyl radical or 1 -oxo-indan- 5-ilo. R5 is preferably a hydrogen atom or a hydroxyl radical, more preferably, a hydrogen atom. R6 is preferably a hydrogen atom or a hydroxyl radical, more preferably, a hydrogen atom. R7 is preferably a hydroxyl or amino radical, more preferably, hydroxyl. R8 is suitably an atom of, hydrogen, 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 atoms of carbon substituted with hydroxy, alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cyano, -C (= 0) H, phenyl, (cycloalkyl of 3 to 6 carbon atoms) -alkyl of 1 to 6 carbon atoms(C 3 -C 6 -cycloalkyl) -alkoxy of 1 to 6 carbon atoms, (C 1 -C 6 -alkoxycarbonylamino) -alkoxy of 1 to 6 carbon atoms or (C 1 -C 6 -alkyl) alkoxy carbon) -alkoxy of 1 to 6 carbon atoms, (amino) -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. R8 is also, suitably, a hydrogen atom, - a phenyl radical, - an alkyl radical of 1 to 6 carbon atoms substituted with hydroxy, for example, 1-hydroxypropyl, 1-hydroxyethyl, 1-hydroxy- 2-methylpropyl, 1-hydroxybutyl, 1-hydroxy-2-methylpropyl, 1-hydroxy-2,2-dimethylpropyl, hydroxymethyl or 1-hydroxy-1-methyl-ethyl (3-6-carbon-cycloalkyl) -alkyl 1 to 6 carbon atoms substituted with hydroxy, wherein the cycloalkyl radical is selected from cyclopropyl, cyclobutyl and cyclohexyl, and wherein the alkyl radical substituted with hydroxyl, suitably, is 1-hydroxymethyl, phenyl-alkyl from 1 to 6 carbon atoms substituted with hydroxy, for example 1-hydroxyphenylethyl or 1-hydroxybenzyl, heteroaryl-alkyl of 1 to 6 carbon atoms substituted with hydroxy, for example 1-hydroxy-2- or 3-pi Imethyl, alkylcarbonyl of 1 to 6 carbon atoms, for example ethylcarbonyl, propylcarbonyl, isoprop ilcarbonyl or methylcarbonyl, -alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, for example methoxyethoxy, or heteroarylalkyl of 1 to 6 carbon atoms, for example 2-pyridylmethyl. R8, more preferably, is a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms substituted with hydroxy, for example hydroxymethyl, 1-hydroxyethyl or 1-hydroxypropyl. The term "alkoxy of 1 to 8 carbon atoms" denotes an 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 straight or branched chain; for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or ferf-butyl. The term "alkenyl of 2 to 6 carbon atoms" denotes an alkenyl radical of 2 to 6 carbon atoms straight or branched chain, for example ethenyl, n-propenyl or isopropenyl. The term "C 1-6 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 may be I, Br, Cl or F. The term "esterified hydroxy" denotes an acyloxy radical, preferably an alkanoyloxy of 1 to 6 carbon atoms, more preferably an alkanoyloxy of 1. to 4 carbon atoms. The term "etherified hydroxy" denotes an alkoxy radical of 1 to 6 carbon atoms, preferably alkoxy of 1 to 4 carbon atoms. The term "heteroaryl" denotes a 5-6 membered aromatic ring comprising one or more nitrogen, oxygen and sulfur atoms in the ring, as appropriate, for example, pyridyl or pyrimidyl. The quinazolinone compounds of the present invention exist in free form or in salt form. It is to be understood that the invention includes the compounds of Formula (I) in free form or in salt form. According to an alternative aspect, there is provided a process for preparing an intermediate compound of Formula (I I), wherein Ri is an H atom or a suitable protecting group, and wherein R 2 is as described below.

The compounds of Formula (II) are useful in the preparation of compounds of the present invention or of compounds described in International Patent Publication WO 20051 2051 0, which compounds are incorporated herein, for the benefit of this invention, In its whole . A compound of the Formula (I I) can be prepared from a compound of the Formula (I I I) wherein R-, is a suitable protecting group, by a series of oxidation and reduction / acylation steps, which are illustrated in Reaction Scheme 1. Reaction Scheme 1 The International Patent Publication WO 2005120510, describes the synthesis of compounds of the Formula (II) wherein Ri is an H atom, from compounds of the Formula (III) wherein R-, is an H atom, by the methods described above. The inventors found that the overall production yield of the compound of the Formula (II) is improved when the compound of the Formula (I I) is protected in the OH position by a suitable protecting group. Suitable protecting groups include those selected from the group consisting of alkyl of 1 to 6 carbon atoms, for example methyl, aralkyl of 1 to 6 carbon atoms, for example benzyl, alkoxy of 1 to 6 carbon atoms alkyl of 1 to 6 carbon atoms, for example methoxymethyl or methoxyethoxymethyl, aralkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, for example benzyloxymethyl, trialk or ilsilylalkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 atoms! carbon, tetrahydropyranyl, trialkylsilyl having 1 to 6 carbon atoms, for example triisopropylsilyl or t-butyldimethylsilyl, or diaryl-alkylsilyl having 1 to 6 carbon atoms, for example t-butyldiphenylsilyl. A compound of the Formula (I I I) can be prepared from the corresponding compound wherein Ri is a H atom, by standard protection methods. ! With reference to the reaction Scheme, the oxidation step can be carried out directly in the methyl group, or in a dialkylaminovinyl derivative. The oxidation can be carried out with any suitable oxidation reagent, for example KM n04, under the standard conditions. The dialkylaminovinyl derivative can be prepared from the corresponding methyl derivative, by means of a treatment with the Bredrereck reagent (t-butoxy-bis (dimethylamino) -methane), under the standard conditions. The reduction step can be carried out with any suitable reducing agent, for example a metal, such as iron, zinc or tin, under normal conditions, and the acylation can be carried out with any suitable acylating agent, for example R2COCI, under the conditions standard. A compound of the Formula (I I) wherein Ri is an H atom, can be prepared from a protected form of a compound of the Formula (I I), by standard deprotection methods known to those skilled in the art. Alternatively, the protected form of a compound of Formula (I I) can be taken to the next step to prepare compounds of the invention or without deprotection, followed by deprotection as the final step. Then, a process for the manufacture of a compound of Formula (II) is provided, wherein R is an H atom or an appropriate protecting group and 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-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, R9-0- (alkyl of 1 to 6 carbon atoms) -, wherein the alkyl chain is optionally substituted with trifluoromethyl, (NC) -alkyl of 1 to 6 carbon atoms, (R 0R N -) - alkyl of 1 to 6 carbon atoms - (alkyl of 1 to 6 carbon atoms) -S02- (alkyl of 1 to 6 carbon atoms) -, where R9, R 0 and R each, independently, it is an H atom or an alkyl radical of 1 to 6 carbon atoms; phenyl optionally substituted with one, two or three substituents which are 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, hydroxy-alkyl of 1 to 6 carbon atoms, cyano or a group - (C = 0) -R2a, wherein R2a is an alkyl radical of 1 to 6 carbon atoms; or a heterocyclic ring of 5; 6 or 7 members, saturated or unsaturated, 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 of N, O and S, and optionally substituted with one, two or three substituents which are selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, R10Rn N-, R9-0- (C = 0) -, - (C = O) -N-R1 0Rn, = 0 and phenyl; from a compound of the Formula (I I I), by one of the following sequential steps: a) oxidation using a suitable oxidizing agent, reduction using a suitable reducing agent and acylation with a suitable acylating agent; or b) reduction using a suitable reducing agent, acylation with a suitable acylating agent, and oxidation using a suitable oxidizing agent; or c) transformation of the methyl group into a dialkylaminovinyl group, using a suitable agent; oxidation using a suitable oxidizing agent, reduction using a suitable reducing agent and acylation with a suitable acylating agent; or d) reduction using an appropriate reducing agent; acylation with a suitable acylating agent, transformation of the methyl group into a dialkylaminovinyl group, using a suitable agent; and oxidation using a suitable oxidizing agent, followed by optional deprotection of the protecting group, under standard conditions. The present invention also provides processes for preparing compounds of Formula (I), as defined above, in the manner illustrated in the following Reaction Schemes. The following Reaction Scheme 2 is applicable for the manufacture of a wide variety of compounds of the invention, but is exemplified by compounds wherein R 2 is isopropyl, Rs, Re and Re each are hydrogen, and R 7 is hydroxyl. Reaction scheme 2 The following Reaction Scheme 3 is applicable for the manufacture of a wide range of compounds of the invention, but is exemplified by compounds wherein R 3 is chlorophenyl, R 5, F < 6 and Re each are hydronogen and R7 is hydroxyl. Reaction scheme 3 Other compounds of Formula I can be prepared analogously to the previous one. The following Reaction Scheme 4 is applicable for the manufacture of a wide variety of compounds, but is exemplified by compounds wherein R 3 is a phenyl radical substituted with R, R 5, R 6 and R 8, wherein each of them is an atom of hydrogen and R7 is hydroxyl.

Reaction scheme 4 The following Reaction Scheme 5 is applicable for the manufacture of a wide range of compounds of the invention, but is exemplified by compounds wherein R3 is a phenyl radical substituted with R, R5, R6 and Re, of which each u is not hydrogen and R7 is hydroxyl. N-substituted R2 and R3 substituted quinazolinones.

Reaction scheme 5 Reaction Scheme 6 is applicable to a wide variety of substituents, but is exemplified by compounds wherein R3 is a phenyl radical substituted with R, R5, R6 and Rs, of which each is hydrogen and R7 is hydroxyl, to illustrate the synthesis of the substituted quinazolinones in R2 and R3: Reaction scheme 6 Reaction Scheme 7 is applicable to a wide variety of substituents, but is exemplified by compounds wherein R 3 is a phenyl radical substituted with R, R 5, R 6 and Re, of which each is a hydrogen atom and R 7 is hydroxyl , to illustrate the synthesis of substituted quinazolinones in R2 and R3: Reaction scheme 7 Reaction Scheme 8 is applicable to a wide variety of substituents, but is exemplified by compounds wherein R 3 is a phenyl radical substituted with R, R 5 and R 6, of which each is hydrogen and R 7 is hydroxyl, to illustrate the synthesis of substituted quinazolinones in R2, R3 and Reaction scheme 8 After the reaction, the steps include reducing the aldehyde or reducing it with an organometallic reagent. The hydroxyalkyl- or hydroxyaryl-hyd compound, subsequently, can be oxidized or reduced. Reaction scheme 9 is applicable to a wide variety of substituents, but is exemplified by compounds wherein R 3 is phenyl substituted with R, R 5 and R 6, of which each is a hydrogen atom and R 7 is a hydroxyl radical, illustrate the synthesis of substituted quinazolinones in R2, R3 and Ra: Reaction Scheme 9 The steps subsequent to the reaction using the compound 8-iodo-, include palladium-mediated cross coupling reactions. The processing of the reaction mixtures according to the above processes and the purification of the compounds thus obtained, can be carried out in accordance with known procedures. Acid addition salts can be produced from the free bases, in a known manner, and vice versa. The compounds of Formula (I) in optically pure form can be obtained from the corresponding racemates, in accordance with known procedures, for example CLAR with chiral matrix. Alternatively, optically pure raw materials can be used. Stereoisomeric mixtures, for example mixtures of diastereomers, can be separated into their corresponding isomers in a manner known per se by means of suitable separation methods. The diastereomeric mixtures, for example, can be separated into their individual diastereoisomers, by fractional crystallization, chromatography, solvent distribution and similar procedures. This separation can be carried out at the level of a raw material compound, or in a compound of the Formula (I) itself. The enantiomers can be separated by the formation of diastereomeric salts, for example by the formation of salts with a; chiral enantiomerically pure acid, or by chromatography, for example by CLAR, using chromatographic substrates with qiral ligands. In any additional process step, carried out in the desired manner, there may be present functional groups of the raw material compounds, which must not take part in the reaction, and which may be in unprotected form or may be protected, for example by one or more of the protective groups mentioned below. The protective groups are subsequently removed partially or completely, in accordance with any of the methods described herein. Protective groups may already be present in the precursors and should protect the desired functional groups against undesired side reactions. It is a characteristic of the protective groups, that they are eliminated quickly; that is, without unwanted sequester reactions, to be removed, typically by solvolysis, reduction, photolysis or also by enzymatic activity, for example under conditions analogous to physiological conditions, and not present in the finished products. Those skilled in the art know or can easily establish which protective groups are suitable for the reactions mentioned above and those which 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, condensing 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 temperature , normal or high, for example in the range from -100 to approximately 190 ° C, preferably from approximately -80 to approximately 150 ° C, for example at a temperature of -80 to 60 ° C, at room temperature, au 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 to the ion, 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 pharmaceutical prod ucts. In particular, the compounds of Formula (I) exhibit vanilloid antagonist activity in humans. More particularly, the compounds of Formula (I) are active in the TRPVI receptor as demonstrated by their ability to inhibit capsaiciria and / or decrease the activation by pH of the TRPVI ion channel, in the following manner: Hamster Ovary Chinese-K1 (CHO-K1), transfected to express the TRPV1 receptor either from humans, rat or guinea pig, in Minimum Essential Medium (M EM) medium alpha, without nucleoside supplement, with fetal bovine serum (at 10% ), 2 mM L-glutamine, 1 00 UI / m L of penicillin, 1 00 pg / mL of streptomycin and 350-700 pg / mL of geneticin. All reagents were provided by I nvitrogen. The cells were cultivated in T-1 75 flasks or in transparent plates of 96 or 384 wells and kept at 37 ° C in an incubator with 90% humidity, with an atmosphere of 5% C02 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 a rate of 35,000-40,000 cells per well, at 1000 ppm medium, and they cultivated overnight. Mobilization assay with calcium On the day of the assay, the medium is aspirated and the cells are washed with N-2- (hydroxyethylpiperazine-N '- [2-ethanesulfonic acid]] (H EPES) 10 mM, buffered with Balanced Saline solution. Hank (SSBH), pH 7.4.The cells are then incubated with a fluorescence-sensitive calcium-binding dye, typically fluo-4 / (from Molecular Probes), prepared in HEPES buffered with SSBH, containing pluronic F-1. 27 with or without probenecid For the pH test, the H EPES 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 The TRPV1 receptor is stimulated by the addition of capsaicin at an approximate concentration of CE8o, or a solution with low buffered pH [2- [N-morpholino] -ethanesulfonic acid (M ES) 60 μM, in SSBH], to obtain a final pH of 5.5.The cellular responses are monitored in a fluorescent plate reader, you only a Molecular Devices Flexstation device. The response in the presence of the antagonist is calculated as a 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 by 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 assay with capsaicin, the medium is aspirated and the cells are washed with 100 μl of N-2- (hydroxyethylpiperazine-N) '- [2-ethanesulfonic acid] (H EPES) 1 0 mM, buffered with Hank's Balanced Saline Solution (SSBH), pH 7.4.The cells are then incubated for 40-60 minutes with the dye of a fluo calcium ion -4 / ?? 2.3 μ? (From Molecular Probes), prepared in HEPES buffered with SSBH, containing 0.01% pluronic F-1 27 and 2 mM probenecid.For the pH test, the H EPES and pH SSBH is adjusted to 7.4 After washing twice with 1000 μl of assay buffer, the cells were incubated for 10 minutes with 1000 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 psaicin or, of a low pH. To test the effect of the compounds with respect to a possible antagonism, capsaicin was used at an approximate concentration CE8o of 0.05 μ? . 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 the antagonist Cl50 values (concentrations of the antagonist that inhibits the response either at pH 5.5 or at 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 plotted against the concentration of antagonist. The Cl50 was estimated by a non-linear regression analysis, sigmoid-logistic curves, with the Activity-Base software (v 5.0.1 0) or the M icrocal Origina software (v 7.03). These values were averaged (mean and standard error of the mean) 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. VR 1. Some disorders include, in particular, acute or chronic pain of somatic or visceral origin, inflammatory or obstructive airway 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 VR 1 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 pain io traumatic, including dental pain, for example after a third molar extraction, pain after the mastectomy and pain associated with sprains or fractures; musculoskeletal pain such as fibromyalgia; myofascial pain syndromes; headache, including migraine, acute or chronic tension headache, cluster cephalography, 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, neuropathy induced by chemotherapy, 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 nervous lesions; complex regional pain syndromes; glossodynia or burnt mouth syndrome; central nervous system pain, such as pain caused by damage to the spine or I in the 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 VI H), alcohol and narcotic abuse, pain and other symptoms associated with sunburn or UV, exposure to VR1 agonists (eg, capsaicin, acid, tear gas, heat noxious or pepper spray), picadu ras or bites of snakes, spiders or insects, and picadu ras jellyfish. 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 (SU), 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. Untreated 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, UI u rgent / mixed stress , Neurogenic UI, bladder detrusor hyperreflexia (neurogenic detrusor overactivity), detrusor instability (idiopathic detrusor overactivity), decreased bladder performance, sphincter or retral 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 gastrointestinal disorders, such as gastroesophageal reflux. The agents of the invention may also have a therapeutic benefit in inflammatory skin disorders, 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 1000 mg / kg of the animal's 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; 5HT4 receptor agonists, for example cisapride, cinitapride, mosapride, renzapride, prucalopride, tegaserod and compounds described in International Patent Publication WO 2005068461 (from 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, W0 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; neurokinin receptor antagonists, 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; i? absorbers and fiber supplements, for example whole fiber laxatives, such as bran, methylcellulose, ispaghula husk 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 I compounds described in the International Publications of i Patent WO 2002076946, WO 2004033435, WO 20051 21 1 1 6 and WO 20051 2051 0; I anticonvulsants, for example carbamazepine, oxycarbamazepine, lamotrigine, gabapentin and pregabalin; I non-steroidal anti-inflammatory drugs (FAI N Es), for example aspirin, acetaminophen, ibuprofen, diclofenac, naproxen, flurbiprofen, indomethacin, piroxicam, ketoprofenp, 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; I modulators of GABA, 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; inhibitors of the selective reuptake of serotonin, 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 d antagonists, for example almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmatriptan; and bradykinin receptor antagonists, for example compounds described in International Patent Publications WO 20000751 07, WO 2002092556 and WO 20050851 298. 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, in accordance with the present invention, can be prepared in a manner known per se and compositions suitable for enteral administration, for example oral or rectal, and parenteral administration. mammals, including humans, 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 active ingredients. Pharmaceutical preparations for combination therapy for enteral or parenteral administration, for example, are those in dosage unit dosage forms, such as tablets, including sugar-coated tablets, capsules, suppositories and ampoules. These are prepared in a manner already known, 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 by itself an effective amount, since the effective amount needed can be achieved by administering a plurality of unit doses. 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 van Iloid 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 performs a function or is involved; (3) a method for the treatment of 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 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 particulars specified above.; (7) a combination comprising a therapeutically effective amount of a compound of the 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. In the Examples which are presented below, which are not intended to limit in any way the scope of the present invention, the following abbreviations were used: The invention is illustrated by the following Examples. The following Examples were prepared using the process described herein.

Abbreviations 2-Iyer-butylimino-2-diethylammon-1, 3-BEMP dimethylperhydro-1, 3,2-diaza foforin; BOP-CI - bis (2-oxo-3-oxazolidinyl) phosphinic chloride; n-BuL-n-butyllithium; t-BuOH-t-butanol; t-BuOK - potassium ferf-butoxide; DBU-1, 8-diazabicyclo [5.4.0] -undec-7-ene; DC-dichloromethane; DMAP-4-dimethylaminopyridine; DMF -dimethylformamide; DMSO - dimethylsulfoxide; DPPP - 1,3-bis (diphenylphosphine) propane; EtOAc - ethyl acetate; EtOH-ethanol; Et20 - diethyl ether; Et3SiH-triethylsilanó; HMDS hexamedildisilazane; HOBt-1-hydroxybenzotriazole monohydrate; CLAR - High Performance Liquid Chromatography; AIP - isopropyl alcohol; MeOH-methanol; NEt3 - triethylamine; PS-EDCI-N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride supported on polymer; TFA - trifluoroacetic acid; THF - tetrahydrofuran; TIPSCI - tripropylsilyl chloride. Preparation of Specific Examples - General experimental conditions The LCMS was recorded in an Agilent 1100 LC system, with a Phenomenex Gemini C18 3.0 x 50 mm, 3 μ ?, analytical column eluting with 5-95% acetonitrile + 0.1% NH3 in water + 0.1% of NH3, for a period of 2.5 minutes, with ionization by electroaspersion with negative ions or 5-95% of acetonitrile + 0.1% of TFA in water + 0.1% of TFA, for a period of 2.5 minutes in ionization by electroaspersion with positive ions The flow rate of the mobile phase for the CLEM experiments was 1 mL min. "1. [M + H] + refers to the monoisotopic molecular weights. The preparative chiral HPLC was carried out using a Quiralpak semipreparative column. -AD, Chiralcel-OD or Chiralcel-OJ 25 cm x 20 mm, 10 μ ?, eluting with nano-hexane / EtOH, often with the addition of 0.1% TFA to the mobile phase, to improve selectivity. The separated enantiomeric pairs were arbitrarily assigned as er? F1 (for the shortest retention time) and ent2 (for the longest retention time), respectively.The microwave reactions were carried out using a microwave reactor Personal Chemistry Emrys Optimizer ™ Preparation of Intermediates: Intermediate A 2-chloro-3- (4-chlorophenyl) -7-methoxy-3H-quinazolin-4-one A1) N- (4-chlorophenyl) -4-methoxy-2-nitrobenzamide: A suspension of 4-methoxy-2-nitrobenzoic acid (2.5 g, 12.68 mmol) and sulfuryl chloride (4.6 mL, 63.2 mmol) in toluene (100 mL) was stirred at 90 [deg.] C. for 1 hour. After cooling to room temperature, the solvent was removed in vacuo and the resulting solid was treated with 4-chlorophenylamine (0.153 g, 1.19 mmol) in THF (100 ml_) and then stirred at room temperature overnight. The mixture was extracted by partion in water and ethyl acetate and the organic phase was separated, dried (MgSO 4) and concentrated in vacuo to obtain the title compound as a brown solid. (MH + 307). ! A2) 2-amino-N- (4-chlorophenyl) -4-methoxybenzamide: A suspension of N- (4-chlorophenyl) -4-methoxy-2-i-nitrobenzamide (compound A1) (2.5 g, 8.15 mmol) and iron (1.9 g, 315 mesh, 32.6 mmol) in glacial acetic acid ( 100 ml_), stirred to 60 ° C for 20 minutes. After cooling to room temperature, the mixture was diluted with water and subjected to ethyl acetate (3 times). The organic extracts were combined and the combined was dried (MgSO4) and concentrated in vacuo to obtain the title compound as an off-white solid (MH + 277). A3) 3- (4-chlorophenyl) -7-methoxy-1 H-quinazoline-2,4-dione: An orophenyl susp) -4- methoxybenzamide (compound A2) (0.1 g, 0.36 mmol) in THF (4 ml_) was treated with phosgene (510 μl of 20% w / v phosgene in toluene, 1.04 mmol) and then heated using microwave radiation in a Chemistry Emrys ™ Optimizer personal microwave reactor, at 100 ° C for 90 minutes. The resulting suspension was filtered to obtain the title compound as a white solid (Mhf 303.2). A4) 2-chloro-3- (4-chlorophenyl) -7-methoxy-3H-quinazolin-4-one: A suspension of 3- (4-chlorophenyl) -7-methoxy-1 H-quinazoline-2,4-dione (compound A3) (0.4 g, 1.32 mmol) in phosphorus oxychloride (20 ml_), was heated by microwave in a microwave reactor Personal Chemistry Emrys ™ Optimizer, at 120 ° C for 30 minutes, followed by 150 ° C for 60 minutes. The resulting mixture was concentrated in vacuo, and the resulting crude product was triturated with anhydrous diethyl ether, to obtain the title compound as a beige solid. (MH + 321.1). Intermediary B 2-methyl-5-triisopropylsilanyloxy-phenylamine B1) Triisopropyl- (4-methyl-3-nitrophenoxy) -salon: To a solution of 4-methyl-3-nitrophenol (10 g, 65.2 mmol) in DMF (30 mL), imidazole (8.89 g, 130 mmol) was added. The solution was cooled (0 ° C) and treated with a solution of triisopropylsilyl chloride (13.9 mL, 65.2 mmol) in DMF (10 mL) and stirred at room temperature overnight. The reaction mixture was poured into water (100 mL) and extracted with diethyl ether (2 x 100 mL). The organic extracts were combined and the combined was washed with water (100 mL), with citric acid (100 mL), with brine (50 mL), dried (MgSO) and concentrated in vacuo, to obtain the title compound in vacuo. shape of a yellow oil. The crude product was used in the next step without further purification. B2) 2-methyl-5-triisopropylsilanyloxy-phen sheet To a solution of triisopropyl- (4-methyl-3-nitrophenoxy) -silane (compound B1) (5 g, 16.15 mmol) in ethanol (30 mL), tin (II) chloride (18.22 g, 80.7 mmol) was added. ), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the pH adjusted to 7-8, by the addition of a sodium acid carbonate solution. An emulsion was formed which was filtered under vacuum and the product was extracted with ethyl acetate (3 x 100 mL). The organic phases were combined and the combined was washed with water (100 mL), brine (100 mL), dried (MgSO4) and concentrated in vacuo to obtain the title compound as a brown oil. The crude product was used in the next step if further purification. Intermediary C 2-Isobutyrylamino-4-triisopropylsilanyloxy-benzoic acid C1) N- (2-methyl-5-triisopropylsilanyloxy-phenyl) -isobutyramide: A solution comprising 2-methyl-5-triisopropylsilanyloxy-phenylamine (compound B2) (80 g, 0.286 mol) in DCM (500 mL) was treated with TEA (43.8 mL, 0.315 mol) and then chloride was added dropwise. isobutyryl (33 mL, 0.315 mol) in a period of 30 minutes. The resulting mixture was stirred overnight and then washed with water (2 x 200 mL), with brine (50 mL), dried (MgSO 4) and concentrated in vacuo. The crude product was dissolved in a minimum volume of boiling n-hexane and then allowed to stand at room temperature for 2 days. The resulting suspension of the product was filtered and washed with cold n-hexane, to obtain the title product as a colorless crystalline solid. C2) 2-Isobutyrylamino-4-triisopropylsilanyloxy-benzoic acid: To a hot solution of N- (2-methyl-5-triisopropylsilanyloxy-phenyl) -isobutyramide (compound C 1) (5 g, 14.3 mmol) in 2-methylpropan-2-ol / water (140 mL of a mixture 1: 1), potassium permanganate (1 1 .3 g, 71.5 mmol) was carefully added in portions over a period of 1 hour. The reaction mixture was allowed to cool to room temperature and was stirred overnight. Then, the mixture was partitioned into ethyl acetate (1 00 mL) and 2M HCl (100 mL), and stirred for 20 minutes before separation. The aqueous phase was further extracted with ethyl acetate (2 x 70 mL) and the organic phases were combined and the combined was washed with water (100 mL), with brine (100 mL), dried (MgSO4) and concentrated in vacuo to obtain the title compound. (MH + 380.4). Intermediate D 4-chloro-2-dimethylaminomethyl-phenylamine: D1) (5-chloro-2-nitrobenzyl) -dimethylamine: A solution of 5-chloro-2-nitrobenzaldehyde (1 g, 5.38 mmol) in THF (10 mL) was treated with 2M dimethylamine in THF (2.69 mL, 5.38 mmol). The solution was cooled (0 ° C) and then sodium triacetoxyborohydride (1.59 g, 7.54 mmol) was added carefully. The reaction mixture was stirred overnight and then diluted with water (50 mL). The product was extracted with ethyl acetate (3 x 50 mL) and the organic phases were combined and the combined was washed with water (50 mL), with brine (50 mL), dried (MgSO 4) and concentrated by evaporation. vacuum, to obtain the title compound in the form of a yellow oil. (MH + 215). D2) 4-chloro-2-dimethylaminomethyl-phenylamine: This compound was prepared analogously to 2-methyl-5-triisopropylsilanyloxy-phenylamine (compound B2), replacing triisopropyl- (4-methylene-3-nitrophenoxy) -silane (compound B1) by (5-chloro-2-nitrobenzyl) -dimethylamine (compound D1). Intermediate E 4-chloro-3-dimethylaminomethyl-phen plate: This compound was prepared in a manner analogous to 4-chloro-2-dimethylaminomethyl-phenylamine (Intermediary D), replacing 5-chloro-2-nitrobenzaldehyde with 2-chloro-5-nitrobenzaldehyde. Intermediate F 2-chloro-3-methyl-5-pyridyl-3-yl-amine: A mixture of 2-chloro-3-methyl-5-nitropyridine (1.0 g, 5.8 mmol) and dihydrated tin (II) chloride (6.5 g, 29.0 mmol) was refluxed in EtOH (50 μl). ) for 2 hours, The reaction mixture was concentrated in vacuo and then partitioned into CH 2 Cl 2 and 2M NaOH. The organic phase was washed with water and with brine and dried (MgSO4). The organic phase was concentrated in vacuo to obtain the title compound. (400 MHz, CDCI3) H-NMR d? 7.72 (1H, d), 6.90 (1H, d), 3.63 (2H, br s), 2.30 (3H, s). Intermediate G 5-methyl-6-trifluoromethyl-pyridin-3-l-amine: G1) 3-methyl-5-nitro-2-trifluoromethyl-pyridine: To a mixture of 2-chloro-3-methyl-5-nitropyridine (2.0 g, 11.6 mmol) and copper powder (4.4 g, 69.6 mmol) in dimethylacetamide (20 ml_), was added dibromodifluoromethane (5 mL, 54.8 mmol ). The reaction mixture was heated at 100 ° C for 18 hours. The reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with water and with brine, dried (MgSO 4), then concentrated in vacuo. The crude material was purified by flash chromatography on silica gel, using isohexane / EtOAc (50: 1 to 25: 1) as eluent, to obtain the title compound (400 MHz CDCl 3) 1 H-NMR d? 9.32 (1H, d), 8.49 (1H, d), 2.69 (3H, s).

G2) 5-methyl-6-trifluoromethyl-pyrid i -3-i-amine: The title compound was prepared analogously to Intermediate F, replacing 2-chloro-3-methyl-5-nitropyridine with 3-methyl-5-nitro-2-trifluoromethyl-pyridine (compound G1). 1H-NMR d? (400 MHz CDCI3) 7.93 (1H, d), 6.83 (1H, d), 3.95 (1H, bs), 2.40 (3H, s). Intermediate H 5-methoxy-6-trifluoromethyl-pyridin-3-ylamine: The title intermediate was prepared analogously to 5-methyl-6-trifluoromethyl-pyridin-3-yl-amine (Intermediate G), replacing 2-chloro-3-methyl-5-nitropyridine with 2-chloro-3. -methoxy-5-nitropyridine. H-NMR d? (400 MHz CDCI3) 7.70 (1H, d), 6.60 (1H, d), 4.04 (1H, br s), 3.89 (3H, s). Intermediate I 5-amino-3-methyl-pyridine-2-carbonitrile: 11) 3-methyl-5-nitropyridine-2-carbonitrile: A mixture of 2-chloro-3-methyl-5-nitropyridine (1.0 g, 5.8 mmol) and copper (I) cyanide in dimethylacetamide (4 mL), in a microwave reaction vessel, was heated by microwave 200 ° C for 2 hours. The reaction mixture was partitioned into EtOAc and water, and then filtered to remove the insoluble material. The organic phase was washed with brine, dried (MgSO 4) and concentrated in vacuo. Purified by flash chromatography on silica gel using isohexane / EtOAc (10: 1) as eluent, to obtain the title compound. 1H-NMR d? (400 MHz, CDCl 3) 9.37 (1H, d), 8.51 (1H, d), 2.73 (3H, s). 12) 5-amino-3-methylpyridine-2-carbonitrile: The title compound was prepared analogously to Intermediate F, replacing 2-chloro-3-methyl-5-nitropyridine with 3-methyl-5-nitropyridine-2-carbonitrile (compound 11). 1H-NMR d? (400 MHz, CDCl 3) 7.98 (1H, d), 6.82 (1H, d), 4.14 (2H, br s), 2.47 (3H, s). Intermediate J 5-amino-3-methoxy-pyridine-2-carbonitrile: The title broker was prepared in accordance with the U.S. Patent Application No. US 2004/0077605 A1 (p281), starting with 3-methoxypyridine. (400 MHz, CDCI3) H-NMR d? 7.72 (1H, d), 6.50 (1H, d), 4.27 (2H, br s), 3.92 (3H, s). Intermediate K 5-amino-3-methoxy-pyridine-2-carbonitrile: K1) 2-chloro-3-iodo-5-nitropyridine: 2-Hydroxy-3-iodo-5-nitropyridine (2.0 g, 7.52 mmol) was added to a mixture of POCI3 (0.7 mL, 7.52 mmol) and quinoline (0.44 mL_, 3.76 mmol) at room temperature. The reaction mixture was heated at 1-20 ° C for 2 hours. Then, the reaction mixture was cooled to 96 ° C and the reaction was carefully stopped by the dropwise addition of water (32 mol). The reaction mixture was cooled to room temperature and filtered. The collected solid was dissolved in EtOAc and dried (MgSO 4) and then concentrated in vacuo to obtain the title compound. K2) 5-amino-3-methoxypyridine-2-carbonitrile: The title intermediate was prepared analogously to intermediate F, replacing 2-chloro-3-methyl-5-nitropyridine with 2-chloro-3-iodo-5-nitropyridine (compound K1). Intermediate L 4-chloro-3-propoxy-phen sheet: 1 - . 1-Chloro-4-nitro-2-propoxy-benzene A mixture of 2-chloro-5-nitrophenol (500 mg, 2.89 mmol), 1-bromopropane (355 mg, 2.89 mmol) and potassium carbonate (593 mg, 4.34 mmol), was heated in 2-butanone (10 mL) at 40 ° C for 2 hours. The reaction mixture was diluted with 1N NaOH (20 mL) and subjected to extraction with CH2Cl2 (2 x 40 mL). The organic phase was dried (MgSO 4) and concentrated in vacuo to obtain the title compound: L2) 4-chloro-3-propoxyphenylamine: To a solution of 1-chloro-4-nitro-2-propoxybenzene (compound L1) (500 mg, 2.33 mmol) in glacial acetic acid (30 mL), powdered iron (384 mg, 6.98 mmol) was added. The reaction mixture was heated at 60 ° C for 2 hours. The reaction mixture was concentrated in vacuo, diluted with water (60 mL) and subjected to extraction with EtOAc (3 x 50 mL). The organic phases were combined and the combined dried (MgSO 4) and concentrated in vacuo to obtain the title compound. [M + H] + 1 86. Intermediate M 3- (4-chloro-3-chloromethyl-phenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one: M 1) (5-amino-2-chlorophenyl) -methanol The title intermediate was prepared analogously to intermediate F, replacing 2-chloro-3-methyl-5-nitropyridine with (2-chloro-5-nitrophenyl) -methanol. M2) 3- (4-chloro-3-chloromethyl-phenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one: The title intermediate was prepared analogously to Example 4, replacing 4-chloro-3-fluorophenollamine with (5-amino-2-chlorophenyl) -methanol (compound M1), to obtain the title compound. N 2 -pyridyllithium intermediate: To a solution of 2-bromopyridine (30.5 μ? _, 0.32 mmol) in anhydrous Et20 (10 ml_) at -78 ° C, n-BuLi (128 μ? _, 0.32 mmol; 2.5M in hexane) was added dropwise. ), in a period of 5 minutes. The orange solution was stirred at -78 ° C for 10 min. and then it was used as a solution for the next reaction. Intermediary O 3-pyridyllithium: The title compound was prepared analogously to intermediate N, replacing 2-bromopyridine with 3-bromopyridine. Intermediate P 2-amino-N- (4-chlorophenyl) -4-methoxybenzamide: P1) 4-Methoxy-2-nitrobenzoyl chloride: To a suspension of 4-methoxy-2-nitrobenzoic acid (8.0 g, 40.5 mmol) in CH 2 Cl 2 (250 mL) containing DM F (2 drops), oxalyl chloride (3.8 mL, 44.6 mmol) was added dropwise. The suspension was stirred at room temperature for 2 hours. The reaction solvent was removed in vacuo to obtain the title compound as a white solid. P2) N- (4-chlorophenyl) -4-methoxy-2-nitrobenzamide: To a solution of 4-methoxy-2-nitrobenzoyl chloride (Compound P 1) (8.8 g, 40.8 mmol) in TH F (200 mL) at room temperature, 4-chloroaniline (5.73 g, 44.9 mmol) was added. ). The reaction mixture was stirred at room temperature for 1 8 hours. E | The reaction solvent was removed in vacuo to obtain the title compound. P3) 2-amino-N- (4-chlorophenyl) -4-methoxybenzamide: To a suspension of N- (4-chloropheyl) -4-methoxy-2-nitrobenzamide (compound P2) (7.8 g, 25.4 mmol) in EtO H (1 25 ml_), tin (II) chloride dihydrate (28.7 g, 1 27 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (350 mL) and basified to pH 7 with a saturated solution of NaHCO 3. The suspension was allowed to settle and the supernatant was decanted and extracted with EtOAc (2 x 200 mL). The organic phases were combined and the combined dried (MgSO 4) and concentrated to dryness in vacuo to obtain the title compound. [M + H] + 277. Intermediate Q 2- (2, 2-dimethylpropionylamino) -4-methoxybenzoic acid: To a solution of 2-amino-4-methoxybenzoic acid (500 mg, 2.9 mmol) and triethylamine (560 μl, 4 mmol), in CH2Cl2 (5 mL), pivaloyl chloride (370 μl) was added dropwise. 4 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (10 mL), the organic phase was separated and dried (MgSO4). The reaction mixture was concentrated in vacuo to obtain the title compound. [+ H] + 252. Intermediate R 2- (2-Hydroxy-2-methy1propylamino) -4-triisopropylsilanyloxy-benzoic acid: R1) 2, 2, 2-trifluoro-N- (2-methyl-5-triisopropylsilanyloxy-phenyl) -acetamide: To a solution of 2-methyl-5-triisopropylsilanyloxy-phenylamine (compound B2) (7.35 g, 26.3 mmol) in CH 2 Cl 2 (100 mL), pyridine (2.29 g, 29.0 mmol) was added at room temperature. The reaction mixture was cooled to 0 ° C in an ice bath and trifluoroacetic anhydride (6.09 g, 29.0 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, with stirring for 1 hour. The reaction mixture was diluted with water and subjected to extraction with CH2Cl2. The organic phase was washed with an aqueous solution of 0.1M HCl, with water and with brine, and dried (MgSO4). The reaction mixture was concentrated in vacuo and then purified by flash chromatography on silica gel, using isohexane / EtOAc (10: 1) as eluent, to obtain the title compound. (400 MHz, CDCl 3) 1 H-NMR d? 7.64 (1H, br s), 7.52 (1H, d), 7.07 (1H, d), 6.72 (1H, d I of d), 2.23 (3H, s), 1.29 (3H, m), 1.10 (18H, d). ! R2) 2- (2,2,2-Trifluoroacetylamino) -4-triisopropylsilanyloxy-benzoic acid: i IIA a solution of 2,2,2-trifluoro-N- (2-methyl-5-triisopropylsilanyloxy-phenyl) -acetamide (8.0 g, 21.3 mmol) (compound R1) in t-BuOH (125 mL) and water ( 100 mL), cooled to CPC in an ice bath, KMn04 (16.8 g, ^ 07 mmol) was added portionwise. The reaction mixture was allowed to warm to room temperature I with stirring for 16 hours. The reaction mixture was treated with HCl 2M (200 mL) and stirred at room temperature for 10 minutes. It was diluted with EtOAc (400 mL) and filtered through Celite ™ (filter agent). The organic phase was separated, washed with water and with brine, and dried (MgSO4). The solvent was removed in vacuo to obtain the title compound. (400 MHz, CDCI3) H-NMR d? 12.15 (1H, s), 8.29 (1H, d), 8.10 (1H, d), 6.78 (1H, d of d), 1.35 (3H, m), 1.15 (18H, d). R3) 2-amino-4-triisopropylsilanyloxy-benzoic acid: To a solution of 2- (2,2,2-trifluoroacetylamino) -4-triisopropylsilanyloxy-benzoic acid (6.60 g, 16.3 mmol) (compound R2) in MeOH (50 ml_) at room temperature was added an aqueous solution of 10% K2C03 (10 ml_). The reaction mixture was stirred at room temperature for 16 hours. Then more aqueous 10% K2C03 solution (20 ml_) was added and the reaction mixture was heated at 50 ° C for 6 hours. The solution was neutralized to pH 7 with 2M HCl and extracted with EtOAc. The organic phase was washed with water and with brine, and dried (MgSO4). The solvent was removed in vacuo to obtain the title compound. (400 MHz, CDCI3) H-NMR d? 7.82 (1H, d), 6.24 (1H, d of d), 6.15 (1H, d), 1.30 (3H, s), 1.12 (18H, d). R4) 2- (2-Acetoxy-2-methylpropionylamino) -4-triisopropylsilanyloxy-benzoic acid: To a solution of 2-amino-4-triisopropylsilanyloxy-benzoic acid (550 mg, 1.78 mmol) (compound R3) in anhydrous pyridine ( 5 ml), a solution of 1-chlorocarbonyl-1-methylethyl acetate (293 mg, 1.78 mmol) in CH 2 Cl 2 (2 ml) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned into CH2Cl2 and 1M HCl. The organic phase was washed with water and with brine and dried (MgSO4). The reaction mixture was concentrated in vacuo and then purified by flash chromatography on silica gel, using isohexane / EtOAc (2: 1) as eluent. (400 MHz, CDCl 3) 1 H-NMR d? 12.52 (1H, s), 8.40 (1H, d), 8.00 (1H, d), 6.61 (1H, d of d), 2.20 (3H, s), 1.75 (6H, s), 1.33 (3H, m) , 1.13 (18H, d). R5) 2- (2-Hydroxy-2-methylpropionylamino) -4-triisopropylsilanyloxy-benzoic acid: a solution of 2- (2-acetoxy-2-methylpropionylamino) -4-triisopropylsilanyloxy-benzoic acid (300 mg, 0.69 mmol) (compound R4) in MeOH (10 ml_), was added K2C03 (284 mg, 2.06 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned into EtOAc and 1M HCl. The organic phase was washed with water and with brine, and dried (MgSO4). The solvent was removed in vacuo, and the crude product was triturated with isohexane / EtOAc (3: 1), to obtain the title compound. [M + H] + 396. Intermediate S 2-amino-N- (4-cyanophenyl) -4-methoxybenzamide: S1) 4-methoxy-2-nitrobenzoyl chloride To a solution of 4-methoxy-2-nitrobenzoic acid (10.0 g, 51 mmol) in CH2Cl2 (500 mL), oxalyl chloride (4.8 mL, 54 mmol) was added dropwise, followed by DMF (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction solvent was removed in vacuo to obtain the title compound. S2) N- (4-cyanophenyl) -4-methoxy-2-nitrobenzamide: To a solution of 4-methoxy-2-nitrobenzoyl chloride (5.1 1 g, 23.7 mmol) (compound S1) in CH2Cl2 (200 ml_) cooled to 0 ° C, was added 4-aminobenzonitrile (2.94 g, 24.9 mmol ), followed by triethylamine (6.9 ml_, 50 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 2M HCl, with water, followed by a saturated solution of NaHCO 3. S3) 2-amino-N- (4-cyanophenyl) -4-methoxybenzamide: To a solution of N- (4-cyanophenyl) -4-methoxy-2-nitrobenzamide (Compound S2) (6.57 g, 22 mmol) in MeOH (250 ml_), ammonium formate (3.86 g, 220 mg) was added. mmol), followed by palladium on 10% carbon. The reaction mixture was heated to reflux temperature and then stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite ™ (filtering agent) and concentrated in vacuo. The residue was dissolved in EtOAc, washed with water, dried (MgSO 4) and concentrated in vacuo. Purification was carried out using an Isolute ™ SCX cartridge (cation exchange), eluting with N H 3 2 N / MeOH, to obtain the title compound. Intermediate T N- (4-chlorophenyl) -2- (2-methyl-acryloylamino) -4-triisopropylsilanyloxy-benzamide: A suspension of 4-methoxy-2-nitrobenzoic acid (1.0 g, 50.72 mmol) in 48% H Br in aqueous solution (1 00 mL) and glacial acetic acid (1 00 mL) was heated to 1 30 ° C. for 16 hours. Then, the reaction mixture was heated at 150 ° C for 6 hours.

The reaction mixture was partially concentrated in vacuo, filtered and I dissolved in EtOAc. It was washed with a saturated solution of NaHCO 3 (1000 m I), and with brine (100 μl), and dried (MgSO 4). The mixture was concentrated in vacuo to obtain the title compound as a white solid. T2) Chloride of 4-hydroxy-2-nitrobenzoyl: The title compound was prepared analogously to intermediate S1, replacing 4-methoxy-2-nitrobenzoic acid with 4-hydroxy-2-nitrobenzoic acid (compound T1). The reaction mixture was concentrated in vacuo and used crude in the next step. T3) N- (4-chlorophenyl) -4-hydroxy-2-nitrobenzamide: E-1 1 961 - 127 DB To a solution of 4-chloroaniline (2.1 g, 16.4 mmol) in CH2Cl2 (25 mL), a solution of 4-hydroxy-2-nitrobenzoyl chloride (3.3 g, 16.4 mmol) (compound T2) in CH2Cl2 was added slowly. . Triethylamine (1.66 g, 6.4 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with CH2Cl2 and with water, and then filtered through Celite ™ (filter agent). The organic phase was washed with water and with brine, and dried (MgSO4). The mixture was concentrated in vacuo to obtain the title compound. T4) N- (4-chlorophenyl) -2-nitro-4-triisopropylsilanyloxy-benzamide: To a solution of N- (4-chloropheryl) -4-hydroxy-2-nitrobenzamide (2.4 g, 8.2 mmol) (compound T3) and imidazole (1.12 g), 16.4 mmol) in anhydrous DMF (20 mL) at room temperature, TIPSCI (1.58 g, 8.2 mmol) was added slowly. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was subjected to extraction by partition in Et20 and 0.5M HCl. The organic phase was washed with water and with brine, and dried (MgSO4). The mixture was concentrated in vacuo and purified by flash chromatography on silica gel, using isohexane / EtOAc (10: 1) as eluent, to obtain the title compound. (400 MHz, CDCI3) 1 H-R N d? 7.58 (2H, d), 7.51 (1H, d), 7.47 (1H, d), 7.37 (1H, d), 7.20 (1H, d of d), 1.32 (3H, m), 1.14 (18H, d) .; T5) 2-amino-N- (4-chlorophenyl) -4-triisopropylsilanyloxy-benzamide: To a solution of N- (4-chlorophenyl) -2-nitro-4-triisopropylsilanyloxy-benzamide (1.2 g, 2.68 mmol) (compound T4) in EtOH (50 μl), tin (II) chloride dihydrate (3.0 g, 13.4 mmol) was added. The reaction mixture was subjected to reflux temperature for 2 hours. The solvent was removed in vacuo and the residue partitioned into CH2Cl2 and 2M NaOH. The organic phase was washed with water and with brine and dried (MgSO4). The mixture was concentrated in vacuo and purified by flash chromatography, using isohexane / EtOAc (10: 1) as eluent. (400 MHz, CDCl 3) 1 H-NMR d? 7.62 (1H, s), 7.51 (2H, d), 7. 34 (3H, m), 6.27 (1H, d of d), 6.22 (1H, d), 5.61 (2H, s), 1.29 (3H, m), 1.13 (18H, d). T6) N- (4-chlorophenyl) -2- (2-methylacryloylamino) -4-triisopropylsilanyloxy-benzamide: To a solution of 2-amino-N- (4-chlorophenyl) -4-triisopropylsilanyloxy-benzamide (100 0.24 mmol) (compound T5) and triethylamine (48 mg, 0.48 mmol) in CH2Cl2 (10 ml_), was added dropwise methacryloyl chloride (37 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with CH2Cl2, washed with 1M HCl, with water, with a saturated solution of NaHCO3 and with brine, and dried (MgSO4). The mixture was concentrated in vacuo to obtain the title compound. (400 MHz, CDCI3) H-NMR d? 11.60 (1H, s), 8.40 (1H, d), 7.77 (1H, s), 7.53 (3H, m), 7.38 (2H, d), 6.64 (1H, d of d), 6.00 (1H, s) , 5.51 (1H, s), 2.10 (3H, s), 1.32 (3H, m), 1.13 (18H, d). Intermediary U 2-Butyrylamino-6-methoxybenzoic acid: The title intermediate was prepared analogously to Intermediate Q, replacing 2-amino-4-methoxybenzoic acid with 2-amino-6-methoxybenzoic acid and pivaloyl chloride with isobutyryl chloride, respectively. Intermediate V 2-amino-N- (4-chlorophenyl) -4,6-dimethoxybenzamide: To a solution of 2,4-dimethoxy-6-nitrobenzoic acid (4.0 g, 17.62 mmol) in MeOH (40 mL) and DMF (4 mL), palladium on charcoal 10% (0.8 g) was added. The reaction mixture was subjected to catalytic hydrogenation (0.35 bar) for 24 h at room temperature. The reaction mixture was filtered through Celite ™ (filtering agent) and the filtrate was concentrated to dryness in vacuo to obtain the title compound. [M + H] 198. V2) 5,7-dimethoxy-1 H-benzo [d] [1,3] oxazin-2,4-dione: To a solution of 2-amino-4,6-dimethoxybenzoic acid (4.0 g, 20.3 mmol) (compound V1) in THF (60 mL), under a nitrogen atmosphere and cooled to 0 ° C, was added triphosgene (1 .8 g, 6.1 mmol). The reaction mixture was allowed to warm to room temperature with stirring for 2 hours. The reaction mixture was slowly poured into an ice-water mixture (70 mL), then filtered and washed with water to obtain the title compound. [M + H] + 224. V3) 2-amino-N- (4-chlorophenyl) -4,6-dimethoxybenzamide: To a solution of 5,7-dimethoxy-1H-benzo [d] [1,3] oxazin-2,4-dione (500 mg, 2.2 mmol) (Compound V2) in dimethylacetamide (5 mL) was added. DMAP (26.8 mg, 0.22 mmol) was added followed by 4-chloroaniline (71 1 mg, 5.6 mmol). The reaction mixture was heated at 1110 ° C for 16 hours. The reaction mixture was diluted with water (50 mL), extracted with EtOAc, washed with brine and dried (MgSO4). The mixture was concentrated in vacuo and dried under high vacuum for 16 h, to obtain the title compound. [M + H] + 307. Intermediate W 4-Hydroxy-2-isobutyrylamino-5-methoxybenzoic acid: W1) 2-amino-4-hydroxy-5-methoxybenzoic acid: A solution of 4-benzyl-5-methoxy-2-nitrobenzoic acid (5.0 g, 16.48 mmol) in MeOH (100 ml_) containing palladium in 10% carbon (0.5 g) was subjected to catalytic hydrogenation (0.35 bar) at room temperature for 2 hours. The reaction mixture was filtered through Celite ™ (filter agent) and washed with MeOH. The filtrate was concentrated to dryness in vacuo to obtain the title compound. [M + H] + 184.! W2) 4-Hydroxy-2-isobutyrylamino-5-methoxybenzoic acid: The title intermediate was prepared analogously to Intermediate Q, replacing 2-amino-4-methoxybenzoic acid with 2-amino-4-hydroxy-5-methoxybenzoic acid (compound W1). PREPARATION OF THE EXAMPLES Example 1 3- (4-chlorophenyl) -2-d-ethylamino-7-hydroxy-3H-quinazol-n-4-one i) 3- (4-chlorophenyl) -2-diethylamino-7- methoxy-3H-quinazolin-4-one: A suspension of 2-chloro-3- (4-chlorophenyl) -7-methoxy-3H-quinazolin-4-one (Intermediate A) (0.1 1 3 g, 0.353 mmol) in diethylamine (1.5 μl) and TH F (0.5 ml_), was heated by microwave radiation in a microwave reactor. Personal Chemistry Emrys ™ Optimizer, at 1 50 ° C for 2 hours. The reaction mixture was diluted with a saturated solution of sodium hydrogen carbonate and ethyl acetate, and stirred until all the solid dissolved. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and the combined was dried (MgSO4) and concentrated in vacuo to obtain the crude product, which was recrystallized from ethyl acetate, to remove the unreacted raw material. The solid was further purified by flash chromatography on silica gel, eluting with a solvent gradient of dichloromethane / ethyl acetate (1: 00: 0, by volume), changing to dichloromethane / ethyl acetate (90: 10, by volume). , to obtain the title compound. 1 b) 3- (4-chlorophenyl) -2-diethylamino-7-hydroxy-3H-quinazolin-4-one: A solution of 3- (4-chlorophenyl) -2-diethylamino-7-methoxy-3H-quinazolin-4-one (0.057 g, 0.161 mmol) in H Br (4 mL of a 47% aqueous solution), it was heated at 1 30 ° C for 5 hours and then allowed to cool to room temperature overnight. The crude suspension was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic extracts were combined and the combined was dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel, eluting with a solvent gradient of dichloromethane / ethyl acetate (95: 5, by volume), changing to dichloromethane / ethyl acetate (50:50, by volume), to obtain the title compound in the form of a white crystalline solid. (M H + 344.2). EXAMPLE 2 ((R) -1-F3- (4-Chlorophenyl) -7-hydroxy-4-oxo-3,4-d-hydroquinoline-2-ethyl-2-carbamic acid benzyl ester 2a) Acid benzyl ester [(R) -1- (2-methyl-5-triisopropylsilanyloxy-phenylcarbamoyl) -ethyl] -carbamic acid: To a solution of (R) -2-benzyloxycarbonylamino-propionic acid (3.19 g, 14.3 mmol) in DCM (200 mL ), EDCI supported on a polymer (20.7 g, 28.6 mmol) was added, followed by HOBt (2.18 g, 14.3 mmol). The mixture was stirred gently for 30 minutes, and then treated with a solution of 2-methyl-5-triisopropylsilanyloxy-phenylamine (Intermediate B) (4 g, 14.3 mmol) in DCM (10 mL). The reaction mixture was allowed to stir gently for 3 days and then filtered to remove the polymer-supported resin. The resin was washed with DCM (100 mL) and with MeOH (100 mL) and the filtrate was concentrated in vacuo. The crude residue was dissolved in DCM (100 mL) and washed with water (100 mL) and with brine (100 mL), dried (MgSO 4) and concentrated in vacuo to obtain the title compound as an oil. dark red (MH + 485.5). 2b) 2 - ((R) -2-Benzyloxycarbonylamino-propionylamino) -4-triisopropylsilanyloxy-benzoic acid: This compound was prepared analogously to 2-isobutyrylamino-4-triisopropylsilanyloxy-benzoic acid (Intermediate C), replacing N- (2-methyl-5-triisopropylsilanyloxy-phenyl) -isobutyramide (compound C 1) with benzylester of acid [ (R) -1 - (2-Methyl-5-triisopropylsilanyloxy-phenylcarbamoyl) -ethyl] -carbamic acid (compound 2a). 2c) Acid benzyl ester. { (R) -1 - [3- (4-chlorophenyl) -4-oxo-7-triisopropylsilanyloxy-3,4-dihydroquinazolin-2-yl] -ethyl} -carbamic: A mixture of 2 - ((R) -2-benzyloxycarbonylamino-propionylamino) -4-triisopropylsilanyloxy-benzoic acid (0. 1 g, 0.204 mmol) and 4-chlorophenylamine (31.2 mg, 0.244 mmol) in MeC N (3 mL), treated with phosphorus trichloride (71 .1 μ? _, 0.816 mmol) and then heated by microwave radiation, in a Personalysmistry Emrys ™ Optimizer microwave reactor at 1000 ° C for 60 minutes. After allowing to stand at room temperature for 2 days, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phases were combined and the combined was washed with a sodium hydrogen carbonate solution and with brine, dried (MgSO4) and concentrated in vacuo to obtain a white solid. The solid was washed with hexane and filtered to obtain the title compound.

Example 3 3- (4-chlorophenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one 3a) 2-Isobutylamino-4-nitrobenzoic acid: To a cooled solution (at 0 ° C) of 2-amino-4-nitrobenzoic acid (25 g, 0.1 37 mol) in DC M (500 mL), TEA (42.0 mL, 0.302 mol) was added, followed by the dropwise addition of isobutyryl chloride (1 73 mL, 0.166 mol). After stirring at room temperature overnight, the reaction mixture was washed with a solution of sodium bicarbonate (200 mL), with a solution of ammonium chloride (200 mL) and with brine (200 mL). The organic phase was dried (MgSO 4) and concentrated in vacuo to obtain the crude product, which was purified by flash chromatography on silica gel, eluting with a solvent gradient of ethyl acetate / methanol (100: 0, in volume) changing to ethyl acetate / methanol (90: 1 O, by volume). The resulting solid was dissolved in ethyl acetate (50 mL) and washed with 1 M HCl (20 mL), dried (MgSO) and concentrated in vacuo to obtain the title compound. (M H + 253.0). 3b) 3- (4-chlorophenyl) -2-isopropyl-7-nitro-3H-quinazolin-4-one: A stirred solution of 2-isobutyrylamino-4-nitrobenzoic acid (21.3 g, 0.085 mol) in MeCN (290 mL) was treated with 4-chlorophenylamine (12.96 g, 0.10 mol), followed by more MeCN (100 mL). After stirring at room temperature for 30 minutes, phosphorus trichloride (22 mL, 0.25 mol) was added dropwise over a period of 15 minutes, and then the reaction mixture was heated at 70 ° C for 90 minutes. The solvent was removed in vacuo and the residue partitioned into ethyl acetate (300 mL) and a saturated solution of sodium bicarbonate (200 mL). The organic phase was separated, dried (MgSO 4) and concentrated in vacuo. The residue was washed with isopropyl ether (100 mL) and filtered to obtain the title compound. (MH + 344.20). 3c) 7-amino-3- (4-chlorophenyl) -2-isopropyl-3H-quinazolin-4-one: A solution of 3- (4-chlorophenyl) -2-isopropyl-7-nitro-3H-quinazolin-4-one (26.04 g, 0.076 mol) in glacial acetic acid (775 mL) was treated with iron powder (19.05 g. g, 0.34 mol) and stirred at 60 ° C for 1 hour. After cooling to room temperature, 2 M HCl was added to stop the reaction of the remaining iron powder. The solvent was removed in vacuo and a 1: 1 mixture of water / 2M HCl (500 mL) was added to the resulting residue. The mixture was extracted with ethyl acetate (3 x 500 mL) and the organic extracts were combined and the combined was dried (MgSO) and concentrated in vacuo. The residue was washed with isopropyl ether (1000 m L) and filtered to obtain the title compound. (MH + 300.2). 3d) 3- (4-chlorophenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one: A cooled mixture (at 0 ° C) comprising 7-amino-3- (4-chlorophenyl) -2-isopropyl-3H-quinazolin-4-one (1 8.57 g, 0.059 mol) in concentrated sulfuric acid / water ( 50 mL of a 2: 3 mixture), was added dropwise to a solution of sodium nitrite (6.07 g, 0.089 mol) in water (1 6.7 mL), making sure that the temperature did not rise to more than 5 ° C. The mixture was stirred for 45 minutes and then slowly treated with concentrated sulfuric acid / water (71 μL of acid / 46 mL of water). The reaction mixture was stirred and heated at 150 ° C for 2 hours and then allowed to cool to room temperature. A solution of NaOH (71 g, in 300 mL of water) was added to neutralize the mixture, which was extracted with ethyl acetate (3 x 250 mL_). The organic extracts were combined, the combined was dried (MgSO4) and concentrated in vacuo. The residue was washed with isopropyl ether (100 ml) and filtered to obtain the title compound. (M H + 301). EXAMPLE 4 3- (4-Chloro-3-fluorophenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one A mixture of 2-isobutyrylamino-4-triisopropylsilanyloxy-benzoic acid (Intermediate C) was treated. ) (0.5 g, 1.32 mmol) and 4- chloro-3-fluorophenylamine (0.21 g, 1.45 mmol) in MeCN (4 ml_), with phosphorus trichloride (0.23 ml_, 2.6 mmol) and then heated by microwave radiation in a microwave reactor Personal Chemistry Emrys ™ Optimizer, at 1 00 ° C for 80 minutes. After standing at ambient temperature for 2 days, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phases were combined, the combined was washed with a sodium acid carbonate solution and with brine, dried (MgSO4) and concentrated in vacuo to obtain a white solid. The solid was washed with hexane and filtered to obtain the title compound. [M H + 333.3]. Example 5-30 These compounds, namely 3- (6-chloropyridin-3-yl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 5), 3- (6-bromopyridine -3-yl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (400 M Hz, DMSO) 1 H-RM N d? (400 M Hz, CDCI3) 1 0.6 (1 H, s), 8.6 (1 H, s), 8.1 (1 H, d), 7.9 (1 H), 7.75 (1 H, d), 7.0-6.9 (2 H, m) , 2.55-2.4 (1H, m), 1.15-1.05 (6H, m); (compound of Example 6), 7-hydroxy-2-isopropyl-3- (6-trifluoromethyl-pyridin-3-yl) -3H-quinazolin-4-one (compound of Example 7), 7-hydroxy-2-isopropyl-3-p-tolyl-3H-quinazolin-4-one (compound of Example 8), 5- (7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin- 3-l) -pyridine-2-carbonitrile (compound of Example 9), 3- (4-acetyl-phenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 10) ), 7-hydroxy-3- (4-iodophenyl) -2-isopropyl-3H-quinazolin-4-one (compound of Example 11), 4- (7-hydroxy-2-isopropyl-4-oxo-4H) -quazolin-3-yl) -benzonitrile (compound of Example 12), 3- (2-chloropyrimidin-5-yl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 13), 3- (4-ethylphenyl) -7-hydroxy-2-ylpropyl-3H-quinazolin-4-one (compound of Example 14), 3- (4-chlorophenol) -7-hydroxy- 2-isopropyl-3H-quinazolin-4-one (compound of Example 15), hydroxy-3- (1 H -ndazol-6-yl) -2-isopropyl-3H-quinazolin-4-one (compound of Example 16), 3- (4-chloro-2-fluorophenyl) -7-hydroxy-2-isopropy-3H-quinazolin-4-one (compound of Example 17), 3- (6-chloro-5-methylpyrid) n-3-yl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-o Na (compound of Example 1 8), 3- (6-chloro-5-methoxypyridin-3-M) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 1 9), 4- (7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -2-methoxy-benzonitrile- (4-iodophenyl) -2-isopropyl-3H-quinazoline-4- ona (compound of Example 20), 3- (4-chloro-3-hydroxyphenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 21), 3- (5.6 -dichloropyridin-3-yl) -7-hydroxy-2-ylpropyl-3H-quinazolin-4-one (compound of Example 22), 7-hydroxy-2-isopropyl-3- (5-methyl-6-trifluoromethyl) -pyridin-3-yl) -3H-quinazolin-4-one (compound of Example 23), 7-hydroxy-2-isopropyl-3- (5-methyloxy-6-trifluoromethylpyridin-3-yl) - 3H-quinazolin-4-one (compound of Example 24), 5-8 / -hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -3-methylpyridine-2-carbonitrile (compound of Example 25), 5- (7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -3-methoxypyridine-2-carbonitrile (compound of Example 26), 3- (6-chloro) -5-iodopyridin-yl) -7-hydroxy-2-isopr opyl-3H-quinazolin-4-one (compound of Example 27), 3- (4-chloro-3-propoxyphenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 28), 7-hydroxy-2-isopropyl-3- (1-oxo-i nd a n-5-yl) -3H -quinazo I insula (compound of Example 29), 7-hydroxy-2-ysopropyl-3- (6 -methylpyridin-3-N) -3H-quinazoln-4-one; 1H-NMR d? (400 MHz, DMSO) 10.6 (1H, s), 8.5 (1H, d), 7.95 (1H, d), 7.85 (1H, dd), 7.45 (1H, d), 7.0-6.9 (2H, m), 2.6 (3H, s), 1.2-1.0 (7H, m) (composed of Example 30) were prepared analogously to Example 4, replacing 4-chloro-3-fluoro-phenylamine with the appropriate amine. Those that are not commercially available are described in the "Preparing intermediaries" section. Example 31 Example 31a 3- (4-Chloro-3-methoxymethyl-phenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one: A 3- (4-chloro-3-chloromethyl-phenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (Intermediate M) (100 mg, 0.28 mmol), was added MeOH / 1N NaOH, 1: 1 (10 mL). The reaction mixture was stirred at room temperature for 16 h, to obtain the title compound as the main product. [M + H] + 359. EXAMPLE 31b 3- (4-Chloro-3-hydroxymethylphenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one The title compound was prepared in accordance with the preparation of the compound of Example 31a, to obtain the title compound in the form of the minor product. [M + H] + 345. Example 32 (+/-) - 4-f7-hydroxy-8- (1-hydroxypropyl) -2-isopropyl-4-oxo-4H-quinazolin-3-ill-benzonitrile: a) 4- (8-formyl-7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -benzonitrile: SAF502-NX-2 E-12588-107 DB A mixture of 4- (7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -benzonitrile (compound of Example 12) (0.5 g, 1.64 mmol), hexamethylenetetraamine (1.63 g, 11.6 mmol) ) and glacial acetic acid (20 mL), was heated at 120 ° C for 2 hours .. The reaction mixture was concentrated in vacuo, 5M HCl (20 mL) was added and the reaction mixture was subjected to reflux temperature for 1 hour. The reaction mixture was cooled to room temperature and then emptied on ice. The solution / suspension was extracted with EtOAc, washed with water, followed by a saturated solution of NaHCO 3, brine, and dried (MgSO 4). The mixture was concentrated in vacuo to obtain the title compound. [M + H] + 334. b) (+/-) - 4- [7-hydroxy-8- (1-hydroxypropyl) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -benzonitrile: To a solution of 4- (8-formyl-7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -benzonitrile (compound of Example 32a) (0.3 g, 0.90 mmol) in anhydrous THF ( 20 mL) at 0 ° C, ethylmagnesium bromide (1.35 mL, 1 M in THF) was added. The reaction was stopped with water, and extracted with EtOAc. The organic phase was washed with water and with brine, and dried (MgSO4). The mixture was concentrated in vacuo and purified by flash chromatography on silica gel, using isohexane / EtOAc (4: 1) as eluent, to obtain the title compound. [M + H] + 364. Examples 33-56 These compounds, namely (+/-) - 5- [7-hydroxy-8- (1-hydroxyethyl) -2-isopropyl-4-oxo-4H-quinazolin -3-yl] -pyridine-2-carbonitrile (compound of Example 33), (+/-) - 5- [7-h id roxy-8- (h idroxypropyl) -2-isopropyl-4-oxo-4 H -quinazolin-3-yl] -pyridine-2-carbonitrile (compound of Example 34), (+/-) - 5- [7-hydroxy-8- (1-hydroxy-2-methylpropyl) -2-isopropyl-4 -oxo-4H-quinazolin-3-yl] -pyridine-2-carbonitrile (compound of Example 35), (+/-) - 7-hydroxy-8- (1-hydroxy-2-methylpropyl) -2-isopropyl- 3- (6-trifluoromethyl-pyridin-3-yl) -3H-quinazolin-4-one (400 MHz, DMSO) 1H-NMR d? 10.75 (1H, s), 9.0 (1H, s), 8.4 (1H, d), 8.2 (1H, d), 7.9 (1H, d), 7.0 (1H, d), 6.5 (1H, m), 5.25 (1H, m), 2.45 (1H, m), 2.15 (1H, m), 1.15 (6H, d), 0.95 (3H, d), 0.9 (3H, d); (composed of Example 36), (+/-) - 7-hydroxy-8- (1-hydroxybutyl) -2-isopropyl-3- (6-trifluoromethyl-pyridin-3-yl) -3H-quinazolin-4-one (compound of Example 37), (+/-) - 8- (cyclopropyl-hydroxymethyl) -7-hydroxy-2-isopropyl-3- (6-trifluoromethyl-pyridin-3-yl) -3H-quinazolin-4-one (composed of the Example 38), (+/-) - 4- [7-hydroxy-8- (1-hydroxy-2-methylpropyl) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -benzonitrile (compound of Example 39), (+/-) - 7-hydroxy-8- (1-hydroxy-3-methylbutyl) -2-isopropyl-3- (6-trifluoromethyl-pyridin-3-yl) -3H-quinazolin-4-one (compound of Example 40), (+/-) - 8 - (cyclobutyl-hydroxymethyl) -7-hydroxy-2-isopropyl-3- (6-trifluoromethyl) -pyridin-3-yl) -3H-quinazoline-4- ona (500 MHz, DMSO) H-NMR d? 10.65 (1H, br), 8.96 (1H, m), 8.38 (1H, m), 8.20 (1H, d), 7.89 (1H, d), 7.01 (1H, 8.70), 6.44 (1H, br), 5.46 (1H, m), 2.86 (1H, m), 2.48 (1H, m), 1.99 (2H, m), 1.80 (2H, m), 1.99-1.75 (2H, m), 1.15 (6H, m) (compound of Example 41), (+/-) - 4- [7-hydroxy-8- (1-hydroxy-3-methylbutyl) -2-isopropyl-4-oxo-4H-quinazolin-3 -yl] -benzonthylene (compound of Example 42), (+/-) - 7-hydroxy-8- (1-hydroxy-2,2-dimethylpropyl) -2-isopropyl-3 - (6-trifluoromethyl-pyridin-3-yl) -3H-quinazolin-4-one (compound of Example 43), (+/-) - 3- (4-chlorophenyl) -7- hydroxy-8- (1-hydroxy-2-phenylethyl) -2-isopropyl-3H-quinazolin-4-one (compound of Example 44), (+/-) - 5- [7-hydroxy-8- ( 1-hydroxybutyl) -2-isopropyl-4-oxo-4H-quinazoln-3-yl] -pyridine-2-carbonitrile (compound of Example 45), (+/-) - 5- [7-hydroxy -8- (1-hydroxy-2-methylpropyl) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -3-methylpyridin-2-carbonitrile (compound of Example 46), (+ / -) - 5- [7-hydroxy-8- (1-hydroxy-3-methylbutyl) -2-isopropyl-4-oxo-4H-quinazolin-3-i l] -pyridine-2-carbonitrile (compound of Example 47), (+/-) - 8- (cyclohexyl-hydroxymethyl) -7-hydroxy-2-isopropyl-3- (6-trifluoromethyl-pyridin-3-) L) -3H-quinozolin-4-one (400 MHz, DMSO) 10.7 (1H, s), 9.0 (1H, q), 8.4 (1H, m), 8.2 (1H, d), 7.9 (1H , d), 7.0 (1H, d), 6.45 (1H, bs), 5.3 (1H, s), 2.45 (1H, m), 1.9 (2H, m), 1.7 (4H, m), 1.45 (1H, m), 1.25 (3H, m), 1.1 (6H, d); (compound of Example 48), (+/-) - 3- (4-chlorophenyl) -8- (cyclohexylhydroxymethyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 49), (+/-) - 5- [8- (Cyclobutyl-hydroxymethyl) -7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl] -pyridine-2-carbonitrile ( compound of Example 50), (+/-) - 5- [7-hydroxy-8- (1-hydroxy-2,2-dimethylpropyl) -2-isopropyl-4-oxo-4H-quinazine; n-3-yl] -pyridin-2-carbonyltryl (compound of Example 51), (+/-) - 7-hydroxy-8- (1-hydroxy-2-methylpropyl) -2- isopropyl-3-p-tolyl-3H-quinazolin-4-one (compound of Example 52), (+/-) - 7-hydroxy-8- (1-hydroxy-2-methylpropyl) -2- isopropyl-3- (6-methylpyridin-3-yl) -3H-quinazolin-4-one (compound of Example 53), (+/-) - 5- [7-hydroxy-8- (1-hydroxy-2 -methylpropyl) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -3-methoxypyridine-2-carbonitrile (compound of Example 54), 0 (+/-) - 3- (4-chlorophenyl) - 7-h id roxy-8- (1-h idroxyethyl) -2-isopropyl-3 H -quinazolin-4-one; (compound of Example 55), (+/-) - 4- [7-h id roxy-8- (1-h idroxyethyl) -2-isopropyl-4-oxo-4 H -quinazolin-3-yl] -benzonitrile (composed of Example 56), were prepared analogously to the compound of Example 32, replacing 4- (6-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -benzonitrile (compound of Example 12 ) by the appropriate quinazolinone, followed by the treatment of the aldehyde formed with the appropriate Grignard reagent, under similar conditions. Example 57 Example 57a 4-r7-Hydroxy-8- (1-hydroxypropyl) -2-isopropyl-4-oxo-4H-quinazolin-3-n-benzonitrile: (ent 1) The title compound was prepared by preparative chiral HPLC of (+/-) - 4- [7-hydroxy-8- (1-hydroxypropyl) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -benzonitrile (composed of Example 32), to obtain the title compound. [M + H] + 364. Example 57b 4-f7-hydroxy-8- (1-hydroxy ropil) -2-isopropyl-4-oxo-4H-quinazolin-3-ill-benzonitrile: (ent 2) The title compound was prepared by preparative chiral HPLC of (+/-) - 4- [7-hydroxy-8- (1-hydroxypropyl) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -benzonitrile (composed of Example 30). [M + H] + 364. Examples 58-79 These compounds, namely 4- [7-hydroxy-8- (1-hydroxy-2-methylpropyl) -2-isopropyl-4-oxo-4H-quinazoline-3 -yl] -benzonitrile (ent 1) (compound of Example 58), 4- [7-hydroxy-8- (1-hydroxy-2-methyl-propyl) -2-ysopropyl-4-oxo-4H- quinazolin-3-yl] -benzonitrile (ent 2) (compound of Example 59), 7-hydroxy-8- (1-hydroxy-2-methylpropyl) -2-isopropyl-3-p-tol 1-3H-quinazolin-4-one (ent 1) (compound of Example 60), 7-hydroxy-8- (1-hydroxy-2-methylpropyl) -2-isopropyl-3-p-tol l-3H-quinazolin-4-one (ent 2) (compound of Example 61), 5- [7-hydroxy-8- (1-hydroxy-2,2-dimethylpropyl) -2 -sopropyl-4- oxo-4H-quinazolin-3-yl] -pyridyl-2-carbonitrile (ent 1) (compound of Example 62), 5- [7-hydroxy-8- (1-hydroxy-2,2-dimethylpropyl ) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -pyridine-2-carbonitrile (ent 2) (compound of Example 63), 5- [8- (cyclobutyl-hydroxymethyl) -7-hydroxy- 2-isopropyl-4-oxo-4H-quinazolin-3-yl] -pyridine-2-carbonitrile (ent 1) (compound of Example 64), | 5- [8- (Cyclobutyl-hydroxymethyl) -7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl] -pyridine-2-carbonitrile (ent 2) (compound of Example 65) 5- [7-hydroxy-8- (1-hydroxy-3-methylbutyl) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -pyridin-2-carbonitrile (ent 1) (ent 1) ( compound of the Example 66), 5- [7-hydroxy-8- (1-hydroxy-3-methylbutyl) -2-isoprbp-1-4-oxo-4H-quinazolin-3-yl] -pyridine-2-carbonitrile (ent 2) (composed of the Example 67), 5- [7-hydroxy-8- (1-hydroxy-2-methylpropyl) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -3-methylpyridine-2-carbonitrile (ent 1 ) (composed of Example 68),! 5- [7-hydroxy-8- (1-hydroxy-2-methylpropyl) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -3-methylpyridine-2-carbonyl ether (ent 2) ) (composed of Example 69), 5- [7-hydroxy-8- (1-hydroxybutyl) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -pyridine-2-carbonitrile (ent 1) (compound of Example 70), 5- [7-hydroxy-8- (1-hydroxybutyl) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -pyridine-2-carbonitrile (ent 2) (compound of Example 71), 8- (cyclobutyl-hydroxymethyl) -7-hydroxy-2-isopropM-3- (6-trifluoromethyl-pyridin-3-yl) -3 H -quinazin-4-one (ent 1) (compound of Example 72), 8- (cyclobutyl-hydroxymethyl) -7-hydroxy-2-isopropyl-3- (6-trifluoromethyl-pyridin-3-yl) -3H-quinazolin-4-one (ent 2) (ent 2) ( compound of Example 73), 7-hydroxy-8- (1-hydroxy-3-methylbutyl) -2-isopropyl-3- (6-trifluoromethylpyridin-3-yl) -3H-quinazolin-4-one (ent. 1) (compound of Example 74), 7-hydroxy-8- (1-hydroxy-3-methylbutyl) -2-isopropyl-3- (6-trifluoromethylpyridin-3-yl) -3H-quinazolin-4-one (ent 2) (compound of Example 75), 7-hydroxy-8- (1-hydroxy-2-methylpropyl) -2-isopropyl-3- (6-trifluoromethylpyridin-3-yl) -3H- quinazolin-4-one (ent 1) (compound of Example 76), 7-hydroxy-8- (1-hydroxy-2-methylpropyl) -2-isopropyl-3- (6-trifluoromethylpyridin-3-yl) -3H- quinazolin-4-one (ent 2) (compound of Example 77), 7-hydroxy-8- (1-hydroxybutyl) -2-isopropyl-3- (6-trifluoromethylpyridin-3-yl) -3H-qui Nazolin-4-one (ent 1) (compound of Example 78), 7-hydro oxy-8- (1-hydroxybutyl) -2-isopropyl-3- (6-trifluoromethylpyridin-3-yl) -3H-quinazolin-4-one (ent 2) (compound of Example 79), were prepared in a manner analogous to composed of Example 57.

Example 80 7-hydroxy-8-hydroxymethyl-2-isopropyl-3-p-tolyl-3H-quinazolin-4-one: a) 7-hydroxy-2-isopropyl-4-oxo-3-p-tolyl-3 , 4- dihydroq uinazolin-8-carbaldeh ído: The title compound was prepared analogously to the compound of Example 32a, replacing 4- (7-hydroxy-2-isopropyl-4-oxo-4H-q uinazolin-3-yl) -benzonitrile (compound of Example 1 ) by 7-hydroxy-2-isopropyl-3-p-tolyl-3H-quinazoln-4-one (compound of Example 8). [M + H] + 323. b) 7-hydroxy-8-hydroxymethyl-2-isopropyl-3-p-tolyl-3H-quinazolin-4-one To a suspension of 7-hydroxy-2-isopropyl-4-oxo-3-p-tolyl-3,4-dihydro-quinazlin-8-carbaldehyde (1000 mg, 0.29 mmol) (compound i of Example 80a) in MeOH (5 mL), NaBH'4 (11 mg, 0.29 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction was stopped with a 10% citric acid solution and extracted with CH 2 Cl 2, dried (MgSO 4) and then concentrated in vacuo. Purification by flash chromatography on silica gel, using isohexane / EtOAc (2: 1 to 4: 1) as eluent, afforded the title compound. [M + H] + 325. EXAMPLE 81 3- (4-Chlorophenyl) -7-hydroxy-8-hydroxymethyl-2-iso-pyrrol-3H-quinazolinone: The title compound was prepared analogously to the preparation of the compound of Example 80, replacing 7-hydroxy-2-isopropyl-3-p-tolyl-3H-quinazolin-4-one (compound of Example 8) with 3- (4-chlorophenyl) -7-hydroxy-2- isopropyl-3H-quinazolin-4-one (compound of Example 1 5). [M + H] + 345. EXAMPLE 82 4- (7-Hydroxy-8-hydroxymethyl-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -benzonitrile: The title compound was prepared analogously to the compound of the title compound. Example 80, replacing 7-hydroxy-2-isopropyl-3-p-toli-3H-quinazolin-4-one (compound of Example 8) with 4- (7-hydroxy-2-isopropyl-4-oxo-4H- quinazolin-3-yl) -benzonitrile (compound of Example 1 2). [M + H] + 336. EXAMPLE 83 5- (7-Hydroxy-8-hydroxymethyl-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -pyridine-2-carbonitrile: The compound of the title was prepared analogously to the compound of Example 80, replacing 7-hydroxy-2-isopropyl-3-p-tolyl-3H-quinazoln-4-one (compound of Example 8) by 5- (7-) hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -pyridine-2-carbonitrile (compound of Example 9). [M + H] + 337. EXAMPLE 84 4- (7-Hydroxy-2-isopropyl-4-oxo-8-propionyl-4H-quinazolin-3-yl) -benzonitrile: To a solution of 4- [ 7-Hydroxy-8- (1-hydroxypropyl) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -benzonitrile (compound of Example 32b) (18 mg, 0.32 mmol) in CH 2 Cl 2 (5 mL), pyridinium chlorochromate (04.04 mg, 0.49 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with Et20 (20 μL) and stirred for 5 minutes. The mixture was filtered and concentrated in vacuo. Purified by flash chromatography on silica gel, using isohexane / EtOAc (3: 1) as eluent, to yield the title compound. [M + H] + 362. Examples 85-88 These compounds, namely 5- (8-butyryl-7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -pyridin-2 -carbonitrile (compound of Example 85), 5- [7-hydroxy-2-isopropyl-8- (3-methylbutyryl) -4-oxo-4H-quinazolin-3-yl] -pyridine-2-carbonitrile (compound of Example 86), 4- (7-hydroxy-8-isobutyryl-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -benzonitrile (compound of Example 87), 7-hydroxy-8-isobutyryl-2-isopropyl -3-p-tolyl-3H-quinazolin-4-one (compound of Example 88), were prepared analogously to the compound of Example 84, replacing 4- [7-hydroxy-8- (1-hydroxypropyl) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -benzonitrile (compound of Example; 32b) by the appropriate 8- (hyd roxyalkyl) -substituted quinazoline. Example 89 (+/-) - 3- (4-chlorophenyl) -7-hydroxy-8- (hydroxyphenylmethyl) -2-isopropyl-3H-quinazolin-4-one: a) 3- (4-chlorophenyl) -7 -hydroxy-2-isopropyl-4-oxo-3,4-dihydroquinazolin-8-carbaldehyde: The title compound was prepared analogously to the compound of Example 32a, replacing 4- (7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -benzonitrile (compound of Example 1 2) by 3- (4-chlorophenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 1 5). [M + H] + 343. b) (+/-) - 3- (4-chlorophenyl) -7-hydroxy-8- (hydroxyphenylmethyl) -2-isopropyl-3H-quinazolin-4-one: QBA906-NX- 1 E-1 5985-082 KB To a solution of 3- (4-chlorophenyl) -7-hydroxy-2-isopropyl-4-oxo-3,4-dihydroquinnazoline-8-carbaldehyde (compound, 89a) (70 mg, 0.20 mmol) in THF anhydrous / Et20 (5 ml_: 1 0 ml_) at -78 ° C under a nitrogen atmosphere, phenyllithium (0.22 ml_, 0.45 mmol) was added dropwise.; 2M in Et20). The reaction mixture was warmed to room temperature and extracted with EtOAc (2 x 20 ml_). The organic phases were combined and the combined was washed with water (10 mL) and with brine (10 mL) and dried (MgSO4). It was concentrated in vacuo and then purified by flash chromatography on silica gel, using isohexane / EtOAc (5: 2) as eluent, to obtain the title compound. [M + H] + 421. Example 90 (+/-) - 3- (4-chlorophenyl) -7-hydroxy-8- (hydroxypyridin-2-yl-methyl) -2-isopropyl-3H-quinazolin-4-one: The title compound is prepared analogously to the compound of Example 89b, replacing the phenyllithium with 2-pyridyllithium (Intermediate N). [M + Hf 422. i Example 91 (+/-) - 3- (4-chlorophenyl) -7-hydroxy-8- (hydroxypyridin-3-yl-methyl) -2-isopropyl-3H-quinazolin- 4-one: The title compound was prepared analogously to the compound of Example 89b, replacing the phenyllithium with 3-pyridyllithium (Intermediate O). [M + H] + 433. Example 92 (+/-) - 3- (4-chlorophenin-7-hydroxy-8- (1-hydroxy-2-pyridin-2-yl-etin-2-isopropyl) -3H-quinazolnone: To a solution of diisopropylamine (94 μl, 0.67 mmol) in anhydrous Et20 (10 mL) at 0 ° C, n-Bu Li (268 μl) was added dropwise, 0.67 mmol; 2.5M in hexane). The reaction mixture was stirred at 0 ° C for 20 minutes, and then a solution of 2-picoline (63 μ?, 0.64 mmol) in anhydrous Et20 (3 mL) was added dropwise. The reaction mixture was stirred at 0 ° C for 1 hour and then was added to a solution of 3- (4-chlorophenyl) -7-hydroxy-2-isopropyl-4-oxo-3,4-dihydroxynazoline- 8-carbaldehyde (compound 89a) (1 00 mg, 0.29 mmol) in anhydrous THF (5 mL), under a nitrogen atmosphere at -78 ° C. The reaction mixture was stirred at -78 ° C for 2 hours. and then treated with a saturated solution of N H4CI (20 mL) and warmed to room temperature The product was extracted with EtOAc (3 x 20 mL), the organic phases s were combined and the combined was washed with water (20 mL) and with brine (20 mL), and dried (MgSO4). The mixture was concentrated in vacuo and then purified by flash chromatography on silica gel, using isohexane / EtOAc (2: 1) as eluent, to obtain the title compound. [M + H] + 435.

Example 93 4- (8-Acetyl-7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -benzonitrile: a) 4- (7-Hydroxy-8-iodo-2-isopropyl -4-oxo-4H-quinazolin-3-yl) -benzonitrile: To a suspension of 4- (7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -benzonitrile (compound of Example 1 2) (5.0 g, 1 6.4 mmol) in C H 2 Cl 2 (300 ml_) cooled to 0 ° C, N-iodosuccinimide (4.42 g, 1 9.7 mmol) was added. The reaction mixture was stirred at 0 ° C for 2 hours. The reaction mixture was poured into water and the organic phase was separated, washed with water and with brine, and dried (MgSO4). The organic phase was concentrated in vacuo to obtain the title compound. [M + H] + 432. b) 4- (8-Acetyl-7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -benzonitrile: To a solution of 4- (7-hydroxy-8-iodo-2-isopropyl-4-oxo-I 4H-quinazolin-3-yl) -benzonitrile (compound 93a) (1.0 g, 2.3 mmol) in DMF (13 ml. ), DPPP (210 mg, 0.5 mmol), potassium carbonate (368 mg, 2.80 mmol) was added, followed by butyl vinyl ether (1.5 mL) and water (2 mL). Palladium (II) acetate (52 mg, 0.23 mmol) was added and the reaction mixture was heated in a microwave oven at 80 ° C for 1 hour. More DPPP (210 mg, 0.5 mmol), potassium carbonate (368 mg, 2.80 mmol), butyl vinyl ether (1.5 mil) and palladium (II) acetate (52 mg, 0.23 mmol) was added. The reaction mixture was heated in a microwave oven at 80 ° C for 1 hour. The reaction mixture was poured into water (100 mL) and subjected to extraction with EtOAc (2 x 100 mL). The extracts were combined and the combined was washed with brine and dried (MgSO4). The mixture was concentrated in vacuo and then purified by flash chromatography on silica gel, using isohexane / EtOAc (4: 1) as eluent, to obtain the title compound. [M + H] + 348. 'Example 94' 3- (4-chlorophenyl) -7-hydroxy-8-vodo-2-isopropyl-3H-quinazolin-4-one: To a solution of 4- (8- acetyl-7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -benzonitrile (compound 93b) (100 mg, 0.29 mmol) in anhydrous THF (5 mL) under an atmosphere of nitrogen at 0 ° C, methylmagnesium bromide (192 μ ?, 0.58 mmol; 3M in Et20) was added. The reaction mixture was stirred at 0 ° C for 2 hours. The reaction was quenched with a saturated solution of NH 4 Cl, diluted with Et 20 i and filtered. The organic phase was separated, washed with brine and dried (MgSO 4). The crude material was recrystallized from MeOH, | i get the title compound. [M + H] + 364. EXAMPLE 95 8-Acetyl-3- (4-chlorophenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one: The title compound was prepared analogously to the compound of the title compound. Example 93, replacing 4- (7-hydroxy-2-isopropM-4-oxo-4H-quinazolin-3-yl) -benzonitrile (compound of Example 12) with 3- (4-chlorophenyl) -7-hydroxy- 2-isopropyl-3 H -quinazin-4-one (compound of Example 1 5). [M + H] + 35. Example 96 4- (7-Hydroxy-2-ylpropyl-8-methoxymethyl-4-oxo-4H-quinazolin-3-D-benzonitrile: a) 4- [8- formyl-2-isopropyl-7- (4-methoxybenzyloxy) -4-oxo-4H-quinazolin-3-yl] -benzonitrile: To a solution of 4- (8-formyl-7-hydroxy-2-isopropyl-4-oxo-4H-quinazol-n-3-yl) -benzonitrile (1.90 g, 5.7 mmol) (compound 32a) in DM F (40 mL) under a nitrogen atmosphere at room temperature, K2C03 (2.4 g, 7.1 mmol) was added portionwise, followed by 4-methoxybenzyl bromide (1.64 mL, 1.1.4 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (150 mL) and subjected to extraction with CH2Cl2 (2 x 80 mL). The organic phases were combined and the combined was washed with brine, dried (MgSO4) and concentrated in vacuo. The mixture was triturated with EtOAc (40 mL) and filtered to obtain the title compound. [M + H] + 454. b) 4- [8-hydroxymethyl-2-isopropyl-7- (4-methoxybenzyloxy) -4-oxo-4H-q uinazolin-3-yl] -benzonitrile: The title compound was prepared analogously to compound 80b, replacing 7-hydroxy-2-isopropyl-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-8-carbaldehyde (compound 80a) by 4- [ 8-formyl-2-isopropyl-7- (4-methoxybenzyloxy) -4-oxo-4H-quinazolin-3-yl] -benzonitrile (compound 96a). [M + H] + 456. c) 4- [2-isopropyl-7- (4-methoxybenzyloxy) -8-methoxymethyl-4-oxo-4H-quinazolin-3-yl] -benzonitrile: To a solution of 4- [8-hydroxymethyl-2-isopropyl-7- (4-methoxybenzyloxy) -4-oxo-4H-quinazolin-3-yl] -benzonitrile (compound 96b) (200 mg, 0.44 mmol) in THF anhydrous (10 ml_), sejle added NaH (26 mg, 0.66 mmol, 60% dispersion in mineral oil). The reaction mixture i was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C and Me; l (60 pL, 0.97 mmol) was added. The reaction mixture was allowed to warm to room temperature with stirring for 16 hours. Additional NaH (13.2 mg, 0.33 mmol) was added and the reaction mixture was stirred at room temperature for 15 minutes before adding Mel (30 pL, 0.49 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. The reaction was quenched with j MeOH (10 mL), concentrated in vacuo and partition extracted with EtOAc (20 mL) and water (20 mL). The organic phase was separated and dried (MgSO4). The mixture was concentrated in vacuo and then purified by flash chromatography on silica gel, using CH2Cl2 / MeOH (99: 1) as eluent, to obtain the title compound. [M + H] + 470. (d) 4- (7-hydroxy-2-isopropyl-8-methoxymethyl-4-oxo-4H-quinazolin-3-yl) -benzonitrile:! 4- [2-Isopropyl-7- (4-methoxybenzyloxy) -8-methoxymethyl-4-oxo-4H-quinazolin-3-yl] -benzonitrile (148 mg, 0.32 mmol) (compound 96c) was dissolved in 5% TFA. % / CH 2 Cl 2 (5 mL), and the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 72 hours. The reaction mixture was neutralized with a saturated solution of NaHCO 3 (10 mL) and subjected to extraction with C H 2 Cl 2 (2 x 20 mL). The organic extracts were combined and the combined was washed with brine and dried (MgSO4). The mixture was concentrated in vacuo and then purified by flash chromatography on silica gel, using isohexane / EtOAc (3: 1) as eluent, to obtain the title compound. [M + H] + 350. EXAMPLE 97 7-Hydroxy-2-isopropyl-8- (2-methoxy-ethoxymethyl) -3-p-tolyl-3H-quinazolin-4-one: A vial of microwaves was loaded with 7-hydroxy-8-hydroxymethyl-2-isopropyl-3-p-tolyl-3H-q uinazolin-4-one (1000 mg, 0.31 mmol) (compound 80b) and 2-methoxyethanol (3 mL). The reaction mixture was heated to 1 30 ° C in a microwave oven for 15 minutes. The reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel, using isohexane / EtOAc (5: 1) as eluent, to obtain the title compound. [M + H] + 383. EXAMPLE 98 7-Hydroxy-3-isopropyl-8-methoxymethyl-3-p-tolyl-3H-quinazolin-4-one: A vial of microwells was loaded with 7-Hydroxy-8-hydroxymethyl-2-isopropyl-3-p-tolyl-3H-quinazolin-4-one (1000 mg, 0.31 mmol) (compound 80b) and anhydrous MeOH (3 mL). The reaction mixture was heated to 130 ° C in a microwave oven for 10 minutes. The reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel, using isohexane / EtOAc (5: 1) as eluent, to obtain the title compound. [M + H] + 339. EXAMPLE 99 4- (7-Hydroxy-2-isopropyl-4-oxo-8-phenyl-4H-quinazolin-4-yl) -benzonitrile: To a solution of 4- (7-hydroxy) -8-iodo-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -benzonitrile (50 mg, 0.12 mmol) (compound 93a) in toluene (1 ml_), was added K2C03 (48 mg, 0.35 mmol) in water (1 mL). Phenylboronic acid (21.2 mg, 0.17 mmol) was added, followed by tetrakis (triphenylphosphine) palladium (0) (6.7 mg, 0.0058 mmol). The reaction mixture was heated in a microwave oven at 100 ° C for 30 minutes. The reaction mixture was diluted with EtOAc and water. The organic phase was separated, washed with water and dried (MgSO4). The mixture was concentrated in vacuo and then purified by flash chromatography on silica gel, using isohexane / EtOAc (4: 1 to 2: 1) as eluent. The mixture was triturated with MeOH and the solid formed was filtered to obtain the title compound. (400 MHz, CDCl 3) 1 H-NMR d? 8.22 (1H, d), 7.87 (2H, d), 7.38-7.57 (5H, m), 7.19 (1H, d), 5.93 (1H, s), 2.50 (1H, m), 1.02 (6H, d) . Example 100 4- (7-h id roxy-2-isopropyl-4-oxo-8-propyl-4H -quinazo I i n-3-P-benzonitrile: To a solution of (+/-) - 4- [ 7-Hydroxy-8- (1-hydroxypropyl) -2- isopropyl-4-oxo-4H-quinazolin-3-yl] -benzonitrile (243 mg, 0.69 mmol) (compound 32b) in anhydrous CH 2 Cl 2 (3 mL), added Et3SiH (170 μ ?, 1.06 mmol) The solution was cooled to 0 ° C and treated with TFA (1.24 mL, 16.7 mmol) The reaction mixture was heated in a microwave oven at 100 ° C for 10 minutes. minutes The reaction mixture was neutralized with a saturated solution of NaHCO 3 and; it was extracted with CH2Cl2 (2 x 20 mL). The organic phases were combined and the combined was washed with water (20 mL) and with brine (20 mL), and dried (MgSO4). The reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel, using isohexane / EtOAc (3: 1) as eluent, to obtain the title compound. [M + H] + 348. Example 101 3- (4-chlorophenyl) -7-hydroxy-2-isopropyl-8-pyridin-2-yl-methyl-3H-quinazolin-4-one: The title compound is prepared analogously to preparation 100, replacing (+/-) - 4- [7-hydroxy-8- (1-hydroxypropyl) -2-isopropyl-4-oxo-4H-quinazolin-3-yl] -benzonitrile (compound 32b) by (+/-) - 3- (4-chlorophenyl) -7-hydroxy-8j- (hydroxypyrdin-2-yl-methyl) -2-isopropyl-3H-quinazolin-4-one (compound 90). [M + H] + 406. Example 102 3- (4-chlorophenyl) -2-ethyl-7-hydroxy-3H-quinazolin-4-one: ja) 3- (4-chlorophenyl) -2-ethyl-7- methoxy-3H-quinazolin-4-one: 2-amino-N- (4-chlorophenyl) -4-methoxybenzamide (Intermediate P) (500 mg, 0.36 mmol) was suspended in triethyl orthopropionate (7 mL) and heated at 100 ° C in a microwave oven for 3 hours. The reaction mixture was further heated to 140 ° C in a microwave oven for 2 hours. The reaction mixture was allowed to stand at room temperature for 72 hours. The crystalline compound was isolated by filtration. [M + H] 315. b) 3- (4-chlorophenyl) -2-ethyl-7-hydroxy-3H-quinazolin-4-one: A suspension of 3- (4-chlorophenyl) -2-ethyl-7-methoxy-3H-quinazolin-4-one (compound 102a) (50 mg, 0.16 mmol) in 48% aqueous HBr (3 mL) was heated at 120 ° C in a microwave oven for 1 hour. The reaction mixture was cooled to room temperature, filtered and washed with water (2 x 5 mL), to obtain the title compound. [M + H] + 301. EXAMPLE 103 2-Ferbutyl-3- (4-chlorophenyl) -7-hydroxy-3H-quinazolin-4-one: a) 2-ferf-butyl-3- (4- chlorophenyl) -7-methoxy-3H-quinazolin-4- na: The title intermediate was prepared analogously to preparation 4, replacing intermediate C2 with 2- (2,2-dimethyl-propionylamino) -4-methoxybenzoic acid (intermediate Q) and 4-chloro-3-fluorophenylamine for 4. -chloroaniline, respectively. [M + H] + 343. b) 2-Fery-butyl-3- (4-chlorophenyl) -7-hydroxy-3H-quinazolin-4-one: The title compound was prepared analogously to preparation 1 02b, replacing 3- (4-chlorophenyl) -2-ethyl-7-methoxy-3H-quinazolin-4-one (compound 1 02a) with 2-ferf- butyl-3- (4-chlorophenyl) -7-methoxy-3H-quinazolin-4-one (compound 1 03a). [M + H] + 329. EXAMPLE 104 3- (4-Chlorophenyl) -7-hydroxy-2- (1-hydroxy-1-methyl-ethyl) -3H-q-uinazolin-4-one: The title compound was prepared from analogously to preparation 4, replacing 2-isobutyrylamino-4-triisopropylsilanyloxy-benzoic acid (Intermediate C) with 2- (2-hydroxy-2-methyl-propionylamino) -4-triisopropylsilanyloxy-benzoic acid (Intermediate? R) and 4-chloro-3-fluorophenylamine by 4-chloroaniline, respectively. [M + H] + 331. Example 105 '4- (2-d.ethylamino-7-hydroxy-4-oxo-4H-quinazolin-3-yl) -benzonitrile: a) 4- (7-methoxy-2,4-dioxo-1,4) -dihydro-2H-quinazolin-3-yl) -benzonitrile: To a solution of 2-amino-N- (4-cyanophenyl) -4-methoxybenzamide (500 mg, 1.87 mmol) (Intermediate! S) in CH2Cl2, triphosgene (556 mg, 1.87 mmol) was added. . The reaction mixture was heated for 1 h at 1 00 ° C in a microwave oven. The reaction mixture was cooled and washed, and the solid was washed with CH2Cl2 and dried, to obtain the title compound. Without mass spectrometry. b) 4- (2-diethylamino-7-methoxy-4-oxo-4H-quinazolin-3-yl) -benzonitrile: To a suspension of 4- (7-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -benzonitrile (293 mg, 1 mmol) (compound 1 05a) in MeCN ( 10 ml_), BOP-Cl (331 mg, 1.3 mmol) was added, followed by DBU (226 μ? _, 1.5 mmol) and diethylamine (522 μ? _, 5 mmol). The reaction mixture was heated in a microwave oven for 2 h at 80 ° C. The reaction mixture was cooled, concentrated in vacuo and the residue suspended in EtOAc. It was filtered, washed with EtOAc and the filtrate was dried (MgSO4) and concentrated in vacuo. The mixture was purified by flash chromatography on silica gel, using isohexane / EtOAc (from 10: 1 to 4: 1) as eluent, to obtain the title compound. Without mass spectrometry. c) 4- (2-diethylamino-7-hydroxy-4-oxo-4H-quinazolin-3-yl) -benzonitrile: To a solution of 4- (2-diethylamino-7-methoxy-4-oxo-4H-quinazolin-3-yl) -benzonitrile (260 mg, 0.75 mmol) (105 b) in DMF (7 mL) was added. sodium methoxide (122 mg, 2.25 mmol) and 1-dodecanethiol (612 μ ?, 2.55 mmol). The reaction mixture was heated at 100 ° C for 1 h and then cooled and diluted with water. It was extracted with EtOAc, dried (MgSO4) and concentrated in vacuo. Purified by flash chromatography on silica gel, using isohexane / EtOAc (from 10: 1 to 4: 1) as eluent, to obtain the title compound. [M + H] + 335.

EXAMPLE 106 3- (4-Chlorophenyl) -7-hydroxy-2-isopropenyl-3H-quinazolin-4-one: To a suspension of N- (4-chlorophenyl) -2- (2-methylacrylolamino) -4-triisopropylsilanyloxy- benzamide (100 mg, 0.21 mmol) (Intermediate T) in EtOH (1 mL), concentrated H2SO4 (~ 4 drops) was added and the reaction mixture was heated in a microwave oven at 100 ° C for 30 minutes. The reaction mixture was partitioned into CH2Cl2 and water and then passed through an Isolute ™ phase separator. The mixture was concentrated in vacuo and purified by flash chromatography on silica gel, using isohexane / EtOAc (2: 1), to obtain the title compound. [M + H] + 313. EXAMPLE 107 3- (4-Chlorophenyl) -2-isopropyl-5-methoxy-3H-quinazolin-4-one: The title compound was prepared in a manner analogous to preparation 4, replacing the Intermediary C2 by 2-isobutyrylamino-6-methoxybenzoic acid (Intermediate U) and 4-chloro-3-fluorophenylamine by 4-chloroaniline, respectively. [M + H] 329. EXAMPLE 108 3- (4-Chlorophenyl) -5,7-d, hydroxy-2-ylpropyl-3H-quinazolin-4-one: a) 3- (4-chlorophenyl) -2- isopropyl-5,7-dimethoxy-3H-quinazolin-4-one: A solution of 2-amino-N- (4-chlorophenyl) -4,6-dimethoxybenzamide (700 mg, 2.29 mmol) (Intermediate V) in 1,1,1-trimethoxy-2-methylpropane (5 mL) was heated at reflux temperature for 4 hours. The reaction mixture was evaporated in vacuo and purified by reverse phase chromatography (C18), using MeCN / H20 containing 0.1% TFA as eluent. It was further purified by flash chromatography on silica gel, using isohexane / EtOAc (2: 1) as eluent, to obtain the title compound. [M + H] + 359. b) 3- (4-chlorophenyl) -5,7-dihydroxy-2-isopropyl-3H-quinazolin-4-one: To a solution of 3- (4-chlorophenyl) -2-isopropyl-5,7-dimethoxy-3H-quinazolin-4-one (84 mg, 0.24 mmol) (compound 108a) in anhydrous CH 2 Cl 2 (5 mL) under a nitrogen atmosphere at 0 ° C, BBr3 was added. The reaction mixture was allowed to warm to room temperature with stirring for 4 days. The reaction mixture was cooled to 0 ° C and a saturated solution of NaHCO 3 was added. The mixture was extracted with CH2Cl2, washed with brine and dried (MgSO4). The mixture was concentrated in vacuo and purified by reverse phase chromatography (C18), using MeCN / H20 containing 0.1% TFA as eluent, to obtain the title compound. [M + H] + 331. EXAMPLE 109 3- (4-Chlorophenyl) -7-hydroxy-2-isopropyl-6-methoxy-3H-quinazolin-4-one: The title compound was prepared analogously to the compound of the title compound. Example 4, replacing Intermediary C2 with 4-hydroxy-2-isobutyrylamino-5-methoxybenzoic (Intermediate W) and 4-chloro-3-fluorophenylamine with 4-chloroaniline, respectively, to obtain the title compound. [M + H] + 345. EXAMPLE 110 3- (4-Chlorophenyl) -6,7-dihydroxy-2-ylpropyl-3H-quinazolin-4-one: A solution of 3- (4-chlorophenyl) -7-hydroxy -2-isopropyl-7-methoxy-3H-quinazolin-4-one (compound 109) (100 mg, 0.29 mmol) in 48% aqueous HBr (1.5 mL) and glacial acetic acid (1.5 mL), was heated in a Microwave oven at 100 ° C for 1 hour, followed by 130 ° C for 2 hours. The reaction mixture was cooled to room temperature and then treated with a 1 M NaOH solution until pH 6-7. The mixture was extracted with EtOAc (3 x 10 mL), the organic phases were combined and the combined was washed with brine (20 mL), dried (MgSO 4) and concentrated in vacuo. The product was recrystallized from MeCN / H20 (1: 1) (4 mL), to obtain the title compound. [M + H] + 331. Example 1 1 1 4- (7-amino-2-isopropyl-4-oxo-4H-quinazolin-3-i0-benzonitrile: The title compound was prepared analogously to the compound of Example 3, replacing 4-chloroaniline with 4-aminobenzonitrile [M + H] + 305. The following compounds, viz. 2-amino-3- (4-chlorophenyl) -7-hydroxy-3H-quinazolin-4-one (compound of Example 11) , 3- (4-chlorophenyl) -7-hydroxy-2-pyrrolidin-1-yl-3H-quinazolin-4-one (compound of Example 1 1 2), 3- (4-chlorophenyl) -7-hydroxy-2 -morpholin-4-yl-3H-quinazolin-4-one (compound of Example 1 1 3), 3- (4-chlorophenyl) -7-hydroxy-2- (2-hydroxyethylamino) -3H-quinazolin-4- ona (compound of Example 1 14), 2- (2-aminoethylamino) -3- (4-chlorophenyl) -7-hydroxy-3H-quinazolin-4-one (compound of Example 1 1 5), 5- (2- dimethylamino-7-hydroxy-4-oxo-4H-q uinazolin-3-yl) -pyridine-2-carbonitrile (compound of Example 1 16), 3- (4-chlorobenzyl) -2-dimethylamino-7-hydroxy- 3 H -quinazolin-4-one (compound of Example 1 17), 2-dimethylamino-7-hydroxy-3-isoprop l-3H-quinazolin-4-one, can be prepared analogously to 3- (4-chlorophenyl) -2-diethylamino-7-hydroxy-3H-quinazolin-4-one (compound of Example 1), replacing the diethylamine for the appropriate amine. Some of these examples may also require replacing 2-chloro-3- (4-chlorophenyl) -7-methoxy-3H-quinazolin-4-one (Intermediate A) by. an alternative raw material prepared analogously to Intermediate A, with the appropriate aniline / alkylamine, in step A1. The following compounds, namely 3- (4-chlorophenyl) -7-hydroxy-2- (2,2,2-trifluoro-1-trifluoromethylethyl) -3H-quinazolin-4-one (compound of Example 118), - (4-chlorophenyl) -7-hydroxy-2- (1-hydroxyethyl) -3H-quinazolin-4-one (compound of Example 119), 3- (4-chlorophenyl) -7-hydroxy-2- (2- hydroxy-1,1-dimethylethyl) -3H-quinazolin-4-one (compound of Example 120), 3- (4-chlorophenyl) -7-hydroxy-2- (2,2,2-trifluoro-1-hydroxymethylethyl) -3H-quinazolin-4-one (compound of Example 121), [3- (4-chlorophenyl) -7-hydroxy-4-oxo-3,4-dihydroquinazolin-2-yl] -acetonitrile (compound of Example 122) 3- (4-chlorophenyl) -7-hydroxy-2-methoxymethyl-3H-quinazolin-4-one, 3- (4-chlorophenyl) -2-dimethylaminomethyl-7-hydroxy-3H-quinazolin-4-one (compound of Example 123), 2- (1-aminoethyl) -3- (4-chlorophenyl) -7-hydroxy-3H-quinazolin-4-one, (compound of Example 124), 3- (4-chlorophenyl) -2- furan-2-yl-methyl-7-hydroxy-3H-quinazolin-4-one, (compound of Example 125), 3- (4-chlorophenyl) -7-hydroxy-2- (1-methyl-1H-imidazole) -2-il-methyl) -3H -quinazolin-4-one (compound of Example 126), 2,3-bis- (4-chlorophenyl) -7-hydroxy-3H-quinazolin-4-one (compound of Example 1 27), can be prepared analogously to the acid benzyl ester. { (R) -1 - [3- (4-chlorophenyl) -7-hydroxy-4-oxo-3,4-d ihydroquinazolin-2-yl] -ethyl} -carbamic (compound of Example 2), replacing the (R) -2-benzyloxycarbonylamino-propionic acid (3.1 9 g, 14.3 mmol) by the appropriate acid. Compounds containing free hydroxyl groups should be protected using, for example, a reagent such as triisopropylsilyl chloride, as described in the preparation of triisopropyl- (4-methyl-3-nitrophenoxy) -silane (B 1) . The following compounds, namely 3- (4-chloro-3-dimethylaminomethyl-phenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 1 28), 3- (4-chloro) -2-fluoro-5-hydroxyphenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 1 29), 3- (4-chloro-2,5-dimethoxyphenyl) -7-hyd Roxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 1 30), 3- (4-chloro-2-fluoro-3-methyl-6-trifluoromethyl-phenyl) -7-hydroxy-2-isopropyl-3H -quinazolin-4-one (compound of Example 1 31), 3- [4- (4-chlorophenyl) -thiazol-2-yl] -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 1 32), 7-hydroxy-2-isopropyl-3- (3-methylisoxazol-5-yl) -3H-q uinazolin-4-one (compound of Example 1 33), 3- (5-chlorobenzothiazole-2- il) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 1 34), 3- (5-chlorothiazol-2-yl) -7-hydroxy-2-isopropyl-3H-quinazolin -4-one (compound of Example 1 35), 7-hydroxy-2-isopropyl-3- (1-methylpiperidin-4-yl) -3H-quinazolin-4-one (compound of Example 1 36), 7-hydroxy-2-isopropyl-3-propyl-3H- quinazolin-4-one (compound of Example 1 37), 7-hydroxy-2,3-diisopropyl-3H-quinazoln-4-one (compound of Example 1 38), 7-hydroxy-3- (2- hydroxyethyl) -2-isopropyl-3H-quinozolin-4-one (compound of Example 1 39), 7-hydroxy-3- [2- (2-hydroxyethoxy) -ethyl] -2-isopropyl-3H- quinazolin-4-one (compound of Example 140), 7-hydroxy-2-isopropyl-3- (2-methylaminoethyl) -3H-quinazolin-4-one (compound of Example 141), 3-furan-3-yl- methyl-7-hydroxy-2-ylpropyl-3H-quinazolin-4-one (compound of Example 142), 7-hydroxy-2-isopropyl-3-pyridin-4-yl-methyl- 3 H -quinazin-4-one (compound of Example 143), 7-hydroxy-2-ylpropyl-3-pyridin-3-yl-methyl-3 H -quinazin-4-one (compound of Example 144), 7-hydroxy-2-isopropyl-3-pyrrolidin-1-methyl-3H-quinazolin-4-one (compound of Example 145), 7-hydroxy-2-isopropyl-3- (1-phenylethyl) -3H-quinazolin-4- ona (compound of Example 146), 7-hydroxy-2-isopropyl-3- [2- (3-methyl-3H-imidazol-4-yl) -etl] -3H-quinazolin-4-one ( compound of Example 147), 7-hydroxy-2-isopropyl-3- (2-oxo-2-phenylethyl) -3H-quinazolin-4-one (compound of Example 148), 1 - [2- ( 7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -ethyl] -pyrrole-2,5-dione (compound of Example 149), 3- (2-chlorobenzyl) -7- hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 1 50), 3-benzo [1,3] dioxol-4-yl-methyl-7-hydroxy-2-isopropyl-3H -cyanolin-4-one (compound of Example 1 51), 7-hydroxy-2-isopropyl-3-naphthalen-1-methyl-3H-q-uinazolin-4-one (compound of Example 1 52), 3- (4-iyeryl-butyl-benzyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 1 53), 3-benzothiazol-2-yl-methyl -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 1 54), 3-cyclopropylmethyl-7-hydroxy-2-isopropyl-3H-q uinazoln-4-one ( compound of Example 1 55), 3-cyclobutylmethyl-7-h idroxy-2-isopropyl-3H-quinazole in-4-one (compound of Example 1 56), 7-hydroxy-2-isopropyl-3-isoxazol-3-yl-3H-quinazolin-4-one (compound of Example 1 57), 3-cyclopentyl- 7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 1 58), 7-hydroxy-2-isopropyl-3-pyridin-4-yl-3H-quinazolin-4-one (compound of Example 1 59), 7-hydroxy-2-isopropyl-3-pyridin-2-yl-3H-quinazolin-4-one (compound of Example 160), 7-hydroxy-2-isopropyl-3-pyridine 2-yl-3H-q uinazoln-4-one (compound of Example 1 61), 7-h id roxl-2-isoprop i l-3- (3-methylisoxazol-5-yl) -3H -quinazo lin-4-one (compound of Example 162), 3-cyclohexyl-7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 163), 7-hydroxy-2-isopropyl-3- (4 -methoxyphenyl) -3H-quinazolin-4-one (compound of Example 1 64), 7-hydroxy-2-isopropyl-3- (3-methoxyphenyl) -3H-quinazolin-4-one (compound of Example 165), -hydroxy-2-isopropyl-3- (2-methoxyphenyl) -3H-quinazolin-4-one (compound of Example 166), 7-hydroxy-2-isopropyl-3- (5-methylpyrazin-2-yl-methyl) ) -3H-quinazolin-4-one (compound of Example 167), 3-benzo [1, 3] dioxol-5-yl-7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 168), 7-hydroxy-3- (3-hydroxynaphthalen-2-yl) -2-isopropyl-3H-quinazolin-4-one (compound of Example 169), 7-hydroxy-2-isopropyl-3-naphthalene-1 -yl-3H-quinazolin-4-one (compound of Example 1 70), 7-hydroxy-2-isopropyl-3-isoquinolin-1-yl-3H-quinazolin-4-one (compound of Example 1 71), -hydroxy-2-isopropyl-3-quinolin-8-yl-3H-quinazolin-4-one (compound of Example 1 72), 3-benzothiazol-6-yl-7-hydroxy-2-ysopropyl-3H -quinazolin-4-one (compound of Example 1 73), 4- (7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -benzoic acid methyl ester (compound of Example 1 74), 2- (7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -thiophene-3-carboxylic acid methyl ester (compound of Example 1 75), and 2- (7-hydric acid ester Roxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -cyclopentanecarboxylic acid (compound of Example 1 76) was They can be prepared analogously to 3- (4-chloro-3-fluorophen-yl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 4), replacing 4-chloro-3-fluorophenylamine with the appropriate aniline. Some of the compounds can also be prepared analogously to 3- (4-chlorophenyl) -7-hydroxy-2-isopropyl-3H-quinazolin-4-one (compound of Example 3), replacing 4-chlorophenylamine ( Step 1 b) by the appropriate aniline. Those compounds that are not commercially available are described in the "Preparing intermediaries" section.

Claims

CLAIMS j 1. A quinazolinone compound of the Formula where is a simple link or a double link; R2 is selected from the group consisting of i (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) NH2, 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, R9-0- (alkyl of 1 to 6 carbon atoms) -, wherein the alkyl chain is optionally substituted by trifluoromethyl, (NC) -j alkyl of 1 to 6 carbon atoms-, (R10-RiiN -) - alkyl of 1 to 6 carbon atoms-, (alkyl of 1 to 6 carbon atoms) -S02- (alkyl of 1 to 6 carbon atoms) -, wherein R9, R10 and 'Rn 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 oung rupo - (C = 0) -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-, which contains one, two or three heteroatoms which are selected from the group which 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, R1 0Rn N-, R9-0- (C = 0) -, - (C = O) -N-R10R, = 0 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, alkyloyl 1 to 6 carbon atoms substituted with halogen, hydroxyalkyl of 1 to 6 carbon atoms, cyano or a group -C (= 0) -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-, R9-0- (alkyl of 1 to 6 carbon atoms) -, R9-0 - (alkyl of 1 to 6 carbon atoms) -0- (alkyl of 1 to 6 carbon atoms) -, Ri 0R N- (alkyl of 1 to 6 carbon atoms) -, R10R N- (C = O) - (alkyl of 1 to 6 carbon atoms) - or (alkyl of 1 to 6 carbon atoms) -S02- (alkyl of 1 to 6 carbon atoms) -, wherein R9, R 0 and R each are selected independently 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 -C 6 -alkoxy) -, RIOR-M-, R 10 R N- (alkyl of 1) radicals to 6 carbon atoms), -S02- (alkyl of 1 to 6 carbon atoms, R9-0- (C = 0) -, wherein R9, R1 0 and Rn are as defined above, or with a phenyl radical substituted with halo or a 5 or 6 membered saturated or unsaturated 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 that is selected of 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 linked through a radical - alkyl from 1 to 6 carbon atoms - and which is optionally substituted by 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, R10R N- , R9-0- (C = 0) -, - (C = O) -N-R10R, and phenyl; or benzyl, or phenyl- (alkyl of 1 to 6 carbon atoms) -, phenoxy- (alkyl of 1 to 6 carbon atoms) - or phenyl- (C = 0) - (alkyl of 1 to 6 carbon atoms) -, 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, R10RnN-, R9-0 - (C = 0) -, - (C = 0) -N- i 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 R N-, R 9-0- (C = P) -, - (C = 0) -N-R 10 R, = 0 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 select from the group consisting of N, O and S, and optionally substituted with one, two, three or four substituents that are selected! of the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, R10Ri 1 N-,! R9-0- (C = 0) -, - (C = O) -N-R10R and phenyl; R7 is hydroxy, esterified hydroxy, amino, (alkyl from 1 to 6 carbon atoms) -amino, a group or a group wherein R7a is an alkyl radical of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms substituted with halogen, or a group wherein R7 b is a benzyl or phenylethyl group; and 5, R6 and Re 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 (= 0) H, phenyl, (cycloalkyl of 3 to 6 atoms carbon) -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 atoms carbon or (alkylcarbonylamino of 1 to 6 carbon atoms) -alkoxy of 1 to 6 carbon atoms, (amino) -alkoxy of 1 to 6 carbon atoms, (dimethylamino) -alkoxy of 1 to 6 carbon atoms, or (C 1 -C 6 alkoxycarbonyl) -alkoxy of 1 to 6 carbon atoms, and R 8 furthermore, suitably, is a radical (C 3 -C 6 cycloalkyl) -alkyl of 1 to 6 carbon atoms substituted with hydroxy, phenyl-alkyl of 1 to 6 carbon atoms substituted with hydroxy, heteroaryl-alkyl of 1 to 6 carbon atoms substituted with hydroxy, alkylcarbonyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms or heteroaryl-alkyl of 1 to 6 carbon atoms, in free form or in the form of a salt, provided that, in Formula (I), when R2 is selected from the group of part (a), R3 is selected from the group of part (b ') and when R3 is selected from the group of part (b), R3 is selected from the group of part (a') and excluding the components in which R7 is a hydroxyl radical and R5, 6 and Re. each, independently, without hydrogen, and R2 is isopropyl and R3 is pyridin-5-yl substituted at the 2-position with Cl or CN.
2. A compound according to claim 1, wherein R2 is an isopropyl, ethyl, t-butyl, hydroxyisopropyl, dimethylamino or 2-isopropenyl radical.
3. A compound according to any of claims 1-2, wherein R3 is a phenyl, pyridyl or pyrimidyl radical, wherein each ring is substituted with one or two halo, trifluoromethyl, alkyl groups 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, hydroxyalkyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, cyano or hydroxyl , or R3 is indazolyl or 1-oxo-indan-5-yl.
4. A compound according to any of claims 1 to 3, wherein R5 and R6 are hydrogen.
5. A compound according to any of claims 1 to 4, wherein R7 is hydroxyl or amino.
6. A compound according to any of claims 1 to 5, wherein R8 is hydrogen or alkyl of 1 to 6 carbon atoms substituted with hydroxy.
7. The use of a quinazolinone compound of the! Formula (I) as defined in any of claims 1 to 6, 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.
8. 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 quinazolinone compound of the Formula (I), as defined in any of claims 1 to 6.
9. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 6 of Formula I, in free form or in the form of a pharmaceutically acceptable salt, in association with a pharmaceutical carrier or diluent.
10. A process for the manufacture of a compound of the Formula (II) wherein R1 is H or a suitable protecting group and 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) NH 2, 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, R9-0- (alkoxy of 1 to 6 carbon atoms) -, wherein the alkyl chain is optionally substituted by trifluoromethyl, (NC) -alkyl of 1 to 6 carbon atoms-, (R10- Rn N -) - alkyl of 1 to 6 carbon atoms-, (alkyl of 1 to 6 carbon atoms) -S02- (alkyl of 1 to 6 carbon atoms) -, where R9, Rio and R each or no , 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 = 0) -R2a, wherein R2a is an alkenyl radical of 1 to 6 carbon atoms; or a saturated, unsaturated, 5-, 6- or 7-membered 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 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, R10RN-, R9-0- (C = 0) -, - (C = O) -N-Ri0Ri 1, -O and phenyl; from a compound of Formula (III) by one of the following sequential steps: a) oxidation using a suitable oxidizing agent, reduction using a suitable reducing agent and acylation with a suitable acylating agent; or b) reduction using a suitable reducing agent, acylation with a suitable acylating agent, and oxidation using a suitable oxidizing agent; or c) transformation of the methyl group into a dialkylaminovinyl group, using a suitable agent; oxidation using a suitable oxidizing agent, reduction using a suitable reducing agent and acylation with a suitable acylating agent; or d) reduction using an appropriate reducing agent; acylation with a suitable acylating agent, transformation of the methyl group into a dialkylaminovinyl group, using a suitable agent; and oxidation using a suitable oxidizing agent, followed by optional deprotection of the protecting group, under standard conditions.